Minocycline Effectively Protects the Rabbit's Spinal Cord From Aortic Occlusion-Related Ischemia.

PubMed

Drenger, Benjamin; Fellig, Yakov; Ben-David, Dror; Mintz, Bella; Idrees, Suhel; Or, Omer; Kaplan, Leon; Ginosar, Yehuda; Barzilay, Yair

2016-04-01

To identify the minocycline anti-inflammatory and antiapoptotic mechanisms through which it is believed to exert spinal cord protection during aortic occlusion in the rabbit model. An animal model of aortic occlusion-related spinal cord ischemia. Randomized study with a control group and pre-ischemia and post-ischemia escalating doses of minocycline to high-dose minocycline in the presence of either hyperglycemia, a pro-apoptotic maneuver, or wortmannin, a specific phosphatidylinositol 3-kinase antagonist. Tertiary medical center and school of medicine laboratory. Laboratory animals-rabbits. Balloon obstruction of infrarenal aorta introduced via femoral artery incision. Severe hindlimb paralysis (mean Tarlov score 0.36±0.81 out of 3) was observed in all the control group animals (9 of 11 with paraplegia and 2 of 11 with paraparesis) compared with 11 of 12 neurologically intact animals (mean Tarlov score 2.58±0.90 [p = 0.001 compared with control]) in the high-dose minocycline group. This protective effect was observed partially during a state of hyperglycemia and was completely abrogated by wortmannin. Minocycline administration resulted in higher neurologic scores (p = 0.003) and a shift to viable neurons and more apoptotic-stained nuclei resulting from reduced necrosis (p = 0.001). In a rabbit model of infrarenal aortic occlusion, minocycline effectively reduced paraplegia by increasing the number of viable neurons in a dose-dependent manner. Its action was completely abrogated by inhibiting the phosphatidylinositol 3-kinase pathway and was inhibited partially by the pro-apoptotic hyperglycemia maneuver, indicating that the activation of cell salvage pathways and mitochondrial sites are possible targets of minocycline action in an ischemic spinal cord. Copyright © 2016. Published by Elsevier Inc.

SU-F-I-38: Patient Organ Specific Dose Assessment in Coronary CT Angiograph Using Voxellaized Volume Dose Index in Monte Carlo Simulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fallal, Mohammadi Gh.; Riyahi, Alam N.; Graily, Gh.

Purpose: Clinical use of multi detector computed tomography(MDCT) in diagnosis of diseases due to high speed in data acquisition and high spatial resolution is significantly increased. Regarding to the high radiation dose in CT and necessity of patient specific radiation risk assessment, the adoption of new method in the calculation of organ dose is completely required and necessary. In this study by introducing a conversion factor, patient organ dose in thorax region based on CT image data using MC system was calculated. Methods: The geometry of x-ray tube, inherent filter, bow tie filter and collimator were designed using EGSnrc/BEAMnrc MC-systemmore » component modules according to GE-Light-speed 64-slices CT-scanner geometry. CT-scan image of patient thorax as a specific phantom was voxellised with 6.25mm3 in voxel and 64×64×20 matrix size. Dose to thorax organ include esophagus, lung, heart, breast, ribs, muscle, spine, spinal cord with imaging technical condition of prospectively-gated-coronary CT-Angiography(PGT) as a step and shoot method, were calculated. Irradiation of patient specific phantom was performed using a dedicated MC-code as DOSXYZnrc with PGT-irradiation model. The ratio of organ dose value calculated in MC-method to the volume CT dose index(CTDIvol) reported by CT-scanner machine according to PGT radiation technique has been introduced as conversion factor. Results: In PGT method, CTDIvol was 10.6mGy and Organ Dose/CTDIvol conversion factor for esophagus, lung, heart, breast, ribs, muscle, spine and spinal cord were obtained as; 0.96, 1.46, 1.2, 3.28. 6.68. 1.35, 3.41 and 0.93 respectively. Conclusion: The results showed while, underestimation of patient dose was found in dose calculation based on CTDIvol, also dose to breast is higher than the other studies. Therefore, the method in this study can be used to provide the actual patient organ dose in CT imaging based on CTDIvol in order to calculation of real effective dose(ED) based on organ dose. This work has been supported by the research chancellor of tehran university of medical sciences(tums), school of medicine, Tehran, Iran.« less

Reduction of microhemorrhages in the spinal cord of symptomatic ALS mice after intravenous human bone marrow stem cell transplantation accompanies repair of the blood-spinal cord barrier.

PubMed

Eve, David J; Steiner, George; Mahendrasah, Ajay; Sanberg, Paul R; Kurien, Crupa; Thomson, Avery; Borlongan, Cesar V; Garbuzova-Davis, Svitlana

2018-02-13

Blood-spinal cord barrier (BSCB) alterations, including capillary rupture, have been demonstrated in animal models of amyotrophic lateral sclerosis (ALS) and ALS patients. To date, treatment to restore BSCB in ALS is underexplored. Here, we evaluated whether intravenous transplantation of human bone marrow CD34 + (hBM34 + ) cells into symptomatic ALS mice leads to restoration of capillary integrity in the spinal cord as determined by detection of microhemorrhages. Three different doses of hBM34 + cells (5 × 10 4 , 5 × 10 5 or 1 × 10 6 ) or media were intravenously injected into symptomatic G93A SOD1 mice at 13 weeks of age. Microhemorrhages were determined in the cervical and lumbar spinal cords of mice at 4 weeks post-treatment, as revealed by Perls' Prussian blue staining for ferric iron. Numerous microhemorrhages were observed in the gray and white matter of the spinal cords in media-treated mice, with a greater number of capillary ruptures within the ventral horn of both segments. In cell-treated mice, microhemorrhage numbers in the cervical and lumbar spinal cords were inversely related to administered cell doses. In particular, the pervasive microvascular ruptures determined in the spinal cords in late symptomatic ALS mice were significantly decreased by the highest cell dose, suggestive of BSCB repair by grafted hBM34 + cells. The study results provide translational outcomes supporting transplantation of hBM34 + cells at an optimal dose as a potential therapeutic strategy for BSCB repair in ALS patients.

Pathology of radiation injury to the canine spinal cord.

PubMed

Powers, B E; Beck, E R; Gillette, E L; Gould, D H; LeCouter, R A

1992-01-01

The histopathologic response of the canine spinal cord to fractionated doses of radiation was investigated. Forty-two dogs received 0, 44, 52, 60, or 68 Gy in 4 Gy fractions to the thoracic spinal cord. Dogs were evaluated for neurologic signs and were observed for 1 or 2 years after irradiation. Six major lesion types were observed; five in the irradiated spinal cord and one in irradiated dorsal root ganglia. The three most severe spinal cord lesions were white matter necrosis, massive hemorrhage, and segmental parenchymal atrophy which had an ED50 of 56.9 Gy (51.3-63.3 Gy 95% CI) in 4 Gy fractions. These lesions were consistently associated with abnormal neurologic signs. Radiation damage to the vasculature was the most likely cause of these three lesions. The two less severe spinal cord lesions were focal fiber loss, which had an ED50 of 49.5 Gy (44.8-53.6 Gy 95% CI) in 4 gy fractions and scattered white matter vacuolation that occurred at all doses. These less severe lesions were not consistently associated with neurologic signs and indicated the presence of residual damage that may occur after lower doses of radiation. Radiation damage to glial cells, axons, and/or vasculature were possible causes of these lesions. In the irradiated dorsal root ganglia, affected sensory neurons contained large intracytoplasmic vacuoles, and there was loss of neurons and satellite cells. Such alterations could affect sensory function. The dog is a good model for spinal cord irradiation studies as tolerance doses for lesions causing clinical signs are close to the estimated tolerance doses for humans, and studies involving volume and long-term observation can be done.

Comparison of three and four-field radiotherapy technique and the effect of laryngeal shield on vocal and spinal cord radiation dose in radiotherapy of non-laryngeal head and neck tumors

NASA Astrophysics Data System (ADS)

Pour, Noushin Hassan; Farajollahi, Alireza; Jamali, Masoud; Zeinali, Ahad; Jangjou, Amir Ghasemi

2018-03-01

Introduction: Due to the effect of radiation on both the tumor and the surrounding normal tissues, the side effects of radiation in normal tissues are expected. One of the important complications in the head and neck radiotherapy is the doses reached to the larynx and spinal cord of patients with non-laryngeal head and neck tumors. Materials and Methods: In this study, CT scan images of 25 patients with non-laryngeal tumors including; lymph nodes, tongue, oropharynx and nasopharynx were used. A three-field and a four-field treatment planning with and without laryngeal shield in 3D CRT technique were planned for each patient. Subsequently, the values of Dmin, Dmean, Dmax and Dose Volume Histogram from the treatment planning system and NTCP values of spinal cord and larynx were calculated with BIOPLAN and MATLAB software for all patients. Results: Statistical results showed that mean values of doses of larynx in both three and four-field methods were significantly different between with and without shield groups. Comparison of absorbed dose didn't show any difference between the three and four field methods (P>0.05). Using Shield, just the mean and minimum doses of spinal cord decreased in both three and four fields. The NTCP of the spinal cord and larynx by three and four-field methods with shield in the LKB and EUD models significantly are less than that of the three and four fields without shields, and in the four-field method NTCP of larynx is less than three radiation field. Conclusion: The results of this study indicate that there is no significant difference in doses reached to larynx and spinal cord between the treatments techniques, but laryngeal shield reduce dose and NTCP values in larynx considerably.

Overcoming the Practical Barriers to Spinal Cord Cell Transplantation for ALS

DTIC Science & Technology

2012-10-01

ABSTRACT: This grant will provide critical data on tolerance and toxicity of cell dosing and numbers of permissible spinal cord injections. Rigorous...Surgical Technique) will provide critical data on tolerance and toxicity of cell dosing and numbers of permissible spinal cord injections. Aim 2 (Graft...connected to a rigid needle of the same gauge as the floating cannula one – Figure 7) using the maximum volume/number of injections could result in

Targeting L-Selectin to Improve Neurologic and Urologic Function After Spinal Cord Injury

DTIC Science & Technology

2015-10-01

demonstrated locomotor recovery in mice receiving 40mg/kg DFA up to 3 hours following spinal cord injury -We demonstrated improved locomotor recovery...health, as evaluated by body weight -We identified no added locomotor recovery due to multiple, successive doses of DFA. Moreover, additional doses...bladder function Significance: We have identified robust locomotor recovery in both mild and severe spinal cord injured mice that received DFA up

A case study of IMRT planning (Plan B) subsequent to a previously treated IMRT plan (Plan A)

NASA Astrophysics Data System (ADS)

Cao, F.; Leong, C.; Schroeder, J.; Lee, B.

2014-03-01

Background and purpose: Treatment of the contralateral neck after previous ipsilateral intensity modulated radiation therapy (IMRT) for head and neck cancer is a challenging problem. We have developed a technique that limits the cumulative dose to the spinal cord and brainstem while maximizing coverage of a planning target volume (PTV) in the contralateral neck. Our case involves a patient with right tonsil carcinoma who was given ipsilateral IMRT with 70Gy in 35 fractions (Plan A). A left neck recurrence was detected 14 months later. The patient underwent a neck dissection followed by postoperative left neck radiation to a dose of 66 Gy in 33 fractions (Plan B). Materials and Methods: The spinal cord-brainstem margin (SCBM) was defined as the spinal cord and brainstem with a 1.0 cm margin. Plan A was recalculated on the postoperative CT scan but the fluence outside of SCBM was deleted. A further modification of Plan A resulted in a base plan that was summed with Plan B to evaluate the cumulative dose received by the spinal cord and brainstem. Plan B alone was used to evaluate for coverage of the contralateral neck PTV. Results: The maximum cumulative doses to the spinal cord with 0.5cm margin and brainstem with 0.5cm margin were 51.96 Gy and 45.60 Gy respectively. For Plan B, 100% of the prescribed dose covered 95% of PTVb1. Conclusion: The use of a modified ipsilateral IMRT plan as a base plan is an effective way to limit the cumulative dose to the spinal cord and brainstem while enabling coverage of a PTV in the contralateral neck.

SU-F-T-446: Improving Craniospinal Irradiation Technique Using Volumetric Modulated Arc Therapy (VMAT) Planning and Its Dosimetric Verification

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, X; Tejani, M; Jiang, X

2016-06-15

Purpose: The purpose of this study is to investigate a volumetric modulated arc therapy (VMAT) treatment planning technique for supine craniospinal irradiation (CSI). Evaluate the suitability of VMAT for CSI with dosimetric measurements and compare it to 3D conformal planning using specific plan metrics such as dose conformity, homogeneity, and dose of organs at risk (OAR). Methods: Ten CSI patients treated with conventional 3D technique were re-planned with VMAT. The PTV was contoured to include the whole contents of the brain and spinal canal with a uniform margin of 5 mm. VMAT plans were generated with two partial arcs coveringmore » the brain, two partial arcs for the superior portion of the spinal cord and two partial arcs covering the remaining inferior portion of the spinal cord. Conformity index (CI), heterogeneity indexes (HI) and max and mean doses of OAR were compared to 3D plans. VMAT plans were delivered onto an anthropomorphic phantom loaded with Gafchromic films and OSLDs placed at specific positions to evaluate the plan dose at the junctions and as well as the plan dose distributions. Results: This VMAT technique was validated with a clinical study of 10 patients. The average CI was 1.03±0.02 for VMAT plans and 1.96±0.32 for conformal plans. And the average HI was 1.15±0.01 for VMAT plans and 1.51±0.21 for conformal plans. The mean and max doses to the all OARs for VMAT plans were significantly lower than conformal plans. The measured dose in phantom for VAMT plans was comparable to the calculated dose in Eclipse and the doses at junctions were verified. Conclusion: VMAT CSI was able to achieve better dose conformity and heterogeneity as well as significantly reducing the dose to Heart, esophagus and larynx. VMAT CSI appears to be a dosimterically advantageous, faster delivery, has better reproducibility CSI treatment.« less

Spinal cord protection during radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coia, L.; Chu, J.; Larsen, R.

1986-09-01

Treating intrathoracic malignancies to high doses, particularly those of lung and esophagus, requires limiting the radiation dose delivered to the spinal cord. Several factors are important in determining the cord dose. These are: The distance from the block or collimator edge to the cord, the variation of dose with distance from the block or collimator edge and, the expected variation of this distance for clinical set-up from day-to-day. When treating with an oblique beam, the position of the cord may be difficult to identify. A technique for localizing the spinal cord on a simulator film at an arbitrary gantry anglemore » is presented. The technique requires determination of distances from the central axis of the beam to the medial aspect of the pedicle and posterior vertebral body. These can readily be obtained from measurements on orthogonal, AP/PA and lateral isocentric simulator radiographs. A mathematical transformation is applied to determine the corresponding cord locations on the oblique radiographs for any arbitrary gantry angle. The accuracy of cord localization was within 2-3 mm with a precision of 2 mm for five physicians who used this technique. The beam edge characteristics for 60Co, 6 MV, and 10 MV teletherapy unit were measured for various depths and field sizes. For the 6 and 10 MV units, the beam penumbra is nearly independent of the field size, depth and field defining devices (inner and outer collimator jaws, trimmer bars, and shielding blocks). Because the beam penumbra is dependent on the design of the linear accelerator, its measurement should be made individually for each linear accelerator. Our preliminary data on patient positioning uncertainty did not exceed the 6-8 mm limit documented in the literature.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Yao; Chen, Josephine; Leary, Celeste I.

Radiation of the low neck can be accomplished using split-field intensity-modulated radiation therapy (sf-IMRT) or extended-field intensity-modulated radiation therapy (ef-IMRT). We evaluated the effect of these treatment choices on target coverage and thyroid and larynx doses. Using data from 14 patients with cancers of the oropharynx, we compared the following 3 strategies for radiating the low neck: (1) extended-field IMRT, (2) traditional split-field IMRT with an initial cord-junction block to 40 Gy, followed by a full-cord block to 50 Gy, and (3) split-field IMRT with a full-cord block to 50 Gy. Patients were planned using each of these 3 techniques.more » To facilitate comparison, extended-field plans were normalized to deliver 50 Gy to 95% of the neck volume. Target coverage was assessed using the dose to 95% of the neck volume (D{sub 95}). Mean thyroid and larynx doses were computed. Extended-field IMRT was used as the reference arm; the mean larynx dose was 25.7 ± 7.4 Gy, and the mean thyroid dose was 28.6 ± 2.4 Gy. Split-field IMRT with 2-step blocking reduced laryngeal dose (mean larynx dose 15.2 ± 5.1 Gy) at the cost of a moderate reduction in target coverage (D{sub 95} 41.4 ± 14 Gy) and much higher thyroid dose (mean thyroid dose 44.7 ± 3.7 Gy). Split-field IMRT with initial full-cord block resulted in greater laryngeal sparing (mean larynx dose 14.2 ± 5.1 Gy) and only a moderately higher thyroid dose (mean thyroid dose 31 ± 8 Gy) but resulted in a significant reduction in target coverage (D{sub 95} 34.4 ± 15 Gy). Extended-field IMRT comprehensively covers the low neck and achieves acceptable thyroid and laryngeal sparing. Split-field IMRT with a full-cord block reduces laryngeal doses to less than 20 Gy and spares the thyroid, at the cost of substantially reduced coverage of the low neck. Traditional 2-step split-field IMRT similarly reduces the laryngeal dose but also reduces low-neck coverage and delivers very high doses to the thyroid.« less

Spinal Cord Tolerance to Reirradiation With Single-Fraction Radiosurgery: A Swine Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.edu; Foster, Ryan D.; Kogel, Albert J. van der

2012-07-01

Purpose: This study was performed to determine swine spinal cord tolerance to single-fraction, partial-volume irradiation 1 year after receiving uniform irradiation to 30 Gy in 10 fractions. Methods and Materials: A 10-cm length of spinal cord (C3-T1) was uniformly irradiated to 30 Gy in 10 consecutive fractions and reirradiated 1 year later with a single radiosurgery dose centered within the previously irradiated segment. Radiosurgery was delivered to a cylindrical volume approximately 5 cm in length and 2 cm in diameter, which was positioned laterally to the cervical spinal cord, resulting in a dose distribution with the 90%, 50%, and 10%more » isodose lines traversing the ipsilateral, central, and contralateral spinal cord, respectively. Twenty-three pigs were stratified into six dose groups with mean maximum spinal cord doses of 14.9 {+-} 0.1 Gy (n = 2), 17.1 {+-} 0.3 Gy (n = 3), 19.0 {+-} 0.1 Gy (n = 5), 21.2 {+-} 0.1 Gy (n = 5), 23.4 {+-} 0.2 Gy (n = 5), and 25.4 {+-} 0.4 Gy (n = 3). The mean percentage of spinal cord volumes receiving {>=}10 Gy for the same groups were 34% {+-} 1%, 40% {+-} 1%, 46% {+-} 3%, 52% {+-} 1%, 56 {+-} 3%, and 57% {+-} 1%. The study endpoint was motor neurologic deficit as determined by a change in gait during a 1- year follow-up period. Results: A steep dose-response curve was observed with a 50% incidence of paralysis (ED{sub 50}) for the maximum point dose of 19.7 Gy (95% confidence interval, 17.4-21.4). With two exceptions, histology was unremarkable in animals with normal neurologic status, while all animals with motor deficits showed some degree of demyelination and focal white matter necrosis on the irradiated side, with relative sparing of gray matter. Histologic comparison with a companion study of de novo irradiated animals revealed that retreatment responders had more extensive tissue damage, including infarction of gray matter, only at prescription doses >20 Gy. Conclusion: Pigs receiving spinal radiosurgery 1 year after receiving 30 Gy in 10 fractions were not at significantly higher risk of developing motor deficits than pigs that received radiosurgery alone.« less

Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers.

PubMed

Farace, Paolo; Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

2014-01-06

Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step-and-shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose < 45 Gy to spinal cord and < 50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5 ± 2.2 Gy and 36.7 ± 14.0 Gy), without significant changes on the other OARs. A marked difference (-15.9 ± 1.9 Gy and -10.1 ± 5.7 Gy) was obtained at the expense of a small difference (-1.3% ± 0.9%) from initial PTV195% coverage (96.6% ± 0.9%). Similar difference (-15.7 ± 2.2 Gy and -10.2 ± 6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (-0.3% ± 0.3% from the initial 98.3% ± 0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer.

Systemic effects induced by intralesional injection of ω-conotoxin MVIIC after spinal cord injury in rats

PubMed Central

2014-01-01

Background Calcium channel blockers such as conotoxins have shown a great potential to reduce brain and spinal cord injury. MVIIC neuroprotective effects analyzed in in vitro models of brain and spinal cord ischemia suggest a potential role of this toxin in preventing injury after spinal cord trauma. However, previous clinical studies with MVIIC demonstrated that clinical side effects might limit the usefulness of this drug and there is no research on its systemic effects. Therefore, the present study aimed to investigate the potential toxic effects of MVIIC on organs and to evaluate clinical and blood profiles of rats submitted to spinal cord injury and treated with this marine toxin. Rats were treated with placebo or MVIIC (at doses of 15, 30, 60 or 120 pmol) intralesionally following spinal cord injury. Seven days after the toxin administration, kidney, brain, lung, heart, liver, adrenal, muscles, pancreas, spleen, stomach, and intestine were histopathologically investigated. In addition, blood samples collected from the rats were tested for any hematologic or biochemical changes. Results The clinical, hematologic and biochemical evaluation revealed no significant abnormalities in all groups, even in high doses. There was no significant alteration in organs, except for degenerative changes in kidneys at a dose of 120 pmol. Conclusions These findings suggest that MVIIC at 15, 30 and 60 pmol are safe for intralesional administration after spinal cord injury and could be further investigated in relation to its neuroprotective effects. However, 120 pmol doses of MVIIC may provoke adverse effects on kidney tissue. PMID:24739121

SU-F-J-29: Dosimetric Effect of Image Registration ROI Size and Focus in Automated CBCT Registration for Spine SBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Magnelli, A; Smith, A; Chao, S

2016-06-15

Purpose: Spinal stereotactic body radiotherapy (SBRT) involves highly conformal dose distributions and steep dose gradients due to the proximity of the spinal cord to the treatment volume. To achieve the planning goals while limiting the spinal cord dose, patients are setup using kV cone-beam CT (kV-CBCT) with 6 degree corrections. The kV-CBCT registration with the reference CT is dependent on a user selected region of interest (ROI). The objective of this work is to determine the dosimetric impact of ROI selection. Methods: Twenty patients were selected for this study. For each patient, the kV-CBCT was registered to the reference CTmore » using three ROIs including: 1) the external body, 2) a large anatomic region, and 3) a small region focused in the target volume. Following each registration, the aligned CBCTs and contours were input to the treatment planning system for dose evaluation. The minimum dose, dose to 99% and 90% of the tumor volume (D99%, D90%), dose to 0.03cc and the dose to 10% of the spinal cord subvolume (V10Gy) were compared to the planned values. Results: The average deviations in the tumor minimum dose were 2.68%±1.7%, 4.6%±4.0%, 14.82%±9.9% for small, large and the external ROIs, respectively. The average deviations in tumor D99% were 1.15%±0.7%, 3.18%±1.7%, 10.0%±6.6%, respectively. The average deviations in tumor D90% were 1.00%±0.96%, 1.14%±1.05%, 3.19%±4.77% respectively. The average deviations in the maximum dose to the spinal cord were 2.80%±2.56%, 7.58%±8.28%, 13.35%±13.14%, respectively. The average deviation in V10Gy to the spinal cord were 1.69%±0.88%, 1.98%±2.79%, 2.71%±5.63%. Conclusion: When using automated registration algorithms for CBCT-Reference alignment, a small target-focused ROI results in the least dosimetric deviation from the plan. It is recommended to focus narrowly on the target volume to keep the spinal cord dose below tolerance.« less

Inadequacy of Plasma Acyclovir Levels at Delivery in Patients with Genital Herpes Receiving Oral Acyclovir Suppressive Therapy in Late Pregnancy

PubMed Central

Leung, Daniel T.; Henning, Paul A.; Wagner, Emily C.; Blasig, Audrey; Wald, Anna; Sacks, Stephen L.; Corey, Lawrence; Money, Deborah M.

2009-01-01

Objective: Acyclovir therapy in late pregnancy among women with recurrent genital herpes is effective in decreasing genital lesion frequency and subclinical viral shedding rates at delivery, thereby decreasing the need for caesarean delivery. Despite good adherence and increased dosing schedules, breakthrough lesions and viral shedding are still observed in some women at or near delivery. Anecdotal data suggests that low levels of HSV replication at delivery may result in transmission to the neonate. Therefore, defining optimal acyclovir dosing during labor and delivery is warranted. Our objectives were to determine actual acyclovir levels at delivery, and explore associations between acyclovir levels, duration of labour and time since last acyclovir dose. Methods: Twenty-seven patients were prescribed oral acyclovir 400 mg three times daily from 36 weeks gestation. Cord blood (venous and arterial) and maternal venous blood samples were collected at delivery, and acyclovir levels measured using capillary electrophoresis. Correlations between duration of labour and time since last acyclovir dose with acyclovir blood levels were calculated. Results: Acyclovir levels were below the published mean steady-state trough value (180 ng/ml) in 52% of venous cord, 55% of arterial cord, and 36% of maternal samples. There was a significant inverse correlation between time since last dose and venous cord (rs19=−0.57, p<0.015), arterial cord (rs16=−0.63, p<0.01), and maternal acyclovir levels (r10=−0.69, p<0.03). Conclusions: Oral dosing of acyclovir in late pregnancy may result in insufficient levels at delivery to prevent viral shedding. Alternative approaches should evaluate dosing through labor, perhaps intravenously, and its effect on viral shedding. PMID:20085679

Challenges of transcutaneous laser application for the potential of photobiomodulation of the spinal cord at the scale of a large companion animal

NASA Astrophysics Data System (ADS)

Piao, Daqing; Sypniewski, Lara A.; Bartels, Kenneth E.

2017-02-01

Photobiomodulation (PBM) has been used successfully for the treatment of nervous system and has been demonstrated in the rodent model. In contrast, the percutaneous use of PBM to treat spinal cord of companion animals is expected to be challenging due to the significant attenuation of light energy as it travels through the thick and heterogeneous layers of tissue and bone to reach the level of the spinal cord. This pilot study was performed on a cadaverous dog to determine if the recommended bio-stimulatory treatment dose can be delivered to the spinal canal via percutaneous application of a clinically acceptable surface dose. The dose reaching the spinal canal after percutaneous application was measured at 980nm by using a miniature photo-diode sensor with a dose-response sensitivity of 1V per 1mW/cm2 dose and a 2mm spherical isotropic fiber-optical diffusor probe. The two sensors were embedded in different longitudinal positions along the dorsal portion of the spinal canal just below the soft tissues and vertebral processes in a 40lbs cadaverous dog. The spinal cord was then accessed via a hemilaminectomy. Once embedded in the target tissue, 1W-10 W surface irradiation was applied. At the T12/13 and T13/L1 intervertebral disc positions, photo-diode sensors detected the intra-spinal dose above the noise floor at the 10W surface dose. A narrow treatment window for percutaneous PBM in large dog may exist only for the shallowest segment of the spinal cord, which may be important to avoid potential collateral photothermal effects. Works for simultaneous multi-site intra-spinal measurements are on-going.

Evaluation of image-guided helical tomotherapy for the retreatment of spinal metastasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mahan, Stephen L.; Ramsey, Chester R.; Scaperoth, Daniel D.

Introduction: Patients with vertebral metastasis that receive radiation therapy are typically treated to the spinal cord tolerance dose. As such, it is difficult to successfully deliver a second course of radiation therapy for patients with overlapping treatment volumes. In this study, an image-guided helical tomotherapy system was evaluated for the retreatment of previously irradiated vertebral metastasis. Methods and Materials: Helical tomotherapy dose gradients and maximum cord doses were measured in a cylindrical phantom for geometric test cases with separations between the planning target volume (PTV) and the spinal cord organ at risk (OAR) of 2 mm, 4 mm, 6 mm,more » 8 mm, and 10 mm. Megavoltage computed tomography (CT) images were examined for their ability to localize spinal anatomy for positioning purposes by repeat imaging of the cervical spine in an anthropomorphic phantom. In addition to the phantom studies, 8 patients with cord compressions that had received previous radiation therapy were retreated to a mean dose of 28 Gy using conventional fractionation. Results and Discussion: Megavoltage CT images were capable of positioning an anthropomorphic phantom to within {+-}1.2 mm (2{sigma}) superior-inferiorly and within {+-}0.6 mm (2{sigma}) anterior-posteriorly and laterally. Dose gradients of 10% per mm were measured in phantom while PTV uniformity indices of less than 11% were maintained. The calculated maximum cord dose was 25% of the prescribed dose for a 10-mm PTV-to-OAR separation and 71% of the prescribed dose for a PTV-to-OAR separation of 2 mm. Eight patients total have been treated without radiation-induced myelopathy or any other adverse effects from treatment. Conclusions: A technique has been evaluated for the retreatment of vertebral metastasis using image-guided helical tomotherapy. Phantom and patient studies indicated that a tomotherapy system is capable of delivering dose gradients of 10% per mm and positioning the patient within 1.2 mm without the use of special stereotactic immobilization.« less

Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis

PubMed Central

Merega, Elisa; Di Prisco, Silvia; Padolecchia, Cristina; Grilli, Massimo; Milanese, Marco; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Bonanno, Giambattista; Marchi, Mario

2017-01-01

Fingolimod, the first oral, disease-modifying therapy for MS, has been recently proposed to modulate glutamate transmission in the central nervous system (CNS) of mice suffering from Experimental Autoimmune Encephalomyelitis (EAE) and in MS patients. Our study aims at investigating whether oral fingolimod recovers presynaptic defects that occur at different stages of disease in the CNS of EAE mice. In vivo prophylactic (0.3 mg/kg for 14 days, from the 7th day post immunization, d.p.i, the drug dissolved in the drinking water) fingolimod significantly reduced the clinical symptoms and the anxiety-related behaviour in EAE mice. Spinal cord inflammation, demyelination and glial cell activation are markers of EAE progression. These signs were ameliorated following oral fingolimod administration. Glutamate exocytosis was shown to be impaired in cortical and spinal cord terminals isolated from EAE mice at 21 ± 1 d.p.i., while GABA alteration emerged only at the spinal cord level. Prophylactic fingolimod recovered these presynaptic defects, restoring altered glutamate and GABA release efficiency. The beneficial effect occurred in a dose-dependent, region-specific manner, since lower (0.1–0.03 mg/kg) doses restored, although to a different extent, synaptic defects in cortical but not spinal cord terminals. A delayed reduction of glutamate, but not of GABA, exocytosis was observed in hippocampal terminals of EAE mice at 35 d.p.i. Therapeutic (0.3 mg/kg, from 21 d.p.i. for 14 days) fingolimod restored glutamate exocytosis in the cortex and in the hippocampus of EAE mice at 35 ± 1 d.p.i. but not in the spinal cord, where also GABAergic defects remained unmodified. These results improve our knowledge of the molecular events accounting for the beneficial effects elicited by fingolimod in demyelinating disorders. PMID:28125677

Stem cell transplantation (cord blood transplants).

PubMed

Chao, Nelson J; Emerson, Stephen G; Weinberg, Kenneth I

2004-01-01

Allogeneic stem cell transplantation is an accepted treatment modality for selected malignant and non-malignant diseases. However, the ability to identify suitably matched related or unrelated donors can be difficult in some patients. Alternative sources of stem cells such as cord blood provide a readily available graft for such patients. Data accumulated over the past several years have demonstrated that the use of cord blood is an accepted source of stem cells for pediatric patients. Since the cell numbers of hematopoietic progenitors in cord blood is limited and the collection can occur only in a single occasion, its use in adult patients can be more problematic. Here, new developments in the use of cord blood for adults and studies aimed at expansion of cord blood cells and immune reconstitution are described. In Section I, Dr. Nelson Chao describes the early data in cord blood transplantation in adult patients. The patient outcomes are reviewed and analyzed for various factors such as cell dose, HLA typing, and patient selection that could have contributed to the final outcome of these adult patients. Myeloablative as well as nonmyeloablative approaches are presented. Discussion of the various benefits and risks are presented. More recent data from multiple single institutions as well as larger registry data comparisons are also provided. Analyses of these studies suggest methods to improve on the outcome. These newer data should lead to a logical progression in the use of cord blood cells in adult patients. In Section II, Dr. Stephen Emerson describes the historical efforts associated with expansion of hematopoietic stem cells, specifically with cord blood cells. These efforts to expand cord blood cells continue with novel methods. Moreover, a better understanding of stem cell biology and signaling is critical if we are to be able to effectively expand these cells for clinical use. An alternative, more direct, approach to expanding stem cells could be achieved by specific genetic pathways known or believed to support primitive HSC proliferation such as Notch-1 receptor activation, Wnt/LEF-1 pathway induction, telomerase or the Homeobox (Hox) gene products. The clinical experience with the use of expanded cord blood cells is also discussed. In Section III, Dr. Kenneth Weinberg describes immune reconstitution or lack thereof following cord blood transplantation. One of the hallmarks of successful hematopoietic stem cell transplantation is the ability to fully reconstitute the immune system of the recipient. Thus, the relationship between stem cell source and the development of T lymphocyte functions required for protection of the recipient from infection will be described, and cord blood recipients will be compared with those receiving other sources of stem cells. T cell development is described in detail, tracking from prethymic to postthymic lymphocytes with specific attention to umbilical cord blood as the source of stem cells. Moreover, a discussion of the placenta as a special microenvironment for umbilical cord blood is presented. Strategies to overcome the immunological defects are presented to improve the outcome of these recipients.

Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers

PubMed Central

Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

2014-01-01

Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step‐and‐shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose <45 Gy to spinal cord and <50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5±2.2 Gy and 36.7±14.0 Gy), without significant changes on the other OARs. A marked difference (−15.9±1.9 Gy and −10.1±5.7 Gy) was obtained at the expense of a small difference (−1.3%±0.9%) from initial PTV195% coverage (96.6%±0.9%). Similar difference (−15.7±2.2 Gy and −10.2±6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (−0.3%±0.3% from the initial 98.3%±0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer. PACS number: 87.55.D PMID:24423836

SU-E-T-397: Evaluation of Planned Dose Distributions by Monte Carlo (0.5%) and Ray Tracing Algorithm for the Spinal Tumors with CyberKnife

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cho, H; Brindle, J; Hepel, J

2015-06-15

Purpose: To analyze and evaluate dose distribution between Ray Tracing (RT) and Monte Carlo (MC) algorithms of 0.5% uncertainty on a critical structure of spinal cord and gross target volume and planning target volume. Methods: Twenty four spinal tumor patients were treated with stereotactic body radiotherapy (SBRT) by CyberKnife in 2013 and 2014. The MC algorithm with 0.5% of uncertainty is used to recalculate the dose distribution for the treatment plan of the patients using the same beams, beam directions, and monitor units (MUs). Results: The prescription doses are uniformly larger for MC plans than RT except one case. Upmore » to a factor of 1.19 for 0.25cc threshold volume and 1.14 for 1.2cc threshold volume of dose differences are observed for the spinal cord. Conclusion: The MC recalculated dose distributions are larger than the original MC calculations for the spinal tumor cases. Based on the accuracy of the MC calculations, more radiation dose might be delivered to the tumor targets and spinal cords with the increase prescription dose.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Badkul, R; Nicolai, W; Pokhrel, D

Purpose: To compare the impact of Pencil Beam(PB) and Anisotropic Analytic Algorithm(AAA) dose calculation algorithms on OARs and planning target volume (PTV) in thoracic spine stereotactic body radiation therapy (SBRT). Methods: Ten Spine SBRT patients were planned on Brainlab iPlan system using hybrid plan consisting of 1–2 non-coplanar conformal-dynamic arcs and few IMRT beams treated on NovalisTx with 6MV photon. Dose prescription varied from 20Gy to 30Gy in 5 fractions depending on the situation of the patient. PB plans were retrospectively recalculated using the Varian Eclipse with AAA algorithm using same MUs, MLC pattern and grid size(3mm).Differences in dose volumemore » parameters for PTV, spinal cord, lung, and esophagus were analyzed and compared for PB and AAA algorithms. OAR constrains were followed per RTOG-0631. Results: Since patients were treated using PB calculation, we compared all the AAA DVH values with respect to PB plan values as standard, although AAA predicts the dose more accurately than PB. PTV(min), PTV(Max), PTV(mean), PTV(D99%), PTV(D90%) were overestimated with AAA calculation on average by 3.5%, 1.84%, 0.95%, 3.98% and 1.55% respectively as compared to PB. All lung DVH parameters were underestimated with AAA algorithm mean deviation of lung V20, V10, V5, and 1000cc were 42.81%,19.83%, 18.79%, and 18.35% respectively. AAA overestimated Cord(0.35cc) by mean of 17.3%; cord (0.03cc) by 12.19% and cord(max) by 10.5% as compared to PB. Esophagus max dose were overestimated by 4.4% and 5cc by 3.26% for AAA algorithm as compared to PB. Conclusion: AAA overestimated the PTV dose values by up to 4%.The lung DVH had the greatest underestimation of dose by AAA versus PB. Spinal cord dose was overestimated by AAA versus PB. Given the critical importance of accuracy of OAR and PTV dose calculation for SBRT spine, more accurate algorithms and validation of calculated doses in phantom models are indicated.« less

The radiation dosimetry of intrathecally administered radionuclides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stabin, M.G.; Evans, J.F.

The radiation dose to the spine, spinal cord, marrow, and other organs of the body from intrathecal administration of several radiopharmaceuticals was studied. Anatomic models were developed for the spine, spinal cerebrospinal fluid (CSF), spinal cord, spinal skeleton, cranial skeleton, and cranial CSF. A kinetic model for the transport of CSF was used to determine residence times in the CSF; material leaving the CSF was thereafter assumed to enter the bloodstream and follow the kinetics of the radiopharmaceutical as if intravenously administered. The radiation transport codes MCNP and ALGAMP were used to model the electron and photon transport and energymore » deposition. The dosimetry of Tc-99m DTPA and HSA, In-111 DTPA, I-131 HSA, and Yb-169 DTPA was studied. Radiation dose profiles for the spinal cord and marrow in the spine were developed and average doses to all other organs were estimated, including dose distributions within the bone and marrow.« less

Reduced intensity haplo plus single cord transplant compared to double cord transplant: improved engraftment and graft-versus-host disease-free, relapse-free survival

PubMed Central

van Besien, Koen; Hari, Parameswaran; Zhang, Mei-Jie; Liu, Hong-Tao; Stock, Wendy; Godley, Lucy; Odenike, Olatoyosi; Larson, Richard; Bishop, Michael; Wickrema, Amittha; Gergis, Usama; Mayer, Sebastian; Shore, Tsiporah; Tsai, Stephanie; Rhodes, Joanna; Cushing, Melissa M.; Korman, Sandra; Artz, Andrew

2016-01-01

Umbilical cord blood stem cell transplants are commonly used in adults lacking HLA-identical donors. Delays in hematopoietic recovery contribute to mortality and morbidity. To hasten recovery, we used co-infusion of progenitor cells from a partially matched related donor and from an umbilical cord blood graft (haplo-cord transplant). Here we compared the outcomes of haplo-cord and double-cord transplants. A total of 97 adults underwent reduced intensity conditioning followed by haplo-cord transplant and 193 patients received reduced intensity conditioning followed by double umbilical cord blood transplantation. Patients in the haplo-cord group were more often from minority groups and had more advanced malignancy. Haplo-cord recipients received fludarabine-melphalan-anti-thymocyte globulin. Double umbilical cord blood recipients received fludarabine-cyclophosphamide and low-dose total body irradiation. In a multivariate analysis, haplo-cord had faster neutrophil (HR=1.42, P=0.007) and platelet (HR=2.54, P<0.0001) recovery, lower risk of grade II–IV acute graft-versus-host disease (HR=0.26, P<0.0001) and chronic graft-versus-host disease (HR=0.06, P<0.0001). Haplo-cord was associated with decreased risk of relapse (HR 0.48, P=0.001). Graft-versus-host disease-free, relapse-free survival was superior with haplo-cord (HR 0.63, P=0.002) but not overall survival (HR=0.97, P=0.85). Haplo-cord transplantation using fludarabine-melphalan-thymoglobulin conditioning hastens hematopoietic recovery with a lower risk of relapse relative to double umbilical cord blood transplantation using the commonly used fludarabine-cyclophosphamide-low-dose total body irradiation conditioning. Graft-versus-host disease-free and relapse-free survival is significantly improved. Haplo-cord is a readily available graft source that improves outcomes and access to transplant for those lacking HLA-matched donors. Trials registered at clinicaltrials.gov identifiers 00943800 and 01810588. PMID:26869630

Gender-specific association of exposure to non-dioxin-like polychlorinated biphenyls during pregnancy with methylation levels of H19 and long interspersed nuclear element-1 in cord blood in the Hokkaido study.

PubMed

Kobayashi, Sumitaka; Sata, Fumihiro; Miyashita, Chihiro; Miura, Ryu; Azumi, Kaoru; Kobayashi, Sachiko; Goudarzi, Houman; Araki, Atsuko; Ishizuka, Mayumi; Todaka, Takashi; Kajiwara, Jumboku; Hori, Tsuguhide; Kishi, Reiko

2017-09-01

Associations between prenatal exposure to polychlorinated biphenyls (PCBs) and reduced birth-size, and between DNA methylation of insulin-like growth factor-2 (IGF-2), H19 locus, and long interspersed nuclear element-1 (LINE-1) and reduced birth-size are well established. To date, however, studies on the associations between prenatal exposure to PCBs and alterations in methylation of IGF-2, H19, and LINE-1 are lacking. Thus, in this study, we examined these associations with infant-gender stratification. We performed a prospective birth cohort study using the Sapporo cohort from the previously described Hokkaido Birth Cohort Study on Environment and Children's Health conducted between 2002 and 2005 in Japan. In the final 169 study participants included in this study, we measured the concentrations of various non-dioxin-like PCBs in maternal blood during pregnancy using high-resolution gas chromatography/high-resolution mass spectrometry. IGF-2, H19 and LINE-1 methylation levels in cord blood were measured using the bisulfite pyrosequencing methods Finally, we assessed the associations between prenatal exposure to various PCBs and the gene methylation levels using multiple regression models stratified by infant gender. We observed a 0.017 (95% confidence interval [CI]: 0.003-0.031) increase in the log 10 -transformed H19 methylation levels (%) in cord blood for each ten-fold increase in the levels of decachlorinated biphenyls (decaCBs) in maternal blood among all infants. Similarly, a 0.005 (95% CI: 0.000-0.010) increase in the log 10 -transformed LINE-1 methylation levels (%) in cord blood was associated with each ten-fold increase in heptachlorinated biphenyls (heptaCBs) in maternal blood among all infants. In particular, we observed a dose-dependent association of the decaCB levels in maternal blood with the H19 methylation levels among female infants (P value for trend=0.040); likewise a dose-dependent association of heptaCB levels was observed with LINE-1 methylation levels among female infants (P value for trend=0.015). Moreover, these associations were only observed among infants of primiparous women. Our results suggest that the dose-dependent association between prenatal exposure to specific non-dioxin-like PCBs and increases in the H19 and LINE-1 methylation levels in cord blood might be more predominant in females than in males. Copyright © 2017 Elsevier B.V. All rights reserved.

Refractory orthostatic hypotension in a patient with a spinal cord injury: Treatment with droxidopa.

PubMed

Canosa-Hermida, Eva; Mondelo-García, Cristina; Ferreiro-Velasco, María Elena; Salvador-de la Barrera, Sebastián; Montoto-Marqués, Antonio; Rodríguez-Sotillo, Antonio; Vizoso-Hermida, José Ramón

2018-01-01

Orthostatic hypotension (OH) is a common complication in patients with a spinal cord injury, mainly affecting complete injuries above neurological level T6. It is generally more severe during the acute phase but can remain symptomatic for several years. A 65-year-old male with a grade ASIA A post-traumatic cervical spinal cord injury, at neurological level C4, presenting with symptomatic refractory OH. Increased blood pressure (BP) levels and an overall clinical improvement was observed after administering an increasing dose of droxidopa. Treatment was started at a dose of 100 mg twice daily (bid), one to be taken upon rising in the morning and another one in the afternoon, at least three hours before bedtime. According to the patient's symptomatic response, each individual dose was increased by 100 mg at 48-hour intervals. Both increased mean BP levels and a subjective symptomatic improvement were evidenced at a dose of 300 mg bid. Treatment with droxidopa increases BP levels and improves symptoms related to refractory OH using all physical and pharmacological measures available. It could therefore constitute an effective alternative treatment for OH in patients with a spinal cord injury.

WE-AB-207B-10: On Spinal Nerve Toxicity from Single-Session SAbR in Pigs and the Translation of Small Animal NTCP Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hrycushko, B; Medin, P

Purpose: The incidence of peripheral neuropathy has risen with increased utilization of SAbR. There is no consensus regarding the dose-tolerance of the peripheral nervous system. In 2015, we commenced an investigation to test the hypotheses that single-session irradiation to the pig spinal nerves exhibit a similar dose-tolerance as that of the spinal cord and that a dose-length effect exists. This work evaluates the direct application of small animal NTCP models to both large animal spinal cord and preliminary peripheral nerve data. Methods: To date, 16 of 25 Yucatan minipigs have received single-session SAbR to a 1.5cm length and 4 ofmore » 25 have received irradiation to a 0.5cm length of left-sided C6-C8 spinal nerves. Toxicity related gait change has been observed in 13 animals (9 from the long length group and 4 from the short). This preliminary data is overlaid on several dose-response models which have been fit to rodent spinal cord tolerance experiments. Model parameters define a toxicity profile between a completely serial or parallel behaving organ. Adequacy of model application, including how length effects are handled, to published minipig spinal cord dose-response data and to preliminary peripheral nerve response data was evaluated through residual analysis. Results: No rodent-derived dose-response models were directly applicable to all pig data for the different lengths irradiated. Several models fit the long-length irradiated spinal cord data well, with the more serial-like models fitting best. Preliminary data on the short-length irradiation suggests no length effect exists, disproving our hypothesis. Conclusion: Direct application of small-animal NTCP models to pig data suggests dose-length effect predictions from small animal data may not translate clinically. However, the small animal models used have not considered dose heterogeneity and it is expected that including the low-to-mid dose levels in the penumbral region will improve this match. This work was funded by the Cancer Prevention Research Institute of Texas (CPRIT).« less

Cardiovascular effects of spinal cord substance P: studies with a stable receptor agonist.

PubMed

Keeler, J R; Charlton, C G; Helke, C J

1985-06-01

The role of spinal cord substance P (SP) in regulating sympathetic outflow to the cardiovascular system was assessed with the stable active analog [pGlu5,MePhE8,MeGly9]-SP(5-11) (DiME-SP). The interaction of DiME-SP with spinal cord SP receptors was evaluated initially in binding studies. Saturable, high-affinity binding of [125I]Bolton-Hunter-SP to rat spinal cord membranes was dose-dependently inhibited by DiME-SP (IC50 = 1.5 microM). Intrathecal (i.t.) injections of DiME-SP (1.0-33 nmol) in anesthetized rats produced dose-dependent increases in blood pressure and heart rate that were accompanied by increases in plasma epinephrine and norepinephrine. Intravenous injections of the ganglionic blocker pentolinium blocked the cardiovascular and plasma catecholamine responses to i.t. injections of DiME-SP. Bulbospinal sympathoexcitatory pathways originating in the ventral medulla and their mediation by SP were also assessed. As demonstrated previously, application of bicuculline, the gamma-aminobutyric acid receptor antagonist, to the ventral surface of the medulla produced sympathetic mediated increases in blood pressure and these effects were blocked by i.t. injection of the SP receptor antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-SP. In this study, we studied the specificity of the SP antagonist for SP receptors by attempting to alter the actions of the SP antagonist with a SP agonist. Administration of DiME-SP (33 nmol i.t.) blocked the effects of [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-SP (3.3 nmol i.t.). Specifically, the SP agonist countered the SP antagonist-mediated 1) hypotensive response and 2) inhibitory effect on bicuculline-induced sympathoexcitatory responses elicited from the ventral surface of the medulla. These data provide further evidence that SP transmits excitatory information to the cardiovascular system via spinal sympathetic pathways.

Radiation Doses to Structures Within and Adjacent to the Larynx are Correlated With Long-Term Diet- and Speech-Related Quality of Life

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dornfeld, Ken; Simmons, Joel R.; Karnell, Lucy

Purpose: To test the hypothesis that radiation dose to key sites in the upper aerodigestive tract is associated with long-term functional outcome after (chemo)radiotherapy for head-and-neck cancers. Methods and Materials: This study examined the outcome for 27 patients treated with intensity-modulated radiotherapy for definitive management of their head-and-neck cancer who were disease free for at least 1 year after treatment. Head-and-neck cancer-specific quality of life (QoL) was assessed before treatment and at 1 year after treatment. Type of diet tolerated, presence of a feeding tube, and degree of weight loss 1 year after treatment were also used as outcome measures.more » Radiation doses delivered to various points along the upper aerodigestive tract, including base of tongue, lateral pharyngeal walls, and laryngeal structures, were determined from each treatment plan. Radiation doses for each of these points were tested for correlation with outcome measures. Results: Higher doses delivered to the aryepiglottic folds, false vocal cords, and lateral pharyngeal walls near the false cords correlated with a more restrictive diet, and higher doses to the aryepiglottic folds correlated with greater weight loss (p < 0.05) 1 year after therapy. Better posttreatment speech QoL scores were associated with lower doses delivered to structures within and surrounding the larynx. Conclusion: Our data show an inverse relationship between radiation dose delivered to laryngeal structures and speech and diet and QoL outcomes after definitive (chemo)radiation treatment. These findings suggest that efforts to deliver lower doses to laryngeal structures may improve outcomes after definitive (chemo)radiation therapy.« less

'Full dose' reirradiation of human cervical spinal cord.

PubMed

Ryu, S; Gorty, S; Kazee, A M; Bogart, J; Hahn, S S; Dalal, P S; Chung, C T; Sagerman, R H

2000-02-01

With the progress of modern multimodality cancer treatment, retreatment of late recurrences or second tumors became more commonly encountered in management of patients with cancer. Spinal cord retreatment with radiation is a common problem in this regard. Because radiation myelopathy may result in functional deficits, many oncologists are concerned about radiation-induced myelopathy when retreating tumors located within or immediately adjacent to the previous radiation portal. The treatment decision is complicated because it requires a pertinent assessment of prognostic factors with and without reirradiation, radiobiologic estimation of recovery of occult spinal cord damage from the previous treatment, as well as interactions because of multimodality treatment. Recent studies regarding reirradiation of spinal cord in animals using limb paralysis as an endpoint have shown substantial and almost complete recovery of spinal cord injury after a sufficient time after the initial radiotherapy. We report a case of "full" dose reirradiation of the entire cervical spinal cord in a patient who has not developed clinically detectable radiation-induced myelopathy on long-term follow-up of 17 years after the first radiotherapy and 5 years after the second radiotherapy.

Dosimetric quality, accuracy, and deliverability of modulated radiotherapy treatments for spinal metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kairn, Tanya, E-mail: t.kairn@gmail.com; School of Chemistry, Physics, and Mechanical Engineering, Queensland University of Technology, Brisbane; Papworth, Daniel

2016-10-01

Cancer often metastasizes to the vertebra, and such metastases can be treated successfully using simple, static posterior or opposed-pair radiation fields. However, in some cases, including when re-irradiation is required, spinal cord avoidance becomes necessary and more complex treatment plans must be used. This study evaluated 16 sample intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) treatment plans designed to treat 6 typical vertebral and paraspinal volumes using a standard prescription, with the aim of investigating the advantages and limitations of these treatment techniques and providing recommendations for their optimal use in vertebral treatments. Treatment plan quality and beammore » complexity metrics were evaluated using the Treatment And Dose Assessor (TADA) code. A portal-imaging–based quality assurance (QA) system was used to evaluate treatment delivery accuracy, and radiochromic film measurements were used to provide high-resolution verification of treatment plan dose accuracy, especially in the steep dose gradient regions between each vertebral target and spinal cord. All treatment modalities delivered approximately the same doses and the same levels of dose heterogeneity to each planning target volume (PTV), although the minimum PTV doses in the vertebral plans were substantially lower than the prescription, because of the requirement that the plans meet a strict constraint on the dose to the spinal cord and cord planning risk volume (PRV). All plans met required dose constraints on all organs at risk, and all measured PTV-cord dose gradients were steeper than planned. Beam complexity analysis suggested that the IMRT treatment plans were more deliverable (less complex, leading to greater QA success) than the VMAT treatment plans, although the IMRT plans also took more time to deliver. The accuracy and deliverability of VMAT treatment plans were found to be substantially increased by limiting the number of monitor units (MU) per beam at the optimization stage, and thereby limiting beam modulation complexity. The VMAT arcs that were optimized with MU limitation had higher QA pass rates as well as higher modulation complexity scores (less complexity), lower modulation indices (less modulation), lower MU per beam, larger beam segments, and fewer small apertures than the VMAT arcs that were optimized without MU limitation. It is recommended that VMAT treatments for vertebral volumes, where the PTV abuts or surrounds the spinal cord, should be optimized with MU limitation. IMRT treatments may be preferable to the VMAT treatments, for dosimetry and deliverability reasons, but may be inappropriate for some patients because of their increased treatment delivery time.« less

TH-EF-BRB-03: Significant Cord and Esophagus Dose Reduction by 4π Non-Coplanar Spine Stereotactic Body Radiation Therapy and Stereotactic Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, V; Tran, A; Nguyen, D

Purpose: To demonstrate significant organ-at-risk (OAR) sparing achievable with 4π non-coplanar radiotherapy on spine SBRT and SRS patients. Methods: Twenty-five stereotactic spine cases previously treated with VMAT (n = 23) or IMRT (n = 2) were included in this study. A computer-aided-design model of a Linac with a 3D-scanned human surface was utilized to determine the feasible beam space throughout the 4π steradian and beam specific source-to-target-distances (STD) required for collision avoidance. 4π radiotherapy plans integrating beam orientation and fluence map optimization were then created using a column-generation algorithm. Twenty optimal beams were selected for each case. To evaluate themore » tradeoff between dosimetric benefit and treatment complexity, 4π plans including only isocentrically deliverable beams were also created. Beam angles of all standard and isocentric 4π plans were imported into Eclipse to recalculate the dose using the same calculation engine as the clinical plans for unbiased comparison. OAR and PTV dose statistics for the clinical, standard-4π, and isocentric-4π plans were compared. Results: Comparing standard-4π to clinical plans, particularly significant average percent reduction in the [mean, maximum] dose of the cord and esophagus of [41%, 21.7%], and [38.7%, 36.4%] was observed, along with global decrease in all other OAR dose statistics. The average cord volume receiving more than 50% prescription dose was substantially decreased by 76%. In addition, improved PTV coverage was demonstrated with a maximum dose reduction of 0.93% and 1.66% increase in homogeneity index (D95/D5). All isocentric-4π plans achieved dosimetric performance equivalent to that of the standard-4π plans with higher delivery complexity. Conclusion: 4π radiotherapy significantly improves stereotactic spine treatment dosimetry. With the substantial OAR dose sparing, PTV dose escalation is considerably safer. Isocentric-4π is sufficient to achieve the dosimetric gain. The successful implementation of 4π using an FDA approved planning system paves the way for a prospective clinical trial. Varian Medical Systems, NIH R43CA183390 and R01CA188300, NSF graduate research fellowship DGE-1144087.« less

Identifying risk factors for L'Hermitte's sign after IMRT for head and neck cancer.

PubMed

Laidley, Hannah M; Noble, David J; Barnett, Gill C; Forman, Julia R; Bates, Amy M; Benson, Richard J; Jefferies, Sarah J; Jena, Rajesh; Burnet, Neil G

2018-05-04

L'Hermitte's sign (LS) after chemoradiotherapy for head and neck cancer appears related to higher spinal cord doses. IMRT plans limit spinal cord dose, but the incidence of LS remains high. One hundred seventeen patients treated with TomoTherapy™ between 2008 and 2015 prospectively completed a side-effect questionnaire (VoxTox Trial Registration: UK CRN ID 13716). Baseline patient and treatment data were collected. Radiotherapy plans were analysed; mean and maximum spinal cord dose and volumes receiving 10, 20, 30 and 40 Gy were recorded. Dose variation across the cord was examined. These data were included in a logistic regression model. Forty two patients (35.9%) reported LS symptoms. Concurrent weekly cisplatin did not increase LS risk (p = 0.70, OR = 1.23 {95% CI 0.51-2.34}). Of 13 diabetic participants (9 taking metformin), only 1 developed LS (p = 0.025, OR = 0.13 {95% CI 0.051-3.27}). A refined binary logistic regression model showed that patients receiving unilateral radiation (p = 0.019, OR = 2.06 {95% CI 0.15-0.84}) were more likely to develop LS. Higher V 40Gy (p = 0.047, OR = 1.06 {95% CI 1.00-1.12}), and younger age (mean age 56.6 vs 59.7, p = 0.060, OR = 0.96 {95% CI 0.92-1.00}) were associated with elevated risk of LS, with borderline significance. In this cohort, concomitant cisplatin did not increase risk, and LS incidence was lower in diabetic patients. Patient age and dose gradients across the spinal cord may be important factors.

SU-E-J-32: Dosimetric Evaluation Based On Pre-Treatment Cone Beam CT for Spine Stereotactic Body Radiotherapy: Does Region of Interest Focus Matter?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Magnelli, A; Xia, P

2015-06-15

Purpose: Spine stereotactic body radiotherapy requires very conformal dose distributions and precise delivery. Prior to treatment, a KV cone-beam CT (KV-CBCT) is registered to the planning CT to provide image-guided positional corrections, which depend on selection of the region of interest (ROI) because of imperfect patient positioning and anatomical deformation. Our objective is to determine the dosimetric impact of ROI selections. Methods: Twelve patients were selected for this study with the treatment regions varied from C-spine to T-spine. For each patient, the KV-CBCT was registered to the planning CT three times using distinct ROIs: one encompassing the entire patient, amore » large ROI containing large bony anatomy, and a small target-focused ROI. Each registered CBCT volume, saved as an aligned dataset, was then sent to the planning system. The treated plan was applied to each dataset and dose was recalculated. The tumor dose coverage (percentage of target volume receiving prescription dose), maximum point dose to 0.03 cc of the spinal cord, and dose to 10% of the spinal cord volume (V10) for each alignment were compared to the original plan. Results: The average magnitude of tumor coverage deviation was 3.9%±5.8% with external contour, 1.5%±1.1% with large ROI, 1.3%±1.1% with small ROI. Spinal cord V10 deviation from plan was 6.6%±6.6% with external contour, 3.5%±3.1% with large ROI, and 1.2%±1.0% with small ROI. Spinal cord max point dose deviation from plan was: 12.2%±13.3% with external contour, 8.5%±8.4% with large ROI, and 3.7%±2.8% with small ROI. Conclusion: A small ROI focused on the target results in the smallest deviation from planned dose to target and cord although rotations at large distances from the targets were observed. It is recommended that image fusion during CBCT focus narrowly on the target volume to minimize dosimetric error. Improvement in patient setups may further reduce residual errors.« less

Activation of p38 MAP Kinase is Involved in Central Neuropathic Pain Following Spinal Cord Injury

PubMed Central

Crown, Eric D; Gwak, Young Seob; Ye, Zaiming; Johnson, Kathia M; Hulsebosch, Claire E

2008-01-01

Recent work regarding chronic central neuropathic pain (CNP) following spinal cord injury (SCI) suggests that activation of key signaling molecules such as members of the mitogen activated protein kinase (MAPK) family play a role in the expression of at-level mechanical allodynia. Specifically, Crown and colleagues (2005, 2006) have shown that the development of at-level CNP following moderate spinal cord injury is correlated with increased expression of the activated (and thus phosphorylated) forms of the MAPKs extracellular signal related kinase and p38 MAPK. The current study extends this work by directly examining the role of p38 MAPK in the maintenance of at-level CNP following spinal cord injury. Using a combination of behavioral, immunocytochemical, and electrophysiological measures we demonstrate that increased activation of p38 MAPK occurs in the spinal cord just rostral to the site of injury in rats that develop at-level mechanical allodynia after moderate SCI. Immunocytochemical analyses indicate that the increases in p38 MAPK activation occurred in astrocytes, microglia, and dorsal horn neurons in the spinal cord rostral to the site of injury. Inhibiting the enzymatic activity of p38 MAPK dose dependently reverses the behavioral expression of at-level mechanical allodynia and also decreases the hyperexcitability seen in thoracic dorsal horn neurons after moderate SCI. Taken together, these novel data are the first to demonstrate causality that increased activation of p38 MAPK in multiple cell types play an important role in the maintenance of at-level CNP following spinal cord injury. PMID:18590729

SU-E-J-85: The Effect of Different Imaging Modalities On the Delineation of the True Spinal Cord for Spinal Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goddard, L; Brodin, P; Mani, K

Purpose: SBRT allows the delivery of high dose radiation treatments to localized tumors while minimizing dose to surrounding tissues. Due to the large doses delivered, accurate contouring of organs at risk is essential. In this study, differences between the true spinal cord as seen using MRI and CT myelogram (CTM) have been assessed in patients with spinal metastases treated using SBRT. Methods: Ten patients were identified that have both a CTM and a MRI. Using rigid registration tools, the MRI was fused to the CTM. The thecal sac and true cord were contoured using each imaging modality. Images were exportedmore » and analyzed for similarity by computing the Dice similarity coefficient and the modified Hausdorff distance (greatest distance from a point in one set to the closest point in the other set). Results: The Dice coefficient was calculated for the thecal sac (0.81 ±0.06) and true cord (0.63 ±0.13). These two measures are correlated; however, some points show a low true cord overlap despite a high overlap for the thecal sac. The Hausdorff distance for structure comparisons was also calculated. For thecal sac structures, the average value, 1.6mm (±1.1), indicates good overlap. For true cord comparison, the average value, 0.3mm (±0.16), indicates very good overlap. The minimum Hausdorff distance between the true cord and thecal sac was on average 1.6mm (±0.9) Conclusion: The true cord position as seen in MRI and CTM is fairly constant, although care should be taken as large differences can be seen in individual patients. Avoidning the true cord in spine SBRT is critical, so the ability to visualize the true cord before performing SBRT to the vertebrae is essential. Here, CT myelogram appears an excellent, robust option, that can be obtained the day of treatment planning and is unaffected by uncertainties in image fusion.« less

Methods for assisting recovery of damaged brain and spinal cord using arrays of X-Ray microplanar beams

DOEpatents

Dilmanian, F. Avraham; McDonald, III, John W.

2007-12-04

A method of assisting recovery of an injury site of brain or spinal cord injury includes providing a therapeutic dose of X-ray radiation to the injury site through an array of parallel microplanar beams. The dose at least temporarily removes regeneration inhibitors from the irradiated regions. Substantially unirradiated cells surviving between the microplanar beams migrate to the in-beam irradiated portion and assist in recovery. The dose may be administered in dose fractions over several sessions, separated in time, using angle-variable intersecting microbeam arrays (AVIMA). Additional doses may be administered by varying the orientation of the microplanar beams. The method may be enhanced by injecting stem cells into the injury site.

Methods for assisting recovery of damaged brain and spinal cord using arrays of X-ray microplanar beams

DOEpatents

Dilmanian, F. Avraham; McDonald, III, John W.

2007-01-02

A method of assisting recovery of an injury site of brain or spinal cord injury includes providing a therapeutic dose of X-ray radiation to the injury site through an array of parallel microplanar beams. The dose at least temporarily removes regeneration inhibitors from the irradiated regions. Substantially unirradiated cells surviving between the microplanar beams migrate to the in-beam irradiated portion and assist in recovery. The dose may be administered in dose fractions over several sessions, separated in time, using angle-variable intersecting microbeam arrays (AVIMA). Additional doses may be administered by varying the orientation of the microplanar beams. The method may be enhanced by injecting stem cells into the injury site.

An alternative approach to account for patient organ doses from imaging guidance procedures.

PubMed

Nelson, Alan P; Ding, George X

2014-07-01

To investigate the feasibility of an alternative method of accounting for additional organ doses resulting from image guidance procedures during patient treatment planning through tabulated values based on scan protocol and scan site. Patient-specific imaging dose to 30 patients resulting from Varian OBI kV-CBCT scans using the Standard Head (17 patients), Low-dose Thorax (8 patients), and Pelvic (5 patients) scan protocols were retrospectively calculated using Monte Carlo methods. Dose dependence on scan location and patient geometry was explored. Patient organ doses were analyzed by using dose-volume histograms and expressed by the mean, minimum dose delivered to 50% of the organ volume, D50. The reported doses are dose-to-medium instead of dose-to-water. The organ doses from all patient-specific calculations show predictable and limited ranges across patients. For brain isocenters using Standard Head Scans: Bone: 0.7-1.1 cGy, Brain: 0.2-0.3 cGy, Brainstem: 0.2-0.3 cGy, Skin: 0.3-0.4 cGy, Eye: 0.03-0.3 cGy. For head and neck patients using the Standard Head Scan: Bone: 0.3-0.6 cGy, Parotids: 0.3-0.4 cGy, Spinal Cord: 0.15-0.25 cGy, Thyroid: 0.1-0.25 cGy, Skin: 0.2-0.3 cGy, Trachea-Esophagus: 0.1-0.2 cGy. For chest using Thorax Scans: Bone: 1.1-1.8 cGy, Soft tissue organs (Bowel, Lung, Heart, Kidney, Esophagus, and Spinal Cord): 0.3-0.6 cGy. For abdominal site using Pelvic Scans: Bone: 3.2-4.2 cGy. Soft tissue organs (Bladder, Bowel, Rectum, Prostate, and Skin) D50s fell between 1.2 and 2.2 cGy. Femoral Heads: 2.5-3.4 cGy. It is adequate to estimate and account for organ dose by using tabulated values based on scan procedure and site because organ doses from imaging procedures are only modestly dependent upon scan location and body size. Considering the dose variation and magnitude of dose from each scan protocol in comparison to therapeutic doses, this approach provides a simple alternative to account for additional imaging guidance doses during patient treatment planning. Clinicians can use these tabulated values to make informed decisions in selecting the appropriate imaging procedures and imaging frequency during radiotherapy treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI) and Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) analysis.

PubMed

Ruggeri, Annalisa; Rocha, Vanderson; Masson, Emeline; Labopin, Myriam; Cunha, Renato; Absi, Lena; Boudifa, Ali; Coeffic, Brigitte; Devys, Anne; De Matteis, Muriel; Dubois, Valérie; Hanau, Daniel; Hau, Françoise; Jollet, Isabelle; Masson, Dominique; Pedron, Beatrice; Perrier, Pascale; Picard, Christophe; Ramouneau-Pigot, Annie; Volt, Fernanda; Charron, Dominique; Gluckman, Eliane; Loiseau, Pascale

2013-07-01

Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. To analyze the effect of anti-HLA antibodies on unrelated cord blood transplantation outcomes, we analyzed 294 unrelated cord blood transplant recipients after reduced intensity conditioning regimen. The majority of the patients (82%) were transplanted for malignancies, 60% with double-unrelated cord blood transplant, 63% were HLA mismatched. Retrospectively, pre-unrelated cord blood transplant serum was tested for HLA-Ab using Luminex™ platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. Among 62 recipients (23%) who had anti-HLA antibodies before unrelated cord blood transplant, 14 patients had donor specific anti-HLA antibodies (DSA) (7 were donor-specific anti-HLA antibodies for single unrelated cord blood transplant and 7 for double unrelated cord blood transplant). Donor specific anti-HLA antibodies threshold ranged from 1620-17629 of mean fluorescence intensity (MFI). Cumulative incidence of Day-60 neutrophil engraftment was 76%: 44% for recipients with donor specific anti-HLA antibodies and 81% in those without donor specific anti-HLA antibodies (P=0.006). The cumulative incidence of 1-year transplant related mortality was 46% in patients with donor specific anti-HLA antibodies and 32% in those without antibodies (P=0.06). The presence of donor specific anti-HLA antibodies was associated with a trend for decreased survival rate (42% vs. 29%; P=0.07). Donor specific anti-HLA antibody in recipients of unrelated cord blood transplant is associated with graft failure and decreased survival. Patient's screening for donor specific anti-HLA antibodies before unrelated cord blood transplantation is recommended before choosing an HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit for which the patient has donor specific anti-HLA antibodies.

On the impact of improved dosimetric accuracy on head and neck high dose rate brachytherapy.

PubMed

Peppa, Vasiliki; Pappas, Eleftherios; Major, Tibor; Takácsi-Nagy, Zoltán; Pantelis, Evaggelos; Papagiannis, Panagiotis

2016-07-01

To study the effect of finite patient dimensions and tissue heterogeneities in head and neck high dose rate brachytherapy. The current practice of TG-43 dosimetry was compared to patient specific dosimetry obtained using Monte Carlo simulation for a sample of 22 patient plans. The dose distributions were compared in terms of percentage dose differences as well as differences in dose volume histogram and radiobiological indices for the target and organs at risk (mandible, parotids, skin, and spinal cord). Noticeable percentage differences exist between TG-43 and patient specific dosimetry, mainly at low dose points. Expressed as fractions of the planning aim dose, percentage differences are within 2% with a general TG-43 overestimation except for the spine. These differences are consistent resulting in statistically significant differences of dose volume histogram and radiobiology indices. Absolute differences of these indices are however small to warrant clinical importance in terms of tumor control or complication probabilities. The introduction of dosimetry methods characterized by improved accuracy is a valuable advancement. It does not appear however to influence dose prescription or call for amendment of clinical recommendations for the mobile tongue, base of tongue, and floor of mouth patient cohort of this study. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Late effects of radiation on the lumbar spinal cord of guinea pigs: Re-treatment tolerance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mason, K.A.; Withers, H.R.; Chiang, Chi-Shiun

Using a guinea pig model of lumbar myelopathy, various factors affecting the tolerance of spinal cord to irradiation were assessed: (a) extent of initial injury; (b) time interval between priming and test doses; and (c) animal age at the time of initial radiation treatment. A 3 cm section of lumbar spinal cord of guinea pigs was irradiated with fractionated doses of 4.5 Gy gamma rays given as 9 fractions per week. Guinea pigs were primed with 9 x 4.5 Gy in 7 days which is 60% of the ED[sub 50] for a continuous course of treatment. After 28 or 40more » weeks, animal were retreated with 6-14 fractions of 4.5 Gy. Animals were observed for 2 years following the priming dose and both the incidence and latency of myelopathy recorded. Young adult guinea pigs (8 wk old) showed both a decreased radiation tolerance and latency compared to old individuals (40 wk old). At 28 or 40 wk after 9 x 4.5 Gy, only about 8% of the initial injury was remembered in young adult guinea pigs. The amount of residual injury was dependent on the initial damage as a proportion of the tolerance dose. The spinal cord shows a greater capacity for long-term recovery than generally appreciated and re-treatment doses clinically prescribed may be lower than necessary. 8 refs., 3 figs., 2 tabs.« less

Spine SBRT using VMAT

NASA Astrophysics Data System (ADS)

Goddard, L.; Bodner, W.; Brodin, N. P.; Garg, M.; Lee, A.; Mani, K.; Tomé, W. A.

2017-01-01

Metastases of the spinal column are common amongst cancer patients with approximately 18,000 new cases in North America each year that require urgent treatment. Historically radiation therapy doses have been limited due to the proximity of the spinal cord. However as image guidance and localization techniques have improved it has become possible to deliver higher radiation doses to the tumour whilst sparing the spinal cord. This paper presents some of the techniques undertaken at our center.

[Evaluation of the role of combined TES-MEP and CSEP monitoring during the spinal surgery].

PubMed

Chen, Yu-guang; Peng, Xin-sheng; Wan, Yong; Yang, Jun-lin; Zheng, Zhao-min; Zou, Xue-nong; Li, Fo-bao; Shu, Hai-hua; Xia, Jie-hua; Dou, Yun-ling

2010-02-01

To evaluate of the role of transcranial electrical stimulation motor evoked potential (TES-MEP) in combination with cortical somatosensory evoked potential (CSEP) monitoring during the spinal surgery. TES-MEP on bilateral anterior tibial muscle and flexor hallucal brevis and CSEP on bilateral posterior tibial nerve were observed simultaneously on 293 patients during spinal surgery from July 2006 to April 2009. Intravenous anesthesia was employed in all the patients, a part of which were added low dose of sevoflurane or muscle relaxant. The results of TES-MEP, CSEP and combined monitoring were analyzed statistically. Pre-operative and post-operative motor and sensory functions of spinal cord were compared. Success rate of TES-MEP, CSEP and combined monitoring was 90.8%, 96.9% and 100% respectively. For the judgment of motor function of spinal cord, the sensitivity of TES-MEP and CSEP was 100% and 89.3% respectively and the specificity of 98.4% and 96.9%. The Youden index of the two methods was 0.984 and 0.862. For sensory function, the sensitivity of them was 76.7% and 93.3% respectively and the specificity of 98.7% and 98.0%. The Youden index was 0.754 and 0.913. The sensitivity of combined monitoring was 100%, with the specificity of 96.9%. The Youden index was 0.969. The precision of monitoring motor function of spinal cord with TES-MEP is higher than that with CSEP, however, for sensory function, CSEP is more precise. The sensitivity and precision of combined monitoring for spinal cord function were apparently better than that of unitary TES-MEP or CSEP. The combined TES-MEP and CSEP monitoring is a relatively ideal method.

Local delivery of thyroid hormone enhances oligodendrogenesis and myelination after spinal cord injury

NASA Astrophysics Data System (ADS)

Shultz, Robert B.; Wang, Zhicheng; Nong, Jia; Zhang, Zhiling; Zhong, Yinghui

2017-06-01

Objective. Traumatic spinal cord injury (SCI) causes apoptosis of myelin-forming oligodendrocytes (OLs) and demyelination of surviving axons, resulting in conduction failure. Remyelination of surviving denuded axons provides a promising therapeutic target for spinal cord repair. While cell transplantation has demonstrated efficacy in promoting remyelination and functional recovery, the lack of ideal cell sources presents a major obstacle to clinical application. The adult spinal cord contains oligodendrocyte precursor cells and multipotent neural stem/progenitor cells that have the capacity to differentiate into mature, myelinating OLs. However, endogenous oligodendrogenesis and remyelination processes are limited by the upregulation of remyelination-inhibitory molecules in the post-injury microenvironment. Multiple growth factors/molecules have been shown to promote OL differentiation and myelination. Approach. In this study we screened these therapeutics and found that 3, 3‧, 5-triiodothyronine (T3) is the most effective in promoting oligodendrogenesis and OL maturation in vitro. However, systemic administration of T3 to achieve therapeutic doses in the injured spinal cord is likely to induce hyperthyroidism, resulting in serious side effects. Main results. In this study we developed a novel hydrogel-based drug delivery system for local delivery of T3 to the injury site without eliciting systemic toxicity. Significance. Using a clinically relevant cervical contusion injury model, we demonstrate that local delivery of T3 at doses comparable to safe human doses promoted new mature OL formation and myelination after SCI.

TU-H-CAMPUS-IeP1-04: Combined Organ Dose for Digital Subtraction Angiography and Computed Tomography Using Monte Carlo Simulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakabe, D; Ohno, T; Araki, F

Purpose: The purpose of this study was to evaluate the combined organ dose of digital subtraction angiography (DSA) and computed tomography (CT) using a Monte Carlo (MC) simulation on the abdominal intervention. Methods: The organ doses for DSA and CT were obtained with MC simulation and actual measurements using fluorescent-glass dosimeters at 7 abdominal portions in an Alderson-Rando phantom. DSA was performed from three directions: posterior anterior (PA), right anterior oblique (RAO), and left anterior oblique (LAO). The organ dose with MC simulation was compared with actual radiation dose measurements. Calculations for the MC simulation were carried out with themore » GMctdospp (IMPS, Germany) software based on the EGSnrc MC code. Finally, the combined organ dose for DSA and CT was calculated from the MC simulation using the X-ray conditions of a patient with a diagnosis of hepatocellular carcinoma. Results: For DSA from the PA direction, the organ doses for the actual measurements and MC simulation were 2.2 and 2.4 mGy/100 mAs at the liver, respectively, and 3.0 and 3.1 mGy/100 mAs at the spinal cord, while for CT, the organ doses were 15.2 and 15.1 mGy/100 mAs at the liver, and 14.6 and 13.5 mGy/100 mAs at the spinal cord. The maximum difference in organ dose between the actual measurements and the MC simulation was 11.0% of the spleen at PA, 8.2% of the spinal cord at RAO, and 6.1% of left kidney at LAO with DSA and 9.3% of the stomach with CT. The combined organ dose (4 DSAs and 6 CT scans) with the use of actual patient conditions was found to be 197.4 mGy for the liver and 205.1 mGy for the spinal cord. Conclusion: Our method makes it possible to accurately assess the organ dose to patients for abdominal intervention with combined DSA and CT.« less

Safety and efficacy of stereotactic radiosurgery for tumors of the spine.

PubMed

Benzil, Deborah L; Saboori, Mehran; Mogilner, Alon Y; Rocchio, Ronald; Moorthy, Chitti R

2004-11-01

The extension of stereotactic radiosurgery treatment of tumors of the spine has the potential to benefit many patients. As in the early days of cranial stereotactic radiosurgery, however, dose-related efficacy and toxicity are not well understood. The authors report their initial experience with stereotactic radiosurgery of the spine with attention to dose, efficacy, and toxicity. All patients who underwent stereotactic radiosurgery of the spine were treated using the Novalis unit at Westchester Medical Center between December 2001 and January 2004 are included in a database consisting of demographics on disease, dose, outcome, and complications. A total of 31 patients (12 men, 19 women; mean age 61 years, median age 63 years) received treatment for 35 tumors. Tumor types included 26 metastases (12 lung, nine breast, five other) and nine primary tumors (four intradural, five extradural). Thoracic tumors were most common (17 metastases and four primary) followed by lumbar tumors (four metastases and four primary). Lesions were treated to the 85 to 90% isodose line with spinal cord doses being less than 50%. The dose per fraction and total dose were selected on the basis of previous treatment (particularly radiation exposure), size of lesion, and proximity to critical structures. Rapid and significant pain relief was achieved after stereotactic radiosurgery in 32 of 34 treated tumors. In patients treated for metastases, pain was relieved within 72 hours and remained reduced 3 months later. Pain relief was achieved with a single dose as low as 500 cGy. Spinal cord isodoses were less than 50% in all patients except those with intradural tumors (mean single dose to spinal cord 268 cGy and mean total dose to spinal cord 689 cGy). Two patients experienced transient radiculitis (both with a biological equivalent dose (BED) > 60 Gy). One patient who suffered multiple recurrences of a conus ependymoma had permanent neurological deterioration after initial improvement. Pathological evaluation of this lesion at surgery revealed radiation necrosis with some residual/recurrent tumor. No patient experienced other organ toxicity. Stereotactic radiosurgery of the spine is safe at the doses used and provides effective pain relief. In this study, BEDs greater than 60 Gy were associated with an increased risk of radiculitis.

(R)- and (S)-methadone and buprenorphine concentration ratios in maternal and umbilical cord plasma following chronic maintenance dosing in pregnancy

PubMed Central

Gordon, Andrea L; Lopatko, Olga V; Somogyi, Andrew A; Foster, David J R; White, Jason M

2010-01-01

AIMS The aim of this study was to compare the transfer of buprenorphine and methadone between maternal and cord blood in women under chronic dosing conditions and to determine if differences exist in the transfer of the two methadone enantiomers. METHODS Maternal and cord blood samples were collected at delivery from women maintained on methadone (35, 25–140 mg day−1) (median; range) or buprenorphine (6.00, 2–20 mg day−1) during pregnancy. Plasma concentration ratios are presented as an indicator of foetal exposure relative to the mother. RESULTS Methadone was quantified in all samples, with cord : maternal plasma methadone concentration ratios (n = 15 mother-infant pairs) being significantly higher (P < 0.0001; mean difference (MD) 0.07; 95% confidence interval (CI) 0.048, 0.092) for the active (R)-methadone enantiomer (0.41; 0.19, 0.56) (median; range) compared with (S)-methadone (0.36; 0.15, 0.53). (R)- : (S)-methadone concentration ratios were also significantly higher (P < 0.0001; MD 0.24 95% CI 0.300, 0.180) for cord (1.40; 0.95, 1.67) compared with maternal plasma (1.16; 0.81, 1.38). Half the infant buprenorphine samples were below the assay lower limit of quantification (LLOQ) (0.125 ng ml−1). The latter was four-fold lower than the LLOQ for methadone (0.50 ng ml−1). The cord : maternal plasma buprenorphine concentration ratio (n = 9 mother-infant pairs) was 0.35; 0.14, 0.47 and for norbuprenorphine 0.49; 0.24, 0.91. CONCLUSIONS The transfer of the individual methadone enantiomers to the foetal circulation is stereoselective. Infants born to buprenorphine maintained women are not exposed to a greater proportion of the maternal dose compared with methadone and may be exposed to relatively less of the maternal dose compared with infants born to women maintained on methadone during pregnancy. PMID:21175445

Brain protection by methylprednisolone in rats with spinal cord injury.

PubMed

Chang, Chia-Mao; Lee, Ming-Hsueh; Wang, Ting-Chung; Weng, Hsu-Huei; Chung, Chiu-Yen; Yang, Jen-Tsung

2009-07-01

Traumatic spinal cord injury is clinically treated by high doses of methylprednisolone. However, the effect of methylprednisolone on the brain in spinal cord injury patients has been little investigated. This experimental study examined Bcl-2 and Bax protein expression and Nissl staining to evaluate an apoptosis-related intracellular signaling event and final neuron death, respectively. Spinal cord injury produced a significant apoptotic change and cell death not only in the spinal cord but also in the supraventricular cortex and hippocampal cornu ammonis 1 region in the rat brains. The treatment of methylprednisolone increased the Bcl-2/Bax ratio and prevented neuron death for 1-7 days after spinal cord injury. These findings suggest that rats with spinal cord injury show ascending brain injury that could be restricted through methylprednisolone management.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Foster, R; Ding, C; Jiang, S

Purpose Spine SRS/SAbR treatment plans typically require very steep dose gradients to meet spinal cord constraints and it is crucial that the dose distribution be accurate. However, these plans are typically calculated on helical free-breathing CT scans, which often contain motion artifacts. While the spine itself doesn’t exhibit very much intra-fraction motion, tissues around the spine, particularly the liver, do move with respiration. We investigated the dosimetric effect of liver motion on dose distributions calculated on helical free-breathing CT scans for spine SAbR delivered to the T and L spine. Methods We took 5 spine SAbR plans and used densitymore » overrides to simulate an average reconstruction CT image set, which would more closely represent the patient anatomy during treatment. The value used for the density override was 0.66 g/cc. All patients were planned using our standard beam arrangement, which consists of 13 coplanar step and shoot IMRT beams. The original plan was recalculated with the same MU on the “average” scan and target coverage and spinal cord dose were compared to the original plan. Results The average changes in minimum PTV dose, PTV coverage, max cord dose and volume of cord receiving 10 Gy were 0.6%, 0.8%, 0.3% and 4.4% (0.012 cc), respectively. Conclusion SAbR spine plans are surprisingly robust relative to surrounding organ motion due to respiration. Motion artifacts in helical planning CT scans do not cause clinically significant differences when these plans are re-calculated on pseudo-average CT reconstructions. This is likely due to the beam arrangement used because only three beams pass through the liver and only one beam passes completely through the density override. The effect of the respiratory motion on VMAT plans for spine SAbR is being evaluated.« less

Human umbilical-cord-blood mononucleated cells enhance the survival of lethally irradiated mice: dosage and the window of time.

PubMed

Kovalenko, Olga A; Azzam, Edouard I; Ende, Norman

2013-11-01

The purpose of this study was to evaluate the window of time and dose of human umbilical-cord-blood (HUCB) mononucleated cells necessary for successful treatment of radiation injury in mice. Female A/J mice (27-30 weeks old) were exposed to an absorbed dose of 9-10 Gy of (137)Cs γ-rays delivered acutely to the whole body. They were treated either with 1 × 10(8) or 2 × 10(8) HUCB mononucleated cells at 24-52 h after the irradiation. The antibiotic Levaquin was applied 4 h postirradiation. The increased dose of cord-blood cells resulted in enhanced survival. The enhancement of survival in animals that received 2 × 10(8) HUCB mononucleated cells relative to irradiated but untreated animals was highly significant (P < 0.01). Compared with earlier studies, the increased dose of HUCB mononucleated cells, coupled with early use of an antibiotic, extended the window of time for effective treatment of severe radiation injury from 4 to 24-52 h after exposure.

The dose response relation for rat spinal cord paralysis analyzed in terms of the effective size of the functional subunit

NASA Astrophysics Data System (ADS)

Adamus-Górka, Magdalena; Mavroidis, Panayiotis; Brahme, Anders; Lind, Bengt K.

2008-11-01

Radiobiological models for estimating normal tissue complication probability (NTCP) are increasingly used in order to quantify or optimize the clinical outcome of radiation therapy. A good NTCP model should fulfill at least the following two requirements: (a) it should predict the sigmoid shape of the corresponding dose-response curve and (b) it should accurately describe the probability of a specified response for arbitrary non-uniform dose delivery for a given endpoint as accurately as possible, i.e. predict the volume dependence. In recent studies of the volume effect of a rat spinal cord after irradiation with narrow and broad proton beams the authors claim that none of the existing NTCP models is able to describe their results. Published experimental data have been used here to try to quantify the change in the effective dose (D50) causing 50% response for different field sizes. The present study was initiated to describe the induction of white matter necrosis in a rat spinal cord after irradiation with narrow proton beams in terms of the mean dose to the effective volume of the functional subunit (FSU). The physically delivered dose distribution was convolved with a function describing the effective size or, more accurately, the sensitivity distribution of the FSU to obtain the effective mean dose deposited in it. This procedure allows the determination of the mean D50 value of the FSUs of a certain size which is of interest for example if the cell nucleus of the oligodendrocyte is the sensitive target. Using the least-squares method to compare the effective doses for different sizes of the functional subunits with the experimental data the best fit was obtained with a length of about 9 mm. For the non-uniform dose distributions an effective FSU length of 8 mm gave the optimal fit with the probit dose-response model. The method could also be used to interpret the so-called bath and shower experiments where the heterogeneous dose delivery was used in the convolution process. The assumption of an effective FSU size is consistent with most of the effects seen when different portions of the rat spinal cord are irradiated to different doses. The effective FSU length from these experiments is about 8.5 ± 0.5 mm. This length could be interpreted as an effective size of the functional subunits in a rat spinal cord, where multiple myelin sheaths are connected by a single oligodendrocyte and repair is limited by the range of oligodendrocyte progenitor cell diffusion. It was even possible to suggest a more likely than uniform effective FSU sensitivity distribution from the experimental data.

Regional peripheral and CNS hemodynamic effects of intrathecal administration of a substance P receptor agonist.

PubMed

Helke, C J; Phillips, E T; O'Neill, J T

1987-11-01

Regional CNS and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P receptor agonist, [pGlu5,MePhe8,MeGly9]-substance P5-11 ([DiMe]-SP), were studied in anesthetized rats with the radioactive microsphere technique. It was previously shown that [DiMe]-SP caused a sympathetically mediated increase in mean arterial pressure (MAP) by an action within the spinal cord. In this study, [DiMe]-SP (5 and 33 nmol, i.t.) increased MAP. The 5 nmol dose increased resistance in cutaneous, renal, splanchnic, and adrenal vascular beds but decreased resistance, and increased blood flow in some skeletal muscle beds. Total peripheral resistance was unchanged. The 33 nmol dose increased resistance in each peripheral vascular bed analyzed and increased total peripheral resistance. Whereas each dose increased heart rate, stroke volume and cardiac output were unchanged with the 5 nmol dose and were reduced with the 33 nmol dose. Neither dose of [DiMe]-SP significantly altered regional brain or spinal cord blood flows. These data show that the i.t. administration of the SP agonist, [DiMe]-SP, increased vascular tone to most peripheral vascular beds whereas the low dose caused a vasodilation of skeletal muscle. These effects are consistent with the notion of a dose-related activation of SP receptors in the spinal cord affecting sympathetic outflow to the adrenals and to the vasculature.

SU-F-T-585: A Novel Phantom for Dosimetric Validation of SBRT for Spinal Lesions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Papanikolaou, KN; Ha, C; Kirby, N

2016-06-15

Purpose: SBRT is proving to be a very efficacious treatment modality for an increasing number of indications, including spine lesions. We have developed a novel phantom to serve as an end-to-end QA tool for either patient specific QA or commissioning QA of SBRT for spine lesions. Methods: In this feasibility study, we have selected a patient with a single metastatic lesion in the L5 vertebral body. The patient’s CT simulation scan was used to develop a VMAT treatment plan delivering 18Gy to at least 90% of the target volume, following the guidelines of RTOG 0631. The treatment plan was developedmore » with the Pinnacle planning system using the adaptive convolution superposition calculation mode. The approved plan was re-calculated using the Monaco planning system. We performed a pseudo-in-vivo study whereby we manufactured two copies of a phantom to the exact shape and anatomy of the patient. The phantom was made from the CT images of the patient using a 3D printer with sub-millimeter accuracy. One phantom was filled with a gel dosimeter and the other was made with two ion chamber inserts to allow us to obtain point dose measurements in the target’s center and the spinal cord. Results: The prescribed dose of 18Gy was planned for the target while keeping the maximum spinal cord dose to less than 14Gy in 0.03cc of the cord. The VMAT plan was delivered to both the gel dosimeter filed phantom and the phantom with the ion chambers. The 3D gel dosimetry revealed a very good agreement between the monte carlo and measured point and volumetric dose. Conclusion: A patient like phantom was developed and validated for use as an end-to-end tool of dose verification for SBRT of spine lesions. We found that gel dosimetry is ideally suited to assess positional and dosimetric accuracy in 3D. RTsafe provided the phantoms and the gel dosimeter used for this study.« less

SU-E-J-100: The Combination of Deformable Image Registration and Regions-Of-Interest Mapping Technique to Accomplish Accurate Dose Calculation On Cone Beam Computed Tomography for Esophageal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, B-T; Lu, J-Y

Purpose: We introduce a new method combined with the deformable image registration (DIR) and regions-of-interest mapping (ROIM) technique to accurately calculate dose on daily CBCT for esophageal cancer. Methods: Patients suffered from esophageal cancer were enrolled in the study. Prescription was set to 66 Gy/30 F and 54 Gy/30 F to the primary tumor (PTV66) and subclinical disease (PTV54) . Planning CT (pCT) were segmented into 8 substructures in terms of their differences in physical density, such as gross target volume (GTV), venae cava superior (SVC), aorta, heart, spinal cord, lung, muscle and bones. The pCT and its substructures weremore » transferred to the MIM software to readout their mean HU values. Afterwards, a deformable planning CT to daily KV-CBCT image registration method was then utilized to acquire a new structure set on CBCT. The newly generated structures on CBCT were then transferred back to the treatment planning system (TPS) and its HU information were overridden manually with mean HU values obtained from pCT. Finally, the treatment plan was projected onto the CBCT images with the same beam arrangements and monitor units (MUs) to accomplish dose calculation. Planning target volume (PTV) and organs at risk (OARs) from both of the pCT and CBCT were compared to evaluate the dose calculation accuracy. Results: It was found that the dose distribution in the CBCT showed little differences compared to the pCT, regardless of whether PTV or OARs were concerned. Specifically, dose variation in GTV, PTV54, PTV66, SVC, lung and heart were within 0.1%. The maximum dose variation was presented in the spinal cord, which was up to 2.7% dose difference. Conclusion: The proposed method combined with DIR and ROIM technique to accurately calculate dose distribution on CBCT for esophageal cancer is feasible.« less

Quality of tri-Co-60 MR-IGRT treatment plans in comparison with VMAT treatment plans for spine SABR.

PubMed

Choi, Chang Heon; Park, So-Yeon; Kim, Jung-In; Kim, Jin Ho; Kim, Kyubo; Carlson, Joel; Park, Jong Min

2017-02-01

To investigate the plan quality of tri-Co-60 intensity-modulated radiation therapy (IMRT) plans for spine stereotactic ablative radiotherapy (SABR). A total of 20 patients with spine metastasis were retrospectively selected. For each patient, a tri-Co-60 IMRT plan and a volumetric-modulated arc therapy (VMAT) plan were generated. The spinal cords were defined based on MR images for the tri-Co-60 IMRT, while isotropic 1-mm margins were added to the spinal cords for the VMAT plans. The VMAT plans were generated with 10-MV flattening filter-free photon beams of TrueBeam STx ™ (Varian Medical Systems, Palo Alto, CA), while the tri-Co-60 IMRT plans were generated with the ViewRay ™ system (ViewRay inc., Cleveland, OH). The initial prescription dose was 18 Gy (1 fraction). If the tolerance dose of the spinal cord was not met, the prescription dose was reduced until the spinal cord tolerance dose was satisfied. The mean dose to the target volumes, conformity index and homogeneity index of the VMAT and tri-Co-60 IMRT were 17.8 ± 0.8 vs 13.7 ± 3.9 Gy, 0.85 ± 0.20 vs 1.58 ± 1.29 and 0.09 ± 0.04 vs 0.24 ± 0.19, respectively. The integral doses and beam-on times were 16,570 ± 1768 vs 22,087 ± 2.986 Gy cm 3 and 3.95 ± 1.13 vs 48.82 ± 10.44 min, respectively. The tri-Co-60 IMRT seems inappropriate for spine SABR compared with VMAT. Advances in knowledge: For spine SABR, the tri-Co-60 IMRT is inappropriate owing to the large penumbra, large leaf width and low dose rate of the ViewRay system.

Quality of tri-Co-60 MR-IGRT treatment plans in comparison with VMAT treatment plans for spine SABR

PubMed Central

Choi, Chang Heon; Park, So-Yeon; Kim, Jung-in; Kim, Jin Ho; Kim, Kyubo; Carlson, Joel

2017-01-01

Objective: To investigate the plan quality of tri-Co-60 intensity-modulated radiation therapy (IMRT) plans for spine stereotactic ablative radiotherapy (SABR). Methods: A total of 20 patients with spine metastasis were retrospectively selected. For each patient, a tri-Co-60 IMRT plan and a volumetric-modulated arc therapy (VMAT) plan were generated. The spinal cords were defined based on MR images for the tri-Co-60 IMRT, while isotropic 1-mm margins were added to the spinal cords for the VMAT plans. The VMAT plans were generated with 10-MV flattening filter-free photon beams of TrueBeam STx™ (Varian Medical Systems, Palo Alto, CA), while the tri-Co-60 IMRT plans were generated with the ViewRay™ system (ViewRay inc., Cleveland, OH). The initial prescription dose was 18 Gy (1 fraction). If the tolerance dose of the spinal cord was not met, the prescription dose was reduced until the spinal cord tolerance dose was satisfied. Results: The mean dose to the target volumes, conformity index and homogeneity index of the VMAT and tri-Co-60 IMRT were 17.8 ± 0.8 vs 13.7 ± 3.9 Gy, 0.85 ± 0.20 vs 1.58 ± 1.29 and 0.09 ± 0.04 vs 0.24 ± 0.19, respectively. The integral doses and beam-on times were 16,570 ± 1768 vs 22,087 ± 2.986 Gy cm3 and 3.95 ± 1.13 vs 48.82 ± 10.44 min, respectively. Conclusion: The tri-Co-60 IMRT seems inappropriate for spine SABR compared with VMAT. Advances in knowledge: For spine SABR, the tri-Co-60 IMRT is inappropriate owing to the large penumbra, large leaf width and low dose rate of the ViewRay system. PMID:27781486

Stereotactic body radiotherapy reirradiation for recurrent epidural spinal metastases.

PubMed

Mahadevan, Anand; Floyd, Scott; Wong, Eric; Jeyapalan, Suriya; Groff, Michael; Kasper, Ekkehard

2011-12-01

When patients show progression after conventional fractionated radiation for spine metastasis, further radiation and surgery may not be options. Stereotactic body radiotherapy (SBRT) has been successfully used in treatment of the spine and may be applicable in these cases. We report the use of SBRT for 60 consecutive patients (81 lesions) who had radiological progressive spine metastasis with epidural involvement after previous radiation for spine metastasis. SBRT was used with fiducial and vertebral anatomy-based targeting. The radiation dose was prescribed based on the extent of spinal canal involvement; the dose was 8 Gy×3=24 Gy when the tumor did not touch the spinal cord and 5 to 6 Gyx5=25 to 30 Gy when the tumor abutted the cord. The cord surface received up to the prescription dose with no hot spots in the cord. The median overall survival was 11 months, and the median progression-free survival was 9 months. Overall, 93% of patients had stable or improved disease while 7% of patients showed disease progression; 65% of patients had pain relief. There was no significant toxicity other than fatigue. SBRT is feasible and appears to be an effective treatment modality for reirradiation after conventional palliative radiation fails for spine metastasis patients. Copyright © 2011 Elsevier Inc. All rights reserved.

Multifractionated image-guided and stereotactic intensity-modulated radiotherapy of paraspinal tumors: a preliminary report.

PubMed

Yamada, Yoshiya; Lovelock, D Michael; Yenice, Kamil M; Bilsky, Mark H; Hunt, Margaret A; Zatcky, Joan; Leibel, Steven A

2005-05-01

The use of image-guided and stereotactic intensity-modulated radiotherapy (IMRT) techniques have made the delivery of high-dose radiation to lesions within close proximity to the spinal cord feasible. This report presents clinical and physical data regarding the use of IMRT coupled with noninvasive body frames (stereotactic and image-guided) for multifractionated radiotherapy. The Memorial Sloan-Kettering Cancer Center (Memorial) stereotactic body frame (MSBF) and Memorial body cradle (MBC) have been developed as noninvasive immobilizing devices for paraspinal IMRT using stereotactic (MSBF) and image-guided (MBC) techniques. Patients were either previously irradiated or prescribed doses beyond spinal cord tolerance (54 Gy in standard fractionation) and had unresectable gross disease involving the spinal canal. The planning target volume (PTV) was the gross tumor volume with a 1 cm margin. The PTV was not allowed to include the spinal cord contour. All treatment planning was performed using software developed within the institution. Isocenter verification was performed with an in-room computed tomography scan (MSBF) or electronic portal imaging devices, or both. Patients were followed up with serial magnetic resonance imaging every 3-4 months, and no patients were lost to follow-up. Kaplan-Meier statistics were used for analysis of clinical data. Both the MSBF and MBC were able to provide setup accuracy within 2 mm. With a median follow-up of 11 months, 35 patients (14 primary and 21 secondary malignancies) underwent treatment. The median dose previously received was 3000 cGy in 10 fractions. The median dose prescribed for these patients was 2000 cGy/5 fractions (2000-3000 cGy), which provided a median PTV V100 of 88%. In previously unirradiated patients, the median prescribed dose was 7000 cGy (5940-7000 cGy) with a median PTV V100 of 90%. The median Dmax to the cord was 34% and 68% for previously irradiated and never irradiated patients, respectively. More than 90% of patients experienced palliation from pain, weakness, or paresthesia; 75% and 81% of secondary and primary lesions, respectively, exhibited local control at the time of last follow-up. No cases of radiation-induced myelopathy or radiculopathy have thus far been encountered. Precision stereotactic and image-guided paraspinal IMRT allows the delivery of high doses of radiation in multiple fractions to tumors within close proximity to the spinal cord while respecting cord tolerance. Although preliminary, the clinical results are encouraging.

Validation of a Preclinical Spinal Safety Model: Effects of Intrathecal Morphine in the Neonatal Rat

PubMed Central

Westin, B. David; Walker, Suellen M.; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L.

2010-01-01

Background Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long term function following intrathecal morphine in the neonatal rat. Methods Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P)3, 10 and 21. The relationship between injectate volume and segmental spread was assessed post mortem and by in-vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 minutes following intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis and glial response were evaluated 1 and 7 days following P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally-mediated analgesia at all ages with lower dose requirements in younger pups. High dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions The therapeutic ratio for intrathecal morphine (toxic dose / antinociceptive dose) was at least 300 at P3, and at least 20 at P21 (latter doses limited by side effects). This data provides relative efficacy and safety data for comparison with other analgesic preparations and contributes supporting evidence for the validity of this preclinical neonatal safety model. PMID:20526189

Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat.

PubMed

Westin, B David; Walker, Suellen M; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L

2010-07-01

Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation.

PubMed

Iskandar, Bermans J; Rizk, Elias; Meier, Brenton; Hariharan, Nithya; Bottiglieri, Teodoro; Finnell, Richard H; Jarrard, David F; Banerjee, Ruma V; Skene, J H Pate; Nelson, Aaron; Patel, Nirav; Gherasim, Carmen; Simon, Kathleen; Cook, Thomas D; Hogan, Kirk J

2010-05-01

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.

Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

PubMed Central

Iskandar, Bermans J.; Rizk, Elias; Meier, Brenton; Hariharan, Nithya; Bottiglieri, Teodoro; Finnell, Richard H.; Jarrard, David F.; Banerjee, Ruma V.; Skene, J.H. Pate; Nelson, Aaron; Patel, Nirav; Gherasim, Carmen; Simon, Kathleen; Cook, Thomas D.; Hogan, Kirk J.

2010-01-01

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries. PMID:20424322

Omega-conotoxin MVIIC attenuates neuronal apoptosis in vitro and improves significant recovery after spinal cord injury in vivo in rats

PubMed Central

Oliveira, Karen M; Lavor, Mário Sérgio L; Silva, Carla Maria O; Fukushima, Fabíola B; Rosado, Isabel R; Silva, Juneo F; Martins, Bernardo C; Guimarães, Laís B; Gomez, Marcus Vinícius; Melo, Marília M; Melo, Eliane G

2014-01-01

Excessive accumulation of intracellular calcium is the most critical step after spinal cord injury (SCI). Reducing the calcium influx should result in a better recovery from SCI. Calcium channel blockers have been shown a great potential in reducing brain and spinal cord injury. In this study, we first tested the neuroprotective effect of MVIIC on slices of spinal cord subjected to ischemia evaluating cell death and caspase-3 activation. Thereafter, we evaluated the efficacy of MVIIC in ameliorating damage following SCI in rats, for the first time in vivo. The spinal cord slices subjected a pretreatment with MVIIC showed a cell protection with a reduction of dead cells in 24.34% and of caspase-3-specific protease activation. In the in vivo experiment, Wistar rats were subjected to extradural compression of the spinal cord at the T12 vertebral level using a weigh of 70 g/cm, following intralesional treatment with either placebo or MVIIC in different doses (15, 30 and 60 pmol) five minutes after injury. Behavioral testing of hindlimb function was done using the Basso Beattie Bresnahan locomotor rating scale, and revealed significant recovery with 15 pmol (G15) compared to other trauma groups. Also, histological bladder structural revealed significant outcome in G15, with no morphological alterations, and anti-NeuN and TUNEL staining showed that G15 provided neuron preservation and indicated that this group had fewer neuron cell death, similar to sham. These results showed the neuroprotective effects of MVIIC in in vitro and in vivo model of SCI with neuronal integrity, bladder and behavioral improvements. PMID:25120731

Dose-Response Outcomes Associated with Different Forms of Locomotor Training in Persons with Chronic Motor-Incomplete Spinal Cord Injury.

PubMed

Sandler, Evan B; Roach, Kathryn E; Field-Fote, Edelle C

2017-05-15

Outcomes of training are thought to be related to the amount of training (training dose). Although various approaches to locomotor training have been used to improve walking function in persons with spinal cord injury (SCI), little is known about the relationship between dose of locomotor training and walking outcomes. This secondary analysis aimed to identify the relationship between training dose and improvement in walking distance and speed associated with locomotor training in participants with chronic motor-incomplete spinal cord injury (MISCI). We compared the dose-response relationships associated with each of four different locomotor training approaches. Participants were randomized to either: treadmill-based training with manual assistance (TM = 17), treadmill-based training with stimulation (TS = 18), overground training with stimulation (OG = 15), and treadmill-based training with locomotor robotic device assistance (LR = 14). Subjects trained 5 days/week for 12 weeks, with a target of 60 training sessions. The distance-dose and time-dose were calculated based on the total distance and total time, respectively, participants engaged in walking over all sessions combined. Primary outcome measures included walking distance (traversed in 2 min) and walking speed (over 10 m). Only OG training showed a good correlation between distance-dose and change in walking distance and speed walked over ground (r = 0.61, p = 0.02; r = 0.62, p = 0.01). None of the treadmill-based training approaches were associated with significant correlations between training dose and improvement of functional walking outcome. The findings suggest that greater distance achieved over the course of OG training is associated with better walking outcomes in the studied population. Further investigation to identify the essential elements that determine outcomes would be valuable for guiding rehabilitation.

SU-F-BRF-12: Investigating Dosimetric Effects of Inter-Fraction Deformation in Lung Cancer Stereotactic Body Radiotherapy (SBRT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jia, J; Tian, Z; Gu, X

2014-06-15

Purpose: We studied dosimetric effects of inter-fraction deformation in lung stereotactic body radiotherapy (SBRT), in order to investigate the necessity of adaptive re-planning for lung SBRT treatments. Methods: Six lung cancer patients with different treatment fractions were retrospectively investigated. All the patients were immobilized and localized with a stereotactic body frame and were treated under cone-beam CT (CBCT) image guidance at each fraction. We calculated the actual delivered dose of the treatment plan using the up-to-date patient geometry of each fraction, and compared the dose with the intended plan dose to investigate the dosimetric effects of the inter-fraction deformation. Deformablemore » registration was carried out between the treatment planning CT and the CBCT of each fraction to obtain deformed planning CT for more accurate dose calculations of the delivered dose. The extent of the inter-fraction deformation was also evaluated by calculating the dice similarity coefficient between the delineated structures on the planning CT and those on the deformed planning CT. Results: The average dice coefficients for PTV, spinal cord, esophagus were 0.87, 0.83 and 0.69, respectively. The volume of PTV covered by prescription dose was decreased by 23.78% on average for all fractions and all patients. For spinal cord and esophagus, the volumes covered by the constraint dose were increased by 4.57% and 3.83%. The maximum dose was also increased by 4.11% for spinal cord and 4.29% for esophagus. Conclusion: Due to inter-fraction deformation, large deterioration was found in both PTV coverage and OAR sparing, which demonstrated the needs for adaptive re-planning of lung SBRT cases to improve target coverage while reducing radiation dose to nearby normal tissues.« less

Direct plan comparison of RapidArc and CyberKnife for spine stereotactic body radiation therapy

NASA Astrophysics Data System (ADS)

Choi, Young Eun; Kwak, Jungwon; Song, Si Yeol; Choi, Eun Kyung; Ahn, Seung Do; Cho, Byungchul

2015-07-01

We compared the treatment planning performance of RapidArc (RA) vs. CyberKnife (CK) for spinal stereotactic body radiation therapy (SBRT). Ten patients with spinal lesions who had been treated with CK were re-planned with RA, which consisted of two complete arcs. Computed tomography (CT) and volumetric dose data of CK, generated using the Multiplan (Accuray) treatment planning system (TPS) and the Ray-trace algorithm, were imported to Varian Eclipse TPS in Dicom format, and the data were compared with the RA plan by using an analytical anisotropic algorithm (AAA) dose calculation. The optimized dose priorities for both the CK and the RA plans were similar for all patients. The highest priority was to provide enough dose coverage to the planned target volume (PTV) while limiting the maximum dose to the spinal cord. Plan quality was evaluated with respect to PTV coverage, conformity index (CI), high-dose spillage, intermediate-dose spillage (R50% and D2cm), and maximum dose to the spinal cord, which are criteria recommended by the RTOG 0631 spine and 0915 lung SBRT protocols. The mean CI' SD values of the PTV were 1.11' 0.03 and 1.17' 0.10 for RA and CK ( p = 0.02), respectively. On average, the maximum dose delivered to the spinal cord in CK plans was approximately 11.6% higher than that in RA plans, and this difference was statistically significant ( p < 0.001). High-dose spillages were 0.86% and 2.26% for RA and CK ( p = 0.203), respectively. Intermediate-dose spillage characterized by D2cm was lower for RA than for CK; however, R50% was not statistically different. Even though both systems can create highly conformal volumetric dose distributions, the current study shows that RA demonstrates lower high- and intermediate-dose spillages than CK. Therefore, RA plans for spinal SBRT may be superior to CK plans.

Endogenous stem cell proliferation induced by intravenous hedgehog agonist administration after contusion in the adult rat spinal cord.

PubMed

Bambakidis, Nicholas C; Horn, Eric M; Nakaji, Peter; Theodore, Nicholas; Bless, Elizabeth; Dellovade, Tammy; Ma, Chiyuan; Wang, Xukui; Preul, Mark C; Coons, Stephen W; Spetzler, Robert F; Sonntag, Volker K H

2009-02-01

Sonic hedgehog (Shh) is a glycoprotein molecule that upregulates the transcription factor Gli1. The Shh protein plays a critical role in the proliferation of endogenous neural precursor cells when directly injected into the spinal cord after a spinal cord injury in adult rodents. Small-molecule agonists of the hedgehog (Hh) pathway were used in an attempt to reproduce these findings through intravenous administration. The expression of Gli1 was measured in rat spinal cord after the intravenous administration of an Hh agonist. Ten adult rats received a moderate contusion and were treated with either an Hh agonist (10 mg/kg, intravenously) or vehicle (5 rodents per group) 1 hour and 4 days after injury. The rats were killed 5 days postinjury. Tissue samples were immediately placed in fixative. Samples were immunohistochemically stained for neural precursor cells, and these cells were counted. Systemic dosing with an Hh agonist significantly upregulated Gli1 expression in the spinal cord (p < 0.005). After spinal contusion, animals treated with the Hh agonist had significantly more nestin-positive neural precursor cells around the rim of the lesion cavity than in vehicle-treated controls (means +/- SDs, 46.9 +/- 12.9 vs 20.9 +/- 8.3 cells/hpf, respectively, p < 0.005). There was no significant difference in the area of white matter injury between the groups. An intravenous Hh agonist at doses that upregulate spinal cord Gli1 transcription also increases the population of neural precursor cells after spinal cord injury in adult rats. These data support previous findings based on injections of Shh protein directly into the spinal cord.

[Experimental study on the impact of photodynamic therapy on the normal vocal cord injury].

PubMed

Liu, Haiyan; Huang, Yongwang; Wang, Shanshan; Li, Yingxin; Yin, Huijuan; Gao, Xiaowei

2015-12-01

To investigate the reactive characteristics of normal vocal cord tissues to photodynamic therapy (PDT) and the damage effects of different concentration of photosensitizer and different light on normal rabbit vocal cord. Making the preliminary research of PDT in clinical treatment of chronic inflammation of the vocal cords and precancerous lesions. Twenty-five healthy Japanese big ear experimental rabbits were randomly divided into 5 groups: low work rate low dose group A (100 mW, 10%5-ALA), high work rate low dose group B (200 mW, 10%5-ALA), high work rate high dose group C (200 mW, 20%5-ALA), low work rate high dose group D (100 mW, 20%5-ALA) and normal control group E. The issue damage and wound recovery were observed in 1 d, 3 d, 7 d, 14 d, 28 d after intervention. A severe inflammation reaction was observed in group A, B, C, D after intervened with PDT compared to normal group. The reaction of group A was lighter, and the reaction of group C was the most serious. The content of collagenous fiber, hyaluronic acid and fibronectin in vocal fold lamina layer was significantly higher than that in normal group (P<0.05). Different degrees of fiber proliferation were observed in all groups. The content of each component of vocal fold lamina layer tended to be normal slightly higher level in 28 d. Observation by electron microscope showed that there were no significant differences in A, B, C, D, E in 28 d after intervention. Recoverable damage repair process can be detected in rabbit vocal after intervened with PDT, which began in 7 d and basically completed in 28 d. In a certain concentration (10%-20%) and dose range (100-200 mW). The higher of photodynamic dose, the more serious of the damage. And the damage was basically reversible.

"Curcumin-loaded Poly (d, l-lactide-co-glycolide) nanovesicles induce antinociceptive effects and reduce pronociceptive cytokine and BDNF release in spinal cord after acute administration in mice".

PubMed

Pieretti, Stefano; Ranjan, Amalendu P; Di Giannuario, Amalia; Mukerjee, Anindita; Marzoli, Francesca; Di Giovannandrea, Rita; Vishwanatha, Jamboor K

2017-10-01

Given the poor bioavailability of curcumin, its antinociceptive effects are produced after chronic intravenous administration of high doses, while poly (d,l-lactide-co-glycolide)-loaded vesicles (PLGA) can improve drug delivery. This paper investigates the antinociceptive effects of curcumin-loaded PLGA nanovesicles (PLGA-CUR) administered via intravenous (i.v.) or intrathecal (i.t.) routes at low and high doses. The following models of pain were used: formalin test, zymosan-induced hyperalgesia and sciatic nerve ligation inducing neuropathic allodynia and hyperalgesia. PLGA-CUR administered intravenously was able to reduce the response to nociceptive stimuli in the formalin test and hyperalgesia induced by zymosan. Curcumin, instead, was inactive. Low-dose i.t. administration of PLGA-CUR significantly reduced allodynia produced by sciatic nerve ligation, whereas low doses of curcumin did not change the response to nociceptive stimuli. Long-lasting antinociceptive effects were observed when high doses of PLGA-CUR were administered intrathecally. At high doses, i.t. administration of curcumin only exerted rapid and transient antinociceptive effects. Measurement of cytokine and BDNF in the spinal cord of neuropathic mice demonstrate that the antinociceptive effects of PLGA-CUR depend on the reduction in cytokine release and BDNF in the spinal cord. The results demonstrate the effectiveness of PLGA-CUR and suggest that PLGA-CUR nanoformulation might be a new potential drug in the treatment of pain. Copyright © 2017 Elsevier B.V. All rights reserved.

Kilovoltage Imaging Doses in the Radiotherapy of Pediatric Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deng Jun, E-mail: jun.deng@yale.edu; Chen Zhe; Roberts, Kenneth B.

Purpose: To investigate doses induced by kilovoltage cone-beam computed tomography (kVCBCT) to pediatric cancer patients undergoing radiotherapy, as well as strategies for dose reduction. Methods and Materials: An EGS4 Monte Carlo code was used to calculate three-dimensional dose deposition due to kVCBCT on 4 pediatric cancer patients. Absorbed doses to various organs were analyzed for both half-fan and full-fan modes. Clinical conditions, such as distance from organ at risk (OAR) to CBCT field border, kV peak energy, and testicular shielding, were studied. Results: The mean doses induced by one CBCT scan operated at 125 kV in half-fan mode to testes,more » liver, kidneys, femoral heads, spinal cord, brain, eyes, lens, and optical nerves were 2.9, 4.7, 7.7, 10.5, 8.8, 7.6, 7.7, 7.8, and 7.2 cGy, respectively. Increasing the distances from OARs to CBCT field border greatly reduced the doses to OARs, ranging from 33% reduction for spinal cord to 2300% reduction for testes. As photon beam energy increased from 60 to 125 kV, the dose increase due to kVCBCT ranged from 170% for lens to 460% for brain and spinal cord. A testicular shielding made of 1-cm cerrobend could reduce CBCT doses down to 31%, 51%, 68%, and 82%, respectively, for 60, 80, 100, and 125 kV when the testes lay within the CBCT field. Conclusions: Generally speaking, kVCBCT deposits much larger doses to critical structures in children than in adults, usually by a factor of 2 to 3. Increasing the distances from OARs to CBCT field border greatly reduces doses to OARs. Depending on OARs, kVCBCT-induced doses increase linearly or exponentially with photon beam energy. Testicular shielding works more efficiently at lower kV energies. On the basis of our study, it is essential to choose an appropriate scanning protocol when kVCBCT is applied to pediatric cancer patients routinely.« less

Intensity-modulated radiotherapy for locally advanced non-small-cell lung cancer: a dose-escalation planning study.

PubMed

Lievens, Yolande; Nulens, An; Gaber, Mousa Amr; Defraene, Gilles; De Wever, Walter; Stroobants, Sigrid; Van den Heuvel, Frank

2011-05-01

To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT. Copyright © 2011 Elsevier Inc. All rights reserved.

Dosimetric comparison of photon and proton treatment techniques for chondrosarcoma of thoracic spine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yadav, Poonam, E-mail: yadav@humonc.wisc.edu; Department of Medical Physics, University of Wisconsin, Madison, WI; University of Wisconsin Riverview Cancer Center, Wisconsin Rapids, WI

2013-10-01

Chondrosarcomas are relatively radiotherapy resistant, and also delivering high radiation doses is not feasible owing to anatomic constraints. In this study, the feasibility of helical tomotherapy for treatment of chondrosarcoma of thoracic spine is explored and compared with other available photon and proton radiotherapy techniques in the clinical setting. A patient was treated for high-grade chondrosarcoma of the thoracic spine using tomotherapy. Retrospectively, the tomotherapy plan was compared with intensity-modulated radiation therapy, dynamic arc photon therapy, and proton therapy. Two primary comparisons were made: (1) comparison of normal tissue sparing with comparable target volume coverage (plan-1), and (2) comparison ofmore » target volume coverage with a constrained maximum dose to the cord center (plan-2). With constrained target volume coverage, proton plans were found to yield lower mean doses for all organs at risk (spinal cord, esophagus, heart, and both lungs). Tomotherapy planning resulted in the lowest mean dose to all organs at risk amongst photon-based methods. For cord dose constrained plans, the static-field intensity-modulated radiation therapy and dynamic arc plans resulted target underdosing in 20% and 12% of planning target volume2 volumes, respectively, whereas both proton and tomotherapy plans provided clinically acceptable target volume coverage with no portion of planning target volume2 receiving less than 90% of the prescribed dose. Tomotherapy plans are comparable to proton plans and produce superior results compared with other photon modalities. This feasibility study suggests that tomotherapy is an attractive alternative to proton radiotherapy for delivering high doses to lesions in the thoracic spine.« less

Willingness to pay for a 4% chlorhexidine (7.1% chlorhexidine digluconate) product for umbilical cord care in rural Bangladesh: a contingency valuation study

PubMed Central

2013-01-01

Background Recent trials in Bangladesh, Nepal, and Pakistan have shown that chlorhexidine is an effective antiseptic for umbilical cord care compared to existing community-based cord care practices. Because of the aggregate reduction in neonatal mortality in these trials, interest is high in introducing a 7.1% chlorhexidine digluconate liquid or gel that delivers 4% chlorhexidine for umbilical cord care in Bangladesh and elsewhere. Methods In 2010, we conducted a household survey applying a contingent valuation method with 1717 eligible couples (pregnant women or women with a first child younger than 6 months old, and their husbands) in the rural subdistricts of Abhoynagar and Mirsarai in Bangladesh to assess their willingness to pay for three types of umbilical cord care products at different price points. Each respondent was asked about willingness to pay prefixed prices for any one of three 7.1% chlorhexidine digluconate products: 1) a single-dose liquid, 2) a multi-dose liquid, or 3) a gel formulation. Each also reported the maximum price they were independently willing to pay for their selected product. We compared participant willingness-to-pay responses to the prefixed prices with their independently reported maximum prices for each type of the product separately. The comparison identified to what extent the respondents’ positive responses to the prefixed prices matched their independently reported maximum prices. Results This cross matching revealed that willingness to pay the prefixed prices was 41% for the single-dose liquid, 33% for the multi-dose liquid, and 31% for the gel formulation. Although the majority of the respondents were unwilling to pay the prefixed prices, all were willing to pay some amount and reported they could borrow money if necessary. Subsequent analysis of responses to the multi-dose liquid showed borrowing money would not be required if the unit price was Bangladeshi taka 15–25. Conclusions A unit price of Bangladeshi taka 15–25 (US$0.21–0.35) for multi-dose 7.1% chlorhexidine digluconate liquid would be affordable to the primary target population in Bangladesh. Although a large market demand could be generated if the product were available at this price point, subsidization may be required to achieve optimal coverage, especially among poorer families. PMID:24139384

Willingness to pay for a 4% chlorhexidine (7.1% chlorhexidine digluconate) product for umbilical cord care in rural Bangladesh: a contingency valuation study.

PubMed

Coffey, Patricia S; Metzler, Mutsumi; Islam, Ziaul; Koehlmoos, Tracey P

2013-10-18

Recent trials in Bangladesh, Nepal, and Pakistan have shown that chlorhexidine is an effective antiseptic for umbilical cord care compared to existing community-based cord care practices. Because of the aggregate reduction in neonatal mortality in these trials, interest is high in introducing a 7.1% chlorhexidine digluconate liquid or gel that delivers 4% chlorhexidine for umbilical cord care in Bangladesh and elsewhere. In 2010, we conducted a household survey applying a contingent valuation method with 1717 eligible couples (pregnant women or women with a first child younger than 6 months old, and their husbands) in the rural subdistricts of Abhoynagar and Mirsarai in Bangladesh to assess their willingness to pay for three types of umbilical cord care products at different price points. Each respondent was asked about willingness to pay prefixed prices for any one of three 7.1% chlorhexidine digluconate products: 1) a single-dose liquid, 2) a multi-dose liquid, or 3) a gel formulation. Each also reported the maximum price they were independently willing to pay for their selected product. We compared participant willingness-to-pay responses to the prefixed prices with their independently reported maximum prices for each type of the product separately. The comparison identified to what extent the respondents' positive responses to the prefixed prices matched their independently reported maximum prices. This cross matching revealed that willingness to pay the prefixed prices was 41% for the single-dose liquid, 33% for the multi-dose liquid, and 31% for the gel formulation. Although the majority of the respondents were unwilling to pay the prefixed prices, all were willing to pay some amount and reported they could borrow money if necessary. Subsequent analysis of responses to the multi-dose liquid showed borrowing money would not be required if the unit price was Bangladeshi taka 15-25. A unit price of Bangladeshi taka 15-25 (US$0.21-0.35) for multi-dose 7.1% chlorhexidine digluconate liquid would be affordable to the primary target population in Bangladesh. Although a large market demand could be generated if the product were available at this price point, subsidization may be required to achieve optimal coverage, especially among poorer families.

A systematic study of posterior cervical lymph node irradiation with electrons: Conventional versus customized planning.

PubMed

Jankowska, Petra J; Kong, Christine; Burke, Kevin; Harrington, Kevin J; Nutting, Christopher

2007-10-01

High dose irradiation of the posterior cervical lymph nodes usually employs applied electron fields to treat the target volume and maintain the spinal cord dose within tolerance. In the light of recent advances in elective lymph node localisation we investigated optimization of field shape and electron energy to treat this target volume. In this study, three sequential hypotheses were tested. Firstly, that customization of the electron fields based on the nodal PTV outlined gives better PTV coverage than conventional field delineation. Using the consensus guidelines, customization of the electron field shape was compared to conventional fields based on bony landmarks. Secondly, that selection of electron energy using DVHs for spinal cord and PTV improves the minimum dose to PTV. Electron dose-volume histograms (DVHs) for the PTV, spinal cord and para-vertebral muscles, were generated using the Monte Carlo electron algorithm. These DVHs were used to compare standard vs optimized electron energy calculations. Finally, that combination of field customization and electron energy optimization improves both the minimum and mean doses to PTV compared with current standard practice. Customized electron beam shaping based on the consensus guidelines led to fewer geographical misses than standard field shaping. Customized electron energy calculation led to higher minimum doses to the PTV. Overall, the customization of field shape and energy resulted in an improved mean dose to the PTV (92% vs 83% p=0.02) and a 27% improvement in the minimum dose delivered to the PTV (45% vs 18% p=0.0009). Optimization of electron field shape and beam energy based on current consensus guidelines led to significant improvement in PTV coverage and may reduce recurrence rates.

Comparing Treatment Plan in All Locations of Esophageal Cancer

PubMed Central

Lin, Jang-Chun; Tsai, Jo-Ting; Chang, Chih-Chieh; Jen, Yee-Min; Li, Ming-Hsien; Liu, Wei-Hsiu

2015-01-01

Abstract The aim of this study was to compare treatment plans of volumetric modulated arc therapy (VMAT) with intensity-modulated radiotherapy (IMRT) for all esophageal cancer (EC) tumor locations. This retrospective study from July 2009 to June 2014 included 20 patients with EC who received definitive concurrent chemoradiotherapy with radiation doses >50.4 Gy. Version 9.2 of Pinnacle3 with SmartArc was used for treatment planning. Dosimetric quality was evaluated based on doses to several organs at risk, including the spinal cord, heart, and lung, over the same coverage of gross tumor volume. In upper thoracic EC, the IMRT treatment plan had a lower lung mean dose (P = 0.0126) and lung V5 (P = 0.0037) compared with VMAT; both techniques had similar coverage of the planning target volumes (PTVs) (P = 0.3575). In middle thoracic EC, a lower lung mean dose (P = 0.0010) and V5 (P = 0.0145), but higher lung V20 (P = 0.0034), spinal cord Dmax (P = 0.0262), and heart mean dose (P = 0.0054), were observed for IMRT compared with VMAT; IMRT provided better PTV coverage. Patients with lower thoracic ECs had a lower lung mean dose (P = 0.0469) and V5 (P = 0.0039), but higher spinal cord Dmax (P = 0.0301) and heart mean dose (P = 0.0020), with IMRT compared with VMAT. PTV coverage was similar (P = 0.0858) for the 2 techniques. IMRT provided a lower mean dose and lung V5 in upper thoracic EC compared with VMAT, but exhibited different advantages and disadvantages in patients with middle or lower thoracic ECs. Thus, choosing different techniques for different EC locations is warranted. PMID:25929910

Comparing treatment plan in all locations of esophageal cancer: volumetric modulated arc therapy versus intensity-modulated radiotherapy.

PubMed

Lin, Jang-Chun; Tsai, Jo-Ting; Chang, Chih-Chieh; Jen, Yee-Min; Li, Ming-Hsien; Liu, Wei-Hsiu

2015-05-01

The aim of this study was to compare treatment plans of volumetric modulated arc therapy (VMAT) with intensity-modulated radiotherapy (IMRT) for all esophageal cancer (EC) tumor locations.This retrospective study from July 2009 to June 2014 included 20 patients with EC who received definitive concurrent chemoradiotherapy with radiation doses >50.4 Gy. Version 9.2 of Pinnacle with SmartArc was used for treatment planning. Dosimetric quality was evaluated based on doses to several organs at risk, including the spinal cord, heart, and lung, over the same coverage of gross tumor volume.In upper thoracic EC, the IMRT treatment plan had a lower lung mean dose (P = 0.0126) and lung V5 (P = 0.0037) compared with VMAT; both techniques had similar coverage of the planning target volumes (PTVs) (P = 0.3575). In middle thoracic EC, a lower lung mean dose (P = 0.0010) and V5 (P = 0.0145), but higher lung V20 (P = 0.0034), spinal cord Dmax (P = 0.0262), and heart mean dose (P = 0.0054), were observed for IMRT compared with VMAT; IMRT provided better PTV coverage. Patients with lower thoracic ECs had a lower lung mean dose (P = 0.0469) and V5 (P = 0.0039), but higher spinal cord Dmax (P = 0.0301) and heart mean dose (P = 0.0020), with IMRT compared with VMAT. PTV coverage was similar (P = 0.0858) for the 2 techniques.IMRT provided a lower mean dose and lung V5 in upper thoracic EC compared with VMAT, but exhibited different advantages and disadvantages in patients with middle or lower thoracic ECs. Thus, choosing different techniques for different EC locations is warranted.

Pre-existing central nervous system lesions negate cytokine requirements for regional experimental autoimmune encephalomyelitis development.

PubMed

Li, Xin; Lees, Jason R

2013-03-01

In region-specific forms of experimental autoimmune encephalomyelitis (EAE), lesion initiation is regulated by T-cell-produced interferon-γ (IFN-γ) resulting in spinal cord disease in the presence of IFN-γ and cerebellar disease in the absence of IFN-γ. Although this role for IFN-γ in regional disease initiation is well defined, little is known about the consequences of previous tissue inflammation on subsequent regional disease, information vital to the development of therapeutics in established disease states. This study addressed the hypothesis that previous establishment of regional EAE would determine subsequent tissue localization of new T-cell invasion and associated symptoms regardless of the presence or absence of IFN-γ production. Serial transfer of optimal or suboptimal doses of encephalitogenic IFN-γ-sufficient or -deficient T-cell lines was used to examine the development of new clinical responses associated with the spinal cord and cerebellum at various times after EAE initiation. Previous inflammation within either cerebellum or spinal cord allowed subsequent T-cell driven inflammation within that tissue regardless of IFN-γ presence. Further, T-cell IFN-γ production after initial lesion formation exacerbated disease within the cerebellum, suggesting that IFN-γ plays different roles at different stages of cerebellar disease. For the spinal cord, IFN-γ-deficient cells (that are ordinarily cerebellum disease initiators) were capable of driving new spinal-cord-associated clinical symptoms more than 60 days after the initial acute EAE resolution. These data suggest that previous inflammation modulates the molecular requirements for new neuroinflammation development. © 2012 Blackwell Publishing Ltd.

Method of predicting the mean lung dose based on a patient's anatomy and dose-volume histograms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zawadzka, Anna, E-mail: a.zawadzka@zfm.coi.pl; Nesteruk, Marta; Department of Radiation Oncology, University Hospital Zurich and University of Zurich, Zurich

The aim of this study was to propose a method to predict the minimum achievable mean lung dose (MLD) and corresponding dosimetric parameters for organs-at-risk (OAR) based on individual patient anatomy. For each patient, the dose for 36 equidistant individual multileaf collimator shaped fields in the treatment planning system (TPS) was calculated. Based on these dose matrices, the MLD for each patient was predicted by the homemade DosePredictor software in which the solution of linear equations was implemented. The software prediction results were validated based on 3D conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT) plans previously prepared formore » 16 patients with stage III non–small-cell lung cancer (NSCLC). For each patient, dosimetric parameters derived from plans and the results calculated by DosePredictor were compared. The MLD, the maximum dose to the spinal cord (D{sub max} {sub cord}) and the mean esophageal dose (MED) were analyzed. There was a strong correlation between the MLD calculated by the DosePredictor and those obtained in treatment plans regardless of the technique used. The correlation coefficient was 0.96 for both 3D-CRT and VMAT techniques. In a similar manner, MED correlations of 0.98 and 0.96 were obtained for 3D-CRT and VMAT plans, respectively. The maximum dose to the spinal cord was not predicted very well. The correlation coefficient was 0.30 and 0.61 for 3D-CRT and VMAT, respectively. The presented method allows us to predict the minimum MLD and corresponding dosimetric parameters to OARs without the necessity of plan preparation. The method can serve as a guide during the treatment planning process, for example, as initial constraints in VMAT optimization. It allows the probability of lung pneumonitis to be predicted.« less

Transplantation of spinal cord-derived neural stem cells for ALS: Analysis of phase 1 and 2 trials.

PubMed

Glass, Jonathan D; Hertzberg, Vicki S; Boulis, Nicholas M; Riley, Jonathan; Federici, Thais; Polak, Meraida; Bordeau, Jane; Fournier, Christina; Johe, Karl; Hazel, Tom; Cudkowicz, Merit; Atassi, Nazem; Borges, Lawrence F; Rutkove, Seward B; Duell, Jayna; Patil, Parag G; Goutman, Stephen A; Feldman, Eva L

2016-07-26

To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers. This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale-Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups. Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression. Intraspinal transplantation of human spinal cord-derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers. This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues. © 2016 American Academy of Neurology.

Administration of low dose estrogen attenuates persistent inflammation, promotes angiogenesis, and improves locomotor function following chronic spinal cord injury in rats.

PubMed

Samantaray, Supriti; Das, Arabinda; Matzelle, Denise C; Yu, Shan P; Wei, Ling; Varma, Abhay; Ray, Swapan K; Banik, Naren L

2016-05-01

Spinal cord injury (SCI) causes loss of neurological function and, depending upon the severity of injury, may lead to paralysis. Currently, no FDA-approved pharmacotherapy is available for SCI. High-dose methylprednisolone is widely used, but this treatment is controversial. We have previously shown that low doses of estrogen reduces inflammation, attenuates cell death, and protects axon and myelin in SCI rats, but its effectiveness in recovery of function is not known. Therefore, the goal of this study was to investigate whether low doses of estrogen in post-SCI would reduce inflammation, protect cells and axons, and improve locomotor function during the chronic phase of injury. Injury (40 g.cm force) was induced at thoracic 10 in young adult male rats. Rats were treated with 10 or 100 μg 17β-estradiol (estrogen) for 7 days following SCI and compared with vehicle-treated injury and laminectomy (sham) controls. Histology (H&E staining), immunohistofluorescence, Doppler laser technique, and Western blotting were used to monitor tissue integrity, gliosis, blood flow, angiogenesis, the expression of angiogenic factors, axonal degeneration, and locomotor function (Basso, Beattie, and Bresnahan rating) following injury. To assess the progression of recovery, rats were sacrificed at 7, 14, or 42 days post injury. A reduction in glial reactivity, attenuation of axonal and myelin damage, protection of cells, increased expression of angiogenic factors and microvessel growth, and improved locomotor function were found following estrogen treatment compared with vehicle-treated SCI rats. These results suggest that treatment with a very low dose of estrogen has significant therapeutic implications for the improvement of locomotor function in chronic SCI. Experimental studies with low dose estrogen therapy in chronic spinal cord injury (SCI) demonstrated the potential for multi-active beneficial outcomes that could ameliorate the degenerative pathways in chronic SCI as shown in (a). Furthermore, the alterations in local spinal blood flow could be significantly alleviated with low dose estrogen therapy. This therapy led to the preservation of the structural integrity of the spinal cord (b), which in turn led to the improved functional recovery as shown (c). © 2016 International Society for Neurochemistry.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chau, Ricky; Teo, Peter; Kam, Michael

The aim of this study is to evaluate the deficiencies in target coverage and organ protection of 2-dimensional radiation therapy (2DRT) in the treatment of advanced T-stage (T3-4) nasopharyngeal carcinoma (NPC), and assess the extent of improvement that could be achieved with intensity modulated radiation therapy (IMRT), with special reference to of the dose to the planning organ-at-risk volume (PRV) of the brainstem and spinal cord. A dosimetric study was performed on 10 patients with advanced T-stage (T3-4 and N0-2) NPC. Computer tomography (CT) images of 2.5-mm slice thickness of the head and neck were acquired with the patient immobilizedmore » in semi-extended-head position. A 2D plan based on Ho's technique, and an IMRT plan based on a 7-coplanar portals arrangement, were established for each patient. 2DRT was planned with the field borders and shielding drawn on the simulator radiograph with reference to bony landmarks, digitized, and entered into a planning computer for reconstruction of the 3D dose distribution. The 2DRT and IMRT treatment plans were evaluated and compared with respect to the dose-volume histograms (DVHs) of the targets and the organs-at-risk (OARs), tumor control probability (TCP), and normal tissue complication probabilities (NTCPs). With IMRT, the dose coverage of the target was superior to that of 2DRT. The mean minimum dose of the GTV and PTV were increased from 33.7 Gy (2DRT) to 62.6 Gy (IMRT), and 11.9 Gy (2DRT) to 47.8 Gy (IMRT), respectively. The D{sub 95} of the GTV and PTV were also increased from 57.1 Gy (2DRT) to 67 Gy (IMRT), and 45 Gy (2DRT) to 63.6 Gy (IMRT), respectively. The TCP was substantially increased to 78.5% in IMRT. Better protection of the critical normal organs was also achieved with IMRT. The mean maximum dose delivered to the brainstem and spinal cord were reduced significantly from 61.8 Gy (2DRT) to 52.8 Gy (IMRT) and 56 Gy (2DRT) to 43.6 Gy (IMRT), respectively, which were within the conventional dose limits of 54 Gy for brainstem and of 45 Gy for spinal cord. The mean maximum doses deposited on the PRV of the brainstem and spinal cord were 60.7 Gy and 51.6 Gy respectively, which were above the conventional dose limits. For the chiasm, the mean dose maximum and the dose to 5% of its volume were reduced from 64.3 Gy (2DRT) to 53.7 Gy (IMRT) and from 62.8 Gy (2DRT) to 48.7 Gy (IMRT), respectively, and the corresponding NTCP was reduced from 18.4% to 2.1%. For the temporal lobes, the mean dose to 10% of its volume (about 4.6 cc) was reduced from 63.8 Gy (2DRT) to 55.4 Gy (IMRT) and the NTCP was decreased from 11.7% to 3.4%. The therapeutic ratio for T3-4 NPC tumors can be significantly improved with IMRT treatment technique due to improvement both in target coverage and the sparing of the critical normal organ. Although the maximum doses delivered to the brainstem and spinal cord in IMRT can be kept at or below their conventional dose limits, the maximum doses deposited on the PRV often exceed these limits due to the close proximity between the target and OARs. In other words, ideal dosimetric considerations cannot be fulfilled in IMRT planning for T3-4 NPC tumors. A compromise of the maximal dose limit to the PRV of the brainstem and spinal cord would need be accepted if dose coverage to the targets is not to be unacceptably compromised. Dosimetric comparison with 2DRT plans show that these dose limits to PRV were also frequently exceeded in 2DRT plans for locally advanced NPC. A dedicated retrospective study on the incidence of clinical injury to neurological organs in a large series of patients with T3-4 NPC treated by 2DRT may provide useful reference data in exploring how far the PRV dose constraints may be relaxed, to maximize the target coverage without compromising the normal organ function.« less

SU-E-T-548: How To Decrease Spine Dose In Patients Who Underwent Sterotactic Spine Radiosurgery?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Acar, H; Altinok, A; Kucukmorkoc, E

2014-06-01

Purpose: Stereotactic radiosurgery for spine metastases involves irradiation using a single high dose fraction. The purpose of this study was to dosimetrically compare stereotactic spine radiosurgery(SRS) plans using a recently new volumetric modulated arc therapy(VMAT) technique against fix-field intensity-modulated radiotherapy(IMRT). Plans were evaluated for target conformity and spinal cord sparing. Methods: Fifteen previously treated patients were replanned using the Eclipse 10.1 TPS AAA calculation algorithm. IMRT plans with 7 fields were generated. The arc plans used 2 full arc configurations. Arc and IMRT plans were normalized and prescribed to deliver 16.0 Gy in a single fraction to 90% of themore » planning target volume(PTV). PTVs consisted of the vertebral body expanded by 3mm, excluding the PRV-cord, where the cord was expanded by 2mm.RTOG 0631 recommendations were applied for treatment planning. Partial spinal cord volume was defined as 5mm above and below the radiosurgery target volume. Plans were compared for conformity and gradient index as well as spinal cord sparing. Results: The conformity index values of fifteen patients for two different treatment planning techniques were shown in table 1. Conformity index values for 2 full arc planning (average CI=0.84) were higher than that of IMRT planning (average CI=0.79). The gradient index values of fifteen patients for two different treatment planning techniques were shown in table 2. Gradient index values for 2 full arc planning (average GI=3.58) were higher than that of IMRT planning (average GI=2.82).The spinal cord doses of fifteen patients for two different treatment planning techniques were shown in table 3. D0.35cc, D0.03cc and partial spinal cord D10% values in 2 full arc plannings (average D0.35cc=819.3cGy, D0.03cc=965.4cGy, 10%partial spinal=718.1cGy) were lower than IMRT plannings (average D0.35cc=877.4cGy, D0.03c=1071.4cGy, 10%partial spinal=805.1cGy). Conclusions: The two arc VMAT technique is superior to 7 field IMRT technique in terms of both spinal cord sparing and better conformity and gradient indexes.« less

WE-AB-209-12: Quasi Constrained Multi-Criteria Optimization for Automated Radiation Therapy Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watkins, W.T.; Siebers, J.V.

Purpose: To introduce quasi-constrained Multi-Criteria Optimization (qcMCO) for unsupervised radiation therapy optimization which generates alternative patient-specific plans emphasizing dosimetric tradeoffs and conformance to clinical constraints for multiple delivery techniques. Methods: For N Organs At Risk (OARs) and M delivery techniques, qcMCO generates M(N+1) alternative treatment plans per patient. Objective weight variations for OARs and targets are used to generate alternative qcMCO plans. For 30 locally advanced lung cancer patients, qcMCO plans were generated for dosimetric tradeoffs to four OARs: each lung, heart, and esophagus (N=4) and 4 delivery techniques (simple 4-field arrangements, 9-field coplanar IMRT, 27-field non-coplanar IMRT, and non-coplanarmore » Arc IMRT). Quasi-constrained objectives included target prescription isodose to 95% (PTV-D95), maximum PTV dose (PTV-Dmax)< 110% of prescription, and spinal cord Dmax<45 Gy. The algorithm’s ability to meet these constraints while simultaneously revealing dosimetric tradeoffs was investigated. Statistically significant dosimetric tradeoffs were defined such that the coefficient of determination between dosimetric indices which varied by at least 5 Gy between different plans was >0.8. Results: The qcMCO plans varied mean dose by >5 Gy to ipsilateral lung for 24/30 patients, contralateral lung for 29/30 patients, esophagus for 29/30 patients, and heart for 19/30 patients. In the 600 plans computed without human interaction, average PTV-D95=67.4±3.3 Gy, PTV-Dmax=79.2±5.3 Gy, and spinal cord Dmax was >45 Gy in 93 plans (>50 Gy in 2/600 plans). Statistically significant dosimetric tradeoffs were evident in 19/30 plans, including multiple tradeoffs of at least 5 Gy between multiple OARs in 7/30 cases. The most common statistically significant tradeoff was increasing PTV-Dmax to reduce OAR dose (15/30 patients). Conclusion: The qcMCO method can conform to quasi-constrained objectives while revealing significant variations in OAR doses including mean dose reductions >5 Gy. Clinical implementation will facilitate patient-specific decision making based on achievable dosimetry as opposed to accept/reject models based on population derived objectives.« less

SU-E-I-28: Evaluating the Organ Dose From Computed Tomography Using Monte Carlo Calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ono, T; Araki, F

Purpose: To evaluate organ doses from computed tomography (CT) using Monte Carlo (MC) calculations. Methods: A Philips Brilliance CT scanner (64 slice) was simulated using the GMctdospp (IMPS, Germany) based on the EGSnrc user code. The X-ray spectra and a bowtie filter for MC simulations were determined to coincide with measurements of half-value layer (HVL) and off-center ratio (OCR) profile in air. The MC dose was calibrated from absorbed dose measurements using a Farmer chamber and a cylindrical water phantom. The dose distribution from CT was calculated using patient CT images and organ doses were evaluated from dose volume histograms.more » Results: The HVLs of Al at 80, 100, and 120 kV were 6.3, 7.7, and 8.7 mm, respectively. The calculated HVLs agreed with measurements within 0.3%. The calculated and measured OCR profiles agreed within 3%. For adult head scans (CTDIvol) =51.4 mGy), mean doses for brain stem, eye, and eye lens were 23.2, 34.2, and 37.6 mGy, respectively. For pediatric head scans (CTDIvol =35.6 mGy), mean doses for brain stem, eye, and eye lens were 19.3, 24.5, and 26.8 mGy, respectively. For adult chest scans (CTDIvol=19.0 mGy), mean doses for lung, heart, and spinal cord were 21.1, 22.0, and 15.5 mGy, respectively. For adult abdominal scans (CTDIvol=14.4 mGy), the mean doses for kidney, liver, pancreas, spleen, and spinal cord were 17.4, 16.5, 16.8, 16.8, and 13.1 mGy, respectively. For pediatric abdominal scans (CTDIvol=6.76 mGy), mean doses for kidney, liver, pancreas, spleen, and spinal cord were 8.24, 8.90, 8.17, 8.31, and 6.73 mGy, respectively. In head scan, organ doses were considerably different from CTDIvol values. Conclusion: MC dose distributions calculated by using patient CT images are useful to evaluate organ doses absorbed to individual patients.« less

DTI and pathological changes in a rabbit model of radiation injury to the spinal cord after 125I radioactive seed implantation

PubMed Central

Cao, Xia; Fang, Le; Cui, Chuan-yu; Gao, Shi; Wang, Tian-wei

2018-01-01

Excessive radiation exposure may lead to edema of the spinal cord and deterioration of the nervous system. Magnetic resonance imaging can be used to judge and assess the extent of edema and to evaluate pathological changes and thus may be used for the evaluation of spinal cord injuries caused by radiation therapy. Radioactive 125I seeds to irradiate 90% of the spinal cord tissue at doses of 40–100 Gy (D90) were implanted in rabbits at T10 to induce radiation injury, and we evaluated their safety for use in the spinal cord. Diffusion tensor imaging showed that with increased D90, the apparent diffusion coefficient and fractional anisotropy values were increased. Moreover, pathological damage of neurons and microvessels in the gray matter and white matter was aggravated. At 2 months after implantation, obvious pathological injury was visible in the spinal cords of each group. Magnetic resonance diffusion tensor imaging revealed the radiation injury to the spinal cord, and we quantified the degree of spinal cord injury through apparent diffusion coefficient and fractional anisotropy. PMID:29623940

The dosimetric impact of implants on the spinal cord dose during stereotactic body radiotherapy.

PubMed

Yazici, Gozde; Sari, Sezin Yuce; Yedekci, Fazli Yagiz; Yucekul, Altug; Birgi, Sumerya Duru; Demirkiran, Gokhan; Gultekin, Melis; Hurmuz, Pervin; Yazici, Muharrem; Ozyigit, Gokhan; Cengiz, Mustafa

2016-05-25

The effects of spinal implants on dose distribution have been studied for conformal treatment plans. However, the dosimetric impact of spinal implants in stereotactic body radiotherapy (SBRT) treatments has not been studied in spatial orientation. In this study we evaluated the effect of spinal implants placed in sawbone vertebra models implanted as in vivo instrumentations. Four different spinal implant reconstruction techniques were performed using the standard sawbone lumbar vertebrae model; 1. L2-L4 posterior instrumentation without anterior column reconstruction (PI); 2. L2-L4 anterior instrumentation, L3 corpectomy, and anterior column reconstruction with a titanium cage (AIAC); 3. L2-L4 posterior instrumentation, L3 corpectomy, and anterior column reconstruction with a titanium cage (PIAC); 4. L2-L4 anterior instrumentation, L3 corpectomy, and anterior column reconstruction with chest tubes filled with bone cement (AIABc). The target was defined as the spinous process and lamina of the lumbar (L) 3 vertebra. A thermoluminescent dosimeter (TLD, LiF:Mg,Ti) was located on the measurement point anterior to the spinal cord. The prescription dose was 8 Gy and the treatment was administered in a single fraction using a CyberKnife® (Accuray Inc., Sunnyvale, CA, USA). We performed two different treatment plans. In Plan A beam interaction with the rod was not limited. In plan B the rod was considered a structure of avoidance, and interaction between the rod and beam was prevented. TLD measurements were compared with the point dose calculated by the treatment planning system (TPS). In plan A, the difference between TLD measurement and the dose calculated by the TPS was 1.7 %, 2.8 %, and 2.7 % for the sawbone with no implant, PI, and PIAC models, respectively. For the AIAC model the TLD dose was 13.8 % higher than the TPS dose; the difference was 18.6 % for the AIABc model. In plan B for the AIAC and AIABc models, TLD measurement was 2.5 % and 0.9 % higher than the dose calculated by the TPS, respectively. Spinal implants may be present in the treatment field in patients scheduled to undergo SBRT. For the types of implants studied herein anterior rod instrumentation resulted in an increase in the spinal cord dose, whereas use of a titanium cage had a minimal effect on dose distribution. While planning SBRT in patients with spinal reconstructions, avoidance of the rod and preventing interaction between the rod and beam might be the optimal solution for preventing unexpectedly high spinal cord doses.

Low doses of urethane effectively inhibit spinal seizures evoked by sudden cooling of toad isolated spinal cord

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pina-crespo, J.C.; Dalo, N.L.

1992-01-01

The effect of low doses of urethane on three phases of spinal seizures evoked by sudden cooling (SSSC) of toad isolated spinal cord was studied. In control toads, SSSC began with a latency of 91[plus minus]3 sec exhibiting brief tremors, followed by clonic muscle contractions and finally reaching a tonic contraction. The latency of onset of seizures was significantly enhanced. The tonic phase was markedly abolished in toads pretreated intralymphaticaly with 0.15 g/kg of urethane. Tremors were the only phase observed in 55% of toads that received doses of 0.2 g/kg, and a total blockage of seizures was seen aftermore » doses of 0.25 g/kg of urethane in 50% of the preparations. A possible depressant effect of urethane on transmission mediated by excitatory amino acids is suggested.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, D; Sood, S; Badkul, R

Purpose: To compare dose distributions calculated using PB-hete vs. XVMC algorithms for SRT treatments of cavernous sinus tumors. Methods: Using PB-hete SRT, five patients with cavernous sinus tumors received the prescription dose of 25 Gy in 5 fractions for planning target volume PTV(V100%)=95%. Gross tumor volume (GTV) and organs at risk (OARs) were delineated on T1/T2 MRI-CT-fused images. PTV (range 2.1–84.3cc, mean=21.7cc) was generated using a 5mm uniform-margin around GTV. PB-hete SRT plans included a combination of non-coplanar conformal arcs/static beams delivered by Novalis-TX consisting of HD-MLCs and a 6MV-SRS(1000 MU/min) beam. Plans were re-optimized using XVMC algorithm with identicalmore » beam geometry and MLC positions. Comparison of plan specific PTV(V99%), maximal, mean, isocenter doses, and total monitor units(MUs) were evaluated. Maximal dose to OARs such as brainstem, optic-pathway, spinal cord, and lenses as well as normal tissue volume receiving 12Gy(V12) were compared between two algorithms. All analysis was performed using two-tailed paired t-tests of an upper-bound p-value of <0.05. Results: Using either algorithm, no dosimetrically significant differences in PTV coverage (PTVV99%,maximal, mean, isocenter doses) and total number of MUs were observed (all p-values >0.05, mean ratios within 2%). However, maximal doses to optic-chiasm and nerves were significantly under-predicted using PB-hete (p=0.04). Maximal brainstem, spinal cord, lens dose and V12 were all comparable between two algorithms, with exception of one patient with the largest PTV who exhibited 11% higher V12 with XVMC. Conclusion: Unlike lung tumors, XVMC and PB-hete treatment plans provided similar PTV coverage for cavernous sinus tumors. Majority of OARs doses were comparable between two algorithms, except for small structures such as optic chiasm/nerves which could potentially receive higher doses when using XVMC algorithm. Special attention may need to be paid on a case-by-case basis when planning for sinus SRT based on tumor size and location to OARs particularly the optic apparatus.« less

Performance Characteristics of an Independent Dose Verification Program for Helical Tomotherapy

PubMed Central

Chang, Isaac C. F.; Chen, Jeff; Yartsev, Slav

2017-01-01

Helical tomotherapy with its advanced method of intensity-modulated radiation therapy delivery has been used clinically for over 20 years. The standard delivery quality assurance procedure to measure the accuracy of delivered radiation dose from each treatment plan to a phantom is time-consuming. RadCalc®, a radiotherapy dose verification software, has released specifically for beta testing a module for tomotherapy plan dose calculations. RadCalc®'s accuracy for tomotherapy dose calculations was evaluated through examination of point doses in ten lung and ten prostate clinical plans. Doses calculated by the TomoHDA™ tomotherapy treatment planning system were used as the baseline. For lung cases, RadCalc® overestimated point doses in the lung by an average of 13%. Doses within the spinal cord and esophagus were overestimated by 10%. Prostate plans showed better agreement, with overestimations of 6% in the prostate, bladder, and rectum. The systematic overestimation likely resulted from limitations of the pencil beam dose calculation algorithm implemented by RadCalc®. Limitations were more severe in areas of greater inhomogeneity and less prominent in regions of homogeneity with densities closer to 1 g/cm3. Recommendations for RadCalc® dose calculation algorithms and anatomical representation were provided based on the results of the study. PMID:28974862

Bone architecture adaptations after spinal cord injury: impact of long-term vibration of a constrained lower limb.

PubMed

Dudley-Javoroski, S; Petrie, M A; McHenry, C L; Amelon, R E; Saha, P K; Shields, R K

2016-03-01

This study examined the effect of a controlled dose of vibration upon bone density and architecture in people with spinal cord injury (who eventually develop severe osteoporosis). Very sensitive computed tomography (CT) imaging revealed no effect of vibration after 12 months, but other doses of vibration may still be useful to test. The purposes of this report were to determine the effect of a controlled dose of vibratory mechanical input upon individual trabecular bone regions in people with chronic spinal cord injury (SCI) and to examine the longitudinal bone architecture changes in both the acute and chronic state of SCI. Participants with SCI received unilateral vibration of the constrained lower limb segment while sitting in a wheelchair (0.6g, 30 Hz, 20 min, three times weekly). The opposite limb served as a control. Bone mineral density (BMD) and trabecular micro-architecture were measured with high-resolution multi-detector CT. For comparison, one participant was studied from the acute (0.14 year) to the chronic state (2.7 years). Twelve months of vibration training did not yield adaptations of BMD or trabecular micro-architecture for the distal tibia or the distal femur. BMD and trabecular network length continued to decline at several distal femur sub-regions, contrary to previous reports suggesting a "steady state" of bone in chronic SCI. In the participant followed from acute to chronic SCI, BMD and architecture decline varied systematically across different anatomical segments of the tibia and femur. This study supports that vibration training, using this study's dose parameters, is not an effective anti-osteoporosis intervention for people with chronic SCI. Using a high-spatial-resolution CT methodology and segmental analysis, we illustrate novel longitudinal changes in bone that occur after spinal cord injury.

Baicalin effects on rats with spinal cord injury by anti-inflammatory and regulating the serum metabolic disorder.

PubMed

Kang, Shufeng; Liu, Shizhao; Li, Hongzhu; Wang, Dapeng; Qi, Xiangbei

2018-06-15

Baicalin had neuroprotective effects on inhibiting neuronal cell apoptosis induced by spinal cord ischemic injury. This study aimed to explore the protective effects of Baicalin on rats with spinal cord injury (SCI) and its mechanism of action. The recovery of spinal cord nerve function in rats was evaluated by the Basso, Beattie, and Bresnahan (BBB) score and the combine behavioral score (CBS). The expressions of cytokines tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 were detected by the enzyme-linked immunosorbent assay method. Expressions of inflammation-related proteins were detected by Western blot. Multivariate statistical analysis was performed for serum metabolites. The BBB and CBS score results showed that Baicalin had a certain improvement on rats with SCI. SCI symptoms were significantly improved in low-dose and high-dose groups. The levels of TNF-α, IL-1β, and IL-6 in the SCI group were significantly increased. The expressions of NF-κB p65, NF-κB p50, p-IκBα, and IKKα in the SCI group showed the opposite trend compared with the low-dose and high-dose groups. Compared with the sham group, glutamine, levels of 3-OH-butyrate, N-acetylaspartate, and glutathione were significantly reduced, and the levels of glutamate and betaine were significantly increased in the SCI group. When Baicalin was administered, the contents of glutamine synthase (GS) and glutaminase (GLS) were significantly reduced, indicating that Baicalin had the effect of improving GS and GLS. Baicalin has protective effects on improving SCI and lower extremity motor function, has a significant anti-inflammatory effect, and regulates the serum metabolic disorder caused by SCI in rats. © 2018 Wiley Periodicals, Inc.

PHASE II STUDY OF HIGH DOSE PHOTON/PROTON RADIOTHERAPY IN THE MANAGEMENT OF SPINE SARCOMAS

PubMed Central

DeLaney, Thomas F.; Liebsch, Norbert J.; Pedlow, Francis X.; Adams, Judith; Dean, Susan; Yeap, Beow Y.; McManus, Patricia; Rosenberg, Andrew E.; Nielsen, G. Petur; Harmon, David C.; Spiro, Ira J.; Raskin, Kevin A.; Suit, Herman D.; Yoon, Sam S.; Hornicek, Francis J.

2009-01-01

Purpose Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of ≥ 66 Gy are recommended. A Phase II clinical trial evaluated high dose photon/proton XRT for spine sarcomas. Materials/Methods Eligible patients had non-metastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or post-op photon/proton XRT +/- radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (GyRBE) to subclinical disease, 70.2 GyRBE to microscopic disease in the tumor bed, and 77.4 GyRBE to gross disease at 1.8 GyRBE q.d. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 GyRBE to surface/center. Intra-operative boost doses of 7.5-10 Gy could be given by dural plaque. Results 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n=25) or subtotal (n=12) resection or biopsy (n=13). With 48 month median follow-up, five-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence, p<0.001. Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared following 77.12-77.4 GyRBE. Conclusions Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 GyRBE are at risk for late toxicity. PMID:19095372

Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nieder, Carsten; Grosu, Anca L.; Andratschke, Nicolaus H.

Purpose: Driven by numerous reports on recovery of occult radiation injury, reirradiation of the spinal cord today is considered a realistic option. In rodents, long-term recovery was observed to start at approximately 8 weeks. However, prospective clinical studies are lacking. Therefore, a combined analysis of all published clinical data might provide a valuable basis for future trials. Methods and materials: We collected data from 40 individual patients published in eight different reports after a comprehensive MEDLINE search. These represent all patients with data available for dose per fraction and total dose of each of both treatment courses. We recalculated themore » biologically effective dose (BED) according to the linear-quadratic model using an {alpha}/{beta} value of 2 Gy for the cervical and thoracic cord and 4 Gy for the lumbar cord. In this model, a dose of 50 Gy given in single daily fractions of 2 Gy is equivalent to a BED of 100 Gy{sub 2} or 75 Gy{sub 4}. For treatment with two daily fractions, a correction term was introduced to take incomplete repair of sublethal damage into account. Results: The cumulative doses ranged from 108 to 205 Gy{sub 2} (median dose, 135 Gy{sub 2}). The median interval between both series was 20 months. Three patients were treated to the lumbar segments only. The median follow-up was 17 months for patients without myelopathy. Eleven patients developed myelopathy after 4-25 months (median, 11 months). Myelopathy was seen only in patients who had received one course to a dose of {>=}102 Gy{sub 2} (n = 9) or were retreated after 2 months (n = 2). In the absence of these two risk factors, no myelopathy developed in 19 patients treated with {<=}135.5 Gy{sub 2} or 7 patients treated with 136-150 Gy{sub 2}. A risk score based on the cumulative BED, the greatest BED for all treatment series in a particular individual, and interval was developed. Low-risk patients remained free of myelopathy and 33% of intermediate-risk patients and 90% of high-risk patients developed myelopathy. Conclusion: On the basis of these literature data (and with due caution), the risk of myelopathy appears small after {<=}135.5 Gy{sub 2} when the interval is not shorter than 6 months and the dose of each course is {<=}98 Gy{sub 2}. We would recommend limiting the dose to this level, whenever technically feasible. However, it appears prudent to propose the collection of prospective data from a greater number of patients receiving doses in the range of 136-150 Gy{sub 2} to assess the safety of higher retreatment doses for those patients in whom limited doses might compromise tumor control.« less

An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain From Spinal Cord Injury and Disease.

PubMed

Wilsey, Barth; Marcotte, Thomas D; Deutsch, Reena; Zhao, Holly; Prasad, Hannah; Phan, Amy

2016-09-01

Using 8-hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, most of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta 9-THC on 3 separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was used to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model showed a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (eg, good drug effect, feeling high, etc) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all P < .0004). Psychoactive and subjective effects were dose-dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. Because the 2 active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord. A crossover, randomized, placebo-controlled human laboratory experiment involving administration of vaporized cannabis was performed in patients with neuropathic pain related to spinal cord injury and disease. This study supports consideration of future research that would include longer duration studies over weeks to months to evaluate the efficacy of medicinal cannabis in patients with central neuropathic pain. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Susceptibility of various areas of the nervous system of hens to TOCP-induced delayed neuropathy.

PubMed

Classen, W; Gretener, P; Rauch, M; Weber, E; Krinke, G J

1996-01-01

Sensitivity of in-life parameters, biochemical endpoints, and susceptibility of various areas of the chicken nervous system to delayed neuropathy induced by tri-orthocresyl phosphate (TOCP) was assessed. Groups of hens were exposed to a single oral dose of TOCP of 0, 50, 200 or 500 mg/kg and the animals observed for 21 days. Perfusion fixed, paraffin embedded tissue sections were stained with Bodian's silver and Luxol blue and semi-thin epoxy sections with toluidine blue. Sciatic and tibial nerves, lumbosacral, midthoracic, and upper cervical spinal cord, medulla oblongata and cerebellum were examined using a semiquantitative scoring system. In pair-dosed hens inhibition of brain and spinal cord neurotoxic esterase (NTE) and cholinesterase and of plasma and erythrocyte cholinesterases was determined 24 hr and 48 hr after administration. At all dose levels NTE in brain and spinal cord and plasma cholinesterase was inhibited markedly. Quantitative inhibition of NTE was seen also in absence of neuropathy. Ataxia and body weight loss occurred in high-dose animals only, while dose-related neuropathy was seen in the distal tibial nerve, medulla oblongata and cerebellum. Ataxia was correlated best with neuropathy in peripheral nerves while degeneration of nerve fibers in the cerebellum, seen best in mid-longitudinal sections, was the most sensitive histological indicator of TOCP-induced delayed neuropathy. The particular susceptibility of spinocerebellar neurons was recognized long ago, but often has been neglected in delayed neurotoxicity studies and respective guidelines. Optimal sensitivity of toxicity tests is a prerequisite for risk assessment, can be cost efficient, and nowadays should be a main interest of animal welfare in order to reduce animals' suffering. Based on these data, determination of NTE inhibition together with histopathological examination of longitudinal sections of distal tibial nerves, mid-longitudinal sections of rostral cerebellum and cross sections of upper cervical spinal cord represents an optimally sensitive and cost efficient test requirement.

An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain from Spinal Cord Injury and Disease

PubMed Central

Wilsey, Barth; Marcotte, Thomas D.; Deutsch, Reena; Zhao, Holly; Prasad, Hannah; Phan, Amy

2016-01-01

Using eight hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, the majority of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta-9-tetrahydrocannabinol on three separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was utilized to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model demonstrated a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (e.g., good drug effect, feeling high, etc.) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all p<0.0004). Psychoactive and subjective effects were dose dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. As the two active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord. PMID:27286745

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wong, M; Lee, V; Leung, R

Purpose: Investigating the relative sensitivity of Monte Carlo (MC) and Pencil Beam (PB) dose calculation algorithms to low-Z (titanium) metallic artifacts is important for accurate and consistent dose reporting in post¬operative spinal RS. Methods: Sensitivity analysis of MC and PB dose calculation algorithms on the Monaco v.3.3 treatment planning system (Elekta CMS, Maryland Heights, MO, USA) was performed using CT images reconstructed without (plain) and with Orthopedic Metal Artifact Reduction (OMAR; Philips Healthcare system, Cleveland, OH, USA). 6MV and 10MV volumetric-modulated arc (VMAT) RS plans were obtained for MC and PB on the plain and OMAR images (MC-plain/OMAR and PB-plain/OMAR).more » Results: Maximum differences in dose to 0.2cc (D0.2cc) of spinal cord and cord +2mm for 6MV and 10MV VMAT plans were 0.1Gy between MC-OMAR and MC-plain, and between PB-OMAR and PB-plain. Planning target volume (PTV) dose coverage changed by 0.1±0.7% and 0.2±0.3% for 6MV and 10MV from MC-OMAR to MC-plain, and by 0.1±0.1% for both 6MV and 10 MV from PB-OMAR to PB-plain, respectively. In no case for both MC and PB the D0.2cc to spinal cord was found to exceed the planned tolerance changing from OMAR to plain CT in dose calculations. Conclusion: Dosimetric impacts of metallic artifacts caused by low-Z metallic spinal hardware (mainly titanium alloy) are not clinically important in VMAT-based spine RS, without significant dependence on dose calculation methods (MC and PB) and photon energy ≥ 6MV. There is no need to use one algorithm instead of the other to reduce uncertainty for dose reporting. The dose calculation method that should be used in spine RS shall be consistent with the usual clinical practice.« less

Neuroprotection and Acute Spinal Cord Injury: A Reappraisal

PubMed Central

Hall, Edward D.; Springer, Joe E.

2004-01-01

Summary: It has long been recognized that much of the post-traumatic degeneration of the spinal cord following injury is caused by a multi-factorial secondary injury process that occurs during the first minutes, hours, and days after spinal cord injury (SCI). A key biochemical event in that process is reactive oxygen-induced lipid peroxidation (LP). In 1990 the results of the Second National Acute Spinal Cord Injury Study (NASCIS II) were published, which showed that the administration of a high-dose regimen of the glucocorticoid steroid methylprednisolone (MP), which had been previously shown to inhibit post-traumatic LP in animal models of SCI, could improve neurological recovery in spinal-cord-injured humans. This resulted in the registration of high-dose MP for acute SCI in several countries, although not in the U.S. Nevertheless, this treatment quickly became the standard of care for acute SCI since the drug was already on the U.S. market for many other indications. Subsequently, it was demonstrated that the non-glucocorticoid 21-aminosteroid tirilazad could duplicate the antioxidant neuroprotective efficacy of MP in SCI models, and evidence of human efficacy was obtained in a third NASCIS trial (NASCIS III). In recent years, the use of high-dose MP in acute SCI has become controversial largely on the basis of the risk of serious adverse effects versus what is perceived to be on average a modest neurological benefit. The opiate receptor antagonist naloxone was also tested in NASCIS II based upon the demonstration of its beneficial effects in SCI models. Although it did not a significant overall effect, some evidence of efficacy was seen in incomplete (i.e., paretic) patients. The monosialoganglioside GM1 has also been examined in a recently completed clinical trial in which the patients first received high-dose MP treatment. However, GM1 failed to show any evidence of a significant enhancement in the extent of neurological recovery over the level afforded by MP therapy alone. The present paper reviews the past development of MP, naloxone, tirilazad, and GM1 for acute SCI, the ongoing MP-SCI controversy, identifies the regulatory complications involved in future SCI drug development, and suggests some promising neuroprotective approaches that could either replace or be used in combination with high-dose MP. PMID:15717009

Activation of mitochondria-mediated apoptotic pathway in tri-ortho-cresyl phosphate-induced delayed neuropathy.

PubMed

Zou, Chaoshuang; Kou, Ruirui; Gao, Yuan; Xie, Keqin; Song, Fuyong

2013-06-01

Previous studies suggest that abnormal neurons death has been implicated in organophosphate-induced delayed neuropathy (OPIDN). However, the precise mechanism of neuronal death in OPIDN remains largely unknown. In this study, adult hens were treated with a dosage of 750 mg/kg tri-ortho-cresyl phosphate (TOCP) by gavage, and then sacrificed on the time-points of 1, 5, 10, and 21 days after dosing TOCP, respectively. The apoptotic change of spinal cord neurons induced by TOCP was examined, and the role of mitochondria-mediated apoptosis of neurons during OPIDN was investigated. TUNEL assays showed that apoptotic neurons in hen spinal cords began to appear on day 5 following TOCP exposure. Immunohistochemistry and western blot analysis revealed a translocation of cytochrome C from mitochondria to cytoplasm after dosing TOCP. Moreover, the level of Bcl-2, Bcl-xl, Pro-caspase3 and Pro-caspase9 in hen spinal cord was significantly decreased, whereas that of Bax and cleaved-PARP was significantly elevated. Taken together, these findings indicate that the administration of TOCP can induce neuron apoptosis in hen spinal cords, which might be mediated by the activation of mitochondrial apoptotic pathway. Copyright © 2013 Elsevier Ltd. All rights reserved.

Development of a multi-electrode array for spinal cord epidural stimulation to facilitate stepping and standing after a complete spinal cord injury in adult rats.

PubMed

Gad, Parag; Choe, Jaehoon; Nandra, Mandheerej Singh; Zhong, Hui; Roy, Roland R; Tai, Yu-Chong; Edgerton, V Reggie

2013-01-21

Stimulation of the spinal cord has been shown to have great potential for improving function after motor deficits caused by injury or pathological conditions. Using a wide range of animal models, many studies have shown that stimulation applied to the neural networks intrinsic to the spinal cord can result in a dramatic improvement of motor ability, even allowing an animal to step and stand after a complete spinal cord transection. Clinical use of this technology, however, has been slow to develop due to the invasive nature of the implantation procedures, the lack of versatility in conventional stimulation technology, and the difficulty of ascertaining specific sites of stimulation that would provide optimal amelioration of the motor deficits. Moreover, the development of tools available to control precise stimulation chronically via biocompatible electrodes has been limited. In this paper, we outline the development of this technology and its use in the spinal rat model, demonstrating the ability to identify and stimulate specific sites of the spinal cord to produce discrete motor behaviors in spinal rats using this array. We have designed a chronically implantable, rapidly switchable, high-density platinum based multi-electrode array that can be used to stimulate at 1-100 Hz and 1-10 V in both monopolar and bipolar configurations to examine the electrophysiological and behavioral effects of spinal cord epidural stimulation in complete spinal cord transected rats. In this paper, we have demonstrated the effectiveness of using high-resolution stimulation parameters in the context of improving motor recovery after a spinal cord injury. We observed that rats whose hindlimbs were paralyzed can stand and step when specific sets of electrodes of the array are stimulated tonically (40 Hz). Distinct patterns of stepping and standing were produced by stimulation of different combinations of electrodes on the array located at specific spinal cord levels and by specific stimulation parameters, i.e., stimulation frequency and intensity, and cathode/anode orientation. The array also was used to assess functional connectivity between the cord dorsum to interneuronal circuits and specific motor pools via evoked potentials induced at 1 Hz stimulation in the absence of any anesthesia. Therefore the high density electrode array allows high spatial resolution and the ability to selectively activate different neural pathways within the lumbosacral region of the spinal cord to facilitate standing and stepping in adult spinal rats and provides the capability to evoke motor potentials and thus a means for assessing connectivity between sensory circuits and specific motor pools and muscles.

Intrathecal administration of a substance P receptor antagonist: studies on peripheral and central nervous system hemodynamics and on specificity of action.

PubMed

Helke, C J; Phillips, E T; O'Neill, J T

1987-07-01

Regional central nervous system and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P (SP) receptor antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P ([D-Arg]-SP), were studied in anesthetized rats. It was found that [D-Arg]-SP (3.3 nmol i.t.) reduced mean arterial pressure and cardiac output due to a reduction in stroke volume. Total peripheral resistance was not altered. Whereas most vascular beds showed no alterations in vascular resistance, a renal vasoconstriction was noted. The hypotensive effect of [D-Arg]-SP was blocked by phentolamine (10 mg/kg i.v.) but not by propranolol (1 mg/kg i.v.). In the absence of changes in vascular arterial resistance due to [D-Arg]-SP, it appears that a change in venous return may contribute to the [D-Arg]-SP-induced reduction in stroke volume. These data provide evidence that a spinal cord SP system may tonically affect sympathetic neurons controlling venous, but not arterial, vasomotor tone. [D-Arg]-SP (i.t.) did not alter brain blood flow but significantly decreased blood flow in the thoracolumbar spinal cord 15 to 20 min after administration. The reduction in spinal cord flow did not appear to be responsible for the [D-Arg]-SP-induced hypotension because kainic acid (i.t.), an agent that interacts with glutamate receptors, produced similar pressor responses in the presence and absence of [D-Arg]-SP. In addition, whereas the pressor effect of low doses of a SP agonist [pGlu5, MePhe8, MeGly9]-substance P (5-11) were blocked by [D-Arg]-SP, a higher dose produced the typical pressor effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihyperalgesic and antiallodynic effect of sirolimus in rat model of adjuvant arthritis.

PubMed

Orhan, Cahide Elif; Önal, Aytül; Uyanıkgil, Yiğit; Ülker, Sibel

2013-04-05

Sirolimus is an immunosupressive drug that specifically inhibit the activation of T-lymphocytes. This study was undertaken to investigate whether treatment with sirolimus exert analgesic effect in rat adjuvant-induced arthritis, an animal model of rheumatoid arthritis. Arthritis was induced by a single subcutaneous injection of Freund's complete adjuvant to male Wistar rats that were divided into four groups; control (saline), vehicle (ethanol), sirolimus 0.75 and sirolimus 1.5. Sirolimus (0.75 and 1.5mg/kg/day) was administered intraperitoneally using Monday-Wednesday-Friday dosing schedule for 29 days, this dosing regimen revealed acceptable trough blood concentrations in arthritic rats. Adjuvant inoculation resulted in paw inflammation, hyperalgesia and allodynia as assessed by pletismometer, analgesymeter and dynamic plantar aesthesiometer respectively. Light microscopic evaluation of the arthritic metacarpophalangeal joints revealed synovial hypertrophy with inflammatory cellular infiltration, cartilage destruction and partial subchondral bone resorption. ELISA tests of serum TNF-α, IL-1β or IL-6 did not show any change in arthritic rats, while Western blotting analysis revealed a significant increase in TNF-α (P<0.001), but not IL-1β or IL-6, protein expression in the lumbar spinal cord of arthritic rats. Treatment with sirolimus significantly decreased the arthritic lesions (P<0.001) and paw swelling (P<0.05), alleviated the histological features in the metacarpophalangeal joint, resulted in antihyperalgesic and antiallodynic effects without affecting the locomotor activity and prevented the increased spinal cord TNF-α level (P<0.05). It seems that prevention of the increased TNF-α expression in the spinal cord may partially contribute to the antihyperalgesic effect of sirolimus in adjuvant arthritic rats and sirolimus could be a promising immunosupressive agent in the treatment of arthritic pain. Copyright © 2013 Elsevier B.V. All rights reserved.

Differentiation stage-specific regulation of primitive human hematopoietic progenitor cycling by exogenous and endogenous inhibitors in an in vivo model.

PubMed

Cashman, J D; Clark-Lewis, I; Eaves, A C; Eaves, C J

1999-12-01

Nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice transplanted with human cord blood or adult marrow cells and injected 6 weeks posttransplant with 2 daily doses of transforming growth factor-beta(1) (TGF-beta(1)), monocyte chemoattractant protein-1 (MCP-1), or a nonaggregating form of macrophage inflammatory protein-1alpha (MIP-1alpha) showed unique patterns of inhibition of human progenitor proliferation 1 day later. TGF-beta(1) was active on long-term culture initiating cells (LTC-IC) and on primitive erythroid and granulopoietic colony-forming cells (HPP-CFC), but had no effect on mature CFC. MCP-1 inhibited the cycling of both types of HPP-CFC but not LTC-IC. MIP-1alpha did not inhibit either LTC-IC or granulopoietic HPP-CFC but was active on erythroid HPP-CFC and mature granulopoietic CFC. All of these responses were independent of the source of human cells transplanted. LTC-IC of either human cord blood or adult marrow origin continue to proliferate in NOD/SCID mice for many weeks, although the turnover of all types of human CFC in mice transplanted with adult human marrow (but not cord blood) is downregulated after 6 weeks. Interestingly, administration of either MIP-1beta, an antagonist of both MIP-1alpha and MCP-1 or MCP-1(9-76), an antagonist of MCP-1 (and MCP-2 and MCP-3), into mice in which human marrow-derived CFC had become quiescent, caused the rapid reactivation of these progenitors in vivo. These results provide the first definition of stage-specific inhibitors of human hematopoietic progenitor cell cycling in vivo. In addition they show that endogenous chemokines can contribute to late graft failure, which can be reversed by the administration of specific antagonists.

Involuntary expiratory phonation as a dose-related consequence of L-dopa therapy in a patient with Parkinson's disease.

PubMed

Ishii, Kosuke; Kumada, Masanobu; Ueki, Akira; Yamamoto, Masanori; Hirose, Hajime

2003-12-01

We report a case of involuntary phonation caused by abnormal vocal cord movements during expiration in a patient with Parkinson's disease. A 60-year-old woman had been treated for parkinsonism at the outpatient clinic of the Department of Neurology since August 1999. She began to groan involuntarily in the daytime in September 2001. She could not eat well while groaning. Stridor was not noted during sleep at night. Endoscopic examination of the larynx revealed insufficient abduction of the bilateral vocal cords, although the glottis was not so small as to cause stridor during inspiration. During expiration, however, the vocal cords adducted, resulting in the involuntary production of voice. Electromyography showed an increase in the activity of the thyroarytenoid and lateral cricoarytenoid muscles. This muscle activity was further enhanced during inspiration. The involuntary phonation disappeared when the patient's dose of L-dopa was decreased, although she had a decrease in her systemic mobility as well. When the dose of L-dopa was increased to the therapeutic level, involuntary phonation recurred, and her voluntary systemic activity improved. In the present case, it was considered that excessive dopaminergic denervation occurred in the nerve innervating the laryngeal adductors. Involuntary voice appeared to be produced by hypertonus of the laryngeal adductors because of a lowering in the threshold level for L-dopa, even though the drug was administered at the usual dose.

Progenitor cell dose determines the pace and completeness of engraftment in a xenograft model for cord blood transplantation

PubMed Central

Liu, Congxiao; Chen, Benny J.; DeOliveira, Divinomar; Sempowski, Gregory D.; Chao, Nelson J.

2010-01-01

Two critical concerns in clinical cord blood transplantation are the initial time to engraftment and the subsequent restoration of immune function. These studies measured the impact of progenitor cell dose on both the pace and strength of hematopoietic reconstitution by transplanting nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-gamma–null (NSγ) mice with lineage-depleted aldehyde dehydrogenase-bright CD34+ human cord blood progenitors. The progress of each transplant was monitored over an extended time course by repeatedly analyzing the peripheral blood for human hematopoietic cells. In vivo human hematopoietic development was complete. After long-term transplantation assays (≥ 19 weeks), human T-cell development was documented within multiple tissues in 16 of 32 NSγ mice. Human T-cell differentiation was active within NSγ thymuses, as documented by the presence of CD4+ CD8+ T-cell progenitors as well as T-cell receptor excision circles. It is important to note that although myeloid and B-cell engraftment was detected as early as 4 weeks after transplantation, human T-cell development was exclusively late onset. High progenitor cell doses were associated with a robust human hematopoietic chimerism that accelerated both initial time to engraftment and subsequent T-cell development. At lower progenitor cell doses, the chimerism was weak and the human hematopoietic lineage development was frequently incomplete. PMID:20833978

"White Cord Syndrome" of Acute Hemiparesis After Posterior Cervical Decompression and Fusion for Chronic Cervical Stenosis.

PubMed

Antwi, Prince; Grant, Ryan; Kuzmik, Gregory; Abbed, Khalid

2018-05-01

"White cord syndrome" is a very rare condition thought to be due to acute reperfusion of chronically ischemic areas of the spinal cord. Its hallmark is the presence of intramedullary hyperintense signal on T2-weighted magnetic resonance imaging sequences in a patient with unexplained neurologic deficits following spinal cord decompression surgery. The syndrome is rare and has been reported previously in 2 patients following anterior cervical decompression and fusion. We report an additional case of this complication. A 68-year-old man developed acute left-sided hemiparesis after posterior cervical decompression and fusion for cervical spondylotic myelopathy. The patient improved with high-dose steroid therapy. The rare white cord syndrome following either anterior cervical decompression and fusion or posterior cervical decompression and fusion may be due to ischemic-reperfusion injury sustained by chronically compressed parts of the spinal cord. In previous reports, patients have improved following steroid therapy and acute rehabilitation. Copyright © 2018 Elsevier Inc. All rights reserved.

Targeting L-Selectin to Improve Neurologic and Urologic Function After Spinal Cord Injury

DTIC Science & Technology

2014-10-01

doses of DFA, male C57BL/6 mice were subjected to a 2g weight dropped 7.5 cm onto the exposed spinal cord at the thoracic 9 vertebral level (mild...detect the absence of L-selectin on leukocytes 1 day post-SCI. Male C57BL/6 mice were subjected to a 2g weight dropped 7.5 cm onto the exposed spinal...subjected to a 2g weight dropped 7.5 cm onto the exposed spinal cord at the thoracic 9 vertebral level. DFA (40mg/kg) or vehicle was administered

DOE Office of Scientific and Technical Information (OSTI.GOV)

Venencia, C; Pino, M; Caussa, L

Purpose: The purpose of this work was to quantify the dosimetric impact of Monte Carlo (MC) dose calculation algorithm compared to Pencil Beam (PB) on Spine SBRT with HybridARC (HA) and sliding windows IMRT (dMLC) treatment modality. Methods: A 6MV beam (1000MU/min) produced by a Novalis TX (BrainLAB-Varian) equipped with HDMLC was used. HA uses 1 arc plus 8 IMRT beams (arc weight between 60–40%) and dIMRT 15 beams. Plans were calculated using iPlan v.4.5.3 (BrainLAB) and the treatment dose prescription was 27Gy in 3 fractions. Dose calculation was done by PB (4mm spatial resolution) with heterogeneity correction and MCmore » dose to water (4mm spatial resolution and 4% mean variance). PTV and spinal cord dose comparison were done. Study was done on 12 patients. IROC Spine Phantom was used to validate HA and quantify dose variation using PB and MC algorithm. Results: The difference between PB and MC for PTV D98%, D95%, Dmean, D2% were 2.6% [−5.1, 6.8], 0.1% [−4.2, 5.4], 0.9% [−1.5, 3.8] and 2.4% [−0.5, 8.3]. The difference between PB and MC for spinal cord Dmax, D1.2cc and D0.35cc were 5.3% [−6.4, 18.4], 9% [−7.0, 17.0] and 7.6% [−0.6, 14.8] respectively. IROC spine phantom shows PTV TLD dose variation of 0.98% for PB and 1.01% for MC. Axial and sagittal film plane gamma index (5%-3mm) was 95% and 97% for PB and 95% and 99% for MC. Conclusion: PB slightly underestimates the dose for the PTV. For the spinal cord PB underestimates the dose and dose differences could be as high as 18% which could have unexpected clinical impact. CI shows no variation between PB and MC for both treatment modalities Treatment modalities have no impact with the dose calculation algorithms used. Following the IROC pass-fail criteria, treatment acceptance requirement was fulfilled for PB and MC.« less

TH-A-9A-01: Active Optical Flow Model: Predicting Voxel-Level Dose Prediction in Spine SBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, J; Wu, Q.J.; Yin, F

2014-06-15

Purpose: To predict voxel-level dose distribution and enable effective evaluation of cord dose sparing in spine SBRT. Methods: We present an active optical flow model (AOFM) to statistically describe cord dose variations and train a predictive model to represent correlations between AOFM and PTV contours. Thirty clinically accepted spine SBRT plans are evenly divided into training and testing datasets. The development of predictive model consists of 1) collecting a sequence of dose maps including PTV and OAR (spinal cord) as well as a set of associated PTV contours adjacent to OAR from the training dataset, 2) classifying data into fivemore » groups based on PTV's locations relative to OAR, two “Top”s, “Left”, “Right”, and “Bottom”, 3) randomly selecting a dose map as the reference in each group and applying rigid registration and optical flow deformation to match all other maps to the reference, 4) building AOFM by importing optical flow vectors and dose values into the principal component analysis (PCA), 5) applying another PCA to features of PTV and OAR contours to generate an active shape model (ASM), and 6) computing a linear regression model of correlations between AOFM and ASM.When predicting dose distribution of a new case in the testing dataset, the PTV is first assigned to a group based on its contour characteristics. Contour features are then transformed into ASM's principal coordinates of the selected group. Finally, voxel-level dose distribution is determined by mapping from the ASM space to the AOFM space using the predictive model. Results: The DVHs predicted by the AOFM-based model and those in clinical plans are comparable in training and testing datasets. At 2% volume the dose difference between predicted and clinical plans is 4.2±4.4% and 3.3±3.5% in the training and testing datasets, respectively. Conclusion: The AOFM is effective in predicting voxel-level dose distribution for spine SBRT. Partially supported by NIH/NCI under grant #R21CA161389 and a master research grant by Varian Medical System.« less

Effect of Polyether Ether Ketone on Therapeutic Radiation to the Spine: A Pilot Study.

PubMed

Jackson, J Benjamin; Crimaldi, Anthony J; Peindl, Richard; Norton, H James; Anderson, William E; Patt, Joshua C

2017-01-01

Cadaveric model. To compare the effect of PEEK versus conventional implants on scatter radiation to a simulated tumor bed in the spine SUMMARY OF BACKGROUND DATA.: Given the highly vasculature nature of the spine, it is the most common place for bony metastases. After surgical treatment of a spinal metastasis, adjuvant radiation therapy is typically administered. Radiation dosing is primarily limited by toxicity to the spinal cord. The scatter effect caused by metallic implants decreases the accuracy of dosing and can unintentionally increase the effective dose seen by the spinal cord. This represents a dose-limiting factor for therapeutic radiation postoperatively. A cadaveric thorax specimen was utilized as a metastatic tumor model with two separate three-level spine constructs (one upper thoracic and one lower thoracic). Each construct was examined independently. All four groups compared included identical posterior instrumentation. The anterior constructs consisted of either: an anterior polyether ether ketone (PEEK) cage, an anterior titanium cage, an anterior bone cement cage (polymethyl methacrylate), or a control group with posterior instrumentation alone. Each construct had six thermoluminescent detectors to measure the radiation dose. The mean dose was similar across all constructs and locations. There was more variability in the upper thoracic spine irrespective of the construct type. The PEEK construct had a more uniform dose distribution with a standard deviation of 9.76. The standard deviation of the others constructs was 14.26 for the control group, 19.31 for the titanium cage, and 21.57 for the cement (polymethyl methacrylate) construct. The PEEK inter-body cage resulted in a significantly more uniform distribution of therapeutic radiation in the spine when compared with the other constructs. This may allow for the application of higher effective dosing to the tumor bed for spinal metastases without increasing spinal cord toxicity with either fractionated or hypofractionated radiotherapy. N/A.

Baclofen or nNOS inhibitor affect molecular and behavioral alterations evoked by traumatic spinal cord injury in rat spinal cord.

PubMed

Kisucká, Alexandra; Hricová, Ľudmila; Pavel, Jaroslav; Strosznajder, Joanna B; Chalimoniuk, Malgorzata; Langfort, Jozef; Gálik, Ján; Maršala, Martin; Radoňak, Jozef; Lukáčová, Nadežda

2015-06-01

The loss of descending control after spinal cord injury (SCI) and incessant stimulation of Ia monosynaptic pathway, carrying proprioceptive impulses from the muscles and tendons into the spinal cord, evoke exaggerated α-motoneuron activity leading to increased reflex response. Previous results from our laboratory have shown that Ia monosynaptic pathway is nitrergic. The aim of this study was to find out whether nitric oxide produced by neuronal nitric oxide synthase (nNOS) plays a role in setting the excitability of α-motoneurons after thoracic spinal cord transection. We tested the hypothesis that the inhibition of nNOS in α-motoneurons after SCI could have a neuroprotective effect on reflex response. Rats underwent spinal cord transection at Th10 level followed by 7, 10, and 14 days of survival. The animals were treated with Baclofen (a gamma aminobutyric acid B receptor agonist, 3 μg/two times per day/intrathecally) applied for 3 days from the seventh day after transection; N-nitro-l-arginine (NNLA) (nNOS blocator) applied for the first 3 days after injury (20 mg/kg per day, intramuscularly); NNLA and Baclofen; or NNLA (60 mg/kg/day, single dose) applied on the 10th day after transection. We detected the changes in the level of nNOS protein, nNOS messenger RNA, and nNOS immunoreactivity. To investigate the reflex response to heat-induced stimulus, tail-flick test was monitored in treated animals up to 16 days after SCI. Our data indicate that Baclofen therapy is more effective than the combined treatment with NNLA and Baclofen therapy. The single dose of NNLA (60 mg/kg) applied on the 10th day after SCI or Baclofen therapy reduced nNOS expression in α-motoneurons and suppressed symptoms of increased reflex activity. The results clearly show that increased nNOS expression in α-motoneurons after SCI may be pharmacologically modifiable with Baclofen or bolus dose of nNOS blocker. Copyright © 2015. Published by Elsevier Inc.

Are there endogenous stem cells in the spinal cord?

PubMed

Ferrucci, Michela; Ryskalin, Larisa; Busceti, Carla L; Gaglione, Anderson; Biagioni, Francesca; Fornai, Francesco

2017-12-01

Neural progenitor cells (NPC) represent the stem-like niche of the central nervous system that maintains a regenerative potential also in the adult life. Despite NPC in the brain are well documented, the presence of NPC in the spinal cord has been controversial for a long time. This is due to a scarce activity of NPC within spinal cord, which also makes difficult their identification. The present review recapitulates the main experimental studies, which provided evidence for the occurrence of NPC within spinal cord, with a special emphasis on spinal cord injury and amyotrophic lateral sclerosis. By using experimental models, here we analyse the site-specificity, the phenotype and the main triggers of spinal cord NPC. Moreover, data are reported on the effect of specific neurogenic stimuli on these spinal cord NPC in an effort to comprehend the endogenous neurogenic potential of this stem cell niche.

Engineering cord blood to improve engraftment after cord blood transplant

PubMed Central

Dave, Hema; Bollard, Catherine M.; Shpall, Elizabeth J.

2017-01-01

Umbilical cord blood transplant (CBT) has traditionally been associated with slower engraftment of neutrophils, delayed immune reconstitution and consequently higher risk of infections as compared with peripheral blood progenitor cell (PBPC) or bone marrow (BM) transplants. This is primarily due to low numbers of total nucleated cells (TNCs) and the naive nature of CB immune cells. The use of double unit CB transplant (DCBT) increases the total cell dose in the graft, but it still does not produce as rapid engraftment as seen with PBPC or even BM transplants. Herein, we discuss strategies to improve engraftment after CBT. We describe methods of (I) expansion of CB graft ex vivo to increase the total cell dose; and (II) enhancement of BM homing capability of CB progenitor cells; (III) ex vivo expansion of CB derived T cells for improving T cell function against viruses, tumors and protection from graft versus host disease (GVHD). With these novel approaches, engraftment after CBT is now reaching levels comparable to that of other graft types. PMID:28607915

Novel Radiobiological Gamma Index for Evaluation of 3-Dimensional Predicted Dose Distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sumida, Iori, E-mail: sumida@radonc.med.osaka-u.ac.jp; Yamaguchi, Hajime; Kizaki, Hisao

2015-07-15

Purpose: To propose a gamma index-based dose evaluation index that integrates the radiobiological parameters of tumor control (TCP) and normal tissue complication probabilities (NTCP). Methods and Materials: Fifteen prostate and head and neck (H&N) cancer patients received intensity modulated radiation therapy. Before treatment, patient-specific quality assurance was conducted via beam-by-beam analysis, and beam-specific dose error distributions were generated. The predicted 3-dimensional (3D) dose distribution was calculated by back-projection of relative dose error distribution per beam. A 3D gamma analysis of different organs (prostate: clinical [CTV] and planned target volumes [PTV], rectum, bladder, femoral heads; H&N: gross tumor volume [GTV], CTV,more » spinal cord, brain stem, both parotids) was performed using predicted and planned dose distributions under 2%/2 mm tolerance and physical gamma passing rate was calculated. TCP and NTCP values were calculated for voxels with physical gamma indices (PGI) >1. We propose a new radiobiological gamma index (RGI) to quantify the radiobiological effects of TCP and NTCP and calculate radiobiological gamma passing rates. Results: The mean RGI gamma passing rates for prostate cases were significantly different compared with those of PGI (P<.03–.001). The mean RGI gamma passing rates for H&N cases (except for GTV) were significantly different compared with those of PGI (P<.001). Differences in gamma passing rates between PGI and RGI were due to dose differences between the planned and predicted dose distributions. Radiobiological gamma distribution was visualized to identify areas where the dose was radiobiologically important. Conclusions: RGI was proposed to integrate radiobiological effects into PGI. This index would assist physicians and medical physicists not only in physical evaluations of treatment delivery accuracy, but also in clinical evaluations of predicted dose distribution.« less

Intrathecal Baclofen Dosing Regimens: A Retrospective Chart Review.

PubMed

Clearfield, Jacob S; Nelson, Mary Elizabeth S; McGuire, John; Rein, Lisa E; Tarima, Sergey

2016-08-01

To examine dosing patterns in patients receiving baclofen via intrathecal baclofen pumps to assess for common patterns by diagnosis, ambulation ability, and affected limbs distribution. This trial study included 25 patients with baclofen pumps selected from the 356 patients enrolled in our center's baclofen pump program. Selection was done by splitting all patients into diagnostic categories of stroke, multiple sclerosis, traumatic/anoxic brain injury, cerebral palsy, and spinal cord injury, and then, five patients were randomly selected from each diagnosis.A systematic chart review was then conducted for each patient from Jan 1, 2008, through September 16, 2013, to look at factors including mean daily dose at end of study, and among those implanted during the study mean initial stable dose and time to initial stable dose. Analysis of mean daily dose across diagnoses found significant differences, with brain injury, cerebral palsy, and spinal cord injury patients having higher doses while multiple sclerosis and stroke patients required lower doses. Nonambulatory patients strongly trended to have higher daily doses than ambulatory patients. Similar trends of mean initial stable dose being higher in a similar pattern as that of end mean daily dose were seen according to diagnoses and ambulatory status, although statistical significance could not be achieved with the small sample size. Significant differences in dosing were found between diagnoses and trended to differ by ambulatory status at the end of the study, and similar trends could be observed in achieving initial stable dose. © 2015 International Neuromodulation Society.

Breaking the Blood-Brain Barrier With Mannitol to Aid Stem Cell Therapeutics in the Chronic Stroke Brain.

PubMed

Tajiri, Naoki; Lee, Jea Young; Acosta, Sandra; Sanberg, Paul R; Borlongan, Cesar V

2016-01-01

Blood-brain barrier (BBB) permeabilizers, such as mannitol, can facilitate peripherally delivered stem cells to exert therapeutic benefits on the stroke brain. Although this BBB permeation-aided stem cell therapy has been demonstrated in the acute stage of stroke, such BBB permeation in the chronic stage of the disease remains to be examined. Adult Sprague-Dawley rats initially received sham surgery or experimental stroke via the 1-h middle cerebral artery occlusion (MCAo) model. At 1 month after the MCAo surgery, stroke animals were randomly assigned to receive human umbilical cord stem cells only (2 million viable cells), mannitol only (1.1 mol/L mannitol at 4°C), combined human umbilical cord stem cells (200,000 viable cells) and mannitol (1.1 mol/L mannitol at 4°C), and vehicle (phosphate-buffered saline) only. Stroke animals that received human umbilical cord blood cells alone or combined human umbilical cord stem cells and mannitol exhibited significantly improved motor performance and significantly better brain cell survival in the peri-infarct area compared to stroke animals that received vehicle or mannitol alone, with mannitol treatment reducing the stem cell dose necessary to afford functional outcomes. Enhanced neurogenesis in the subventricular zone accompanied the combined treatment of human umbilical cord stem cells and mannitol. We showed that BBB permeation facilitates the therapeutic effects of a low dose of peripherally transplanted stem cells to effectively cause functional improvement and increase neurogenesis in chronic stroke.

On the use of volumetric-modulated arc therapy for single-fraction thoracic vertebral metastases stereotactic body radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, Damodar, E-mail: damodar.pokhrel@uky.edu; Sood, Sumit; McClinton, Christopher

To retrospectively evaluate quality, efficiency, and delivery accuracy of volumetric-modulated arc therapy (VMAT) plans for single-fraction treatment of thoracic vertebral metastases using image-guided stereotactic body radiosurgery (SBRS) after RTOG 0631 dosimetric compliance criteria. After obtaining credentialing for MD Anderson spine phantom irradiation validation, 10 previously treated patients with thoracic vertebral metastases with noncoplanar hybrid arcs using 1 to 2 3D-conformal partial arcs plus 7 to 9 intensity-modulated radiation therapy beams were retrospectively re-optimized with VMAT using 3 full coplanar arcs. Tumors were located between T2 and T12. Contrast-enhanced T1/T2-weighted magnetic resonance images were coregistered with planning computed tomography and planningmore » target volumes (PTV) were between 14.4 and 230.1 cc (median = 38.0 cc). Prescription dose was 16 Gy in 1 fraction with 6 MV beams at Novalis-TX linear accelerator consisting of micro multileaf collimators. Each plan was assessed for target coverage using conformality index, the conformation number, the ratio of the volume receiving 50% of the prescription dose over PTV, R50%, homogeneity index (HI), and PTV-1600 coverage per RTOG 0631 requirements. Organs-at-risk doses were evaluated for maximum doses to spinal cord (D{sub 0.03} {sub cc}, D{sub 0.35} {sub cc}), partial spinal cord (D{sub 10%}), esophagus (D{sub 0.03} {sub cc} and D{sub 5} {sub cc}), heart (D{sub 0.03} {sub cc} and D{sub 15} {sub cc}), and lung (V{sub 5}, V{sub 10}, and maximum dose to 1000 cc of lung). Dose delivery efficiency and accuracy of each VMAT-SBRS plan were assessed using quality assurance (QA) plan on MapCHECK device. Total beam-on time was recorded during QA procedure, and a clinical gamma index (2%/2 mm and 3%/3 mm) was used to compare agreement between planned and measured doses. All 10 VMAT-SBRS plans met RTOG 0631 dosimetric requirements for PTV coverage. The plans demonstrated highly conformal and homogenous coverage of the vertebral PTV with mean HI, conformality index, conformation number, and R{sub 50%} values of 0.13 ± 0.03 (range: 0.09 to 0.18), 1.03 ± 0.04 (range: 0.98 to 1.09), 0.81 ± 0.06 (range: 0.72 to 0.89), and 4.2 ± 0.94 (range: 2.7 to 5.4), respectively. All 10 patients met protocol guidelines with maximum dose to spinal cord (average: 8.83 ± 1.9 Gy, range: 5.9 to 10.9 Gy); dose to 0.35 cc of spinal cord (average: 7.62 ± 1.7 Gy, range: 5.4 to 9.6 Gy); and dose to 10% of partial spinal cord (average 6.31 ± 1.5 Gy, range: 3.5 to 8.5 Gy) less than 14, 10, and 10 Gy, respectively. For all 10 patients, the maximum dose to esophagus (average: 9.41 ± 4.3 Gy, range: 1.5 to 14.9 Gy) and dose to 5 cc of esophagus (average: 7.43 ± 3.8 Gy, range: 1.1 to 11.8 Gy) were kept less than protocol requirements 16 Gy and 11.9 Gy, respectively. In a similar manner, all 10 patients met protocol compliance criteria with maximum dose to heart (average: 4.62 ± 3.5 Gy, range: 1.3 to 10.2 Gy) and dose to 15 cc of heart (average: 2.23 ± 1.8 Gy, range: 0.3 to 5.6 Gy) less than 22 and 16 Gy, respectively. The dose to the lung was retained much lower than protocol guidelines for all 10 patients. The total number of monitor units was, on average, 6919 ± 1187. The average beam-on time was 11.5 ± 2.0 minutes. The VMAT plans demonstrated dose delivery accuracy of 95.8 ± 0.7%, on average, for clinical gamma passing rate with 2%/2 mm criteria and 98.3 ± 0.8%, on average, with 3%/3 mm criteria. All VMAT-SBRS plans were considered clinically acceptable per RTOG 0631 dosimetric compliance criteria. VMAT planning provided highly conformal and homogenous dose distributions for the lower-dose vertebral PTV and the spinal cord as well as organs-at-risk such as esophagus, heart, and lung. Higher QA pass rates and shorter beam-on time suggest that VMAT-SBRS is a clinically feasible, fast, and effective treatment option for patients with thoracic vertebral metastases.« less

Involvement of the Spinal Cord in Mitochondrial Disorders.

PubMed

Finsterer, Josef; Zarrouk-Mahjoub, Sinda

2018-01-01

This review aims at summarising and discussing the current status concerning the clinical presentation, pathogenesis, diagnosis, and treatment of spinal cord affection in mitochondrial disorders (MIDs). A literature search using the database Pubmed was carried out by application of appropriate search terms and their combinations. Involvement of the spinal cord in MIDs is more frequent than anticipated. It occurs in specific and non-specific MIDs. Among the specific MIDs it has been most frequently described in LBSL, LS, MERRF, KSS, IOSCA, MIRAS, and PCH and only rarely in MELAS, CPEO, and LHON. Clinically, spinal cord involvement manifests as monoparesis, paraparesis, quadruparesis, sensory disturbances, hypotonia, spasticity, urinary or defecation dysfunction, spinal column deformities, or as transverse syndrome. Diagnosing spinal cord involvement in MIDs requires a thoroughly taken history, clinical exam, and imaging studies. Additionally, transcranial magnetic stimulation, somato-sensory-evoked potentials, and cerebro-spinal fluid can be supportive. Treatment is generally not at variance compared to the underlying MID but occasionally surgical stabilisation of the spinal column may be necessary. It is concluded that spinal cord involvement in MIDs is more frequent than anticipated but may be missed if cerebral manifestations prevail. Spinal cord involvement in MIDs may strongly determine the mobility of these patients.

Brain necrosis after fractionated radiation therapy: Is the halftime for repair longer than we thought?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bender, Edward T.

Purpose: To derive a radiobiological model that enables the estimation of brain necrosis and spinal cord myelopathy rates for a variety of fractionation schemes, and to compare repair effects between brain and spinal cord. Methods: Sigmoidal dose response relationships for brain radiation necrosis and spinal cord myelopathy are derived from clinical data using nonlinear regression. Three different repair models are considered and the repair halftimes are included as regression parameters. Results: For radiation necrosis, a repair halftime of 38.1 (range 6.9-76) h is found with monoexponential repair, while for spinal cord myelopathy, a repair halftime of 4.1 (range 0-8) hmore » is found. The best-fit alpha beta ratio is 0.96 (range 0.24-1.73)Conclusions: A radiobiological model that includes repair corrections can describe the clinical data for a variety of fraction sizes, fractionation schedules, and total doses. Modeling suggests a relatively long repair halftime for brain necrosis. This study suggests that the repair halftime for late radiation effects in the brain may be longer than is currently thought. If confirmed in future studies, this may lead to a re-evaluation of radiation fractionation schedules for some CNS diseases, particularly for those diseases where fractionated stereotactic radiation therapy is used.« less

Evaluation of the impact of banking umbilical cord blood units with high cell dose for ethnically diverse patients.

PubMed

Stritesky, Gretta; Wadsworth, Kimberly; Duffy, Merry; Buck, Kelly; Dehn, Jason

2018-02-01

Umbilical cord blood units provide an important stem cell source for transplantation, particularly for patients of ethnic diversity who may not have suitably matched available, adult-unrelated donors. However, with the cost of cord blood unit acquisition from public banks significantly higher than that for adult-unrelated donors, attention is focused on decreasing cost yet still providing cord blood units to patients in need. Historical practices of banking units with low total nucleated cell counts, including units with approximately 90 × 10 7 total nucleated cells, indicates that most banked cord blood units have much lower total nucleated cell counts than are required for transplant. The objective of this study was to determine the impact on the ability to identify suitable cord blood units for transplantation if the minimum total nucleated cell count for banking were increased from 90 × 10 7 to 124 or 149 × 10 7 . We analyzed ethnically diverse patients (median age, 3 years) who underwent transplantation of a single cord blood unit in 2005 to 2016. A cord blood unit search was evaluated to identify units with equal or greater human leukocyte antigen matching and a greater total nucleated cell count than that of the transplanted cord blood unit (the replacement cord blood unit). If the minimum total nucleated cell count for banking increased to 124 or 149 × 10 7 , then from 75 to 80% of patients would still have at least 1 replacement cord blood unit in the current (2016) cord blood unit inventory. The best replacement cord blood units were often found among cords with the same ethnic background as the patient. The current data suggest that, if the minimum total nucleated cell count were increased for banking, then it would likely lead to an inventory of more desirable cord blood units while having minimal impact on the identification of suitable cord blood units for transplantation. © 2017 AABB.

Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeLaney, Thomas F.; Liebsch, Norbert J.; Pedlow, Francis X.

Purpose: Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of {>=}66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. Methods and Materials: Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to grossmore » disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. Results: A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. Conclusions: Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.« less

Carbon Ion Irradiation of the Rat Spinal Cord: Dependence of the Relative Biological Effectiveness on Linear Energy Transfer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saager, Maria, E-mail: m.saager@dkfz.de; Department of Medical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg; Glowa, Christin

2014-09-01

Purpose: To measure the relative biological effectiveness (RBE) of carbon ions in the rat spinal cord as a function of linear energy transfer (LET). Methods and Materials: As an extension of a previous study, the cervical spinal cord of rats was irradiated with single doses of carbon ions at 6 positions of a 6-cm spread-out Bragg peak (16-99 keV/μm). The TD{sub 50} values (dose at 50% complication probability) were determined according to dose-response curves for the development of paresis grade 2 within an observation time of 300 days. The RBEs were calculated using TD{sub 50} for photons of our previous study. Results:more » Minimum latency time was found to be dose-dependent, but not significantly LET-dependent. The TD{sub 50} values for the onset of paresis grade 2 within 300 days were 19.5 ± 0.4 Gy (16 keV/μm), 18.4 ± 0.4 Gy (21 keV/μm), 17.7 ± 0.3 Gy (36 keV/μm), 16.1 ± 1.2 Gy (45 keV/μm), 14.6 ± 0.5 Gy (66 keV/μm), and 14.8 ± 0.5 Gy (99 keV/μm). The corresponding RBEs increased from 1.26 ± 0.05 (16 keV/μm) up to 1.68 ± 0.08 at 66 keV/μm. Unexpectedly, the RBE at 99 keV/μm was comparable to that at 66 keV/μm. Conclusions: The data suggest a linear relation between RBE and LET at high doses for late effects in the spinal cord. Together with additional data from ongoing fractionated irradiation experiments, these data will provide an extended database to systematically benchmark RBE models for further improvements of carbon ion treatment planning.« less

Low dose Photofrin PDT for recurrent in-situ squamous cell tumors of the head and neck

NASA Astrophysics Data System (ADS)

Allison, R. R.; Austerlitz, C.; Sheng, C.; Mota, H.; Brodish, B.; Camnitz, P.; Sibata, C. H.

2009-06-01

Multifocal recurrence of in-situ squamous cell cancer of the oral cavity, pharynx and vocal cord following surgical failure can be a therapeutic dilemma. Salvage surgery or radiation may be an option but morbidity can be significant. We evaluated the potential role of low dose Photofrin (1.2mg/Kg) Photodynamic Therapy for this cohort of patients. A total of 25 patients with multifocal recurrent in-situ squamous cell cancer of the oral cavity, pharynx and vocal cord who had failed local resection, and where additional surgery or radiation therapy would likely result in permanent morbidity, were offered Photodynamic Therapy. PDT consisted of off label infusion of Photofrin (1.2mg/kg) followed 48 hours later by illumination at 630nm employing a light diffuser (300J) and/or microlens (150Jcm2). All patients completed their prescribed PDT and no patient has been lost to follow up (minimum 1 year). No photosensitivity reactions were noted. No significant morbidity was seen. All patients were able to maintain oral nutrition. Procedure related pain was well controlled by one week of oral narcotics. At one month post PDT all patients were biopsy negative in the treatment region and no failures within the treatment region have been noted. No fibrosis or permanent PDT morbidity has been seen with follow up to three years. Vocal cord and voice function were excellent. Three patients developed new regions of in-situ disease outside the PDT fields, two underwent additional PDT and one had laser resection. Low dose Photofrin PDT offers excellent palliation and durable local control of recurrent in-situ squamous cell cancers of the oral cavity, pharynx and true cords. This is a well tolerated therapy. Low dose Photofrin appears to improve selectivity and minimize normal tissue injury. It should be tested in a larger patient population.

Bone architecture adaptations after spinal cord injury: impact of long-term vibration of a constrained lower limb

PubMed Central

Dudley-Javoroski, S.; Petrie, M. A.; McHenry, C. L.; Amelon, R. E.; Saha, P. K.

2015-01-01

Summary This study examined the effect of a controlled dose of vibration upon bone density and architecture in people with spinal cord injury (who eventually develop severe osteoporosis). Very sensitive computed tomography (CT) imaging revealed no effect of vibration after 12 months, but other doses of vibration may still be useful to test. Introduction The purposes of this report were to determine the effect of a controlled dose of vibratory mechanical input upon individual trabecular bone regions in people with chronic spinal cord injury (SCI) and to examine the longitudinal bone architecture changes in both the acute and chronic state of SCI. Methods Participants with SCI received unilateral vibration of the constrained lower limb segment while sitting in a wheelchair (0.6g, 30 Hz, 20 min, three times weekly). The opposite limb served as a control. Bone mineral density (BMD) and trabecular micro-architecture were measured with high-resolution multi-detector CT. For comparison, one participant was studied from the acute (0.14 year) to the chronic state (2.7 years). Results Twelve months of vibration training did not yield adaptations of BMD or trabecular micro-architecture for the distal tibia or the distal femur. BMD and trabecular network length continued to decline at several distal femur sub-regions, contrary to previous reports suggesting a “steady state” of bone in chronic SCI. In the participant followed from acute to chronic SCI, BMD and architecture decline varied systematically across different anatomical segments of the tibia and femur. Conclusions This study supports that vibration training, using this study’s dose parameters, is not an effective antiosteoporosis intervention for people with chronic SCI. Using a high-spatial-resolution CT methodology and segmental analysis, we illustrate novel longitudinal changes in bone that occur after spinal cord injury. PMID:26395887

Evaluation of purinergic mechanism for the treatment of voiding dysfunction: a study in conscious spinal cord-injured rats.

PubMed

Lu, Shing-Hwa; Groat, William C de; Lin, Alex T L; Chen, Kuang-Kuo; Chang, Luke S

2007-10-01

To investigate the effect of a selective P2X(3-)P2X(2/3) purinergic receptor antagonist (a-317491) on detrusor hyperreflexia in conscious chronic spinal cord-injured female rats. Six chronic spinal cord-transected female Sprague-Dawley rats (290-336 g) were used in this study. Spinal transection at the T8-T9 segmental level was performed using aseptic techniques under halothane anesthesia. Fourteen to 16 weeks after spinal transection, A-317491, a selective P2X(3-)P2X(2/3) purinergic receptor antagonist, was administered intravenously in cystometry studies at increasing doses of 0.03, 0.1, 0.3, 1, 3, 10 and 30 micromol/kg at 40-50 minute intervals. Cystometrograms (CMGs) were performed before and after the administration of each dose of the drug. The continuous filling of CMGs revealed a large number of small-amplitude (> 8 cmH(2)O), non-voiding contractions (NVCs) (average, 9.7 per voiding cycle) preceding voiding contractions (mean amplitude, 31 cmH(2)O; duration, 2.5 minutes), which occurred at an interval of 539 seconds and at a pressure threshold of 5.7 cmH(2)O. When tested in a range of doses (0.03-30 micromol/kg, intravenous), A-317491 in doses between 1 and 30 micromol/kg significantly (p < 0.05) increased the interval between voids by 25%, reduced the number of NVCs by 42-62%, and increased the pressure threshold for voiding by 53-73%, but did not change the amplitude of the duration of the voiding contractions. The effects of the drug were apparent within 10 minutes following administration. These results indicate that purinergic mechanisms, presumably involving P2X(3) or P2X(2/3) receptors on bladder C-fiber afferent nerves, play an important role in the detrusor hyperreflexia that occurs after spinal cord injury in rats.

Dose-mass inverse optimization for minimally moving thoracic lesions

NASA Astrophysics Data System (ADS)

Mihaylov, I. B.; Moros, E. G.

2015-05-01

In the past decade, several different radiotherapy treatment plan evaluation and optimization schemes have been proposed as viable approaches, aiming for dose escalation or an increase of healthy tissue sparing. In particular, it has been argued that dose-mass plan evaluation and treatment plan optimization might be viable alternatives to the standard of care, which is realized through dose-volume evaluation and optimization. The purpose of this investigation is to apply dose-mass optimization to a cohort of lung cancer patients and compare the achievable healthy tissue sparing to that one achievable through dose-volume optimization. Fourteen non-small cell lung cancer (NSCLC) patient plans were studied retrospectively. The range of tumor motion was less than 0.5 cm and motion management in the treatment planning process was not considered. For each case, dose-volume (DV)-based and dose-mass (DM)-based optimization was performed. Nine-field step-and-shoot IMRT was used, with all of the optimization parameters kept the same between DV and DM optimizations. Commonly used dosimetric indices (DIs) such as dose to 1% the spinal cord volume, dose to 50% of the esophageal volume, and doses to 20 and 30% of healthy lung volumes were used for cross-comparison. Similarly, mass-based indices (MIs), such as doses to 20 and 30% of healthy lung masses, 1% of spinal cord mass, and 33% of heart mass, were also tallied. Statistical equivalence tests were performed to quantify the findings for the entire patient cohort. Both DV and DM plans for each case were normalized such that 95% of the planning target volume received the prescribed dose. DM optimization resulted in more organs at risk (OAR) sparing than DV optimization. The average sparing of cord, heart, and esophagus was 23, 4, and 6%, respectively. For the majority of the DIs, DM optimization resulted in lower lung doses. On average, the doses to 20 and 30% of healthy lung were lower by approximately 3 and 4%, whereas lung volumes receiving 2000 and 3000 cGy were lower by 3 and 2%, respectively. The behavior of MIs was very similar. The statistical analyses of the results again indicated better healthy anatomical structure sparing with DM optimization. The presented findings indicate that dose-mass-based optimization results in statistically significant OAR sparing as compared to dose-volume-based optimization for NSCLC. However, the sparing is case-dependent and it is not observed for all tallied dosimetric endpoints.

Extracellular matrix-derived hydrogels for dental stem cell delivery.

PubMed

Viswanath, Aiswarya; Vanacker, Julie; Germain, Loïc; Leprince, Julian G; Diogenes, Anibal; Shakesheff, Kevin M; White, Lisa J; des Rieux, Anne

2017-01-01

Decellularized mammalian extracellular matrices (ECM) have been widely accepted as an ideal substrate for repair and remodelling of numerous tissues in clinical and pre-clinical studies. Recent studies have demonstrated the ability of ECM scaffolds derived from site-specific homologous tissues to direct cell differentiation. The present study investigated the suitability of hydrogels derived from different source tissues: bone, spinal cord and dentine, as suitable carriers to deliver human apical papilla derived mesenchymal stem cells (SCAP) for spinal cord regeneration. Bone, spinal cord, and dentine ECM hydrogels exhibited distinct structural, mechanical, and biological characteristics. All three hydrogels supported SCAP viability and proliferation. However, only spinal cord and bone derived hydrogels promoted the expression of neural lineage markers. The specific environment of ECM scaffolds significantly affected the differentiation of SCAP to a neural lineage, with stronger responses observed with spinal cord ECM hydrogels, suggesting that site-specific tissues are more likely to facilitate optimal stem cell behavior for constructive spinal cord regeneration. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 319-328, 2017. © 2016 Wiley Periodicals, Inc.

Spine Radiosurgery: A Dosimetric Analysis in 124 Patients Who Received 18 Gy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schipani, Stefano; Wen, Winston; Jin, Jain-Yue

2012-12-01

Purpose: To define the safely tolerated doses to organs at risk (OARs) adjacent to the target volume (TV) of spine radiosurgery (SRS) with 18-Gy in a single fraction. Methods and Materials: A total of 124 patient cases with 165 spine metastases were reviewed. An 18-Gy single-fraction regimen was prescribed to the 90% isodose line encompassing the TV. A constraint of 10 Gy to 10% of the spinal cord outlined 6 mm above and below the TV was used. Dosimetric data to OARs were analyzed. Results: A total of 124 patients (100%) were followed-up, and median follow-up time was 7 monthsmore » (1-50 months). Symptoms and local control were achieved in 114 patients (92%). Acute Radiation Therapy Oncology Group (RTOG) grade 1 oral mucositis occurred in 11 of 11 (100%) patients at risk for oropharyngeal toxicity after cervical spine treatment. There were no RTOG grade 2-4 acute or late complications. Median TV was 43.2 cc (5.3-175.4 cc) and 90% of the TV received median dose of 19 Gy (17-19.8 Gy). Median (range) of spinal cord maximum dose (Dmax), dose to spinal cord 0.35 cc (Dsc0.35), and cord volume receiving 10 Gy (Vsc10) were 13.8 Gy (5.4-21 Gy), 8.9 Gy (2.6-11.4 Gy) and 0.33 cc (0-1.6 cc), respectively. Other OARs were evaluated when in proximity to the TV. Esophagus (n=58), trachea (n=28), oropharynx (n=11), and kidneys (n=34) received median (range) V10 and V15 of 3.1 cc (0-5.8 cc) and 1.2 cc (0-2.9 cc), 2.8 cc (0-4.9 cc), and 0.8 cc (0-2.1 cc), 3.4 cc (0-6.2 cc) and 1.6 cc (0-3.2 cc), 0.3 cc (0-0.8 cc) and 0.08 cc (0-0.1 cc), respectively. Conclusions: Cord Dmax of 14 Gy and D0.35 of 10 Gy are safe dose constraints for 18-Gy single-fraction SRS. Esophagus V10 of 3 cc and V15 of 1 cc, trachea V10 of 3 cc, and V15 of 1 cc, oropharynx V10 of 3.5 cc and V15 of 1.5 cc, kidney V10 of 0.3 cc, and V15 of 0.1 cc are planning guidelines when these OARs are in proximity to the TV.« less

Functional characterization of mouse spinal cord infiltrating CD8+ lymphocytes

PubMed Central

Deb, Chandra; Howe, Charles L

2011-01-01

Understanding the immunopathogenesis of neuroimmunological diseases of the CNS requires a robust method for isolating and characterizing the immune effector cells that infiltrate the spinal cord in animal models. We have developed a simple and rapid isolation method that produces high yields of spinal cord infiltrating leukocytes from a single demyelinated spinal cord and which maintains high surface expression of key immunophenotyping antigens. Using this method and the Theiler’s virus model of chronic demyelination, we report the presence of spinal cord infiltrating acute effector CD8+ lymphocytes that are CD45hiCD44loCD62L− and a population of spinal cord infiltrating target effector memory CD8+ lymphocytes that are CD45hiCD44hiCD62L−. These cells respond robustly to ex vivo stimulation by producing interferon γ but do not exhibit specificity for Theiler’s virus in a cytotoxicity assay. We conclude that target-derived lymphocytes in a mouse model of chronic spinal cord demyelination may have unique functional specificities. PMID:19596449

Limitations of the planning organ at risk volume (PRV) concept.

PubMed

Stroom, Joep C; Heijmen, Ben J M

2006-09-01

Previously, we determined a planning target volume (PTV) margin recipe for geometrical errors in radiotherapy equal to M(T) = 2 Sigma + 0.7 sigma, with Sigma and sigma standard deviations describing systematic and random errors, respectively. In this paper, we investigated margins for organs at risk (OAR), yielding the so-called planning organ at risk volume (PRV). For critical organs with a maximum dose (D(max)) constraint, we calculated margins such that D(max) in the PRV is equal to the motion averaged D(max) in the (moving) clinical target volume (CTV). We studied margins for the spinal cord in 10 head-and-neck cases and 10 lung cases, each with two different clinical plans. For critical organs with a dose-volume constraint, we also investigated whether a margin recipe was feasible. For the 20 spinal cords considered, the average margin recipe found was: M(R) = 1.6 Sigma + 0.2 sigma with variations for systematic and random errors of 1.2 Sigma to 1.8 Sigma and -0.2 sigma to 0.6 sigma, respectively. The variations were due to differences in shape and position of the dose distributions with respect to the cords. The recipe also depended significantly on the volume definition of D(max). For critical organs with a dose-volume constraint, the PRV concept appears even less useful because a margin around, e.g., the rectum changes the volume in such a manner that dose-volume constraints stop making sense. The concept of PRV for planning of radiotherapy is of limited use. Therefore, alternative ways should be developed to include geometric uncertainties of OARs in radiotherapy planning.

Synergistic anti-hyperalgesia of electroacupuncture and low dose of celecoxib in monoarthritic rats: involvement of the cyclooxygenase activity in the spinal cord.

PubMed

Mi, Wen-Li; Mao-Ying, Qi-Liang; Liu, Qiong; Wang, Xiao-Wei; Wang, Yan-Qing; Wu, Gen-Cheng

2008-09-30

Electroacupuncture (EA) can effectively control the exaggerated pain in humans with inflammatory disease and animals with experimental inflammatory pain. However, there have been few investigations on the effect of co-administration of EA and analgesics and the underlying synergistic mechanism. Using behavioral test, RT-PCR analysis, enzyme immunoassay (EIA) and enzyme-linked immunosorbent assay (ELISA), the present study demonstrated that (1) Unilateral intra-articular injection of complete Freund's adjuvant (CFA) produced a constant hyperalgesia and an up-regulation of the prostaglandin E(2) (PGE(2)) level as well as the tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 levels in the spinal cord; (2) Celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2), at a dose of 2, 10, and 20 mg/kg (twice daily, p.o.), presented a dose-dependent anti-hyperalgesic effect; (3) Repeated EA stimulation of ipsilateral 'Huan-Tiao' (GB30) and 'Yang-Ling-Quan' (GB34) acupoints significantly suppressed CFA-induced hyperalgesia, and markedly inhibited the CFA-induced increase of the level of PGE(2) as well as IL-1beta, IL-6, and TNF-alpha in the spinal cord; (4) EA combined with low dose of celecoxib (2 mg/kg, twice daily, p.o.) greatly enhanced the anti-hyperalgesic effects of EA, with a synergistic reversing effect on CFA-induced up-regulation of spinal PGE(2), but not on the IL-1beta, IL-6, or TNF-alpha. These data indicated that repeated EA combined with low dose of celecoxib produced synergistic anti-hyperalgesic effect in the CFA-induced monoarthritic rats, which could be made possible by regulating the activity of spinal COX, hence the spinal PGE(2) level. Thus, this combination may provide an effective strategy for pain management.

Transcript analysis of laser capture microdissected white matter astrocytes and higher phenol sulfotransferase 1A1 expression during autoimmune neuroinflammation.

PubMed

Guillot, Flora; Garcia, Alexandra; Salou, Marion; Brouard, Sophie; Laplaud, David A; Nicot, Arnaud B

2015-07-04

Astrocytes, the most abundant cell population in mammal central nervous system (CNS), contribute to a variety of functions including homeostasis, metabolism, synapse formation, and myelin maintenance. White matter (WM) reactive astrocytes are important players in amplifying autoimmune demyelination and may exhibit different changes in transcriptome profiles and cell function in a disease-context dependent manner. However, their transcriptomic profile has not yet been defined because they are difficult to purify, compared to gray matter astrocytes. Here, we isolated WM astrocytes by laser capture microdissection (LCM) in a murine model of multiple sclerosis to better define their molecular profile focusing on selected genes related to inflammation. Based on previous data indicating anti-inflammatory effects of estrogen only at high nanomolar doses, we also examined mRNA expression for enzymes involved in steroid inactivation. Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL6 mice with MOG35-55 immunization. Fluorescence activated cell sorting (FACS) analysis of a portion of individual spinal cords at peak disease was used to assess the composition of immune cell infiltrates. Using custom Taqman low-density-array (TLDA), we analyzed mRNA expression of 40 selected genes from immuno-labeled laser-microdissected WM astrocytes from lumbar spinal cord sections of EAE and control mice. Immunohistochemistry and double immunofluorescence on control and EAE mouse spinal cord sections were used to confirm protein expression in astrocytes. The spinal cords of EAE mice were infiltrated mostly by effector/memory T CD4+ cells and macrophages. TLDA-based profiling of LCM-astrocytes identified EAE-induced gene expression of cytokines and chemokines as well as inflammatory mediators recently described in gray matter reactive astrocytes in other murine CNS disease models. Strikingly, SULT1A1, but not other members of the sulfotransferase family, was expressed in WM spinal cord astrocytes. Moreover, its expression was further increased in EAE. Immunohistochemistry on spinal cord tissues confirmed preferential expression of this enzyme in WM astrocytic processes but not in gray matter astrocytes. We described here for the first time the mRNA expression of several genes in WM astrocytes in a mouse model of multiple sclerosis. Besides expected pro-inflammatory chemokines and specific inflammatory mediators increased during EAE, we evidenced relative high astrocytic expression of the cytoplasmic enzyme SULT1A1. As the sulfonation activity of SULT1A1 inactivates estradiol among other phenolic substrates, its high astrocytic expression may account for the relative resistance of this cell population to the anti-neuroinflammatory effects of estradiol. Blocking the activity of this enzyme during neuroinflammation may thus help the injured CNS to maintain the anti-inflammatory activity of endogenous estrogens or limit the dose of estrogen co-regimens for therapeutical purposes.

Clinical and imaging features of spinal cord type of neuro Behçet disease: A case report and systematic review.

PubMed

Liu, Hui-Miao; Dong, Ci; Zhang, Yong-Zhi; Tian, Ya-Yun; Chen, Hong-Xu; Zhang, Sai; Li, Na; Gu, Ping

2017-10-01

To investigate the clinical and MRI characteristics of spinal cord nerve Behçet's disease. One patient with spinal cord nerve Behçet's disease was admitted to our hospital at October 20, 2015. Spinal cord nerve Behçet's disease. Retrospective analysis was performed on such case as well as 16 cases of spinal cord nerve Behçet's disease reported in China or abroad. Seventeen cases of spinal cord type of neuro Behçet's disease include 13 men and 4 women, with an average age of onset of 34.8 years old. The mean time from Behçet's disease symptoms to spinal cord involvement were 10.8 years. The initial symptom in one case was spinal cord injury, and another 4 cases had a recurrence course. The most common performance of spinal cord injury was sensory disturbance (82.4%), following by weakness (76.5%), sphincter or sexual dysfunction (58.8%), and pain in back, backside of neck or lower chest (29.4%). The number of cells was slightly increased or the protein level was increased in cerebrospinal fluid test. And the water channel protein antibody and oligoclonal band of serum levels were all negative. The spinal cord injury involved more than 3 vertebral bodies in 10 cases, and involved more than half of spinal cord in sagittal plane in 8 cases. In acute stage, shock therapy with large dose of glucocorticoid was generally applied both in China and abroad. The clinical features of spinal cord nerve Behçet's disease were various, making it easily misdiagnosed. Longitudinal extensive transverse myelitis performs as a characteristic manifestation.

TEMPORAL NEUROTRANSMITTER CONDITIONING RESTORES THE FUNCTIONAL ACTIVITY OF ADULT SPINAL-CORD NEURONS IN LONG-TERM CULTURE

PubMed Central

Das, Mainak; Bhargava, Neelima; Bhalkikar, Abhijeet; Kang, Jung Fong; Hickman, James J

2008-01-01

The ability to culture functional adult mammalian spinal-cord neurons represents an important step in the understanding and treatment of a spectrum of neurological disorders including spinal cord injury. Previously, the limited functional recovery of these cells, as characterized by a diminished ability to initiate action potentials and to exhibit repetitive firing patterns, has arisen as a major impediment to their physiological relevance. In this report we demonstrate that single temporal doses of the neurotransmitters serotonin, glutamate (N-acetyl-DL-glutamic acid) and acetylcholine-chloride leads to the full electrophysiological functional recovery of adult mammalian spinal-cord neurons, when they are cultured under defined serum-free conditions. Approximately 60% of the neurons treated regained their electrophysiological signature, often firing single, double and, most importantly, multiple action potentials. PMID:18005959

Automatic contour propagation using deformable image registration to determine delivered dose to spinal cord in head-and-neck cancer radiotherapy.

PubMed

Yeap, P L; Noble, D J; Harrison, K; Bates, A M; Burnet, N G; Jena, R; Romanchikova, M; Sutcliffe, M P F; Thomas, S J; Barnett, G C; Benson, R J; Jefferies, S J; Parker, M A

2017-07-12

To determine delivered dose to the spinal cord, a technique has been developed to propagate manual contours from kilovoltage computed-tomography (kVCT) scans for treatment planning to megavoltage computed-tomography (MVCT) guidance scans. The technique uses the Elastix software to perform intensity-based deformable image registration of each kVCT scan to the associated MVCT scans. The registration transform is then applied to contours of the spinal cord drawn manually on the kVCT scan, to obtain contour positions on the MVCT scans. Different registration strategies have been investigated, with performance evaluated by comparing the resulting auto-contours with manual contours, drawn by oncologists. The comparison metrics include the conformity index (CI), and the distance between centres (DBC). With optimised registration, auto-contours generally agree well with manual contours. Considering all 30 MVCT scans for each of three patients, the median CI is [Formula: see text], and the median DBC is ([Formula: see text]) mm. An intra-observer comparison for the same scans gives a median CI of [Formula: see text] and a DBC of ([Formula: see text]) mm. Good levels of conformity are also obtained when auto-contours are compared with manual contours from one observer for a single MVCT scan for each of 30 patients, and when they are compared with manual contours from six observers for two MVCT scans for each of three patients. Using the auto-contours to estimate organ position at treatment time, a preliminary study of 33 patients who underwent radiotherapy for head-and-neck cancers indicates good agreement between planned and delivered dose to the spinal cord.

Automatic contour propagation using deformable image registration to determine delivered dose to spinal cord in head-and-neck cancer radiotherapy

NASA Astrophysics Data System (ADS)

Yeap, P. L.; Noble, D. J.; Harrison, K.; Bates, A. M.; Burnet, N. G.; Jena, R.; Romanchikova, M.; Sutcliffe, M. P. F.; Thomas, S. J.; Barnett, G. C.; Benson, R. J.; Jefferies, S. J.; Parker, M. A.

2017-08-01

To determine delivered dose to the spinal cord, a technique has been developed to propagate manual contours from kilovoltage computed-tomography (kVCT) scans for treatment planning to megavoltage computed-tomography (MVCT) guidance scans. The technique uses the Elastix software to perform intensity-based deformable image registration of each kVCT scan to the associated MVCT scans. The registration transform is then applied to contours of the spinal cord drawn manually on the kVCT scan, to obtain contour positions on the MVCT scans. Different registration strategies have been investigated, with performance evaluated by comparing the resulting auto-contours with manual contours, drawn by oncologists. The comparison metrics include the conformity index (CI), and the distance between centres (DBC). With optimised registration, auto-contours generally agree well with manual contours. Considering all 30 MVCT scans for each of three patients, the median CI is 0.759 +/- 0.003 , and the median DBC is (0.87 +/- 0.01 ) mm. An intra-observer comparison for the same scans gives a median CI of 0.820 +/- 0.002 and a DBC of (0.64 +/- 0.01 ) mm. Good levels of conformity are also obtained when auto-contours are compared with manual contours from one observer for a single MVCT scan for each of 30 patients, and when they are compared with manual contours from six observers for two MVCT scans for each of three patients. Using the auto-contours to estimate organ position at treatment time, a preliminary study of 33 patients who underwent radiotherapy for head-and-neck cancers indicates good agreement between planned and delivered dose to the spinal cord.

Fluoxetine and vitamin C synergistically inhibits blood-spinal cord barrier disruption and improves functional recovery after spinal cord injury.

PubMed

Lee, Jee Y; Choi, Hae Y; Yune, Tae Y

2016-10-01

Recently we reported that fluoxetine (10 mg/kg) improves functional recovery by attenuating blood spinal cord barrier (BSCB) disruption after spinal cord injury (SCI). Here we investigated whether a low-dose of fluoxetine (1 mg/kg) and vitamin C (100 mg/kg), separately not possessing any protective effect, prevents BSCB disruption and improves functional recovery when combined. After a moderate contusion injury at T9 in rat, a low-dose of fluoxetine and vitamin C, or the combination of both was administered intraperitoneally immediately after SCI and further treated once a day for 14 d. Co-treatment with fluoxetine and vitamin C significantly attenuated BSCB permeability at 1 d after SCI. When only fluoxetine or vitamin C was treated after injury, however, there was no effect on BSCB disruption. Co-treatment with fluoxetine and vitamin C also significantly inhibited the expression and activation of MMP-9 at 8 h and 1 d after injury, respectively, and the infiltration of neutrophils (at 1 d) and macrophages (at 5 d) and the expression of inflammatory mediators (at 2 h, 6 h, 8 h or 24 h after injury) were significantly inhibited by co-treatment with fluoxetine and vitamin C. Furthermore, the combination of fluoxetine and vitamin C attenuated apoptotic cell death at 1 d and 5 d and improved locomotor function at 5 weeks after SCI. These results demonstrate the synergistic effect combination of low-dose fluoxetine and vitamin C on BSCB disruption after SCI and furthermore support the effectiveness of the combination treatment regimen for the management of acute SCI. Copyright © 2016 Elsevier Ltd. All rights reserved.

ARTERIAL HYPERTENSION AND IRRADIATION DAMAGE TO THE NERVOUS SYSTEM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asscher, A.W.; Anson, S.G.

1962-12-29

On the basis of previous studies it appeared that irradiation damage to the nervous system might be more severe and more easily produced in hypertensive than in normotensive subjects. This hypothesis was investigated by studying the frequency of neurological complications and vascular lesions in the spinal cord after x irradiation of the cord in hypertensive and normotensive rats. Two weeks before irradiation of the spinal cord, a clip was applied to the right renal artery of the animals to produce hypertension. Single doses of 1500, 2000, or 3000 r were administered to the spinal cord in the cervical and uppermore » thoracic region of hypertensive rats (systolic blood pressure higher than 145 mm Hg) and normotensive rats. After 1500 r to spinal cord, no abnormalities were noted in the normotensive controls during the period of observation. Some hypertensive animaIs showed transient abnormalities of gait, and during the following week died suddenly. Those remaining died unexpectedly 35-259 days after irradiation without apparent preceding neurological manifestations, although acute vascular lesions were found in the irradiated regions of the spinal cord. The normotensive controls of the 2000-r group showed no abnormalities of gait or of tail sensation, but the hypertensive rats died 67-243 days after irradiation, and ntaxic episodes preceding these unexpected deaths in one animal. Ristologically, the irradiated segments of the cords showed multiple focal acute vascular necrosis. The smaller arteries in irradiated segments of the cords showed hyaline thickening; some of the smaller vessels were widely dilated and filled with blood, and their walls were necrotic. The white matter of the irradiated parts of these cords showed numerous holes (status spongiosus) in the lateral and dorsal columns. The anterior-horn cells in the irradiated zones were swollen, their nuclei pyknotic and cytoplasm devoid of Nissl granules. No abnormalities, besides thickening of the meninges in the irradiated areas, were found in the cords of the normotensive controls. After 3000 r the normotensive animals of this group showed no abnormalities of gait and Survived normally; no vascular lesions were found in their spinal cords. The hypentensive animals died suddenly 43-70 days after irradiation of the cord, and in all, death was preceded by ataxic episodes. Postmortem, numerous foci of acute vascular necrosis were found in the irradiated cord. These experiments suggest that moderate arterial hypertension seriously modifies the effect of x irradiation of the spinal cord. The transience of the ataxia in irradiated hypertensive rats suggests a possible origin in reversible vasoconstriction. When such episodes were followed by sudden death, arterial necrosis was invariably present in the irradiated region of the cord. Moreover, in hypertensive animals in which paraplegia developed, there was widespread necrosis of nerve tissue as well as organized vascular necrosis. A search of hospital records revealed three cases in which high blood pressure was recorded along with necrosis of the brain or spinal cord following therapeutic irradiation. In two of these, large doses of irradiation had been administered, and the necrosis might have been due to irradiation alone. In the third case, however, necrosis of the spinal cord occurred artd one factor which may have determined this individual sensitivity was high blood pressure. (BBB)« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Camingue, Pamela; Christian, Rochelle; Ng, Davin

The purpose of this study was to compare 4 different external beam radiation therapy treatment techniques for the treatment of T1-2, N0, M0 glottic cancers: traditional lateral beams with wedges (3D), 5-field intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and proton therapy. Treatment plans in each technique were created for 10 patients using consistent planning parameters. The photon treatment plans were optimized using Philips Pinnacle{sub 3} v.9 and the IMRT and VMAT plans used the Direct Machine Parameter Optimization algorithm. The proton treatment plans were optimized using Varian Eclipse Proton v.8.9. The prescription used for each plan wasmore » 63 Gy in 28 fractions. The contours for spinal cord, right carotid artery, left carotid artery, and normal tissue were created with respect to the patient's bony anatomy so that proper comparisons of doses could be made with respect to volume. An example of the different isodose distributions will be shown. The data collection for comparison purposes includes: clinical treatment volume coverage, dose to spinal cord, dose to carotid arteries, and dose to normal tissue. Data comparisons will be displayed graphically showing the maximum, mean, median, and ranges of doses.« less

Methylmercury dose estimation from umbilical cord concentrations in patients with Minamata disease.

PubMed

Akagi, H; Grandjean, P; Takizawa, Y; Weihe, P

1998-05-01

The methylmercury exposure of patients with congenital or infantile Minamata disease is known only from a small number of analyses of umbilical cords. Four laboratories in Japan have analyzed a total of 176 samples of umbilical cord tissue obtained from Minamata. The highest concentrations were seen in cord tissue from children born during 1950-1965, i.e., the peak period of acetaldehyde production in Minamata before installation of waste water treatment. Twenty-four samples from patients diagnosed with Minamata disease showed a median mercury concentration of 1.63 microg/g and differed significantly from levels seen in cord tissue from control children. However, children diagnosed with mental retardation had mercury concentrations in cord that were intermediate between the two other groups. Using regression coefficients obtained at a study conducted at the Faroe Islands, the median cord mercury concentration from the children with Minamata disease is estimated to correspond to about 216 microg/L cord blood and 41 microg/g in maternal hair. Based on correlations reported in the literature, the median daily mercury intake of the women whose children developed Minamata disease can then be estimated at about 225 microg. Although these children had fully developed Minamata disease, the estimates of median mercury levels are only four to five times higher than current mercury exposure limits. Copyright 1998 Academic Press.

Tract-Specific Volume Loss on 3T MRI in Patients with Cervical Spondylotic Myelopathy.

PubMed

Hopkins, Benjamin S; Weber, Kenneth A; Cloney, Michael Brendan; Paliwal, Monica; Parrish, Todd B; Smith, Zachary A

2018-04-11

Case-control. The aim of this study was to understand the role of high-resolution magnetic resonance (MR) in identifying regional cord volume loss in cervical spondylotic myelopathy (CSM). Preliminary studies suggest that compression of the ventral region of the cord may contribute disproportionately to CSM symptomology; however, tract-specific data are lacking in the CSM population. The current study is the first to use 3T MR imaging (MRI) images of CSM patients to determine specific volume loss at the level of detail of individual descending white matter tracts. Twelve patients with CSM and 14 age-matched were enrolled prospectively and underwent 3-Tesla MRI of the cervical spine. Using the high-resolution images of the spinal cord, straightening and alignment with a template was performed and specific spinal cord tract volumes were measured using Spinal Cord Tool-box version 3.0.7. Modified Japanese orthopedic association (mJOA) and Nurick disability scores were collected in a prospective manner and were analyzed in relation to descending spinal tract volumes. Having CSM was predicted by anterior/posterior diameter, eccentricity of the cord [odds ratio (OR) 0.000000621, P = 0.004], ventral reticulospinal tract volume (OR 1.167, P = 0.063), lateral corticospinal tract volume (OR 1.034, P = 0.046), rubrospinal tract volume (OR 1.072, P = 0.011), and ventrolateral reticulospinal tract volume (OR 1.474, P = 0.005) on single variable logistic regression. Single variable linear regression showed decreases in anterior/posterior spinal cord diameter (P = 0.022), ventral reticulospinal tract volumes (P = 0.007), and ventrolateral reticulospinal tract volumes (P = 0.017) to significantly predict worsening mJOA scores. Similarly, decreases in ventral reticulospinal tract volumes significantly predicted increasing Nurick scores (P = 0.039). High-resolution 3T MRI can detect tract-specific volume loss in descending spinal cord tracts in CSM patients. Anterior/posterior spinal cord diameter, ventral reticulospinal tract, ventrolateral reticulospinal tract, lateral corticospinal tract, and rubrospinal tract volume loss are associated with CSM symptoms. 2.

SU-F-P-26: Study of Radiation Dose Evaluation for Organs at Risk Using MRI in Intensity Modulated Radiation Therapy for Nasopharyngeal Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gong, G; Guo, Y; Yin, Y

Purpose: To study the contour and dosimetric feature of organs at risk (OARs) applying magnetic resonance imaging (MRI) images in intensity modulated radiation therapy (IMRT) of nasopharyngeal carcinoma (NPC) compared to computed tomography (CT) images. Methods: 35 NPC patients was selected into this trail. CT simulation with non-contrast and contrast enhanced scan, MRI simulation with non-contrast and contrast enhanced T1, T2 and diffusion weighted imaging were achieved sequentially. And the OARs were contoured on the CT and MRI images after rigid registration respectively. 9 beams IMRT plan with equal division angle were designed for every patients, and the prescription dosemore » for tumor target was set as 72Gy (2.4Gy/ fration). The boundary display, volume and dose-volume indices of each organ were compared between on MRI and CT images. Results: Compared to CT, MRI showed clearer boundary of brainstem, spinal cord, the deep lobe of Parotid gland and the optical nerve in canal. MRI images increase the volume of lens, optical nerve, while reducing the volume of eye slightly, and the maximum dose of lens, the mean dose of eyes and optical raised in different percentage, while there was no statistical differences were found. The left and right parotid volume on MRI increased by 7.07%, 8.13%, and the mean dose raised by 14.95% (4.01Gy), 18.76% (4.95Gy) with statistical significant difference (p<0.05). The brainstem volume reduced by 9.33% (p<0.05), and the dose of 0.1cm3 volume (D0.1cm3) reduced by mean 8.46% (4.32Gy), and D0.1cm3 of spinal cord increased by 1.5Gy on MRI. Conclusion: It is credible to evaluate the radiation dose of lens, eye and the spinal cord, while it should be necessary to evaluate the dose of brainstem, parotid and the optical nerve applying MRI images sometime, it will be more meaningful for these organs with high risk of radiation injury.« less

Systemic panca-associated vasculitis with central nervous involvement causing recurrent myelitis: case report.

PubMed

Hamilton, Alexander J; Whitehead, Duncan J; Bull, Matthew D; D'Souza, Richard J

2010-11-30

We report on the case of an established perinuclear antineutrophil cytoplasmic antibody (pANCA) associated renal vasculitis being treated with prednisolone and rituximab, where the patient presented with leg weakness, urinary and faecal incontinence and buttock pain consistent with transverse myelitis. The patient underwent MRI scanning showing patchy cord enhancement from T10 to the conus, which was suggestive of a cord malignancy. Prior to a cord biopsy, he was treated with steroids and a repeat MRI showed resolution of the original lesion with a new similar lesion from C7 to T3. He made a marked recovery after further treatment with high dose steroids and plasma exchange.

SU-E-J-52: Dosimetric Benefit of Adaptive Re-Planning in Lung Cancer Stereotactic Body Radiotherapy (SBRT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jia, J; Tian, Z; Gu, X

Purpose: To investigate the dosimetric benefit of adaptive re-planning for lung stereotactic body radiotherapy(SBRT). Methods: Five lung cancer patients with SBRT treatment were retrospectively investigated. Our in-house supercomputing online re-planning environment (SCORE) was used to realize the re-planning process. First a deformable image registration was carried out to transfer contours from treatment planning CT to each treatment CBCT. Then an automatic re-planning using original plan DVH guided fluence-map optimization is performed to get a new plan for the up-to-date patient geometry. We compared the re-optimized plan to the original plan projected on the up-to-date patient geometry in critical dosimetric parameters,more » such as PTV coverage, spinal cord maximum and volumetric constraint dose, esophagus maximum and volumetric constraint dose. Results: The average volume of PTV covered by prescription dose for all patients was improved by 7.56% after the adaptive re-planning. The volume of the spinal cord receiving 14.5Gy and 23Gy (V14.5, V23) decreased by 1.48% and 0.68%, respectively. For the esophagus, the volume receiving 19.5Gy (V19.5) reduced by 1.37%. Meanwhile, the maximum dose dropped off by 2.87% for spinal cord and 4.80% for esophagus. Conclusion: Our experimental results demonstrate that adaptive re-planning for lung SBRT has the potential to minimize the dosimetric effect of inter-fraction deformation and thus improve target coverage while reducing the risk of toxicity to nearby normal tissues.« less

HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in a rat model of bone cancer pain by restoring μ-opioid receptor in spinal cord.

PubMed

Hou, Xinran; Weng, Yingqi; Ouyang, Bihan; Ding, Zhuofeng; Song, Zongbin; Zou, Wangyuan; Huang, Changsheng; Guo, Qulian

2017-08-15

Bone cancer pain (BCP) is a common complication with inadequate management in patients suffering from advanced cancer. Histone deacetylase inhibitors showed significant analgesic effect in multiple inflammatory and neuropathic pain models, but their effect in bone cancer pain has never been explored. In this study, we utilized a BCP rat model with intra-tibial inoculation of Walker 256 mammary gland carcinoma cells, which developed progressive mechanical hypersensitivity but not thermal hypersensitivity. Intrathecal application of trichostatin A (TSA), a classic pan-HDAC inhibitor, ameliorated tactile hypersensitivity and enhanced the analgesic effect of morphine in BCP rats. The analgesic effect of TSA was blocked by co-administration of CTAP, a specific MOR antagonist, confirming the involvement of mu-opioid receptor (MOR). A reduction of MOR expression was observed in the lumbar spinal cord of BCP rats and TSA treatment was able to partially reverse it. In vitro study in PC12 cells also demonstrated the dose-dependent enhancement of MOR expression by TSA treatment. Taking all into consideration, we could draw the conclusion that HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in BCP rats, probably by restoring MOR expression in spinal cord. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug delivery, cell-based therapies, and tissue engineering approaches for spinal cord injury.

PubMed

Kabu, Shushi; Gao, Yue; Kwon, Brian K; Labhasetwar, Vinod

2015-12-10

Spinal cord injury (SCI) results in devastating neurological and pathological consequences, causing major dysfunction to the motor, sensory, and autonomic systems. The primary traumatic injury to the spinal cord triggers a cascade of acute and chronic degenerative events, leading to further secondary injury. Many therapeutic strategies have been developed to potentially intervene in these progressive neurodegenerative events and minimize secondary damage to the spinal cord. Additionally, significant efforts have been directed toward regenerative therapies that may facilitate neuronal repair and establish connectivity across the injury site. Despite the promise that these approaches have shown in preclinical animal models of SCI, challenges with respect to successful clinical translation still remain. The factors that could have contributed to failure include important biologic and physiologic differences between the preclinical models and the human condition, study designs that do not mirror clinical reality, discrepancies in dosing and the timing of therapeutic interventions, and dose-limiting toxicity. With a better understanding of the pathobiology of events following acute SCI, developing integrated approaches aimed at preventing secondary damage and also facilitating neuroregenerative recovery is possible and hopefully will lead to effective treatments for this devastating injury. The focus of this review is to highlight the progress that has been made in drug therapies and delivery systems, and also cell-based and tissue engineering approaches for SCI. Copyright © 2015 Elsevier B.V. All rights reserved.

The Effects of Ionizing Radiation and Hyperthermia on Mouse Spinal Cord.

NASA Astrophysics Data System (ADS)

Lo, Yeh-Chi

Assays were developed to quantify spinal cord damage in the mouse following radiation (X), hyperthermia (H) and their combination. The spinal cord (T_9-L _5) of C3Hf/Sed//Kam mice was irradiated with single (12-75 Gy) or fractionated doses (2 Gy to 23 Gy per fraction). Four arbitrary scales of neurological change were used. Findings for X were: (1) Radiation induces progressive damage, from mild to severe. (2) The latency to damage depended on the dose and the level of damage. Following doses around the ED50 (20-27 Gy), the onset of paralysis occurred between 6 and 8 months. (3) For the NSD equation, the exponent for N was 0.36-0.33 for mild to severe paralysis (score 1-3). Comparison of ED_{rm 50s} for 2 fractions separated by various intervals showed no time effect until 30-60 days. (4) If the data for higher doses per fraction were excluded (>10 Gy), the alpha/beta ratios were 3.5-5.6 for score 1-3. (5) Histological evidence of demyelination was evident at the time of paralysis. Using a water bath, the spinal cord was heated at 42.0 to 43.0^circC for 10-100 min. The results were: (1) Hyperthermia produces an acute reversible damage in the surviving mice. (2) No detectable late effects were seen up to 1.5 years. (3) A value of 0.48 for R in the thermal dose equation was found. (4) Heat lesions included neuronal and vascular damage, but this was seen only at high thermal dose. Mild thermal doses (42.5^circ C for 20-50 min.) were combined with single radiation doses ranging from 12 to 35 Gy in various sequences and time intervals. Findings were: (1) An acute and reversible potentiated damage (score 1) was found when H was given 5 min. before or 5 min., 7, 30, 60 and 150 days after X, but not in 7 days before or 1 day or 90 days after X. (2) An enhanced late effect was found when H was given 5 min. or 150 days after X. (3) Late effects were reduced when heat was given 5 min. or 1 day before or 1 day after X. (4) It seems that target cells (or targets within cells) for H and X may be different but may partially overlap. (5) Histological examination revealed both demyelination and vascular lesions in paralyzed animals. Comparison of human and the present data for paralysis following X, H and the combined treatment suggested that it may be possible to predict responses of humans using mouse data.

Effects of vitamin D supplementation in pregnancy.

PubMed

Marya, R K; Rathee, S; Lata, V; Mudgil, S

1981-01-01

Serum calcium, inorganic phosphate and heat-labile alkaline phosphatase (HLAP) have been estimated in maternal and cord sera of 120 pregnant women at labour. 75 women who did not take any vitamin D supplements during pregnancy showed statistically significant hypocalcaemia, hypophosphataemia and elevation of HLAP. Hypocalcaemia and hypophosphataemia were present in cord blood, too. 25 women who had received 1,200 U vitamin D/day throughout the 3rd trimester, showed significantly lower HLAP levels and increased fetal birth weight but there was no other improvement in maternal or cord blood chemistry. Administration of vitamin D in two large doses of 600,000 U each in the 7th and 8th months of pregnancy in 20 women proved more efficacious. Statistically significant improvement was observed in all the three biochemical parameters in maternal as well as cord sera. Fetal birth weight was also significantly greater with this mode of therapy.

Knowledge-based IMRT planning for individual liver cancer patients using a novel specific model.

PubMed

Yu, Gang; Li, Yang; Feng, Ziwei; Tao, Cheng; Yu, Zuyi; Li, Baosheng; Li, Dengwang

2018-03-27

The purpose of this work is to benchmark RapidPlan against clinical plans for liver Intensity-modulated radiotherapy (IMRT) treatment of patients with special anatomical characteristics, and to investigate the prediction capability of the general model (Model-G) versus our specific model (Model-S). A library consisting of 60 liver cancer patients with IMRT planning was used to set up two models (Model-S, Model-G), using the RapidPlan knowledge-based planning system. Model-S consisted of 30 patients with special anatomical characteristics where the distance from planning target volume (PTV) to the right kidney was less than three centimeters and Model-G was configurated using all 60 patients in this library. Knowledge-based IMRT plans were created for the evaluation group formed of 13 patients similar to those included in Model-S by Model-G, Model-S and manually (M), named RPG-plans, RPS-plans and M-plans, respectively. The differences in the dose-volume histograms (DVHs) were compared, not only between RP-plans and their respective M-plans, but also between RPG-plans and RPS-plans. For all 13 patients, RapidPlan could automatically produce clinically acceptable plans. Comparing RP-plans to M-plans, RP-plans improved V 95% of PTV and had greater dose sparing in the right kidney. For the normal liver, RPG-plans delivered similar doses, while RPS-plans delivered a higher dose than M-plans. With respect to RapidPlan models, RPS-plans had better conformity index (CI) values and delivered lower doses to the right kidney V 20Gy and maximizing point doses to spinal cord, while delivering higher doses to the normal liver. The study shows that RapidPlan can create high-quality plans, and our specific model can improve the CI of PTV, resulting in more sparing of OAR in IMRT for individual liver cancer patients.

Occupational vocal cord dysfunction due to exposure to wood dust and xerographic toner.

PubMed

Muñoz, Xavier; Roger, Alex; De la Rosa, David; Morell, Ferran; Cruz, Maria J

2007-04-01

Vocal cord dysfunction is a poorly understood entity that is often misdiagnosed as asthma. Both irritant and non-irritant vocal cord dysfunction have been described. This report presents two cases of irritant vocal cord dysfunction secondary to specific environmental exposure, the first to iroko and western red cedar wood (a carpenter) and the second to xerographic printing toner (a secretary). Several tests were performed, including chest radiographs, measurements of total serum immunoglobulin E, skin prick tests with common pneumoallergens (as well as iroko and western red cedar in the first case), pulmonary function studies, methacholine challenge testing, specific inhalation challenge performed with suspected agents in a single-blinded fashion, and peak expiratory flow testing and fiberoptic rhinolaryngoscopy (in case 1). During the specific inhalation challenge, the patients showed dysphonia, chest tightness, inspiratory stridor, and flattening of the inspiratory limb of the maximum flow-volume loop in spirometry, with no significant decreases in the level of forced expiratory volume in 1 second; fiberoptic rhinolaryngoscopy confirmed the diagnosis of vocal cord dysfunction in case 1. It is important to know that agents that can cause occupational asthma can also cause vocal cord dysfunction. The mechanisms by which these agents produce vocal cord dysfunction are unknown. The differences in the clinical presentation of the patients described relative to the reported cases suggest that more than one pathophysiological mechanism may be implicated in the genesis of this entity.

IMRT head and neck treatment planning with a commercially available Monte Carlo based planning system

NASA Astrophysics Data System (ADS)

Boudreau, C.; Heath, E.; Seuntjens, J.; Ballivy, O.; Parker, W.

2005-03-01

The PEREGRINE Monte Carlo dose-calculation system (North American Scientific, Cranberry Township, PA) is the first commercially available Monte Carlo dose-calculation code intended specifically for intensity modulated radiotherapy (IMRT) treatment planning and quality assurance. In order to assess the impact of Monte Carlo based dose calculations for IMRT clinical cases, dose distributions for 11 head and neck patients were evaluated using both PEREGRINE and the CORVUS (North American Scientific, Cranberry Township, PA) finite size pencil beam (FSPB) algorithm with equivalent path-length (EPL) inhomogeneity correction. For the target volumes, PEREGRINE calculations predict, on average, a less than 2% difference in the calculated mean and maximum doses to the gross tumour volume (GTV) and clinical target volume (CTV). An average 16% ± 4% and 12% ± 2% reduction in the volume covered by the prescription isodose line was observed for the GTV and CTV, respectively. Overall, no significant differences were noted in the doses to the mandible and spinal cord. For the parotid glands, PEREGRINE predicted a 6% ± 1% increase in the volume of tissue receiving a dose greater than 25 Gy and an increase of 4% ± 1% in the mean dose. Similar results were noted for the brainstem where PEREGRINE predicted a 6% ± 2% increase in the mean dose. The observed differences between the PEREGRINE and CORVUS calculated dose distributions are attributed to secondary electron fluence perturbations, which are not modelled by the EPL correction, issues of organ outlining, particularly in the vicinity of air cavities, and differences in dose reporting (dose to water versus dose to tissue type).

Effects of cerebrolysin on motor-neuron-like NSC-34 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keilhoff, Gerburg, E-mail: Gerburg.keilhoff@med.ovgu.de; Lucas, Benjamin; Pinkernelle, Josephine

Although the peripheral nervous system is capable of regeneration, this capability is limited. As a potential means of augmenting nerve regeneration, the effects of cerebrolysin (CL) – a proteolytic peptide fraction – were tested in vitro on the motor-neuron-like NSC-34 cell line and organotypic spinal cord cultures. Therefore, NSC-34 cells were subjected to mechanical stress by changing media and metabolic stress by oxygen glucose deprivation. Afterwards, cell survival/proliferation using MTT and BrdU-labeling (FACS) and neurite sprouting using ImageJ analysis were evaluated. Calpain-1, Src and α-spectrin protein expression were analyzed by Western blot. In organotypic cultures, the effect of CL onmore » motor neuron survival and neurite sprouting was tested by immunohistochemistry. CL had a temporary anti-proliferative but initially neuroprotective effect on OGD-stressed NSC-34 cells. High-dosed or repeatedly applied CL was deleterious for cell survival. CL amplified neurite reconstruction to limited extent, affected calpain-1 protein expression and influenced calpain-mediated spectrin cleavage as a function of Src expression. In organotypic spinal cord slice cultures, CL was not able to support motor neuron survival/neurite sprouting. Moreover, it hampered astroglia and microglia activities. The data suggest that CL may have only isolated positive effects on injured spinal motor neurons. High-dosed or accumulated CL seemed to have adverse effects in treatment of spinal cord injury. Further experiments are required to optimize the conditions for a safe clinical administration of CL in spinal cord injuries. - Highlights: • Cerebrolysin (CL) is anti-proliferative but initially neuroprotective in OGD-stressed NSC-34 cells. • CL amplified neurite reconstruction of NSC-34 cells. • CL affected calpain-1 expression and calpain-mediated spectrin cleavage as function of Src expression. • In organotypic spinal cord cultures, CL hampered motor neuron survival and glia activity. • Findings pose a contraindication for unchallenged use of CL in spinal cord injuries.« less

Therapeutic Effect of Platelet-Rich Plasma in Rat Spinal Cord Injuries

PubMed Central

Chen, Nan-Fu; Sung, Chun-Sung; Wen, Zhi-Hong; Chen, Chun-Hong; Feng, Chien-Wei; Hung, Han-Chun; Yang, San-Nan; Tsui, Kuan-Hao; Chen, Wu-Fu

2018-01-01

Platelet-rich plasma (PRP) is prepared by centrifuging fresh blood in an anticoagulant state, and harvesting the platelet-rich portion or condensing platelets. Studies have consistently demonstrated that PRP concentrates are an abundant source of growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), and epithelial growth factor (EGF). The complex mechanisms underlying spinal cord injury (SCI) diminish intrinsic repair and neuronal regeneration. Several studies have suggested that growth factor-promoted axonal regeneration can occur for an extended period after injury. More importantly, the delivery of exogenous growth factors contained in PRP, such as EGF, IGF-1, and TGF-β, has neurotrophic effects on central nervous system (CNS) injuries and neurodegenerative diseases. However, only a few studies have investigated the effects of PRP on CNS injuries or neurodegenerative diseases. According to our review of relevant literature, no study has investigated the effect of intrathecal (i.t.) PRP injection into the injured spinal cord and activation of intrinsic mechanisms. In the present study, we directly injected i.t. PRP into rat spinal cords and examined the effects of PRP on normal and injured spinal cords. In rats with normal spinal cords, PRP induced microglia and astrocyte activation and PDGF-B and ICAM-1 expression. In rats with SCIs, i.t. PRP enhanced the locomotor recovery and spared white matter, promoted angiogenesis and neuronal regeneration, and modulated blood vessel size. Furthermore, a sustained treatment (a bolus of PRP followed by a 1/3 dose of initial PRP concentration) exerted more favorable therapeutic effects than a single dose of PRP. Our findings suggest by i.t. PRP stimulate angiogenesis, enhancing neuronal regeneration after SCI in rats. Although PRP induces minor inflammation in normal and injured spinal cords, it has many advantages. It is an autologous, biocompatible, nontoxic material that does not result in a major immune response. In addition, based on its safety and ease of preparation, we hypothesize that PRP is a promising therapeutic agent for SCI. PMID:29740270

Age, gender and normalization covariates for spinal cord gray matter and total cross-sectional areas at cervical and thoracic levels: A 2D phase sensitive inversion recovery imaging study.

PubMed

Papinutto, Nico; Schlaeger, Regina; Panara, Valentina; Zhu, Alyssa H; Caverzasi, Eduardo; Stern, William A; Hauser, Stephen L; Henry, Roland G

2015-01-01

The source of inter-subject variability and the influence of age and gender on morphometric characteristics of the spinal cord, such as the total cross-sectional area (TCA), the gray matter (GM) and white matter (WM) areas, currently remain under investigation. Understanding the effect of covariates such as age, gender, brain volumes, and skull- and vertebra-derived metrics on cervical and thoracic spinal cord TCA and GM areas in healthy subjects would be fundamental for exploring compartment specific changes in neurological diseases affecting the spinal cord. Using Magnetic Resonance Imaging at 3T we investigated 32 healthy subjects using a 2D phase sensitive inversion recovery sequence and we measured TCA, GM and WM areas at 4 cervical and thoracic levels of the spinal cord. We assessed age and gender relationships of cord measures and explored associations between cord measures and a) brain volumes and b) skull- and vertebra-derived metrics. Age and gender had a significant effect on TCA, WM and GM areas (with women and elderly having smaller values than men and younger people respectively), but not on the GM area/TCA ratio. The total intracranial volume and C3 vertebra dimensions showed the highest correlations with cord measures. When used in multi-regression models, they reduced cord areas group variability by approximately a third. Age and gender influences on cord measures and normalization strategies here presented might be of use in the study of compartment specific changes in various neurological diseases affecting the spinal cord.

From waste to (fool's) gold: promissory and profit values of cord blood.

PubMed

Haw, Jennie

2015-12-01

According to biomedical discourse, cord blood has been transformed from 'waste' to 'clinical gold' because of its potential for use in treatments. Private cord blood banks deploy clinical discourse to market their services to prospective parents, encouraging them to pay to bank cord blood as a form of 'biological insurance' to ensure their child's future health. Social scientists have examined new forms of (bio)value produced in biological materials emergent with contemporary biotechnologies. This paper contributes to this literature by examining the social and technical production of value in cord blood units collected for private banking. Value, in this paper is defined as a socio-cultural concept in which an object is made meaningful, or valuable, through its relations with social actors and within specific regimes of value. I draw on in-depth interviews with women who banked cord blood and key informants in private banks in Canada, to analyze how social actors produced cord blood as a valuable biological object. I show that a cord blood unit holds promissory value for women who bank and profit value for private banks and that these values are folded into each other and the biological material itself. Analyzing how specific cord blood units are made valuable provides insight into the multiple and possibly competing values of biological materials and the tensions that may arise between social actors and forms of knowledge during the valuing process.

Translational Pharmacologic Efficacy Studies of Glial Growth Factor 2 (GGF2) in Spinal Cord Injury Models and in the Veterinary Clinical Setting

DTIC Science & Technology

2015-07-01

optimal dosage was examined using a model of rodent SCI and testing several dose levels delivered either subcutaneously (SC) or intravenously (IV...to saline treated controls. ANOVA with Dunett’s post hoc test , pɘ.05. Based on these results, the studies in year 2 compared effects of SC...ventrally and ventral- laterally . The lesion in the Acorda model was characterized by a dorsal-ventral flattening of the cord profile with a highly

Prolonged Minocycline Treatment Impairs Motor Neuronal Survival and Glial Function in Organotypic Rat Spinal Cord Cultures

PubMed Central

Pinkernelle, Josephine; Fansa, Hisham; Ebmeyer, Uwe; Keilhoff, Gerburg

2013-01-01

Background Minocycline, a second-generation tetracycline antibiotic, exhibits anti-inflammatory and neuroprotective effects in various experimental models of neurological diseases, such as stroke, Alzheimer’s disease, amyotrophic lateral sclerosis and spinal cord injury. However, conflicting results have prompted a debate regarding the beneficial effects of minocycline. Methods In this study, we analyzed minocycline treatment in organotypic spinal cord cultures of neonatal rats as a model of motor neuron survival and regeneration after injury. Minocycline was administered in 2 different concentrations (10 and 100 µM) at various time points in culture and fixed after 1 week. Results Prolonged minocycline administration decreased the survival of motor neurons in the organotypic cultures. This effect was strongly enhanced with higher concentrations of minocycline. High concentrations of minocycline reduced the number of DAPI-positive cell nuclei in organotypic cultures and simultaneously inhibited microglial activation. Astrocytes, which covered the surface of the control organotypic cultures, revealed a peripheral distribution after early minocycline treatment. Thus, we further analyzed the effects of 100 µM minocycline on the viability and migration ability of dispersed primary glial cell cultures. We found that minocycline reduced cell viability, delayed wound closure in a scratch migration assay and increased connexin 43 protein levels in these cultures. Conclusions The administration of high doses of minocycline was deleterious for motor neuron survival. In addition, it inhibited microglial activation and impaired glial viability and migration. These data suggest that especially high doses of minocycline might have undesired affects in treatment of spinal cord injury. Further experiments are required to determine the conditions for the safe clinical administration of minocycline in spinal cord injured patients. PMID:23967343

SU-E-J-86: Functional Conformal Planning for Stereotactic Body Radiation Therapy with CT-Pulmonary Ventilation Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kurosawa, T; Moriya, S; Sato, M

2015-06-15

Purpose: To evaluate the functional planning using CT-pulmonary ventilation imaging for conformal SBRT. Methods: The CT-pulmonary ventilation image was generated using the Jacobian metric in the in-house program with the NiftyReg software package. Using the ventilation image, the normal lung was split into three lung regions for functionality (high, moderate and low). The anatomical plan (AP) and functional plan (FP) were made for ten lung SBRT patients. For the AP, the beam angles were optimized with the dose-volume constraints for the normal lung sparing and the PTV coverage. For the FP, the gantry angles were also optimized with the additionalmore » constraint for high functional lung. The MLC aperture shapes were adjusted to the PTV with the additional 5 mm margin. The dosimetric parameters for PTV, the functional volumes, spinal cord and so on were compared in both plans. Results: Compared to the AP, the FP showed better dose sparing for high- and moderate-functional lungs with similar PTV coverage while not taking care of the low functional lung (High:−12.9±9.26% Moderate: −2.0±7.09%, Low: +4.1±12.2%). For the other normal organs, the FP and AP showed similar dose sparing in the eight patients. However, the FP showed that the maximum doses for spinal cord were increased with the significant increment of 16.4Gy and 21.0Gy in other two patients, respectively. Because the beam direction optimizer chose the unexpected directions passing through the spinal cord. Conclusion: Even the functional conformal SBRT can selectively reduce high- and moderatefunctional lung while keeping the PTV coverage. However, it would be careful that the optimizer would choose unexpected beam angles and the dose sparing for the other normal organs can be worse. Therefore, the planner needs to control the dose-volume constraints and also limit the beam angles in order to achieve the expected dose sparing and coverage.« less

SU-E-T-87: Comparison Study of Dose Reconstruction From Cylindrical Diode Array Measurements, with TLD Measurements and Treatment Planning System Calculations in Anthropomorphic Head and Neck and Lung Phantoms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Benhabib, S; Cardan, R; Huang, M

Purpose: To assess dose calculated by the 3DVH software (Sun Nuclear Systems, Melbourne, FL) against TLD measurements and treatment planning system calculations in anthropomorphic phantoms. Methods: The IROC Houston (RPC) head and neck (HN) and lung phantoms were scanned and plans were generated using Eclipse (Varian Medical Systems, Milpitas, CA) following IROC Houston procedures. For the H and N phantom, 6 MV VMAT and 9-field dynamic MLC (DMLC) plans were created. For the lung phantom 6 MV VMAT and 15 MV 9-field dynamic MLC (DMLC) plans were created. The plans were delivered to the phantoms and to an ArcCHECK (Sunmore » Nuclear Systems, Melbourne, FL). The head and neck phantom contained 8 TLDs located at PTV1 (4), PTV2 (2), and OAR Cord (2). The lung phantom contained 4 TLDs, 2 in the PTV, 1 in the cord, and 1 in the heart. Daily outputs were recorded before each measurement for correction. 3DVH dose reconstruction software was used to project the calculated dose to patient anatomy. Results: For the HN phantom, the maximum difference between 3DVH and TLDs was -3.4% and between 3DVH and Eclipse was 1.2%. For the lung plan the maximum difference between 3DVH and TLDs was 4.3%, except for the spinal cord for which 3DVH overestimated the TLD dose by 12%. The maximum difference between 3DVH and Eclipse was 0.3%. 3DVH agreed well with Eclipse because the dose reconstruction algorithm uses the diode measurements to perturb the dose calculated by the treatment planning system; therefore, if there is a problem in the modeling or heterogeneity correction, it will be carried through to 3DVH. Conclusion: 3DVH agreed well with Eclipse and TLD measurements. Comparison of 3DVH with film measurements is ongoing. Work supported by PHS grant CA10953 and CA81647 (NCI, DHHS)« less

Computed Tomography Number Changes Observed During Computed Tomography–Guided Radiation Therapy for Head and Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Mei; Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu; Yang, Cungeng

2015-04-01

Purpose: To investigate CT number (CTN) changes in gross tumor volume (GTV) and organ at risk (OAR) according to daily diagnostic-quality CT acquired during CT-guided intensity modulated radiation therapy for head and neck cancer (HNC) patients. Methods and Materials: Computed tomography scans acquired using a CT-on-rails during daily CT-guided intensity modulated radiation therapy for 15 patients with stage II to IVa squamous cell carcinoma of the head and neck were analyzed. The GTV, parotid glands, spinal cord, and nonspecified tissue were generated on each selected daily CT. The changes in CTN distributions and the mean and mode values were collected.more » Pearson analysis was used to assess the correlation between the CTN change, organ volume reduction, and delivered radiation dose. Results: Volume and CTN changes for GTV and parotid glands can be observed during radiation therapy delivery for HNC. The mean (±SD) CTNs in GTV and ipsi- and contralateral parotid glands were reduced by 6 ± 10, 8 ± 7, and 11 ± 10 Hounsfield units, respectively, for all patients studied. The mean CTN changes in both spinal cord and nonspecified tissue were almost invisible (<2 Hounsfield units). For 2 patients studied, the absolute mean CTN changes in GTV and parotid glands were strongly correlated with the dose delivered (P<.001 and P<.05, respectively). For the correlation between CTN reductions and delivered isodose bins for parotid glands, the Pearson coefficient varied from −0.98 (P<.001) in regions with low-dose bins to 0.96 (P<.001) in high-dose bins and were patient specific. Conclusions: The CTN can be reduced in tumor and parotid glands during the course of radiation therapy for HNC. There was a fair correlation between CTN reduction and radiation doses for a subset of patients, whereas the correlation between CTN reductions and volume reductions in GTV and parotid glands were weak. More studies are needed to understand the mechanism for the radiation-induced CTN changes.« less

Beam Attenuators and the Risk of Unrecognized Large-Fraction Irradiation of Critical Tissues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luka, S.; Marks, J.E.

2015-01-15

The use of radiation beam attenuators led to radiation injury of the spinal cord in one patient and of the peripheral nerve in another due to unsuspected large-fraction irradiation. The anatomic distribution of radiation dose was reconstructed in the sagittal plane for the patient who developed radiation myelopathy and in the axial plane for the patient who developed peripheral neuropathy. The actual dose delivered to the injured structure in each patient was taken from the dose distribution and recorded along with the time, number of fractions, and dose per fraction. The patient who developed radiation myelopathy received a total ofmore » 46.5 Gy in twenty-three 2.1 Gy fractions in 31 days to the upper cervical spinal cord where the thickness of the neck was less than the central axis thickness due to cervical lordosis and absence of a posterior compensating filter. The patient who developed peripheral neuropathy received 55 Gy in twenty-five 2.2 Gy fractions in 50 days to the femoral nerve using bolus over the groins and an anterior one-half value layer Cerrobend pelvic block to bias the dose anteriorly. Compensating filters and other beam attenuators should be used with caution because they may result in unsuspected large-fraction irradiation and total doses of radiation that exceed the tolerance of critical structures.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dogan, N; Padgett, K; Evans, J

Purpose: Adaptive Radiotherapy (ART) with frequent CT imaging has been used to improve dosimetric accuracy by accounting for anatomical variations, such as primary tumor shrinkage and/or body weight loss, in Head and Neck (H&N) patients. In most ART strategies, the difference between the planned and the delivered dose is estimated by generating new plans on repeated CT scans using dose-volume constraints used with the initial planning CT without considering already delivered dose. The aim of this study was to assess the dosimetric gains achieved by re-planning based on prior dose by comparing them to re-planning not based-on prior dose formore » H&N patients. Methods: Ten locally-advanced H&N cancer patients were selected for this study. For each patient, six weekly CT imaging were acquired during the course of radiotherapy. PTVs, parotids, cord, brainstem, and esophagus were contoured on both planning and six weekly CT images. ART with weekly re-plans were done by two strategies: 1) Generating a new optimized IMRT plan without including prior dose from previous fractions (NoPriorDose) and 2) Generating a new optimized IMRT plan based on the prior dose given from previous fractions (PriorDose). Deformable image registration was used to accumulate the dose distributions between planning and six weekly CT scans. The differences in accumulated doses for both strategies were evaluated using the DVH constraints for all structures. Results: On average, the differences in accumulated doses for PTV1, PTV2 and PTV3 for NoPriorDose and PriorDose strategies were <2%. The differences in Dmean to the cord and brainstem were within 3%. The esophagus Dmean was reduced by 2% using PriorDose. PriorDose strategy, however, reduced the left parotid D50 and Dmean by 15% and 14% respectively. Conclusion: This study demonstrated significant parotid sparing, potentially reducing xerostomia, by using ART with IMRT optimization based on prior dose for weekly re-planning of H&N cancer patients.« less

Gating window dependency on scanned carbon-ion beam dose distribution and imaging dose for thoracoabdominal treatment.

PubMed

Mori, Shinichiro; Karube, Masataka; Yasuda, Shigeo; Yamamoto, Naoyoshi; Tsuji, Hiroshi; Kamada, Tadashi

2017-06-01

To explore the trade-off between dose assessment and imaging dose in respiratory gating with radiographic fluoroscopic imaging, we evaluated the relationship between dose assessment and fluoroscopic imaging dose in various gating windows, retrospectively. Four-dimensional (4D) CT images acquired for 10 patients with lung and liver tumours were used for 4D treatment planning for scanned carbon ion beam. Imaging dose from two oblique directions was calculated by the number of images multiplied by the air kerma per image. Necessary beam-on time was calculated from the treatment log file. Accumulated dose distribution was calculated. The gating window was defined as tumour position not respiratory phase and changed from 0-100% duty cycle on 4DCT. These metrics were individually evaluated for every case. For lung cases, sufficient dose conformation was achieved in respective gating windows [D 95 -clinical target volume (CTV) > 99%]. V 20 -lung values for 50%- and 30%-duty cycles were 2.5% and 6.0% of that for 100%-duty cycle. Maximum doses (cord/oesophagus) for 30%-duty cycle decreased 6.8%/7.4% to those for 100%-duty cycle. For liver cases, V 10 -liver values for 50%- and 30%-duty cycles were 9.4% and 12.8% of those for 100%-duty cycle, respectively. Maximum doses (cord/oesophagus) for 50%- and 30%-duty cycles also decreased 17.2%/19.3% and 24.6%/29.8% to those for 100%-duty cycle, respectively. Total imaging doses increased 43.5% and 115.8% for 50%- and 30%-duty cycles to that for the 100%-duty cycle. When normal tissue doses are below the tolerance level, the gating window should be expanded to minimize imaging dose and treatment time. Advances in knowledge: The skin dose from imaging might not be counterbalanced to the OAR dose; however, imaging dose is a particularly important factor.

Low-Dose Cannabinoid Type 2 Receptor Agonist Attenuates Tolerance to Repeated Morphine Administration via Regulating μ-Opioid Receptor Expression in Walker 256 Tumor-Bearing Rats.

PubMed

Zhang, Mingyue; Wang, Kun; Ma, Min; Tian, Songyu; Wei, Na; Wang, Guonian

2016-04-01

Morphine is widely used in patients with moderate and severe cancer pain, whereas the development of drug tolerance remains a major problem associated with opioid use. Previous studies have shown that cannabinoid type 2 (CB2) receptor agonists induce morphine analgesia, attenuate morphine tolerance in normal and neuropathic pain animals, induce transcription of the μ-opioid receptor (MOR) gene in Jurkat T cells, and increase morphine analgesia in cancer pain animals. However, no studies of the effects of CB2 receptor agonists on morphine tolerance in cancer pain have been performed. Therefore, we investigated the effect of repeated intrathecal (IT) injection of the low-dose CB2 receptor agonist AM1241 on the development of morphine tolerance in walker 256 tumor-bearing rats. We also tested the influence of the CB2 receptor agonist AM1241 on MOR protein and messenger ribonucleic acid (mRNA) expression in the rat spinal cord and dorsal root ganglia (DRG). Walker 256 cells were implanted into the plantar region of each rat's right hindpaw. Tumor-bearing rats received IT injection of the CB2 receptor agonist AM1241 or antagonist AM630 with or without morphine subcutaneously twice daily for 8 days. Rats receiving drug vehicle only served as the control group. Mechanical paw withdrawal threshold and thermal paw withdrawal latency were assessed by a von Frey test and hot plate test 30 minutes after drug administration every day. MOR protein and mRNA expression in the spinal cord and DRG were detected after the last day (day 8) of drug administration via Western blot and real-time reverse transcription polymerase chain reaction. The data were analyzed via analysis of variance followed by Student t test with Bonferroni correction for multiple comparisons. Repeated morphine treatments reduced the mechanical withdrawal threshold and thermal latency. Coadministration of a nonanalgetic dose of the CB2 receptor agonist AM1241 with morphine significantly inhibited the development of morphine tolerance and increased the MOR protein expression in the spinal cord and DRG and mRNA expression in the spinal cord in tumor-bearing rats. Our findings indicate that IT injection of a nonanalgetic dose of a CB2 receptor agonist increased the analgesia effect and alleviated tolerance to morphine in tumor-bearing rats, potentially by regulating MOR expression in the spinal cord and DRG. This receptor may be a new target for prevention of the development of opioid tolerance in cancer pain.

Directing Spinal Cord Plasticity: The Impact of Stretch Therapy on Functional Recovery after Spinal Cord Injury

DTIC Science & Technology

2014-10-01

atrophy. Interestingly, there is a clinical phenomenon that stretching can lead to muscle fiber hypertrophy , but that doesn’t appear to be...specific muscle groups) on functional recovery after spinal cord injury in a rat model. We have undertaken these studies because of an observation we...spinal cord injury, locomotor recovery, physical therapy, muscle stretch, joint range- of-motion, rat. Overall Project Summary: In this, the

Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent Neuro-Inflammation in Brain, Cognitive Deficits, and Alterations in Apurinic Endonuclease 1

DOE PAGES

Suresh Kumar, M. A.; Peluso, Michael; Chaudhary, Pankaj; ...

2015-07-24

Ionizing radiation causes degeneration of myelin, the insulating sheaths of neuronal axons, leading to neurological impairment. As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells ’ differentiation. Apurinic endonuclease-1 is predominantly upregulated in response to oxidative stress by low- energy radiation, and previous studies show significant induction ofmore » Apurinic Endonucle- ase-1 in neurons and astrocytes. Our studies show for the first time, that fractionation of pro- tons cause latent damage to spinal cord architecture while fractionation of HZE ( 28Si) induce increase in APE1 with single dose, which then decreased with fractionation. In conclusion, the oligoden- drocyte progenitor cells differentiation was skewed with increase in immature oligodendro- cytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects« less

Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent Neuro-Inflammation in Brain, Cognitive Deficits, and Alterations in Apurinic Endonuclease 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suresh Kumar, M. A.; Peluso, Michael; Chaudhary, Pankaj

Ionizing radiation causes degeneration of myelin, the insulating sheaths of neuronal axons, leading to neurological impairment. As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells ’ differentiation. Apurinic endonuclease-1 is predominantly upregulated in response to oxidative stress by low- energy radiation, and previous studies show significant induction ofmore » Apurinic Endonucle- ase-1 in neurons and astrocytes. Our studies show for the first time, that fractionation of pro- tons cause latent damage to spinal cord architecture while fractionation of HZE ( 28Si) induce increase in APE1 with single dose, which then decreased with fractionation. In conclusion, the oligoden- drocyte progenitor cells differentiation was skewed with increase in immature oligodendro- cytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects« less

Effect of GABA receptor agonists or antagonists injected spinally on the blood glucose level in mice.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kang, Yu-Jung; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Suh, Hong-Won

2013-05-01

The possible roles of gamma-amino butyric acid (GABA) receptors located in the spinal cord for the regulation of the blood glucose level were studied in ICR mice. We found in the present study that intrathecal (i.t.) injection with baclofen (a GABAB receptor agonist; 1-10 μg/5 μl) or bicuculline (a GABAA receptor antagonist; 1-10 μg/5 μl) caused an elevation of the blood glucose level in a dose-dependent manner. The hyperglycemic effect induced by baclofen was more pronounced than that induced by bicuculline. However, muscimol (a GABAA receptor agonist; 1-5 μg/5 μl) or phaclofen (a GABAB receptor antagonist; 5-10 μg/5 μl) administered i.t. did not affect the blood glucose level. Baclofen-induced elevation of the blood glucose was dose-dependently attenuated by phaclofen. Furthermore, i.t. pretreatment with pertussis toxin (PTX; 0.05 or 0.1 μg/5 μl) for 6 days dose-dependently reduced the hyperglycemic effect induced by baclofen. Our results suggest that GABAB receptors located in the spinal cord play important roles for the elevation of the blood glucose level. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by baclofen. Furthermore, inactivation of GABAA receptors located in the spinal cord appears to be responsible for tonic up-regulation of the blood glucose level.

The effects of subarachnoid administration of preservative-free S(+)-ketamine on spinal cord and meninges in dogs.

PubMed

Rojas, Alfredo Cury; Alves, Juliana Gaiotto; Moreira E Lima, Rodrigo; Esther Alencar Marques, Mariângela; Moreira de Barros, Guilherme Antônio; Fukushima, Fernanda Bono; Modolo, Norma Sueli Pinheiro; Ganem, Eliana Marisa

2012-02-01

The N-methyl-d-aspartate receptor antagonist ketamine and its active enantiomer, S(+)-ketamine, have been injected in the epidural and subarachnoid spaces to treat acute postoperative pain and relieve neuropathic pain syndrome. In this study we evaluated the effects of a single dose of preservative-free S(+)-ketamine, in doses usually used in clinical practice, in the spinal cord and meninges of dogs. Under anesthesia (IV etomidate (2 mg/kg) and fentanyl (0.005 mg/kg), 16 dogs (6 to 15 kg) were randomized to receive a lumbar intrathecal injection (L5/6) of saline solution of 0.9% (control group) or S(+)-ketamine 1 mg/kg(-1) (ketamine group). All doses were administered in a volume of 1 mL over a 10-second interval. Accordingly, injection solution ranged from 0.6% to 1.5%. After 21 days of clinical observation, the animals were killed; spinal cord, cauda equina root, and meninges were removed for histological examination with light microscopy. Tissues were examined for demyelination (Masson trichrome), neuronal death (hematoxylin and eosin) and astrocyte activation (glial fibrillary acidic protein). No clinical or histological alterations of spinal tissue or meninges were found in animals from either control or ketamine groups. A single intrathecal injection of preservative-free S(+)-ketamine, at 1 mg/kg(-1) dosage, over a concentration range of 6 to 15 mg/mL injected in the subarachnoid space in a single puncture, did not produce histological alterations in this experimental model.

Impact of length of cryopreservation and origin of cord blood units on hematologic recovery following cord blood transplantation.

PubMed

Kurita, N; Frassoni, F; Chiba, S; Podestà, M

2015-06-01

As the history of the cord blood banking system has lengthened, the number of cord blood units (CBUs) cryopreserved for years has increased. The global expansion of cord blood banking resulted in active international exchange of CBUs. To determine whether long-term cryopreservation and international shipment of CBUs affect the quality of the units and outcome after transplantation, we retrospectively analyzed the quality of 95 CBUs and the hematologic recovery of 127 patients with hematological malignancy following single-unit cord blood transplantation. Of the 127 CBUs used to transplant, 42 units were cryopreserved for long periods (5-11.8 years), and 44 units were shipped from distant countries. We found that length of cryopreservation and origin of CBUs did not affect the ratio of viable total-nucleated cells after thawing. Also, neutrophil engraftment was not affected by long-term cryopreservation (> 5 years) or origin (from distant countries), (hazard ratio, 0.91 and 1.2; P=0.65 and 0.41; respectively). The number of CD34(+) cells before freezing (> 1.4 cells/kg recipient) was the only factor that enhanced neutrophil engraftment (hazard ratio, 1.8; P<0.01). This suggests that length of cryopreservation and origin need not be prioritized over the CD34(+) cell dose when selecting CBUs.

Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release.

PubMed

Kondo, Ichiro; Marvizon, Juan Carlos G; Song, Bingbing; Salgado, Frances; Codeluppi, Simone; Hua, Xiao-Ying; Yaksh, Tony L

2005-04-06

Opioid mu- and delta-receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor (NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices and in vivo. In slices, NK1R internalization evoked by dorsal root stimulation at C-fiber intensity was abolished by the mu agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) (1 microM) and decreased by the delta agonist [D-Phe2,5]-enkephalin (DPDPE) (1 microM). In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the kappa agonist trans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), delivered at spinal cord segment L2 using intrathecal catheters. These doses of the mu and delta agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviorally as analgesic.

Choice of surrogate tissue influences neonatal EWAS findings.

PubMed

Lin, Xinyi; Teh, Ai Ling; Chen, Li; Lim, Ives Yubin; Tan, Pei Fang; MacIsaac, Julia L; Morin, Alexander M; Yap, Fabian; Tan, Kok Hian; Saw, Seang Mei; Lee, Yung Seng; Holbrook, Joanna D; Godfrey, Keith M; Meaney, Michael J; Kobor, Michael S; Chong, Yap Seng; Gluckman, Peter D; Karnani, Neerja

2017-12-05

Epigenomes are tissue specific and thus the choice of surrogate tissue can play a critical role in interpreting neonatal epigenome-wide association studies (EWAS) and in their extrapolation to target tissue. To develop a better understanding of the link between tissue specificity and neonatal EWAS, and the contributions of genotype and prenatal factors, we compared genome-wide DNA methylation of cord tissue and cord blood, two of the most accessible surrogate tissues at birth. In 295 neonates, DNA methylation was profiled using Infinium HumanMethylation450 beadchip arrays. Sites of inter-individual variability in DNA methylation were mapped and compared across the two surrogate tissues at birth, i.e., cord tissue and cord blood. To ascertain the similarity to target tissues, DNA methylation profiles of surrogate tissues were compared to 25 primary tissues/cell types mapped under the Epigenome Roadmap project. Tissue-specific influences of genotype on the variable CpGs were also analyzed. Finally, to interrogate the impact of the in utero environment, EWAS on 45 prenatal factors were performed and compared across the surrogate tissues. Neonatal EWAS results were tissue specific. In comparison to cord blood, cord tissue showed higher inter-individual variability in the epigenome, with a lower proportion of CpGs influenced by genotype. Both neonatal tissues were good surrogates for target tissues of mesodermal origin. They also showed distinct phenotypic associations, with effect sizes of the overlapping CpGs being in the same order of magnitude. The inter-relationship between genetics, prenatal factors and epigenetics is tissue specific, and requires careful consideration in designing and interpreting future neonatal EWAS. This birth cohort is a prospective observational study, designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875 .

SU-E-T-269: Quality Assurance of Spine Volumetric Modulated Arc Therapy with Flattening Filter Free Beams Using Gafchromic EBT3 Films

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Y; Cho, B; Kwak, J

2014-06-01

Purpose: We implemented the Gafchromic film-based patient specific QA of volumetric modulated arc therapy (VMAT) with flattening-filter free (FFF) beams for spine metastases and validated the accuracy of fast arc delivery. Methods: EBT3 films and a homemade cylindrical QA phantom were employed for dosimetric verification of VMATs. For 14 FFF VMAT plans (10 with 10-MV FFF beams and 4 with 6-MV FFF beams), the doses were recalculated on the phantom and delivered by a TrueBeam STx accelerator equipped with a high-definition 120 leaf MLC. The EBT3 films were scanned using an Epson 10000XL scanner through the FilmQA Pro software. Allmore » the irradiated film images were converted to dose map using a calibration response curve. The resulting dose map of film measurement was compared with treatment plan and evaluated using gamma analysis with dose tolerance of 2% within 2 mm. In addition, the point-dose measurement in the phantom using an ion chamber was evaluated as a reference in a ratio of measured and planned doses. Results: The gamma pass rates averaged over all FFF plans for composite-field measurements were 96.0 ± 3.6% (88.9%–99.5%). When adopting a tolerance level of 3% - 3 mm, the gamma pass rates were improved with the ranges from 98% to 100%. In addition, dose profiles and dose distributions showed that spinal cord was protected by the rapid dose fall-off and by delivering the treatment with high precision. In point-dose measurements, the average differences between the measured and planned doses were 0.5% ± 1.0% of the prescription dose. Conclusion: We demonstrated that Gafchromic EBT3 film would be an effective patient-specific QA tool, especially for VMAT of spine SBRT with treatment of small fields and highly gradient dose distributions. The results of film QA verified that the dosimetric accuracy of spine SBRT utilizing RapidArc with FFF beams in our institution is reliable.« less

Generation of mesenchymal stromal cells in the presence of platelet lysate: a phenotypic and functional comparison of umbilical cord blood- and bone marrow-derived progenitors

PubMed Central

Avanzini, Maria Antonietta; Bernardo, Maria Ester; Cometa, Angela Maria; Perotti, Cesare; Zaffaroni, Nadia; Novara, Francesca; Visai, Livia; Moretta, Antonia; Del Fante, Claudia; Villa, Raffaella; Ball, Lynne M.; Fibbe, Willem E.; Maccario, Rita; Locatelli, Franco

2009-01-01

Background Mesenchymal stromal cells are employed in various different clinical settings in order to modulate immune response. However, relatively little is known about the mechanisms responsible for their immunomodulatory effects, which could be influenced by both the cell source and culture conditions. Design and Methods We tested the ability of a 5% platelet lysate-supplemented medium to support isolation and ex vivo expansion of mesenchymal stromal cells from full-term umbilical-cord blood. We also investigated the biological/functional properties of umbilical cord blood mesenchymal stromal cells, in comparison with platelet lysate-expanded bone marrow mesenchymal stromal cells. Results The success rate of isolation of mesenchymal stromal cells from umbilical cord blood was in the order of 20%. These cells exhibited typical morphology, immunophenotype and differentiation capacity. Although they have a low clonogenic efficiency, umbilical cord blood mesenchymal stromal cells may possess high proliferative potential. The genetic stability of these cells from umbilical cord blood was demonstrated by a normal molecular karyotype; in addition, these cells do not express hTERT and telomerase activity, do express p16ink4a protein and do not show anchorage-independent cell growth. Concerning alloantigen-specific immune responses, umbilical cord blood mesenchymal stromal cells were able to: (i) suppress T- and NK-lymphocyte proliferation, (ii) decrease cytotoxic activity and (iii) only slightly increase interleukin-10, while decreasing interferon-γ secretion, in mixed lymphocyte culture supernatants. While an indoleamine 2,3-dioxygenase-specific inhibitor did not reverse mesenchymal stromal cell-induced suppressive effects, a prostaglandin E2-specific inhibitor hampered the suppressive effect of both umbilical cord blood- and bone marrow-mesenchymal stromal cells on alloantigen-induced cytotoxic activity. Mesenchymal stromal cells from both sources expressed HLA-G. Conclusions Umbilical cord blood- and bone marrow-mesenchymal stromal cells may differ in terms of clonogenic efficiency, proliferative capacity and immunomodulatory properties; these differences may be relevant for clinical applications. PMID:19773264

Childhood Obesity Research Demonstration Project: Cross-Site Evaluation Methods

PubMed Central

Lee, Rebecca E.; Mehta, Paras; Thompson, Debbe; Bhargava, Alok; Carlson, Coleen; Kao, Dennis; Layne, Charles S.; Ledoux, Tracey; O'Connor, Teresia; Rifai, Hanadi; Gulley, Lauren; Hallett, Allen M.; Kudia, Ousswa; Joseph, Sitara; Modelska, Maria; Ortega, Dana; Parker, Nathan; Stevens, Andria

2015-01-01

Abstract Introduction: The Childhood Obesity Research Demonstration (CORD) project links public health and primary care interventions in three projects described in detail in accompanying articles in this issue of Childhood Obesity. This article describes a comprehensive evaluation plan to determine the extent to which the CORD model is associated with changes in behavior, body weight, BMI, quality of life, and healthcare satisfaction in children 2–12 years of age. Design/Methods: The CORD Evaluation Center (EC-CORD) will analyze the pooled data from three independent demonstration projects that each integrate public health and primary care childhood obesity interventions. An extensive set of common measures at the family, facility, and community levels were defined by consensus among the CORD projects and EC-CORD. Process evaluation will assess reach, dose delivered, and fidelity of intervention components. Impact evaluation will use a mixed linear models approach to account for heterogeneity among project-site populations and interventions. Sustainability evaluation will assess the potential for replicability, continuation of benefits beyond the funding period, institutionalization of the intervention activities, and community capacity to support ongoing program delivery. Finally, cost analyses will assess how much benefit can potentially be gained per dollar invested in programs based on the CORD model. Conclusions: The keys to combining and analyzing data across multiple projects include the CORD model framework and common measures for the behavioral and health outcomes along with important covariates at the individual, setting, and community levels. The overall objective of the comprehensive evaluation will develop evidence-based recommendations for replicating and disseminating community-wide, integrated public health and primary care programs based on the CORD model. PMID:25679060

Assessment of serum magnesium levels and its outcome in neonates of eclamptic mothers treated with low-dose magnesium sulfate regimen

PubMed Central

Das, Monalisa; Chaudhuri, Patralekha Ray; Mondal, Badal C.; Mitra, Sukumar; Bandyopadhyay, Debasmita; Pramanik, Sushobhan

2015-01-01

Objectives: Magnesium historically has been used for treatment and/or prevention of eclampsia. Considering the low body mass index of Indian women, a low-dose magnesium sulfate regime has been introduced by some authors. Increased blood levels of magnesium in neonates is associated with increased still birth, early neonatal death, birth asphyxia, bradycardia, hypotonia, gastrointestinal hypomotility. The objective of this study was to assess safety of low-dose magnesium sulfate regimen in neonates of eclamptic mothers treated with this regimen. Materials and Methods: This was a cross-sectional observational study of 100 eclampsia patients and their neonates. Loading dose and maintenance doses of magnesium sulfate were administered to patients by combination of intravenous and intramuscular routes. Maternal serum and cord blood magnesium levels were estimated. Neonatal outcome was assessed. Results: Bradycardia was observed in 18 (19.15%) of the neonates, 16 (17.02%) of the neonates were diagnosed with hypotonia. Pearson Correlation Coefficient showed Apgar scores decreased with increase in cord blood magnesium levels. Unpaired t-test showed lower Apgar scores with increasing dose of magnesium sulfate. The Chi-square/Fisher's exact test showed significant increase in hypotonia, birth asphyxia, intubation in delivery room, Neonatal Intensive Care Unit (NICU) care requirement, with increasing dose of magnesium sulfate. (P ≤ 0.05). Conclusion: Several neonatal complications are significantly related to increasing serum magnesium levels. Overall, the low-dose magnesium sulfate regimen was safe in the management of eclamptic mothers, without toxicity to their neonates. PMID:26600638

Dosimetric effects of rotational offsets in stereotactic body radiation therapy (SBRT) for lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Yun; Catalano, Suzanne; Kelsey, Chris R.

2014-04-01

To quantitatively evaluate dosimetric effects of rotational offsets in stereotactic body radiation therapy (SBRT) for lung cancer. Overall, 11 lung SBRT patients (8 female and 3 male; mean age: 75.0 years) with medially located tumors were included. Treatment plans with simulated rotational offsets of 1°, 3°, and 5° in roll, yaw, and pitch were generated and compared with the original plans. Both clockwise and counterclockwise rotations were investigated. The following dosimetric metrics were quantitatively evaluated: planning target volume coverage (PTV V{sub 100%}), max PTV dose (PTV D{sub max}), percentage prescription dose to 0.35 cc of cord (cord D{sub 0.35} {submore » cc}), percentage prescription dose to 0.35 cc and 5 cc of esophagus (esophagus D{sub 0.35} {sub cc} and D{sub 5} {sub cc}), and volume of the lungs receiving at least 20 Gy (lung V{sub 20}). Statistical significance was tested using Wilcoxon signed rank test at the significance level of 0.05. Overall, small differences were found in all dosimetric matrices at all rotational offsets: 95.6% of differences were < 1% or < 1 Gy. Of all rotational offsets, largest change in PTV V{sub 100%}, PTV D{sub max}, cord D{sub 0.35} {sub cc}, esophagus D{sub 0.35} {sub cc}, esophagus D{sub 5} {sub cc}, and lung V{sub 20} was − 8.36%, − 6.06%, 11.96%, 8.66%, 6.02%, and − 0.69%, respectively. No significant correlation was found between any dosimetric change and tumor-to-cord/esophagus distances (R{sup 2} range: 0 to 0.44). Larger dosimetric changes and intersubject variations were observed at larger rotational offsets. Small dosimetric differences were found owing to rotational offsets up to 5° in lung SBRT for medially located tumors. Larger intersubject variations were observed at larger rotational offsets.« less

Reducing dose to the lungs through loosing target dose homogeneity requirement for radiotherapy of non small cell lung cancer.

PubMed

Miao, Junjie; Yan, Hui; Tian, Yuan; Ma, Pan; Liu, Zhiqiang; Li, Minghui; Ren, Wenting; Chen, Jiayun; Zhang, Ye; Dai, Jianrong

2017-11-01

It is important to minimize lung dose during intensity-modulated radiation therapy (IMRT) of nonsmall cell lung cancer (NSCLC). In this study, an approach was proposed to reduce lung dose by relaxing the constraint of target dose homogeneity during treatment planning of IMRT. Ten NSCLC patients with lung tumor on the right side were selected. The total dose for planning target volume (PTV) was 60 Gy (2 Gy/fraction). For each patient, two IMRT plans with six beams were created in Pinnacle treatment planning system. The dose homogeneity of target was controlled by constraints on the maximum and uniform doses of target volume. One IMRT plan was made with homogeneous target dose (the resulting target dose was within 95%-107% of the prescribed dose), while another IMRT plan was made with inhomogeneous target dose (the resulting target dose was more than 95% of the prescribed dose). During plan optimization, the dose of cord and heart in two types of IMRT plans were kept nearly the same. The doses of lungs, PTV and organs at risk (OARs) between two types of IMRT plans were compared and analyzed quantitatively. For all patients, the lung dose was decreased in the IMRT plans with inhomogeneous target dose. On average, the mean dose, V5, V20, and V30 of lung were reduced by 1.4 Gy, 4.8%, 3.7%, and 1.7%, respectively, and the dose to normal tissue was also reduced. These reductions in DVH values were all statistically significant (P < 0.05). There were no significant differences between the two IMRT plans on V25, V30, V40, V50 and mean dose for heart. The maximum doses of cords in two type IMRT plans were nearly the same. IMRT plans with inhomogeneous target dose could protect lungs better and may be considered as a choice for treating NSCLC. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Isl1 Is required for multiple aspects of motor neuron development

PubMed Central

Liang, Xingqun; Song, Mi-Ryoung; Xu, ZengGuang; Lanuza, Guillermo M.; Liu, Yali; Zhuang, Tao; Chen, Yihan; Pfaff, Samuel L.; Evans, Sylvia M.; Sun, Yunfu

2011-01-01

The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in multiple organs and plays essential roles during embryogenesis. Isl1 is required for the survival and specification of spinal cord motor neurons. Due to early embryonic lethality and loss of motor neurons, the role of Isl1 in other aspects of motor neuron development remains unclear. In this study, we generated Isl1 mutant mouse lines expressing graded doses of Isl1. Our study has revealed essential roles of Isl1 in multiple aspects of motor neuron development, including motor neuron cell body localization, motor column formation and axon growth. In addition, Isl1 is required for survival of cranial ganglia neurons. PMID:21569850

Finite element simulation and experimental verification of steel cord extraction of steel cord conveyor belt splice

NASA Astrophysics Data System (ADS)

Li, X. G.; Long, X. Y.; Jiang, H. Q.; Long, H. B.

2018-05-01

The splice is the weakest part of the entire steel cord conveyor belt. And it occurs steel cord twitch fault frequently. If this fault cannot be dealt with timely and accurately, broken belt accidents would be occurred that affecting the safety of production seriously. In this paper, we investigate the steel cord pullout of the steel cord conveyor belt splice by using ABAQUS software. We selected the strength of steel cord conveyor belt ST630, the same as experiment sample in type specification. The finite element model consists of rubber, steel cord and failure unit. And the failure unit is used to simulate the bonding relationship between the steel cord and the rubber. Mooney-Rivlin hyper-elastic model for rubber was employed in the numerical simulations. The pullout force of length 50.0 mm single steel cord, on both sides of a single steel cord and on both sides of the double steel cords each impacted at steel cord conveyor belt splice were numerically computer and typical results obtained have been validated by experimental result. It shows that the relative error between simulation results and experimental results is within 10% and can be considered that the simulation model is reliable. A new method is provided for studying the steel cord twitch fault of the steel cord conveyor belt splice.

Estimation of patient-specific imaging dose for real-time tumour monitoring in lung patients during respiratory-gated radiotherapy

NASA Astrophysics Data System (ADS)

Shiinoki, Takehiro; Onizuka, Ryota; Kawahara, Daisuke; Suzuki, Tatsuhiko; Yuasa, Yuki; Fujimoto, Koya; Uehara, Takuya; Hanazawa, Hideki; Shibuya, Keiko

2018-03-01

Purpose: To quantify the patient-specific imaging dose for real-time tumour monitoring in the lung during respiratory-gated stereotactic body radiotherapy (SBRT) in clinical cases using SyncTraX. Methods and Materials: Ten patients who underwent respiratory-gated SBRT with SyncTraX were enrolled in this study. The imaging procedure for real-time tumour monitoring using SyncTraX was simulated using Monte Carlo. We evaluated the dosimetric effect of a real-time tumour monitoring in a critical organ at risk (OAR) and the planning target volume (PTV) over the course of treatment. The relationship between skin dose and gating efficiency was also investigated. Results: For all patients, the mean D50 to the PTV, ipsilateral lung, liver, heart, spinal cord and skin was 118.3 (21.5–175.9), 31.9 (9.5–75.4), 15.4 (1.1–31.6), 10.1 (1.3–18.1), 25.0 (1.6–101.8), and 3.6 (0.9–7.1) mGy, respectively. The mean D2 was 352.0 (26.5–935.8), 146.4 (27.3–226.7), 90.7 (3.6–255.0), 42.2 (4.8–82.7), 88.0 (15.4–248.5), and 273.5 (98.3–611.6) mGy, respectively. The D2 of the skin dose was found to increase as the gating efficiency decreased. Conclusions: The additional dose to the PTV was at most 1.9% of the prescribed dose over the course of treatment for real-time tumour monitoring. For OARs, we could confirm the high dose region, which may not be susceptible to radiation toxicity. However, to reduce the skin dose from SyncTraX, it is necessary to increase the gating efficiency.

Precision IORT - Image guided intraoperative radiation therapy (igIORT) using online treatment planning including tissue heterogeneity correction.

PubMed

Schneider, Frank; Bludau, Frederic; Clausen, Sven; Fleckenstein, Jens; Obertacke, Udo; Wenz, Frederik

2017-05-01

To the present date, IORT has been eye and hand guided without treatment planning and tissue heterogeneity correction. This limits the precision of the application and the precise documentation of the location and the deposited dose in the tissue. Here we present a set-up where we use image guidance by intraoperative cone beam computed tomography (CBCT) for precise online Monte Carlo treatment planning including tissue heterogeneity correction. An IORT was performed during balloon kyphoplasty using a dedicated Needle Applicator. An intraoperative CBCT was registered with a pre-op CT. Treatment planning was performed in Radiance using a hybrid Monte Carlo algorithm simulating dose in homogeneous (MCwater) and heterogeneous medium (MChet). Dose distributions on CBCT and pre-op CT were compared with each other. Spinal cord and the metastasis doses were evaluated. The MCwater calculations showed a spherical dose distribution as expected. The minimum target dose for the MChet simulations on pre-op CT was increased by 40% while the maximum spinal cord dose was decreased by 35%. Due to the artefacts on the CBCT the comparison between MChet simulations on CBCT and pre-op CT showed differences up to 50% in dose. igIORT and online treatment planning improves the accuracy of IORT. However, the current set-up is limited by CT artefacts. Fusing an intraoperative CBCT with a pre-op CT allows the combination of an accurate dose calculation with the knowledge of the correct source/applicator position. This method can be also used for pre-operative treatment planning followed by image guided surgery. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Effect of prenatal and early life paracetamol exposure on the level of neurotransmitters in rats--Focus on the spinal cord.

PubMed

Blecharz-Klin, Kamilla; Joniec-Maciejak, Ilona; Jawna, Katarzyna; Pyrzanowska, Justyna; Piechal, Agnieszka; Wawer, Adriana; Widy-Tyszkiewicz, Ewa

2015-12-01

The present study has examined the influence of the prenatal and early life administration of paracetamol on the level of neurotransmitters in the spinal cord of rat pups. The effect of the drug was evaluated in 2-month old Wistar male rats exposed to paracetamol in doses of 5 (P5, n=9) or 15 mg/kg (P15, n=9) p.o. during the prenatal period and after birth until the completion of the second month of life. A parallel control group received tap water (Con, n=9). In this study we have determined the level of monoamines, their metabolites and amino acids in the spinal cord of rats using high performance liquid chromatography (HPLC) in the second month of life. The present experiment demonstrates the action of paracetamol at the molecular level associated with significant modulation of neurotransmission in the spinal cord related to dopaminergic and noradrenergic systems. Simultaneously, paracetamol administration increases the content of an aspartic and glutamic acids in the spinal cord at a critical time during development. Copyright © 2015 Elsevier Ltd. All rights reserved.

Spinal cord distribution of sup 3 H-morphine after intrathecal administration: Relationship to analgesia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishio, Y.; Sinatra, R.S.; Kitahata, L.M.

1989-09-01

The distribution of intrathecally administered {sup 3}H-morphine was examined by light microscopic autoradiography in rat spinal cord and temporal changes in silver grain localization were compared with results obtained from simultaneous measurements of analgesia. After tissue processing, radio-activity was found to have penetrated in superficial as well as in deeper layers (Rexed lamina V, VII, and X) of rat spinal cord within minutes after application. Silver grain density reached maximal values at 30 min in every region of cord studied. Radioactivity decreased rapidly between 30 min and 2 hr and then more slowly over the next 24 hr. In ratsmore » tested for responses to a thermal stimulus (tail flick test), intrathecal administration of morphine (5 and 15 micrograms) resulted in significant dose dependent analgesia that peaked at 30 min and lasted up to 5 hr (P less than 0.5). There was a close relationship between analgesia and spinal cord silver grain density during the first 4 hr of the study. It is postulated that the onset of spinal morphine analgesia depends on appearance of molecules at sites of action followed by the activation of anti-nociceptive mechanisms.« less

Activity-specific aquatic therapy targeting gait for a patient with incomplete spinal cord injury.

PubMed

Wall, Tracy; Falvo, Lisa; Kesten, Adam

2017-04-01

Aquatic therapy can lead to improved mobility and health in individuals with various conditions. This case report looks at an activity-specific aquatic therapy targeting gait for a patient with incomplete spinal cord injury (iSCI). The patient participated in an individualized aquatic therapy program two times a week for 6 weeks. Assessment occurred prior to the intervention. There were two follow-up assessments after the intervention. Follow-up assessment 1 was completed within the same week as the final intervention. Follow-up assessment 2 was completed 4 weeks after the first follow-up to assess for carryover. Improvements that met minimal detectable change and minimal clinically important difference were noted in The Walking for Spinal Cord Injury Index-II, Spinal Cord Injury Functional Ambulation Index gait parameters, and gait speed. An activity-specific aquatic therapy program improved gait in a patient with iSCI. The properties of water create a practical environment for safe practice of skills. Further studies are warranted in large samples.

Investigation of the effect of traditional Chinese medicine on pain and inflammation in chronic nonbacterial prostatitis in rats.

PubMed

Liu, Y-J; Song, G-H; Liu, G T

2016-08-01

According to traditional Chinese medicine, the symptoms of chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CNP/CPPS) may be treated using a cocktail of herbs that stimulate blood circulation ('activating blood circulation formula'). We investigated the effect of three doses of this formula on a rat model of CNP/CPPS. Male Wistar rats were injected with a saline extract of male sex accessory glands on days 0 and 30 to induce prostatitis and then treated daily by gavage between days 32 and 60. Treatment with low, medium and high doses of activating blood circulation formula resulted in an almost total rescue of paw withdrawal threshold at day 60, and treatment with the highest dose also significantly decreased prostate inflammation (assessed histopathologically). We further observed elevated serum prostaglandin E2 levels in the CNP/CPPS model which decreased upon high-dose treatment, and increased Cox-2 expression in the prostate and spinal cord dorsal horn which was rescued in both tissues in the high-dose group and in the prostate in the medium-dose group. These results shed light on a possible mechanism by which activating blood circulation therapy may alleviate pain in a rat model of CNP/CPPS by downregulating Cox-2 expression in the spinal cord, thereby raising the pain threshold. Further research will be needed to fully characterise the mechanism by which activating blood circulation therapy produces this therapeutic effect. © 2016 Blackwell Verlag GmbH.

The adaptation to pregnancy of spinal cord injured women.

PubMed

Craig, D I

1990-01-01

This study explored the experiences encountered by spinal cord injured women during pregnancy. The spinal cord injured women experienced complications associated with pregnancy: recurring urinary tract infections, an increase in incontinence, and autonomic dysreflexia. (The first two of these are not unique to spinal cord injury, but are common in all pregnancies.) They neither developed pressure areas nor experienced premature deliveries, major complications predicted by the literature. All felt they were victims of inadequate environmental design that hindered their mobility and inhibited their independence. Many of the psychosocial aspects studied proved to be common to pregnant women in general and not specific to the spinal cord injured population.

The changing nature of admissions to a spinal cord injury center: violence on the rise.

PubMed

Farmer, J C; Vaccaro, A R; Balderston, R A; Albert, T J; Cotler, J

1998-10-01

The purpose of this study was to analyze changing etiologies for admission to a spinal cord injury center. This study was designed to retrospectively analyze the etiology of admissions to a spinal cord injury center during a 15-year period, specifically gunshot versus nongunshot wound injuries. Gunshot wounds are a well-recognized cause of spinal cord injury. In some centers, up to 52% of admissions are due to this, and these trends are believed to be increasing. All patients with spinal cord injury admitted to our center between 1979 and 1993 were analyzed. Frequencies of specific etiologies were determined and then comparisons were made between gunshot wound and nongunshot wound groups. Factors analyzed included age, male/female ratio, ethnic make-up, marital status, employment status, level of injury, and neurologic status. One thousand eight hundred seventeen patients were included. Overall, gunshot wound spinal cord injuries compromised 16.9% of injuries. A clear trend of increasing numbers of admissions was seen between 1984 and 1993 because of this. Gunshot wounds and nongunshot wounds differed dramatically in terms of age, ethnic make-up, marital status, employment status, and neurologic status. Cost attributed to treating gunshot wound injuries at our center for 1993 was 5.4 million dollars. Gunshot wounds as a cause of spinal cord injury are increasing at an alarming rate. The demographics of the gunshot wounds and nongunshot wound spine cord injuries differ significantly.

In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [(18)F]GE-180 and effect of docosahexaenoic acid.

PubMed

Tremoleda, J L; Thau-Zuchman, O; Davies, M; Foster, J; Khan, I; Vadivelu, K C; Yip, P K; Sosabowski, J; Trigg, W; Michael-Titus, A T

2016-08-01

Traumatic spinal cord injury (SCI) is a devastating condition which affects millions of people worldwide causing major disability and substantial socioeconomic burden. There are currently no effective treatments. Modulating the neuroinflammatory (NI) response after SCI has evolved as a major therapeutic strategy. PET can be used to detect the upregulation of the 18-kDa translocator protein (TSPO), a hallmark of activated microglia in the CNS. We investigated whether PET imaging using the novel TSPO tracer [(18)F]GE-180 can be used as a clinically relevant biomarker for NI in a contusion SCI rat model, and we present data on the modulation of NI by the lipid docosahexaenoic acid (DHA). A total of 22 adult male Wistar rats were subjected to controlled spinal cord contusion at the T10 spinal cord level. Six non-injured and ten T10 laminectomy only (LAM) animals were used as controls. A subset of six SCI animals were treated with a single intravenous dose of 250 nmol/kg DHA (SCI-DHA group) 30 min after injury; a saline-injected group of six animals was used as an injection control. PET and CT imaging was carried out 7 days after injury using the [(18)F]GE-180 radiotracer. After imaging, the animals were killed and the spinal cord dissected out for biodistribution and autoradiography studies. In vivo data were correlated with ex vivo immunohistochemistry for TSPO. In vivo dynamic PET imaging revealed an increase in tracer uptake in the spinal cord of the SCI animals compared with the non-injured and LAM animals from 35 min after injection (P < 0.0001; SCI vs. LAM vs. non-injured). Biodistribution and autoradiography studies confirmed the high affinity and specific [(18)F]GE-180 binding in the injured spinal cord compared with the binding in the control groups. Furthermore, they also showed decreased tracer uptake in the T10 SCI area in relation to the non-injured remainder of the spinal cord in the SCI-DHA group compared with the SCI-saline group (P < 0.05), supporting a NI modulatory effect of DHA. Immunohistochemistry showed a high level of TSPO expression (38 %) at the T10 injury site in SCI animals compared with that in the non-injured animals (6 %). [(18)F]GE-180 PET imaging can reveal areas of increased TSPO expression that can be visualized and quantified in vivo after SCI, offering a minimally invasive approach to the monitoring of NI in SCI models and providing a translatable clinical readout for the testing of new therapies.

Brn3a/Pou4f1 Regulates Dorsal Root Ganglion Sensory Neuron Specification and Axonal Projection into the Spinal Cord

PubMed Central

Zou, Min; Li, Shengguo; Klein, William H.; Xiang, Mengqing

2012-01-01

The sensory neurons of the dorsal root ganglia (DRG) must project accurately to their central targets to convey proprioceptive, nociceptive and mechanoreceptive information to the spinal cord. How these different sensory modalities and central connectivities are specified and coordinated still remains unclear. Given the expression of the POU homeodomain transcription factors Brn3a/Pou4f1 and Brn3b/Pou4f2 in DRG and spinal cord sensory neurons, we determined the subtype specification of DRG and spinal cord sensory neurons as well as DRG central projections in Brn3a and Brn3b single and double mutant mice. Inactivation of either or both genes causes no gross abnormalities in early spinal cord neurogenesis; however, in Brn3a single and Brn3a;Brn3b double mutant mice, sensory afferent axons from the DRG fail to form normal trajectories in the spinal cord. The TrkA+ afferents remain outside the dorsal horn and fail to extend into the spinal cord, while the projections of TrkC+ proprioceptive afferents into the ventral horn are also impaired. Moreover, Brn3a mutant DRGs are defective in sensory neuron specification, as marked by the excessive generation of TrkB+ and TrkC+ neurons as well as TrkA+/TrkB+ and TrkA+/TrkC+ double positive cells at early embryonic stages. At later stages in the mutant, TrkB+, TrkC+ and parvalbumin+ neurons diminish while there is a significant increase of CGRP+ and c-ret+ neurons. In addition, Brn3a mutant DRGs display a dramatic down-regulation of Runx1 expression, suggesting that the regulation of DRG sensory neuron specification by Brn3a is mediated in part by Runx1. Our results together demonstrate a critical role for Brn3a in generating DRG sensory neuron diversity and regulating sensory afferent projections to the central targets. PMID:22326227

Dynamic membrane depolarization is an early regulator of ependymoglial cell response to spinal cord injury in axolotl

PubMed Central

Sabin, Keith; Santos-Ferreira, Tiago; Essig, Jaclyn; Rudasill, Sarah; Echeverri, Karen

2016-01-01

Salamanders, such as the Mexican axolotl, are some of the few vertebrates fortunate in their ability to regenerate diverse structures after injury. Unlike mammals they are able to regenerate a fully functional spinal cord after injury. However, the molecular circuitry required to initiate a pro-regenerative response after spinal cord injury is not well understood. To address this question we developed a spinal cord injury model in axolotls and used in vivo imaging of labeled ependymoglial cells to characterize the response of these cells to injury. Using in vivo imaging of ion sensitive dyes we identified that spinal cord injury induces a rapid and dynamic change in the resting membrane potential of ependymoglial cells. Prolonged depolarization of ependymoglial cells after injury inhibits ependymoglial cell proliferation and subsequent axon regeneration. Using transcriptional profiling we identified c-Fos as a key voltage sensitive early response gene that is expressed specifically in the ependymoglial cells after injury. This data establishes that dynamic changes in the membrane potential after injury are essential for regulating the specific spatiotemporal expression of c-Fos that is critical for promoting faithful spinal cord regeneration in axolotl. PMID:26477559

Site-specific gene transfer into the rat spinal cord by photomechanical waves

NASA Astrophysics Data System (ADS)

Ando, Takahiro; Sato, Shunichi; Toyooka, Terushige; Uozumi, Yoichi; Nawashiro, Hiroshi; Ashida, Hiroshi; Obara, Minoru

2011-10-01

Nonviral, site-specific gene delivery to deep tissue is required for gene therapy of a spinal cord injury. However, an efficient method satisfying these requirements has not been established. This study demonstrates efficient and targeted gene transfer into the spinal cord by using photomechanical waves (PMWs), which were generated by irradiating a black laser absorbing rubber with 532-nm nanosecond Nd:YAG laser pulses. After a solution of plasmid DNA coding for enhanced green fluorescent protein (EGFP) or luciferase was intraparenchymally injected into the spinal cord, PMWs were applied to the target site. In the PMW application group, we observed significant EGFP gene expression in the white matter and remarkably high luciferase activity only in the spinal cord segment exposed to the PMWs. We also assessed hind limb movements 24 h after the application of PMWs based on the Basso-Beattie-Bresnahan (BBB) score to evaluate the noninvasiveness of this method. Locomotor evaluation showed no significant decrease in BBB score under optimum laser irradiation conditions. These findings demonstrated that exogenous genes can be efficiently and site-selectively delivered into the spinal cord by applying PMWs without significant locomotive damage.

Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice

PubMed Central

Bates, EA; Nikai, T; Brennan, KC; Fu, Y-H; Charles, AC; Basbaum, AI; Ptáček, LJ; Ahn, AH

2016-01-01

The association between the clinical use of nitroglycerin (NTG) and headache has led to the examination of NTG as a model trigger for migraine and related headache disorders, both in humans and laboratory animals. In this study in mice, we hypothesized that NTG could trigger behavioural and physiological responses that resemble a common manifestation of migraine in humans. We report that animals exhibit a dose-dependent and prolonged NTG-induced thermal and mechanical allodynia, starting 30–60 min after intraperitoneal injection of NTG at 5–10 mg/kg. NTG administration also induced Fos expression, an anatomical marker of neuronal activity in neurons of the trigeminal nucleus caudalis and cervical spinal cord dorsal horn, suggesting that enhanced nociceptive processing within the spinal cord contributes to the increased nociceptive behaviour. Moreover, sumatriptan, a drug with relative specificity for migraine, alleviated the NTG-induced allodynia. We also tested whether NTG reduces the threshold for cortical spreading depression (CSD), an event considered to be the physiological substrate of the migraine aura. We found that the threshold of CSD was unaffected by NTG, suggesting that NTG stimulates migraine mechanisms that are independent of the regulation of cortical excitability. PMID:19489890

Spinal Anesthesia in Infant Rats: Development of a Model and Assessment of Neurological Outcomes

PubMed Central

Yahalom, Barak; Athiraman, Umeshkumar; Soriano, Sulpicio G.; Zurakowski, David; Carpino, Elizabeth; Corfas, Gabriel; Berde, Charles B.

2012-01-01

Background Previous studies in infant rats and case-control studies of human infants undergoing surgery have raised concerns about potential neurodevelopmental toxicities of general anesthesia. Spinal anesthesia is an alternative to general anesthesia for some infant surgeries. To test for potential toxicity, we developed a spinal anesthesia model in infant rats. Methods Rats of postnatal ages 7, 14, and 21 days were assigned to: no treatment; 1% isoflurane for either 1 h or 6 h, or lumbar spinal injection of saline or bupivacaine, at doses of 3.75 mg/kg (low dose) or 7.5 mg/kg (high dose). Subgroups of animals underwent neurobehavioral testing and blood gas analysis. Brain and lumbar spinal cord sections were examined for apoptosis using cleaved caspase-3 immunostaining. Lumbar spinal cord was examined histologically. Rats exposed to spinal or general anesthesia as infants underwent Rotarod testing of motor performance as adults. Data were analyzed using analysis of variance (ANOVA) using general linear models, Friedman Tests, and Mann–Whitney U tests, as appropriate. Results Bupivacaine 3.75 mg/kg was effective for spinal anesthesia in all age groups, and produced sensory and motor function recovered in 40 to 60 min. Blood gases were similar among groups. Brain and spinal cord apoptosis increased in rats receiving 6 h of 1% isoflurane, but not among the other treatments. All groups showed intact motor performance at adulthood. Conclusions Spinal anesthesia is technically feasible in infant rats, and appears benign in terms of neuroapoptotic and neuromotor sequelae. PMID:21555934

Epithelioid hemangioendothelioma of the spine treated with RapidArc volumetric-modulated radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guy, Jean-Baptiste; Trone, Jane-Chloé; Chargari, Cyrus

2014-10-01

Radiotherapy for epithelioid hemangioendothelioma (EHE) using volumetric intensity-modulated arc radiotherapy (VMAT). A 48-year-old woman was referred for curative irradiation of a vertebral EHE after failure of surgery. A comparison between VMAT and conventional conformal tridimensional (3D) dosimetry was performed and potential advantage of VMAT for sparing critical organs from irradiation's side effects was discussed. The total delivered dose on the planning target volume was 54 Gy in 27 fractions. The patient was finally treated with VMAT. The tolerance was excellent. There was no acute toxicity, including no increase in pain. With a follow-up of 18 months, no delayed toxicity wasmore » reported. The clinical response consisted of a decrease in the dorsal pain. The D{sub max} for the spinal cord was reduced from 55 Gy (3D-radiotherapy [RT]) (which would be an unacceptable dose to the spine because of the risk of myelopathy) to 42.8 Gy (VMAT), which remains below the recommended dose threshold (45 Gy). The dose delivered to 20% of organ volume (D{sub 20}) was reduced from 47 Gy (3D-RT) to 3 Gy (VMAT) for the spinal cord. The study shows that VMAT allows the delivery of curative treatment for vertebral EHEs because of critical organ sparing.« less

Changes in the retreatment radiation tolerance of the spinal cord with time after the initial treatment.

PubMed

Woolley, Thomas E; Belmonte-Beitia, Juan; Calvo, Gabriel F; Hopewell, John W; Gaffney, Eamonn A; Jones, Bleddyn

2018-06-01

To estimate, from experimental data, the retreatment radiation 'tolerances' of the spinal cord at different times after initial treatment. A model was developed to show the relationship between the biological effective doses (BEDs) for two separate courses of treatment with the BED of each course being expressed as a percentage of the designated 'retreatment tolerance' BED value, denoted [Formula: see text] and [Formula: see text]. The primate data of Ang et al. ( 2001 ) were used to determine the fitted parameters. However, based on rodent data, recovery was assumed to commence 70 days after the first course was complete, and with a non-linear relationship to the magnitude of the initial BED (BED init ). The model, taking into account the above processes, provides estimates of the retreatment tolerance dose after different times. Extrapolations from the experimental data can provide conservative estimates for the clinic, with a lower acceptable myelopathy incidence. Care must be taken to convert the predicted [Formula: see text] value into a formal BED value and then a practical dose fractionation schedule. Used with caution, the proposed model allows estimations of retreatment doses with elapsed times ranging from 70 days up to three years after the initial course of treatment.

A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy.

PubMed

Cordes, Henrik; Thiel, Christoph; Aschmann, Hélène E; Baier, Vanessa; Blank, Lars M; Kuepfer, Lars

2016-10-01

Due to its high early bactericidal activity, isoniazid (INH) plays an essential role in tuberculosis treatment. Genetic polymorphisms of N-acetyltransferase type 2 (NAT2) cause a trimodal distribution of INH pharmacokinetics in slow, intermediate, and fast acetylators. The success of INH-based chemotherapy is associated with acetylator and patient health status. Still, a standard dose recommended by the FDA is administered regardless of acetylator type or immune status, even though adverse effects occur in 5 to 33% of all patients. Slow acetylators have a higher risk of development of drug-induced toxicity, while fast acetylators and immune-deficient patients face lower treatment success rates. To mechanistically assess the trade-off between toxicity and efficacy, we developed a physiologically based pharmacokinetic (PBPK) model describing the NAT2-dependent pharmacokinetics of INH and its metabolites. We combined the PBPK model with a pharmacodynamic (PD) model of antimycobacterial drug effects in the lungs. The resulting PBPK/PD model allowed the simultaneous simulation of treatment efficacies at the site of infection and exposure to toxic metabolites in off-target organs. Subsequently, we evaluated various INH dosing regimens in NAT2-specific immunocompetent and immune-deficient virtual populations. Our results suggest the need for acetylator-specific dose adjustments for optimal treatment outcomes. A reduced dose for slow acetylators substantially lowers the exposure to toxic metabolites and thereby the risk of adverse events, while it maintains sufficient treatment efficacies. Vice versa, intermediate and fast acetylators benefit from increased INH doses and a switch to a twice-daily administration schedule. Our analysis outlines how PBPK/PD modeling may be used to design and individualize treatment regimens. Copyright © 2016 Cordes et al.

Adult-type myogenesis of the frog Xenopus laevis specifically suppressed by notochord cells but promoted by spinal cord cells in vitro.

PubMed

Yamane, Hitomi; Ihara, Setsunosuke; Kuroda, Masaaki; Nishikawa, Akio

2011-08-01

Larval-to-adult myogenic conversion occurs in the dorsal muscle but not in the tail muscle during Xenopus laevis metamorphosis. To know the mechanism for tail-specific suppression of adult myogenesis, response character was compared between adult myogenic cells (Ad-cells) and larval tail myogenic cells (La-cells) to a Sonic hedgehog (Shh) inhibitor, notochord (Nc) cells, and spinal cord (SC) cells in vitro. Cyclopamine, an Shh inhibitor, suppressed the differentiation of cultured Ad (but not La) cells, suggesting the significance of Shh signaling in promoting adult myogenesis. To test the possibility that Shh-producing axial elements (notochord and spinal cord) regulate adult myogenesis, Ad-cells or La-cells were co-cultured with Nc or SC cells. The results showed that differentiation of Ad-cells were strongly inhibited by Nc cells but promoted by SC cells. If Ad-cells were "separately" co-cultured with Nc cells without direct cell-cell interactions, adult differentiation was not inhibited but rather promoted, suggesting that Nc cells have two roles, one is a short-range suppression and another is a long-range promotion for adult myogenesis. Immunohistochemical analysis showed both notochord and spinal cord express the N-terminal Shh fragment throughout metamorphosis. The "spinal cord-promotion" and long-range effect by Nc cells on adult myogenesis is thus involved in Shh signaling, while the signaling concerning the short-range "Nc suppression" will be determined by future studies. Interestingly, these effects, "Nc suppression" and "SC promotion" were not observed for La-cells. Situation where the spinal cord/notochord cross-sectional ratio is quite larger in tadpole trunk than in the tail seems to contribute to trunk-specific promotion and tail-specific suppression of adult myogenesis during Xenopus metamorphosis.

Beam-specific planning volumes for scattered-proton lung radiotherapy

NASA Astrophysics Data System (ADS)

Flampouri, S.; Hoppe, B. S.; Slopsema, R. L.; Li, Z.

2014-08-01

This work describes the clinical implementation of a beam-specific planning treatment volume (bsPTV) calculation for lung cancer proton therapy and its integration into the treatment planning process. Uncertainties incorporated in the calculation of the bsPTV included setup errors, machine delivery variability, breathing effects, inherent proton range uncertainties and combinations of the above. Margins were added for translational and rotational setup errors and breathing motion variability during the course of treatment as well as for their effect on proton range of each treatment field. The effect of breathing motion and deformation on the proton range was calculated from 4D computed tomography data. Range uncertainties were considered taking into account the individual voxel HU uncertainty along each proton beamlet. Beam-specific treatment volumes generated for 12 patients were used: a) as planning targets, b) for routine plan evaluation, c) to aid beam angle selection and d) to create beam-specific margins for organs at risk to insure sparing. The alternative planning technique based on the bsPTVs produced similar target coverage as the conventional proton plans while better sparing the surrounding tissues. Conventional proton plans were evaluated by comparing the dose distributions per beam with the corresponding bsPTV. The bsPTV volume as a function of beam angle revealed some unexpected sources of uncertainty and could help the planner choose more robust beams. Beam-specific planning volume for the spinal cord was used for dose distribution shaping to ensure organ sparing laterally and distally to the beam.

Analgesia Induced by Isolated Bovine Chromaffin Cells Implanted in Rat Spinal Cord

NASA Astrophysics Data System (ADS)

Sagen, Jacqueline; Pappas, George D.; Pollard, Harvey B.

1986-10-01

Chromaffin cells synthesize and secrete several neuroactive substances, including catecholamines and opioid peptides, that, when injected into the spinal cord, induce analgesia. Moreover, the release of these substances from the cells can be stimulated by nicotine. Since chromaffin cells from one species have been shown to survive when transplanted to the central nervous system of another species, these cells are ideal candidates for transplantation to alter pain sensitivity. Bovine chromaffin cells were implanted into the subarachnoid space of the lumbar spinal region in adult rats. Pain sensitivity and response to nicotine stimulation was determined at various intervals following cell implantation. Low doses of nicotine were able to induce potent analgesia in implanted animals as early as one day following their introduction into the host spinal cord. This response could be elicited at least through the 4 months the animals were tested. The induction of analgesia by nicotine in implanted animals was dose related. This analgesia was blocked by the opiate antagonist naloxone and partially attenuated by the adrenergic antagonist phentolamine. These results suggest that the analgesia is due to the stimulated release of opioid peptides and catecholamines from the implanted bovine chromaffin cells and may provide a new therapeutic approach for the relief of pain.

Botulinum toxin in spinal cord injury patients with neurogenic detrusor overactivity

PubMed Central

Cho, Young Sam; Kim, Khae Hawn

2016-01-01

Evidence for the efficacy and safety of intravesical onabotulinum toxin A (onabotA) injections has led to them being licensed in many countries, including Korea, for the treatment of patients with urinary incontinence due to neurogenic detrusor overactivity (NDO) resulting from spinal cord injury or multiple sclerosis who are refractory or intolerant to anticholinergic medications. OnabotA injections have an inhibitory effect on acetylcholine release for up to 10 months, with a recommended dose of 200 U. OnabotA treatment has a beneficial effect not only on urinary symptoms, but also on quality of life. Several clinical studies have shown onabotA to have better effects than placebo in achieving continence, reducing incontinence episodes, improving urodynamic parameters, and improving health-related quality of life. Urinary tract infections and postvoid residual volume are the most prevalent side effects. In patients with residual volume, clean intermittent catheterization may be necessary. In patients with spinal cord injury or multiple sclerosis, it is recommended to evaluate physical and cognitive function before intravesical onabotA injection to ensure that the patient and caregiver are able to perform catheterization if necessary. Further controlled trials should assess the optimal dose, injection technique, long-term safety of repeated injections, and optimal timing of onabotA treatment in the treatment of NDO. PMID:28119887

Spinal radiosurgery: a neurosurgical perspective

PubMed Central

Angelov, Lilyana; Rock, Jack; Weaver, Jason; Sheehan, Jason; Rhines, Laurence; Azeem, Syed; Gerszten, Peter

2011-01-01

Spine stereotactic radiosurgery (SSRS) is proving to be one of the most significant advances in the treatment of both metastatic and primary spine tumors. High-dose hypofractionated and single fraction radiation appear to convey better local tumor control than conventional radiation for tumors considered radioresistant, such as renal cell carcinoma and melanoma. Multiple series have demonstrated control rates greater than 85% which appears to be histology independent. The markedly improved local control rates compared to conventional radiation techniques are beginning to change the treatment paradigms for spine tumors. Recent evidence in the literature reflects the integration of SSRS in the treatment of metastatic and primary malignant and benign spine tumors as the principle treatment or as a neoadjuvant or postoperative adjuvant therapy. For instance, as confidence grows with the use of SSRS as a postoperative adjuvant, surgical resection of metastatic disease has become less aggressive with the expectation that radiation can control residual disease. Despite high dose radiation delivery within millimeters of the spinal cord, toxicity has been limited with rare cases of radiation-induced myelopathy. The establishment of spinal cord and other critical structure tolerances is essential to the continued evolution of SSRS, as radiation oncologists begin to use this modality to treat spinal cord compression. This paper reviews the neurosurgical integration of SRS into spine practice. PMID:29296297

Association of prenatal antibiotics with foetal size and cord blood leptin and adiponectin.

PubMed

Mueller, N T; Rifas-Shiman, S L; Blaser, M J; Gillman, M W; Hivert, M-F

2017-04-01

Early postnatal antibiotic use has been shown to promote excess weight gain, but it is unclear whether intrauterine exposure to antibiotics is associated with foetal growth and adiposity. The objective of this study was to examine associations of antibiotic prescription in each trimester of pregnancy with foetal size and adipokine levels at birth. In 2128 pregnant women from the pre-birth Project Viva cohort, from electronic medical records, we estimated antibiotic prescribing by timing during pregnancy. Outcomes were sex-specific birth weight-for-gestational-age z-score (BW/GA-z) and levels of umbilical cord leptin and adiponectin. We used linear regression models adjusted for maternal age, pre-pregnancy body mass index, parity, race/ethnicity, education, smoking during pregnancy, household income and child sex and additionally adjusted cord blood leptin and adiponectin models for gestation length. Of the 2128 women in our sample, 643 (30.2%) were prescribed with oral antibiotics during pregnancy. Mean (standard deviation) BW/GA-z was 0.17 (0.97), cord blood leptin was 9.0 ng mL -1 (6.6) and cord blood adiponectin was 28.8 ng mL -1 (6.8). Overall, antibiotic prescription in pregnancy was associated with lower BW/GA-z [multivariable adjusted β -0.11; 95% confidence interval {CI} -0.20, -0.01]. In trimester-specific analyses, only second trimester antibiotic prescription was associated with lower BW/GA-z (β -0.23; 95% CI -0.37, -0.08). Overall, antibiotic prescription in pregnancy was not associated with cord blood leptin or adiponectin levels. However, in trimester-specific analyses, third trimester antibiotic prescription was associated with higher cord blood leptin (β 2.28 ng mL -1 ; 95% CI 0.38, 4.17). Antibiotics in mid-pregnancy were associated with lower birth weight for gestational age, whereas third trimester antibiotics were associated with higher cord blood leptin. © 2016 World Obesity Federation.

Estimation of the maternal vitamin D intake that maintains circulating 25-hydroxyvitamin D in late gestation at a concentration sufficient to keep umbilical cord sera ≥25-30 nmol/L: a dose-response, double-blind, randomized placebo-controlled trial in pregnant women at northern latitude.

PubMed

O'Callaghan, Karen M; Hennessy, Áine; Hull, George Lj; Healy, Karina; Ritz, Christian; Kenny, Louise C; Cashman, Kevin D; Kiely, Mairead E

2018-06-06

In the absence of dose-response data, Dietary Reference Values for vitamin D in nonpregnant adults are extended to pregnancy. The aim was to estimate vitamin D intake needed to maintain maternal 25-hydroxyvitamin D [25(OH)D] in late gestation at a concentration sufficient to prevent newborn 25(OH)D <25-30 nmol/L, a threshold indicative of increased risk of nutritional rickets. We conducted a 3-arm, dose-response, double-blind, randomized placebo-controlled trial in Cork, Ireland (51.9oN). A total of 144 white-skinned pregnant women were assigned to receive 0, 10 (400 IU), or 20 (800 IU) µg vitamin D3/d from ≤18 wk of gestation. Vitamin D metabolites at 14, 24, and 36 wk of gestation and in cord sera, including 25(OH)D3, 3-epi-25(OH)D3, 24,25(OH)2D3, and 25(OH)D2 were quantified by liquid chromatography-tandem mass spectrometry. A curvilinear regression model predicted the total vitamin D intake (from diet and antenatal supplements plus treatment dose) that maintained maternal 25(OH)D in late gestation at a concentration sufficient to maintain cord 25(OH)D at ≥25-30 nmol/L. Mean ± SD baseline 25(OH)D was 54.9 ± 10.7 nmol/L. Total vitamin D intakes at the study endpoint (36 wk of gestation) were 12.1 ± 8.0, 21.9 ± 5.3, and 33.7 ± 5.1 µg/d in the placebo and 10-µg and 20-µg vitamin D3 groups, respectively; and 25(OH)D was 24.3 ± 5.8 and 29.2 ± 5.6 nmol/L higher in the 10- and 20-µg groups, respectively, compared with placebo (P < 0.001). For maternal 25(OH)D concentrations ≥50 nmol/L, 95% of cord sera were ≥30 nmol/L and 99% were >25 nmol/L. The estimated vitamin D intake required to maintain serum 25(OH)D at ≥50 nmol/L in 97.5% of women was 28.9 µg/d. Thirty micrograms of vitamin D per day safely maintained serum 25(OH)D concentrations at ≥50 nmol/L in almost all white-skinned women during pregnancy at a northern latitude, which kept 25(OH)D at >25 nmol/L in 99% and ≥30 nmol/L in 95% of umbilical cord sera. This trial was registered at www.clinicaltrials.gov as NCT02506439.

SU-E-T-309: Dosimetric Comparison of Simultaneous Integrated Boost Treatment Plan Between Intensity Modulated Radiotherapies (IMRTs), Dual Arc Volumetric Modulated Arc Therapy (DA-VMAT) and Single Arc Volumetric Modulated Arc Therapy (SA-VMAT) for Nasopharyngeal Carcinoma (NPC)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sivakumar, R; Janardhan, N; Bhavani, P

Purpose: To compare the plan quality and performance of Simultaneous Integrated Boost (SIB) Treatment plan between Seven field (7F) and Nine field(9F) Intensity Modulated Radiotherapies and Single Arc (SA) and Dual Arc (DA) Volumetric Modulated Arc Therapy( VMAT). Methods: Retrospective planning study of 16 patients treated in Elekta Synergy Platform (mlci2) by 9F-IMRT were replanned with 7F-IMRT, Single Arc VMAT and Dual Arc VMAT using CMS, Monaco Treatment Planning System (TPS) with Monte Carlo simulation. Target delineation done as per Radiation Therapy Oncology Protocols (RTOG 0225&0615). Dose Prescribed as 70Gy to Planning Target Volumes (PTV70) and 61Gy to PTV61 inmore » 33 fraction as a SIB technique. Conformity Index(CI), Homogeneity Index(HI) were used as analysis parameter for Target Volumes as well as Mean dose and Max dose for Organ at Risk(OAR,s).Treatment Delivery Time(min), Monitor unit per fraction (MU/fraction), Patient specific quality assurance were also analysed. Results: A Poor dose coverage and Conformity index (CI) was observed in PTV70 by 7F-IMRT among other techniques. SA-VMAT achieved poor dose coverage in PTV61. No statistical significance difference observed in OAR,s except Spinal cord (P= 0.03) and Right optic nerve (P=0.03). DA-VMAT achieved superior target coverage, higher CI (P =0.02) and Better HI (P=0.03) for PTV70 other techniques (7F-IMRT/9F-IMRT/SA-VMAT). A better dose spare for Parotid glands and spinal cord were seen in DA-VMAT. The average treatment delivery time were 5.82mins, 6.72mins, 3.24mins, 4.3mins for 7F-IMRT, 9F-IMRT, SA-VMAT and DA-VMAT respectively. Significance difference Observed in MU/fr (P <0.001) and Patient quality assurance pass rate were >95% (Gamma analysis (Γ3mm, 3%). Conclusion: DA-VAMT showed better target dose coverage and achieved better or equal performance in sparing OARs among other techniques. SA-VMAT offered least Treatment Time than other techniques but achieved poor target coverage. DA-VMAT offered shorter delivery time than 7F-IMRT and 9F-IMRT without compromising the plan quality.« less

Factors affecting Israeli women's decision whether to donate cord blood.

PubMed

Ben Natan, Merav; Grinberg, Keren; Galula, Sharon; Biton, Michal

2014-01-01

To examine whether Israeli mothers' intention to donate cord blood can be predicted using the Theory of Planned Behavior (TPB). A descriptive correlation study, employing the TPB. A questionnaire constructed based on a literature review of research on cord blood donation and on the TPB was administered to 207 Israeli women of childbearing age. Behavioral attitudes (women's total appraisal of cord blood donation), subjective norms (women's perception of the opinion of significant others regarding the specific behavior), and perceived behavioral control (women's total appraisal of their control of the behavior and perceived ease or difficulty of cord blood donation) were found to predict women's intention to donate cord blood. Since behavioral attitudes, subjective norms, and behavioral control can predict cord blood donations, it is important for the medical and nursing staff to understand and use these concepts if they hope to obtain women's cooperation concerning cord blood donation. Nurses should receive education on the subject of cord blood donation, increasing their awareness. It is possible that this could lead to a rise in such donations in the future. Both mothers and fathers should be consulted about the option of donating cord blood.

SU-F-T-224: Importance of Timely Review of Daily Cone-Beam CTs: Dosimetric Evaluation of Rejected CBCTs for Head and Neck Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andrews, M; Yu, N; Joshi, N

Purpose: To dosimetrically evaluate the importance of timely reviewing daily CBCTs for patients with head and neck cancer. Methods: After each fraction daily cone-beam CT (CBCT) for head and neck patients are reviewed by physicians prior to next treatment. Physician rejected image registrations of CBCT were identified and analyzed for 17 patients. These CBCT images were rigidly fused with planning CT images and the contours from the planning CT were transferred to CBCTs. Because of limited extension in the superior-inferior dimension contours with partial volumes in CBCTs were discarded. The treatment isocenter was placed by applying the clinically recorded shiftsmore » to the volume isocenter of the CBCT. Dose was recalculated at the shifted isocenter using a homogeneous dose calculation algorithm. Dosimetrically relevant changes defined as greater than 5% deviation from the clinically accepted plans but with homogeneous dose calculation were evaluated for the high dose (HD), intermediate dose (ID), and low dose (LD) CTVs, spinal cord, larynx, oropharynx, parotids, and submandibular glands. Results: Among seventeen rejected CBCTS, HD-CTVs, ID-CTVs, and LD-CTVs were completely included in the CBCTs for 17, 1, and 15 patients, respectively. The prescription doses to the HD-CTV, ID-CTV, and LD-CTV were received by < 95% of the CTV volumes in 5/17, 1/1, and 5/15 patients respectively. For the spinal cord, the maximum doses (D0.03cc) were increased > 5% in 13 of 17 patients. For the oropharynx, larynx, parotid, and submandibular glands, the mean dose of these organs at risk was increased > 5% in 7/17, 8/12, 11/16 and 6/16 patients, respectively. Conclusion: Timely review daily CBCTs for head and neck patients under daily CBCT guidance is important, and uncorrected setup errors can translate to dosimetrically relevant dose increases in organsat- risk and dose decreases in the clinical target volumes.« less

TU-G-BRD-05: Results From Multi-Institutional Measurements with An Anthropomorphic Spine Phantom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Molineu, A; Hernandez, N; Alvarez, P

Purpose: To analyze the results from an anthropomorphic spine phantom used for credentialing institutions for National Cancer Institute (NCI) sponsored clinical trial. Methods: An anthropomorphic phantom that contains left and right lungs, a heart, an esophagus, spinal cord, bony material and a PTV was sent to institutions wishing to be credentialed for NCI trials. The PTV holds 4 TLD and radiochromic film in the axial and sagittal planes. The heart holds one TLD. Institutions created IMRT plans to cover ≥90% of the PTV with 6 Gy and limit the cord dose to <0.35cc receiving 3.75 Gy and <1.2cc receiving 2.63more » Gy. They were instructed to treat the phantom as they would a patient, including making plan specific IMRT/SBRT QA measurements before treatment. The TLD results in the PTV were required to be within ±7% of the plan dose. A gamma calculation was performed using the film results and the submitted DICOM plan. ≥85% of the analyzed region was required to pass a 5%/3 mm criteria. Results: 176 institutions irradiated the spine phantom for a total of 255 results. The pass rate was 73% (187 irradiations) overall. 44 irradiations failed only the gamma criteria, 2 failed only the dose criteria and 22 failed both. The most used planning systems were Eclipse (116) and Pinnacle (52) and they had pass rates of 76% and 71%, respectively. The AAA algorithm had a pass rate of 77% while superposition type algorithms had a 71% pass rate. The average TLD measurement to institution calculation ratio was 0.99 (0.04 std dev.). The average percent pixels passing the gamma criteria for films was 89% (12% std dev.) Conclusion: Results show that this phantom is an important part of credentialing and that we have room for improvement in IMRT/SBRT spine treatments. This work was supported by PHS CA180803 and CA037422 awarded by NCI, DHHS.« less

SU-E-T-233: Cyberknife Versus Linac IMRT for Dose Comparision in Hypofractionated Hemi Larynx Irradiation of Early Stage True Vocal Cord Cancer: A Dosimetric Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, C; Lee, P; Jiang, S

2015-06-15

Purpose: To compare dosimetric data of patients treated for early-stage larynx cancer on Cyberknife and Linac IMRT. Methods: Nine patients were treated with Cyberknife to a dose of 45 Gy in 10 fractions of the involved hemilarynx. The prescription dose provided at least 95% of PTV coverage. After Cyberknife treatment, the CT images and contours were sent to Pinnacle treatment planning system for IMRT planning on a regular SBRT linac with same dose prescription and constrains. Dose to target and normal tissue, including the arytenoids, cord, carotid arteries, thyroid, and skin, were analyzed using dose volume histograms. Results: For Cyberknifemore » plan, the conformity indices are within 1.11–1.33. The average dose to the contralateral arytenoids for Cyberknife plans was 28.9±6.5Gy), which is lower than the same mean dose for IMRT plans (34.0±5.2 Gy). The average maximum dose to the ipsilateral and contralateral carotid artery were 20.6 ±9.1 Gy and 10.2±6.0 Gy respectively for Cybeknife comparing with 22.1±8.0 Gy and 12.0±5.1 Gy for IMRT. The mean dose to the thyroid was 3.6±2.2 Gy for Cyberknife and 3.4±2.4 Gy for IMRT. As shown in DVH, the Cyberknife can deliver less dose to the normal tissue which is close to target area comparing with IMRT Plans. However, IMRT plan’s can give more sparing for the critical organs which is far away from the target area. Conclusion: We have compared the dosimetric parameters of Cyberknife and linac IMRT plans for patients with early-stage larynx cancer. Both Cyberknife and IMRT plans can achieve conformal dose distribution to the target area. Cyberknife was able to reduce normal tissue dose in high doses region while IMRT plans can reduce the dose of the normal tissue at the low dose region. These dosimetric parameters can be used to guide future prospective protocols using SBRT for larynx cancer.« less

Tacrolimus placental transfer at delivery and neonatal exposure through breast milk.

PubMed

Zheng, Songmao; Easterling, Thomas R; Hays, Karen; Umans, Jason G; Miodovnik, Menachem; Clark, Shannon; Calamia, Justina C; Thummel, Kenneth E; Shen, Danny D; Davis, Connie L; Hebert, Mary F

2013-12-01

The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk. Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject. Mean (±SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng ml(-1)) were 71 ± 18% (range 45-99%) of maternal concentrations (9.0 ± 3.4 ng ml(-1)). The mean umbilical cord venous plasma (0.09 ± 0.04 ng ml(-1)) and unbound drug concentrations (0.003 ± 0.001 ng ml(-1)) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant. © 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Specific factors for prenatal lead exposure in the border area of China.

PubMed

Kawata, Kimiko; Li, Yan; Liu, Hao; Zhang, Xiao Qin; Ushijima, Hiroshi

2006-07-01

The objectives of this study are to examine the prevalence of increased blood lead concentrations in mothers and their umbilical cords, and to identify risk factors for prenatal lead exposure in Kunming city, Yunnan province, China. The study was conducted at two obstetrics departments, and 100 peripartum women were enrolled. The mean blood lead concentrations of the mothers and the umbilical cords were 67.3microg/l and 53.1microg/l, respectively. In multiple linear regression analysis, maternal occupational exposure, maternal consumption of homemade dehydrated vegetables and maternal habitation period in Kunming city were significantly associated with an increase of umbilical cord blood lead concentration. In addition, logistic regression analysis was used to assess the association of umbilical cord blood lead concentrations that possibly have adverse effects on brain development of newborns with each potential risk factor. Maternal frequent use of tableware with color patterns inside was significantly associated with higher cord blood lead concentration in addition to the three items in the multiple linear regression analysis. These points should be considered as specific recommendations for maternal and fetal lead exposure in this city.

Isl1 is required for multiple aspects of motor neuron development.

PubMed

Liang, Xingqun; Song, Mi-Ryoung; Xu, ZengGuang; Lanuza, Guillermo M; Liu, Yali; Zhuang, Tao; Chen, Yihan; Pfaff, Samuel L; Evans, Sylvia M; Sun, Yunfu

2011-07-01

The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in multiple organs and plays essential roles during embryogenesis. Isl1 is required for the survival and specification of spinal cord motor neurons. Due to early embryonic lethality and loss of motor neurons, the role of Isl1 in other aspects of motor neuron development remains unclear. In this study, we generated Isl1 mutant mouse lines expressing graded doses of Isl1. Our study has revealed essential roles of Isl1 in multiple aspects of motor neuron development, including motor neuron cell body localization, motor column formation and axon growth. In addition, Isl1 is required for survival of cranial ganglia neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

Vocal cord dysfunction in a child.

PubMed

Juliá, J C; Martorell, A; Armengot, M A; Lluch, R; Boluda, C F; Cerdá, J C; Alvarez, V

1999-07-01

Vocal cord dysfunction (VCD) involves paradoxical adduction of the vocal cord during the respiratory cycle. This usually occurs during inspiration, but can also be seen in expiration. Vocal cord appositioning produces airflow obstruction sufficient to cause wheezing, shortness of breath, chest tightness, and coughing. These symptoms often imitate the respiratory alterations of asthma, thus leading to inappropriate treatment; intubation or tracheotomy may prove necessary. An 11-year-old girl was admitted with intractable dyspnea. She had been diagnosed with atopic asthma, although she failed to respond to an increase in antiasthma medication, including high-dose oral steroids. Flow-volume loops were abnormal, with evidence of variable extrathoracic airway obstruction, manifested as a flat inspiratory loop. No structural abnormalities were seen with either computed tomography (CT) or magnetic resonance imaging (MRI). Fibroscopy revealed paradoxical adduction of the vocal cords during the respiratory cycle, no obstructive disorder being observed. After the diagnosis of VCD, the clinical manifestations resolved with psychiatric treatment. Adduction was not demonstrable at repeat fibroscopy after treatment. VCD may simulate bronchial asthma; it may also be associated with that disorder, thus masking the diagnosis. It should be suspected in patients with recurrent wheezing who fail to respond to usual asthma treatment. An early diagnosis avoids unnecessary aggressive management. Treatment should consist of respiratory and phonatory exercises; psychotherapy may be useful.

4D CT-based Treatment Planning for Intensity-Modulated Radiation Therapy and Proton Therapy for Distal Esophagus Cancer

PubMed Central

Zhang, Xiaodong; Zhao, Kuai-Le; Guerrero, Thomas M.; McGuire, Sean E.; Yaremko, Brian; Komaki, Ritsuko; Cox, James D.; Hui, Zhouguang; Li, Yupeng; Newhauser, Wayne D.; Mohan, Radhe; Liao, Zhongxing

2008-01-01

Purpose To compare three-dimensional (3D) and 4D computed tomography (CT)– based treatment plans for proton therapy or intensity-modulated radiation therapy (IMRT) for esophageal cancer in terms of doses to the lung, heart, and spinal cord and variations in target coverage and normal tissue sparing. Materials and Methods IMRT and proton plans for 15 patients with distal esophageal cancer were designed from the 3D average CT scans and then recalculated on 10 4D CT data sets. Dosimetric data were compared for tumor coverage and normal tissue sparing. Results Compared with IMRT, median lung volumes exposed to 5,10, and 20 Gy and mean lung dose were reduced by 35.6%, 20.5%,5.8%, and 5.1 Gy for a two-beam proton plan and by 17.4%,8.4%,5%, and 2.9 Gy for a three-beam proton plan. The greater lung sparing in the two-beam proton plan was achieved at the expense of less conformity to the target (conformity index CI=1.99) and greater irradiation of the heart (heart-V40=41.8%) compared with the IMRT plan(CI=1.55, heart-V40=35.7%) or the three-beam proton plan (CI=1.46, heart-V40=27.7%). Target coverage differed by more than 2% between the 3D and 4D plans for patients with substantial diaphragm motion in the three-beam proton and IMRT plans. The difference in spinal cord maximum dose between 3D and 4D plans could exceed 5 Gy for the proton plans partly owing to variations in stomach gas-filling. Conclusions Proton therapy provided significantly better sparing of lung than did IMRT. Diaphragm motion and stomach gas-filling must be considered in evaluating target coverage and cord doses. PMID:18722278

Four-dimensional computed tomography-based treatment planning for intensity-modulated radiation therapy and proton therapy for distal esophageal cancer.

PubMed

Zhang, Xiaodong; Zhao, Kuai-le; Guerrero, Thomas M; McGuire, Sean E; Yaremko, Brian; Komaki, Ritsuko; Cox, James D; Hui, Zhouguang; Li, Yupeng; Newhauser, Wayne D; Mohan, Radhe; Liao, Zhongxing

2008-09-01

To compare three-dimensional (3D) and four-dimensional (4D) computed tomography (CT)-based treatment plans for proton therapy or intensity-modulated radiation therapy (IMRT) for esophageal cancer in terms of doses to the lung, heart, and spinal cord and variations in target coverage and normal tissue sparing. The IMRT and proton plans for 15 patients with distal esophageal cancer were designed from the 3D average CT scans and then recalculated on 10 4D CT data sets. Dosimetric data were compared for tumor coverage and normal tissue sparing. Compared with IMRT, median lung volumes exposed to 5, 10, and 20 Gy and mean lung dose were reduced by 35.6%, 20.5%, 5.8%, and 5.1 Gy for a two-beam proton plan and by 17.4%, 8.4%, 5%, and 2.9 Gy for a three-beam proton plan. The greater lung sparing in the two-beam proton plan was achieved at the expense of less conformity to the target (conformity index [CI], 1.99) and greater irradiation of the heart (heart-V40, 41.8%) compared with the IMRT plan(CI, 1.55, heart-V40, 35.7%) or the three-beam proton plan (CI, 1.46, heart-V40, 27.7%). Target coverage differed by more than 2% between the 3D and 4D plans for patients with substantial diaphragm motion in the three-beam proton and IMRT plans. The difference in spinal cord maximum dose between 3D and 4D plans could exceed 5 Gy for the proton plans partly owing to variations in stomach gas filling. Proton therapy provided significantly better sparing of lung than did IMRT. Diaphragm motion and stomach gas-filling must be considered in evaluating target coverage and cord doses.

SU-D-201-01: A Multi-Institutional Study Quantifying the Impact of Simulated Linear Accelerator VMAT Errors for Nasopharynx

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pogson, E; Liverpool and Macarthur Cancer Therapy Centres, Liverpool, NSW; Ingham Institute for Applied Medical Research, Sydney, NSW

Purpose: To quantify the impact of differing magnitudes of simulated linear accelerator errors on the dose to the target volume and organs at risk for nasopharynx VMAT. Methods: Ten nasopharynx cancer patients were retrospectively replanned twice with one full arc VMAT by two institutions. Treatment uncertainties (gantry angle and collimator in degrees, MLC field size and MLC shifts in mm) were introduced into these plans at increments of 5,2,1,−1,−2 and −5. This was completed using an in-house Python script within Pinnacle3 and analysed using 3DVH and MatLab. The mean and maximum dose were calculated for the Planning Target Volume (PTV1),more » parotids, brainstem, and spinal cord and then compared to the original baseline plan. The D1cc was also calculated for the spinal cord and brainstem. Patient average results were compared across institutions. Results: Introduced gantry angle errors had the smallest effect of dose, no tolerances were exceeded for one institution, and the second institutions VMAT plans were only exceeded for gantry angle of ±5° affecting different sided parotids by 14–18%. PTV1, brainstem and spinal cord tolerances were exceeded for collimator angles of ±5 degrees, MLC shifts and MLC field sizes of ±1 and beyond, at the first institution. At the second institution, sensitivity to errors was marginally higher for some errors including the collimator error producing doses exceeding tolerances above ±2 degrees, and marginally lower with tolerances exceeded above MLC shifts of ±2. The largest differences occur with MLC field sizes, with both institutions reporting exceeded tolerances, for all introduced errors (±1 and beyond). Conclusion: The plan robustness for VMAT nasopharynx plans has been demonstrated. Gantry errors have the least impact on patient doses, however MLC field sizes exceed tolerances even with relatively low introduced errors and also produce the largest errors. This was consistent across both departments. The authors acknowledge funding support from the NSW Cancer Council.« less

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

PubMed Central

Largent-Milnes, Tally M.; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H.; Vanderah, Todd W.

2017-01-01

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)–G protein coupling from Gi/o to Gs that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L5/L6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to Gs in the damaged (ipsilateral) spinal dorsal horn. This MOR-Gs coupling occurred without changing Gi/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-Gs coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-Gs coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this Gs coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-Gs coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. PMID:18468954

Critical dose and toxicity index of organs at risk in radiotherapy: Analyzing the calculated effects of modified dose fractionation in non–small cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pedicini, Piernicola, E-mail: ppiern@libero.it; Strigari, Lidia; Benassi, Marcello

2014-04-01

To increase the efficacy of radiotherapy for non–small cell lung cancer (NSCLC), many schemes of dose fractionation were assessed by a new “toxicity index” (I), which allows one to choose the fractionation schedules that produce less toxic treatments. Thirty-two patients affected by non resectable NSCLC were treated by standard 3-dimensional conformal radiotherapy (3DCRT) with a strategy of limited treated volume. Computed tomography datasets were employed to re plan by simultaneous integrated boost intensity-modulated radiotherapy (IMRT). The dose distributions from plans were used to test various schemes of dose fractionation, in 3DCRT as well as in IMRT, by transforming the dose-volumemore » histogram (DVH) into a biological equivalent DVH (BDVH) and by varying the overall treatment time. The BDVHs were obtained through the toxicity index, which was defined for each of the organs at risk (OAR) by a linear quadratic model keeping an equivalent radiobiological effect on the target volume. The less toxic fractionation consisted in a severe/moderate hyper fractionation for the volume including the primary tumor and lymph nodes, followed by a hypofractionation for the reduced volume of the primary tumor. The 3DCRT and IMRT resulted, respectively, in 4.7% and 4.3% of dose sparing for the spinal cord, without significant changes for the combined-lungs toxicity (p < 0.001). Schedules with reduced overall treatment time (accelerated fractionations) led to a 12.5% dose sparing for the spinal cord (7.5% in IMRT), 8.3% dose sparing for V{sub 20} in the combined lungs (5.5% in IMRT), and also significant dose sparing for all the other OARs (p < 0.001). The toxicity index allows to choose fractionation schedules with reduced toxicity for all the OARs and equivalent radiobiological effect for the tumor in 3DCRT, as well as in IMRT, treatments of NSCLC.« less

The effect of umbilical cord cleansing with chlorhexidine on omphalitis and neonatal mortality in community settings in developing countries: a meta-analysis

PubMed Central

2013-01-01

Background There is an increased risk of serious neonatal infection arising through exposure of the umbilical cord to invasive pathogen in home and facility births where hygienic practices are difficult to achieve. The World Health Organization currently recommends ‘dry cord care’ because of insufficient data in favor of or against topical application of an antiseptic. The primary objective of this meta-analysis is to evaluate the effects of application of chlorhexidine (CHX) to the umbilical cord to children born in low income countries on cord infection (omphalitis) and neonatal mortality. Standardized guidelines of Child Health Epidemiology Reference Group (CHERG) were followed to generate estimates of effectiveness of topical chlorhexidine application to umbilical cord for prevention of sepsis specific mortality, for inclusion in the Lives Saved Tool (LiST). Methods Systematic review and meta-analysis. Data sources included Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, CINHAL and WHO international clinical trials registry. Only randomized trials were included. Studies of children in hospital settings were excluded. The comparison group received no application to the umbilical cord (dry cord care), no intervention, or a non-CHX intervention. Primary outcomes were omphalitis and all-cause neonatal mortality. Results There were three cluster-randomised community trials (total participants 54,624) conducted in Nepal, Bangladesh and Pakistan that assessed impact of CHX application to the newborn umbilical cord for prevention of cord infection and mortality. Application of any CHX to the umbilical cord of the newborn led to a 23% reduction in all-cause neonatal mortality in the intervention group compared to control [RR 0.77, 95 % CI 0.63, 0.94; random effects model, I2=50 %]. The reduction in omphalitis ranged from 27 % to 56 % compared to control group depending on severity of infection. Based on CHERG rules, effect size for all-cause mortality was used for inclusion to LiST model as a proxy for sepsis specific mortality. Conclusions Application of CHX to newborn umbilical cord can significantly reduce incidence of umbilical cord infection and all-cause mortality among home births in community settings. This inexpensive and simple intervention can save a significant number of newborn lives in developing countries. PMID:24564621

Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats.

PubMed

Mattioli, Theresa-Alexandra M; Milne, Brian; Cahill, Catherine M

2010-04-16

The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance. Spinal cord sections from rats administered chronic morphine showed significantly increased immuno-labelling of astrocytes and microglia compared to saline controls, consistent with activation. 3-D images of astrocytes from animals administered chronic morphine had significantly larger volumes compared to saline controls. Co-injection of ultra-low dose naltrexone attenuated this increase in volume, but the mean volume differed from saline-treated and naltrexone-treated controls. Astrocyte and microglial immuno-labelling was attenuated in rats co-administered ultra-low dose naltrexone compared to morphine-treated rats and did not differ from controls. Glial activation, as characterized by immunohistochemical labelling and cell size, was positively correlated with the extent of tolerance developed. Morphine-induced glial activation was not due to cell proliferation as there was no difference observed in the total number of glial cells following chronic morphine treatment compared to controls. Furthermore, using 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed following chronic morphine administration. Taken together, we demonstrate a positive correlation between the prevention of analgesic tolerance and the inhibition of spinal gliosis by treatment with ultra-low dose naltrexone. This research provides further validation for using ultra-low dose opioid receptor antagonists in the treatment of various pain syndromes.

Intrathecal Morphine Attenuates Recovery of Function after a Spinal Cord Injury

PubMed Central

Moreno, Georgina; Woller, Sarah; Puga, Denise; Hoy, Kevin; Balden, Robyn; Grau, James W.

2009-01-01

Abstract Prior work has shown that a high dose (20 mg/kg) of systemic morphine, required to produce significant analgesia in the acute phase of a contusion injury, undermines the long-term health of treated subjects and increases lesion size. Moreover, a single dose of systemic morphine in the early stage of injury (24 h post-injury) led to symptoms of neuropathic pain 3 weeks later, in the chronic phase. The present study examines the locus of the effects using intrathecal morphine administration. Subjects were treated with one of three doses (0, 30, or 90 μg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-μg dose produced significant analgesia when subjects were exposed to noxious stimuli (thermal and incremented shock) below the level of injury. Yet, despite analgesic efficacy, intrathecal morphine significantly attenuated the recovery of locomotor function and increased lesion size rostral to the injury site. A single dose of 30 or 90 μg of intrathecal morphine also decreased weight gain, and more than doubled the incidence of mortality and autophagia when compared to vehicle-treated controls. Morphine is one of the most effective pharmacological agents for the treatment of neuropathic pain and, therefore, is indispensable for the spinally injured. Treatment can, however, adversely affect the recovery process. A morphine-induced attenuation of recovery may result from increases in immune cell activation and, subsequently, pro-inflammatory cytokine concentrations in the contused spinal cord. PMID:19388818

A quantitative study of IMRT delivery effects in commercial planning systems for the case of oesophagus and prostate tumours.

PubMed

Seco, J; Clark, C H; Evans, P M; Webb, S

2006-05-01

This study focuses on understanding the impact of intensity-modulated radiotherapy (IMRT) delivery effects when applied to plans generated by commercial treatment-planning systems such as Pinnacle (ADAC Laboratories Inc.) and CadPlan/Helios (Varian Medical Systems). These commercial planning systems have had several version upgrades (with improvements in the optimization algorithm), but the IMRT delivery effects have not been incorporated into the optimization process. IMRT delivery effects include head-scatter fluence from IMRT fields, transmission through leaves and the effect of the rounded shape of the leaf ends. They are usually accounted for after optimization when leaf sequencing the "optimal" fluence profiles, to derive the delivered fluence profile. The study was divided into two main parts: (a) analysing the dose distribution within the planning-target volume (PTV), produced by each of the commercial treatment-planning systems, after the delivered fluence had been renormalized to deliver the correct dose to the PTV; and (b) studying the impact of the IMRT delivery technique on the surrounding critical organs such as the spinal cord, lungs, rectum, bladder etc. The study was performed for tumours of (i) the oesophagus and (ii) the prostate and pelvic nodes. An oesophagus case was planned with the Pinnacle planning system for IMRT delivery, via multiple-static fields (MSF) and compensators, using the Elekta SL25 with a multileaf collimator (MLC) component. A prostate and pelvic nodes IMRT plan was performed with the Cadplan/Helios system for a dynamic delivery (DMLC) using the Varian 120-leaf Millennium MLC. In these commercial planning systems, since IMRT delivery effects are not included into the optimization process, fluence renormalization is required such that the median delivered PTV dose equals the initial prescribed PTV dose. In preparing the optimum fluence profile for delivery, the PTV dose has been "smeared" by the IMRT delivery techniques. In the case of the oesophagus, the critical organ, spinal cord, received a greater dose than initially planned, due to the delivery effects. The increase in the spinal cord dose is of the order of 2-3 Gy. In the case of the prostate and pelvic nodes, the IMRT delivery effects led to an increase of approximately 2 Gy in the dose delivered to the secondary PTV, the pelvic nodes. In addition to this, the small bowel, rectum and bladder received an increased dose of the order of 2-3 Gy to 50% of their total volume. IMRT delivery techniques strongly influence the delivered dose distributions for the oesophagus and prostate/pelvic nodes tumour sites and these effects are not yet accounted for in the Pinnacle and the CadPlan/Helios planning systems. Currently, they must be taken into account during the optimization stage by altering the dose limits accepted during optimization so that the final (sequenced) dose is within the constraints.

Discrimination of heterogenous mRNAs encoding strychnine-sensitive glycine receptors in Xenopus oocytes by antisense oligonucleotides.

PubMed Central

Akagi, H; Patton, D E; Miledi, R

1989-01-01

Three synthetic oligodeoxynucleotides complementary to different parts of an RNA encoding a glycine receptor subunit were used to discriminate heterogenous mRNAs coding for glycine receptors in adult and neonatal rat spinal cord. Injection of the three antisense oligonucleotides into Xenopus oocytes specifically inhibited the expression of glycine receptors by adult spinal cord mRNA. In contrast, the antisense oligonucleotides were much less potent in inhibiting the expression of glycine receptors encoded by neonatal spinal cord mRNA. Northern blot analysis revealed that the oligonucleotides hybridized mostly to an adult cord transcript of approximately 10 kilobases in size. This band was also present in neonatal spinal cord mRNA but its density was about one-fourth of the adult cord message. There was no intense band in the low molecular weight position (approximately 2 kilobases), the existence of which was expected from electrophysiological studies with size-fractionated mRNA of neonatal spinal cord. Our results suggest that in the rat spinal cord there are at least three different types of mRNAs encoding functional strychnine-sensitive glycine receptors. Images PMID:2479016

Experimental spinal cord trauma: a review of mechanically induced spinal cord injury in rat models.

PubMed

Abdullahi, Dauda; Annuar, Azlina Ahmad; Mohamad, Masro; Aziz, Izzuddin; Sanusi, Junedah

2017-01-01

It has been shown that animal spinal cord compression (using methods such as clips, balloons, spinal cord strapping, or calibrated forceps) mimics the persistent spinal canal occlusion that is common in human spinal cord injury (SCI). These methods can be used to investigate the effects of compression or to know the optimal timing of decompression (as duration of compression can affect the outcome of pathology) in acute SCI. Compression models involve prolonged cord compression and are distinct from contusion models, which apply only transient force to inflict an acute injury to the spinal cord. While the use of forceps to compress the spinal cord is a common choice due to it being inexpensive, it has not been critically assessed against the other methods to determine whether it is the best method to use. To date, there is no available review specifically focused on the current compression methods of inducing SCI in rats; thus, we performed a systematic and comprehensive publication search to identify studies on experimental spinalization in rat models, and this review discusses the advantages and limitations of each method.

Regulation of dorso‐ventral polarity by the nerve cord during annelid regeneration: A review of experimental evidence

PubMed Central

Boilly‐Marer, Yolande; Bely, Alexandra E.

2017-01-01

Abstract An important goal for understanding regeneration is determining how polarity is conferred to the regenerate. Here we review findings in two groups of polychaete annelids that implicate the ventral nerve cord in assigning dorso‐ventral polarity, and specifically ventral identity, to the regenerate. In nereids, surgical manipulations indicate that parapodia develop where dorsal and ventral body wall territories contact. Without a nerve cord at the wound site, the regenerate differentiates no evident polarity (with no parapodia) and only dorsal identity, while with two nerve cords the regenerate develops a twinned dorso‐ventral axis (with four parapodia per segment instead of the normal two). In sabellids, a striking natural dorso‐ventral inversion in parapodial morphology occurs along the body axis and this inversion is morphologically correlated with the position of the nerve cord. Parapodial inversion also occurs in segments in which the nerve cord has been removed, even without any segment amputation. Together, these data strongly support a role for the nerve cord in annelid dorso‐ventral pattern regulation, with the nerve cord conferring ventral identity. PMID:28616245

Transverse myelitis-like presentation of methanol intoxication: A case report and review of the literature.

PubMed

Algahtani, Hussein; Shirah, Bader; Ahmad, Raafat; Abobaker, Hind; Hmoud, Mohammed

2018-01-01

Methanol is the simplest member of alcohol family. However, it is an extremely toxic substance to humans upon exposure with severe and detrimental effects that range from visual loss to death. Spinal cord involvement in methanol intoxication is a rare occurrence. In this article, we are reporting a case of methanol intoxication with extensive spinal cord involvement possibly due to necrosis. A literature review yielded only two cases of spinal cord involvement due to methanol intoxication. Our article is the first to discuss the spinal cord involvement specifically including interesting neuroimaging features. We recommend performing MRI of the cervicothoracic spine in every methanol intoxication case to exclude both asymptomatic and symptomatic cases of spinal cord involvement.

Does combined therapy of curcumin and epigallocatechin gallate have a synergistic neuroprotective effect against spinal cord injury?

PubMed

Ruzicka, Jiri; Urdzikova, Lucia Machova; Svobodova, Barbora; Amin, Anubhav G; Karova, Kristyna; Dubisova, Jana; Zaviskova, Kristyna; Kubinova, Sarka; Schmidt, Meic; Jhanwar-Uniyal, Meena; Jendelova, Pavla

2018-01-01

Systematic inflammatory response after spinal cord injury (SCI) is one of the factors leading to lesion development and a profound degree of functional loss. Anti-inflammatory compounds, such as curcumin and epigallocatechin gallate (EGCG) are known for their neuroprotective effects. In this study, we investigated the effect of combined therapy of curcumin and EGCG in a rat model of acute SCI induced by balloon compression. Immediately after SCI, rats received curcumin, EGCG, curcumin + EGCG or saline [daily intraperitoneal doses (curcumin, 6 mg/kg; EGCG 17 mg/kg)] and weekly intramuscular doses (curcumin, 60 mg/kg; EGCG 17 mg/kg)] for 28 days. Rats were evaluated using behavioral tests (the Basso, Beattie, and Bresnahan (BBB) open-field locomotor test, flat beam test). Spinal cord tissue was analyzed using histological methods (Luxol Blue-cresyl violet staining) and immunohistochemistry (anti-glial fibrillary acidic protein, anti-growth associated protein 43). Cytokine levels (interleukin-1β, interleukin-4, interleukin-2, interleukin-6, macrophage inflammatory protein 1-alpha, and RANTES) were measured using Luminex assay. Quantitative polymerase chain reaction was performed to determine the relative expression of genes (Sort1, Fgf2, Irf5, Mrc1, Olig2, Casp3, Gap43, Gfap, Vegf, NfκB, Cntf) related to regenerative processes in injured spinal cord. We found that all treatments displayed significant behavioral recovery, with no obvious synergistic effect after combined therapy of curcumin and ECGC. Curcumin and EGCG alone or in combination increased axonal sprouting, decreased glial scar formation, and altered the levels of macrophage inflammatory protein 1-alpha, interleukin-1β, interleukin-4 and interleukin-6 cytokines. These results imply that although the expected synergistic response of this combined therapy was less obvious, aspects of tissue regeneration and immune responses in severe SCI were evident.

SU-D-BRC-05: Effects of Motion and Variable RBE in a Lung Patient Treated with Passively Scattered Protons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mirkovic, D; Titt, U; Mohan, R

2016-06-15

Purpose: To evaluate effects of motion and variable relative biological effectiveness (RBE) in a lung cancer patient treated with passively scattered proton therapy using dose volume histograms associated with patient dose computed using three different methods. Methods: A proton treatment plan of a lung cancer patient optimized using clinical treatment planning system (TPS) was used to construct a detailed Monte Carlo (MC) model of the beam delivery system and the patient specific aperture and compensator. A phase space file containing all particles transported through the beam line was collected at the distal surface of the range compensator and subsequently transportedmore » through two different patient models. The first model was based on the average CT used by the TPS and the second model included all 10 phases of the corresponding 4DCT. The physical dose and proton linear energy transfer (LET) were computed in each voxel of two models and used to compute constant and variable RBE MC dose on average CT and 4D CT. The MC computed doses were compared to the TPS dose using dose volume histograms for relevant structures. Results: The results show significant differences in doses to the target and critical structures suggesting the need for more accurate proton dose computation methods. In particular, the 4D dose shows reduced coverage of the target and higher dose to the spinal cord, while variable RBE dose shows higher lung dose. Conclusion: The methodology developed in this pilot study is currently used for the analysis of a cohort of ∼90 lung patients from a clinical trial comparing proton and photon therapy for lung cancer. The results from this study will help us in determining the clinical significance of more accurate dose computation models in proton therapy.« less

Absence of Association between Cord Specific Antibody Levels and Severe Respiratory Syncytial Virus (RSV) Disease in Early Infants: A Case Control Study from Coastal Kenya.

PubMed

Nyiro, Joyce Uchi; Sande, Charles Jumba; Mutunga, Martin; Kiyuka, Patience Kerubo; Munywoki, Patrick Kioo; Scott, John Anthony G; Nokes, David James

2016-01-01

The target group for severe respiratory syncytial virus (RSV) disease prevention is infants under 6 months of age. Vaccine boosting of antibody titres in pregnant mothers could protect these young infants from severe respiratory syncytial virus (RSV) associated disease. Quantifying protective levels of RSV-specific maternal antibody at birth would inform vaccine development. A case control study nested in a birth cohort (2002-07) was conducted in Kilifi, Kenya; where 30 hospitalised cases of RSV-associated severe disease were matched to 60 controls. Participants had a cord blood and 2 subsequent 3-monthly blood samples assayed for RSV-specific neutralising antibody by the plaque reduction neutralisation test (PRNT). Two sample paired t test and conditional logistic regression were used in analyses of log2PRNT titres. The mean RSV log2PRNT titre at birth for cases and controls were not significantly different (P = 0.4) and remained so on age-stratification. Cord blood PRNT titres showed considerable overlap between cases and controls. The odds of RSV disease decreased with increase in log2PRNT cord blood titre. There was a 30% reduction in RSV disease per unit increase in log2PRNT titre (<3months age group) but not significant (P = 0.3). From this study, there is no strong evidence of protection by maternal RSV specific antibodies from severe RSV disease. Cord antibody levels show wide variation with considerable overlap between cases and controls. It is likely that, there are additional factors to specific PRNT antibody levels which determine susceptibility to severe RSV disease. In addition, higher levels of neutralizing antibody beyond the normal range may be required for protection; which it is hoped can be achieved by a maternal RSV vaccine.

Is neuroinflammation in the injured spinal cord different than in the brain? Examining intrinsic differences between the brain and spinal cord.

PubMed

Zhang, B; Gensel, J C

2014-08-01

The field of neuroimmunology is rapidly advancing. There is a growing appreciation for heterogeneity, both in inflammatory composition and region-specific inflammatory responses. This understanding underscores the importance of developing targeted immunomodulatory therapies for treating neurological disorders. Concerning neurotrauma, there is a dearth of publications directly comparing inflammatory responses in the brain and spinal cord after injury. The question therefore remains as to whether inflammatory cells responding to spinal cord vs. brain injury adopt similar functions and are therefore amenable to common therapies. In this review, we address this question while revisiting and modernizing the conclusions from publications that have directly compared inflammation across brain and spinal cord injuries. By examining molecular differences, anatomical variations, and inflammatory cell phenotypes between the injured brain and spinal cord, we provide insight into how neuroinflammation relates to neurotrauma and into fundamental differences between the brain and spinal cord. Copyright © 2014 Elsevier Inc. All rights reserved.

Intricacies of Using Kevlar Cord and Thermal Knives in a Deployable Release System: Issues and Solutions

NASA Technical Reports Server (NTRS)

Stewart, Alphonso; Hair, Jason H.

2002-01-01

The utilization of Kevlar cord and thermal knives in a deployable release system produces a number of issues that must be addressed in the design of the system. This paper proposes design considerations that minimize the major issues, thermal knife failure, Kevlar cord relaxation, and the measurement of the cord tension. Design practices can minimize the potential for thermal knife laminate and element damage that result in failure of the knife. A process for in-situ inspection of the knife with resistance, rather than continuity, checks and 10x zoom optical imaging can detect damaged knives. Tests allow the characterization of the behavior of the particular Kevlar cord in use and the development of specific prestretching techniques and initial tension values needed to meet requirements. A new method can accurately measure the tension of the Kevlar cord using a guitar tuner, because more conventional methods do not apply to arimid cords such as Kevlar.

Intricacies of Using Kevlar Cord and Thermal Knives in a Deployable Release System: Issues and Solutions

NASA Astrophysics Data System (ADS)

Stewart, Alphonso; Hair, Jason H.

2002-04-01

The utilization of Kevlar cord and thermal knives in a deployable release system produces a number of issues that must be addressed in the design of the system. This paper proposes design considerations that minimize the major issues, thermal knife failure, Kevlar cord relaxation, and the measurement of the cord tension. Design practices can minimize the potential for thermal knife laminate and element damage that result in failure of the knife. A process for in-situ inspection of the knife with resistance, rather than continuity, checks and 10x zoom optical imaging can detect damaged knives. Tests allow the characterization of the behavior of the particular Kevlar cord in use and the development of specific prestretching techniques and initial tension values needed to meet requirements. A new method can accurately measure the tension of the Kevlar cord using a guitar tuner, because more conventional methods do not apply to arimid cords such as Kevlar.

Extreme umbilical cord lengths, cord knot and entanglement: Risk factors and risk of adverse outcomes, a population-based study

PubMed Central

Kessler, Jörg

2018-01-01

Objectives To determine risk factors for short and long umbilical cord, entanglement and knot. Explore their associated risks of adverse maternal and perinatal outcome, including risk of recurrence in a subsequent pregnancy. To provide population based gestational age and sex and parity specific reference ranges for cord length. Design Population based registry study. Setting Medical Birth Registry of Norway 1999–2013. Population All singleton births (gestational age>22weeks<45 weeks) (n = 856 300). Methods Descriptive statistics and odds ratios of risk factors for extreme cord length and adverse outcomes based on logistic regression adjusted for confounders. Main outcome measures Short or long cord (<10th or >90th percentile), cord knot and entanglement, adverse pregnancy outcomes including perinatal and intrauterine death. Results Increasing parity, maternal height and body mass index, and diabetes were associated with increased risk of a long cord. Large placental and birth weight, and fetal male sex were factors for a long cord, which again was associated with a doubled risk of intrauterine and perinatal death, and increased risk of adverse neonatal outcome. Anomalous cord insertion, female sex, and a small placenta were associated with a short cord, which was associated with increased risk of fetal malformations, placental complications, caesarean delivery, non-cephalic presentation, perinatal and intrauterine death. At term, cord knot was associated with a quadrupled risk of perinatal death. The combination of a cord knot and entanglement had a more than additive effect to the association to perinatal death. There was a more than doubled risk of recurrence of a long or short cord, knot and entanglement in a subsequent pregnancy of the same woman. Conclusion Cord length is influenced both by maternal and fetal factors, and there is increased risk of recurrence. Extreme cord length, entanglement and cord knot are associated with increased risk of adverse outcomes including perinatal death. We provide population based reference ranges for umbilical cord length. PMID:29584790

Inter- and Intrafraction Target Motion in Highly Focused Single Vocal Cord Irradiation of T1a Larynx Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kwa, Stefan L.S., E-mail: s.kwa@erasmusmc.nl; Al-Mamgani, Abrahim; Osman, Sarah O.S.

2015-09-01

Purpose: The purpose of this study was to verify clinical target volume–planning target volume (CTV-PTV) margins in single vocal cord irradiation (SVCI) of T1a larynx tumors and characterize inter- and intrafraction target motion. Methods and Materials: For 42 patients, a single vocal cord was irradiated using intensity modulated radiation therapy at a total dose of 58.1 Gy (16 fractions × 3.63 Gy). A daily cone beam computed tomography (CBCT) scan was performed to online correct the setup of the thyroid cartilage after patient positioning with in-room lasers (interfraction motion correction). To monitor intrafraction motion, CBCT scans were also acquired just after patient repositioning and aftermore » dose delivery. A mixed online-offline setup correction protocol (“O2 protocol”) was designed to compensate for both inter- and intrafraction motion. Results: Observed interfraction, systematic (Σ), and random (σ) setup errors in left-right (LR), craniocaudal (CC), and anteroposterior (AP) directions were 0.9, 2.0, and 1.1 mm and 1.0, 1.6, and 1.0 mm, respectively. After correction of these errors, the following intrafraction movements derived from the CBCT acquired after dose delivery were: Σ = 0.4, 1.3, and 0.7 mm, and σ = 0.8, 1.4, and 0.8 mm. More than half of the patients showed a systematic non-zero intrafraction shift in target position, (ie, the mean intrafraction displacement over the treatment fractions was statistically significantly different from zero; P<.05). With the applied CTV-PTV margins (for most patients 3, 5, and 3 mm in LR, CC, and AP directions, respectively), the minimum CTV dose, estimated from the target displacements observed in the last CBCT, was at least 94% of the prescribed dose for all patients and more than 98% for most patients (37 of 42). The proposed O2 protocol could effectively reduce the systematic intrafraction errors observed after dose delivery to almost zero (Σ = 0.1, 0.2, 0.2 mm). Conclusions: With adequate image guidance and CTV-PTV margins in LR, CC, and AP directions of 3, 5, and 3 mm, respectively, excellent target coverage in SVCI could be ensured.« less

TH-A-9A-03: Dosimetric Effect of Rotational Errors for Lung Stereotactic Body Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, J; Kim, H; Park, J

2014-06-15

Purpose: To evaluate the dosimetric effects on target volume and organs at risk (OARs) due to roll rotational errors in treatment setup of stereotactic body radiation therapy (SBRT) for lung cancer. Methods: There were a total of 23 volumetric modulated arc therapy (VMAT) plans for lung SBRT examined in this retrospective study. Each CT image of VMAT plans was intentionally rotated by ±1°, ±2°, and ±3° to simulate roll rotational setup errors. The axis of rotation was set at the center of T-spine. The target volume and OARs in the rotated CT images were re-defined by deformable registration of originalmore » contours. The dose distributions on each set of rotated images were re-calculated to cover the planning target volume (PTV) with the prescription dose before and after the couch translational correction. The dose-volumetric changes of PTVs and spinal cords were analyzed. Results: The differences in D95% of PTVs by −3°, −2°, −1°, 1°, 2°, and 3° roll rotations before the couch translational correction were on average −11.3±11.4%, −5.46±7.24%, −1.11±1.38% −3.34±3.97%, −9.64±10.3%, and −16.3±14.7%, respectively. After the couch translational correction, those values were −0.195±0.544%, −0.159±0.391%, −0.188±0.262%, −0.310±0.270%, −0.407±0.331%, and −0.433±0.401%, respectively. The maximum dose difference of spinal cord among the 23 plans even after the couch translational correction was 25.9% at −3° rotation. Conclusions: Roll rotational setup errors in lung SBRT significantly influenced the coverage of target volume using VMAT technique. This could be in part compensated by the translational couch correction. However, in spite of the translational correction, the delivered doses to the spinal cord could be more than the calculated doses. Therefore if rotational setup errors exist during lung SBRT using VMAT technique, the rotational correction would rather be considered to prevent over-irradiation of normal tissues than the translational correction.« less

Mechanisms of inhibitory action of TRK-130 (Naltalimide), a μ-opioid receptor partial agonist, on the micturition reflex.

PubMed

Fujimura, Morihiro; Izumimoto, Naoki; Kanie, Sayoko; Kobayashi, Ryosuke; Yoshikawa, Satoru; Momen, Shinobu; Hirakata, Mikito; Komagata, Toshikazu; Okanishi, Satoshi; Iwata, Masashi; Hashimoto, Tadatoshi; Doi, Takayuki; Yoshimura, Naoki; Kawai, Koji

2017-04-01

To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique µ-opioid receptor partial agonist, on the micturition reflex. The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats. TRK-130 (0.001-0.01 mg/kg, iv) dose-dependently inhibited RBCs, which was dose-dependently antagonized by naloxone; however, the antagonism susceptibility was different from morphine (1 mg/kg, iv). The minimum effective dose (0.003 mg/kg) of TRK-130 remained similar in spinal cord-transected animals. TRK-130 (0.0025 mg/kg, iv) increased bladder capacity without changing the voiding efficiency, maximum flow rate, and intravesical pressure at the maximum flow rate, whereas oxybutynin (1 mg/kg, iv) increased the bladder capacity but affected the other parameters. TRK-130 (0.005 mg/kg, iv) did not produce significant changes on the bladder contractions induced by peripheral stimulation of the pelvic nerve, while oxybutynin (1 mg/kg, iv) significantly suppressed the bladder contractions. These results suggest that TRK-130 enhances the bladder storage function by modulating the afferent limb of the micturition reflex through µ-opioid receptors in the spinal cord. TRK-130 could be a more effective and safer therapeutic agent with a different fashion from antimuscarinics and conventional opioids for overactive bladder.

A Dosimetric Evaluation of The Eclipse and Pinnacle Treatment Planning Systems in Treatment of Vertebral Bodies Using IMRT and VMAT with Modeled and Commissioned Flattening Filter Free (FFF) Fields

NASA Astrophysics Data System (ADS)

Ajo, Ramzi, Jr.

Modern treatment planning systems (TPS's) utilize different algorithms in computing dose within the patient medium. The algorithms rely on properly modeled clinical setups in order to perform optimally. Aside from various parameters of the beam, modifiers, such as multileaf collimators (MLC's), must also be modeled properly. That could not be more true today, where dynamic delivery such as intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) are being increasingly utilized due to their ability to deliver higher dose precisely to the target while sparing more surrounding normal tissue. Two of the most popular TPS's, Pinnacle (Philips) and Eclipse (Varian), were compared, with special emphasis placed on parameterization of the dosimetric leaf gap (DLG) in Eclipse. The DLG is a parameter that accounts for Varian's rounded MLC leaf ends. While Pinnacle accounts for the rounded leaf end by modeling the MLC's, Eclipse uses a measured parameter. This study investigated whether a single value measured DLG is sufficient for dynamic delivery. Using five planning volumes for vertebral body SBRT treatments, each prescribed for 3000 cGy in 5 fractions, an array of 20 treatment plans was generated using varying energies of 6MV-FFF and 10MV-FFF. Treatment techniques consisted of 9-field Step-and-shoot IMRT, and dual-arc VMAT using patient specific optimization criteria in the Pinnacle TPS v9.8. Each plan was normalized to ensure coverage of 3000cGy to 95% of the target volume. The dose was computed in Pinnacle v9.8, with the Collapsed Cone Convolution Superposition algorithm and Eclipse v11, with the Acuros XB algorithm, using a dose grid resolution of 2 mm in both systems. Dose volume histograms (DVH's) were generated for a comparison of max and mean dose to the targets and spinal cord, as well as 95% coverage of the targets and the volume of the spinal cord receiving 14.5 Gy (V14.5). Patient specific quality assurance (PSQA) fields were generated and then delivered, using a Varian Edge linear accelerator, to a 4D QA phantom for a gamma analysis and distance to agreement (DTA) comparison. All Eclipse calculations were made for both measured and optimized DLG parameters. Calculated vs. measured point dose for the Pinnacle TPS had an average difference of 2.79 +/- 2.00%. Gamma analysis using a 3% and 3 mm DTA had 99/100 fields passing at > 95%. Using measured values of the DLG in Eclipse, calculated vs. measured point dose was -4.44 +/- 1.97%, and DTA had 33/110 fields passing at > 95%. After an optimization of the DLG in Eclipse, calculated vs. measured point dose had an average difference of 2.20 +/- 2.23%, and DTA with 95/110 fields passing at > 95%. This study looked at the performance of the Pinnacle and Eclipse TPS's, with special consideration given to the DLG parameterization used by Eclipse. The results support the idea that a single valued DLG is not sufficient for dynamic delivery. An optimization of the parameter is necessary to account for the high modulation of IMRT and VMAT techniques.

Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC)

PubMed Central

Lattka, Eva; Koletzko, Berthold; Zeilinger, Sonja; Hibbeln, Joseph R.; Klopp, Norman; Ring, Susan M.; Steer, Colin D.

2012-01-01

Fetal supply with long-chain PUFA (LC-PUFA) during pregnancy is important for brain growth and visual and cognitive development and is provided by materno–fetal placental transfer. We recently showed that maternal fatty acid desaturase (FADS) genotypes modulate the amounts of LC-PUFA in maternal blood. Whether FADS genotypes influence the amounts of umbilical cord fatty acids has not been investigated until now. The aim of the present study was to investigate the influence of maternal and child FADS genotypes on the amounts of LC-PUFA in umbilical cord venous plasma as an indicator of fetal fatty acid supply during pregnancy. A total of eleven cord plasma n-6 and n-3 fatty acids were analysed for association with seventeen FADS gene cluster SNP in over 2000 mothers and children from the Avon Longitudinal Study of Parents and Children. In a multivariable analysis, the maternal genotype effect was adjusted for the child genotype and vice versa to estimate which of the two has the stronger influence on cord plasma fatty acids. Both maternal and child FADS genotypes and haplotypes influenced amounts of cord plasma LC-PUFA and fatty acid ratios. Specifically, most analysed maternal SNP were associated with cord plasma levels of the precursor n-6 PUFA, whereas the child genotypes were mainly associated with more highly desaturated n-6 LC-PUFA. This first study on FADS genotypes and cord fatty acids suggests that fetal LC-PUFA status is determined to some extent by fetal fatty acid conversion. Associations of particular haplotypes suggest specific effects of SNP rs498793 and rs968567 on fatty acid metabolism. PMID:22877655

Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC).

PubMed

Lattka, Eva; Koletzko, Berthold; Zeilinger, Sonja; Hibbeln, Joseph R; Klopp, Norman; Ring, Susan M; Steer, Colin D

2013-04-14

Fetal supply with long-chain PUFA (LC-PUFA) during pregnancy is important for brain growth and visual and cognitive development and is provided by materno-fetal placental transfer. We recently showed that maternal fatty acid desaturase (FADS) genotypes modulate the amounts of LC-PUFA in maternal blood. Whether FADS genotypes influence the amounts of umbilical cord fatty acids has not been investigated until now. The aim of the present study was to investigate the influence of maternal and child FADS genotypes on the amounts of LC-PUFA in umbilical cord venous plasma as an indicator of fetal fatty acid supply during pregnancy. A total of eleven cord plasma n-6 and n-3 fatty acids were analysed for association with seventeen FADS gene cluster SNP in over 2000 mothers and children from the Avon Longitudinal Study of Parents and Children. In a multivariable analysis, the maternal genotype effect was adjusted for the child genotype and vice versa to estimate which of the two has the stronger influence on cord plasma fatty acids. Both maternal and child FADS genotypes and haplotypes influenced amounts of cord plasma LC-PUFA and fatty acid ratios. Specifically, most analysed maternal SNP were associated with cord plasma levels of the precursor n-6 PUFA, whereas the child genotypes were mainly associated with more highly desaturated n-6 LC-PUFA. This first study on FADS genotypes and cord fatty acids suggests that fetal LC-PUFA status is determined to some extent by fetal fatty acid conversion. Associations of particular haplotypes suggest specific effects of SNP rs498793 and rs968567 on fatty acid metabolism.

Release of neuropeptide FF (FLFQPQRF-NH2) from rat spinal cord.

PubMed

Zhu, J; Jhamandas, K; Yang, H Y

1992-10-02

Neuropeptide FF (FLFQPQRF-NH2), originally isolated from bovine brain, is an FMRF-NH2-like peptide with morphine-modulating activity. Neuropeptide FF (NPFF) is highly localized in the dorsal spinal cords where there are also specific NPFF binding sites. Furthermore, there have been studies indicating that NPFF may participate in the regulation of pain threshold in the spinal cord. However, whether NPFF can be released from the spinal cord is not known. The present experiments, using an in vitro superfusion of an isolated whole rat spinal cord, demonstrated that high concentrations of KCl or substance P caused a release of NPFF immunoreactive material (IR) from the spinal cord into the perfusion medium in a calcium-dependent manner. Substance P (1-11) also produced a detectable release of NPFF-IR in vivo although the response was quite variable. The released NPFF-IR was analyzed by an HPLC study and found to consist of NPFF and other minor immunoreactive peptides. Further studies with substance P-related peptides showed that the in vitro release of NPFF-IR could also be induced by substance P (1-7) but not by [pGlu5,Me-Phe8,Sar9]-substance P (5-11) or substance K. These results suggest that the specific substance P receptor (SP-N), which is recognized by both substance P (1-11) and substance P (1-7) rather than the tachykinin receptor, is involved in NPFF secretion from the spinal cord. In view of the role of substance P (1-11) and substance P (1-7) in sensory transmission, the results of this study further support the role of NPFF in the modulation of antinociception in the spinal cord.

Impact of 4.0% chlorhexidine cord cleansing on the bacteriologic profile of the newborn umbilical stump in rural Sylhet District, Bangladesh: a community-based, cluster-randomized trial.

PubMed

Mullany, Luke C; Saha, Samir K; Shah, Rasheduzzaman; Islam, Mohammad Shahidul; Rahman, Mostafiz; Islam, Maksuda; Talukder, Radwanur Rahman; El Arifeen, Shams; Darmstadt, Gary L; Baqui, Abdullah H

2012-05-01

Randomized trials from South Asia indicate umbilical cord chlorhexidine cleansing reduces mortality and omphalitis. No community-based data are available on bacteriological profile of the cord, early neonatal colonization dynamics, or impact of cord cleansing on colonizing organisms. Such data could clarify the design of scaled chlorhexidine interventions. Umbilical swabs were collected at home (days 1, 3, 6) after birth from infants participating in a trial of 3 cord-care regimens (no chlorhexidine, single cleansing, multiple cleansing) in Sylhet, Bangladesh. Overall and organism-specific positivity rates were estimated by cord-care regimen and by day of collection. Between September 2008 and October 2009, 1923 infants contributed 5234 umbilical swabs. Positivity rate was high (4057 of 5234, 77.5%) and varied substantially across groups. Immediate (day 1) reductions in cord colonization were observed in single- (prevalence rate ratio = 0.75, 95% confidence interval: 0.70-0.81) and multiple- (prevalence rate ratio = 0.71, 95% confidence interval: 0.66-0.77) cleansing groups. Reductions persisted and increased in magnitude through day 6 only if babies received multiple applications. On days 1, 3, and 6, respectively, multiple cleansing consistently reduced invasive organisms such as Escherichia coli (49%, 64%, and 42% lower), Klebsiella pneumoniae (46%, 53%, and 33% lower), and Staphylococcus aureus (34%, 84%, and 85% lower). Cord cleansing with 4.0% chlorhexidine immediately after birth reduces overall and organism-specific colonization of the stump. Reductions are greater and sustained longer with daily cleansing through the first week of life, suggesting that programs promoting chlorhexidine cleansing should favor multiple over single applications.

Effect of high-dose vocal fold injection of cidofovir and bevacizumab in a porcine model.

PubMed

Ahmed, Mostafa M; Connor, Matthew P; Palazzolo, Mitzi; Thompson, Michelle E; Lospinoso, Josh; O'Connor, Peter; Howard, N Scott; Maturo, Stephen C

2017-03-01

Perform a follow-up study to investigate the histologic impact of high-dose intralaryngeal cidofovir injections in porcine vocal cords, either alone or in combination with bevacizumab, and compared to saline controls. This was an in vivo study involving 24 pigs with blinded pathologist review of specimens. Six groups were created, with four subjects in each group. Each subject received 10 or 20 mg of either cidofovir or bevacizumab alone, or in combination, injected into the right vocal cord. The left vocal fold was used as a saline control. Three separate injections were made at 2-week intervals. Larynges were harvested at 8 and 12 weeks, stained with hematoxylin and eosin and trichrome stain, and reviewed for histologic changes by two blinded pathologists. Minimal inflammation, edema, and atypia were noted with all treatments. Increased glandular inflammation was noted with 10 mg bevacizumab (P < 0.05), which decreased when combined with 10 mg cidofovir (P < 0.05). No lamina propria or muscle fibrosis was observed. Drug duration had no statistically significant histologic impact. High-dose cidofovir and bevacizumab do not induce detrimental vocal fold changes. Combination cidofovir and bevacizumab do not cause vocal fold scarring. Further work is needed to assess systemic concentration with this high-dose combination in humans. N/A. Laryngoscope, 127:671-675, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Feasibility of tomotherapy to reduce normal lung and cardiac toxicity for distal esophageal cancer compared to three-dimensional radiotherapy.

PubMed

Nguyen, Nam P; Krafft, Shane P; Vinh-Hung, Vincent; Vos, Paul; Almeida, Fabio; Jang, Siyoung; Ceizyk, Misty; Desai, Anand; Davis, Rick; Hamilton, Russ; Modarresifar, Homayoun; Abraham, Dave; Smith-Raymond, Lexie

2011-12-01

To compare the effectiveness of tomotherapy and three-dimensional (3D) conformal radiotherapy to spare normal critical structures (spinal cord, lungs, and ventricles) from excessive radiation in patients with distal esophageal cancers. A retrospective dosimetric study of nine patients who had advanced gastro-esophageal (GE) junction cancer (7) or thoracic esophageal cancer (2) extending into the distal esophagus. Two plans were created for each of the patients. A three-dimensional plan was constructed with either three (anteroposterior, right posterior oblique, and left posterior oblique) or four (right anterior oblique, left anterior oblique, right posterior oblique, and left posterior oblique) fields. The second plan was for tomotherapy. Doses were 45 Gy to the PTV with an integrated boost of 5 Gy for tomotherapy. Mean lung dose was respectively 7.4 and 11.8 Gy (p=0.004) for tomotherapy and 3D plans. Corresponding values were 12.4 and 18.3 Gy (p=0.006) for cardiac ventricles. Maximum spinal cord dose was respectively 31.3 and 37.4 Gy (p < 0.007) for tomotherapy and 3D plans. Homogeneity index was two for both groups. Compared to 3D conformal radiotherapy, tomotherapy decreased significantly the amount of normal tissue irradiated and may reduce treatment toxicity for possible dose escalation in future prospective studies. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain

PubMed Central

Gao, Yong-Jing; Zhang, Ling; Samad, Omar Abdel; Suter, Marc R.; Yasuhiko, Kawasaki; Xu, Zhen-Zhong; Park, Jong-Yeon; Lind, Anne-Li; Ma, Qiufu; Ji, Ru-Rong

2009-01-01

Our previous study showed that activation of c-jun-N-terminal kinase (JNK) in spinal astrocytes plays an important role in neuropathic pain sensitization. We further investigated how JNK regulates neuropathic pain. In cultured astrocytes, TNF-α transiently activated JNK via TNF receptor-1. Cytokine array indicated that the chemokine CCL2/MCP-1 (monocyte chemoattractant protein-1) was strongly induced by the TNF-α/JNK pathway. MCP-1 upregulation by TNF-α was dose-dependently inhibited by the JNK inhibitors SP600125 and D-JNKI-1. Spinal injection of TNF-α produced JNK-dependent pain hypersensitivity and MCP-1 upregulation in the spinal cord. Further, spinal nerve ligation (SNL) induced persistent neuropathic pain and MCP-1 upregulation in the spinal cord, and both were suppressed by D-JNKI-1. Remarkably, MCP-1 was primarily induced in spinal cord astrocytes after SNL. Spinal administration of MCP-1 neutralizing antibody attenuated neuropathic pain. Conversely, spinal application of MCP-1 induced heat hyperalgesia and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial spinal cord dorsal horn neurons, indicative of central sensitization (hyperactivity of dorsal horn neurons). Patch clamp recordings in lamina II neurons of isolated spinal cord slices showed that MCP-1 not only enhanced spontaneous excitatory synaptic currents (sEPSCs) but also potentiated NMDA- and AMPA-induced currents. Finally, the MCP-1 receptor CCR2 was expressed in neurons and some non-neuronal cells in the spinal cord. Taken together, we have revealed a previously unknown mechanism of MCP-1 induction and action. MCP-1 induction in astrocytes following JNK activation contributes to central sensitization and neuropathic pain facilitation by enhancing excitatory synaptic transmission. Inhibition of the JNK/MCP-1 pathway may provide a new therapy for neuropathic pain management. PMID:19339605

SU-G-BRC-02: A Novel Multi-Criteria Optimization Approach to Generate Deliverable Intensity-Modulated Radiation Therapy (IMRT) Treatment Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirlik, G; D’Souza, W; Zhang, H

2016-06-15

Purpose: To present a novel multi-criteria optimization (MCO) solution approach that generates treatment plans with deliverable apertures using column generation. Methods: We demonstrate our method with 10 locally advanced head-and-neck cancer cases retrospectively. In our MCO formulation, we defined an objective function for each structure in the treatment volume. This resulted in 9 objective functions, including 3 distinct objectives for primary target volume, high-risk and low-risk target volumes, 5 objectives for each of the organs-at-risk (OARs) (two parotid glands, spinal cord, brain stem and oral cavity), and one for the non-target non-OAR normal tissue. Conditional value-at-risk (CVaR) constraints were utilizedmore » to ensure at least certain fraction of the target volumes receiving the prescription doses. To directly generate deliverable plans, column generation algorithm was embedded within our MCO approach for aperture shape generation. Final dose distributions for all plans were generated using a Monte Carlo kernel-superposition dose calculation. We compared the MCO plans with the clinical plans, which were created by clinicians. Results: At least 95% target coverage was achieved by both MCO plans and clinical plans. However, the average conformity indices of clinical plans and the MCO plans were 1.95 and 1.35, respectively (31% reduction, p<0.01). Compared to the conventional clinical plan, the proposed MCO method achieved average reductions in left parotid mean dose of 5% (p=0.06), right parotid mean dose of 18% (p<0.01), oral cavity mean dose of 21% (p=0.03), spinal cord maximum dose of 20% (p<0.01), brain stem maximum dose of 61% (p<0.01), and normal tissue maximum dose of 5% (p<0.01), respectively. Conclusion: We demonstrated that the proposed MCO method was able to obtain deliverable IMRT treatment plans while achieving significant improvements in dosimetric plan quality.« less

Individualized Radical Radiotherapy of Non-Small-Cell Lung Cancer Based on Normal Tissue Dose Constraints: A Feasibility Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baardwijk, Angela van; Bosmans, Geert; Boersma, Liesbeth

2008-08-01

Purpose: Local recurrence is a major problem after (chemo-)radiation for non-small-cell lung cancer. We hypothesized that for each individual patient, the highest therapeutic ratio could be achieved by increasing total tumor dose (TTD) to the limits of normal tissues, delivered within 5 weeks. We report first results of a prospective feasibility trial. Methods and Materials: Twenty-eight patients with medically inoperable or locally advanced non-small-cell lung cancer, World Health Organization performance score of 0-1, and reasonable lung function (forced expiratory volume in 1 second > 50%) were analyzed. All patients underwent irradiation using an individualized prescribed TTD based on normal tissuemore » dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8-Gy fractions twice daily. No concurrent chemoradiation was administered. Toxicity was scored using the Common Terminology Criteria for Adverse Events criteria. An {sup 18}F-fluoro-2-deoxy-glucose-positron emission tomography-computed tomography scan was performed to evaluate (metabolic) response 3 months after treatment. Results: Mean delivered dose was 63.0 {+-} 9.8 Gy. The TTD was most often limited by the mean lung dose (32.1%) or spinal cord (28.6%). Acute toxicity generally was mild; only 1 patient experienced Grade 3 cough and 1 patient experienced Grade 3 dysphagia. One patient (3.6%) died of pneumonitis. For late toxicity, 2 patients (7.7%) had Grade 3 cough or dyspnea; none had severe dysphagia. Complete metabolic response was obtained in 44% (11 of 26 patients). With a median follow-up of 13 months, median overall survival was 19.6 months, with a 1-year survival rate of 57.1%. Conclusions: Individualized maximal tolerable dose irradiation based on normal tissue dose constraints is feasible, and initial results are promising.« less

Dosimetric effect of multileaf collimator leaf width on volumetric modulated arc stereotactic radiotherapy for spine tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amoush, Ahmad, E-mail: aamoush@augusta.edu; Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; Long, Huang

This work aimed to study the dosimetric effect of multileaf collimator (MLC) leaf widths in treatment plans for patients receiving volumetric modulated arc therapy (VMAT) for spine stereotactic body radiation therapy (SBRT). Thirteen patients treated with spine SBRT were retrospectively selected for this study. The patients were treated following the protocol of the Radiation Therapy Oncology Group 0631 (RTOG 0631) for spine metastasis. The prescription dose was 16 Gy in 1 fraction to 90% of the target volume (V16 > 90%). The maximum spinal cord dose of 14 Gy and 10% of the spinal cord receiving < 10 Gy (V10) were the acceptable tolerance doses. For themore » purpose of this study, 2 dual-arc VMAT plans were created for each patient using 3 different MLC leaf widths: 2.5 mm, 4 mm, and 5 mm. The compliance with the RTOG 0631 protocol, conformity index (CI), dose gradient index (DGI), and number of monitor units (MUs) were compared. The average V16Gy of the targets was 91.8 ± 1.2%, 92.2 ± 2.1%, and 91.7 ± 2.3% for 2.5-mm, 4-mm, and 5-mm leaf widths, respectively (p = 0.78). Accordingly, the average CI was 1.45 ± 0.4, 1.47 ± 0.29, and 1.47 ± 0.31 (p = 0.98), respectively. The average DGI was 0.22 ± 0.04, 0.20 ± 0.06, and 0.22 ± 0.05, respectively (p = 0.77). The average maximum dose to the spinal cord was 12.45 ± 1.0 Gy, 12.80 ± 1.0 Gy, and 12.48 ± 1.1 (p = 0.62) and V10% of the spinal cord was 3.6 ± 2.1%, 5.6 ± 2.8%, and 5.5 ± 3.0% (p = 0.11) for 2.5-mm, 4-mm, and 5-mm leaf widths, respectively. Accordingly, the average number of MUs was 4341 ± 500 MU, 5019 ± 834 MU, and 4606 ± 691 MU, respectively (p = 0.053). The use of 2.5-mm, 4-mm, and 5-mm MLCs achieved similar VMAT plan quality as recommended by the RTOG 0631. The dosimetric parameters were also comparable for the 3 MLCs. In general, any of these leaf widths can be used for spine SBRT using VMAT.« less

Ondansetron Pharmacokinetics in Pregnant Women and Neonates: Towards a New Treatment for Neonatal Abstinence Syndrome

PubMed Central

Elkomy, Mohammed H.; Sultan, Pervez; Carvalho, Brendan; Peltz, Gary; Wu, Manhong; Clavijo, Claudia; Galinkin, Jeffery L.; Drover, David R.

2014-01-01

Ondansetron is the drug of choice to prevent nausea in women undergoing cesarean surgery and can be used to prevent neonatal abstinence syndrome (NAS). Pharmacokinetics of ondansetron has not been characterized in pregnant women or in newborns. A nonlinear mixed-effects modeling approach was used to analyze plasma samples obtained from 20 non-pregnant and 40 pregnant women following single administration of 4 or 8 mg ondansetron, from umbilical cord blood at delivery, and from neonates after birth. The analysis indicates that: ondansetron disposition is not affected by pregnancy (p>0.05), but influenced by dose (p<0.05), and is characterized by rapid transplacental transfer and longer elimination half-life in neonates compared to their mother. A dosing regimen for prevention of NAS was designed based on the model. The regimen involves IV administration of 4 mg to the mothers shortly before cord clamping, or oral administration of 0.07 mg/kg (or equivalently 0.04 mg/kg IV) to neonates. PMID:25670522

Effects of 4-aminopyridine on cardiac repolarization, PR interval, and heart rate in patients with spinal cord injury.

PubMed

Isoda, Wakana C; Segal, Jack L

2003-02-01

To determine the effects of 4-aminopyridine (4-AP) on heart rate and PR, QT, and QTc intervals in patients with longstanding spinal cord injury (SCI). Randomized, active-treatment-controlled, dose level-blinded study, with allocation concealed. University-affiliated, tertiary care medical center. Sixty otherwise healthy male and female outpatients with traumatic SCI of more than 1 year's duration. Intervention. Oral administration and dose titration to tolerance of an immediate-release formulation of 4-AP. The PR interval, heart rate, QT interval, and QTc interval obtained from standard 12-lead electrocardiograms (ECGs) at baseline (before administration of 4-AP) and after 1 month of treatment were compared. The QTc intervals were derived by using Bazett's formula (equation) incorporated into standard computerized analyses of 12-lead ECG printouts. The paired t test was performed to test for the significance of differences between means and variances. No statistically significant differences were noted in heart rate or between ECG time intervals measured at baseline and after 1 month of treatment with 4-AP among all patients with SCI or between subgroups stratified by injury level (tetraplegia, paraplegia) or sex. During the 1-month period that 4-AP was administered, the heart rate and PR, QT, and QTc intervals all remained unchanged and stayed well within normal range in comparison to literature-derived control values. 4-Aminopyridine does not appear to influence the length of cardiac time intervals or heart rate and, hence, is unlikely to cause potentially life-threatening ventricular dysrrhythmias when administered long-term and taken orally in dosages of up to 30 mg/day. Specifically, cardiac repolarization (QTc interval) is unaffected in patients with SCI who continuously receive 4-AP for up to 1 month.

Evaluating diagnosis-based risk-adjustment methods in a population with spinal cord dysfunction.

PubMed

Warner, Grace; Hoenig, Helen; Montez, Maria; Wang, Fei; Rosen, Amy

2004-02-01

To examine performance of models in predicting health care utilization for individuals with spinal cord dysfunction. Regression models compared 2 diagnosis-based risk-adjustment methods, the adjusted clinical groups (ACGs) and diagnostic cost groups (DCGs). To improve prediction, we added to our model: (1) spinal cord dysfunction-specific diagnostic information, (2) limitations in self-care function, and (3) both 1 and 2. Models were replicated in 3 populations. Samples from 3 populations: (1) 40% of veterans using Veterans Health Administration services in fiscal year 1997 (FY97) (N=1,046,803), (2) veteran sample with spinal cord dysfunction identified by codes from the International Statistical Classification of Diseases, 9th Revision, Clinical Modifications (N=7666), and (3) veteran sample identified in Veterans Affairs Spinal Cord Dysfunction Registry (N=5888). Not applicable. Inpatient, outpatient, and total days of care in FY97. The DCG models (R(2) range,.22-.38) performed better than ACG models (R(2) range,.04-.34) for all outcomes. Spinal cord dysfunction-specific diagnostic information improved prediction more in the ACG model than in the DCG model (R(2) range for ACG,.14-.34; R(2) range for DCG,.24-.38). Information on self-care function slightly improved performance (R(2) range increased from 0 to.04). The DCG risk-adjustment models predicted health care utilization better than ACG models. ACG model prediction was improved by adding information.

Zebrafish transgenic constructs label specific neurons in Xenopus laevis spinal cord and identify frog V0v spinal neurons.

PubMed

Juárez-Morales, José L; Martinez-De Luna, Reyna I; Zuber, Michael E; Roberts, Alan; Lewis, Katharine E

2017-09-01

A correctly functioning spinal cord is crucial for locomotion and communication between body and brain but there are fundamental gaps in our knowledge of how spinal neuronal circuitry is established and functions. To understand the genetic program that regulates specification and functions of this circuitry, we need to connect neuronal molecular phenotypes with physiological analyses. Studies using Xenopus laevis tadpoles have increased our understanding of spinal cord neuronal physiology and function, particularly in locomotor circuitry. However, the X. laevis tetraploid genome and long generation time make it difficult to investigate how neurons are specified. The opacity of X. laevis embryos also makes it hard to connect functional classes of neurons and the genes that they express. We demonstrate here that Tol2 transgenic constructs using zebrafish enhancers that drive expression in specific zebrafish spinal neurons label equivalent neurons in X. laevis and that the incorporation of a Gal4:UAS amplification cassette enables cells to be observed in live X. laevis tadpoles. This technique should enable the molecular phenotypes, morphologies and physiologies of distinct X. laevis spinal neurons to be examined together in vivo. We have used an islet1 enhancer to label Rohon-Beard sensory neurons and evx enhancers to identify V0v neurons, for the first time, in X. laevis spinal cord. Our work demonstrates the homology of spinal cord circuitry in zebrafish and X. laevis, suggesting that future work could combine their relative strengths to elucidate a more complete picture of how vertebrate spinal cord neurons are specified, and function to generate behavior. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1007-1020, 2017. © 2017 Wiley Periodicals, Inc.

Private Cord Blood Banking: Experiences And Views Of Pediatric Hematopoietic Cell Transplantation Physicians

PubMed Central

Thornley, Ian; Eapen, Mary; Sung, Lillian; Lee, Stephanie J.; Davies, Stella M.; Joffe, Steven

2011-01-01

Objective Private cord blood banks are for-profit companies that facilitate storage of umbilical cord blood for personal or family use. Pediatric hematopoietic cell transplantation (HCT) physicians are currently best situated to use cord blood therapeutically. We sought to describe the experiences and views of these physicians regarding private cord blood banking. Participants and Methods Emailed cross-sectional survey of pediatric HCT physicians in the United States and Canada. 93/152 potentially eligible physicians (93/130 confirmed survey recipients) from 57 centers responded. Questions addressed the number of transplants performed using privately banked cord blood, willingness to use banked autologous cord blood in specific clinical settings, and recommendations to parents regarding private cord blood banking. Results Respondents reported having performed 9 autologous and 41 allogeneic transplants using privately banked cord blood. In 36/40 allogeneic cases for which data were available, the cord blood had been collected because of a known indication in the recipient. Few respondents would choose autologous cord blood over alternative stem cell sources for treatment of acute lymphoblastic leukemia in second remission. In contrast, 55% would choose autologous cord blood to treat high-risk neuroblastoma, or to treat severe aplastic anemia in the absence of an available sibling donor. No respondent would recommend private cord blood banking for a newborn with one healthy sibling when both parents were of Northern European descent; 11% would recommend banking when parents were of different minority ethnicities. Conclusions Few transplants have been performed using cord blood stored in the absence of a known indication in the recipient. Willingness to use banked autologous cord blood varies depending on disease and availability of alternative stem cell sources. Few pediatric HCT physicians endorse private cord blood banking in the absence of an identified recipient, even for mixed-ethnicity children for whom finding a suitably matched unrelated donor may be difficult. PMID:19255033

Newborn umbilical cord and skin care in Sylhet District, Bangladesh: Implications for promotion of umbilical cord cleansing with topical chlorhexidine

PubMed Central

Alam, Ashraful; Ali, Nabeel Ashraf; Sultana, Nighat; Mullany, Luke C.; Teela, Katherine C.; Khan, Nazib Uz Zaman; Baqui, Abdullah H.; Arifeen, Shams El; Mannan, Ishtiaq; Darmstadt, Gary L.; Winch, Peter J.

2010-01-01

Background Newborn cord care practices may directly contribute to infections, which account for a large proportion of the 4 million annual global neonatal deaths. This formative research study assessed current umbilical and skin care knowledge and practices for neonates in Sylhet, Bangladesh in preparation for a cluster-randomised trial of the impact of topical chlorhexidine cord cleansing on neonatal mortality and omphalitis. Methodology Unstructured interviews (n=60), structured observations (n=20), rating and ranking exercises (n=40), and household surveys (n=400) were conducted to elicit specific behaviours regarding newborn cord and skin care practices. These included hand-washing, skin and cord care at the time of birth, persons engaged in cord care, cord cutting practices, topical applications to the cord at the time of birth, wrapping/dressing of the cord stump, and use of skin-to-skin care. Results Ninety percent of deliveries occurred at home. The umbilical cord was almost always (98%) cut after delivery of the placenta, and cut by mothers in more than half the cases (57%). Substances were commonly (52%) applied to the stump after cord cutting; turmeric was the most common application (83%). Umbilical stump care revolved around bathing, skin massage with mustard oil, and heat massage on the umbilical stump. Forty-two percent of newborns were bathed on the day of birth. Mothers were the principal provider for skin and cord care during the neonatal period and 9% reported umbilical infections in their infants. Discussion Unhygienic cord care practices are prevalent in the study area. Efforts to promote hand washing, cord cutting with clean instruments, and avoiding unclean home applications to the cord may reduce exposure and improve neonatal outcomes. Such efforts should broadly target a range of caregivers, including mothers and other female household members. PMID:19057570

Training unsupported sitting in people with chronic spinal cord injuries: a randomized controlled trial.

PubMed

Boswell-Ruys, C L; Harvey, L A; Barker, J J; Ben, M; Middleton, J W; Lord, S R

2010-02-01

Randomized, assessor-blinded trial. To evaluate the effectiveness of a 6-week task-specific training programme on the abilities of people with chronic spinal cord injuries to sit unsupported. NSW, Australia. Thirty adults with spinal cord injuries of at least 1-year duration were recruited. Participants in the training group (n=15) performed up to 1 h of task-specific training three times a week for 6 weeks. Participants in the control group (n=15) did not receive any training or additional therapy. Primary outcome measures were the Canadian Occupational Performance Measure (COPM), and tests of Upper Body Sway, Maximal Balance Range and donning and doffing a T-shirt (the T-shirt test). The between-group mean difference (95% confidence interval) for the maximal balance range was 64 mm (95% confidence interval 20 to 108 mm; P=0.006). There were no significant between-group mean differences for the COPM and the Upper Body Sway and T-shirt tests. This trial shows initial support for intensive task-specific training for improving the abilities of people with chronic spinal cord injuries to sit unsupported, although the real-world implications of the observed treatment effects are yet to be determined.

The Human Central Pattern Generator for Locomotion.

PubMed

Minassian, Karen; Hofstoetter, Ursula S; Dzeladini, Florin; Guertin, Pierre A; Ijspeert, Auke

2017-03-01

The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to produce the basic rhythm and neural activation patterns underlying locomotion can be demonstrated under specific experimental conditions in reduced animal preparations. The existence of CPGs in humans is a matter of debate. Equally elusive is the contribution of CPGs to normal bipedal locomotion. To address these points, we focus on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion. In the absence of volitional motor control and step-specific sensory feedback, the human lumbar spinal cord can produce rhythmic muscle activation patterns that closely resemble CPG-induced neural activity of the isolated animal spinal cord. In this sense, CPGs in humans can be defined by the activity they produce. During normal locomotion, CPGs could contribute to the activation patterns during specific phases of the step cycle and simplify supraspinal control of step cycle frequency as a feedforward component to achieve a targeted speed. Determining how the human CPGs operate will be essential to advance the theory of neural control of locomotion and develop new locomotor neurorehabilitation paradigms.

Simultaneous Brain–Cervical Cord fMRI Reveals Intrinsic Spinal Cord Plasticity during Motor Sequence Learning

PubMed Central

Cohen-Adad, Julien; Marchand-Pauvert, Veronique; Benali, Habib; Doyon, Julien

2015-01-01

The spinal cord participates in the execution of skilled movements by translating high-level cerebral motor representations into musculotopic commands. Yet, the extent to which motor skill acquisition relies on intrinsic spinal cord processes remains unknown. To date, attempts to address this question were limited by difficulties in separating spinal local effects from supraspinal influences through traditional electrophysiological and neuroimaging methods. Here, for the first time, we provide evidence for local learning-induced plasticity in intact human spinal cord through simultaneous functional magnetic resonance imaging of the brain and spinal cord during motor sequence learning. Specifically, we show learning-related modulation of activity in the C6–C8 spinal region, which is independent from that of related supraspinal sensorimotor structures. Moreover, a brain–spinal cord functional connectivity analysis demonstrates that the initial linear relationship between the spinal cord and sensorimotor cortex gradually fades away over the course of motor sequence learning, while the connectivity between spinal activity and cerebellum gains strength. These data suggest that the spinal cord not only constitutes an active functional component of the human motor learning network but also contributes distinctively from the brain to the learning process. The present findings open new avenues for rehabilitation of patients with spinal cord injuries, as they demonstrate that this part of the central nervous system is much more plastic than assumed before. Yet, the neurophysiological mechanisms underlying this intrinsic functional plasticity in the spinal cord warrant further investigations. PMID:26125597

Simultaneous Brain-Cervical Cord fMRI Reveals Intrinsic Spinal Cord Plasticity during Motor Sequence Learning.

PubMed

Vahdat, Shahabeddin; Lungu, Ovidiu; Cohen-Adad, Julien; Marchand-Pauvert, Veronique; Benali, Habib; Doyon, Julien

2015-06-01

The spinal cord participates in the execution of skilled movements by translating high-level cerebral motor representations into musculotopic commands. Yet, the extent to which motor skill acquisition relies on intrinsic spinal cord processes remains unknown. To date, attempts to address this question were limited by difficulties in separating spinal local effects from supraspinal influences through traditional electrophysiological and neuroimaging methods. Here, for the first time, we provide evidence for local learning-induced plasticity in intact human spinal cord through simultaneous functional magnetic resonance imaging of the brain and spinal cord during motor sequence learning. Specifically, we show learning-related modulation of activity in the C6-C8 spinal region, which is independent from that of related supraspinal sensorimotor structures. Moreover, a brain-spinal cord functional connectivity analysis demonstrates that the initial linear relationship between the spinal cord and sensorimotor cortex gradually fades away over the course of motor sequence learning, while the connectivity between spinal activity and cerebellum gains strength. These data suggest that the spinal cord not only constitutes an active functional component of the human motor learning network but also contributes distinctively from the brain to the learning process. The present findings open new avenues for rehabilitation of patients with spinal cord injuries, as they demonstrate that this part of the central nervous system is much more plastic than assumed before. Yet, the neurophysiological mechanisms underlying this intrinsic functional plasticity in the spinal cord warrant further investigations.

Loss of the type I interferon pathway increases vulnerability of mice to genital herpes simplex virus 2 infection.

PubMed

Conrady, Christopher D; Halford, William P; Carr, Daniel J J

2011-02-01

The mouse model of genital herpes relies on medoxyprogesterone treatment of female mice to render the vaginal lumen susceptible to inoculation with herpes simplex virus 2 (HSV-2). In the present study, we report that mice deficient in the A1 chain of the type I interferon receptor (CD118(-/-)) are susceptible to HSV-2 in the absence of medroxyprogesterone preconditioning. In the absence of hormone pretreatment, 2,000 PFU of a clinical isolate of HSV-2 was sufficient to establish a productive infection in the vagina of 75% ± 17% and in the spinal cord of 71% ± 14% of CD118(-/-) mice, whereas the same dose of HSV-2 replicated to detectable levels in only 13% ± 13% of vaginal samples and 0% of spinal cord samples from wild-type mice, as determined at day 5 postinfection. The susceptibility to HSV-2 infection in the CD118(-/-) mice was associated with a significant reduction in the infiltration of HSV-specific cytotoxic T lymphocytes into the vaginal tissue, the local production of gamma interferon (IFN-γ), and the expression of T cell-recruiting chemokines CCL5, CXCL9, and CXCL10. Collectively, the results underscore the significant contribution of type I IFNs in resistance to genital HSV-2 infection.

Preclinical evaluation of the immunomodulatory properties of cardiac adipose tissue progenitor cells using umbilical cord blood mesenchymal stem cells: a direct comparative study.

PubMed

Perea-Gil, Isaac; Monguió-Tortajada, Marta; Gálvez-Montón, Carolina; Bayes-Genis, Antoni; Borràs, Francesc E; Roura, Santiago

2015-01-01

Cell-based strategies to regenerate injured myocardial tissue have emerged over the past decade, but the optimum cell type is still under scrutiny. In this context, human adult epicardial fat surrounding the heart has been characterized as a reservoir of mesenchymal-like progenitor cells (cardiac ATDPCs) with potential clinical benefits. However, additional data on the possibility that these cells could trigger a deleterious immune response following implantation are needed. Thus, in the presented study, we took advantage of the well-established low immunogenicity of umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) to comparatively assess the immunomodulatory properties of cardiac ATDPCs in an in vitro allostimulatory assay using allogeneic mature monocyte-derived dendritic cells (MDDCs). Similar to UCBMSCs, increasing amounts of seeded cardiac ATDPCs suppressed the alloproliferation of T cells in a dose-dependent manner. Secretion of proinflammatory cytokines (IL6, TNFα, and IFNγ) was also specifically modulated by the different numbers of cardiac ATDPCs cocultured. In summary, we show that cardiac ATDPCs abrogate T cell alloproliferation upon stimulation with allogeneic mature MDDCs, suggesting that they could further regulate a possible harmful immune response in vivo. Additionally, UCBMSCs can be considered as valuable tools to preclinically predict the immunogenicity of prospective regenerative cells.

Asymmetric bone adaptations to soleus mechanical loading after spinal cord injury

PubMed Central

Dudley-Javoroski, S.; Shields, R.K.

2009-01-01

The purpose of this report is to examine longitudinal bone mineral density (BMD) changes in individuals with spinal cord injury (SCI) who began unilateral soleus electrical stimulation early after injury. Twelve men with SCI and seven without SCI underwent peripheral quantitative computed tomography assessment of distal tibia BMD. After 4.5 to 6 years of training, average trained limb BMD was 27.5% higher than untrained limb BMD. The training effect was more pronounced in the central core of the tibia cross-section (40.5% between-limb difference). No between-limb difference emerged in the anterior half of the tibia (19.2 mg/cm3 difference, p>0.05). A robust between-limb difference emerged in the posterior half of the tibia (76.1 mg/cm3 difference, p=0.0439). The posterior tibia BMD of one subject remained within the range of non-SCI values for 3.8 years post-SCI. The results support that the constrained orientation of soleus mechanical loads, administered over several years, elicited bone-sparing effects in the posterior tibia. This study provides a demonstration of the bone-protective potential of a carefully controlled dose of mechanical load. The specific orientation of applied mechanical loads may strongly influence the manifestation of BMD adaptations in humans with SCI. PMID:18799855

Protective effect of nicotinamide adenine dinucleotide (NAD+) against spinal cord ischemia-reperfusion injury via reducing oxidative stress-induced neuronal apoptosis.

PubMed

Xie, Lei; Wang, Zhenfei; Li, Changwei; Yang, Kai; Liang, Yu

2017-02-01

As previous studies demonstrate that oxidative stress and apoptosis play crucial roles in ischemic pathogenesis and nicotinamide adenine dinucleotide (NAD + ) treatment attenuates oxidative stress-induced cell death among primary neurons and astrocytes as well as significantly reduce cerebral ischemic injury in rats. We used a spinal cord ischemia injury (SCII) model in rats to verify our hypothesis that NAD + could ameliorate oxidative stress-induced neuronal apoptosis. Adult male rats were subjected to transient spinal cord ischemia for 60min, and different doses of NAD + were administered intraperitoneally immediately after the start of reperfusion. Neurological function was determined by Basso, Beattie, Bresnahan (BBB) scores. The oxidative stress level was assessed by superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. The degree of apoptosis was analyzed by deoxyuridinetriphosphate nick-end labeling (TUNEL) staining and protein levels of cleaved caspase-3 and AIF (apoptosis inducing factor). The results showed that NAD + at 50 or 100mg/kg significantly decreased the oxidative stress level and neuronal apoptosis in the spinal cord of ischemia-reperfusion rats compared with saline, as accompanied with the decreased oxidative stress, NAD + administration significantly restrained the neuronal apoptosis after ischemia injury while improved the neurological and motor function. These findings suggested that NAD + might protect against spinal cord ischemia-reperfusion via reducing oxidative stress-induced neuronal apoptosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Two cases of sarcoidosis presenting as longitudinally extensive transverse myelitis.

PubMed

Scott, Amanda Mary; Yinh, Janeth; McAlindon, Timothy; Kalish, Robert

2018-05-17

Neurosarcoidosis is uncommon with an incidence of approximately 5 to 15%. Central nervous system involvement can be divided into brain and spinal cord neurosarcoidosis. Spinal cord sarcoidosis is extremely rare, occurring in less than 1% of all sarcoidosis cases. Its manifestations may include cauda equina syndrome, radiculopathy, syringomyelia, cord atrophy, arachnoiditis, and myelopathy or transverse myelitis. We highlight two cases of spinal cord sarcoidosis, each presenting with longitudinally extensive transverse myelitis, that demonstrate the dilemmas that physicians face with regard to diagnosis and treatment. Given its rarity and the diversity of possible manifestations, establishing the diagnosis of spinal cord sarcoidosis is often very difficult. Extensive evaluation must be conducted to rule out primary neurologic, primary rheumatologic, infectious, and neoplastic diseases. MRI often demonstrates hyperintensity on T2-weighted images and enhancement following gadolinium administration. CSF analysis most consistently shows a lymphocytic pleocytosis and elevated proteins. While these less invasive investigations may be helpful, the gold standard for diagnosis is biopsy of neurologic or non-neurologic tissue confirming the presence of non-caseating granulomas. Evidence-based guidelines for the treatment of transverse myelitis secondary to sarcoidosis are lacking due to its rarity; therefore, therapy is based on expert and anecdotal experience and usually consists of high doses of steroids in combination with various immunosuppressive agents. The use of infliximab in particular appears promising, but there is a need for further investigation into the ideal treatment regimen.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Acar, H; Cebe, M; Mabhouti, H

Purpose: Stereotactic body radiosurgery (SBRT) for spine metastases involves irradiation using a single high dose fraction. The purpose of this study was to investigate a Hybrid VMAT/IMRT technique which combines volumetric modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) for spine SBRT in terms of its dosimetric quality and treatment efficiency using Radiation Therapy Oncology Group (RTOG) 0631 guidelines. Methods: 7 fields IMRT, 2 full arcs VMAT and Hybrid VMAT/IMRT were created for ten previously treated patients. The Hybrid VMAT/IMRT technique consisted of 1 full VMAT arc and 5 IMRT fields. Hybrid VMAT/IMRT plans were compared with IMRTmore » and VMAT plans in terms of the dose distribution, spinal cord sparing, homogeneity, conformity and gradient indexies, monitor unit (MU) and beam on time (BOT). RTOG 0631 recommendations were applied for treatment planning. All plans were normalized and prescribed to deliver 18.0 Gy in a single fraction to 90% of the target volume. Results: The Hybrid VMAT/IMRT technique significantly improved target dose homogeneity and conformity compared with IMRT and VMAT techniques. Providing sharp dose gradient Hybrid VMAT/IMRT plans spare the spinal cord and healthy tissue more effectively. Although, both MU and BOT slightly increased in Hybrid VMAT/IMRT plans there is no statistically meaningful difference between VMAT and Hybrid VMAT/IMRT plans. Conclusion: In IMRT, a smaller volume of healthy tissue can be irradiated in the low dose region, VMAT plans provide better target volume coverage, favorable dose gradient, conformity and better OAR sparing and also they require a much smaller number of MUs and thus a shorter treatment time than IMRT plans. Hybrid plan offers a sinergy through combination of these two techniques with slightly increased number of MU and thus more treatment time.« less

CBCT-based volumetric and dosimetric variation evaluation of volumetric modulated arc radiotherapy in the treatment of nasopharyngeal cancer patients

PubMed Central

2013-01-01

Objective To investigate the anatomic and dosimetric variations of volumetric modulated arc therapy (VMAT) in the treatment of nasopharyngeal cancer (NPC) patients based on weekly cone beam CT (CBCT). Materials and methods Ten NPC patients treated by VMAT with weekly CBCT for setup corrections were reviewed retrospectively. Deformed volumes of targets and organs at risk (OARs) in the CBCT were compared with those in the planning CT. Delivered doses were recalculated based on weekly CBCT and compared with the planned doses. Results No significant volumetric changes on targets, brainstem, and spinal cord were observed. The average volumes of right and left parotid measured from the fifth CBCT were about 4.4 and 4.5 cm3 less than those from the first CBCT, respectively. There were no significant dose differences between average planned and delivered doses for targets, brainstem and spinal cord. For right parotid, the delivered mean dose was 10.5 cGy higher (p = 0.004) than the planned value per fraction, and the V26 and V32 increased by 7.5% (p = 0.002) and 7.4% (p = 0.01), respectively. For the left parotid, the D50 (dose to the 50% volume) was 8.8 cGy higher (p = 0.03) than the planned values per fraction, and the V26 increased by 8.8% (p = 0.002). Conclusion Weekly CBCTs were applied directly to study the continuous volume changes and resulting dosimetric variations of targets and OARs for NPC patients undergoing VMAT. Significant volumetric and dosimetric variations were observed for parotids. Replanning after 30 Gy will benefit the protection on parotids. PMID:24289312

Radiobiological evaluation of simultaneously dose-escalated versus non-escalated intensity-modulated radiation therapy for patients with upper thoracic esophageal cancer.

PubMed

Huang, Bao-Tian; Wu, Li-Li; Guo, Long-Jia; Xu, Liang-Yu; Huang, Rui-Hong; Lin, Pei-Xian; Chen, Jian-Zhou; Li, De-Rui; Chen, Chuang-Zhen

2017-01-01

To compare the radiobiological response between simultaneously dose-escalated and non-escalated intensity-modulated radiation therapy (DE-IMRT and NE-IMRT) for patients with upper thoracic esophageal cancer (UTEC) using radiobiological evaluation. Computed tomography simulation data sets for 25 patients pathologically diagnosed with primary UTEC were used in this study. DE-IMRT plan with an escalated dose of 64.8 Gy/28 fractions to the gross tumor volume (GTV) and involved lymph nodes from 25 patients pathologically diagnosed with primary UTEC, was compared to an NE-IMRT plan of 50.4 Gy/28 fractions. Dose-volume metrics, tumor control probability (TCP), and normal tissue complication probability for the lung and spinal cord were compared. In addition, the risk of acute esophageal toxicity (AET) and late esophageal toxicity (LET) were also analyzed. Compared with NE-IMRT plan, we found the DE-IMRT plan resulted in a 14.6 Gy dose escalation to the GTV. The tumor control was predicted to increase by 31.8%, 39.1%, and 40.9% for three independent TCP models. The predicted incidence of radiation pneumonitis was similar (3.9% versus 3.6%), and the estimated risk of radiation-induced spinal cord injury was extremely low (<0.13%) in both groups. Regarding the esophageal toxicities, the estimated grade ≥2 and grade ≥3 AET predicted by the Kwint model were increased by 2.5% and 3.8%. Grade ≥2 AET predicted using the Wijsman model was increased by 14.9%. The predicted incidence of LET was low (<0.51%) in both groups. Radiobiological evaluation reveals that the DE-IMRT dosing strategy is feasible for patients with UTEC, with significant gains in tumor control and minor or clinically acceptable increases in radiation-induced toxicities.

Relationships among Prenatal Aeroallergen Exposure, Maternal and Cord Blood Immunoglobulin E: Project ACCESS

PubMed Central

Peters, Junenette L.; Suglia, Shakira Franco; Platts-Mills, Thomas A.E.; Hosen, Jacob; Gold, Diane R.; Wright, Rosalind J.

2009-01-01

Background While some evidence suggests that antigen sensitization may begin prenatally, the influence of maternal allergen exposure during pregnancy has not been fully elucidated. Objectives We examined the relationship between prenatal maternal aeroallergen exposure and cord blood total immunoglobulin E (IgE) and the potential mediating/indirect effect of maternal immune response. Methods This study was performed in 301 mother-infant pairs enrolled in the Asthma Coalition on Community, Environment, and Social Stress (ACCESS) project, a study examining the effects of prenatal and early life social and physical environmental exposures on urban asthma risk. Dust samples collected prenatally from mothers’ bedrooms were analyzed for cockroach and dust mite allergens. Cord blood was analyzed for total IgE and maternal serum collected during pregnancy for total and specific IgE. We assessed the relationship between prenatal exposure and cord blood total IgE and the potential mediation effect adjusting for maternal age, race, education, smoking status and dust collection season; and child’s gender and season of birth. Results In multivariate models, elevated prenatal dust mite levels (> 0.2 µg/g) increased cord blood IgE concentrations by 29% (p=0.08) and continuous dust mite concentration was associated with a significant non-linear increase in cord blood IgE (p=0.02). Elevated prenatal exposure to cockroach allergen (> 2 U/g) was not associated with cord blood IgE, but showed a significant indirect relationship through maternal total IgE (β=0.23; 95% CI: 0.08, 0.41). Conclusions These results demonstrate that maternal prenatal exposure to household allergens may impact cord blood IgE albeit the underlying mechanism may be allergen-specific. Clinical Implications Maternal prenatal inhalant allergen exposure may precipitate infant immune response although the pathway of the effect may differ by allergen. Capsule Summary Prenatal exposure to dust mite was associated with increased cord blood total IgE whereas the relationship between prenatal cockroach exposure and total cord blood IgE was only observed through the indirect effect of maternal allergic response. PMID:19361844

Spinal Cord Injury in the Geriatric Population: Risk Factors, Treatment Options, and Long-Term Management.

PubMed

Ikpeze, Tochukwu C; Mesfin, Addisu

2017-06-01

Spinal cord injuries (SCIs) are sustained by more than 12 500 patients per year in the United States and more globally. The SCIs disproportionately affect the elderly, especially men. Approximately 60% of these injuries are sustained traumatically through falls, but nontraumatic causes including infections, tumors, and medication-related epidural bleeding have also been documented. Preexisting conditions such as ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis can render the spine stiff and are risk factors as well as cervical spondylosis and ensuing cervical stenosis. Treatment options vary depending on the severity, location, and complexity of the injury. Surgical management has been growing in popularity over the years and remains an option as it helps reduce spinal cord compression and alleviate pain. Elevating mean arterial pressures to prevent spinal cord ischemia and avoiding the second hit of SCI have become more common as opposed to high dose steroids. Ongoing clinical trials with pharmacological agents such as minocycline and riluzole have shown early, promising results in their ability to reduce cellular damage and facilitate recovery. Though SCI can be life changing, the available treatment options have aimed to reduce pain and minimize complications and maintain quality of life alongside rehabilitative services.

Where and When to Cut? Fluorescein Guidance for Brain Stem and Spinal Cord Tumor Surgery-Technical Note.

PubMed

Molina, Eric Suero; Stummer, Walter

2017-12-29

Spinal cord and brain stem lesions require a judicious approach with an optimized trajectory due to a clustering of functions on their surfaces. Intraoperative mapping helps locate function. To confidently locate such lesions, neuronavigation alone lacks the desired accuracy and is of limited use in the spinal cord. To evaluate the clinical value of fluoresceins for initial delineation of such critically located lesions. We evaluated fluorescein guidance in the surgical resection of lesions with blood-brain barrier disruption demonstrating contrast enhancement in magnet resonance imaging in the spinal cord and in the brain stem in 3 different patients. Two patients harbored a diffuse cervical and thoracic spinal cord lesion, respectively. Another patient suffered metastatic lesions in the brain stem and at the floor of the fourth ventricle. Low-dose fluorescein (4 mg/kg body weight) was applied after anesthesia induction and visualized using the Zeiss Pentero 900 Yellow560 filter (Carl Zeiss, Oberkochen, Germany). Fluorescein was helpful for locating lesions and for defining the best possible trajectory. During resection, however, we found unspecific propagation of fluorescein within the brain stem up to 6 mm within 3 h after application. As these lesions were otherwise distinguishable from surrounding tissue, monitoring resection was not an issue. Fluorescein guidance is a feasible tool for defining surgical entry zones when aiming for surgical removal of spinal cord and brain stem lesions. Unselective fluorescein extravasation cautions against using such methodology for monitoring completeness of resection. Providing the right timing, a window of pseudoselectivity could increase fluoresceins' clinical value in these cases. © Congress of Neurological Surgeons 2017.

Valproic Acid Increases Expression of Neuronal Stem/Progenitor Cell in Spinal Cord Injury

PubMed Central

Bang, Woo-Seok; Cho, Dae-Chul; Kim, Hye-Jeong; Sung, Joo-Kyung

2013-01-01

Objective This study investigates the effect of valproic acid (VPA) on expression of neural stem/progenitor cells (NSPCs) in a rat spinal cord injury (SCI) model. Methods Adult male rats (n=24) were randomly and blindly allocated into three groups. Laminectomy at T9 was performed in all three groups. In group 1 (sham), only laminectomy was performed. In group 2 (SCI-VPA), the animals received a dose of 200 mg/kg of VPA. In group 3 (SCI-saline), animals received 1.0 mL of the saline vehicle solution. A modified aneurysm clip with a closing force of 30 grams was applied extradurally around the spinal cord at T9, and then rapidly released with cord compression persisting for 2 minutes. The rats were sacrificed and the spinal cord were collected one week after SCI. Immunohistochemistry (IHC) and western blotting sample were obtained from 5 mm rostral region to the lesion and prepared. We analyzed the nestin immunoreactivity from the white matter of ventral cord and the ependyma of central canal. Nestin and SOX2 were used for markers for NSPCs and analyzed by IHC and western blotting, respectively. Results Nestin and SOX2 were expressed significantly in the SCI groups but not in the sham group. Comparing SCI groups, nestin and SOX2 expression were much stronger in SCI-VPA group than in SCI-saline group. Conclusion Nestin and SOX2 as markers for NSPCs showed increased expression in SCI-VPA group in comparison with SCI-saline group. This result suggests VPA increases expression of spinal NSPCs in SCI. PMID:24044073

Generalizable Class Solutions for Treatment Planning of Spinal Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weksberg, David C.; Palmer, Matthew B.; Vu, Khoi N.

2012-11-01

Purpose: Spinal stereotactic body radiation therapy (SBRT) continues to emerge as an effective therapeutic approach to spinal metastases; however, treatment planning and delivery remain resource intensive at many centers, which may hamper efficient implementation in clinical practice. We sought to develop a generalizable class solution approach for spinal SBRT treatment planning that would allow confidence that a given plan provides optimal target coverage, reduce integral dose, and maximize planning efficiency. Methods and Materials: We examined 91 patients treated with spinal SBRT at our institution. Treatment plans were categorized by lesion location, clinical target volume (CTV) configuration, and dose fractionation scheme,more » and then analyzed to determine the technically achievable dose gradient. A radial cord expansion was subtracted from the CTV to yield a planning CTV (pCTV) construct for plan evaluation. We reviewed the treatment plans with respect to target coverage, dose gradient, integral dose, conformality, and maximum cord dose to select the best plans and develop a set of class solutions. Results: The class solution technique generated plans that maintained target coverage and improved conformality (1.2-fold increase in the 95% van't Riet Conformation Number describing the conformality of a reference dose to the target) while reducing normal tissue integral dose (1.3-fold decrease in the volume receiving 4 Gy (V{sub 4Gy}) and machine output (19% monitor unit (MU) reduction). In trials of planning efficiency, the class solution technique reduced treatment planning time by 30% to 60% and MUs required by {approx}20%: an effect independent of prior planning experience. Conclusions: We have developed a set of class solutions for spinal SBRT that incorporate a pCTV metric for plan evaluation while yielding dosimetrically superior treatment plans with increased planning efficiency. Our technique thus allows for efficient, reproducible, and high-quality spinal SBRT treatment planning.« less

Volumetric modulated arc therapy vs. c-IMRT for the treatment of upper thoracic esophageal cancer.

PubMed

Zhang, Wu-Zhe; Zhai, Tian-Tian; Lu, Jia-Yang; Chen, Jian-Zhou; Chen, Zhi-Jian; Li, De-Rui; Chen, Chuang-Zhen

2015-01-01

To compare plans using volumetric-modulated arc therapy (VMAT) with conventional sliding window intensity-modulated radiation therapy (c-IMRT) to treat upper thoracic esophageal cancer (EC). CT datasets of 11 patients with upper thoracic EC were identified. Four plans were generated for each patient: c-IMRT with 5 fields (5F) and VMAT with a single arc (1A), two arcs (2A), or three arcs (3A). The prescribed doses were 64 Gy/32 F for the primary tumor (PTV64). The dose-volume histogram data, the number of monitoring units (MUs) and the treatment time (TT) for the different plans were compared. All of the plans generated similar dose distributions for PTVs and organs at risk (OARs), except that the 2A- and 3A-VMAT plans yielded a significantly higher conformity index (CI) than the c-IMRT plan. The CI of the PTV64 was improved by increasing the number of arcs in the VMAT plans. The maximum spinal cord dose and the planning risk volume of the spinal cord dose for the two techniques were similar. The 2A- and 3A-VMAT plans yielded lower mean lung doses and heart V50 values than the c-IMRT. The V20 and V30 for the lungs in all of the VMAT plans were lower than those in the c-IMRT plan, at the expense of increasing V5, V10 and V13. The VMAT plan resulted in significant reductions in MUs and TT. The 2A-VMAT plan appeared to spare the lungs from moderate-dose irradiation most effectively of all plans, at the expense of increasing the low-dose irradiation volume, and also significantly reduced the number of required MUs and the TT. The CI of the PTVs and the OARs was improved by increasing the arc-number from 1 to 2; however, no significant improvement was observed using the 3A-VMAT, except for an increase in the TT.

Comparing analgesia and μ-opioid receptor internalization produced by intrathecal enkephalin

PubMed Central

Chen, Wenling; Song, Bingbing; Lao, Lijun; Pérez, Orlando A.; Kim, Woojae; Marvizón, Juan Carlos G.

2007-01-01

Summary Opioid receptors in the spinal cord produce strong analgesia, but the mechanisms controlling their activation by endogenous opioids remain unclear. We have previously shown in spinal cord slices that peptidases preclude μ-opioid receptor (MOR) internalization by opioids. Our present goals were to investigate whether enkephalin-induced analgesia is also precluded by peptidases, and whether it is mediated by MORs or δ-opioid receptors (DORs). Tail-flick analgesia and MOR internalization were measured in rats injected intrathecally with Leu-enkephalin and peptidase inhibitors. Without peptidase inhibitors, Leu-enkephalin produced neither analgesia nor MOR internalization at doses up to 100 nmol, whereas with peptidase inhibitors it produced analgesia at 0.3 nmol and MOR internalization at 1 nmol. Leu-enkephalin was ten times more potent to produce analgesia than to produce MOR internalization, suggesting that DORs were involved. Selective MOR or DOR antagonists completely blocked the analgesia elicited by 0.3 nmol Leu-enkephalin (a dose that produced little MOR internalization), indicating that it involved these two receptors, possibly by an additive or synergistic interaction. The selective MOR agonist endomorphin-2 produced analgesia even in the presence of a DOR antagonist, but at doses substantially higher than Leu-enkephalin. Unlike Leu-enkephalin, endomorphin-2 had the same potencies to induce analgesia and MOR internalization. We concluded that low doses of enkephalins produce analgesia by activating both MORs and DORs. Analgesia can also be produced exclusively by MORs at higher agonist doses. Since peptidases prevent the activation of spinal opioid receptors by enkephalins, the coincident release of opioids and endogenous peptidase inhibitors may be required for analgesia. PMID:17845806

Three-dimensional radiotherapy of head and neck and esophageal carcinomas: a monoisocentric treatment technique to achieve improved dose distributions.

PubMed

Ahmad, M; Nath, R

2001-02-20

The specific aim of three-dimensional conformal radiotherapy is to deliver adequate therapeutic radiation dose to the target volume while concomitantly keeping the dose to surrounding and intervening normal tissues to a minimum. The objective of this study is to examine dose distributions produced by various radiotherapy techniques used in managing head and neck tumors when the upper part of the esophagus is also involved. Treatment planning was performed with a three-dimensional (3-D) treatment planning system. Computerized tomographic (CT) scans used by this system to generate isodose distributions and dose-volume histograms were obtained directly from the CT scanner, which is connected via ethernet cabling to the 3-D planning system. These are useful clinical tools for evaluating the dose distribution to the treatment volume, clinical target volume, gross tumor volume, and certain critical organs. Using 6 and 18 MV photon beams, different configurations of standard treatment techniques for head and neck and esophageal carcinoma were studied and the resulting dose distributions were analyzed. Film validation dosimetry in solid-water phantom was performed to assess the magnitude of dose inhomogeneity at the field junction. Real-time dose measurements on patients using diode dosimetry were made and compared with computed dose values. With regard to minimizing radiation dose to surrounding structures (i.e., lung, spinal cord, etc.), the monoisocentric technique gave the best isodose distributions in terms of dose uniformity. The mini-mantle anterior-posterior/posterior-anterior (AP/PA) technique produced grossly non-uniform dose distribution with excessive hot spots. The dose measured on the patient during the treatment agrees to within +/- 5 % with the computed dose. The protocols presented in this work for simulation, immobilization and treatment planning of patients with head and neck and esophageal tumors provide the optimum dose distributions in the target volume with reduced irradiation of surrounding non-target tissues, and can be routinely implemented in a radiation oncology department. The presence of a real-time dose-measuring system plays an important role in verifying the actual delivery of radiation dose.

Testosterone Dose Dependently Prevents Bone and Muscle Loss in Rodents after Spinal Cord Injury

PubMed Central

Conover, Christine F.; Beggs, Luke A.; Beck, Darren T.; Otzel, Dana M.; Balaez, Alexander; Combs, Sarah M.; Miller, Julie R.; Ye, Fan; Aguirre, J. Ignacio; Neuville, Kathleen G.; Williams, Alyssa A.; Conrad, Bryan P.; Gregory, Chris M.; Wronski, Thomas J.; Bose, Prodip K.; Borst, Stephen E.

2014-01-01

Abstract Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0 mg/week), or (4) SCI+High-dose TE (7.0 mg/week). Twenty-one days post-injury, SCI animals exhibited a 77–85% reduction in hindlimb cancellous bone volume at the distal femur (measured via μCT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13–27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI. PMID:24378197

Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy.

PubMed

Singhmar, Pooja; Huo, XiaoJiao; Li, Yan; Dougherty, Patrick M; Mei, Fang; Cheng, Xiaodong; Heijnen, Cobi J; Kavelaars, Annemieke

2018-05-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer treatment that significantly compromises quality of life of cancer patients and survivors. Identification of targets for pharmacological intervention to prevent or reverse CIPN is needed. We investigated exchange protein regulated by cAMP (Epac) as a potential target. Epacs are cAMP-binding proteins known to play a pivotal role in mechanical allodynia induced by nerve injury and inflammation. We demonstrate that global Epac1-knockout (Epac1-/-) male and female mice are protected against paclitaxel-induced mechanical allodynia. In addition, spinal cord astrocyte activation and intraepidermal nerve fiber (IENF) loss are significantly reduced in Epac1-/- mice as compared to wild-type mice. Moreover, Epac1-/- mice do not develop the paclitaxel-induced deficits in mitochondrial bioenergetics in the sciatic nerve that are a hallmark of CIPN. Notably, mice with cell-specific deletion of Epac1 in Nav1.8-positive neurons (N-Epac1-/-) also show reduced paclitaxel-induced mechanical allodynia, astrocyte activation, and IENF loss, indicating that CIPN develops downstream of Epac1 activation in nociceptors. The Epac-inhibitor ESI-09 reversed established paclitaxel-induced mechanical allodynia in wild-type mice even when dosing started 10 days after completion of paclitaxel treatment. In addition, oral administration of ESI-09 suppressed spinal cord astrocyte activation in the spinal cord and protected against IENF loss. Ex vivo, ESI-09 blocked paclitaxel-induced abnormal spontaneous discharges in dorsal root ganglion neurons. Collectively, these findings implicate Epac1 in nociceptors as a novel target for treatment of CIPN. This is clinically relevant because ESI-09 has the potential to reverse a debilitating and long-lasting side effect of cancer treatment.

From the motor cortex to the movement and back again.

PubMed

Teka, Wondimu W; Hamade, Khaldoun C; Barnett, William H; Kim, Taegyo; Markin, Sergey N; Rybak, Ilya A; Molkov, Yaroslav I

2017-01-01

The motor cortex controls motor behaviors by generating movement-specific signals and transmitting them through spinal cord circuits and motoneurons to the muscles. Precise and well-coordinated muscle activation patterns are necessary for accurate movement execution. Therefore, the activity of cortical neurons should correlate with movement parameters. To investigate the specifics of such correlations among activities of the motor cortex, spinal cord network and muscles, we developed a model for neural control of goal-directed reaching movements that simulates the entire pathway from the motor cortex through spinal cord circuits to the muscles controlling arm movements. In this model, the arm consists of two joints (shoulder and elbow), whose movements are actuated by six muscles (4 single-joint and 2 double-joint flexors and extensors). The muscles provide afferent feedback to the spinal cord circuits. Cortical neurons are defined as cortical "controllers" that solve an inverse problem based on a proposed straight-line trajectory to a target position and a predefined bell-shaped velocity profile. Thus, the controller generates a motor program that produces a task-specific activation of low-level spinal circuits that in turn induce the muscle activation realizing the intended reaching movement. Using the model, we describe the mechanisms of correlation between cortical and motoneuronal activities and movement direction and other movement parameters. We show that the directional modulation of neuronal activity in the motor cortex and the spinal cord may result from direction-specific dynamics of muscle lengths. Our model suggests that directional modulation first emerges at the level of muscle forces, augments at the motoneuron level, and further increases at the level of the motor cortex due to the dependence of frictional forces in the joints, contractility of the muscles and afferent feedback on muscle lengths and/or velocities.

Evaluation of magnetic resonance imaging for the differentiation of inflammatory, neoplastic, and vascular intradural spinal cord diseases in the dog.

PubMed

Masciarelli, Amanda E; Griffin, John F; Fosgate, Geoffrey T; Hecht, Silke; Mankin, Joseph M; Holmes, Shannon P; Platt, Simon R; Kent, Marc; Pancotto, Theresa E; Chen, Annie V; Levine, Jonathan M

2017-07-01

Magnetic resonance imaging (MRI) is a common test for dogs with suspected intradural spinal cord lesions, however studies on diagnostic performance for this test are lacking. Objectives of this multi-institutional, retrospective, case-control study were to estimate sensitivity and specificity of MRI for (1) distinguishing between histopathologically confirmed intradural spinal cord disease versus degenerative myelopathy in dogs, (2) categorizing intradural spinal cord diseases as neoplastic, inflammatory, or vascular; and (3) determining tumor type within the etiologic category of neoplasia. Additional aims were to (1) determine whether knowledge of clinical data affects sensitivity and specificity of MRI diagnoses; and (2) report interrater agreement for MRI classification of intradural spinal lesions. Cases were recruited from participating hospital databases over a 7-year period. Three reviewers independently evaluated each MRI study prior to and after provision of clinical information. A total of 87 cases were sampled (17 degenerative myelopathy, 53 neoplasia, nine inflammatory, and eight vascular). Magnetic resonance imaging had excellent (>97.6%) sensitivity for diagnosis of intradural spinal cord lesions but specificity varied before and after provision of clinical data (68.6% vs. 82.4%, P = 0.023). Magnetic resonance imaging had good sensitivity (86.8%) and moderate specificity (64.7-72.5%) for diagnosing neoplasia. Sensitivity was lower for classifying inflammatory lesions but improved with provision of clinical data (48.1% vs. 81.5%, P = 0.015). Magnetic resonance imaging was insensitive for diagnosing vascular lesions (25.0%). Interrater agreement was very good for correctly diagnosing dogs with intradural lesions (ĸ = 0.882-0.833), and good (ĸ = 0.726-0.671) for diagnosing dogs with neoplasia. © 2017 American College of Veterinary Radiology.

Simultaneous modulated accelerated radiation therapy for esophageal cancer: a feasibility study.

PubMed

Zhang, Wu-Zhe; Chen, Jian-Zhou; Li, De-Rui; Chen, Zhi-Jian; Guo, Hong; Zhuang, Ting-Ting; Li, Dong-Sheng; Zhou, Ming-Zhen; Chen, Chuang-Zhen

2014-10-14

To establish the feasibility of simultaneous modulated accelerated radiation therapy (SMART) in esophageal cancer (EC). Computed tomography (CT) datasets of 10 patients with upper or middle thoracic squamous cell EC undergoing chemoradiotherapy were used to generate SMART, conventionally-fractionated three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiation therapy (cf-IMRT) plans, respectively. The gross target volume (GTV) of the esophagus, positive regional lymph nodes (LN), and suspected lymph nodes (LN ±) were contoured for each patient. The clinical target volume (CTV) was delineated with 2-cm longitudinal and 0.5- to 1.0-cm radial margins with respect to the GTV and with 0.5-cm uniform margins for LN and LN(±). For the SMART plans, there were two planning target volumes (PTVs): PTV66 = (GTV + LN) + 0.5 cm and PTV54 = CTV + 0.5 cm. For the 3DCRT and cf-IMRT plans, there was only a single PTV: PTV60 = CTV + 0.5 cm. The prescribed dose for the SMART plans was 66 Gy/30 F to PTV66 and 54 Gy/30 F to PTV54. The dose prescription to the PTV60 for both the 3DCRT and cf-IMRT plans was set to 60 Gy/30 F. All the plans were generated on the Eclipse 10.0 treatment planning system. Fulfillment of the dose criteria for the PTVs received the highest priority, followed by the spinal cord, heart, and lungs. The dose-volume histograms were compared. Clinically acceptable plans were achieved for all the SMART, cf-IMRT, and 3DCRT plans. Compared with the 3DCRT plans, the SMART plans increased the dose delivered to the primary tumor (66 Gy vs 60 Gy), with improved sparing of normal tissues in all patients. The Dmax of the spinal cord, V20 of the lungs, and Dmean and V50 of the heart for the SMART and 3DCRT plans were as follows: 38.5 ± 2.0 vs 44.7 ± 0.8 (P = 0.002), 17.1 ± 4.0 vs 25.8 ± 5.0 (P = 0.000), 14.4 ± 7.5 vs 21.4 ± 11.1 (P = 0.000), and 4.9 ± 3.4 vs 12.9 ± 7.6 (P = 0.000), respectively. In contrast to the cf-IMRT plans, the SMART plans permitted a simultaneous dose escalation (6 Gy) to the primary tumor while demonstrating a significant trend of a lower irradiation dose to all organs at risk except the spinal cord, for which no significant difference was found. SMART offers the potential for a 6 Gy simultaneous escalation in the irradiation dose delivered to the primary tumor of EC and improves the sparing of normal tissues.

Simultaneous modulated accelerated radiation therapy for esophageal cancer: A feasibility study

PubMed Central

Zhang, Wu-Zhe; Chen, Jian-Zhou; Li, De-Rui; Chen, Zhi-Jian; Guo, Hong; Zhuang, Ting-Ting; Li, Dong-Sheng; Zhou, Ming-Zhen; Chen, Chuang-Zhen

2014-01-01

AIM: To establish the feasibility of simultaneous modulated accelerated radiation therapy (SMART) in esophageal cancer (EC). METHODS: Computed tomography (CT) datasets of 10 patients with upper or middle thoracic squamous cell EC undergoing chemoradiotherapy were used to generate SMART, conventionally-fractionated three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiation therapy (cf-IMRT) plans, respectively. The gross target volume (GTV) of the esophagus, positive regional lymph nodes (LN), and suspected lymph nodes (LN±) were contoured for each patient. The clinical target volume (CTV) was delineated with 2-cm longitudinal and 0.5- to 1.0-cm radial margins with respect to the GTV and with 0.5-cm uniform margins for LN and LN(±). For the SMART plans, there were two planning target volumes (PTVs): PTV66 = (GTV + LN) + 0.5 cm and PTV54 = CTV + 0.5 cm. For the 3DCRT and cf-IMRT plans, there was only a single PTV: PTV60 = CTV + 0.5 cm. The prescribed dose for the SMART plans was 66 Gy/30 F to PTV66 and 54 Gy/30 F to PTV54. The dose prescription to the PTV60 for both the 3DCRT and cf-IMRT plans was set to 60 Gy/30 F. All the plans were generated on the Eclipse 10.0 treatment planning system. Fulfillment of the dose criteria for the PTVs received the highest priority, followed by the spinal cord, heart, and lungs. The dose-volume histograms were compared. RESULTS: Clinically acceptable plans were achieved for all the SMART, cf-IMRT, and 3DCRT plans. Compared with the 3DCRT plans, the SMART plans increased the dose delivered to the primary tumor (66 Gy vs 60 Gy), with improved sparing of normal tissues in all patients. The Dmax of the spinal cord, V20 of the lungs, and Dmean and V50 of the heart for the SMART and 3DCRT plans were as follows: 38.5 ± 2.0 vs 44.7 ± 0.8 (P = 0.002), 17.1 ± 4.0 vs 25.8 ± 5.0 (P = 0.000), 14.4 ± 7.5 vs 21.4 ± 11.1 (P = 0.000), and 4.9 ± 3.4 vs 12.9 ± 7.6 (P = 0.000), respectively. In contrast to the cf-IMRT plans, the SMART plans permitted a simultaneous dose escalation (6 Gy) to the primary tumor while demonstrating a significant trend of a lower irradiation dose to all organs at risk except the spinal cord, for which no significant difference was found. CONCLUSION: SMART offers the potential for a 6 Gy simultaneous escalation in the irradiation dose delivered to the primary tumor of EC and improves the sparing of normal tissues. PMID:25320535

Intricacies of Using Kevlar and Thermal Knives in a Deployable Release System: Issues and Solutions

NASA Technical Reports Server (NTRS)

Stewart, Alphonso C.; Hair, Jason H.; Broduer, Steve (Technical Monitor)

2002-01-01

The utilization of Kevlar cord and thermal knives in a deployable release system produces a number of issues that must be addressed in the design of the system. This paper proposes design considerations that minimize the major issues, thermal knife failure, Kevlar cord relaxation, and the measurement of the cord tension. Design practices can minimize the potential for thermal knife laminate and element damage that result in failure of the knife. A process for in-situ inspection of the knife with resistance, rather than continuity, checks and 10x zoom optical imaging can detect damaged knives. Tests allow the characterization of the behavior of the particular Kevlar cord in use and the development of specific pre-stretching techniques and initial tension values needed to meet requirements. A new method can accurately measure the tension of the Kevlar cord using a guitar tuner, because more conventional methods do not apply to arimid cords such as Kevlar.

The relationship between cord blood immunoglobulin E levels and allergy-related outcomes in young adults.

PubMed

Shah, Purvee S; Wegienka, Ganesa; Havstad, Suzanne; Johnson, Christine Cole; Ownby, Dennis R; Zoratti, Edward M

2011-03-01

Elevated cord blood IgE may be associated with a higher risk of allergic disease. To determine whether cord blood IgE is associated with allergic biomarkers or allergic disorders in young adults. Data was collected from 670 subjects 18-21 years of age that were among 835 original participants in the Detroit Childhood Allergy Study, a general risk, population-based birth cohort. Cord blood IgE was assessed in relation to biomarkers associated with allergy and asthma including total IgE, allergen-specific IgE, blood eosinophilia, and spirometry. Cord blood IgE was also analyzed for associations to subsequent allergic disease including atopic dermatitis, allergic rhinitis, and asthma. Cord blood IgE, analyzed as a continuous measure, was modestly correlated with total IgE (r = 0.18, P < .001) and higher cord IgE was associated with a higher likelihood of sensitization to common allergens in young adults (OR = 1.18, 95% CI, 1.02-1.37; P = .031). The relationship between cord IgE and sensitization was stronger among teens with no pet exposure in the first year of life (OR = 1.43, 95% CI, 1.16-1.77; P = .001). No relationship was found between cord IgE and blood eosinophil counts or lung function. In addition, no consistent association of cord blood IgE to asthma, allergic rhinitis, or atopic dermatitis was apparent. An elevated cord blood IgE level modestly correlates with elevated total IgE and is associated with a slightly higher likelihood of allergic sensitization among young adults. However, cord IgE is not a strong predictor of clinical allergic disorders in this age group. Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Expansion of Human Tregs from Cryopreserved Umbilical Cord Blood for GMP-Compliant Autologous Adoptive Cell Transfer Therapy.

PubMed

Seay, Howard R; Putnam, Amy L; Cserny, Judit; Posgai, Amanda L; Rosenau, Emma H; Wingard, John R; Girard, Kate F; Kraus, Morey; Lares, Angela P; Brown, Heather L; Brown, Katherine S; Balavage, Kristi T; Peters, Leeana D; Bushdorf, Ashley N; Atkinson, Mark A; Bluestone, Jeffrey A; Haller, Michael J; Brusko, Todd M

2017-03-17

Umbilical cord blood is a traditional and convenient source of cells for hematopoietic stem cell transplantation. Thymic regulatory T cells (Tregs) are also present in cord blood, and there is growing interest in the use of autologous Tregs to provide a low-risk, fully human leukocyte antigen (HLA)-matched cell product for treating autoimmune diseases, such as type 1 diabetes. Here, we describe a good manufacturing practice (GMP)-compatible Treg expansion protocol using fluorescence-activated cell sorting, resulting in a mean 2,092-fold expansion of Tregs over a 16-day culture for a median yield of 1.26 × 10 9 Tregs from single-donor cryopreserved units. The resulting Tregs passed prior clinical trial release criteria for Treg purity and sterility, including additional rigorous assessments of FOXP3 and Helios expression and epigenetic analysis of the FOXP3 Treg-specific demethylated region (TSDR). Compared with expanded adult peripheral blood Tregs, expanded cord blood Tregs remained more naive, as assessed by continued expression of CD45RA, produced reduced IFN-γ following activation, and effectively inhibited responder T cell proliferation. Immunosequencing of the T cell receptor revealed a remarkably diverse receptor repertoire within cord blood Tregs that was maintained following in vitro expansion. These data support the feasibility of generating GMP-compliant Tregs from cord blood for adoptive cell transfer therapies and highlight potential advantages in terms of safety, phenotypic stability, autoantigen specificity, and tissue distribution.

SU-E-T-454: Impact of Calculation Grid Size On Dosimetry and Radiobiological Parameters for Head and Neck IMRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srivastava, S; Das, I; Indiana University Health Methodist Hospital, Indianapolis, IN

2014-06-01

Purpose: IMRT has become standard of care for complex treatments to optimize dose to target and spare normal tissues. However, the impact of calculation grid size is not widely known especially dose distribution, tumor control probability (TCP) and normal tissue complication probability (NTCP) which is investigated in this study. Methods: Ten head and neck IMRT patients treated with 6 MV photons were chosen for this study. Using Eclipse TPS, treatment plans were generated for different grid sizes in the range 1–5 mm for the same optimization criterion with specific dose-volume constraints. The dose volume histogram (DVH) was calculated for allmore » IMRT plans and dosimetric data were compared. ICRU-83 dose points such as D2%, D50%, D98%, as well as the homogeneity and conformity indices (HI, CI) were calculated. In addition, TCP and NTCP were calculated from DVH data. Results: The PTV mean dose and TCP decreases with increasing grid size with an average decrease in mean dose by 2% and TCP by 3% respectively. Increasing grid size from 1–5 mm grid size, the average mean dose and NTCP for left parotid was increased by 6.0% and 8.0% respectively. Similar patterns were observed for other OARs such as cochlea, parotids and spinal cord. The HI increases up to 60% and CI decreases on average by 3.5% between 1 and 5 mm grid that resulted in decreased TCP and increased NTCP values. The number of points meeting the gamma criteria of ±3% dose difference and ±3mm DTA was higher with a 1 mm on average (97.2%) than with a 5 mm grid (91.3%). Conclusion: A smaller calculation grid provides superior dosimetry with improved TCP and reduced NTCP values. The effect is more pronounced for smaller OARs. Thus, the smallest possible grid size should be used for accurate dose calculation especially in H and N planning.« less

Levels of PAH-DNA adducts in cord blood and cord tissue and the risk of fetal neural tube defects in a Chinese population.

PubMed

Yi, Deqing; Yuan, Yue; Jin, Lei; Zhou, Guodong; Zhu, Huiping; Finnell, Richard H; Ren, Aiguo

2015-01-01

Maternal exposure to polycyclic aromatic hydrocarbons (PAHs) has been shown to be associated with an elevated risk for neural tube defects (NTDs). In the human body, PAHs are bioactivated and the resultant reactive epoxides can covalently bind to DNA to form PAH-DNA adducts, which may, in turn, cause transcription errors, changes in gene expression or altered patterns of apoptosis. During critical developmental phases, these changes can result in abnormal morphogenesis. We aimed to examine the relationship between the levels of PAH-DNA adducts in cord blood and cord tissue and the risk of NTDs. From 2010 to 2012, 60 NTD cases and 60 healthy controls were recruited from a population-based birth defects surveillance system in five counties of Shanxi Province in Northern China, where the emission of PAHs remains one of the highest in the country and PAHs exposure is highly prevalent. PAH-DNA adducts in cord blood of 15 NTD cases and 15 control infants, and in cord tissue of 60 NTD cases and 60 control infants were measured using the (32)P-postlabeling method. PAH-DNA adduct levels in cord blood tend to be higher in the NTD group (28.5 per 10(8) nucleotides) compared with controls (19.7 per 10(8) nucleotides), although the difference was not statistically significant (P=0.377). PAH-DNA adducts in cord tissue were significantly higher in the NTD group (24.6 per 10(6) nucleotides) than in the control group (15.3 per 10(6) nucleotides), P=0.010. A positive dose-response relationship was found between levels of PAH-DNA adducts in cord tissue and the risk of NTDs (P=0.009). When the lowest tertile was used as the referent and potential confounding factors were adjusted for, a 1.03-fold (95% CI, 0.37-2.89) and 2.96-fold (95% CI, 1.16-7.58) increase in the risk of NTDs was observed for fetuses whose cord tissue PAH-DNA adduct levels were in the second and highest tertile, respectively. High levels of PAH-DNA adducts in fetal tissues were associated with increased risks of NTDs. Copyright © 2014 Elsevier Inc. All rights reserved.

SU-D-BRB-02: Combining a Commercial Autoplanning Engine with Database Dose Predictions to Further Improve Plan Quality

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robertson, SP; Moore, JA; Hui, X

Purpose: Database dose predictions and a commercial autoplanning engine both improve treatment plan quality in different but complimentary ways. The combination of these planning techniques is hypothesized to further improve plan quality. Methods: Four treatment plans were generated for each of 10 head and neck (HN) and 10 prostate cancer patients, including Plan-A: traditional IMRT optimization using clinically relevant default objectives; Plan-B: traditional IMRT optimization using database dose predictions; Plan-C: autoplanning using default objectives; and Plan-D: autoplanning using database dose predictions. One optimization was used for each planning method. Dose distributions were normalized to 95% of the planning target volumemore » (prostate: 8000 cGy; HN: 7000 cGy). Objectives used in plan optimization and analysis were the larynx (25%, 50%, 90%), left and right parotid glands (50%, 85%), spinal cord (0%, 50%), rectum and bladder (0%, 20%, 50%, 80%), and left and right femoral heads (0%, 70%). Results: All objectives except larynx 25% and 50% resulted in statistically significant differences between plans (Friedman’s χ{sup 2} ≥ 11.2; p ≤ 0.011). Maximum dose to the rectum (Plans A-D: 8328, 8395, 8489, 8537 cGy) and bladder (Plans A-D: 8403, 8448, 8527, 8569 cGy) were significantly increased. All other significant differences reflected a decrease in dose. Plans B-D were significantly different from Plan-A for 3, 17, and 19 objectives, respectively. Plans C-D were also significantly different from Plan-B for 8 and 13 objectives, respectively. In one case (cord 50%), Plan-D provided significantly lower dose than plan C (p = 0.003). Conclusion: Combining database dose predictions with a commercial autoplanning engine resulted in significant plan quality differences for the greatest number of objectives. This translated to plan quality improvements in most cases, although special care may be needed for maximum dose constraints. Further evaluation is warranted in a larger cohort across HN, prostate, and other treatment sites. This work is supported by Philips Radiation Oncology Systems.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matney, Jason; Park, Peter C.; The University of Texas Graduate School of Biomedical Sciences, Houston, Texas

Purpose: To quantify and compare the effects of respiratory motion on paired passively scattered proton therapy (PSPT) and intensity modulated photon therapy (IMRT) plans; and to establish the relationship between the magnitude of tumor motion and the respiratory-induced dose difference for both modalities. Methods and Materials: In a randomized clinical trial comparing PSPT and IMRT, radiation therapy plans have been designed according to common planning protocols. Four-dimensional (4D) dose was computed for PSPT and IMRT plans for a patient cohort with respiratory motion ranging from 3 to 17 mm. Image registration and dose accumulation were performed using grayscale-based deformable imagemore » registration algorithms. The dose–volume histogram (DVH) differences (4D-3D [3D = 3-dimensional]) were compared for PSPT and IMRT. Changes in 4D-3D dose were correlated to the magnitude of tumor respiratory motion. Results: The average 4D-3D dose to 95% of the internal target volume was close to zero, with 19 of 20 patients within 1% of prescribed dose for both modalities. The mean 4D-3D between the 2 modalities was not statistically significant (P<.05) for all dose–volume histogram indices (mean ± SD) except the lung V5 (PSPT: +1.1% ± 0.9%; IMRT: +0.4% ± 1.2%) and maximum cord dose (PSPT: +1.5 ± 2.9 Gy; IMRT: 0.0 ± 0.2 Gy). Changes in 4D-3D dose were correlated to tumor motion for only 2 indices: dose to 95% planning target volume, and heterogeneity index. Conclusions: With our current margin formalisms, target coverage was maintained in the presence of respiratory motion up to 17 mm for both PSPT and IMRT. Only 2 of 11 4D-3D indices (lung V5 and spinal cord maximum) were statistically distinguishable between PSPT and IMRT, contrary to the notion that proton therapy will be more susceptible to respiratory motion. Because of the lack of strong correlations with 4D-3D dose differences in PSPT and IMRT, the extent of tumor motion was not an adequate predictor of potential dosimetric error caused by breathing motion.« less

A Detailed Dosimetric Analysis of Spinal Cord Tolerance in High-Dose Spine Radiosurgery.

PubMed

Katsoulakis, Evangelia; Jackson, Andrew; Cox, Brett; Lovelock, Michael; Yamada, Yoshiya

2017-11-01

Dose-volume tolerance of the spinal cord (SC) in spinal stereotactic radiosurgery (SRS) is difficult to define because radiation myelitis rates are low, and published reports document cases of myelopathy but do not account for the total number of patients treated at given dose-volume combinations who do not have myelitis. This study reports SC toxicity from single-fraction spinal SRS and presents a comprehensive atlas of the incidence of adverse events to examine dose-volume predictors. A prospective database of all patients undergoing single-fraction spinal SRS at our institution between 2004 and 2011 was reviewed. SC toxicity was defined by clinical myelitis with accompanying magnetic resonance imaging (MRI) signal changes that were not attributable to tumor progression. Dose-volume histogram (DVH) atlases were created for these endpoints. Rates of adverse events with 95% confidence limits and probabilities that rates of adverse events were <2% and <5% for myelitis were determined as functions of dose and absolute volume. Information about DVH and myelitis was available for 228 patients treated at 259 sites. The median follow-up time was 14.6 months (range, 0.1-138.3 months). The median prescribed dose to the planning treatment volume was 24 Gy (range, 18-24 Gy). There were 2 cases of radiation myelitis (rate r=0.7%) with accompanying MRI signal changes. Myelitis occurred in 2 patients, with Dmax >13.33 Gy, and minimum doses to the hottest 0.1, 0.2, 0.5, and 1 cc were >10.66, 10.9, and 8 Gy, respectively; however, both myelitis cases occurred below the 34th percentile for Dmax and there were 194 DVHs in total with Dmax >13.33 Gy. A median SC Dmax of 13.85 Gy is safe and supports that a Dmax limit of 14 Gy carries a low <1% rate of myelopathy. No dose-volume thresholds or relationships between SC dose and myelitis were apparent. This is the largest study examining dosimetric data and radiation-induced myelitis in de novo spine SRS. Copyright © 2017 Elsevier Inc. All rights reserved.

SU-E-J-124: 18F-FDG PET Imaging to Improve RT Treatment Outcome for Locally Advanced Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shusharina, N; Khan, F; Sharp, G

2015-06-15

Purpose: To investigate spatial correlation between high uptake regions of pre- and 10-days-post therapy{sup 1} {sup 8}F-FDG PET in recurrent lung cancer and to evaluate the feasibility of dose escalation boosting only regions with high FDG uptake identified on baseline PET. Methods: Nineteen patients with stages II– IV inoperable lung cancer were selected. Volumes of interest (VOI) on pre-therapy FDG-PET were defined using an isocontour at ≥50% of SUVmax. VOI of pre- and post-therapy PET images were correlated for the extent of overlap. A highly optimized IMRT plan to 60 Gy prescribed to PTV defined on the planning CT wasmore » designed using clinical dose constraints for the organs at risk. A boost of 18 Gy was prescribed to the VOI defined on baseline PET. A composite plan of the total 78 Gy was compared with the base 60 Gy plan. Increases in dose to the lungs, spinal cord and heart were evaluated. IMRT boost plan was compared with proton RT and SBRT boost plans. Results: Overlap fraction of baseline PET VOI with the VOI on 10 days-post therapy PET was 0.8 (95% CI: 0.7 – 0.9). Using baseline VOI as a boosting volume, dose could be escalated to 78 Gy for 15 patients without compromising the dose constraints. For 4 patients, the dose limiting factors were V20Gy and Dmean for the total lung, and Dmax for the spinal cord. An increase of the dose to OARs correlated significantly with the relative size of the boost volume. Conclusion: VOI defined on baseline 18F-FDG PET by the SUVmax-≥50% isocontour may be a biological target volume for escalated radiation dose. Dose escalation to this volume may provide improved tumor control without breaching predefined dose constraints for OARs. The best treatment outcome may be achieved with proton RT for large targets and with SBRT for small targets.« less

SU-E-T-534: Dosimetric Effect of Multileaf Collimator Leaf Width On Volumetric Modulated Arc Stereotactic Radiotherapy for Spine Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amoush, A; Djemil, T; Subedi, L

2014-06-01

Purpose: To study the dosimetric impact of MLC leaf width in patients treated with Volumetric Modulated Arc Therapy (VMAT) for spine Stereotactic Body radiation Therapy (SBRT). Methods: Twelve spine SBRT patients were retrospectively selected for this study. The patients were treated with IMRT following the RTOG-0631 of spine metastasis. The prescription dose was 16 Gy in one fraction to 90% of the target volume (V16 > 90%). The maximum spinal cord dose of 14 Gy and 10% of the cord receiving < 10 Gy (V10) were set as dose constraints. For purpose of this study, three dual arc VMAT plansmore » were created for each patient using three different MLC leaf widths: 2.5 mm, 4mm, and 5mm. The compliance to RTOG 0631, conformal index (CI), dose gradient index (DGI), and number of monitor units (MUs) were compared. Results: The average V16 of the target was 91.91±1.36%, 93.73±2.38%, and 92.25±2.49% for 2.5 mm, 4 mm, and 5 mm leaf widths, respectively (p=0.39). Accordingly, the average CI was 1.36±0.39, 1.36±0.34, and 1.41±0.3 (0.96), respectively. The average DGI was 0.24 ± 0.05, 0.22 ± 0.05, and 0.23 ± 0.04, respectively (p=0.86). The average spinal cord maximum dose was 12.10 ± 0.88 Gy, 12.52 ± 1.15 Gy, and 12.05 ± 1.12 (p=0.75) and V10 was 2.69 ± 1.71 cc, 5.43 ± 2.16 cc, and 3.71 ± 2.34 cc (p=0.15) for 2.5 mm, 4 mm, and 5 mm leaf widths, respectively. According, the average number of MUs was 4255 ± 431 MU, 5049 ± 1036 MU, and 4231 ± 580 MU respectively (p=0.17). Conclusion: The use of 2.5 mm, 4 mm, and 5 mm MLCs achieved similar VMAT plan quality as recommended by RTOG-0631. The dosimetric parameters were also comparable for the three MLCs.« less

Methods of ex vivo expansion of human cord blood cells: challenges, successes and clinical implications.

PubMed

Baron, Frédéric; Ruggeri, Annalisa; Nagler, Arnon

2016-03-01

More than 40,000 unrelated cord blood transplantations (UCBT) have been performed worldwide as treatment for patients with malignant or non-malignant life threatening hematologic disorders. However, low absolute numbers of hematopoietic stem and progenitor cells (HSPCs) within a single cord blood unit has remained a limiting factor for this transplantation modality, particularly in adult recipients. Further, because UCB contains low numbers of mostly naïve T cells, immune recovery after UCBT is slow, predisposing patients to severe infections. Other causes of UCBT failure has included graft-versus-host disease (GVHD) and relapse of the underlying disease. In this article, we first review the current landscape of cord blood engineering aimed at improving engraftment. This includes approaches of UCB-HSPCs expansion and methods aimed at improving UCB-HSCPs homing. We then discuss recent approaches of cord blood engineering developed to prevent infection [generation of multivirus-specific cytotoxic T cells (VSTs) from UCB], relapse [transduction of UCB-T cells with tumor-specific chimeric receptor antigens (CARs)] and GVHD (expansion of regulatory T cells from UCB). Although many of these techniques of UCB engineering remain currently technically challenging and expensive, they are likely to revolutionize the field of UCBT in the next decades.

Lectin Ulex europaeus agglutinin I specifically labels a subset of primary afferent fibers which project selectively to the superficial dorsal horn of the spinal cord.

PubMed

Mori, K

1986-02-19

To examine differential carbohydrate expression among different subsets of primary afferent fibers, several fluorescein-isothiocyanate conjugated lectins were used in a histochemical study of the dorsal root ganglion (DRG) and spinal cord of the rabbit. The lectin Ulex europaeus agglutinin I specifically labeled a subset of DRG cells and primary afferent fibers which projected to the superficial laminae of the dorsal horn. These results suggest that specific carbohydrates containing L-fucosyl residue is expressed selectively in small diameter primary afferent fibers which subserve nociception or thermoception.

Effects of melatonin on severe crush spinal cord injury-induced reactive astrocyte and scar formation.

PubMed

Krityakiarana, Warin; Sompup, Kamonrapat; Jongkamonwiwat, Nopporn; Mukda, Sujira; Pinilla, Fernando Gomez; Govitrapong, Piyarat; Phansuwan-Pujito, Pansiri

2016-12-01

The present work aimed at analyzing the effects of melatonin on scar formation after spinal cord injury (SCI). Upregulation of reactive astrocyte under SCI pathological conditions has been presented in several studies. It has been proved that the crucial factor in triggering this upregulation is proinflammatory cytokines. Moreover, scar formation is an important barrier to axonal regeneration through the lesion area. Melatonin plays an important role in reducing inflammation, but its effects on scar formation in the injured spinal cord remain unknown. Hence, we used the model of severe crush injury in mice to investigate the effects of melatonin on scar formation. Mice were randomly separated into four groups; SCI, SCI+Melatonin 1 (single dose), SCI+Melatonin 14 (14 daily doses), and control. Melatonin was administered by intraperitoneal injection (10 mg/kg) after injury. Immunohistochemical analysis, Western blot, and behavioral evaluation were used to explore the effects of melatonin after SCI for 14 days. The melatonin-treated mice presented higher expression of neuronal markers (P < 0.001). Remarkably, the inflammatory response appeared to be greatly reduced in the SCI+Melatonin 14 group (P < 0.001), which also displayed less scar formation (P < 0.05). These findings suggest that melatonin inhibits scar formation by acting on inflammatory cytokines after SCI. Overall, our results suggest that melatonin is a promising treatment strategy after SCI that deserves further investigation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Taurine reduces inflammatory responses after spinal cord injury.

PubMed

Nakajima, Yasuhiro; Osuka, Koji; Seki, Yukio; Gupta, Ramesh C; Hara, Masahito; Takayasu, Masakazu; Wakabayashi, Toshihiko

2010-02-01

Taurine has multiple functions in the central nervous system (CNS), serving as an osmoregulator, antioxidant, inhibitory neuromodulator, and regulator of intracellular Ca(2+) flux. Since the role of taurine in traumatic spinal cord injury (SCI) is not fully understood, the present study was conducted with C57 black/6 mice (18-20 g) who underwent severe SCI at the Th-8 level using a weight compression device. Taurine was injected intraperitoneally at doses of 25, 80, 250, and 800 mg/kg within 30 min after SCI. Controls were injected with saline. The contusional cord segments were removed 6 h after SCI, and concentrations of interleukin-6 (IL-6) and myeloperoxidase (MPO) were measured using ELISA kits. Phosphorylation of STAT3, which is activated by IL-6, and expression of inducible cyclooxygenase-2 (COX-2) were also compared between the taurine treatment group (250 mg/kg) and the control group by Western blot analysis. Morphological changes were evaluated with H&E-stained sections. Taurine significantly decreased IL-6 and MPO levels in a dose-dependent manner, significantly reducing the phosphorylation of STAT3 and expression of COX-2 after SCI compared to controls. A reduced accumulation of neutrophils, especially in the subarachnoid spaces, and secondary degenerative changes in gray matter were also noted, and motor disturbances were significantly attenuated with taurine treatment (250 mg/kg). These findings indicate that taurine has anti-inflammatory effects against SCI, and may play a neuroprotective role against secondary damage, and thus it may have therapeutic potential.

Applying the technique of volume-modulated arc radiotherapy to upper esophageal carcinoma.

PubMed

Ma, Pan; Wang, Xiaozhen; Xu, Yingjie; Dai, Jianrong; Wang, Luhua

2014-05-08

This study aims to evaluate the possibility of using the technique of volume-modulated arc therapy (VMAT) to combine the advantages of simplified intensity-modulated radiation therapy (sIMRT) with that of regular intensity-modulated radiation therapy (IMRT) in upper esophageal cancer. Ten patients with upper esophageal carcinoma were randomly chosen in this retrospective study. sIMRT, IMRT, and VMAT plans were generated to deliver 60 Gy in 30 fractions to the planning target volume (PTV). For each patient, with the same clinical requirements (target dose prescription, and dose/dose-volume constraints to organs at risk (OARs)), three plans were designed for sIMRT (five equispaced coplanar beams), IMRT (seven equispaced coplanar beams), and VMAT (two complete arcs). Comparisons were performed for dosimetric parameters of PTV and of OARs (lungs, spinal cord PRV, heart and normal tissue (NT)). All the plans were delivered to a phantom to evaluate the treatment time. The Wilcoxon matched-pairs, signed-rank test was used for intragroup comparison. For all patients, compared to sIMRT plans, VMAT plans statistically provide: a) significant improvement in HI and CI for PTV; b) significant decrease in delivery time, lung V20, MLD, heart V30 and spinal cord PRV D1cc; c) significant increase in NT V5; and d) no significant reduction in lung V5, V10, and heart MD. For all patients, compared to IMRT plans, VMAT plans statistically provide: a) significant improvement in CI for PTV; b) significant decrease in delivery time, lung V20, MLD, NT and spinal cord PRV D1cc; c) significant increase in NT V5; and d) no significant reduction in HI for PTV, lung V5, V10, heart V30 and heart MD. For patients with upper esophageal carcinoma, using VMAT significantly reduces the delivery time and the dose to the lungs compared with IMRT, and consequently saves as much treatment time as sIMRT. Considering those significant advantages, compared to sIMRT and IMRT, VMAT is the first choice of radiotherapy techniques for upper esophageal carcinoma.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ai, H; Zhang, H

Purpose: To evaluate normal tissue toxicity in patients with head and neck cancer by calculating average survival fraction (SF) and equivalent uniform dose (EUD) for normal tissue cells. Methods: 20 patients with head and neck cancer were included in this study. IMRT plans were generated using EclipseTM treatment planning system by dosimetrist following clinical radiotherapy treatment guidelines. The average SF for three different normal tissue cells of each concerned structure can be calculated from dose spectrum acquired from differential dose volume histogram (DVH) using linear quadratic model. The three types of normal tissues include radiosensitive, moderately radiosensitive and radio-resistant thatmore » represents 70%, 50% and 30% survival fractions, respectively, for a 2-Gy open field. Finally, EUDs for three types of normal tissue of each structure were calculated from average SF. Results: The EUDs of the brainstem, spinal cord, parotid glands, brachial plexus and etc were calculated. Our analysis indicated that the brainstem can absorb as much as 14.3% of prescription dose to the tumor if the cell line is radiosensitive. In addition, as much as 16.1% and 18.3% of prescription dose were absorbed by the brainstem for moderately radiosensitive and radio-resistant cells, respectively. For the spinal cord, the EUDs reached up to 27.6%, 35.0% and 42.9% of prescribed dose for the three types of radiosensitivities respectively. Three types of normal cells for parotid glands can get up to 65.6%, 71.2% and 78.4% of prescription dose, respectively. The maximum EUDs of brachial plexsus were calculated as 75.4%, 76.4% and 76.7% of prescription for three types of normal cell lines. Conclusion: The results indicated that EUD can be used to quantify and evaluate the radiation damage to surrounding normal tissues. Large variation of normal tissue EUDs may come from variation of target volumes and radiation beam orientations among the patients.« less

[Fat emulsion tolerance in preterm infants of different gestational ages in the early stage after birth].

PubMed

Tang, Hui; Yang, Chuan-Zhong; Li, Huan; Wen, Wei; Huang, Fang-Fang; Huang, Zhi-Feng; Shi, Yu-Ping; Yu, Yan-Liang; Chen, Li-Lian; Yuan, Rui-Qin; Zhu, Xiao-Yu

2017-06-01

To investigate the fat emulsion tolerance in preterm infants of different gestational ages in the early stage after birth. A total of 98 preterm infants were enrolled and divided into extremely preterm infant group (n=17), early preterm infant group (n=48), and moderate-to-late preterm infant group (n=33). According to the dose of fat emulsion, they were further divided into low- and high-dose subgroups. The umbilical cord blood and dried blood filter papers within 3 days after birth were collected. Tandem mass spectrometry was used to measure the content of short-, medium-, and long-chain acylcarnitines. The extremely preterm infant and early preterm infant groups had a significantly lower content of long-chain acylcarnitines in the umbilical cord blood and dried blood filter papers within 3 days after birth than the moderate-to-late preterm infant group (P<0.05), and the content was positively correlated with gestational age (P<0.01). On the second day after birth, the low-dose fat emulsion subgroup had a significantly higher content of short-, medium-, and long-chain acylcarnitines than the high-dose fat emulsion subgroup among the extremely preterm infants (P<0.05). In the early preterm infant and moderate-to-late preterm infant groups, there were no significant differences in the content of short-, medium-, and long-chain acylcarnitines between the low- and high-dose fat emulsion subgroups within 3 days after birth. Compared with moderate-to-late preterm infants, extremely preterm infants and early preterm infants have a lower capacity to metabolize long-chain fatty acids within 3 days after birth. Early preterm infants and moderate-to-late preterm infants may tolerate high-dose fat emulsion in the early stage after birth, but extremely preterm infants may have an insufficient capacity to metabolize high-dose fat emulsion.

Benchmark Dose Modeling Estimates of the Concentrations of Inorganic Arsenic That Induce Changes to the Neonatal Transcriptome, Proteome, and Epigenome in a Pregnancy Cohort.

PubMed

Rager, Julia E; Auerbach, Scott S; Chappell, Grace A; Martin, Elizabeth; Thompson, Chad M; Fry, Rebecca C

2017-10-16

Prenatal inorganic arsenic (iAs) exposure influences the expression of critical genes and proteins associated with adverse outcomes in newborns, in part through epigenetic mediators. The doses at which these genomic and epigenomic changes occur have yet to be evaluated in the context of dose-response modeling. The goal of the present study was to estimate iAs doses that correspond to changes in transcriptomic, proteomic, epigenomic, and integrated multi-omic signatures in human cord blood through benchmark dose (BMD) modeling. Genome-wide DNA methylation, microRNA expression, mRNA expression, and protein expression levels in cord blood were modeled against total urinary arsenic (U-tAs) levels from pregnant women exposed to varying levels of iAs. Dose-response relationships were modeled in BMDExpress, and BMDs representing 10% response levels were estimated. Overall, DNA methylation changes were estimated to occur at lower exposure concentrations in comparison to other molecular endpoints. Multi-omic module eigengenes were derived through weighted gene co-expression network analysis, representing co-modulated signatures across transcriptomic, proteomic, and epigenomic profiles. One module eigengene was associated with decreased gestational age occurring alongside increased iAs exposure. Genes/proteins within this module eigengene showed enrichment for organismal development, including potassium voltage-gated channel subfamily Q member 1 (KCNQ1), an imprinted gene showing differential methylation and expression in response to iAs. Modeling of this prioritized multi-omic module eigengene resulted in a BMD(BMDL) of 58(45) μg/L U-tAs, which was estimated to correspond to drinking water arsenic concentrations of 51(40) μg/L. Results are in line with epidemiological evidence supporting effects of prenatal iAs occurring at levels <100 μg As/L urine. Together, findings present a variety of BMD measures to estimate doses at which prenatal iAs exposure influences neonatal outcome-relevant transcriptomic, proteomic, and epigenomic profiles.

A rare case of a sharp foreign body on the vocal cord.

PubMed

Nor Hisyam, C I; Misron, K; Mohamad, I

2017-01-01

A foreign body (FB) in the upper aerodigestive tract is a common clinical problem that presents as as acute emergency. Sharp FB, such as fish bone or chicken bone, commonly lodges in the tonsil, base of tongue, vallecula or pyriform fossa. Dislodgement of a FB into the laryngopharynx is very rare and specifically onto the vocal cord is extremely uncommon. This case report illustrates a rare case of a sharp FB that was dislodged into the airway and stuck on to the right vocal cord, which was removed under local anaesthesia.

Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation

PubMed Central

Ramsingh, Arlene I.; Gray, Steven J.; Reilly, Andrew; Koday, Michael; Bratt, Debbie; Koday, Merika Treants; Murnane, Robert; Hu, Yuhui; Messer, Anne

2018-01-01

A critical issue in transgene delivery studies is immune reactivity to the transgene- encoded protein and its impact on sustained gene expression. Here, we test the hypothesis that immunomodulation by rapamycin can decrease immune reactivity after intrathecal AAV9 delivery of a transgene (GFP) in non-human primates, resulting in sustained GFP expression in the CNS. We show that rapamycin treatment clearly reduced the overall immunogenicity of the AAV9/GFP vector by lowering GFP- and AAV9-specific antibody responses, and decreasing T cell responses including cytokine and cytolytic effector responses. Spinal cord GFP protein expression was sustained for twelve weeks, with no toxicity. Immune correlates of robust transgene expression include negligible GFP-specific CD4 and CD8 T cell responses, absence of GFP-specific IFN-γ producing T cells, and absence of GFP-specific cytotoxic T cells, which support the hypothesis that decreased T cell reactivity results in sustained transgene expression. These data strongly support the use of modest doses of rapamycin to modulate immune responses for intrathecal gene therapies, and potentially a much wider range of viral vector-based therapeutics. PMID:29874260

Single fraction spine radiosurgery for myeloma epidural spinal cord compression.

PubMed

Jin, Ryan; Rock, Jack; Jin, Jian-Yue; Janakiraman, Nalini; Kim, Jae Ho; Movsas, Benjamin; Ryu, Samuel

2009-01-01

Radiosurgery delivers highly focused radiation beams to the defined target with high precision and accuracy. It has been demonstrated that spine radiosurgery can be safely used for treatment of spine metastasis with rapid and durable pain control, but without detrimental effects to the spinal cord. This study was carried out to determine the role of single fraction radiosurgery for epidural spinal cord compression due to multiple myeloma. A total of 31 lesions in 24 patients with multiple myeloma, who presented with epidural spinal cord compression, were treated with spine radiosurgery. Single fraction radiation dose of 10-18 Gy (median of 16 Gy) was administered to the involved spine including the epidural or paraspinal tumor. Patients were followed up with clinical exams and imaging studies. Median follow-up was 11.2 months (range 1-55). Primary endpoints of this study were pain control, neurological improvement, and radiographic tumor control. Overall pain control rate was 86%; complete relief in 54%, and partial relief in 32% of the patients. Seven patients presented with neurological deficits. Five patients neurologically improved or became normal after radiosurgery. Complete radiographic response of the epidural tumor was noted in 81% at 3 months after radiosurgery. During the follow-up time, there was no radiographic or neurological progression at the treated spine. The treatment was non-invasive and well tolerated. Single fraction radiosurgery achieved an excellent clinical and radiographic response of myeloma epidural spinal cord compression. Radiosurgery can be a viable treatment option for myeloma epidural compression.

The High Prevalence of Vitamin D Insufficiency in Cord Blood in Calgary, Alberta (APrON-D Study).

PubMed

Aghajafari, Fariba; Field, Catherine J; Kaplan, Bonnie J; Maggiore, Jack A; O'Beirne, Maeve; Hanley, David A; Eliasziw, Misha; Dewey, Deborah; Ross, Sue; Rabi, Doreen

2017-05-01

Vitamin D is important in promoting healthy pregnancy and fetal development. We undertook this study to measure 25-hydroxyvitamin D in maternal and cord blood and to identify maternal factors related to vitamin D status in Calgary. Blood samples collected at the time of delivery from the Alberta Pregnancy Outcomes and Nutrition study cohort (ApronStudy.ca) participants were processed for plasma and assayed using liquid chromatography mass spectrometry methodology for 25(OH)D 3 . Ninety-two pairs of maternal and cord blood samples were obtained. The prevalence of 25(OH)D 3 insufficiency-25(OH)D 3 <75 nmol/L-was 38% and 80% in women and neonates, respectively. Vitamin D supplementation was the only clinical factor associated with 25(OH)D 3 sufficiency, and the odds of sufficiency were 3.75 (95% CI 1.00 to 14.07) higher for women and 5.27 (95% CI 1.37 to 20.27) when over 2000 IU/day were used. Using liquid chromatography mass spectrometry, we demonstrated a very high prevalence of vitamin D insufficiency in cord blood and that the use of high dose vitamin D was associated with greater odds of sufficiency in pregnant women and cord blood in Alberta. Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.

Sex-Specific Associations between Umbilical Cord Blood Testosterone Levels and Language Delay in Early Childhood

ERIC Educational Resources Information Center

Whitehouse, Andrew J. O.; Mattes, Eugen; Maybery, Murray T.; Sawyer, Michael G.; Jacoby, Peter; Keelan, Jeffrey A.; Hickey, Martha

2012-01-01

Background: Preliminary evidence suggests that prenatal testosterone exposure may be associated with language delay. However, no study has examined a large sample of children at multiple time-points. Methods: Umbilical cord blood samples were obtained at 861 births and analysed for bioavailable testosterone (BioT) concentrations. When…

Characterization of Macrophage/Microglial Activation and Effect of Photobiomodulation in the Spared Nerve Injury Model of Neuropathic Pain.

PubMed

Kobiela Ketz, Ann; Byrnes, Kimberly R; Grunberg, Neil E; Kasper, Christine E; Osborne, Lisa; Pryor, Brian; Tosini, Nicholas L; Wu, Xingjia; Anders, Juanita J

2017-05-01

Neuropathic pain is common and debilitating with limited effective treatments. Macrophage/microglial activation along ascending somatosensory pathways following peripheral nerve injury facilitates neuropathic pain. However, polarization of macrophages/microglia in neuropathic pain is not well understood. Photobiomodulation treatment has been used to decrease neuropathic pain, has anti-inflammatory effects in spinal injury and wound healing models, and modulates microglial polarization in vitro. Our aim was to characterize macrophage/microglia response after peripheral nerve injury and modulate the response with photobiomodulation. Adult male Sprague-Dawley rats were randomly assigned to sham (N = 13), spared nerve injury (N = 13), or injury + photobiomodulation treatment groups (N = 7). Mechanical hypersensitivity was assessed with electronic von Frey. Photobiomodulation (980 nm) was applied to affected hind paw (output power 1 W, 20 s, 41cm above skin, power density 43.25 mW/cm 2 , dose 20 J), dorsal root ganglia (output power 4.5W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 85.5 J), and spinal cord regions (output power 1.5 W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 28.5 J) every other day from day 7-30 post-operatively. Immunohistochemistry characterized macrophage/microglial activation. Injured groups demonstrated mechanical hypersensitivity 1-30 days post-operatively. Photobiomodulation-treated animals began to recover after two treatments; at day 26, mechanical sensitivity reached baseline. Peripheral nerve injury caused region-specific macrophages/microglia activation along spinothalamic and dorsal-column medial lemniscus pathways. A pro-inflammatory microglial marker was expressed in the spinal cord of injured rats compared to photobiomodulation-treated and sham group. Photobiomodulation-treated dorsal root ganglion macrophages expressed anti-inflammatory markers. Photobiomodulation effectively reduced mechanical hypersensitivity, potentially through modulating macrophage/microglial activation to an anti-inflammatory phenotype. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. 2016. This work is written by US Government employees and is in the public domain in the US.

Advanced Diffusion-Weighted Magnetic Resonance Imaging Techniques of the Human Spinal Cord

PubMed Central

Andre, Jalal B.; Bammer, Roland

2012-01-01

Unlike those of the brain, advances in diffusion-weighted imaging (DWI) of the human spinal cord have been challenged by the more complicated and inhomogeneous anatomy of the spine, the differences in magnetic susceptibility between adjacent air and fluid-filled structures and the surrounding soft tissues, and the inherent limitations of the initially used echo-planar imaging techniques used to image the spine. Interval advances in DWI techniques for imaging the human spinal cord, with the specific aims of improving the diagnostic quality of the images, and the simultaneous reduction in unwanted artifacts have resulted in higher-quality images that are now able to more accurately portray the complicated underlying anatomy and depict pathologic abnormality with improved sensitivity and specificity. Diffusion tensor imaging (DTI) has benefited from the advances in DWI techniques, as DWI images form the foundation for all tractography and DTI. This review provides a synopsis of the many recent advances in DWI of the human spinal cord, as well as some of the more common clinical uses for these techniques, including DTI and tractography. PMID:22158130

Characterization of murine hepatitis virus (JHM) RNA from rats with experimental encephalomyelitis.

PubMed

Jackson, D P; Percy, D H; Morris, V L

1984-09-01

When Wistar Furth rats are inoculated intracerebrally with the murine hepatitis virus JHM they often develop a demyelinating disease with resulting hind leg paralysis. Using an RNA transfer procedure and hybridization kinetic analysis, the virus-specific RNA in these rats was characterized. The pattern of JHM-specific RNA varied with individual infections of Wistar Furth rats. However, two species of JHM-specific RNA, the nucleocapsid and a 2.1-2.4 X 10(6)-Da RNA species were generally present. A general decrease in JHM-specific RNA in brains and spinal cord samples taken later than 20 days postinoculation was observed; however, JHM-specific RNA persisted in the spinal cord longer than in the brain of these rats.

Combining Adult Learning Theory with Occupational Therapy Intervention for Bladder and Bowel Management after Spinal Cord Injury: A Case Report.

PubMed

Gallagher, Gina; Bell, Alison

2016-01-01

Bladder and bowel management is an important goal of rehabilitation for clients with spinal cord injury. Dependence is these areas have been linked to a variety of secondary complications, including decreased quality of life, urinary tract infections and pressure ulcers (Hammell, 2010; Hicken et al, 2001). Occupational therapists have been identified as important members of the health care team in spinal cord injury rehabilitation; however, specific roles and interventions have not been clearly described. This case report will describe occupational therapy interventions embedded with principles of adult learning theory to address bladder and bowel management with an adult client who sustained an incomplete thoracic level spinal cord injury.

Radiation induced vertebral osteosarcoma following treatment of an intradural extramedullary spinal cord tumor in a dog.

PubMed

Dickinson, P J; McEntee, M C; Lipsitz, D; Keel, K; LeCouteur, R A

2001-01-01

A 2-year-old neutered female Rottweiler diagnosed with an intradural extramedullary spinal cord tumor at T12-T13 was successfully treated with cytoreductive surgery followed by Cobalt 60 teletherapy. The dog was euthanised 5-and-a-half years later following diagnosis of an osteosarcoma involving the L1 and L2 vertebrae. Evidence of the initial tumor was not present at necropsy. The vertebral neoplasm fulfilled all of the accepted criteria for a radiation induced tumor. It was concluded that adjunctive irradiation should be considered for treatment of intradural extramedullary tumors of young dogs when total surgical resection is not possible. Although tumor induction is a rare late effect of radiation therapy, the risk of this occurrence should be considered when irradiating young animals. Radiation induced tumors in dogs have been associated with coarse fractionation schemes, or when large intraoperative doses have been administered. A lower dose per fraction, e.g., 3 Gy/fraction or less, is advisable when irradiating young dogs or any dog in which the life expectancy is 3-5 or more years after irradiation.

Identification of ghost artifact using texture analysis in pediatric spinal cord diffusion tensor images.

PubMed

Alizadeh, Mahdi; Conklin, Chris J; Middleton, Devon M; Shah, Pallav; Saksena, Sona; Krisa, Laura; Finsterbusch, Jürgen; Faro, Scott H; Mulcahey, M J; Mohamed, Feroze B

2018-04-01

Ghost artifacts are a major contributor to degradation of spinal cord diffusion tensor images. A multi-stage post-processing pipeline was designed, implemented and validated to automatically remove ghost artifacts arising from reduced field of view diffusion tensor imaging (DTI) of the pediatric spinal cord. A total of 12 pediatric subjects including 7 healthy subjects (mean age=11.34years) with no evidence of spinal cord injury or pathology and 5 patients (mean age=10.96years) with cervical spinal cord injury were studied. Ghost/true cords, labeled as region of interests (ROIs), in non-diffusion weighted b0 images were segmented automatically using mathematical morphological processing. Initially, 21 texture features were extracted from each segmented ROI including 5 first-order features based on the histogram of the image (mean, variance, skewness, kurtosis and entropy) and 16s-order feature vector elements, incorporating four statistical measures (contrast, correlation, homogeneity and energy) calculated from co-occurrence matrices in directions of 0°, 45°, 90° and 135°. Next, ten features with a high value of mutual information (MI) relative to the pre-defined target class and within the features were selected as final features which were input to a trained classifier (adaptive neuro-fuzzy interface system) to separate the true cord from the ghost cord. The implemented pipeline was successfully able to separate the ghost artifacts from true cord structures. The results obtained from the classifier showed a sensitivity of 91%, specificity of 79%, and accuracy of 84% in separating the true cord from ghost artifacts. The results show that the proposed method is promising for the automatic detection of ghost cords present in DTI images of the spinal cord. This step is crucial towards development of accurate, automatic DTI spinal cord post processing pipelines. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparative studies of mesenchymal stem cells derived from different cord tissue compartments - The influence of cryopreservation and growth media.

PubMed

Dulugiac, Magda; Moldovan, Lucia; Zarnescu, Otilia

2015-10-01

We have identified some critical aspects concerning umbilical cord tissue mesenchymal stem cells: the lack of standards for cell isolation, expansion and cryopreservation, the lack of unanimous opinions upon their multilineage differentiation potential and the existence of very few results related to the functional characterization of the cells isolated from cryopreserved umbilical cord tissue. Umbilical cord tissue cryopreservation appears to be the optimal solution for umbilical cord tissue mesenchymal stem cells storage for future clinical use. Umbilical cord tissue cryopreservation allows mesenchymal stem cells isolation before expected use, according with the specific clinical applications, by different customized isolation and expansion protocols agreed by cell therapy institutions. Using an optimized protocol for umbilical cord tissue cryopreservation in autologous cord blood plasma, isolation explant method and growth media supplemented with FBS or human serum, we performed comparative studies with respect to the characteristics of mesenchymal stem cells (MSC) isolated from different compartments of the same umbilical cord tissue such as Wharton's jelly, vein, arteries, before cryopreservation (pre freeze) and after cryopreservation (post thaw). Expression of histochemical and immunohistochemical markers as well as electron microscopy observations revealed similar adipogenic, chondrogenic and osteogenic differentiation capacity for cells isolated from pre freeze and corresponding post thaw tissue fragments of Wharton's jelly, vein or arteries of the same umbilical cord tissue, regardless growth media used for cells isolation and expansion. Our efficient umbilical cord tissue cryopreservation protocol is reliable for clinical applicability of mesenchymal stem cells that could next be isolated and expanded in compliance with future accepted standards. Copyright © 2015 Elsevier Ltd. All rights reserved.

Gastrointestinal symptoms in spinal cord injury: relationships with level of injury and psychologic factors.

PubMed

Ng, Clinton; Prott, Gillian; Rutkowski, Susan; Li, Yueming; Hansen, Ross; Kellow, John; Malcolm, Allison

2005-08-01

Previous surveys of gastrointestinal symptoms after spinal cord injury have not used validated questionnaires and have not focused on the full spectrum of such symptoms and their relationship to factors, such as level of spinal cord injury and psychologic dysfunction. This study was designed to detail the spectrum and prevalence of gastrointestinal symptoms in spinal cord injury and to determine clinical and psychologic factors associated with such symptoms. Established spinal cord injury patients (>12 months) randomly selected from a spinal cord injury database completed the following three questionnaires: 1) Rome II Integrative Questionnaire, 2) Hospital Anxiety and Depression Scale, and 3) Burwood Bowel Dysfunction after spinal cord injury. A total of 110 patients participated. The prevalence of abdominal bloating and constipation were 22 and 46 percent, respectively. Bloating was associated with cervical (odds ratio = 9.5) and lumbar (odds ratio = 12.1) level but not with thoracic level of injury. Constipation was associated with a higher level of injury (cervical odds ratio = 5.6 vs. lumbar) but not with psychologic factors. In contrast, abdominal pain (33 percent) and fecal incontinence (41 percent) were associated with higher levels of anxiety (odds ratio = 6.8, and odds ratio = 2.4) but not with the level of injury. There is a high prevalence and wide spectrum of gastrointestinal symptoms in spinal cord injury. Abdominal bloating and constipation are primarily related to specific spinal cord levels of injury, whereas abdominal pain and fecal incontinence are primarily associated with higher levels of anxiety. Based on our findings, further physiologic and psychologic research studies in spinal cord injury patients should lead to more rational management strategies for the common gastrointestinal symptoms in spinal cord injury.

Outcomes of Cord Blood Transplantation Using Reduced-Intensity Conditioning for Chronic Lymphocytic Leukemia: A Study on Behalf of Eurocord and Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation, and the Societé Française de Greffe de Moelle et Therapie Cellulaire.

PubMed

Xavier, Erick; Cornillon, Jérôme; Ruggeri, Annalisa; Chevallier, Patrice; Cornelissen, Jan J; Andersen, Niels S; Maillard, Natacha; Nguyen, Stephanie; Blaise, Didier; Deconinck, Eric; Veelken, Hendrik; Milpied, Noel; Van Gelder, Michel; Peffault de Latour, Regis; Gluckman, Eliane; Kröger, Nicolaus; Schetelig, Johannes; Rocha, Vanderson

2015-08-01

Outcomes after umbilical cord blood transplantation (UCBT) for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are unknown. We analyzed outcomes of 68 patients with poor-risk CLL/SLL who underwent reduced-intensity (RIC) UCBT from 2004 to 2012. The median age was 57 years and median follow-up 36 months; 17 patients had del 17p/p53mutation, 19 patients had fludarabine-refractory disease, 11 relapsed after autologous stem cell transplantation, 8 had diagnosis of prolymphocytic leukemia, 4 had Richter syndrome, and 8 underwent transplantation with progressive or refractory disease. The most common RIC used was cyclophosphamide, fludarabine, and total body irradiation (TBI) in 82%; 15 patients received antithymocyte globulin. Most of the cord blood grafts were HLA mismatched and 76% received a double UCBT. Median total nucleated cells collected was 4.7 × 10(7)/kg. The cumulative incidences (CI) of neutrophil and platelet engraftment were 84% and 72% at 60 and 180 days respectively; day 100 graft-versus-host disease (GVHD) (grade II to IV) was 43% and 3-year chronic GVHD was 32%. The CI of relapse, nonrelapse mortality, overall survival, and progression-free survival (PFS) at 3 years were 16%, 39%, 54%, and 45%, respectively. Fludarabine-sensitive disease at transplantation and use of low-dose TBI regimens were associated with acceptable PFS. In conclusion, use of RIC-UCBT seems to be feasible in patients with poor-risk CLL/SLL and improved outcomes were observed in patients with fludarabine-sensitive disease who received low-dose TBI regimens. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

AN IL-1 RECEPTOR ANTAGONIST BLOCKS A MORPHINE-INDUCED ATTENUATION OF LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY

PubMed Central

Hook, Michelle A.; Washburn, Stephanie N.; Moreno, Georgina; Woller, Sarah A.; Puga, Denise; Lee, Kuan H.; Grau, James W.

2010-01-01

Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain (Hook et al., 2009). The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine-induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1β 24 hrs later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 µg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1β at both 30 min and 24 hrs after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 µg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 µg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro-inflammatory cytokines in the spinal cord, and this undermines recovery of function. PMID:20974246

JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain.

PubMed

Gao, Yong-Jing; Zhang, Ling; Samad, Omar Abdel; Suter, Marc R; Yasuhiko, Kawasaki; Xu, Zhen-Zhong; Park, Jong-Yeon; Lind, Anne-Li; Ma, Qiufu; Ji, Ru-Rong

2009-04-01

Our previous study showed that activation of c-jun-N-terminal kinase (JNK) in spinal astrocytes plays an important role in neuropathic pain sensitization. We further investigated how JNK regulates neuropathic pain. In cultured astrocytes, tumor necrosis factor alpha (TNF-alpha) transiently activated JNK via TNF receptor-1. Cytokine array indicated that the chemokine CCL2/MCP-1 (monocyte chemoattractant protein-1) was strongly induced by the TNF-alpha/JNK pathway. MCP-1 upregulation by TNF-alpha was dose dependently inhibited by the JNK inhibitors SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one) and D-JNKI-1. Spinal injection of TNF-alpha produced JNK-dependent pain hypersensitivity and MCP-1 upregulation in the spinal cord. Furthermore, spinal nerve ligation (SNL) induced persistent neuropathic pain and MCP-1 upregulation in the spinal cord, and both were suppressed by D-JNKI-1. Remarkably, MCP-1 was primarily induced in spinal cord astrocytes after SNL. Spinal administration of MCP-1 neutralizing antibody attenuated neuropathic pain. Conversely, spinal application of MCP-1 induced heat hyperalgesia and phosphorylation of extracellular signal-regulated kinase in superficial spinal cord dorsal horn neurons, indicative of central sensitization (hyperactivity of dorsal horn neurons). Patch-clamp recordings in lamina II neurons of isolated spinal cord slices showed that MCP-1 not only enhanced spontaneous EPSCs but also potentiated NMDA- and AMPA-induced currents. Finally, the MCP-1 receptor CCR2 was expressed in neurons and some non-neuronal cells in the spinal cord. Together, we have revealed a previously unknown mechanism of MCP-1 induction and action. MCP-1 induction in astrocytes after JNK activation contributes to central sensitization and neuropathic pain facilitation by enhancing excitatory synaptic transmission. Inhibition of the JNK/MCP-1 pathway may provide a new therapy for neuropathic pain management.

SU-F-T-421: Dosimetry Change During Radiotherapy and Dosimetry Difference for Rigid and Deformed Registration in the Mid-Thoracic Esophageal Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tao, C; Liu, T; Chen, J

Purpose: This study aimed to analyze dosimetry changes during radiotherapy for the mid-thoracic esophageal carcinoma, and investigate dosimetry difference between rigid and deformed registration. Methods: Twelve patients with primary middle thoracic esophageal carcinoma were selected randomly. Based on first CT scanning of each patient, plans-o were generated by experience physicists. After 20 fractions treatment, the corresponding plans-re were created with second CT scanning. And then, these two CT images were rigid and deformed registration respectively, and the dose was accumulated plan-o with plan-re. The dosimetry variation of these plans (plan-o: with 30 fractions, plan-rig: the accumulated dose with rigid registrationmore » and plan-def: the accumulated dose with deformed registration) were evaluated by paired T-test. Results: The V20 value of total lung were 32.68%, 30.3% and 29.71% for plan-o, plan-rig and plan-def respectively. The mean dose of total lung was 17.19 Gy, 16.67 Gy and 16.51 Gy for plan-o plan-rig and plan-def respectively. There were significant differences between plan-o and plan-rig or plan-def for both V20 and mean dose of total lung (with p= 0.003, p= 0.000 for V20 and p=0.008, p= 0.000 for mean dose respectively). There was no significant difference between plan-rig and plan-def (with p=0.118 for V20 and p=0.384 for mean dose). The max dose of spinal-cord was 41.95 Gy, 41.48 Gy and 41.4 Gy for plan-o, plan-rig and plan-def respectively. There were no significant differences for the max dose of spinal-cord between these plans. Conclusion: The target volume changes and anatomic position displacement of mid-thoracic esophageal carcinoma should not be neglected in clinics. These changes would cause overdose in normal tissue. Therefore, it is necessary to have another CT scanning and re-plan during the mid-thoracic esophageal carcinoma radiotherapy. And the dosimetry difference between rigid and deformed fusions was not found in this study.« less

SU-E-P-47: Evaluation of Improvement of Esophagus Sparing in SBRT Lung Patients with Biologically Based IMRT Optimization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liang, X; Penagaricano, J; Paudel, N

2015-06-15

Purpose: To study the potential of improving esophageal sparing for stereotactic body radiation therapy (SBRT) lung cancer patients by using biological optimization (BO) compared to conventional dose-volume based optimization (DVO) in treatment planning. Methods: Three NSCLC patients (PTV (62.3cc, 65.1cc, and 125.1cc) adjacent to the heart) previously treated with SBRT were re-planned using Varian Eclipse TPS (V11) using DVO and BO. The prescription dose was 60 Gy in 5 fractions normalized to 95% of the PTV volume. Plans were evaluated by comparing esophageal maximum doses, PTV heterogeneity (HI= D5%/D95%), and Paddick’s conformity (CI) indices. Quality of the plans was assessedmore » by clinically-used IMRT QA procedures. Results: By using BO, the maximum dose to the esophagus was decreased 1384 cGy (34.6%), 502 cGy (16.5%) and 532 cGy (16.2%) in patient 1, 2 and 3 respectively. The maximum doses to spinal cord and the doses to 1000 cc and 1500 cc of normal lung were comparable in both plans. The mean doses (Dmean-hrt) and doses to 15cc of the heart (V15-hrt) were comparable for patient 1 and 2. However for patient 3, with the largest PTV, Dmean-hrt and V15-hrt increased by 62.2 cGy (18.3%) and 549.9 cGy (24.9%) respectively for the BO plans. The mean target HI of BO plans (1.13) was inferior to the DVO plans (1.07). The same trend was also observed for mean CI in BO plans (0.77) versus DVO plans (0.83). The QA pass rates (3%, 3mm) were comparable for both plans. Conclusion: This study demonstrated that the use of biological models in treatment planning optimization can substantially improve esophageal sparing without compromising spinal cord and normal lung doses. However, for the large PTV case (125.1cc) we studied here, Dmean-hrt and V15-hrt increased substantially. The target HI and CI were inferior in the BO plans.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herrington, J; Price, M; Brindle, J

Purpose: To evaluate the equivalence of spine SBRT treatment plans created in Eclipse for the TrueBeam STx (Varian Medical System, Palo Alto, CA) compared to plans using CyberKnife and MultiPlan (Accuray, Sunnyvale, CA). Methods: CT data and contours for 23 spine SBRT patients previously treated using CyberKnife (CK) were exported from MultiPlan treatment planning system into Eclipse where they were planned using static IMRT 6MV coplanar beams. Plans were created according to the original prescription dose and fractionation schedule while limiting spinal dose according to the RTOG 0631 protocol and maintaining target coverage comparable to the original CK plans. Plansmore » were evaluated using new conformity index (nCI), homogeneity index (HI), dose-volume histogram data, number of MU, and estimated treatment time. To ensure all Eclipse plans were deliverable, standard clinical IMRT QA was performed. The plan results were matched with their complimentary CK plans for paired statistical analysis. Results: Plans generated in Eclipse demonstrated statistically significant (p<0.01) improvements compared to complimentary CK plans in median values of maximum spinal cord dose (17.39 vs. 18.12 Gy), RTOG spinal cord constraint dose (14.50 vs. 16.93 Gy), nCI (1.28 vs. 1.54), HI (1.13 vs. 1.27), MU (3918 vs. 36416), and estimated treatment time (8 vs. 48 min). All Eclipse generated plans passed our clinically used protocols for IMRT QA. Conclusion: CK spine SBRT replanned utilizing Eclipse for LINAC delivery demonstrated dosimetric advantages. We propose improvements in plan quality metrics reviewed in this study may be attributed to dynamic MLCs that facilitate treatment of complicated geometries as well as posterior beams ideal for centrally located and/or posterior targets afforded by gantry-based RT delivery.« less

Normalization of Blood Pressure With Spinal Cord Epidural Stimulation After Severe Spinal Cord Injury

PubMed Central

Harkema, Susan J.; Wang, Siqi; Angeli, Claudia A.; Chen, Yangsheng; Boakye, Maxwell; Ugiliweneza, Beatrice; Hirsch, Glenn A.

2018-01-01

Chronic low blood pressure and orthostatic hypotension remain challenging clinical issues after severe spinal cord injury (SCI), affecting health, rehabilitation, and quality of life. We previously reported that targeted lumbosacral spinal cord epidural stimulation (scES) could promote stand and step functions and restore voluntary movement in patients with chronic motor complete SCI. This study addresses the effects of targeted scES for cardiovascular function (CV-scES) in individuals with severe SCI who suffer from chronic hypotension. We tested the hypothesis that CV-scES can increase resting blood pressure and attenuate chronic hypotension in individuals with chronic cervical SCI. Four research participants with chronic cervical SCI received an implant of a 16-electrode array on the dura (L1–S1 cord segments, T11–L1 vertebrae). Individual-specific CV-scES configurations (anode and cathode electrode selection, voltage, frequency, and pulse width) were identified to maintain systolic blood pressure within targeted normative ranges without skeletal muscle activity of the lower extremities as assessed by electromyography. These individuals completed five 2-h sessions using CV-scES in an upright, seated position during measurement of blood pressure and heart rate. Noninvasive continuous blood pressure was measured from a finger cuff by plethysmograph technique. For each research participant there were statistically significant increases in mean arterial pressure in response to CV-scES that was maintained within normative ranges. This result was reproducible over the five sessions with concomitant decreases or no changes in heart rate using individual-specific CV-scES that was modulated with modest amplitude changes throughout the session. Our study shows that stimulating dorsal lumbosacral spinal cord can effectively and safely activate mechanisms to elevate blood pressures to normal ranges from a chronic hypotensive state in humans with severe SCI with individual-specific CV-scES. PMID:29568266

SU-F-T-106: A Dosimetric Study of Intensity Modulated Radiation Therapy to Decrease Radiation Dose to the Thoracic Vertebral Bodies in Patients Receiving Concurrent Chemoradiation for Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

DiCostanzo, Dominic; Barney, Christian L.; Bazan, Jose G.

Purpose: Recent clinical studies have shown a correlation between radiation dose to the thoracic vertebral bodies (TVB) and the development of hematologic toxicity (HT) in patients receiving chemoradiation (CRT) for lung cancer (LuCa). The feasibility of a bone-marrow sparing (BMS) approach in this group of patients is unknown. We hypothesized that radiation dose to the TVB can be reduced with an intensity modulated radiation therapy(IMRT)/volumetric modulated arc radiotherapy(VMAT) without affecting plan quality. Methods: We identified LuCa cases treated with curative intent CRT using IMRT/VMAT from 4/2009 to 2/2015. The TVBs from T1–T10 were retrospectively contoured. No constraints were placed onmore » the TVB structure initially. A subset were re-planned with BMS-IMRT/VMAT with an objective or reducing the mean TVB dose to <23 Gy. The following data were collected on the initial and BMS plans: mean dose to planning target volume (PTV), lungs-PTV, esophagus, heart; lung V20; cord max dose. Pairwise comparisons were performed using the signed rank test. Results: 94 cases received CRT with IMRT/VMAT. We selected 11 cases (7 IMRT, 4 VMAT) with a range of initial mean TVB doses (median 35.7 Gy, range 18.9–41.4 Gy). Median prescription dose was 60 Gy. BMS-IMRT/VMAT significantly reduced the mean TVB dose by a median of 10.2 Gy (range, 1.0–16.7 Gy, p=0.001) and reduced the cord max dose by 2.9 Gy (p=0.014). BMS-IMRT/VMAT had no impact on lung mean (median +17 cGy, p=0.700), lung V20 (median +0.5%, p=0.898), esophagus mean (median +13 cGy, p=1.000) or heart mean (median +16 cGy, p=0.365). PTV-mean dose was not affected by BMS-IMRT/VMAT (median +13 cGy, p=0.653). Conclusion: BMS-IMRT/VMAT was able to significantly reduce radiation dose to the TVB without compromising plan quality. Prospective evaluation of BMS-IMRT/VMAT in patients receiving CRT for LuCa is warranted to determine if this approach results in clinically significant reductions in HT.« less

Osthole attenuates spinal cord ischemia-reperfusion injury through mitochondrial biogenesis-independent inhibition of mitochondrial dysfunction in rats.

PubMed

Zhou, Yue-fei; Li, Liang; Feng, Feng; Yuan, Hua; Gao, Da-kuan; Fu, Luo-an; Fei, Zhou

2013-12-01

Osthole, the main bioactive compounds isolated from the traditional Chinese medical herb broad Cnidium monnieri (L.) cusson, has been shown to exert spectrum of pharmacologic activities. The aim of this study was to investigate the potential neuroprotective effects of osthole against spinal cord ischemia-reperfusion injury in rats. Osthole was administrated at the concentration of 0.1, 1, 10, 50, or 200 mg/kg (intraperitoneally) 1 h before spinal cord ischemia. The effects on spinal cord injury were measured by spinal cord water content, infarct volume, hematoxylin and eosin staining, and neurologic assessment. Mitochondria were purified from injured spinal cord tissue to determine mitochondrial function. We found that treatment with osthole (10 and 50 mg/kg) significantly decreased spinal cord water content and infarct volume, preserved normal motor neurons, and improved neurologic functions. These protective effects can be also observed even if the treatment was delayed to 4 h after reperfusion. Osthole treatment preserved mitochondrial membrane potential level, reduced reactive oxygen species production, increased adenosine triphosphate generation, and inhibited cytochrome c release in mitochondrial samples. Moreover, osthole increased mitochondria respiratory chain complex activities in spinal cord tissue, with no effect on mitochondrial DNA content and the expression of mitochondrial-specific transcription factors. All these findings demonstrate the neuroprotective effect of osthole in spinal cord ischemia-reperfusion injury model and suggest that oshtole-induced neuroprotection was mediated by mitochondrial biogenesis-independent inhibition of mitochondrial dysfunction. Copyright © 2013 Elsevier Inc. All rights reserved.

Significance of Maternal and Cord Blood Nucleated Red Blood Cell Count in Pregnancies Complicated by Preeclampsia

PubMed Central

Misha, Mehak; Rai, Lavanya

2014-01-01

Objectives. To evaluate the effect of preeclampsia on the cord blood and maternal NRBC count and to correlate NRBC count and neonatal outcome in preeclampsia and control groups. Study Design. This is a prospective case control observational study. Patients and Methods. Maternal and cord blood NRBC counts were studied in 50 preeclamptic women and 50 healthy pregnant women. Using automated cell counter total leucocyte count was obtained and peripheral smear was prepared to obtain NRBC count. Corrected WBC count and NRBC count/100 leucocytes in maternal venous blood and in cord blood were compared between the 2 groups. Results. No significant differences were found in corrected WBC count in maternal and cord blood in cases and controls. Significant differences were found in mean cord blood NRBC count in preeclampsia and control groups (40.0 ± 85.1 and 5.9 ± 6.3, P = 0.006). The mean maternal NRBC count in two groups was 2.4 ± 9.0 and 0.8 ± 1.5, respectively (P = 0.214). Cord blood NRBC count cut off value ≤13 could rule out adverse neonatal outcome with a sensitivity of 63% and specificity of 89%. Conclusion. Cord blood NRBC are significantly raised in preeclampsia. Neonates with elevated cord blood NRBC counts are more likely to have IUGR, low birth weight, neonatal ICU admission, respiratory distress syndrome, and assisted ventilation. Below the count of 13/100 leucocytes, adverse neonatal outcome is quite less likely. PMID:24734183

Gap Junctions Contribute to the Regulation of Walking-Like Activity in the Adult Mudpuppy (Necturus Maculatus).

PubMed

Lavrov, Igor; Fox, Lyle; Shen, Jun; Han, Yingchun; Cheng, Jianguo

2016-01-01

Although gap junctions are widely expressed in the developing central nervous system, the role of electrical coupling of neurons and glial cells via gap junctions in the spinal cord in adults is largely unknown. We investigated whether gap junctions are expressed in the mature spinal cord of the mudpuppy and tested the effects of applying gap junction blocker on the walking-like activity induced by NMDA or glutamate in an in vitro mudpuppy preparation. We found that glial and neural cells in the mudpuppy spinal cord expressed different types of connexins that include connexin 32 (Cx32), connexin 36 (Cx36), connexin 37 (Cx37), and connexin 43 (Cx43). Application of a battery of gap junction blockers from three different structural classes (carbenexolone, flufenamic acid, and long chain alcohols) substantially and consistently altered the locomotor-like activity in a dose-dependent manner. In contrast, these blockers did not significantly change the amplitude of the dorsal root reflex, indicating that gap junction blockers did not inhibit neuronal excitability nonselectively in the spinal cord. Taken together, these results suggest that gap junctions play a significant modulatory role in the spinal neural networks responsible for the generation of walking-like activity in the adult mudpuppy.

From basics to clinical: a comprehensive review on spinal cord injury.

PubMed

Silva, Nuno A; Sousa, Nuno; Reis, Rui L; Salgado, António J

2014-03-01

Spinal cord injury (SCI) is a devastating neurological disorder that affects thousands of individuals each year. Over the past decades an enormous progress has been made in our understanding of the molecular and cellular events generated by SCI, providing insights into crucial mechanisms that contribute to tissue damage and regenerative failure of injured neurons. Current treatment options for SCI include the use of high dose methylprednisolone, surgical interventions to stabilize and decompress the spinal cord, and rehabilitative care. Nonetheless, SCI is still a harmful condition for which there is yet no cure. Cellular, molecular, rehabilitative training and combinatorial therapies have shown promising results in animal models. Nevertheless, work remains to be done to ascertain whether any of these therapies can safely improve patient's condition after human SCI. This review provides an extensive overview of SCI research, as well as its clinical component. It starts covering areas from physiology and anatomy of the spinal cord, neuropathology of the SCI, current clinical options, neuronal plasticity after SCI, animal models and techniques to assess recovery, focusing the subsequent discussion on a variety of promising neuroprotective, cell-based and combinatorial therapeutic approaches that have recently moved, or are close, to clinical testing. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of umbilical cord blood stem cells on healing factors for diabetic foot injuries.

PubMed

Çil, N; Oğuz, E O; Mete, E; Çetinkaya, A; Mete, G A

2017-01-01

The use of stem or progenitor cells from bone marrow, or peripheral or umbilical cord blood is becoming more common for treatment of diabetic foot problems. These cells promote neovascularization by angiogenic factors and they promote epithelium formation by stimulating cell replication and migration under certain pathological conditions. We investigated the role of CD34 + stem cells from human umbilical cord blood in wound healing using a rat model. Rats were randomly divided into a control group and two groups with diabetes induced by a single dose of 55 mg/kg intraperitoneal streptozocin. Scarred areas 5 mm in diameter were created on the feet of all rats. The diabetic rats constituted the diabetes control group and a diabetes + stem cell group with local injection into the wound site of 0.5 × 106 CD34 + stem cells from human umbilical cord blood. The newly formed skin in the foot wounds following CD34 + stem cell treatment showed significantly improvement by immunohistochemistry and TUNEL staining, and were closer to the wound healing of the control group than the untreated diabetic animals. The increase in FGF expression that accompanied the local injection of CD34 + stem cells indicates that FGF stimulation helped prevent apoptosis. Our findings suggest a promising new treatment approach to diabetic wound healing.

Correction of vitamin D deficiency in a cohort of newborn infants using daily 200 IU vitamin D supplementation.

PubMed

Onwuneme, C; Diya, B; Uduma, O; McCarthy, R A; Murphy, N; Kilbane, M T; McKenna, M J; Molloy, E J

2016-08-01

Although the role of vitamin D in the prevention of rickets has long been well established, controversies still exist on the ideal dose of vitamin D supplementation in infants. We assessed serum 25-hydroxyvitamin D (25OHD) status simultaneously in maternal and cord samples and the response to vitamin D3 supplementation in neonates. Serum 25OHD levels were evaluated from maternal, and umbilical cord samples from term normal pregnancies. Repeat 25OHD levels were assessed in neonates with 25OHD below 30 nmol/L following vitamin D3 200 IU daily after 6 weeks. Blood samples were taken including 57 cord samples and 16 follow-up neonatal samples. Maternal and cord serum 25OHD were 43 ± 21 and 29 ± 15 nmol/L, respectively. Infants with 25OHD < 30 nmol/L (19.8 ± 4.7 nmol/L) had a significant increase in serum 25OHD (63.3 ± 14.5 nmol/L) following vitamin D3 200 IU daily after 6 weeks. Healthy Irish infants born at term are at high risk of vitamin D deficiency, but vitamin D3 200 IU daily, rapidly corrects poor vitamin D status.

Alterations to DNA methylation and expression of CXCL14 are associated with suboptimal birth outcomes.

PubMed

Cheong, Clara Y; Chng, Keefe; Lim, Mei Kee; Amrithraj, Ajith I; Joseph, Roy; Sukarieh, Rami; Chee Tan, Yong; Chan, Louiza; Tan, Jun Hao; Chen, Li; Pan, Hong; Holbrook, Joanna D; Meaney, Michael J; Seng Chong, Yap; Gluckman, Peter D; Stünkel, Walter

2014-09-01

CXCL14 is a chemokine that has previously been implicated in insulin resistance in mice. In humans, the role of CXCL14 in metabolic processes is not well established, and we sought to determine whether CXCL14 is a risk susceptibility gene important in fetal programming of metabolic disease. For this purpose, we investigated whether CXCL14 is differentially regulated in human umbilical cords of infants with varying birth weights. We found an elevated expression of CXCL14 in human low birth weight (LBW) cords, as well as in cords from nutritionally restricted Macaca fascicularis macaques. To further analyze the regulatory mechanisms underlying the expression of CXCL14, we examined CXCL14 in umbilical cord-derived mesenchymal stem cells (MSCs) that provide an in vitro cell-based system amenable to experimental manipulation. Using both whole frozen cords and MSCs, we determined that site-specific CpG methylation in the CXCL14 promoter is associated with altered expression, and that changes in methylation are evident in LBW infant-derived umbilical cords that may indicate future metabolic compromise through CXCL14.

Current practice of methylprednisolone administration for acute spinal cord injury in Germany: a national survey.

PubMed

Druschel, Claudia; Schaser, Klaus-Dieter; Schwab, Jan M

2013-05-15

Written mail-out survey. To determine current practice in high-dose methylprednisolone succinate (MPSS) administration for treatment of acute spinal cord injury (SCI) in Germany. Reanalysis of the National Acute Spinal Cord Injury Studies (NASCIS) resulted in criticism of the use of high-dose MPSS for treatment of acute SCI. Subsequently, SCI treatment guidelines were revised leading to a reduction in MPSS use across North America. The impact of these revisions on SCI treatment in Germany is not known. A questionnaire was sent to all trauma, orthopedic and neurosurgical departments of German university centers, affiliated teaching hospitals, and specialized SCI care centers. Survey included 6 questions about the administration of MPSS after acute SCI. Three hundred seventy-two respondents completed the survey (response rate: 51% overall, 76% university hospitals, 85% specialized SCI care centers). Overall, 55% of departments that treat SCI prescribe MPSS. Among them, 73% are "frequent" users administering MPSS to more than 50% of their patients. Ten percent prescribe according to NASCIS I, 43% NASCIS II, 33% NASCIS III, and 13% "generic protocols." As justification for MPSS treatment, "effectiveness" ranked before "common practice" and "medicolegal reasons." "Specialized" SCI care centers differ in that (1) MPSS is administered less frequently, (2) NASCIS I doses are not used, and (3) during the past several years, practice patterns are more likely to have shifted away from the treatment of SCI with MPSS. About one-half of the institutions continue to prescribe MPSS in the setting of acute SCI. A need for further education in almost one-fourth of German departments treating acute SCI is demonstrated through responses indicating use of the outdated NASCIS I protocol, a "legal need" or "unchanged MPSS application during the last years." "Specialized" SCI centers are more likely to change their practice in accordance with evolving literature. 3.

A preclinical physiological assay to test modulation of knee joint pain in the spinal cord: effects of oxycodone and naproxen.

PubMed

Miranda, Jason A; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.

A Preclinical Physiological Assay to Test Modulation of Knee Joint Pain in the Spinal Cord: Effects of Oxycodone and Naproxen

PubMed Central

Miranda, Jason A.; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain. PMID:25157947

International spinal cord injury cardiovascular function basic data set.

PubMed

Krassioukov, A; Alexander, M S; Karlsson, A-K; Donovan, W; Mathias, C J; Biering-Sørensen, F

2010-08-01

To create an International Spinal Cord Injury (SCI) Cardiovascular Function Basic Data Set within the framework of the International SCI Data Sets. An international working group. The draft of the data set was developed by a working group comprising members appointed by the American Spinal Injury Association (ASIA), the International Spinal Cord Society (ISCoS) and a representative of the executive committee of the International SCI Standards and Data Sets. The final version of the data set was developed after review by members of the executive committee of the International SCI Standards and Data Sets, the ISCoS scientific committee, ASIA board, relevant and interested international organizations and societies, individual persons with specific interest and the ISCoS Council. To make the data set uniform, each variable and each response category within each variable have been specifically defined in a way that is designed to promote the collection and reporting of comparable minimal data. The variables included in the International SCI Cardiovascular Function Basic Data Set include the following items: date of data collection, cardiovascular history before the spinal cord lesion, events related to cardiovascular function after the spinal cord lesion, cardiovascular function after the spinal cord lesion, medications affecting cardiovascular function on the day of examination; and objective measures of cardiovascular functions, including time of examination, position of examination, pulse and blood pressure. The complete instructions for data collection and the data sheet itself are freely available on the websites of both ISCoS (http://www.iscos.org.uk) and ASIA (http://www.asia-spinalinjury.org).

Luminex® xMAP® technology is an effective strategy for high-definition human leukocyte antigen typing of cord blood units prior to listing.

PubMed

Guarene, Marco; Badulli, Carla; Cremaschi, Anna L; Sbarsi, Ilaria; Cacciatore, Rosalia; Tinelli, Carmine; Pasi, Annamaria; Bergamaschi, Paola; Perotti, Cesare G

2018-05-01

Allele-level donor-recipient match at HLA-A, HLA-B, HLA-C and HLA-DRB1 loci impacts the outcome after cord blood transplantation for hematologic malignancies and modifies the strategy of donor selection. High definition of both class I and II HLA loci at time of listing is a way to improve the attractiveness of cord blood bank inventories, reducing the time for donor search and procurement and simplifying donor choice, in particular, for patients of non-European heritage. In 2014, Luminex ® xMAP ® technology was introduced in our laboratory practice and was applied to cord blood units typing. In this study, we evaluated the impact of this strategy in comparison with the platform in use until 2013, relying on LiPA reverse polymerase chain reaction-sequence-specific oligonucleotide (revPCR-SSO) plus polymerase chain reaction-sequence-specific primer (PCR-SSP). In 2014, the time for testing was shorter (141 vs 181 days on average), the number of test repetitions was lower (in particular for HLA-A locus, p = 0.026), and the cost reduced (240.7 vs 395.6 euros per unit on average) compared to 2013, demonstrating that Luminex xMAP technology is superior to the previous approach. Luminex xMAP platform has useful application in cord blood banking programs, to achieve high-definition HLA typing of cord blood units at the time of banking in a quick, accurate, and cost-effective manner.

Technical Note: Dosimetric evaluation of Monte Carlo algorithm in iPlan for stereotactic ablative body radiotherapy (SABR) for lung cancer patients using RTOG 0813 parameters.

PubMed

Pokhrel, Damodar; Badkul, Rajeev; Jiang, Hongyu; Kumar, Pravesh; Wang, Fen

2015-01-08

For stereotactic ablative body radiotherapy (SABR) in lung cancer patients, Radiation Therapy Oncology Group (RTOG) protocols currently require radiation dose to be calculated using tissue heterogeneity corrections. Dosimetric criteria of RTOG 0813 were established based on the results obtained from non-Monte Carlo (MC) algorithms, such as superposition/convolutions. Clinically, MC-based algorithms are now routinely used for lung SABR dose calculations. It is essential to confirm that MC calculations in lung SABR meet RTOG guidelines. This report evaluates iPlan MC plans for SABR in lung cancer patients using dose-volume histogram normalization per current RTOG 0813 compliance criteria. Eighteen Stage I-II non-small cell lung cancer (NSCLC) patients with centrally located tumors, who underwent MC-based lung SABR with heterogeneity correction using X-ray Voxel Monte Carlo (XVMC) algorithm (BrainLAB iPlan version 4.1.2), were analyzed. Total dose of 60 Gy in 5 fractions was delivered to planning target volume (PTV) with at least V100% = 95%. Internal target volumes (ITVs) were delineated on maximum intensity projection (MIP) images of 4D CT scans. PTV (ITV + 5 mm margin) volumes ranged from 10.0 to 99.9 cc (mean = 36.8 ± 20.7 cc). Organs at risk (OARs) were delineated on average images of 4D CT scans. Optimal clinical MC SABR plans were generated using a combination of non-coplanar conformal arcs and beams for the Novalis-TX consisting of high definition multileaf collimators (MLCs) and 6 MV-SRS (1000 MU/min) mode. All plans were evaluated using the RTOG 0813 high and intermediate dose spillage criteria: conformity index (R100%), ratio of 50% isodose volume to the PTV (R50%), maximum dose 2 cm away from PTV in any direction (D2 cm), and percent of normal lung receiving 20 Gy (V20) or more. Other organs-at-risk (OARs) doses were tabulated, including the volume of normal lung receiving 5 Gy (V5), maximum cord dose, dose to < 15 cc of heart, and dose to <5 cc of esophagus. Only six out of 18 patients met all RTOG 0813 compliance criteria. Eight of 18 patients had minor deviations in R100%, four in R50%, and nine in D2 cm. However, only one patient had minor deviation in V20. All other OARs doses, such as maximum cord dose, dose to < 15 cc of heart, and dose to < 5 cc of esophagus, were satisfactory for RTOG criteria, except for one patient, for whom the dose to < 15 cc of heart was higher than RTOG guidelines. The preliminary results for our limited iPlan XVMC dose calculations indicate that the majority (i.e., 2/3) of our patients had minor deviations in the dosimetric guidelines set by RTOG 0813 protocol in one way or another. When using an exclusive highly sophisticated XVMC algorithm, the RTOG 0813 dosimetric compliance criteria such as R100% and D2 cm may need to be revisited. Based on our limited number of patient datasets, in general, about 6% for R100% and 9% for D2 cm corrections could be applied to pass the RTOG 0813 compliance criteria in most of those patients. More patient plans need to be evaluated to make recommendation for R50%. No adjustment is necessary for OAR dose tolerances, including normal lung V20. In order to establish new MC specific dose parameters, further investigation with a large cohort of patients including central, as well as peripheral lung tumors, is anticipated and strongly recommended.

Loss of the Type I Interferon Pathway Increases Vulnerability of Mice to Genital Herpes Simplex Virus 2 Infection ▿

PubMed Central

Conrady, Christopher D.; Halford, William P.; Carr, Daniel J. J.

2011-01-01

The mouse model of genital herpes relies on medoxyprogesterone treatment of female mice to render the vaginal lumen susceptible to inoculation with herpes simplex virus 2 (HSV-2). In the present study, we report that mice deficient in the A1 chain of the type I interferon receptor (CD118−/−) are susceptible to HSV-2 in the absence of medroxyprogesterone preconditioning. In the absence of hormone pretreatment, 2,000 PFU of a clinical isolate of HSV-2 was sufficient to establish a productive infection in the vagina of 75% ± 17% and in the spinal cord of 71% ± 14% of CD118−/− mice, whereas the same dose of HSV-2 replicated to detectable levels in only 13% ± 13% of vaginal samples and 0% of spinal cord samples from wild-type mice, as determined at day 5 postinfection. The susceptibility to HSV-2 infection in the CD118−/− mice was associated with a significant reduction in the infiltration of HSV-specific cytotoxic T lymphocytes into the vaginal tissue, the local production of gamma interferon (IFN-γ), and the expression of T cell-recruiting chemokines CCL5, CXCL9, and CXCL10. Collectively, the results underscore the significant contribution of type I IFNs in resistance to genital HSV-2 infection. PMID:21147921

Ultrasonographic evaluation of displaced neurovascular bundle in Dupuytren disease.

PubMed

Uehara, Kosuke; Miura, Toshiki; Morizaki, Yutaka; Miyamoto, Hideaki; Ohe, Takashi; Tanaka, Sakae

2013-01-01

Neurovascular injury is a serious complication after surgery for Dupuytren disease. The purpose of this study was to evaluate the relationship between the cord and the neurovascular bundle ultrasonographically. We included 22 healthy volunteers and 14 Dupuytren disease patients (25 fingers) in this study. We evaluated the cord and the digital artery with high-resolution ultrasound. We first investigated the effect of the angle of metacarpophalangeal joint on the position of the radial and ulnar digital arteries in volunteers without evidence of Dupuytren disease. We compared 3 parameters of the radial and ulnar digital arteries, including differences in depth, differences in lateral shift, and the shape of the cross-section of the artery, between volunteers and patients with Dupuytren disease. None of these parameters changed with flexion of the metacarpophalangeal joint of 0°, 30°, and 60°. Digital arteries and cords could be identified ultrasonographically in all patients, and we confirmed ultrasonographic findings by operative findings in 13 fingers. We classified the fingers into 3 subgroups based on the ultrasonographic findings: type A (n = 13), in which the cord was above the artery; type B (n = 5), in which the cord was below the artery; and type C (n = 7), in which the cord was located between the radial and ulnar digital arteries. Types A, B, and C corresponded to natatory cord/abductor digiti minimi cord, spiral cord, and central cord, respectively. Comparisons among volunteers and patient subgroups showed that the difference in depth in type B patients was significantly larger than that of the other groups. When we set the cutoff point of the difference in depth to 3 mm, sensitivity and specificity to detect the spiral cord were 80% and 76%, respectively. The relationship between the neurovascular bundle and the type of Dupuytren disease cord can be evaluated by high-resolution ultrasound. Diagnostic III. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Volumetric-modulated arc therapy (RapidArc) vs. conventional fixed-field intensity-modulated radiotherapy for {sup 18}F-FDG-PET-guided dose escalation in oropharyngeal cancer: A planning study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teoh, May, E-mail: m.teoh@nhs.net; Beveridge, Sabeena; Wood, Katie

2013-04-01

Fluorine-18-fluorodeoxyglucose-positron emission tomography ({sup 18}F-FDG-PET)–guided focal dose escalation in oropharyngeal cancer may potentially improve local control. We evaluated the feasibility of this approach using volumetric-modulated arc therapy (RapidArc) and compared these plans with fixed-field intensity-modulated radiotherapy (IMRT) focal dose escalation plans. Materials and methods: An initial study of 20 patients compared RapidArc with fixed-field IMRT using standard dose prescriptions. From this cohort, 10 were included in a dose escalation planning study. Dose escalation was applied to {sup 18}F-FDG-PET–positive regions in the primary tumor at dose levels of 5% (DL1), 10% (DL2), and 15% (DL3) above standard radical dose (65 Gymore » in 30 fractions). Fixed-field IMRT and double-arc RapidArc plans were generated for each dataset. Dose-volume histograms were used for plan evaluation and comparison. The Paddick conformity index (CI{sub Paddick}) and monitor units (MU) for each plan were recorded and compared. Both IMRT and RapidArc produced clinically acceptable plans and achieved planning objectives for target volumes. Dose conformity was significantly better in the RapidArc plans, with lower CI{sub Paddick} scores in both primary (PTV1) and elective (PTV2) planning target volumes (largest difference in PTV1 at DL3; 0.81 ± 0.03 [RapidArc] vs. 0.77 ± 0.07 [IMRT], p = 0.04). Maximum dose constraints for spinal cord and brainstem were not exceeded in both RapidArc and IMRT plans, but mean doses were higher with RapidArc (by 2.7 ± 1 Gy for spinal cord and 1.9 ± 1 Gy for brainstem). Contralateral parotid mean dose was lower with RapidArc, which was statistically significant at DL1 (29.0 vs. 29.9 Gy, p = 0.01) and DL2 (29.3 vs. 30.3 Gy, p = 0.03). MU were reduced by 39.8–49.2% with RapidArc (largest difference at DL3, 641 ± 94 vs. 1261 ± 118, p < 0.01). {sup 18}F-FDG-PET–guided focal dose escalation in oropharyngeal cancer is feasible with RapidArc. Compared with conventional fixed-field IMRT, RapidArc can achieve better dose conformity, improve contralateral parotid sparing, and uses fewer MU.« less

Pre-procedural antibiotics for endoscopic urological procedures: Initial experience in individuals with spinal cord injury and asymptomatic bacteriuria.

PubMed

Chong, Julio T; Klausner, Adam P; Petrossian, Albert; Byrne, Michael D; Moore, Jewel R; Goetz, Lance L; Gater, David R; Grob, B Mayer

2015-03-01

The objective of this study was to compare the safety, efficacy, quality-of-life impact, and costs of a single dose or a longer course of pre-procedural antibiotics prior to elective endoscopic urological procedures in individuals with spinal cord injury and disorders (SCI/D) and asymptomatic bacteriuria. A prospective observational study. Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA. Sixty persons with SCI/D and asymptomatic bacteriuria scheduled to undergo elective endoscopic urological procedures. A single pre-procedural dose of antibiotics vs. a 3-5-day course of pre-procedural antibiotics. Objective and subjective measures of health, costs, and quality of life. There were no significant differences in vital signs, leukocytosis, adverse events, and overall satisfaction in individuals who received short-course vs. long-course antibiotics. There was a significant decrease in antibiotic cost (33.1 ± 47.6 vs. 3.6 ± 6.1 US$, P = 0.01) for individuals in the short-course group. In addition, there was greater pre-procedural anxiety (18 vs. 0%, P < 0.05) for individuals who received long-course antibiotics. SCI/D individuals with asymptomatic bacteriuria may be able to safely undergo most endoscopic urological procedures with a single dose of pre-procedural antibiotics. However, further research is required and even appropriate pre-procedural antibiotics may not prevent severe infections.

Revisiting the segmental organization of the human spinal cord.

PubMed

Leijnse, J N; D'Herde, K

2016-09-01

In classic anatomic atlases, the spinal cord is standardly represented in its anatomical form with symmetrically emerging anterior and posterior roots, which at the level of the intervertebral foramen combine into the spinal nerves. The parts of the cord delimited by the boundaries of the roots are called segments or myelomeres. Associated with their regular repetitive appearance is the notion that the cord is segmentally organized. This segmental view is reinforced by clinical practice. Spinal cord roots innervate specific body parts. The level of cord trauma is diagnosed by the de-innervation symptoms of these parts. However, systemically, the case for a segmentally organized cord is not so clear. To date, developmental and genetic research points to a regionally rather than a segmentally organized cord. In the present study, to what degree the fila radicularia are segmentally implanted along the cord was investigated. The research hypothesis was that if the fila radicularia were non-segmentally implanted at the cord surface, it would be unlikely that the internal neuron stratum would be segmented. The visual segmented aspect of the myelomeres would then be the consequence of the necessary bundling of axons towards the vertebral foramen as the only exits of the vertebral canal, rather than of an underlying segment organization of the cord itself. To investigate the research hypothesis, the fila radicularia in the cervical-upper thoracic part of five spinal cords were detached from their spinal nerves and dissected in detail. The principal research question was if the fila radicularia are separated from their spinal nerves and dissected from their connective tissues up to the cord, would it be possible to reconstruct the original spinal segments from the morphology and interspaces of the fila? The dissections revealed that the anterior fila radicularia emerge from the cord at regular regionally modulated interspaces without systematic segmental delineations. The posterior fila radicularia are somewhat more segmentally implanted, but the pattern is individually inconsistent. The posterior and anterior roots have notable morphological differences, and hypotheses are presented to help explain these. The macroscopic observations are consistent with a regionally but not a segmentally organized cord. This conclusion was visually summarized in photographs of spinal cords with ipsilateral intact roots and contralateral individually dissected fila radicularia. It was suggested that this dual view of the spinal cord be added to the standard anatomic textbooks to counterbalance the current possibly biased view of a segmented cord. © 2016 Anatomical Society.

Evaluation of the thoraco-laryngeal reflex ('slap test') as an aid to the diagnosis of cervical spinal cord and brainstem disease in horses.

PubMed

Newton-Clarke, M J; Divers, T J; Delahunta, A; Mohammed, H O

1994-09-01

A study was conducted over a 12 month period to assess the specificity and sensitivity of the 'slap test', using endoscopic evaluation, in the detection of cervical spinal cord and caudal brainstem lesions in horses. Fifteen ataxic horses were subjected to the 'slap test' and subsequently examined post mortem. Twelve out of the 15 had histopathological lesions consistent with their clinical signs. Thirteen horses with no history of neurological dysfunction and no histopathological evidence of cervical spinal cord or brainstem disease were used as controls. The laryngeal adductory responses exhibited by all horses were filmed and later scored independently by 3 assessors. The proportion of animals diagnosed with cervical spinal cord and/or brainstem disease, defined by histopathological criteria, was found to be statistically similar to the proportion with abnormal 'slap test' responses, using the McNemar chi-Square test. Despite statistical significance between proportions, sensitivity of the 'slap test' was low, 50% for the left side on both days and 58% for the right side. Specificity was higher, 69% (Day 1) and 75% (Day 2) for the left side and 75% (Day 1) and 69% (Day 2) for the right side. In contrast to this, conventional neurological examination was found to be 100% sensitive and 81% specific in the detection of lesions of histopathological significance in the cervical spinal cord/caudal brainstem. Agreement between scores for the 'slap test' from the same assessor on different days was good, with values for kappa of 0.59 to 0.85. In contrast, agreement between assessors on the 'slap test' score was poor, with kappa 0.35.(ABSTRACT TRUNCATED AT 250 WORDS)

Single Vocal Cord Irradiation: Image Guided Intensity Modulated Hypofractionated Radiation Therapy for T1a Glottic Cancer: Early Clinical Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Al-Mamgani, Abrahim, E-mail: a.almamgani@nki.nl; Kwa, Stefan L.S.; Tans, Lisa

2015-10-01

Purpose: To report, from a retrospective analysis of prospectively collected data, on the feasibility, outcome, toxicity, and voice-handicap index (VHI) of patients with T1a glottic cancer treated by a novel intensity modulated radiation therapy technique developed at our institution to treat only the involved vocal cord: single vocal cord irradiation (SVCI). Methods and Materials: Thirty patients with T1a glottic cancer were treated by means of SVCI. Dose prescription was set to 16 × 3.63 Gy (total dose 58.08 Gy). The clinical target volume was the entire vocal cord. Setup verification was done by means of an online correction protocol using cone beam computed tomography. Datamore » for voice quality assessment were collected prospectively at baseline, end of treatment, and 4, 6, and 12 weeks and 6, 12, and 18 months after treatment using VHI questionnaires. Results: After a median follow-up of 30 months (range, 7-50 months), the 2-year local control and overall survival rates were 100% and 90% because no single local recurrence was reported and 3 patients died because of comorbidity. All patients have completed the intended treatment schedule; no treatment interruptions and no grade 3 acute toxicity were reported. Grade 2 acute dermatitis or dysphagia was reported in only 5 patients (17%). No serious late toxicity was reported; only 1 patient developed temporary grade 2 laryngeal edema, and responded to a short-course of corticosteroid. The VHI improved significantly, from 33.5 at baseline to 9.5 and 10 at 6 weeks and 18 months, respectively (P<.001). The control group, treated to the whole larynx, had comparable local control rates (92.2% vs 100%, P=.24) but more acute toxicity (66% vs 17%, P<.0001) and higher VHI scores (23.8 and 16.7 at 6 weeks and 18 months, respectively, P<.0001). Conclusion: Single vocal cord irradiation is feasible and resulted in maximal local control rate at 2 years. The deterioration in VHI scores was slight and temporary and subsequently improved to normal levels. Long-term follow-up is needed to consolidate these promising results.« less

Pharmacodynamic evaluation of Lys5, MeLeu9, Nle10-NKA(4–10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats

PubMed Central

Kullmann, F. Aura; Katofiasc, M.; Thor, K.B.; Marson, L.

2017-01-01

Purpose To determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, neurokinin 2 receptor (NK2 receptor) agonist, Lys5, MeLeu9, Nle10-NKA(4–10) (LMN-NKA). Methods Cystometry and colorectal pressure measurements were performed in urethane anesthetized, intact and acutely spinalized, female rats. Bladder pressure and voiding were monitored in response to intravenous LMN-NKA given with the bladder filled to 70% capacity. Results LMN-NKA (0.1–300 µg/kg) produced dose dependent, rapid (< 60 s), short duration (< 15 min) increases in bladder pressure. In intact rats, doses above 0.3–1 µg/kg induced urine release (voiding efficiency of ~ 70% at ≥ 1 µg/kg). In spinalized rats, urine release required higher doses (≥ 10 µg/kg) and was less efficient (30–50%). LMN-NKA (0.1–100 µg/kg) also produced dose dependent increases in colorectal pressure. No tachyphylaxis was observed, and the responses were blocked by an NK2 receptor antagonist (GR159897, 1 mg/kg i.v.). No obvious cardiorespiratory effects were noted. Conclusions These results suggest that rapid-onset, short duration, drug-induced voiding is possible in acute spinal and intact rats with intravenous administration of an NK2 receptor agonist. Future challenges remain in regards to finding alternative routes of administration that produce clinically significant voiding, multiple times per day, in animal models of chronic SCI. PMID:27889808

Obstetricians' attitudes, subjective norms, perceived controls, and intentions on antibiotic prophylaxis in caesarean section.

PubMed

Liabsuetrakul, Tippawan; Chongsuvivatwong, Virasakdi; Lumbiganon, Pisake; Lindmark, Gunilla

2003-11-01

Over 10% of current births in all countries of the world are delivered by caesarean section. Single-dose ampicillin or cefazolin administered after cord clamping has been proven to be effective for the prevention of post-caesarean infections as indicated in many randomised trials and reviews in the Cochrane Library. This study aimed to determine three determinants of behavioural intention using the theory of planned behaviour: attitudes, subjective norms, and perceived controls. Intentions were examined for five aspects of the use of antibiotic prophylaxis, namely whether or not antibiotics were used, used in all caesarean sections, after rather than before cord clamping, whether ampicillin/cefazolin or broader-spectrum antibiotics were used, and whether single or multiple doses were given. Fifty obstetricians selected from university, regional, and general hospitals in southern Thailand, were surveyed using a questionnaire and in-depth interview. Their intentions to use a single dose and to use in all cases were low, and this was related to negative attitudes and reference groups who did not approve of the single dose. The negative attitude was based on scepticism concerning the applicability of well-equipped trials from the developed world and fear of consequences of post-caesarean infections. Norms carried over from residency training had more long-term influence in their practice than newer information from books or journals. Perceived external controls on their practice were less predictive of intentions. Intentions were only partly predictive of behaviour. Changing attitudes, introducing evidence-based information into residency training and strengthening control systems in the hospital are essential to improve intentions.

SU-E-T-62: A Preliminary Experience of Using EPID Transit Dosimetry for Monitoring Daily Dose Variations in Radiation Treatment Delivery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yao, R; Chisela, W

2015-06-15

Purpose: To investigate the use of EPID transit dosimetry for monitoring daily dose variations in radiation treatment delivery. Methods: A patient with head and neck cancer treated using nine field IMRT beams was used in this study. The prescription was 45 Gy in 25 fractions. A KV CBCT was acquired before each treatment on a Varian NTX linear accelerator. Integrated images using MV EPID were acquired for each treatment beam. Planning CT images, treatment plan, and daily integrated images were imported into a commercial QA software Dosimetry Check (v4r4 Math Resolutions, LLC, Columbia, MD) to calculate 3D dose of themore » day assuming 25 fractions treatment. Planning CT images were deformed and registered to each daily CBCT using Varian SmartAdapt (v11.MR2). ROIs were then propagated from planning CT to daily CBCT. The correlation between maximum, average dose of ROIs and ROI volume, center of mass shift, Dice Similarity Coefficient (DSC) were investigated. Results: Not all parameters investigated showed strong correlations. For PTV and CTV, the average dose has inverse correlation with their volume change (correlation coefficient −0.52, −0.50, respectively) and DSC (−0.59, −0.59, respectively). The average dose of right parotid has correlation with its volume change (0.56). The maximum dose of spinal cord has correlation with the center of mass superior-inferior shift (0.52) and inverse correlation with the center of mass anterior-posterior shift (−0.73). Conclusion: Transit dosimetry using EPID images collected during treatment delivery offers great potential to monitor daily dose variations due to patient anatomy change, motion, and setup errors in radiation treatment delivery. It can provide a patient-specific QA tool valuable for adaptive radiation therapy. Further work is needed to validate the technique.« less

Pathogenesis of highly pathogenic avian influenza A virus (H7N1) infection in chickens inoculated with three different doses.

PubMed

Chaves, Aida J; Busquets, Nuria; Campos, Naiana; Ramis, Antonio; Dolz, Roser; Rivas, Raquel; Valle, Rosa; Abad, F Xavier; Darji, Ayub; Majo, Natalia

2011-04-01

To study the pathogenesis of a H7N1 highly pathogenic avian influenza virus strain, specific pathogen free chickens were inoculated with decreasing concentrations of virus: 10(5.5) median embryo lethal dose (ELD(50)) (G1), 10(3.5) ELD(50) (G2) and 10(1.5) ELD(50) (G3). Disease progression was monitored over a period of 16 days and sequential necropsies and tissue samples were collected for histological and immunohistochemical examination. Viral RNA loads were also quantified in different tissues, blood, oropharyngeal swabs, and cloacal swabs using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). Clinical signs of depression, apathy, listlessness, huddling and ruffled feathers were recorded in G1 and a few G2 birds, whilst neurological signs were only observed in chickens inoculated with the highest dose. Gross lesions of haemorrhages were observed in the unfeathered skin of the comb and legs, and skeletal muscle, lung, pancreas and kidneys of birds inoculated with 10(5.5) ELD(50) and 10(3.5) ELD(50) doses. Microscopic lesions and viral antigen were demonstrated in cells of the nasal cavity, lung, heart, skeletal muscle, brain, spinal cord, gastrointestinal tract, pancreas, liver, bone marrow, thymus, bursa of Fabricius, spleen, kidney, adrenal gland and skin. Viral RNA was detected by RT-qPCR in kidney, lung, intestine, and brain samples of G1 and G2 birds. However, in birds infected with the lowest dose, viral RNA was detected only in brain and lung samples in low amounts at 5 and 7 days post infection. Interestingly, viral shedding was observed in oropharyngeal and cloacal swabs with proportionate decrease with the inoculation dose. We conclude that although an adequate infectious dose is critical in reproducing the clinical infection, chickens exposed to lower doses can be infected and shed virus representing a risk for the dissemination of the viral agent.

Cord blood Streptococcus pneumoniae‐specific cellular immune responses predict early pneumococcal carriage in high‐risk infants in Papua New Guinea

PubMed Central

Francis, J. P.; Richmond, P. C.; Strickland, D.; Prescott, S. L.; Pomat, W. S.; Michael, A.; Nadal‐Sims, M. A.; Edwards‐Devitt, C. J.; Holt, P. G.; Lehmann, D.

2016-01-01

Summary In areas where Streptococcus pneumoniae is highly endemic, infants experience very early pneumococcal colonization of the upper respiratory tract, with carriage often persisting into adulthood. We aimed to explore whether newborns in high‐risk areas have pre‐existing pneumococcal‐specific cellular immune responses that may affect early pneumococcal acquisition. Cord blood mononuclear cells (CBMC) of 84 Papua New Guinean (PNG; high endemic) and 33 Australian (AUS; low endemic) newborns were stimulated in vitro with detoxified pneumolysin (dPly) or pneumococcal surface protein A (PspA; families 1 and 2) and compared for cytokine responses. Within the PNG cohort, associations between CBMC dPly and PspA‐induced responses and pneumococcal colonization within the first month of life were studied. Significantly higher PspA‐specific interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α, interleukin (IL)‐5, IL‐6, IL‐10 and IL‐13 responses, and lower dPly‐IL‐6 responses were produced in CBMC cultures of PNG compared to AUS newborns. Higher CBMC PspA‐IL‐5 and PspA‐IL‐13 responses correlated with a higher proportion of cord CD4 T cells, and higher dPly‐IL‐6 responses with a higher frequency of cord antigen‐presenting cells. In the PNG cohort, higher PspA‐specific IL‐5 and IL‐6 CBMC responses were associated independently and significantly with increased risk of earlier pneumococcal colonization, while a significant protective effect was found for higher PspA‐IL‐10 CBMC responses. Pneumococcus‐specific cellular immune responses differ between children born in pneumococcal high versus low endemic settings, which may contribute to the higher risk of infants in high endemic settings for early pneumococcal colonization, and hence disease. PMID:27859014

Volumetric Modulated Arc Therapy vs. c-IMRT for the Treatment of Upper Thoracic Esophageal Cancer

PubMed Central

Lu, Jia-Yang; Chen, Jian-Zhou; Chen, Zhi-Jian; Li, De-Rui; Chen, Chuang-Zhen

2015-01-01

Objective To compare plans using volumetric-modulated arc therapy (VMAT) with conventional sliding window intensity-modulated radiation therapy (c-IMRT) to treat upper thoracic esophageal cancer (EC). Methods CT datasets of 11 patients with upper thoracic EC were identified. Four plans were generated for each patient: c-IMRT with 5 fields (5F) and VMAT with a single arc (1A), two arcs (2A), or three arcs (3A). The prescribed doses were 64 Gy/32 F for the primary tumor (PTV64). The dose-volume histogram data, the number of monitoring units (MUs) and the treatment time (TT) for the different plans were compared. Results All of the plans generated similar dose distributions for PTVs and organs at risk (OARs), except that the 2A- and 3A-VMAT plans yielded a significantly higher conformity index (CI) than the c-IMRT plan. The CI of the PTV64 was improved by increasing the number of arcs in the VMAT plans. The maximum spinal cord dose and the planning risk volume of the spinal cord dose for the two techniques were similar. The 2A- and 3A-VMAT plans yielded lower mean lung doses and heart V50 values than the c-IMRT. The V20 and V30 for the lungs in all of the VMAT plans were lower than those in the c-IMRT plan, at the expense of increasing V5, V10 and V13. The VMAT plan resulted in significant reductions in MUs and TT. Conclusion The 2A-VMAT plan appeared to spare the lungs from moderate-dose irradiation most effectively of all plans, at the expense of increasing the low-dose irradiation volume, and also significantly reduced the number of required MUs and the TT. The CI of the PTVs and the OARs was improved by increasing the arc-number from 1 to 2; however, no significant improvement was observed using the 3A-VMAT, except for an increase in the TT. PMID:25815477

SU-E-J-203: Investigation of 1.5T Magnetic Field Dose Effects On Organs of Different Density

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, H; Rubinstein, A; Ibbott, G

2015-06-15

Purpose: For the combined 1.5T/6MV MRI-linac system, the perpendicular magnetic field to the radiation beam results in altered radiation dose distributions. This Monte Carlo study investigates the change in dose at interfaces for common organs neighboring soft tissue. Methods: MCNP6 was used to simulate the effects of a 1.5T magnetic field when irradiating tissues with a 6 MV beam. The geometries used in this study were not necessarily anatomically representative in size in order to directly compare quantitative dose effects for each tissue at the same depths. For this purpose, a 512 cm{sup 3} cubic material was positioned at themore » center of a 2744 cm{sup 3} cubic soft tissue material phantom. The following tissue materials and their densities were used in this study: lung (0.296 g/cm{sup 3}), fat (0.95), spinal cord (1.038), soft tissue (1.04), muscle (1.05), eye (1.076), trabecular bone (1.40), and cortical bone (1.85). Results: The addition of a 1.5T magnetic field caused dose changes of +46.5%, +2.4%, −0.9%, −0.8%, −1.5%, −6.5%, and −8.8% at the entrance interface between soft tissue and lung, fat, spinal cord, muscle, eye, trabecular bone, and cortical bone tissues respectively. Dose changes of −39.4%, −4.1%, −0.8%, −0.8%, +0.5%, +6.7%, and +10.9% were observed at the second interface between the same tissues respectively and soft tissue. On average, the build-up distance was reduced by 0.6 cm, and a dose increase of 62.7% was observed at the exit interface between soft tissue and air of the entire phantom. Conclusion: The greatest changes in dose were observed at interfaces containing lung and bone tissues. Due to the prevalence and proximity of bony anatomy to soft tissues throughout the human body, these results encourage further examination of these tissues with anatomically representative geometries using multiple beam configurations for safe treatment using the MRI-linac system.« less

SU-E-T-811: Volumetric Modulated Arc Therapy Vs. C-IMRT for the Treatment of Upper Thoracic Esophageal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, W; Wu, L; Lu, J

2015-06-15

Purpose: To compare plans using volumetric-modulated arc therapy (VMAT) with conventional sliding window intensity-modulated radiation therapy (c-IMRT) to treat upper thoracic esophageal cancer (EC). Methods: CT datasets of 11 patients with upper thoracic EC were identified. Four plans were generated for each patient: c-IMRT with 5 fields (5F) and VMAT with a single arc (1A), two arcs (2A), or three arcs (3A). The prescribed doses were 64 Gy/32 F for the primary tumor (planning target volume 64, PTV64). The dose-volume histogram data, the number of monitoring units (MUs) and the treatment time (TT) for the different plans were compared. Results:more » All of the plans generated similar dose distributions for PTVs and organs at risk (OARs), except that the 2A- and 3A-VMAT plans yielded a significantly higher conformity index (CI) than the c-IMRT plan. The CI of the PTV64 was improved by increasing the number of arcs in the VMAT plans. The maximum spinal cord dose and the planning risk volume of the spinal cord dose for the two techniques were similar. The 2A- and 3A-VMAT plans yielded lower mean lung doses and heart V50 than the c-IMRT. The V20 and V30 for the lungs in all of the VMAT plans were lower than those in the c-IMRT plan, at the expense of increasing V5, V10 and V13. The VMAT plan resulted in significant reductions in MUs and TT. Conclusion: The 2A-VMAT plan appeared to spare the lungs from moderate-dose irradiation most effectively of all plans, at the expense of increasing the low-dose irradiation volume, and also significantly reduced the number of required MUs and the TT. The CI of the PTVs and the OARs was improved by increasing the arc-number from 1 to 2. however, no significant improvement was observed using the 3A-VMAT, except for an increase in the TT. This work was sponsored by Shantou University Medical College Clinical Research Enhancement Initiative(NO.201424)« less

SU-E-T-97: An Analysis of Knowledge Based Planning for Stereotactic Body Radiation Therapy of the Spine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Foy, J; Marsh, R; Owen, D

2015-06-15

Purpose: Creating high quality SBRT treatment plans for the spine is often tedious and time consuming. In addition, the quality of treatment plans can vary greatly between treatment facilities due to inconsistencies in planning methods. This study investigates the performance of knowledge-based planning (KBP) for spine SBRT. Methods: Treatment plans were created for 28 spine SBRT patients. Each case was planned to meet strict dose objectives and guidelines. After physician and physicist approval, the plans were added to a custom model in a KBP system (RapidPlan, Varian Eclipse v13.5). The model was then trained to be able to predict estimatedmore » DVHs and provide starting objective functions for future patients based on both generated and manual objectives. To validate the model, ten additional spine SBRT cases were planned manually as well as using the model objectives. Plans were compared based on planning time and quality (ability to meet the plan objectives, including dose metrics and conformity). Results: The average dose to the spinal cord and the cord PRV differed between the validation and control plans by <0.25% demonstrating iso-toxicity. Six out of 10 validation plans met all dose objectives without the need for modifications, and overall, target dose coverage was increased by about 4.8%. If the validation plans did not meet the dose requirements initially, only 1–2 iterations of modifying the planning parameters were required before an acceptable plan was achieved. While manually created plans usually required 30 minutes to 3 hours to create, KBP can be used to create similar quality plans in 15–20 minutes. Conclusion: KBP for spinal tumors has shown to greatly decrease the amount of time required to achieve high quality treatment plans with minimal human intervention and could feasibly be used to standardize plan quality between institutions. Supported by Varian Medical Systems.« less

Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury

PubMed Central

Keefe, Kathleen M.; Sheikh, Imran S.; Smith, George M.

2017-01-01

Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury models. Here we review several members of the classical family of neurotrophins, the receptors they bind to, and their contribution to axonal regeneration and sprouting of sensory and motor pathways after spinal cord injury (SCI). We focus on nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and their effects on populations of neurons within diverse spinal tracts. Understanding the cellular targets of neurotrophins and the responsiveness of specific neuronal populations will allow for the most efficient treatment strategies in the injured spinal cord. PMID:28273811

Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury.

PubMed

Keefe, Kathleen M; Sheikh, Imran S; Smith, George M

2017-03-03

Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury models. Here we review several members of the classical family of neurotrophins, the receptors they bind to, and their contribution to axonal regeneration and sprouting of sensory and motor pathways after spinal cord injury (SCI). We focus on nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and their effects on populations of neurons within diverse spinal tracts. Understanding the cellular targets of neurotrophins and the responsiveness of specific neuronal populations will allow for the most efficient treatment strategies in the injured spinal cord.

A spinal thecal sac constriction model supports the theory that induced pressure gradients in the cord cause edema and cyst formation.

PubMed

Josephson, A; Greitz, D; Klason, T; Olson, L; Spenger, C

2001-03-01

Spinal cord cysts are a devastating condition that occur secondary to obstructions of the spinal canal, which may be caused by congenital malformations, trauma, spinal canal stenosis, tumors, meningitis, or arachnoiditis. A hypothesis that could explain how spinal cord cysts form in these situations has been presented recently. Therefore, a novel spinal thecal sac constriction model was implemented to test various aspects of this hypothesis. Thecal sac constriction was achieved by subjecting rats to an extradural silk ligature at the T8 spinal cord level. Rats with complete spinal cord transection served as a second model for comparison. The animals underwent high-resolution magnetic resonance imaging and histological analysis. Thecal sac constriction caused edema cranial and caudal to the ligation within 3 weeks, and cysts developed after 8 to 13 weeks. In contrast, cysts in rats with spinal cord transection were located predominantly in the cranial spinal cord. Histological sections of spinal cords confirmed the magnetic resonance imaging results. Magnetic resonance imaging provided the specific advantage of enabling characterization of events as they occurred repeatedly over time in the spinal cords of individual living animals. The spinal thecal sac constriction model proved useful for investigation of features of the cerebrospinal fluid pulse pressure theory. Edema and cyst distributions were in accordance with this theory. We conclude that induced intramedullary pressure gradients originating from the cerebrospinal fluid pulse pressure may underlie cyst formation in the vicinity of spinal canal obstructions and that cysts are preceded by edema.

Childhood Obesity Research Demonstration (CORD): The Cross-Site Overview and Opportunities for Interventions Addressing Obesity Community-Wide

PubMed Central

Belay, Brook; Dooyema, Carrie A.; Williams, Nancy; Blanck, Heidi M.

2015-01-01

Abstract Background: This is the first of a set of articles in this issue on the Childhood Obesity Research Demonstration (CORD) project and provides an overview of the multisite approach and community-wide interventions. Innovative multisetting, multilevel approaches that integrate primary healthcare and public health interventions to improve outcomes for children with obesity need to be evaluated. The CORD project aims to improve BMI and obesity-related behaviors among underserved 2- to 12-year-old children by utilizing these approaches. Methods: The CORD consortium, structure, model terminology and key components, and common measures were solidified in year 1 of the CORD project. Demonstration sites applied the CORD model across communities in years 2 and 3. Evaluation plans for year 4 include site-specific analyses as well as cross-site impact, process, and sustainability evaluations. Results: The CORD approach resulted in commonalities and differences in participant, intervention, comparison, and outcome elements across sites. Products are to include analytic results as well as cost assessment, lessons learned, tools, and materials. Discussion: Foreseen opportunities and challenges arise from the similarities and unique aspects across sites. Communities adapted interventions to fit their local context and build on strengths, but, in turn, this flexibility makes cross-site evaluation challenging. Conclusion: The CORD project represents an evidence-based approach that integrates primary care and public health strategies and evaluates multisetting multilevel interventions, thus adding to the limited research in this field. CORD products will be disseminated to a variety of stakeholders to aid the understanding, prevention, and management of childhood obesity. PMID:25679059

A method to acquire CT organ dose map using OSL dosimeters and ATOM anthropomorphic phantoms

PubMed Central

Zhang, Da; Li, Xinhua; Gao, Yiming; Xu, X. George; Liu, Bob

2013-01-01

Purpose: To present the design and procedure of an experimental method for acquiring densely sampled organ dose map for CT applications, based on optically stimulated luminescence (OSL) dosimeters “nanoDots” and standard ATOM anthropomorphic phantoms; and to provide the results of applying the method—a dose data set with good statistics for the comparison with Monte Carlo simulation result in the future. Methods: A standard ATOM phantom has densely located holes (in 3 × 3 cm or 1.5 × 1.5 cm grids), which are too small (5 mm in diameter) to host many types of dosimeters, including the nanoDots. The authors modified the conventional way in which nanoDots are used, by removing the OSL disks from the holders before inserting them inside a standard ATOM phantom for dose measurements. The authors solved three technical difficulties introduced by this modification: (1) energy dependent dose calibration for raw OSL readings; (2) influence of the brief background exposure of OSL disks to dimmed room light; (3) correct pairing between the dose readings and measurement locations. The authors acquired 100 dose measurements at various positions in the phantom, which was scanned using a clinical chest protocol with both angular and z-axis tube current modulations. Results: Dose calibration was performed according to the beam qualities inside the phantom as determined from an established Monte Carlo model of the scanner. The influence of the brief exposure to dimmed room light was evaluated and deemed negligible. Pairing between the OSL readings and measurement locations was ensured by the experimental design. The organ doses measured for a routine adult chest scan protocol ranged from 9.4 to 18.8 mGy, depending on the composition, location, and surrounding anatomy of the organs. The dose distribution across different slices of the phantom strongly depended on the z-axis mA modulation. In the same slice, doses to the soft tissues other than the spinal cord demonstrated relatively small variations, with the maximum COV around 11.4%. This might be attributed to the angular mA modulation, the placement of the dosimeters, the chest cavity of the scanned region, and the size of the phantom. Doses to the spinal cord were consistently lower than those to other soft tissues. Conclusions: The method is suited for acquiring densely sampled organ dose maps, and can be used for studying dose distributions relevant to subject size, organ location, and clinical CT protocols. PMID:23927332

A method to acquire CT organ dose map using OSL dosimeters and ATOM anthropomorphic phantoms.

PubMed

Zhang, Da; Li, Xinhua; Gao, Yiming; Xu, X George; Liu, Bob

2013-08-01

To present the design and procedure of an experimental method for acquiring densely sampled organ dose map for CT applications, based on optically stimulated luminescence (OSL) dosimeters "nanoDots" and standard ATOM anthropomorphic phantoms; and to provide the results of applying the method--a dose data set with good statistics for the comparison with Monte Carlo simulation result in the future. A standard ATOM phantom has densely located holes (in 3×3 cm or 1.5×1.5 cm grids), which are too small (5 mm in diameter) to host many types of dosimeters, including the nanoDots. The authors modified the conventional way in which nanoDots are used, by removing the OSL disks from the holders before inserting them inside a standard ATOM phantom for dose measurements. The authors solved three technical difficulties introduced by this modification: (1) energy dependent dose calibration for raw OSL readings; (2) influence of the brief background exposure of OSL disks to dimmed room light; (3) correct pairing between the dose readings and measurement locations. The authors acquired 100 dose measurements at various positions in the phantom, which was scanned using a clinical chest protocol with both angular and z-axis tube current modulations. Dose calibration was performed according to the beam qualities inside the phantom as determined from an established Monte Carlo model of the scanner. The influence of the brief exposure to dimmed room light was evaluated and deemed negligible. Pairing between the OSL readings and measurement locations was ensured by the experimental design. The organ doses measured for a routine adult chest scan protocol ranged from 9.4 to 18.8 mGy, depending on the composition, location, and surrounding anatomy of the organs. The dose distribution across different slices of the phantom strongly depended on the z-axis mA modulation. In the same slice, doses to the soft tissues other than the spinal cord demonstrated relatively small variations, with the maximum COV around 11.4%. This might be attributed to the angular mA modulation, the placement of the dosimeters, the chest cavity of the scanned region, and the size of the phantom. Doses to the spinal cord were consistently lower than those to other soft tissues. The method is suited for acquiring densely sampled organ dose maps, and can be used for studying dose distributions relevant to subject size, organ location, and clinical CT protocols.

A method to acquire CT organ dose map using OSL dosimeters and ATOM anthropomorphic phantoms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Da; Li, Xinhua; Liu, Bob

Purpose: To present the design and procedure of an experimental method for acquiring densely sampled organ dose map for CT applications, based on optically stimulated luminescence (OSL) dosimeters “nanoDots” and standard ATOM anthropomorphic phantoms; and to provide the results of applying the method—a dose data set with good statistics for the comparison with Monte Carlo simulation result in the future.Methods: A standard ATOM phantom has densely located holes (in 3 × 3 cm or 1.5 × 1.5 cm grids), which are too small (5 mm in diameter) to host many types of dosimeters, including the nanoDots. The authors modified themore » conventional way in which nanoDots are used, by removing the OSL disks from the holders before inserting them inside a standard ATOM phantom for dose measurements. The authors solved three technical difficulties introduced by this modification: (1) energy dependent dose calibration for raw OSL readings; (2) influence of the brief background exposure of OSL disks to dimmed room light; (3) correct pairing between the dose readings and measurement locations. The authors acquired 100 dose measurements at various positions in the phantom, which was scanned using a clinical chest protocol with both angular and z-axis tube current modulations.Results: Dose calibration was performed according to the beam qualities inside the phantom as determined from an established Monte Carlo model of the scanner. The influence of the brief exposure to dimmed room light was evaluated and deemed negligible. Pairing between the OSL readings and measurement locations was ensured by the experimental design. The organ doses measured for a routine adult chest scan protocol ranged from 9.4 to 18.8 mGy, depending on the composition, location, and surrounding anatomy of the organs. The dose distribution across different slices of the phantom strongly depended on the z-axis mA modulation. In the same slice, doses to the soft tissues other than the spinal cord demonstrated relatively small variations, with the maximum COV around 11.4%. This might be attributed to the angular mA modulation, the placement of the dosimeters, the chest cavity of the scanned region, and the size of the phantom. Doses to the spinal cord were consistently lower than those to other soft tissues.Conclusions: The method is suited for acquiring densely sampled organ dose maps, and can be used for studying dose distributions relevant to subject size, organ location, and clinical CT protocols.« less

Excluding Anti-cytomegalovirus Immunoglobulin M-Positive Cord Blood Units Has a Minimal Impact on the Korean Public Cord Blood Bank Inventory

PubMed Central

Shin, Sue; Roh, Eun Youn; Oh, Sohee; Song, Eun Young; Kim, Eui Chong; Yoon, Jong Hyun

2017-01-01

Cord blood units (CBUs) for transplantation should be free of communicable disease and must contain a specific amount of total nucleated cells and CD34+ cells. Although posttransplantation cytomegalovirus (CMV) infections are from latent infection in patients, ensuring CMV-free CBUs by performing CMV-specific IgM and nucleic acid amplification testing (NAT) is one of the mandatory procedures for the safety of CBUs. However, the exclusion policies (based on these test results) vary among nations and institutions. We tested 28,000 processed CBUs between May 2006 and June 2014. The cord blood leukocytes from CMV IgM-positive samples were then subjected to NAT. The total nucleated cell and CD34+ cell counts were measured for each CBU, and the results were compared to the CMV IgM and IgG results. The seroprevalence of CMV among pregnant women was 98.1% (18,459/18,818) for IgG and 1.7% (441/25,293) for IgM. The concentration and the total number of CD34+ cells were significantly higher in CBUs from IgM-negative mothers compared to those from IgM-positive mothers (72.4/μl vs. 57.2/μl, respectively, p < 0.0001; 1.45 × 106/unit vs. 1.15 × 106/unit, respectively, p < 0.0001). Among CBUs with positive CMV IgM in their mothers' plasma or cord blood plasma, only 0.58% of the samples (3/517) had a positive NAT. The number of excluded CBUs from inventory due to positive CMV IgM in the cord blood was 54 of 18,326 (0.3%). For inventory purposes, it is appropriate to remove CBUs with positive cord blood CMV IgM findings irrespective of the NAT status as well as positive maternal CMV IgM in South Korea. PMID:27524276

Excluding Anti-cytomegalovirus Immunoglobulin M-Positive Cord Blood Units Has a Minimal Impact on the Korean Public Cord Blood Bank Inventory.

PubMed

Shin, Sue; Roh, Eun Youn; Oh, Sohee; Song, Eun Young; Kim, Eui Chong; Yoon, Jong Hyun

2017-01-24

Cord blood units (CBUs) for transplantation should be free of communicable disease and must contain a specific amount of total nucleated cells and CD34+ cells. Although posttransplantation cytomegalovirus (CMV) infections are from latent infection in patients, ensuring CMV-free CBUs by performing CMV-specific IgM and nucleic acid amplification testing (NAT) is one of the mandatory procedures for the safety of CBUs. However, the exclusion policies (based on these test results) vary among nations and institutions. We tested 28,000 processed CBUs between May 2006 and June 2014. The cord blood leukocytes from CMV IgM-positive samples were then subjected to NAT. The total nucleated cell and CD34+ cell counts were measured for each CBU, and the results were compared to the CMV IgM and IgG results. The seroprevalence of CMV among pregnant women was 98.1% (18,459/18,818) for IgG and 1.7% (441/25,293) for IgM. The concentration and the total number of CD34+ cells were significantly higher in CBUs from IgM-negative mothers compared to those from IgM-positive mothers (72.4/μl vs. 57.2/μl, respectively, p < 0.0001; 1.45 × 106/unit vs. 1.15 × 106/unit, respectively, p < 0.0001). Among CBUs with positive CMV IgM in their mothers' plasma or cord blood plasma, only 0.58% of the samples (3/517) had a positive NAT. The number of excluded CBUs from inventory due to positive CMV IgM in the cord blood was 54 of 18,326 (0.3%). For inventory purposes, it is appropriate to remove CBUs with positive cord blood CMV IgM findings irrespective of the NAT status as well as positive maternal CMV IgM in South Korea.

Intrathecal Drug Delivery and Spinal Cord Stimulation for the Treatment of Cancer Pain.

PubMed

Xing, Fangfang; Yong, R Jason; Kaye, Alan David; Urman, Richard D

2018-02-05

The purpose of the present investigation is to summarize the body and quality of evidence including the most recent studies in support of intrathecal drug delivery systems and spinal cord stimulation for the treatment of cancer-related pain. In the past 3 years, a number of prospective studies have been published supporting intrathecal drug delivery systems for cancer pain. Additional investigation with adjuvants to morphine-based analgesia including dexmedetomidine and ziconotide support drug-induced benefits of patient-controlled intrathecal analgesia. A study has also been recently published regarding cost-savings for intrathecal drug delivery system compared to pharmacologic management, but an analysis in the Ontario, Canada healthcare system projects additional financial costs. Finally, the Polyanalgesic Consensus Committee has updated its recommendations regarding clinical guidelines for intrathecal drug delivery systems to include new information on dosing, trialing, safety, and systemic opioid reduction. There is still a paucity of clinical evidence for spinal cord stimulation in the treatment of cancer pain. There are new intrathecal drugs under investigation including various conopeptides and AYX1. Large, prospective, modern, randomized controlled studies are still needed to support the use of both intrathecal drug delivery systems as well as spinal cord stimulation for cancer pain populations. There are multiple prospective and small randomized controlled studies that highlight a potential promising future for these interventional modalities. Related to the challenge and urgency of cancer pain, the pain practitioner community is moving toward a multimodal approach that includes discussions regarding the role of intrathecal therapies and spinal cord stimulation to the individualized treatment of patients.

Delayed Imatinib Treatment for Acute Spinal Cord Injury: Functional Recovery and Serum Biomarkers

PubMed Central

Finn, Anja; Hao, Jingxia; Wellfelt, Katrin; Josephson, Anna; Svensson, Camilla I.; Wiesenfeld-Hallin, Zsuzsanna; Eriksson, Ulf; Abrams, Mathew

2015-01-01

Abstract With no currently available drug treatment for spinal cord injury, there is a need for additional therapeutic candidates. We took the approach of repositioning existing pharmacological agents to serve as acute treatments for spinal cord injury and previously found imatinib to have positive effects on locomotor and bladder function in experimental spinal cord injury when administered immediately after the injury. However, for imatinib to have translational value, it needs to have sustained beneficial effects with delayed initiation of treatment, as well. Here, we show that imatinib improves hind limb locomotion and bladder recovery when initiation of treatment was delayed until 4 h after injury and that bladder function was improved with a delay of up to 24 h. The treatment did not induce hypersensitivity. Instead, imatinib-treated animals were generally less hypersensitive to either thermal or mechanical stimuli, compared with controls. In an effort to provide potential biomarkers, we found serum levels of three cytokines/chemokines—monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-3α, and keratinocyte chemoattractant/growth-regulated oncogene (interleukin 8)—to increase over time with imatinib treatment and to be significantly higher in injured imatinib-treated animals than in controls during the early treatment period. This correlated to macrophage activation and autofluorescence in lymphoid organs. At the site of injury in the spinal cord, macrophage activation was instead reduced by imatinib treatment. Our data strengthen the case for clinical trials of imatinib by showing that initiation of treatment can be delayed and by identifying serum cytokines that may serve as candidate markers of effective imatinib doses. PMID:25914996

West Nile virus infection among pregnant women in a northern Colorado community, 2003 to 2004.

PubMed

Paisley, Jan E; Hinckley, Alison F; O'Leary, Daniel R; Kramer, William C; Lanciotti, Robert S; Campbell, Grant L; Hayes, Edward B

2006-03-01

Since West Nile virus (WNV) was first detected in New York in 1999, it has spread across North America and become a major public health concern. In 2002, the first documented case of intrauterine WNV infection was reported, involving an infant with severe brain abnormalities. To determine the frequencies of WNV infections during pregnancy and of intrauterine WNV infections, we measured WNV-specific antibodies in cord blood from infant deliveries after a community-wide epidemic of WNV disease. Five hundred sixty-six pregnant women who presented to Poudre Valley Hospital (Fort Collins, CO) for delivery between September 2003 and May 2004 provided demographic and health history data through self-administered questionnaires and hospital admission records. Umbilical cord blood was collected from 549 infants and screened for WNV-specific IgM and IgG antibodies with enzyme-linked immunosorbent assays, with confirmation by plaque-reduction neutralization tests. Newborn growth parameters, Apgar scores, and hearing test results were recorded. Four percent (95% confidence interval: 2.4-5.7%) of cord blood samples tested positive for WNV-specific IgG antibodies. No cord blood samples were positive for WNV-specific IgM antibodies. There were no significant differences between infants of seropositive and seronegative mothers with respect to any of the growth parameters or outcomes measured. Intrauterine WNV infections seemed to be infrequent. In our study, WNV infection during pregnancy did not seem to affect adversely infant health at birth. Larger prospective studies are necessary to measure more completely the effects of maternal WNV infection on pregnancy and infant health outcomes.

A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury.

PubMed

Curtis, Erik; Martin, Joel R; Gabel, Brandon; Sidhu, Nikki; Rzesiewicz, Teresa K; Mandeville, Ross; Van Gorp, Sebastiaan; Leerink, Marjolein; Tadokoro, Takahiro; Marsala, Silvia; Jamieson, Catriona; Marsala, Martin; Ciacci, Joseph D

2018-06-01

We tested the feasibility and safety of human-spinal-cord-derived neural stem cell (NSI-566) transplantation for the treatment of chronic spinal cord injury (SCI). In this clinical trial, four subjects with T2-T12 SCI received treatment consisting of removal of spinal instrumentation, laminectomy, and durotomy, followed by six midline bilateral stereotactic injections of NSI-566 cells. All subjects tolerated the procedure well and there have been no serious adverse events to date (18-27 months post-grafting). In two subjects, one to two levels of neurological improvement were detected using ISNCSCI motor and sensory scores. Our results support the safety of NSI-566 transplantation into the SCI site and early signs of potential efficacy in three of the subjects warrant further exploration of NSI-566 cells in dose escalation studies. Despite these encouraging secondary data, we emphasize that this safety trial lacks statistical power or a control group needed to evaluate functional changes resulting from cell grafting. Copyright © 2018. Published by Elsevier Inc.

Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study.

PubMed

Weisse, K; Winkler, S; Hirche, F; Herberth, G; Hinz, D; Bauer, M; Röder, S; Rolle-Kampczyk, U; von Bergen, M; Olek, S; Sack, U; Richter, T; Diez, U; Borte, M; Stangl, G I; Lehmann, I

2013-02-01

Vitamin D levels are known to be associated with atopic disease development; however, existing data are controversial. The aim of this study was to investigate whether corresponding maternal and cord blood vitamin D levels are associated with atopic outcomes in early infancy. Within the LINA cohort study (Lifestyle and environmental factors and their Influence on Newborns Allergy risk), 25(OH)D was measured in blood samples of 378 mother-child pairs during pregnancy and at birth. Information about children's atopic manifestations during the first 2 years of life was obtained from questionnaires filled out by the parents during pregnancy and annually thereafter. Cord blood regulatory T cells (Treg) were detected by methylation-specific PCR using a Treg-specific demethylated region in the FOXP3 gene. The median maternal 25(OH)D(3) level was 22.19 ng/ml (IQR 14.40-31.19 ng/ml); the median cord blood 25(OH)D(3) 10.95 ng/ml (6.99-17.39 ng/ml). A high correlation was seen between maternal and cord blood 25(OH)D(3) levels, both showing a seasonal distribution. Maternal and cord blood 25(OH)D(3) was positively associated with children's risk for food allergy within the first 2 years. Further, higher maternal 25(OH)D(3) resulted in a higher risk for sensitization against food allergens at the age of two. Cord blood 25(OH)D(3) levels were negatively correlated with regulatory T cell numbers. Our study demonstrates that high vitamin D levels in pregnancy and at birth may contribute to a higher risk for food allergy and therefore argues against vitamin D supplement to protect against allergy. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Human spinal locomotor control is based on flexibly organized burst generators.

PubMed

Danner, Simon M; Hofstoetter, Ursula S; Freundl, Brigitta; Binder, Heinrich; Mayr, Winfried; Rattay, Frank; Minassian, Karen

2015-03-01

Constant drive provided to the human lumbar spinal cord by epidural electrical stimulation can cause local neural circuits to generate rhythmic motor outputs to lower limb muscles in people paralysed by spinal cord injury. Epidural spinal cord stimulation thus allows the study of spinal rhythm and pattern generating circuits without their configuration by volitional motor tasks or task-specific peripheral feedback. To reveal spinal locomotor control principles, we studied the repertoire of rhythmic patterns that can be generated by the functionally isolated human lumbar spinal cord, detected as electromyographic activity from the legs, and investigated basic temporal components shared across these patterns. Ten subjects with chronic, motor-complete spinal cord injury were studied. Surface electromyographic responses to lumbar spinal cord stimulation were collected from quadriceps, hamstrings, tibialis anterior, and triceps surae in the supine position. From these data, 10-s segments of rhythmic activity present in the four muscle groups of one limb were extracted. Such samples were found in seven subjects. Physiologically adequate cycle durations and relative extension- and flexion-phase durations similar to those needed for locomotion were generated. The multi-muscle activation patterns exhibited a variety of coactivation, mixed-synergy and locomotor-like configurations. Statistical decomposition of the electromyographic data across subjects, muscles and samples of rhythmic patterns identified three common temporal components, i.e. basic or shared activation patterns. Two of these basic patterns controlled muscles to contract either synchronously or alternatingly during extension- and flexion-like phases. The third basic pattern contributed to the observed muscle activities independently from these extensor- and flexor-related basic patterns. Each bifunctional muscle group was able to express both extensor- and flexor-patterns, with variable ratios across the samples of rhythmic patterns. The basic activation patterns can be interpreted as central drives implemented by spinal burst generators that impose specific spatiotemporally organized activation on the lumbosacral motor neuron pools. Our data thus imply that the human lumbar spinal cord circuits can form burst-generating elements that flexibly combine to obtain a wide range of locomotor outputs from a constant, repetitive input. It may be possible to use this flexibility to incorporate specific adaptations to gait and stance to improve locomotor control, even after severe central nervous system damage. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Human spinal locomotor control is based on flexibly organized burst generators

PubMed Central

Danner, Simon M.; Hofstoetter, Ursula S.; Freundl, Brigitta; Binder, Heinrich; Mayr, Winfried; Rattay, Frank

2015-01-01

Constant drive provided to the human lumbar spinal cord by epidural electrical stimulation can cause local neural circuits to generate rhythmic motor outputs to lower limb muscles in people paralysed by spinal cord injury. Epidural spinal cord stimulation thus allows the study of spinal rhythm and pattern generating circuits without their configuration by volitional motor tasks or task-specific peripheral feedback. To reveal spinal locomotor control principles, we studied the repertoire of rhythmic patterns that can be generated by the functionally isolated human lumbar spinal cord, detected as electromyographic activity from the legs, and investigated basic temporal components shared across these patterns. Ten subjects with chronic, motor-complete spinal cord injury were studied. Surface electromyographic responses to lumbar spinal cord stimulation were collected from quadriceps, hamstrings, tibialis anterior, and triceps surae in the supine position. From these data, 10-s segments of rhythmic activity present in the four muscle groups of one limb were extracted. Such samples were found in seven subjects. Physiologically adequate cycle durations and relative extension- and flexion-phase durations similar to those needed for locomotion were generated. The multi-muscle activation patterns exhibited a variety of coactivation, mixed-synergy and locomotor-like configurations. Statistical decomposition of the electromyographic data across subjects, muscles and samples of rhythmic patterns identified three common temporal components, i.e. basic or shared activation patterns. Two of these basic patterns controlled muscles to contract either synchronously or alternatingly during extension- and flexion-like phases. The third basic pattern contributed to the observed muscle activities independently from these extensor- and flexor-related basic patterns. Each bifunctional muscle group was able to express both extensor- and flexor-patterns, with variable ratios across the samples of rhythmic patterns. The basic activation patterns can be interpreted as central drives implemented by spinal burst generators that impose specific spatiotemporally organized activation on the lumbosacral motor neuron pools. Our data thus imply that the human lumbar spinal cord circuits can form burst-generating elements that flexibly combine to obtain a wide range of locomotor outputs from a constant, repetitive input. It may be possible to use this flexibility to incorporate specific adaptations to gait and stance to improve locomotor control, even after severe central nervous system damage. PMID:25582580

Examining the relationship between post-traumatic stress disorder and social participation among Veterans with spinal cord injuries and disorders.

PubMed

Etingen, Bella; Locatelli, Sara M; Miskevics, Scott; LaVela, Sherri L

2017-07-26

The objectives of this study were to examine differences in social participation among Veterans with spinal cord injuries/disorders with and without post-traumatic stress disorder, and determine if lower social participation was independently associated with having post-traumatic stress disorder. A cross-sectional mailed national survey was sent to a national sample of Veterans with spinal cord injuries/disorders who received prior-year Veterans Affairs healthcare. Surveys provided data on: demographics, health conditions, injury characteristics, and social participation. Analyses included bivariate comparisons, and multivariate logistic regression to determine if lower social participation was independently associated with post-traumatic stress disorder. Veterans with (vs. without) post-traumatic stress disorder (n = 896) reported lower social participation (40.2 vs. 43.9, p < 0.0001). Multivariate analyses showed that longer duration of injury (OR = 0.98, 95% CI: 0.97-1.00, p = 0.04) and white race (OR = 0.62, 95% CI: 0.38-1.01, p = 0.05) were associated with lower odds of post-traumatic stress disorder, while a greater number of health conditions (OR = 1.43, 95% CI: 1.25-1.64, p < 0.0001) was associated with greater odds. When controlling for covariates, lower social participation was independently associated with post-traumatic stress disorder (OR = 0.94, 95% CI: 0.90-0.98, p = 0.003). Results indicate post-traumatic stress disorder is associated with lower social participation in Veterans with spinal cord injuries/disorders, independent of other factors that may impact participation. Efforts to screen for and treat post-traumatic stress disorder among persons with spinal cord injuries/disorders, regardless of injury-specific factors, are needed to improve participation. Implications for Rehabilitation Individuals with spinal cord injuries/disorders often have post-traumatic stress disorder; in Veterans with spinal cord injuries/disorders this may be compounded by trauma incurred through military experiences. Social participation, an important aspect of rehabilitation and community integration following spinal cord injury or disorder, may be hindered by symptoms of post-traumatic stress disorder. Our data show that post-traumatic stress disorder is associated with lower social participation in Veterans with spinal cord injuries/disorders, independent of other factors that may impact participation. These results indicate that efforts to screen for and treat post-traumatic stress disorder among persons with spinal cord injuries/disorders, regardless of injury-specific factors, are needed to improve participation in this patient population.

Dosimetric evaluation of synthetic CT for magnetic resonance-only based radiotherapy planning of lung cancer.

PubMed

Wang, Hesheng; Chandarana, Hersh; Block, Kai Tobias; Vahle, Thomas; Fenchel, Matthias; Das, Indra J

2017-06-26

Interest in MR-only treatment planning for radiation therapy is growing rapidly with the emergence of integrated MRI/linear accelerator technology. The purpose of this study was to evaluate the feasibility of using synthetic CT images generated from conventional Dixon-based MRI scans for radiation treatment planning of lung cancer. Eleven patients who underwent whole-body PET/MR imaging following a PET/CT exam were randomly selected from an ongoing prospective IRB-approved study. Attenuation maps derived from the Dixon MR Images and atlas-based method was used to create CT data (synCT). Treatment planning for radiation treatment of lung cancer was optimized on the synCT and subsequently copied to the registered CT (planCT) for dose calculation. Planning target volumes (PTVs) with three sizes and four different locations in the lung were planned for irradiation. The dose-volume metrics comparison and 3D gamma analysis were performed to assess agreement between the synCT and CT calculated dose distributions. Mean differences between PTV doses on synCT and CT across all the plans were -0.1% ± 0.4%, 0.1% ± 0.5%, and 0.4% ± 0.5% for D95, D98 and D100, respectively. Difference in dose between the two datasets for organs at risk (OARs) had average differences of -0.14 ± 0.07 Gy, 0.0% ± 0.1%, and -0.1% ± 0.2% for maximum spinal cord, lung V20, and heart V40 respectively. In patient groups based on tumor size and location, no significant differences were observed in the PTV and OARs dose-volume metrics (p > 0.05), except for the maximum spinal-cord dose when the target volumes were located at the lung apex (p = 0.001). Gamma analysis revealed a pass rate of 99.3% ± 1.1% for 2%/2 mm (dose difference/distance to agreement) acceptance criteria in every plan. The synCT generated from Dixon-based MRI allows for dose calculation of comparable accuracy to the standard CT for lung cancer treatment planning. The dosimetric agreement between synCT and CT calculated doses warrants further development of a MR-only workflow for radiotherapy of lung cancer.

TH-CD-202-08: Feasibility Study of Planning Phase Optimization Using Patient Geometry-Driven Information for Better Dose Sparing of Organ at Risks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, S; Kim, D; Kim, T

2016-06-15

Purpose: To propose a simple and effective cost value function to search optimal planning phase (gating window) and demonstrated its feasibility for respiratory correlated radiation therapy. Methods: We acquired 4DCT of 10 phases for 10 lung patients who have tumor located near OARs such as esophagus, heart, and spinal cord (i.e., central lung cancer patients). A simplified mathematical optimization function was established by using overlap volume histogram (OVH) between the target and organ at risk (OAR) at each phase and the tolerance dose of selected OARs to achieve surrounding OARs dose-sparing. For all patients and all phases, delineation of themore » target volume and selected OARs (esophagus, heart, and spinal cord) was performed (by one observer to avoid inter-observer variation), then cost values were calculated for all phases. After the breathing phases were ranked according to cost value function, the relationship between score and dose distribution at highest and lowest cost value phases were evaluated by comparing the mean/max dose. Results: A simplified mathematical cost value function showed noticeable difference from phase to phase, implying it is possible to find optimal phases for gating window. The lowest cost value which may result in lower mean/max dose to OARs was distributed at various phases for all patients. The mean doses of the OARs significantly decreased about 10% with statistical significance for all 3 OARs at the phase with the lowest cost value. Also, the max doses of the OARs were decreased about 2∼5% at the phase with the lowest cost value compared to the phase with the highest cost value. Conclusion: It is demonstrated that optimal phases (in dose distribution perspective) for gating window could exist differently through each patient and the proposed cost value function can be a useful tool for determining such phases without performing dose optimization calculations. This research was supported by the Mid-career Researcher Program through NRF funded by the Ministry of Science, ICT & Future Planning of Korea (NRF-2014R1A2A1A10050270) and by the Radiation Technology R&D program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (No. 2013M2A2A7038291)« less

Frequency Mapping of Rat Spinal Cord at 7T

NASA Astrophysics Data System (ADS)

Chen, Evan; Rauscher, Alexander; Kozlowski, Piotr; Yung, Andrew

2012-10-01

The spinal cord is an integral part of the nervous system responsible for sensory, motor, and reflex control crucial to all bodily function. Due to its non-invasive nature, MRI is well matched for characterizing and imaging of spinal cord, and is used extensively for clinical applications. Recent developments in magnetic resonance imaging (MRI) at high field (7T) using phase represents a new approach of characterizing spinal cord myelin. Theory suggests that microstructure differences in myelinated white matter (WM) and non-myelinated gray matter (GM) affect MR phase, measurable frequency shifts. Data from pilot experiments using a multi-gradient echo (MGE) sequence to image rat spinal cords placed parallel to main magnetic field B0 has shown frequency shifts between not only between WM and GM, but also between specific WM tracts of the dorsal column, including the fasciculus gracilis, fasciculus cuneatus, and corticospinal tract. Using MGE, frequency maps at multiple echo times (TE) between 4ms and 22ms show a non-linear relationship between WM frequency, contrary to what was previously expected. These results demonstrate the effectiveness of MGE in revealing new information about spinal cord tissue microstructure, and lays important groundwork for in-vivo and human studies.

Motivating Cord Blood Donation with Information and Behavioral Nudges.

PubMed

Grieco, Daniela; Lacetera, Nicola; Macis, Mario; Di Martino, Daniela

2018-01-10

Umbilical cord blood is a source of hematopoietic stem cells essential to treat life-threatening diseases, such as leukemia and lymphoma. However, only a very small percentage of parents donate upon delivery. The decision to donate the cord blood occurs at a very specific time and when parents likely experience emotional, informational, and decisional overloads; these features of cord blood donation make it different from other pro-social activities. In collaboration with an OB-GYN clinic in Milan, Italy, we conducted the first randomized controlled trial that applies tools from behavioral science to foster cord blood donation, and quantified the gains that informational and behavioral "nudges" can achieve. We found that information and "soft" commitments increased donations; approaching expecting parents closer to the delivery date and providing them with multiple reminders, moreover, had the strongest impact. However, a significant portion of women who expressed consent to donate could not do so because of organizational constraints. We conclude that simple, non-invasive behavioral interventions that address information gaps and procrastination, and that increase the salience of the activity can substantially enhance altruistic donations of cord blood, especially when coupled with organizational support.

Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity

PubMed Central

D'Amico, Jessica M.; Condliffe, Elizabeth G.; Martins, Karen J. B.; Bennett, David J.; Gorassini, Monica A.

2014-01-01

The state of areflexia and muscle weakness that immediately follows a spinal cord injury (SCI) is gradually replaced by the recovery of neuronal and network excitability, leading to both improvements in residual motor function and the development of spasticity. In this review we summarize recent animal and human studies that describe how motoneurons and their activation by sensory pathways become hyperexcitable to compensate for the reduction of functional activation of the spinal cord and the eventual impact on the muscle. Specifically, decreases in the inhibitory control of sensory transmission and increases in intrinsic motoneuron excitability are described. We present the idea that replacing lost patterned activation of the spinal cord by activating synaptic inputs via assisted movements, pharmacology or electrical stimulation may help to recover lost spinal inhibition. This may lead to a reduction of uncontrolled activation of the spinal cord and thus, improve its controlled activation by synaptic inputs to ultimately normalize circuit function. Increasing the excitation of the spinal cord with spared descending and/or peripheral inputs by facilitating movement, instead of suppressing it pharmacologically, may provide the best avenue to improve residual motor function and manage spasticity after SCI. PMID:24860447

Supplementation of docosahexaenoic acid (DHA) / Eicosapentaenoic acid (EPA) in a ratio of 1/1.3 during the last trimester of pregnancy results in EPA accumulation in cord blood.

PubMed

Büyükuslu, Nihal; Ovalı, Sema; Altuntaş, Şükriye Leyla; Batırel, Saime; Yiğit, Pakize; Garipağaoğlu, Muazzez

2017-10-01

Omega-3 fatty acids (n-3 FA), specifically DHA, are associated with fetal growth and development. We aimed to determine the levels of DHA and EPA in cord serum after n-3 FA supplementation during the last trimester of pregnancy. Among 55 women, 23 were administered daily one capsule of n-3 FA supplement, involving DHA/EPA in a ratio of 1/1.3. Twenty nine women were enrolled as control group. Blood samples were collected at 22-24 weeks of gestation and at delivery. Fatty acids were analyzed with the method of GC-MS. Cord DHA level increased and EPA level decreased in both groups between the days of 22-24 and delivery. However, decrease in cord EPA level was significant in control group (p < 0.001) but not in supplement group (p > 0.05). Supplementation of DHA/EPA in a ratio of 1/1.3 during the last trimester of pregnancy caused higher cord EPA level compared to control group indicating an accumulation in umbilical cord. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interstitial ultrasound ablation of tumors within or adjacent to bone: Contributions of preferential heating at the bone surface

NASA Astrophysics Data System (ADS)

Scott, Serena J.; Prakash, Punit; Salgaonkar, Vasant; Jones, Peter D.; Cam, Richard N.; Han, Misung; Rieke, Viola; Burdette, E. Clif; Diederich, Chris J.

2013-02-01

Preferential heating of bone due to high ultrasound attenuation may enhance thermal ablation performed with cathetercooled interstitial ultrasound applicators in or near bone. At the same time, thermally and acoustically insulating cortical bone may protect sensitive structures nearby. 3D acoustic and biothermal transient finite element models were developed to simulate temperature and thermal dose distributions during catheter-cooled interstitial ultrasound ablation near bone. Experiments in ex vivo tissues and tissue-mimicking phantoms were performed to validate the models and to quantify the temperature profiles and ablated volumes for various distances between the interstitial applicator and the bone surface. 3D patient-specific models selected to bracket the range of clinical usage were developed to investigate what types of tumors could be treated, applicator configurations, insertion paths, safety margins, and other parameters. Experiments show that preferential heating at the bone surface decreases treatment times compared to when bone is absent and that all tissue between an applicator and bone can be ablated when they are up to 2 cm apart. Simulations indicate that a 5-7 mm safety margin of normal bone is needed to protect (thermal dose < 6 CEM43°C and T < 45°C) sensitive structures behind ablated bone. In 3D patient-specific simulations, tumors 1.0-3.8 cm (L) and 1.3-3.0 cm (D) near or within bone were ablated (thermal dose > 240 CEM43°C) within 10 min without damaging the nearby spinal cord, lungs, esophagus, trachea, or major vasculature. Preferential absorption of ultrasound by bone may provide improved localization, faster treatment times, and larger treatment zones in tumors in and near bone compared to other heating modalities.

Cord blood clinical processing, cryopreservation, and storage.

PubMed

Elmoazzen, Heidi; Holovati, Jelena L

2015-01-01

Allogeneic umbilical cord blood (UCB) hematopoietic stem cell transplantation has become a crucial advancement in the treatment for a variety of diseases including hematopoietic and non-hematopoietic malignancies, BM failure syndromes, hemoglobinopathies, and metabolic and immunodeficiency disorders. It has been well documented that the success of UCB engraftment is tied to UCB banking processes, and now there are established guidelines for standardization of collection, banking, processing, and cryopreservation for unrelated UCB units with purpose of achieving consistent production of high quality placental and UCB units for administration. In 2011, Canada's Ministry of Health has announced Canada's first national, publicly funded umbilical cord blood bank, which aims to provide altruistic donations for unrelated allogeneic hematopoietic stem cell transplant. In this chapter, we describe specific protocols for clinical processing, cryopreservation, and storage of UCB used by the Canadian Blood Services National Public Umbilical Cord Blood Bank.

Why do four NICUs using identical RBC transfusion guidelines have different gestational age-adjusted RBC transfusion rates?

PubMed

Henry, E; Christensen, R D; Sheffield, M J; Eggert, L D; Carroll, P D; Minton, S D; Lambert, D K; Ilstrup, S J

2015-02-01

To compare neonatal red blood cell (RBC) transfusion rates in four large Intermountain Healthcare NICUs, all of which adhere to the same RBC transfusion guidelines. This retrospective analysis was part of a transfusion-management quality-improvement project. De-identified data included RBC transfusions, clinical and laboratory findings, the anemia-prevention strategies in place in each NICU, and specific costs and outcomes. Of 2389 NICU RBC transfusions given during the 4-year period studied, 98.9 ± 2.1% (mean ± S.D.) were compliant with our transfusion guidelines, with no difference in compliance between any of the four NICUs. However, RBC transfusion rates varied widely between the four, with averages ranging from 4.6 transfusions/1000 NICU days to 21.7/1000 NICU days (P < 0.00001). Gestational age-adjusted transfusion rates were correspondingly discordant (P < 0.00001). The lower-transfusing NICUs had written anemia-preventing guidelines, such as umbilical cord milking at very low birth weight delivery, use of cord blood for admission laboratory studies, and darbepoetin dosing for selected neonates. Rates of Bell stage ⩾ 2 necrotizing enterocolitis and grade ⩾ 3 intraventricular hemorrhage were lowest in the two lower-transfusing NICUs (P < 0.0002 and P < 0.0016). Average pharmacy costs for darbepoetin were $84/dose, with an average pharmacy cost of $269 per transfusion averted. With a cost of $900/RBC transfusion, the anemia-preventing strategies resulted in an estimated cost savings to Intermountain Healthcare of about $6970 per 1000 NICU days, or about $282,300 annually. Using transfusion guidelines has been shown previously to reduce practice variability, lower transfusion rates and diminish transfusion costs. Based on our present findings, we maintain that even when transfusion guidelines are in place and adhered to rigorously, RBC transfusion rates are reduced further if anemia-preventing strategies are also in place.

Intraluminal radiation for esophageal cancer: a Howard University technique.

PubMed

Moorthy, C R; Nibhanupudy, J R; Ashayeri, E; Goldson, A L; Espinoza, M C; Nidiry, J J; Warner, O G; Roux, V J

1982-03-01

The objective of radiotherapeutic management in esophageal cancer is to accomplish maximum tumor sterilization with minimal normal tissue damage. This sincere effort is most often countered by the differential in tumor dose response vs normal tissue tolerance. Intraluminal isotope radiation, with its inherent advantage of rapid dose falloff, spares the lungs, the spinal cord, and other vital structures, yet yields adequately high doses to esophageal tumor. Though in existence since the turn of the century, the method of intracavitary radium bougie application dropped out of favor due to technical difficulties imposed by the size of the radium source and radiation exposure to the personnel involved. The authors describe a simple "iridium 192 afterloading intraluminal technique" that eliminates technical problems and reduces radiation exposure considerably.

The excitatory amino acid receptor antagonist MK-801 prevents the hypersensitivity induced by spinal cord ischemia in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hao, J.X.; Xu, X.J.; Aldskogius, H.

1991-08-01

Protection by the NMDA receptor antagonist MK-801 against transient spinal cord ischemia-induced hypersensitivity was studied in rats. The spinal ischemia was initiated by vascular occlusion resulting from the interaction between the photosensitizing dye Erythrosin B and an argon laser beam. The hypersensitivity, termed allodynia, where the animals reacted by vocalization to nonnoxious mechanical stimuli in the flank area, was consistently observed during several days after induction of the ischemia. Pretreatment with MK-801 (0.1-0.5 mg/kg, iv) 10 min before laser irradiation dose dependently prevented the occurrence of allodynia. The neuroprotective effect of MK-801 was not reduced by maintaining normal body temperaturemore » during and after irradiation. There was a significant negative correlation between the delay in the administration of MK-801 after irradiation and the protective effect of the drug. Histological examination revealed slight morphological damage in the spinal cord in 38% of control rats after 1 min of laser irradiation without pretreatment with MK-801. No morphological abnormalities were observed in rats after pretreatment with MK-801 (0.5 mg/kg). The present results provide further evidence for the involvement of excitatory amino acids, through activation of the NMDA receptor, in the development of dysfunction following ischemic trauma to the spinal cord.« less

The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice

PubMed Central

Almad, Akshata; Lash, A. Todd; Wei, Ping; Lovett-Racke, Amy E.; McTigue, Dana M.

2017-01-01

Peroxisome Proliferator Activated Receptor (PPAR)-α is a key regulator of lipid metabolism and recent studies reveal it also regulates inflammation in several different disease models. Gemfibrozil, an agonist of PPAR-α, is a FDA approved drug for hyperlipidemia and has been shown to inhibit clinical signs in a rodent model of multiple sclerosis. Since many studies have shown improved outcome from spinal cord injury (SCI) by anti-inflammatory and neuroprotective agents, we tested the efficacy of oral gemfibrozil given before or after SCI for promoting tissue preservation and behavioral recovery after spinal contusion injury in mice. Unfortunately, the results were contrary to our hypothesis; in our first attempt, gemfibrozil treatment exacerbated locomotor deficits and increased tissue pathology after SCI. In subsequent experiments, the behavioral effects were not replicated but histological outcomes again were worse. We also tested the efficacy of a different PPAR-α agonist, fenofibrate, which also modulates immune responses and is beneficial in several neurodegenerative disease models. Fenofibrate treatment did not improve recovery, although there was a slight trend for a modest increase in histological tissue sparing. Based on our results, we conclude that PPAR-α agonists yield either no effect or worsen recovery from spinal cord injury, at least at the doses and the time points of drug delivery tested here. Further, patients sustaining spinal cord injury while taking gemfibrozil might be prone to exacerbated tissue damage. PMID:21963672

Dosimetric evaluation of the feasibility of stereotactic body radiotherapy for primary lung cancer with lobe-specific selective elective nodal irradiation.

PubMed

Komatsu, Tetsuya; Kunieda, Etsuo; Kitahara, Tadashi; Akiba, Takeshi; Nagao, Ryuta; Fukuzawa, Tsuyoshi

2016-01-01

More than 10% of all patients treated with stereotactic body radiotherapy (SBRT) for primary lung cancer develop regional lymph node recurrence. We evaluated the dosimetric feasibility of SBRT with lobe-specific selective elective nodal irradiation (ENI) on dose-volume histograms. A total of 21 patients were treated with SBRT for Stage I primary lung cancer between January 2010 and June 2012 at our institution. The extents of lobe-specific selective ENI fields were determined with reference to prior surgical reports. The ENI fields included lymph node stations (LNS) 3 + 4 + 11 for the right upper lobe tumors, LNS 7 + 11 for the right middle or lower lobe tumors, LNS 5 + 11 for the left upper lobe tumors, and LNS 7 + 11 for the left lower lobe tumors. A composite plan was generated by combining the ENI plan and the SBRT plan and recalculating for biologically equivalent doses of 2 Gy per fraction, using a linear quadratic model. The V20 of the lung, D(1cm3) of the spinal cord, D(1cm3) and D(10cm3) of the esophagus and D(10cm3) of the tracheobronchial wall were evaluated. Of the 21 patients, nine patients (43%) could not fulfill the dose constraints. In all these patients, the distance between the planning target volume (PTV) of ENI (PTVeni) and the PTV of SBRT (PTVsrt) was ≤2.0 cm. Of the three patients who developed regional metastasis, two patients had isolated lymph node failure, and the lymph node metastasis was included within the ENI field. When the distance between the PTVeni and PTVsrt is >2.0 cm, SBRT with selective ENI may therefore dosimetrically feasible. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

The Glycine Synaptic Receptor: Evidence That Strychnine Binding Is Associated with the Ionic Conductance Mechanism

PubMed Central

Young, Anne B.; Snyder, Solomon H.

1974-01-01

The ability of a series of anions to inhibit [3H]strychnine binding to spinal cord synaptic membranes correlates closely with their neurophysiologic capacity to reverse inhibitory postsynaptic potentials in the mammalian spinal cord. Seven neurophysiologically active anions are also effective inhibitors of [3H]strychnine binding with mean effective doses ranging from 160 to 620 mM. Seven other anions that are ineffective neurophysiologically also fail to alter strychnine binding. Chloride inhibits strychnine binding in a noncompetitive fashion. Hill plots of the displacement of [3H]strychnine by chloride give coefficients of 2.3-2.7. The inhibition of strychnine binding by these anions suggests that strychnine binding is closely associated with the ionic conductance mechanism for chloride in the glycine receptor. PMID:4372600

Intrathecal oxotremorine affects formalin-induced behavior and spinal nitric oxide synthase immunoreactivity in rats.

PubMed

Przewlocka, B; Mika, J; Capone, F; Machelska, H; Pavone, F

1999-03-01

The present research was undertaken to investigate, by behavioral and immunohistochemical methods, the effects of intrathecal (i.th.) injection of the muscarinic agonist oxotremorine on the response to the long-lasting nociceptive stimulus induced by injection of formalin into the rat hind paw. Formalin injection induced a biphasic, pain-induced behavioral response (paw jerks), as well as an increase in the number of nitric oxide (NO) synthase-labeled neurons in laminae I-III, IV, and X, but not in laminae V-VI. Oxotremorine (0.1-10 ng, i.th.) inhibited paw-jerk frequency in both phases of formalin-induced behavior. The immunohistochemical results showed that i.th.-injected oxotremorine differently affected the level of NO synthase in lumbar part of the spinal cord: no change or increase after the dose of 1 ng, and a significant reduction of nitric oxide synthase neurons after the higher dose (10 ng). These results evidenced a role of cholinergic system in the modulation of tonic pain and in nitric oxide synthase expression at the spinal cord level, which further suggests that these two systems could be involved in phenomena induced by long-lasting nociceptive stimulation.

Simultaneous isolation of vascular endothelial cells and mesenchymal stem cells from the human umbilical cord.

PubMed

Kadam, Sachin S; Tiwari, Shubha; Bhonde, Ramesh R

2009-01-01

The umbilical cord represents the link between mother and fetus during pregnancy. This cord is usually discarded as a biological waste after the child's birth; however, its importance as a "store house" of stem cells has been explored recently. We developed a method of simultaneous isolation of endothelial cells (ECs) from the vein and mesenchymal stem cells from umbilical cord Wharton's jelly of the same cord. The isolation protocol has been simplified, modified, and improvised with respect to choice of enzyme and enzyme mixture, digestion time, cell yield, cell growth, and culture medium. Isolated human umbilical vascular ECs (hUVECs) were positive for von-Willibrand factor, a classical endothelial marker, and could form capillary-like structures when seeded on Matrigel, thus proving their functionality. The isolated human umbilical cord mesenchymal stem cells (hUCMSCs) were found positive for CD44, CD90, CD 73, and CD117 and were found negative for CD33, CD34, CD45, and CD105 surface markers; they were also positive for cytoskeleton markers of smooth muscle actin and vimentin. The hUCMSCs showed multilineage differentiation potential and differentiated into adipogenic, chondrogenic, osteogenic, and neuronal lineages under influence of lineage specific differentiation medium. Thus, isolating endothelial cells as well as mesenchymal cells from the same umbilical cord could lead to complete utilization of the available tissue for the tissue engineering and cell therapy.

Dosimetric Factors and Toxicity in Highly Conformal Thoracic Reirradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Binkley, Michael S.; Hiniker, Susan M.; Chaudhuri, Aadel

Purpose: We determined cumulative dose to critical structures, rates of toxicity, and outcomes following thoracic reirradiation. Methods and Materials: We retrospectively reviewed our institutional database for patients treated between 2008 and 2014, who received thoracic reirradiation with overlap of 25% prescribed isodose lines. Patients received courses of hyperfractionated (n=5), hypofractionated (n=5), conventionally fractionated (n=21), or stereotactic ablative radiation therapy (n=51). Doses to critical structures were converted to biologically effective dose, expressed as 2 Gy per fraction equivalent dose (EQD2; α/β = 2 for spinal cord; α/β = 3 for other critical structures). Results: We identified 82 courses (44 for retreatment) in 38 patients reirradiated atmore » a median 16 months (range: 1-71 months) following initial RT. Median follow-up was 17 months (range: 3-57 months). Twelve- and 24-month overall survival rates were 79.6% and 57.3%, respectively. Eighteen patients received reirradiation for locoregionally recurrent non-small cell lung cancer with 12-month rates of local failure and regional recurrence and distant metastases rates of 13.5%, 8.1%, and 15.6%, respectively. Critical structures receiving ≥75 Gy EQD2 included spinal cord (1 cm{sup 3}; n=1), esophagus (1 cm{sup 3}; n=10), trachea (1 cm{sup 3}; n=11), heart (1 cm{sup 3}; n=9), aorta (1 cm{sup 3}; n=16), superior vena cava (1 cm{sup 3}; n=12), brachial plexus (0.2 cm{sup 3}; n=2), vagus nerve (0.2 cm{sup 3}; n=7), sympathetic trunk (0.2 cm{sup 3}; n=4), chest wall (30 cm{sup 3}; n=12), and proximal bronchial tree (1 cm{sup 3}; n=17). Cumulative dose-volume (D cm{sup 3}) toxicity following reirradiation data included esophagitis grade ≥2 (n=3, D1 cm{sup 3} range: 41.0-100.6 Gy), chest wall grade ≥2 (n=4; D30 cm{sup 3} range: 35.0-117.2 Gy), lung grade 2 (n=7; V20{sub combined-lung} range: 4.7%-21.7%), vocal cord paralysis (n=2; vagus nerve D0.2 cm{sup 3} range: 207.5-302.2 Gy), brachial plexopathy (n=1; D0.2 cm{sup 3} = 242.5 Gy), and Horner's syndrome (n=1; sympathetic trunk D0.2 cm{sup 3} = 130.8 Gy). No grade ≥4 toxicity was observed. Conclusions: Overlapping courses of reirradiation can be safely delivered with acceptable toxicity. Some toxicities occurred acutely at doses considered safe for a single course of therapy (esophagus). We observed rib fracture, brachial plexopathy, and Horner's syndrome for patients receiving high cumulative doses to corresponding critical structures.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Besemer, A; Marsh, I; Bednarz, B

Purpose: The calculation of 3D internal dose calculations in targeted radionuclide therapy requires the acquisition and temporal coregistration of a serial PET/CT or SPECT/CT images. This work investigates the dosimetric impact of different temporal coregistration methods commonly used for 3D internal dosimetry. Methods: PET/CT images of four mice were acquired at 1, 24, 48, 72, 96, 144 hrs post-injection of {sup 124}I-CLR1404. The therapeutic {sup 131}I-CLR1404 absorbed dose rate (ADR) was calculated at each time point using a Geant4-based MC dosimetry platform using three temporal image coregistration Methods: (1) no coregistration (NC), whole body sequential CT-CT affine coregistration (WBAC), andmore » individual sequential ROI-ROI affine coregistration (IRAC). For NC, only the ROI mean ADR was integrated to obtain ROI mean doses. For WBAC, the CT at each time point was coregistered to a single reference CT. The CT transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the whole CT volume. For IRAC, each individual ROI was isolated and sequentially coregistered to a single reference ROI. The ROI transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the ROI volumes. Results: The percent differences in the ROI mean doses were as large as 109%, 88%, and 32%, comparing the WBAC vs. IRAC, NC vs. IRAC, and NC vs. WBAC methods, respectively. The CoV in the mean dose between the all three methods ranged from 2–36%. The pronounced curvature of the spinal cord was not adequately coregistered using WBAC which resulted in large difference between the WBAC and IRAC. Conclusion: The method used for temporal image coregistration can result in large differences in 3D internal dosimetry calculations. Care must be taken to choose the most appropriate method depending on the imaging conditions, clinical site, and specific application. This work is partially funded by NIH Grant R21 CA198392-01.« less

Design and implementation of a head-and-neck phantom for system audit and verification of intensity-modulated radiation therapy.

PubMed

Webster, Gareth J; Hardy, Mark J; Rowbottom, Carl G; Mackay, Ranald I

2008-04-16

The head and neck is a challenging anatomic site for intensity-modulated radiation therapy (IMRT), requiring thorough testing of planning and treatment delivery systems. Ideally, the phantoms used should be anatomically realistic, have radiologic properties identical to those of the tissues concerned, and allow for the use of a variety of devices to verify dose and dose distribution in any target or normaltissue structure. A phantom that approaches the foregoing characteristics has been designed and built; its specific purpose is verification for IMRT treatments in the head-andneck region. This semi-anatomic phantom, HANK, is constructed of Perspex (Imperial Chemical Industries, London, U.K.) and provides for the insertion of heterogeneities simulating air cavities in a range of fixed positions. Chamber inserts are manufactured to incorporate either a standard thimble ionization chamber (0.125 cm3: PTW, Freiburg, Germany) or a smaller PinPoint chamber (0.015 cm3: PTW), and measurements can be made with either chamber in a range of positions throughout the phantom. Coronal films can also be acquired within the phantom, and additional solid blocks of Perspex allow for transverse films to be acquired within the head region. Initial studies using simple conventional head-and-neck plans established the reproducibility of the phantom and the measurement devices to within the setup uncertainty of +/- 0.5 mm. Subsequent verification of 9 clinical head-and-neck IMRT plans demonstrated the efficacy of the phantom in making a range of patient-specific dose measurements in regions of dosimetric and clinical interest. Agreement between measured values and those predicted by the Pinnacle3 treatment planning system (Philips Medical Systems, Andover, MA) was found to be generally good, with a mean error on the calculated dose to each point of +0.2% (range: -4.3% to +2.2%; n = 9) for the primary planning target volume (PTV), -0.1% (range: -1.5% to +2.0%; n = 8) for the nodal PTV, and +0.0% (range: -1.8% to +4.3%, n = 9) for the spinal cord. The suitability of the phantom for measuring combined dose distributions using radiographic film was also evaluated. The phantom has proved to be a valuable tool in the development and implementation of clinical head-and-neck IMRT, allowing for accurate verification of absolute dose and dose distributions in regions of clinical and dosimetric interest.

SU-E-T-365: Dosimetric Impact of Dental Amalgam CT Image Artifacts On IMRT and VMAT Head and Neck Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cao, N; Young, L; Parvathaneni, U

Purpose: The presence of high density dental amalgam in patient CT image data sets causes dose calculation errors for head and neck (HN) treatment planning. This study assesses and compares dosimetric variations in IMRT and VMAT treatment plans due to dental artifacts. Methods: Sixteen HN patients with similar treatment sites (oropharynx), tumor volume and extensive dental artifacts were divided into two groups: IMRT (n=8, 6 to 9 beams) and VMAT (n=8, 2 arcs with 352° rotation). All cases were planned with the Pinnacle 9.2 treatment planning software using the collapsed cone convolution superposition algorithm and a range of prescription dosemore » from 60 to 72Gy. Two different treatment plans were produced, each based on one of two image sets: (a)uncorrected; (b)dental artifacts density overridden (set to 1.0g/cm{sup 3}). Differences between the two treatment plans for each of the IMRT and VMAT techniques were quantified by the following dosimetric parameters: maximum point dose, maximum spinal cord and brainstem dose, mean left and right parotid dose, and PTV coverage (V95%Rx). Average differences generated for these dosimetric parameters were compared between IMRT and VMAT plans. Results: The average absolute dose differences (plan a minus plan b) for the VMAT and IMRT techniques, respectively, caused by dental artifacts were: 2.2±3.3cGy vs. 37.6±57.5cGy (maximum point dose, P=0.15); 1.2±0.9cGy vs. 7.9±6.7cGy (maximum spinal cord dose, P=0.026); 2.2±2.4cGy vs. 12.1±13.0cGy (maximum brainstem dose, P=0.077); 0.9±1.1cGy vs. 4.1±3.5cGy (mean left parotid dose, P=0.038); 0.9±0.8cGy vs. 7.8±11.9cGy (mean right parotid dose, P=0.136); 0.021%±0.014% vs. 0.803%±1.44% (PTV coverage, P=0.17). Conclusion: For the HN plans studied, dental artifacts demonstrated a greater dose calculation error for IMRT plans compared to VMAT plans. Rotational arcs appear on the average to compensate dose calculation errors induced by dental artifacts. Thus, compared to VMAT, density overrides for dental artifacts are more important when planning IMRT of HN.« less

Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling.

PubMed

Largent-Milnes, Tally M; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H; Vanderah, Todd W

2008-08-01

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in mu-opioid receptor (MOR)-G protein coupling from G(i/o) to G(s) that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L(5)/L(6) spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G(s) in the damaged (ipsilateral) spinal dorsal horn. This MOR-G(s) coupling occurred without changing G(i/o) coupling levels and without changing the expression of MOR or Galpha proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G(s) coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G(s) coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G(s) coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G(s) coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. The current study investigates whether Oxytrex (oxycodone with an ultra-low dose of naltrexone) alleviates mechanical and thermal hypersensitivities in an animal model of neuropathic pain over a period of 7 days, given locally or systemically. In this report, we first describe an injury-induced shift in mu-opioid receptor coupling from G(i/o) to G(s), suggesting why a mu-opioid agonist may have reduced efficacy in the nerve-injured state. These data present a novel approach to neuropathic pain therapy.

Monitoring Dosimetric Impact of Weight Loss With Kilovoltage (KV) Cone Beam CT (CBCT) During Parotid-Sparing IMRT and Concurrent Chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ho, Kean Fatt, E-mail: hokeanfatt@hotmail.com; Marchant, Tom; Moore, Chris

2012-03-01

Purpose: Parotid-sparing head-and-neck intensity-modulated radiotherapy (IMRT) can reduce long-term xerostomia. However, patients frequently experience weight loss and tumor shrinkage during treatment. We evaluate the use of kilovoltage (kV) cone beam computed tomography (CBCT) for dose monitoring and examine if the dosimetric impact of such changes on the parotid and critical neural structures warrants replanning during treatment. Methods and materials: Ten patients with locally advanced oropharyngeal cancer were treated with contralateral parotid-sparing IMRT concurrently with platinum-based chemotherapy. Mean doses of 65 Gy and 54 Gy were delivered to clinical target volume (CTV)1 and CTV2, respectively, in 30 daily fractions. CBCT wasmore » prospectively acquired weekly. Each CBCT was coregistered with the planned isocenter. The spinal cord, brainstem, parotids, larynx, and oral cavity were outlined on each CBCT. Dose distributions were recalculated on the CBCT after correcting the gray scale to provide accurate Hounsfield calibration, using the original IMRT plan configuration. Results: Planned contralateral parotid mean doses were not significantly different to those delivered during treatment (p > 0.1). Ipsilateral and contralateral parotids showed a mean reduction in volume of 29.7% and 28.4%, respectively. There was no significant difference between planned and delivered maximum dose to the brainstem (p = 0.6) or spinal cord (p = 0.2), mean dose to larynx (p = 0.5) and oral cavity (p = 0.8). End-of-treatment mean weight loss was 7.5 kg (8.8% of baseline weight). Despite a {>=}10% weight loss in 5 patients, there was no significant dosimetric change affecting the contralateral parotid and neural structures. Conclusions: Although patient weight loss and parotid volume shrinkage was observed, overall, there was no significant excess dose to the organs at risk. No replanning was felt necessary for this patient cohort, but a larger patient sample will be investigated to further confirm these results. Nevertheless, kilovoltage CBCT is a valuable tool for patient setup verification and monitoring of dosimetric variation during radiotherapy.« less

SU-E-T-575: To Analyze the Clinical Impact of Esophageal Sparing on Treatment Plans for Patients with Grade 3 Esophagitis.

PubMed

Niedzielski, J; Bluett, J; Williamson, R; Liao, Z; Gomez, D; Court, L

2012-06-01

To analyze the clinical impact of esophageal sparing on treatment plans for patients with grade 3 esophagitis. The treatment plans of 8 patients (project total: 20 patients) who were treated with IMRT and exhibited stage 3 esophagitis were re-planned to give a simulated clinical plan with dose distribution that mirrored our current clinical practice (74Gy to the target, and 5mm margins), and a plan that emphasized esophageal sparing. Doses to the esophagus, heart, cord, lung and PTV were compared. Comparing the esophageal sparing plan to the simulated clinical plan, the mean reduction in esophageal volume receiving 50, 55, 60, 65, and 70Gy were 2.0, 3.2, 5.0, 7.2, and 10.9 cm 3 , respectively. The mean reduction in the continuous length of esophagus receiving 50, 55, 60, 65, and 70Gy were 12, 24, 38, 40, and 47mm, respectively. The associated reduction in dose to 90% and 95% of the PTV was 2.2 and 3.8Gy, respectively. Of the 8 patients examined, 2 showed a significant decrease in PTV coverage (4.6Gy, 12.3Gy for 90% of PTV), 4 showed decreases under 1.1Gy, but 2 showed an increase of 1.4Gy and 0.5Gy for 90% PTV. Cord dose was maintained below 50Gy, and there was a slight increase in mean heart dose and mean lung dose of 2.4Gy, and 2.7Gy, respectively. Data will also be presented comparing these plans with the actual treated plans (for which the patients had grade 3 esophagitis) and plans that emphasize PTV coverage. Treatment planning to emphasize esophageal sparing can reduce the volume and continuous length of the esophagus which receives high doses. There is some associated modest reduction in PTV coverage. In summary, in many cases esophageal sparing can be accomplished for lung cancer cases while maintaining adequate PTV coverage, although there is variability between patients. © 2012 American Association of Physicists in Medicine.

SU-E-T-625: Potential for Reduced Radiation Induced Toxicity for the Treatment of Inoperable Non-Small-Cell Lung Cancer Using RapidArc Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, D; Sood, S; Badkul, R

2015-06-15

Purpose: To investigate the feasibility of using RapidArc (RA) treatment planning to reduce irradiation volume of normal lung and other organs at risk (OARs) in the treatment of inoperable non-small-cell lung cancer (NSCLC) patients. Methods: A retrospective treatment planning and delivery study was performed to compare target coverage and the volumes of the normal lung, spinal cord, heart and esophagus on 4D-CT scan above their dose tolerances delivered by RA vs. IMRT for ten inoperable NSCLC patients (Stage I-IIIB). RA plans consisted of either one-full or two-partial co-planar arcs used to treat 95% of the planning target volume (PTV) withmore » 6MV beam to a prescription of 66Gy in 33 fractions. IMRT plans were generated using 5–7 co-planar fields with 6MV beam. PTV coverage, dose-volume histograms, homogeneity/conformity indices (CI), total number of monitor units(MUs), beam-on time and delivery accuracy were compared between the two treatment plans. Results: Similar target coverage was obtained between the two techniques. RA (CI=1.02) provided more conformal plans without loss of homogeneity compared to IMRT plans (CI=1.12). Compared to IMRT, RA achieved a significant median dose reduction in V10 (3%), V20 (8%), and mean lung dose (3%) on average, respectively. On average, V5 was comparable between the two treatment plans. RA reduced mean esophagus (6%), mean heart (18%), and maximum spinal cord dose (7%), on average, respectively. Total number of MUs and beam-on time were each reduced almost by a factor of 2 when compared to IMRT-patient comfort, reduced intra-fraction-motion and leakage dose. The average IMRT and RA QA pass rate was about 98% for both types of plans for 3%/3mm criterion. Conclusion: Compared to IMRT plans, RA provided not only comparable target coverage, but also improved conformity, treatment time, and significant reduction in irradiation of OARs. This may potentially allow for target dose escalation without increase in normal tissue toxicity.« less

Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced non-small cell lung cancer.

PubMed

Wu, Chen-Ta; Motegi, Atsushi; Motegi, Kana; Hotta, Kenji; Kohno, Ryosuke; Tachibana, Hidenobu; Kumagai, Motoki; Nakamura, Naoki; Hojo, Hidehiro; Niho, Seiji; Goto, Koichi; Akimoto, Tetsuo

2016-08-10

To assess the feasibility of proton beam therapy for the patients with locally advanced non-small lung cancer. The dosimetry was analyzed retrospectively to calculate the doses to organs at risk, such as the lung, heart, esophagus and spinal cord. A dosimetric comparison between proton beam therapy and dummy photon radiotherapy (three-dimensional conformal radiotherapy) plans was performed. Dummy intensity-modulated radiotherapy plans were also generated for the patients for whom curative three-dimensional conformal radiotherapy plans could not be generated. Overall, 33 patients with stage III non-small cell lung cancer were treated with proton beam therapy between December 2011 and August 2014. The median age of the eligible patients was 67 years (range: 44-87 years). All the patients were treated with chemotherapy consisting of cisplatin/vinorelbine or carboplatin. The median prescribed dose was 60 GyE (range: 60-66 GyE). The mean normal lung V20 GyE was 23.6% (range: 14.9-32%), and the mean normal lung dose was 11.9 GyE (range: 6.0-19 GyE). The mean esophageal V50 GyE was 25.5% (range: 0.01-63.6%), the mean heart V40 GyE was 13.4% (range: 1.4-29.3%) and the mean maximum spinal cord dose was 40.7 GyE (range: 22.9-48 GyE). Based on dummy three-dimensional conformal radiotherapy planning, 12 patients were regarded as not being suitable for radical thoracic three-dimensional conformal radiotherapy. All the dose parameters of proton beam therapy, except for the esophageal dose, were lower than those for the dummy three-dimensional conformal radiotherapy plans. In comparison to the intensity-modulated radiotherapy plan, proton beam therapy also achieved dose reduction in the normal lung. None of the patients experienced grade 4 or worse non-hematological toxicities. Proton beam therapy for patients with stage III non-small cell lung cancer was feasible and was superior to three-dimensional conformal radiotherapy for several dosimetric parameters. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shusharina, N; Khan, F; Sharp, G

Purpose: To determine the dose level and timing of the boost in locally advanced lung cancer patients with confirmed tumor recurrence by comparing different boosting strategies by an impact of dose escalation in improvement of the therapeutic ratio. Methods: We selected eighteen patients with advanced NSCLC and confirmed recurrence. For each patient, a base IMRT plan to 60 Gy prescribed to PTV was created. Then we compared three dose escalation strategies: a uniform escalation to the original PTV, an escalation to a PET-defined target planned sequentially and concurrently. The PET-defined targets were delineated by biologically-weighed regions on a pre-treatment 18F-FDGmore » PET. The maximal achievable dose, without violating the OAR constraints, was identified for each boosting method. The EUD for the target, spinal cord, combined lung, and esophagus was compared for each plan. Results: The average prescribed dose was 70.4±13.9 Gy for the uniform boost, 88.5±15.9 Gy for the sequential boost and 89.1±16.5 Gy for concurrent boost. The size of the boost planning volume was 12.8% (range: 1.4 – 27.9%) of the PTV. The most prescription-limiting dose constraints was the V70 of the esophagus. The EUD within the target increased by 10.6 Gy for the uniform boost, by 31.4 Gy for the sequential boost and by 38.2 for the concurrent boost. The EUD for OARs increased by the following amounts: spinal cord, 3.1 Gy for uniform boost, 2.8 Gy for sequential boost, 5.8 Gy for concurrent boost; combined lung, 1.6 Gy for uniform, 1.1 Gy for sequential, 2.8 Gy for concurrent; esophagus, 4.2 Gy for uniform, 1.3 Gy for sequential, 5.6 Gy for concurrent. Conclusion: Dose escalation to a biologically-weighed gross tumor volume defined on a pre-treatment 18F-FDG PET may provide improved therapeutic ratio without breaching predefined OAR constraints. Sequential boost provides better sparing of OARs as compared with concurrent boost.« less

One day of motor training with amphetamine impairs motor recovery following spinal cord injury.

PubMed

Wong, Jamie K; Steward, Oswald

2012-02-01

It has previously been reported that a single dose of amphetamine paired with training on a beam walking task can enhance locomotor recovery following brain injury (Feeney et al., 1982). Here, we investigated whether this same drug/training regimen could enhance functional recovery following either thoracic (T9) or cervical (C5) spinal cord injury. Different groups of female Sprague-Dawley rats were trained on a beam walking task, and in a straight alley for assessment of hindlimb locomotor recovery using the BBB locomotor scale. For rats that received C5 hemisections, forelimb grip strength was assessed using a grip strength meter. Three separate experiments assessed the consequences of training rats on the beam walking task 24 h following a thoracic lateral hemisection with administration of either amphetamine or saline. Beginning 1 h following drug administration, rats either received additional testing/retraining on the beam hourly for 6 h, or they were returned to their home cages without further testing/retraining. Rats with thoracic spinal cord injuries that received amphetamine in conjunction with testing/retraining on the beam at 1 day post injury (DPI) exhibited significantly impaired recovery on the beam walking task and BBB. Rats with cervical spinal cord injuries that received training with amphetamine also exhibited significant impairments in beam walking and locomotion, as well as impairments in gripping and reaching abilities. Even when administered at 14 DPI, the drug/training regimen significantly impaired reaching ability in cervical spinal cord injured rats. Impairments were not seen in rats that received amphetamine without training. Histological analyses revealed that rats that received training with amphetamine had significantly larger lesions than saline controls. These data indicate that an amphetamine/training regimen that improves recovery after cortical injury has the opposite effect of impairing recovery following spinal cord injury because early training with amphetamine increases lesion severity. Copyright © 2011 Elsevier Inc. All rights reserved.

Shigella flexneri 3a Outer Membrane Protein C Epitope Is Recognized by Human Umbilical Cord Sera and Associated with Protective Activity

PubMed Central

Jarząb, Anna; Witkowska, Danuta; Ziomek, Edmund; Dąbrowska, Anna; Szewczuk, Zbigniew; Gamian, Andrzej

2013-01-01

Shigella flexneri 3a is one of the five major strains of the Shigella genus responsible for dysentery, especially among children, in regions of high poverty and poor sanitation. The outer membrane proteins (OMP) of this bacterium elicit immunological responses and are considered a prime target for vaccine development. When injected into mice they elicit a protective immunological response against a lethal dose of the pathogen. The OMPs from S. flexneri 3a were isolated and resolved by two-dimension-SDS-PAGE. Two 38-kDa spots were of particular interest since in our earlier studies OMPs of such molecular mass were found to interact with umbilical cord sera. These two spots were identified as OmpC by ESI-MS/MS spectrometry. By DNA sequencing, the ompC gene from S. flexneri 3a was identical to ompC from S. flexneri 2a [Gene Bank: 24113600]. A 3D model of OmpC was built and used to predict B-cell type (discontinuous) antigenic epitopes. Six epitopes bearing the highest score were selected and the corresponding peptides were synthesized. Only the peptides representing loop V of OmpC reacted strongly with the umbilical cord serum immunoglobulins. To determine which amino acids are essential for the antigenic activity of the epitope, the loop V was scanned with a series of dodecapeptides. The peptide RYDERY was identified as a minimal sequence for the loop V epitope. Truncation at either the C- or N-terminus rendered this peptide inactive. Apart from C-terminal tyrosine, substitution of each of the remaining five amino acids with glycine, led to a precipitous loss of immunological activity. This peptide may serve as a ligand in affinity chromatography of OmpC-specific antibodies and as a component of a vaccine designed to boost human immune defenses against enterobacterial infections. PMID:23940590

The influence of RBE variations in a clinical proton treatment plan for a hypopharynx cancer

NASA Astrophysics Data System (ADS)

Tilly, N.; Johansson, J.; Isacsson, U.; Medin, J.; Blomquist, E.; Grusell, E.; Glimelius, B.

2005-06-01

Currently, most clinical range-modulated proton beams are assumed to have a fixed overall relative biological effectiveness (RBE) of 1.1. However, it is well known that the RBE increases with depth in the spread-out Bragg peak (SOBP) and becomes about 10% higher than mid-SOBP RBE at 2 mm from the distal edge (Paganetti 2003 Technol. Cancer Res. Treat. 2 413-26) and can reach values of 1.3-1.4 in vitro at the distal edge (Robertson et al 1975 Cancer 35 1664-77, Courdi et al 1994 Br. J. Radiol. 67 800-4). We present a fast method for applying a variable RBE correction with linear energy transfer (LET) dependent tissue-specific parameters based on the αref/βref ratios suitable for implementation in a treatment planning system. The influence of applying this variable RBE correction on a clinical multiple beam proton dose plan is presented here. The treatment plan is evaluated by RBE weighted dose volume histograms (DVHs) and the calculation of tumour control probability (TCP) and normal tissue complication probability (NTCP) values. The variable RBE correction yields DVHs for the clinical target volumes (CTVs), a primary advanced hypopharynx cancer and subclinical disease in the lymph nodes, that are slightly higher than those achieved by multiplying the absorbed dose with RBE = 1.1. Although, more importantly, the RBE weighted DVH for an organ at risk, the spinal cord is considerably increased for the variable RBE. As the spinal cord in this particular case is located 8 mm behind the planning target volume (PTV) and hence receives only low total doses, the NTCP values are zero in spite of the significant increase in the RBE weighted DVHs for the variable RBE. However, high NTCP values for the non-target normal tissue were obtained when applying the variable RBE correction. As RBE variations tend to be smaller for in vivo systems, this study—based on in vitro data since human tissue RBE values are scarce and have large uncertainties—can be interpreted as showing the upper limits of the possible effects of utilizing a variable RBE correction. In conclusion, the results obtained here still indicate a significant difference in introducing a variable RBE compared to applying a generic RBE of 1.1, suggesting it is worth considering such a correction in clinical proton therapy planning, especially when risk organs are located immediately behind the target volume.

A comprehensive dosimetric study of pancreatic cancer treatment using three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), volumetric-modulated radiation therapy (VMAT), and passive-scattering and modulated-scanning proton therapy (PT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Xuanfeng; Dionisi, Francesco; Tang, Shikui

With traditional photon therapy to treat large postoperative pancreatic target volume, it often leads to poor tolerance of the therapy delivered and may contribute to interrupted treatment course. This study was performed to evaluate the potential advantage of using passive-scattering (PS) and modulated-scanning (MS) proton therapy (PT) to reduce normal tissue exposure in postoperative pancreatic cancer treatment. A total of 11 patients with postoperative pancreatic cancer who had been previously treated with PS PT in University of Pennsylvania Roberts Proton Therapy Center from 2010 to 2013 were identified. The clinical target volume (CTV) includes the pancreatic tumor bed as wellmore » as the adjacent high-risk nodal areas. Internal (iCTV) was generated from 4-dimensional (4D) computed tomography (CT), taking into account target motion from breathing cycle. Three-field and 4-field 3D conformal radiation therapy (3DCRT), 5-field intensity-modulated radiation therapy, 2-arc volumetric-modulated radiation therapy, and 2-field PS and MS PT were created on the patients’ average CT. All the plans delivered 50.4 Gy to the planning target volume (PTV). Overall, 98% of PTV was covered by 95% of the prescription dose and 99% of iCTV received 98% prescription dose. The results show that all the proton plans offer significant lower doses to the left kidney (mean and V{sub 18} {sub Gy}), stomach (mean and V{sub 20} {sub Gy}), and cord (maximum dose) compared with all the photon plans, except 3-field 3DCRT in cord maximum dose. In addition, MS PT also provides lower doses to the right kidney (mean and V{sub 18} {sub Gy}), liver (mean dose), total bowel (V{sub 20} {sub Gy} and mean dose), and small bowel (V{sub 15} {sub Gy} absolute volume ratio) compared with all the photon plans and PS PT. The dosimetric advantage of PT points to the possibility of treating tumor bed and comprehensive nodal areas while providing a more tolerable treatment course that could be used for dose escalation and combining with radiosensitizing chemotherapy.« less

Analysis of incidental radiation dose to uninvolved mediastinal/supraclavicular lymph nodes in patients with limited-stage small cell lung cancer treated without elective nodal irradiation.

PubMed

Ahmed, Irfan; DeMarco, Marylou; Stevens, Craig W; Fulp, William J; Dilling, Thomas J

2011-01-01

Classic teaching states that treatment of limited-stage small cell lung cancer (L-SCLC) requires large treatment fields covering the entire mediastinum. However, a trend in modern thoracic radiotherapy is toward more conformal fields, employing positron emission tomography/computed tomography (PET/CT) scans to determine the gross tumor volume (GTV). This analysis evaluates the dosimetric results when using selective nodal irradiation (SNI) to treat a patient with L-SCLC, quantitatively comparing the results to standard Intergroup treatment fields. Sixteen consecutive patients with L-SCLC and central mediastinal disease who also underwent pretherapy PET/CT scans were studied in this analysis. For each patient, we created SNI treatment volumes, based on the PET/CT-based criteria for malignancy. We also created 2 ENI plans, the first without heterogeneity corrections, as per the Intergroup 0096 study (ENI(off)) and the second with heterogeneity corrections while maintaining constant the number of MUs delivered between these latter 2 plans (ENI(on)). Nodal stations were contoured using published guidelines, then placed into 4 "bins" (treated nodes, 1 echelon away, >1 echelon away within the mediastinum, contralateral hilar/supraclavicular). These were aggregated across the patients in the study. Dose to these nodal bins and to tumor/normal structures were compared among these plans using pairwise t-tests. The ENI(on) plans demonstrated a statistically significant degradation in dose coverage compared with the ENI(off) plans. ENI and SNI both created a dose gradient to the lymph nodes across the mediastinum. Overall, the gradient was larger for the SNI plans, although the maximum dose to the "1 echelon away" nodes was not statistically different. Coverage of the GTV and planning target volume (PTV) were improved with SNI, while simultaneously reducing esophageal and spinal cord dose though at the expense of modestly reduced dose to anatomically distant lymph nodes within the mediastinum. The ENI(on) plans demonstrate that intergroup-style treatments, as actually delivered, had statistically reduced coverage to the mediastinum and tumor volumes than was reported. Furthermore, SNI leads to improved tumor coverage and reduced esophageal/spinal cord dose, which suggests the possibility of dose escalation using SNI. Copyright © 2011 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Virus-Specific Immune Memory at Peripheral Sites of Herpes Simplex Virus Type 2 (HSV-2) Infection in Guinea Pigs

PubMed Central

Xia, Jingya; Veselenak, Ronald L.; Gorder, Summer R.; Bourne, Nigel; Milligan, Gregg N.

2014-01-01

Despite its importance in modulating HSV-2 pathogenesis, the nature of tissue-resident immune memory to HSV-2 is not completely understood. We used genital HSV-2 infection of guinea pigs to assess the type and location of HSV-specific memory cells at peripheral sites of HSV-2 infection. HSV-specific antibody-secreting cells were readily detected in the spleen, bone marrow, vagina/cervix, lumbosacral sensory ganglia, and spinal cord of previously-infected animals. Memory B cells were detected primarily in the spleen and to a lesser extent in bone marrow but not in the genital tract or neural tissues suggesting that the HSV-specific antibody-secreting cells present at peripheral sites of HSV-2 infection represented persisting populations of plasma cells. The antibody produced by these cells isolated from neural tissues of infected animals was functionally relevant and included antibodies specific for HSV-2 glycoproteins and HSV-2 neutralizing antibodies. A vigorous IFN-γ-secreting T cell response developed in the spleen as well as the sites of HSV-2 infection in the genital tract, lumbosacral ganglia and spinal cord following acute HSV-2 infection. Additionally, populations of HSV-specific tissue-resident memory T cells were maintained at these sites and were readily detected up to 150 days post HSV-2 infection. Unlike the persisting plasma cells, HSV-specific memory T cells were also detected in uterine tissue and cervicothoracic region of the spinal cord and at low levels in the cervicothoracic ganglia. Both HSV-specific CD4+ and CD8+ resident memory cell subsets were maintained long-term in the genital tract and sensory ganglia/spinal cord following HSV-2 infection. Together these data demonstrate the long-term maintenance of both humoral and cellular arms of the adaptive immune response at the sites of HSV-2 latency and virus shedding and highlight the utility of the guinea pig infection model to investigate tissue-resident memory in the setting of HSV-2 latency and spontaneous reactivation. PMID:25485971

Equine platelet lysate as an alternative to fetal bovine serum in equine mesenchymal stromal cell culture - too much of a good thing?

PubMed

Russell, K A; Koch, T G

2016-03-01

Multipotent mesenchymal stromal cells (MSC) are often culture-expanded in vitro. Presently, expansion medium (EM) for MSC is supplemented with fetal bovine serum (FBS). However, increasing cost, variable composition and potential risks associated with bovine antigens call for alternatives. Platelet lysate (PL) has shown promise as an alternative supplement. To determine how equine umbilical cord blood (CB) MSC proliferate in EM enriched with PL or FBS at various concentrations. Randomised dose escalation study. Platelet concentrate was generated from 5 equine whole blood samples through a double centrifugation method and standardised to 1 × 10(12) platelets/l prior to a freeze/thaw cycle to produce PL. Pooled PL or pooled FBS was added to EM at concentrations of 5% to 60%. Proliferation of 4 equine CB-MSC cultures was determined after 4 days using a resazurin semiquantitative assay. Cord blood-MSC proliferated with a dose-dependent response with no significant difference found between PL and FBS up to a 30% concentration. Beyond 30%, proliferation fell in the PL-cultured cells, while continued dose-dependent proliferation was noted in the FBS-cultured cells. Despite reduced cell numbers in high PL concentrations, live/dead staining revealed that adherent cells remained viable. Expansion medium enriched with PL can support short-term equine CB-MSC proliferation at conventional culture concentrations. Based on the unexpected suppression of CB-MSC at higher PL concentrations, an in vivo dose study is indicated to investigate if combinational therapies of CB-MSC and platelet-rich plasma are associated with synergistic or antagonistic effect on CB-MSC function. © 2015 EVJ Ltd.

Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons

PubMed Central

Robarge, Jason D.; Duarte, Djane B.; Shariati, Behzad; Wang, Ruizhong; Flockhart, David A.; Vasko, Michael R.

2016-01-01

Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5 mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5 mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5 mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000 nmol of adenosine 5′-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats. PMID:27072527

Evaluation overview for the Massachusetts Childhood Obesity Research Demonstration (MA-CORD) project.

PubMed

Davison, Kirsten K; Falbe, Jennifer; Taveras, Elsie M; Gortmaker, Steve; Kulldorff, Martin; Perkins, Meghan; Blaine, Rachel E; Franckle, Rebecca L; Ganter, Claudia; Baidal, Jennifer Woo; Kwass, Jo-Ann; Buszkiewicz, James; Smith, Lauren; Land, Thomas

2015-02-01

The Massachusetts Childhood Obesity Research Demonstration (MA-CORD) project is a 2-year, multilevel, multisector community intervention to prevent and control obesity among children 2-12 years of age from two predominantly low-income communities in Massachusetts. MA-CORD includes evidence-based interventions in multiple sectors, including community health centers, early care and education centers, schools, afterschool programs, the Special Supplemental Nutrition Program for Women, Infants and Children, and the broader community. Currently, implementation of MA-CORD is complete and the final year of data collection is in progress. Here, the MA-CORD evaluation plan is described and baseline data are presented. The impact of MA-CORD on children's BMI, lifestyle behaviors, obesity-related care, and quality of life will be assessed using sector-specific, pre/post, time-series, and quasi-experimental designs. Change in the primary outcomes will be compared for intervention and comparison communities. Additionally, change in mean BMI and obesity prevalence in intervention school districts will be compared to similar districts throughout the state. At baseline in 2012, approximately 16% of preschool-aged and 25% of school-aged children were obese. Moreover, 15-40% of children consumed no vegetables on the previous day, 25-75% drank a sugar-sweetened beverage on the previous day, up to 87% had insufficient physical activity, 50-75% had a television in the room where they slept, and 50-80% obtained insufficient sleep. There is ample room for improvement in BMI and health behaviors in children in MA-CORD communities. If successful, MA-CORD may serve as a model for multilevel, multisector approaches to childhood obesity prevention and control.

Spinal cord electrophysiology II: extracellular suction electrode fabrication.

PubMed

Garudadri, Suresh; Gallarda, Benjamin; Pfaff, Samuel; Alaynick, William

2011-02-20

Development of neural circuitries and locomotion can be studied using neonatal rodent spinal cord central pattern generator (CPG) behavior. We demonstrate a method to fabricate suction electrodes that are used to examine CPG activity, or fictive locomotion, in dissected rodent spinal cords. The rodent spinal cords are placed in artificial cerebrospinal fluid and the ventral roots are drawn into the suction electrode. The electrode is constructed by modifying a commercially available suction electrode. A heavier silver wire is used instead of the standard wire given by the commercially available electrode. The glass tip on the commercial electrode is replaced with a plastic tip for increased durability. We prepare hand drawn electrodes and electrodes made from specific sizes of tubing, allowing consistency and reproducibility. Data is collected using an amplifier and neurogram acquisition software. Recordings are performed on an air table within a Faraday cage to prevent mechanical and electrical interference, respectively.

Spinal Cord Electrophysiology II: Extracellular Suction Electrode Fabrication

PubMed Central

Garudadri, Suresh; Gallarda, Benjamin; Pfaff, Samuel; Alaynick, William

2011-01-01

Development of neural circuitries and locomotion can be studied using neonatal rodent spinal cord central pattern generator (CPG) behavior. We demonstrate a method to fabricate suction electrodes that are used to examine CPG activity, or fictive locomotion, in dissected rodent spinal cords. The rodent spinal cords are placed in artificial cerebrospinal fluid and the ventral roots are drawn into the suction electrode. The electrode is constructed by modifying a commercially available suction electrode. A heavier silver wire is used instead of the standard wire given by the commercially available electrode. The glass tip on the commercial electrode is replaced with a plastic tip for increased durability. We prepare hand drawn electrodes and electrodes made from specific sizes of tubing, allowing consistency and reproducibility. Data is collected using an amplifier and neurogram acquisition software. Recordings are performed on an air table within a Faraday cage to prevent mechanical and electrical interference, respectively. PMID:21372792

Management of umbilical cord clamping.

PubMed

Webbon, Lucy

2013-02-01

The Royal College of Midwives (RCM) has updated its third stage of labour guidelines (RCM 2012) to be clearly supportive of a delay in umbilical cord clamping, although specific guidance on timing is yet to be announced. It is therefore imperative that both midwives and student midwives understand and are able to integrate delaying into their practice, as well as communicating to women the benefits; only in this way can we give women fully informed choices on this aspect of care. The main benefit of delayed cord clamping is the protection it can provide in reducing childhood anaemia, which is a major issue, especially in poorer countries. A review of the evidence found no risks linked to delayed clamping, and no evidence that it cannot be used in combination with the administration of uterotonic drugs. Delayed cord clamping can be especially beneficial for pre term and compromised babies.

Clinical, CSF, and MRI findings in Devic's neuromyelitis optica.

PubMed Central

O'Riordan, J I; Gallagher, H L; Thompson, A J; Howard, R S; Kingsley, D P; Thompson, E J; McDonald, W I; Miller, D H

1996-01-01

OBJECTIVES: Since Devic's original description of neuromyelitis optica in 1894 there has been much debate regarding its aetiology. A specific cause has been identified in a minority of cases but in most the question has arisen whether or not Devic's neuromyelitis optica is a variant of multiple sclerosis. This study was undertaken to help clarify this issue. METHODS: Neuromyelitis optica was defined as (1) a severe transverse myelitis; (2) an acute unilateral or bilateral optic neuropathy; (3) no clinical involvement beyond the spinal cord or optic nerves, and (4) a monophasic or multiphasic illness. The clinical and autoantibody status was documented. Patients underwent CSF examination and MRI of brain and spinal cord. RESULTS: Twelve patients, with a mean age of presentation of 35.1 years, were seen. Eleven were women; vision was reduced to counting fingers or worse in 10 patients and seven became confined to a wheelchair. Examination of CSF showed local synthesis of oligoclonal bands in only two patients and a neutrophil pleocytosis in two. A possible aetiology was identified in five: a specific connective tissue disorder (two), pulmonary tuberculosis (one), and possible acute disseminated encephalomyelitis (two). Six had non-specific increases in various autoantibodies. Eleven patients underwent MRI of the brain and spinal cord. In 10 there were diffuse abnormalities involving cervical and thoracic cords with extensive swelling in the acute phase. Brain MRI was normal in five; in five there were multiple deep white matter lesions, and one patient had minor age related changes. CONCLUSION: It is proposed that Devic's neuromyelitis optica is a distinctive disorder with some clinical, CSF, and MRI features different from those found in classic multiple sclerosis. In most cases a specific aetiology is not identified, but an immunological mechanism of tissue damage seems likely. Images PMID:8774400

Effects of propofol anesthesia on the processing of noxious stimuli in the spinal cord and the brain.

PubMed

Lichtner, Gregor; Auksztulewicz, Ryszard; Kirilina, Evgeniya; Velten, Helena; Mavrodis, Dionysios; Scheel, Michael; Blankenburg, Felix; von Dincklage, Falk

2018-05-15

Drug-induced unconsciousness is an essential component of general anesthesia, commonly attributed to attenuation of higher-order processing of external stimuli and a resulting loss of information integration capabilities of the brain. In this study, we investigated how the hypnotic drug propofol at doses comparable to those in clinical practice influences the processing of somatosensory stimuli in the spinal cord and in primary and higher-order cortices. Using nociceptive reflexes, somatosensory evoked potentials and functional magnet resonance imaging (fMRI), we found that propofol abolishes the processing of innocuous and moderate noxious stimuli at low to medium concentration levels, but that intense noxious stimuli evoked spinal and cerebral responses even during deep propofol anesthesia that caused profound electroencephalogram (EEG) burst suppression. While nociceptive reflexes and somatosensory potentials were affected only in a minor way by further increasing doses of propofol after the loss of consciousness, fMRI showed that increasing propofol concentration abolished processing of intense noxious stimuli in the insula and secondary somatosensory cortex and vastly increased processing in the frontal cortex. As the fMRI functional connectivity showed congruent changes with increasing doses of propofol - namely the temporal brain areas decreasing their connectivity with the bilateral pre-/postcentral gyri and the supplementary motor area, while connectivity of the latter with frontal areas is increased - we conclude that the changes in processing of noxious stimuli during propofol anesthesia might be related to changes in functional connectivity. Copyright © 2018 Elsevier Inc. All rights reserved.

Muscarinic receptor activation potentiates the effect of spinal cord stimulation on pain-related behavior in rats with mononeuropathy.

PubMed

Song, Zhiyang; Meyerson, Björn A; Linderoth, Bengt

2008-05-02

Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. Our previous animal experiments performed on rat models of SCS and ensuing clinical trials have demonstrated that intrathecal (i.t.) administration of subeffective doses of certain drugs may enhance the pain relieving effect of SCS in cases with unsatisfactory SCS outcome. Recently, an augmented release of spinal acetylcholine acting on muscarinic receptors has been shown to be one of the mechanisms involved in SCS. The present study was performed to examine whether cold hypersensitivity and heat hyperalgesia in rats with partial sciatic nerve injuries can be attenuated by SCS in the same way as tactile hypersensitivity and to explore a possibly synergistic effect of SCS and a muscarinic receptor agonist, oxotremorine. Rats with signs of neuropathy were subjected to SCS applied in awake, freely moving condition. Oxotremorine was administered intrathecally. Tactile, cold and heat sensitivities were assessed by using von Frey filaments, cold spray and focused radiant heat, respectively. Oxotremorine i.t. dose-dependently suppressed the tactile hypersensitivity. SCS markedly increased withdrawal thresholds (WTs), withdrawal latencies and cold scores. When combining SCS with a subeffective dose of oxotremorine i.t., the suppressive effect of SCS on the pain-related symptoms was dramatically enhanced in rats failing to obtain a satisfactory effect with SCS alone. In conclusion, the combination of SCS and a drug with selective muscarinic receptor agonistic properties could be an optional therapy, when SCS per se has proven inefficient.

Comparison between the four-field box and field-in-field techniques for conformal radiotherapy of the esophagus using dose-volume histograms and normal tissue complication probabilities.

PubMed

Allaveisi, Farzaneh; Moghadam, Amir Nami

2017-06-01

We evaluated and compared the performance of the field-in-field (FIF) to that of the four-field box (4FB) technique regarding dosimetric and radiobiological parameters for radiotherapy of esophageal carcinoma. Twenty patients with esophageal cancer were selected. For each patient, two treatment plans were created: 4FB and FIF. The parameters compared included the conformity index (CI), homogeneity index (HI), D mean , D max , tumor control probability (TCP), V 20Gy and V 30Gy of the heart and lungs, normal tissue complication probability (NTCP), and monitor units per fraction (MU/fr). A paired t-test analysis did not show any significant differences (p > 0.05) between the two techniques in terms of the CI and TCP. However, the HI significantly improved when the FIF was applied. D max of the PTV, lung, and spinal cord were also significantly better with the FIF. Moreover, the lung V 20Gy as well as the NTCPs of the lung and spinal cord significantly reduced when the FIF was used, and the MU/fr was significantly decreased. The FIF showed evident advantages over 4FB: a more homogeneous dose distribution, lower D max values, and fewer required MUs, while it also retained PTV dose conformality. FIF should be considered as a simple technique to use clinically in cases with esophageal malignancies, especially in clinics with no IMRT.

Dosimetric comparison of helical tomotherapy, intensity-modulated radiation therapy, volumetric-modulated arc therapy, and 3-dimensional conformal therapy for the treatment of T1N0 glottic cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ekici, Kemal, E-mail: drkemal06@hotmail.com; Pepele, Eda K.; Yaprak, Bahaddin

2016-01-01

Various radiotherapy planning methods for T1N0 laryngeal cancer have been proposed to decrease normal tissue toxicity. We compare helical tomotherapy (HT), linac-based intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT), and 3-D conformal radiotherapy (3D-CRT) techniques for T1N0 laryngeal cancer. Overall, 10 patients with T1N0 laryngeal cancer were selected and evaluated. Furthermore, 10 radiotherapy treatment plans have been created for all 10 patients, including HT, IMRT, VMAT, and 3D-CRT. IMRT, VMAT, and HT plans vs 3D-CRT plans consistently provided superior planning target volume (PTV) coverage. Similar target coverage was observed between the 3 IMRT modalities. Compared with 3D-CRT, IMRT, HT,more » and VMAT significantly reduced the mean dose to the carotid arteries. VMAT resulted in the lowest mean dose to the submandibular and thyroid glands. Compared with 3D-CRT, IMRT, HT, and VMAT significantly increased the maximum dose to the spinal cord It was observed that the 3 IMRT modalities studied showed superior target coverage with less variation between each plan in comparison with 3D-CRT. The 3D-CRT plans performed better at the D{sub max} of the spinal cord. Clinical investigation is warranted to determine if these treatment approaches would translate into a reduction in radiation therapy–induced toxicities.« less

Biological mechanisms of normal tissue damage: importance for the design of NTCP models.

PubMed

Trott, Klaus-Rüdiger; Doerr, Wolfgang; Facoetti, Angelica; Hopewell, John; Langendijk, Johannes; van Luijk, Peter; Ottolenghi, Andrea; Smyth, Vere

2012-10-01

The normal tissue complication probability (NTCP) models that are currently being proposed for estimation of risk of harm following radiotherapy are mainly based on simplified empirical models, consisting of dose distribution parameters, possibly combined with clinical or other treatment-related factors. These are fitted to data from retrospective or prospective clinical studies. Although these models sometimes provide useful guidance for clinical practice, their predictive power on individuals seems to be limited. This paper examines the radiobiological mechanisms underlying the most important complications induced by radiotherapy, with the aim of identifying the essential parameters and functional relationships needed for effective predictive NTCP models. The clinical features of the complications are identified and reduced as much as possible into component parts. In a second step, experimental and clinical data are considered in order to identify the gross anatomical structures involved, and which dose distributions lead to these complications. Finally, the pathogenic pathways and cellular and more specific anatomical parameters that have to be considered in this pathway are determined. This analysis is carried out for some of the most critical organs and sites in radiotherapy, i.e. spinal cord, lung, rectum, oropharynx and heart. Signs and symptoms of severe late normal tissue complications present a very variable picture in the different organs at risk. Only in rare instances is the entire organ the critical target which elicits the particular complication. Moreover, the biological mechanisms that are involved in the pathogenesis differ between the different complications, even in the same organ. Different mechanisms are likely to be related to different shapes of dose effect relationships and different relationships between dose per fraction, dose rate, and overall treatment time and effects. There is good reason to conclude that each type of late complication after radiotherapy depends on its own specific mechanism which is triggered by the radiation exposure of particular structures or sub-volumes of (or related to) the respective organ at risk. Hence each complication will need the development of an NTCP model designed to accommodate this structure. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Consideration of Dose Limits for Organs at Risk of Thoracic Radiotherapy: Atlas for Lung, Proximal Bronchial Tree, Esophagus, Spinal Cord, Ribs, and Brachial Plexus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kong, Feng-Ming, E-mail: fengkong@med.umich.edu; Ritter, Timothy; Quint, Douglas J.

2011-12-01

Purpose: To review the dose limits and standardize the three-dimenional (3D) radiographic definition for the organs at risk (OARs) for thoracic radiotherapy (RT), including the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. Methods and Materials: The present study was performed by representatives from the Radiation Therapy Oncology Group, European Organization for Research and Treatment of Cancer, and Soutwestern Oncology Group lung cancer committees. The dosimetric constraints of major multicenter trials of 3D-conformal RT and stereotactic body RT were reviewed and the challenges of 3D delineation of these OARs described. Using knowledge of the human anatomy andmore » 3D radiographic correlation, draft atlases were generated by a radiation oncologist, medical physicist, dosimetrist, and radiologist from the United States and reviewed by a radiation oncologist and medical physicist from Europe. The atlases were then critically reviewed, discussed, and edited by another 10 radiation oncologists. Results: Three-dimensional descriptions of the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus are presented. Two computed tomography atlases were developed: one for the middle and lower thoracic OARs (except for the heart) and one focusing on the brachial plexus for a patient positioned supine with their arms up for thoracic RT. The dosimetric limits of the key OARs are discussed. Conclusions: We believe these atlases will allow us to define OARs with less variation and generate dosimetric data in a more consistent manner. This could help us study the effect of radiation on these OARs and guide high-quality clinical trials and individualized practice in 3D-conformal RT and stereotactic body RT.« less

Dynamic regulation of glycinergic input to spinal dorsal horn neurones by muscarinic receptor subtypes in rats.

PubMed

Wang, Xiu-Li; Zhang, Hong-Mei; Li, De-Pei; Chen, Shao-Rui; Pan, Hui-Lin

2006-03-01

Activation of spinal muscarinic acetylcholine receptors (mAChRs) inhibits nociception. However, the cellular mechanisms of this action are not fully known. In this study, we determined the role of mAChR subtypes in regulation of synaptic glycine release in the spinal cord. Whole-cell voltage-clamp recordings were performed on lamina II neurones in the rat spinal cord slices. The mAChR agonist oxotremorine-M significantly increased the frequency of glycinergic sIPSCs but not mIPSCs. Surprisingly, the effect of oxotremorine-M on sIPSCs was largely attenuated at a higher concentration. On the other hand, 1-10 microm oxotremorine-M dose-dependently increased the frequency of sIPSCs in rats pretreated with intrathecal pertussis toxin. Furthermore, oxotremorine-M also dose-dependently increased the frequency of sIPSCs in the presence of himbacine (an M2/M4 mAChR antagonist) or AF-DX116 (an M2 mAChR antagonist). The M3 mAChR antagonist 4-DAMP abolished the stimulatory effect of oxotremorine-M on sIPSCs. Interestingly, the GABA(B) receptor antagonist CGP55845 potentiated the stimulatory effect of oxotremorine-M on sIPSCs. In the presence of CGP55845, both himbacine and AF-DX116 similarly reduced the potentiating effect of oxotremorine-M on sIPSCs. Collectively, these data suggest that the M3 subtype is present on the somatodendritic site of glycinergic neurones and is mainly responsible for muscarinic potentiation of glycinergic input to spinal dorsal horn neurones. Concurrent stimulation of mAChRs on adjacent GABAergic interneurones attenuates synaptic glycine release through presynaptic GABA(B) receptors on glycinergic interneurones. This study illustrates a complex dynamic interaction between GABAergic and glycinergic synapses in the spinal cord dorsal horn.

Alternative Donor/Unrelated Donor Transplants for the β-Thalassemia and Sickle Cell Disease.

PubMed

Fitzhugh, Courtney D; Abraham, Allistair; Hsieh, Matthew M

2017-01-01

Considerable progress with respect to donor source has been achieved in allogeneic stem cell transplant for patients with hemoglobin disorders, with matched sibling donors in the 1980s, matched unrelated donors and cord blood sources in the 1990s, and haploidentical donors in the 2000s. Many studies have solidified hematopoietic progenitors from matched sibling marrow, cord blood, or mobilized peripheral blood as the best source-with the lowest graft rejection and graft versus host disease (GvHD), and highest disease-free survival rates. For patients without HLA-matched sibling donors, but who are otherwise eligible for transplant, fully allelic matched unrelated donor (8/8 HLA-A, B, C, DRB1) appears to be the next best option, though an ongoing study in patients with sickle cell disease will provide data that are currently lacking. There are high GvHD rates and low engraftment rates in some of the unrelated cord transplant studies. Haploidentical donors have emerged in the last decade to have less GvHD; however, improvements are needed to increase the engraftment rate. Thus the decision to use unrelated cord blood units or haploidentical donors may depend on the institutional expertise; there is no clear preferred choice over the other. Active research is ongoing in expanding cord blood progenitor cells to overcome the limitation of cell dose, including the options of small molecule inhibitor compounds added to ex vivo culture or co-culture with supportive cell lines. There are inconsistent data from using 7/8 or lower matched unrelated donors. Before routine use of these less matched donor sources, work is needed to improve patient selection, conditioning regimen, GvHD prophylaxis, and/or other strategies.

Baclofen dosage after traumatic spinal cord injury: a multi-decade retrospective analysis.

PubMed

Veerakumar, Ashan; Cheng, Jennifer J; Sunshine, Abraham; Ye, Xiaobu; Zorowitz, Richard D; Anderson, William S

2015-02-01

To perform an analysis of oral baclofen dosage in patients with traumatic spinal cord injuries over time and to ascertain the clinical determinants of long-term baclofen dosage trends. Retrospective cohort study of patient records from the PM&R units at the Johns Hopkins Bayview Medical Center and the Johns Hopkins Hospital. A total of 115 PM&R patients suffering spinal cord injury due to trauma leading to either complete or incomplete paralysis. The modes of injury included were motor vehicle accidents (MVA) (n=39), gunshot wounds (GSW) (n=55), falls (n=17), diving (n=2), workplace (n=1) and swimming (n=1) accidents. The location of injury in the spinal cord was categorized into either cervical (n=52), thoracic (n=59), lumbar (n=2), or unspecified (n=2). From time of injury, an aggregate of all dosage assignments for each patient demonstrated a significant yearly increase in baclofen dosage (1.26 mg/year, p<0.01). Baclofen dosage for MVA cases were seen to rise at 4.99 mg/year (p<0.0001). Kaplan-Meier analysis revealed that GSW patients received their first baclofen dosage earlier than MVA patients (log-rank p<0.05, unadjusted). We observed a marginal increase in baclofen dosage over nearly 25 years in a single provider's patient database and observed different timings of first dose between two causes of traumatic SCI. These results provide an estimate of baclofen dosage trends over time after spinal cord injury and may be useful for patient counseling or as a method to assess costs of providing SCI patient care. Copyright © 2014 Elsevier B.V. All rights reserved.

Intrathecal injection of carbenoxolone, a gap junction decoupler, attenuates the induction of below-level neuropathic pain after spinal cord injury in rats.

PubMed

Roh, Dae-Hyun; Yoon, Seo-Yeon; Seo, Hyoung-Sig; Kang, Suk-Yun; Han, Ho-Jae; Beitz, Alvin J; Lee, Jang-Hern

2010-07-01

The most common type of chronic pain following spinal cord injury (SCI) is central neuropathic pain and SCI patients typically experience mechanical allodynia and thermal hyperalgesia. The present study was designed to examine the potential role of astrocyte gap junction connectivity in the induction and maintenance of "below-level" neuropathic pain in SCI rats. We examined the effect of intrathecal treatment with carbenoxolone (CARB), a gap junction decoupler, on SCI-induced bilateral thermal hyperalgesia and mechanical allodynia during the induction phase (postoperative days 0 to 5) and the maintenance phase (days 15 to 20) following T13 spinal cord hemisection. Immunohistochemistry was performed to determine potential SCI-induced changes in spinal astrocyte activation and phosphorylation of the NMDA receptor NR1 subunit (pNR1). CARB administered during the induction period dose-dependently attenuated the development of bilateral thermal hyperalgesia and mechanical allodynia. Intrathecal CARB also significantly reduced the bilateral SCI-induced increase in GFAP-immunoreactive (ir) staining and the number of pNR1-ir cell profiles in the spinal cord dorsal horn compared to vehicle-treated rats. In contrast, CARB treatment during the maintenance phase had no effect on the established thermal hyperalgesia and mechanical allodynia nor on spinal GFAP expression or the number of pNR1-ir cell profiles. These results indicate that gap junctions play a critical role in the activation of astrocytes distant from the site of SCI and in the subsequent phosphorylation of NMDA receptors in the lumbar spinal cord. Both of these processes appear to contribute to the induction of bilateral below-level pain in SCI rats. Copyright 2010 Elsevier Inc. All rights reserved.

Anti-apoptotic effect of insulin in the control of cell death and neurologic deficit after acute spinal cord injury in rats.

PubMed

Wu, Xing-Huo; Yang, Shu-Hua; Duan, De-Yu; Cheng, Heng-Hui; Bao, Yu-Ting; Zhang, Yukun

2007-09-01

Recent studies confirmed that the new cell survival signal pathway of Insulin-PI3K-Akt exerted cyto-protective actions involving anti-apoptosis. This study was undertaken to investigate the potential neuroprotective effects of insulin in the pathogenesis of spinal cord injury (SCI) and evaluate its therapeutic effects in adult rats. SCI was produced by extradural compression using modified Allen's stall with damage energy of 40 g-cm force. One group of rats was subjected to SCI in combination with the administration of recombinant human insulin dissolved in 50% glucose solution at the dose of 1 IU/kg day, for 7 days. At the same time, another group of rats was subjected to SCI in combination with the administration of an equal volume of sterile saline solution. Functional recovery was evaluated using open-field walking, inclined plane tests, and motor evoked potentials (MEPs) during the first 14 days post-trauma. Levels of protein for B-cell lymphoma/leukemia-2 gene (Bcl-2), Caspase-3, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were quantified in the injured spinal cord by Western blot analysis. Neuronal apoptosis was detected by TUNEL, and spinal cord blood flow (SCBF) was measured by laser-Doppler flowmetry (LDF). Ultimately, the data established the effectiveness of insulin treatment in improving neurologic recovery, increasing the expression of anti-apoptotic bcl-2 proteins, inhibiting caspase-3 expression decreasing neuronal apoptosis, reducing the expression of proinflammatory cytokines iNOS and COX-2, and ameliorating microcirculation of injured spinal cord after moderate contusive SCI in rats. In sum, this study reported the beneficial effects of insulin in the treatment of SCI, with the suggestion that insulin should be considered as a potential therapeutic agent.

The Selective Glucocorticoid Receptor Modulator Cort 113176 Reduces Neurodegeneration and Neuroinflammation in Wobbler Mice Spinal Cord.

PubMed

Meyer, Maria; Lara, Agustina; Hunt, Hazel; Belanoff, Joseph; de Kloet, E Ronald; Gonzalez Deniselle, Maria Claudia; De Nicola, Alejandro F

2018-06-08

Wobbler mice are experimental models for amyotrophic lateral sclerosis. As such they show motoneuron degeneration, motor deficits, and astrogliosis and microgliosis of the spinal cord. Additionally, Wobbler mice show increased plasma, spinal cord and brain corticosterone levels and focal adrenocortical hyperplasia, suggesting a pathogenic role for glucocorticoids in this disorder. Considering this endocrine background, we examined whether the glucocorticoid receptor (GR) modulator CORT 113176 prevents spinal cord neuropathology of Wobblers. CORT 113176 shows high affinity for the GR, with low or null affinity for other steroid receptors. We employed five-month-old genotyped Wobbler mice that received s.c. vehicle or 30 mg/kg/day for 4 days of CORT 113176 dissolved in sesame oil. The mice were used on the 4th day, 2 h after the last dose of CORT 113176. Vehicle-treated Wobbler mice presented vacuolated motoneurons, increased glial fibrillary acidic protein (GFAP)+ astrocytes and decreased glutamine synthase (GS)+ cells. There was strong neuroinflammation, shown by increased staining for IBA1+ microglia and CD11b mRNA, enhanced expression of tumor necrosis factor-α, its cognate receptor TNFR1, toll-like receptor 4, the inducible nitric oxide synthase, NFkB and the high-mobility group box 1 protein (HMGB1). Treatment of Wobbler mice with CORT 113176 reversed the abnormalities of motoneurons and down-regulated proinflammatory mediators and glial reactivity. Expression of glutamate transporters GLT1 and GLAST mRNAs and GLT1 protein was significantly enhanced over untreated Wobblers. In summary, antagonism of GR with CORT 113176 prevented neuropathology and showed anti-inflammatory and anti-glutamatergic effects in the spinal cord of Wobbler mice. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Apoptosis and proliferation of oligodendrocyte progenitor cells in the irradiated rodent spinal cord

DOE Office of Scientific and Technical Information (OSTI.GOV)

Atkinson, Shelley L.; Li Yuqing; Wong, C. Shun

2005-06-01

Purpose: Oligodendrocytes undergo early apoptosis after irradiation. The aim of this study was to determine the relationship between oligodendroglial apoptosis and proliferation of oligodendrocyte progenitor cells (OPC) in the irradiated central nervous system. Methods and Materials: Adult rats and p53 transgenic mice were given single doses of 2 Gy, 8 Gy, or 22 Gy to the cervical spinal cord. Apoptosis was assessed using TUNEL (Tdt-mediated dUTP terminal nick-end labeling) staining or by examining nuclear morphology. Oligodendrocyte progenitor cells were identified with an NG2 antibody or by in situ hybridization for platelet-derived growth factor receptor {alpha}. Proliferation of OPC was assessedmore » by in vivo bromodeoxyuridine (BrdU) labeling and subsequent immunohistochemistry. Because radiation-induced apoptosis of oligodendroglial cells is p53 dependent, p53 transgenic mice were used to study the relationship between apoptosis and cell proliferation. Results: Oligodendrocyte progenitor cells underwent apoptosis within 24 h of irradiation in the rat. That did not result in a change in OPC density at 24 h. Oligodendrocyte progenitor cell density was significantly reduced by 2-4 weeks, but showed recovery by 6 weeks after irradiation. An increase in BrdU-labeled cells was observed at 2 weeks after 8 Gy or 22 Gy, and proliferating cells in the rat spinal cord were immunoreactive for NG2. The mouse spinal cord showed a similar early cell proliferation after irradiation. No difference was observed in the proliferation response in the spinal cord of p53 -/- mice compared with wild type animals. Conclusions: Oligodendroglial cells undergo early apoptosis and OPC undergo early proliferation after ionizing radiation. However, apoptosis is not likely to be the trigger for early proliferation of OPC in the irradiated central nervous system.« less

SU-E-J-244: Development and Validation of a Knowledge Based Planning Model for External Beam Radiation Therapy of Locally Advanced Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Z; Kennedy, A; Larsen, E

2015-06-15

Purpose: The study aims to develop and validate a knowledge based planning (KBP) model for external beam radiation therapy of locally advanced non-small cell lung cancer (LA-NSCLC). Methods: RapidPlan™ technology was used to develop a lung KBP model. Plans from 65 patients with LA-NSCLC were used to train the model. 25 patients were treated with VMAT, and the other patients were treated with IMRT. Organs-at-risk (OARs) included right lung, left lung, heart, esophagus, and spinal cord. DVH and geometric distribution DVH were extracted from the treated plans. The model was trained using principal component analysis and step-wise multiple regression. Boxmore » plot and regression plot tools were used to identify geometric outliers and dosimetry outliers and help fine-tune the model. The validation was performed by (a) comparing predicted DVH boundaries to actual DVHs of 63 patients and (b) using an independent set of treatment planning data. Results: 63 out of 65 plans were included in the final KBP model with PTV volume ranging from 102.5cc to 1450.2cc. Total treatment dose prescription varied from 50Gy to 70Gy based on institutional guidelines. One patient was excluded due to geometric outlier where 2.18cc of spinal cord was included in PTV. The other patient was excluded due to dosimetric outlier where the dose sparing to spinal cord was heavily enforced in the clinical plan. Target volume, OAR volume, OAR overlap volume percentage to target, and OAR out-of-field volume were included in the trained model. Lungs and heart had two principal component scores of GEDVH, whereas spinal cord and esophagus had three in the final model. Predicted DVH band (mean ±1 standard deviation) represented 66.2±3.6% of all DVHs. Conclusion: A KBP model was developed and validated for radiotherapy of LA-NSCLC in a commercial treatment planning system. The clinical implementation may improve the consistency of IMRT/VMAT planning.« less

Measuring body structures and body functions from the International Classification of Functioning, Disability, and Health perspective: considerations for biomedical parameters in spinal cord injury research.

PubMed

Eriks-Hoogland, Inge E; Brinkhof, Martin W G; Al-Khodairy, Abdul; Baumberger, Michael; Brechbühl, Jörg; Curt, Armin; Mäder, Mark; Stucki, Gerold; Post, Marcel W M

2011-11-01

The aims of this study were to provide a selection of biomedical domains based on the comprehensive International Classification of Functioning, Disability, and Health (ICF) core sets for spinal cord injury (SCI) and to present an overview of the corresponding measurement instruments. Based on the Biomedical Domain Set, the SCI literature, the International Spinal Cord Society international data sets, and the Spinal Cord Injury Rehabilitation Evidence project publications were used to derive category specifications for use in SCI research. Expert opinion was used to derive a priority selection. The same sources were used to determine candidate measurement instruments for the specification of body functions and body structures using an example, and guiding principles were applied to select the most appropriate biomedical measurement instrument(s) for use in an SCI research project. Literature searches were performed for 41 second-level ICF body functions categories and for four second-level ICF body structures categories. For some of these categories, only a few candidate measurement instruments were found with limited variation in the type of measurement instruments. An ICF-based measurement set for biomedical aspects of functioning with SCI was established. For some categories of the ICF core sets for SCI, there is a need to develop measurement instruments.

Can the mammalian lumbar spinal cord learn a motor task?

PubMed

Hodgson, J A; Roy, R R; de Leon, R; Dobkin, B; Edgerton, V R

1994-12-01

Progress toward restoring locomotor function in low thoracic spinal transected cats and the application of similar techniques to patients with spinal cord injury is reviewed. Complete spinal cord transection (T12-T13) in adult cats results in an immediate loss of locomotor function in the hindlimbs. Limited locomotor function returns after several months in cats that have not received specific therapies designed to restore hindlimb stepping. Training transected cats to step on a treadmill for 30 min.d-1 and 5 d.wk-1 greatly improves their stepping ability. The most successful outcome was in cats where training began early, i.e., 1 wk after spinal transection. Cats trained to stand instead of stepping had great difficulty using the hindlimbs for locomotion. These effects were reversible over a 20-month period such that cats unable to step as a result of standing training could be trained to step and, conversely, locomotion in stepping-trained cats could be abolished by standing training. These results indicate that the spinal cord is capable of learning specific motor tasks. It has not been possible to elicit locomotion in patients with clinically complete spinal injuries, but appropriately coordinated EMG activity has been demonstrated in musculature of the legs during assisted locomotion on a treadmill.

Usability assessment of ASIBOT: a portable robot to aid patients with spinal cord injury.

PubMed

Jardón, Alberto; Gil, Ángel M; de la Peña, Ana I; Monje, Concepción A; Balaguer, Carlos

2011-01-01

The usability concept refers to aspects related to the use of products that are closely linked to the user's degree of satisfaction. Our goal is to present a functional evaluation methodology for assessing the usability of sophisticated technical aids, such as a portable robot for helping disabled patients with severe spinal cord injuries. The specific manipulator used for this task is ASIBOT, a personal assistance robot totally developed by RoboticsLab at the University Carlos III of Madrid. Our purpose is also to improve some aspects of the manipulator according to the user's perception. For our case study, a population of six patients with spinal cord injury is considered. These patients have been suffering spinal cord injuries for a period of time longer than 1 year before the tests are carried out. The methodology followed for the information gathering is based on the Quebec User Evaluation of Satisfaction with assistive Technology (QUEST). Different daily functions, such as drinking, brushing one's teeth and washing one's face, are considered to assess the user's perception when using ASIBOT as a technical aid. The human factor in this procedure is the main base to establish the specific needs and tools to make the end product more suitable and usable.

[Extendable Cords to Prevent Tumbling of a Suction Device during Craniotomy].

PubMed

Shimizu, Satoru; Mochizuki, Takahiro; Osawa, Shigeyuki; Sekiguchi, Tomoko; Koizumi, Hiroyuki; Kumabe, Toshihiro

2016-02-01

Suction is necessary during craniotomy, and intraoperative tumbling of the suction device interrupts operative procedures. To avoid this, we developed a technique that would fasten the device to an extendable cord as is used to secure cell phones. We used this technique in more than 300 craniotomies at the specific point of time when the suction device tends to tumble, i. e., during the opening and closure of a wound, which requires frequent instrument exchanges. Extendable cords fastened to the tip of the suction hose using a gift tie were attached to the drapes to secure the suction device next to the operative field. During the operation, the extendable cord followed the suction device manipulations. Consequently, although there was some tension in the cord during its extension, the maneuverability of the suction device was maintained. As the hanging suction device was closer to the operative field than devices stored in conventional pockets, its manipulation was easier and quicker. Upon release, the suction device automatically returned to its original position without distracting the surgeon. Tumbling of the device was prevented, and there were no procedure-related complications. Our simple modification using extendable cords prevented tumbling, avoided unnecessary replacements, and eased the manipulation of a suction device.

Histopathologic correlation of magnetic resonance imaging signal patterns in a spinal cord injury model.

PubMed

Weirich, S D; Cotler, H B; Narayana, P A; Hazle, J D; Jackson, E F; Coupe, K J; McDonald, C L; Langford, L A; Harris, J H

1990-07-01

Magnetic resonance imaging (MRI) provides a noninvasive method of monitoring the pathologic response to spinal cord injury. Specific MR signal intensity patterns appear to correlate with degrees of improvement in the neurologic status in spinal cord injury patients. Histologic correlation of two types of MR signal intensity patterns are confirmed in the current study using a rat animal model. Adult male Sprague-Dawley rats underwent spinal cord trauma at the midthoracic level using a weight-dropping technique. After laminectomy, 5- and 10-gm brass weights were dropped from designated heights onto a 0.1-gm impounder placed on the exposed dura. Animals allowed to regain consciousness demonstrated variable recovery of hind limb paraplegia. Magnetic resonance images were obtained from 2 hours to 1 week after injury using a 2-tesla MRI/spectrometer. Sacrifice under anesthesia was performed by perfusive fixation; spinal columns were excised en bloc, embedded, sectioned, and observed with the compound light microscope. Magnetic resonance axial images obtained during the time sequence after injury demonstrate a distinct correlation between MR signal intensity patterns and the histologic appearance of the spinal cord. Magnetic resonance imaging delineates the pathologic processes resulting from acute spinal cord injury and can be used to differentiate the type of injury and prognosis.

Neuromodulation of lower limb motor control in restorative neurology.

PubMed

Minassian, Karen; Hofstoetter, Ursula; Tansey, Keith; Mayr, Winfried

2012-06-01

One consequence of central nervous system injury or disease is the impairment of neural control of movement, resulting in spasticity and paralysis. To enhance recovery, restorative neurology procedures modify altered, yet preserved nervous system function. This review focuses on functional electrical stimulation (FES) and spinal cord stimulation (SCS) that utilize remaining capabilities of the distal apparatus of spinal cord, peripheral nerves and muscles in upper motor neuron dysfunctions. FES for the immediate generation of lower limb movement along with current rehabilitative techniques is reviewed. The potential of SCS for controlling spinal spasticity and enhancing lower limb function in multiple sclerosis and spinal cord injury is discussed. The necessity for precise electrode placement and appropriate stimulation parameter settings to achieve therapeutic specificity is elaborated. This will lead to our human work of epidural and transcutaneous stimulation targeting the lumbar spinal cord for enhancing motor functions in spinal cord injured people, supplemented by pertinent human research of other investigators. We conclude that the concept of restorative neurology recently received new appreciation by accumulated evidence for locomotor circuits residing in the human spinal cord. Technological and clinical advancements need to follow for a major impact on the functional recovery in individuals with severe damage to their motor system. Copyright © 2012 Elsevier B.V. All rights reserved.

Neuromodulation of lower limb motor control in restorative neurology

PubMed Central

Minassian, Karen; Hofstoetter, Ursula; Tansey, Keith; Mayr, Winfried

2012-01-01

One consequence of central nervous system injury or disease is the impairment of neural control of movement, resulting in spasticity and paralysis. To enhance recovery, restorative neurology procedures modify altered, yet preserved nervous system function. This review focuses on functional electrical stimulation (FES) and spinal cord stimulation (SCS) that utilize remaining capabilities of the distal apparatus of spinal cord, peripheral nerves and muscles in upper motor neuron dysfunctions. FES for the immediate generation of lower limb movement along with current rehabilitative techniques is reviewed. The potential of SCS for controlling spinal spasticity and enhancing lower limb function in multiple sclerosis and spinal cord injury is discussed. The necessity for precise electrode placement and appropriate stimulation parameter settings to achieve therapeutic specificity is elaborated. This will lead to our human work of epidural and transcutaneous stimulation targeting the lumbar spinal cord for enhancing motor functions in spinal cord injured people, supplemented by pertinent human research of other investigators. We conclude that the concept of restorative neurology recently received new appreciation by accumulated evidence for locomotor circuits residing in the human spinal cord. Technological and clinical advancements need to follow for a major impact on the functional recovery in individuals with severe damage to their motor system. PMID:22464657

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, D; Badkul, R; Jiang, H

Purpose: To compare dose distributions calculated using the iPlan XVMC algorithm and heterogeneities corrected/uncorrected Pencil Beam (PB-hete/PB-homo) algorithms for SBRT treatments of lung tumors. Methods: Ten patients with centrally located solitary lung tumors were treated using MC-based SBRT to 60Gy in 5 fractions for PTVV100%=95%. ITV was delineated on MIP-images based on 4D-CT scans. PTVs(ITV+5mm margins) ranged from 10.1–106.5cc(mean=48.6cc). MC-SBRT plans were generated with a combination of non-coplanar conformal arcs/beams using iPlan-XVMC-algorithm (BrainLABiPlan ver.4.1.2) for Novalis-TX consisting of HD-MLCs and 6MV-SRS(1000MU/min) mode, following RTOG 0813 dosimetric criteria. For comparison, PB-hete/PB-homo algorithms were used to re-calculate dose distributions using same beammore » configurations, MLCs/monitor units. Plans were evaluated with isocenter/maximal/mean doses to PTV. Normal lung doses were evaluated with V5/V10/V20 and mean-lung-dose(MLD), excluding PTV. Other OAR doses such as maximal spinal cord/2cc-esophagus/max bronchial tree (BT/maximal heart doses were tabulated. Results: Maximal/mean/isocenter doses to PTV calculated by PB-hete were uniformly larger than MC plans by a factors of 1.09/1.13/1.07, on average, whereas they were consistently lower by PB-homo by a factors of 0.9/0.84/0.9, respectively. The volume covered by 5Gy/10Gy/20Gy isodose-lines of the lung were comparable (average within±3%) when calculated by PB-hete compared to XVMC, but, consistently lower by PB-homo by a factors of 0.90/0.88/0.85, respectively. MLD was higher with PB-hete by 1.05, but, lower by PB-homo by 0.9, on average, compared to XVMC. XVMC max-cord/max-BT/max-heart and 2cc of esophagus doses were comparable to PB-hete; however, PB-homo underestimates by a factors of 0.82/0.89/0.88/0.86, on average, respectively. Conclusion: PB-hete significantly overestimates dose to PTV relative to XVMC -hence underdosing the target. MC is more complex and accurate with tissue-heterogeneities.The magnitude of variation significantly varies with ‘small-island-tumor’ surrounded by low-density lung tissues -PB algorithms lacks later electron scattering. Dose calculation with XVMC for lung SBRT is routinely performed in our clinic, its performance for head'neck/sinus cases will also be investigated.« less

Roof Plate-Derived Radial Glial-like Cells Support Developmental Growth of Rapidly Adapting Mechanoreceptor Ascending Axons.

PubMed

Kridsada, Kim; Niu, Jingwen; Haldipur, Parthiv; Wang, Zhiping; Ding, Long; Li, Jian J; Lindgren, Anne G; Herrera, Eloisa; Thomas, Gareth M; Chizhikov, Victor V; Millen, Kathleen J; Luo, Wenqin

2018-06-05

Spinal cord longitudinal axons comprise some of the longest axons in our body. However, mechanisms that drive this extra long-distance axonal growth are largely unclear. We found that ascending axons of rapidly adapting (RA) mechanoreceptors closely abut a previously undescribed population of roof plate-derived radial glial-like cells (RGLCs) in the spinal cord dorsal column, which form a network of processes enriched with growth-promoting factors. In dreher mutant mice that lack RGLCs, the lengths of ascending RA mechanoreceptor axon branches are specifically reduced, whereas their descending and collateral branches, and other dorsal column and sensory pathways, are largely unaffected. Because the number and intrinsic growth ability of RA mechanoreceptors are normal in dreher mice, our data suggest that RGLCs provide critical non-cell autonomous growth support for the ascending axons of RA mechanoreceptors. Together, our work identifies a developmental mechanism specifically required for long-range spinal cord longitudinal axons. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Analysis and design of lattice materials for large cord and curvature variations in skin panels of morphing wings

NASA Astrophysics Data System (ADS)

Vigliotti, Andrea; Pasini, Damiano

2015-03-01

In the past few decades, several concepts for morphing wings have been proposed with the aim of improving the structural and aerodynamic performance of conventional aircraft wings. One of the most interesting challenges in the design of a morphing wing is represented by the skin, which needs to meet specific deformation requirements. In particular when morphing involves changes of cord or curvature, the skin is required to undergo large recoverable deformation in the actuation direction, while maintaining the desired shape and strength in the others. One promising material concept that can meet these specifications is represented by lattice materials. This paper examines the use of alternative planar lattices in the embodiment of a skin panel for cord and camber morphing of an aircraft wing. We use a structural homogenization scheme capable of capturing large geometric nonlinearity, to examine the structural performance of lattice skin concepts, as well as to tune their mechanical properties in desired directions.

Patterns of Spinal Sensory-Motor Connectivity Prescribed by a Dorsoventral Positional Template

PubMed Central

Sürmeli, Gülşen; Akay, Turgay; Ippolito, Gregory; Tucker, Philip W; Jessell, Thomas M

2011-01-01

Summary Sensory-motor circuits in the spinal cord are constructed with a fine specificity that coordinates motor behavior, but the mechanisms that direct sensory connections with their motor neuron partners remain unclear. The dorsoventral settling position of motor pools in the spinal cord is known to match the distal-to-proximal position of their muscle targets in the limb, but the significance of invariant motor neuron positioning is unknown. An analysis of sensory-motor connectivity patterns in FoxP1 mutant mice, where motor neuron position has been scrambled, shows that the final pattern of sensory-motor connections is initiated by the projection of sensory axons to discrete dorsoventral domains of the spinal cord without regard for motor neuron subtype, or indeed, the presence of motor neurons. By implication, the clustering and dorsoventral settling position of motor neuron pools serves as a determinant of the pattern of sensory input specificity, and thus motor coordination. PMID:22036571

Outcome Measures in Spinal Cord Injury

PubMed Central

Alexander, Marcalee S.; Anderson, Kim; Biering-Sorensen, Fin; Blight, Andrew R.; Brannon, Ruth; Bryce, Thomas; Creasey, Graham; Catz, Amiram; Curt, Armin; Donovan, William; Ditunno, John; Ellaway, Peter; Finnerup, Nanna B.; Graves, Daniel E.; Haynes, Beth Ann; Heinemann, Allen W.; Jackson, Amie B.; Johnston, Mark; Kalpakjian, Claire Z.; Kleitman, Naomi; Krassioukov, Andrei; Krogh, Klaus; Lammertse, Daniel; Magasi, Susan; Mulcahey, MJ; Schurch, Brigitte; Sherwood, Arthur; Steeves, John D.; Stiens, Steven; Tulsky, David S.; van Hedel, Hubertus J.A.; Whiteneck, Gale

2009-01-01

Study Design review by the Spinal Cord Outcomes Partnership Endeavor (SCOPE), which is a broad-based international consortium of scientists and clinical researchers representing academic institutions, industry, government agencies, not-for-profit organizations and foundations. Objectives assessment of current and evolving tools for evaluating human spinal cord injury (SCI) outcomes for both clinical diagnosis and clinical research studies. Methods a framework for the appraisal of evidence of metric properties was used to examine outcome tools or tests for accuracy, sensitivity, reliability and validity for human SCI. Results imaging, neurological, functional, autonomic, sexual health, bladder/bowel, pain, and psycho-social tools were evaluated. Several specific tools for human SCI studies have or are being developed to allow the more accurate determination for a clinically meaningful benefit (improvement in functional outcome or quality of life) being achieved as a result of a therapeutic intervention. Conclusion significant progress has been made, but further validation studies are required to identify the most appropriate tools for specific targets in a human SCI study or clinical trial. PMID:19381157

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumaran Nair, C; Hoffman, D; Wright, C

Purpose: We aim to evaluate a new commercial dose mimicking inverse-planning application that was designed to provide cross-platform treatment planning, for its dosimetric quality and efficiency. The clinical benefit of this application allows patients treated on O-shaped linac to receive an equivalent plan on conventional L-shaped linac as needed for workflow or machine downtime. Methods: The dose mimicking optimization process seeks to create a similar DVH of an O-shaped linac-based plans with an alternative treatment technique (IMRT or VMAT), by maintaining target conformity, and penalizing dose falloff outside the target. Ten head and neck (HN) helical delivery plans, including simplemore » and complex cases were selected for re-planning with the dose mimicking application. All plans were generated for a 6 MV beam model, using 7-field/ 9-field IMRT and VMAT techniques. PTV coverage (D1, D99 and homogeneity index [HI]), and OARs avoidance (Dmean / Dmax) were compared. Results: The resulting dose mimicked HN plans achieved acceptable PTV coverage for HI (VMAT 7.0±2.3, 7-fld 7.3±2.4, and 9-fld 7.0±2.4), D99 (98.0%±0.7%, 97.8%±0.7%, and 98.0%±0.7%), as well as D1 (106.4%±2.1%, 106.5%±2.2%, and 106.4%±2.1%), respectively. The OAR dose discrepancy varied: brainstem (2% to 4%), cord (3% to 6%), esophagus (−4% to −8%), larynx (−4% to 2%), and parotid (4% to 14%). Mimicked plans would typically be needed for 1–5 fractions of a treatment course, and we estimate <1% variance would be introduced in target coverage while maintaining comparable low dose to OARs. All mimicked plans were approved by independent physician and passed patient specific QA within our established tolerance. Conclusion: Dose mimicked plans provide a practical alternative for responding to clinical workflow issues, and provide reliability for patient treatment. The quality of dose mimicking for HN patients highly depends on the delivery technique, field numbers and angles, as well as user selection of structures.« less

SU-E-T-14: A Feasibility Study of Using Modified AP Proton Beam for Post-Operative Pancreatic Cancer Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, X; Witztum, A; Kenton, O

2014-06-01

Purpose: Due to the unpredictability of bowel gas movement, the PA beam direction is always favored for robust proton therapy in post-operative pancreatic cancer treatment. We investigate the feasibility of replacing PA beam with a modified AP beam to take the bowel gas uncertainty into account. Methods: Nine post-operative pancreatic cancer patients treated with proton therapy (5040cGy, 28 fractions) in our institution were randomly selected. The original plan uses PA and lateral direction passive-scattering proton beams. Beam weighting is about 1:1. All patients received weekly verification CTs to assess the daily variations(total 17 verification CTs). The PA direction beam wasmore » replaced by two other groups of AP direction beam. Group AP: takes 3.5% range uncertainty into account. Group APmod: compensates the bowel gas uncertainty by expanding the proximal margin to 2cm more. The 2cm margin was acquired from the average bowel diameter in from 100 adult abdominal CT scans near pancreatic region (+/- 5cm superiorly and inferiorly). Dose Volume Histograms(DVHs) of the verification CTs were acquired for robustness study. Results: Without the lateral beam, Group APmod is as robust as Group PA. In Group AP, more than 10% of iCTV D98/D95 were reduced by 4–8%. LT kidney and Liver dose robustness are not affected by the AP/PA beam direction. There is 10% of chance that RT kidney and cord will be hit by AP proton beam due to the bowel gas. Compared to Group PA, APmod plan reduced the dose to kidneys and cord max significantly, while there is no statistical significant increase in bowel mean dose. Conclusion: APmod proton beam for the target coverage could be as robust as the PA direction without sacrificing too much of bowel dose. When the AP direction beam has to be selected, a 2cm proximal margin should be considered.« less

A Phase I, Randomised, First-in-Human Study of an Antisense Oligonucleotide Directed Against SOD1 Delivered Intrathecally in SOD1-Familial ALS Patients

PubMed Central

Miller, Timothy; Pestronk, Alan; David, William; Rothstein, Jeffrey; Simpson, Ericka; Appel, Stanley H.; Andres, Patricia L.; Mahoney, Katy; Allred, Peggy; Alexander, Katie; Ostrow, Lyle W.; Schoenfeld, David; Macklin, Eric A.; Norris, Daniel A.; Manousakis, Georgios; Crisp, Matthew; Smith, Richard; Bennett, C.F.; Bishop, Kathie; Cudkowicz, Merit E

2013-01-01

Objective To evaluate the safety, tolerability, and pharmacokinetics of an antisense oligonucleotide designed to inhibit SOD1 expression (ISIS 333611) following intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis (ALS). Background Mutations in SOD1 cause 13% of familial ALS. In animal studies, ISIS 333611 delivered to the cerebrospinal fluid (CSF) distributed to the brain and spinal cord, decreased SOD1 mRNA and protein levels in spinal cord tissue, and prolonged survival in the SOD1G93A rat ALS model. Methods In a randomized, placebo controlled Phase 1 trial, ISIS 333611 was delivered by intrathecal infusion using an external pump over 11.5 hours at increasing doses to four cohorts of eight SOD1 positive ALS subjects (randomized 6 drug: 2 placebo/cohort). Subjects were allowed to re-enroll in subsequent cohorts. Safety and tolerability assessments were made during the infusion and periodically over 28 days following the infusion. CSF and plasma drug levels were measured. Findings No dose-limiting toxicities were identified at doses up to 3.0 mg. No safety or tolerability concerns related to ISIS 333611 were identified. There were no serious adverse events (AEs) in ISIS 333611-treated subjects. Re-enrollment and re-dosing of subjects with ISIS 333611 was also well tolerated. Dose-dependent CSF and plasma concentrations were observed. Interpretation In this first clinical study to report intrathecal delivery of an antisense oligonucleotide, ISIS 333611 was well tolerated when administered as an intrathecal infusion in subjects with SOD1 familial ALS. CSF and plasma drug levels were consistent with levels predicted from preclinical studies. These results suggest that antisense oligonucleotide delivery to the central nervous system may be a feasible therapeutic strategy for neurological disorders. Source of funding ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals PMID:23541756

Preliminary analysis of the sequential simultaneous integrated boost technique for intensity-modulated radiotherapy for head and neck cancers.

PubMed

Miyazaki, Masayoshi; Nishiyama, Kinji; Ueda, Yoshihiro; Ohira, Shingo; Tsujii, Katsutomo; Isono, Masaru; Masaoka, Akira; Teshima, Teruki

2016-07-01

The aim of this study was to compare three strategies for intensity-modulated radiotherapy (IMRT) for 20 head-and-neck cancer patients. For simultaneous integrated boost (SIB), doses were 66 and 54 Gy in 30 fractions for PTVboost and PTVelective, respectively. Two-phase IMRT delivered 50 Gy in 25 fractions to PTVelective in the First Plan, and 20 Gy in 10 fractions to PTVboost in the Second Plan. Sequential SIB (SEQ-SIB) delivered 55 Gy and 50 Gy in 25 fractions, respectively, to PTVboost and PTVelective using SIB in the First Plan and 11 Gy in 5 fractions to PTVboost in the Second Plan. Conformity indexes (CIs) (mean ± SD) for PTVboost and PTVelective were 1.09 ± 0.05 and 1.34 ± 0.12 for SIB, 1.39 ± 0.14 and 1.80 ± 0.28 for two-phase IMRT, and 1.14 ± 0.07 and 1.60 ± 0.18 for SEQ-SIB, respectively. CI was significantly highest for two-phase IMRT. Maximum doses (Dmax) to the spinal cord were 42.1 ± 1.5 Gy for SIB, 43.9 ± 1.0 Gy for two-phase IMRT and 40.3 ± 1.8 Gy for SEQ-SIB. Brainstem Dmax were 50.1 ± 2.2 Gy for SIB, 50.5 ± 4.6 Gy for two-phase IMRT and 47.4 ± 3.6 Gy for SEQ-SIB. Spinal cord Dmax for the three techniques was significantly different, and brainstem Dmax was significantly lower for SEQ-SIB. The compromised conformity of two-phase IMRT can result in higher doses to organs at risk (OARs). Lower OAR doses in SEQ-SIB made SEQ-SIB an alternative to SIB, which applies unconventional doses per fraction. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Single-fraction flattening filter–free volumetric modulated arc therapy for lung cancer: Dosimetric results and comparison with flattened beams technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barbiero, Sara; Specialty School in Medical Physics, University of Pisa, Pisa; Rink, Alexandra

2016-01-01

Purpose: To report on single-fraction stereotactic body radiotherapy (RT) (SBRT) with flattening filter (FF)–free (FFF) volumetric modulated arc therapy (VMAT) for lung cancer and to compare dosimetric results with VMAT with FF. Methods and materials: Overall, 25 patients were treated with 6-MV FFF VMAT (Varian TrueBeam STx LINAC) to a prescribed dose of 24 Gy in a single fraction. Treatment plans were recreated using FF VMAT. Dose-volume indices, monitor units (MU), and treatment times were compared between FFF and FF VMAT techniques. Results: Dose constraints to PTV, spinal cord, and lungs were reached in FFF and FF plans. In FFFmore » plans, average conformity index was 1.13 (95% CI: 1.07 to1.38). Maximum doses to spinal cord, heart, esophagus, and trachea were 2.9 Gy (95% CI: 0.4 to 6.7 Gy), 0.8 Gy (95% CI: 0 to 3.6 Gy), 3.3 Gy (95% CI: 0.02 to 13.9 Gy), and 1.5 Gy (95% CI: 0 to 4.9 Gy), respectively. Average V7 Gy, V7.4 Gy, and mean dose to the healthy lung were 126.5 cc (95% CI: 41.3 to 248.9 cc), 107.3 cc (95% CI: 18.7 to 232.8 cc), and 1.1 Gy (95% CI: 0.3 to 2.2 Gy), respectively. No statistically significant differences were found in dosimetric results and MU between FF and FFF treatments. Treatment time was reduced by an average factor of 2.31 (95% CI: 2.15 to 2.43) from FF treatments to FFF, and the difference was statistically significant. Conclusions: FFF VMAT for lung SBRT provides equivalent dosimetric results to the target and organs at risk as FF VMAT while significantly reducing treatment time.« less

Beyond the Laboratory, Into the Clinic: What Dogs with Disk Disease Have Taught Us About Photobiomodulation for Spinal Cord Injury.

PubMed

Robinson, Narda G

2017-11-01

For spinal-cord-injured (SCI) patients, integrative medicine approaches such as photomedicine and acupuncture can renew hope and offer previously unrecognized ways to help regain function and improve quality of life. By understanding the mechanisms of action that these two modalities share, practitioners can better target specific attributes of spinal cord pathophysiology that are limiting recovery. Naturally occurring intervertebral disk disease (IVDD) in dogs affords unparalleled translational opportunities to develop treatment strategies involving photobiomodulation and acupuncture. Insights derived through clinical trials of dogs with IVDD have the potential to raise the standard of care for both human and canine SCI patients.

Predicting Patient-specific Dosimetric Benefits of Proton Therapy for Skull-base Tumors Using a Geometric Knowledge-based Method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hall, David C.; Trofimov, Alexei V.; Winey, Brian A.

Purpose: To predict the organ at risk (OAR) dose levels achievable with proton beam therapy (PBT), solely based on the geometric arrangement of the target volume in relation to the OARs. A comparison with an alternative therapy yields a prediction of the patient-specific benefits offered by PBT. This could enable physicians at hospitals without proton capabilities to make a better-informed referral decision or aid patient selection in model-based clinical trials. Methods and Materials: Skull-base tumors were chosen to test the method, owing to their geometric complexity and multitude of nearby OARs. By exploiting the correlations between the dose and distance-to-targetmore » in existing PBT plans, the models were independently trained for 6 types of OARs: brainstem, cochlea, optic chiasm, optic nerve, parotid gland, and spinal cord. Once trained, the models could estimate the feasible dose–volume histogram and generalized equivalent uniform dose (gEUD) for OAR structures of new patients. The models were trained using 20 patients and validated using an additional 21 patients. Validation was achieved by comparing the predicted gEUD to that of the actual PBT plan. Results: The predicted and planned gEUD were in good agreement. Considering all OARs, the prediction error was +1.4 ± 5.1 Gy (mean ± standard deviation), and Pearson's correlation coefficient was 93%. By comparing with an intensity modulated photon treatment plan, the model could classify whether an OAR structure would experience a gain, with a sensitivity of 93% (95% confidence interval: 87%-97%) and specificity of 63% (95% confidence interval: 38%-84%). Conclusions: We trained and validated models that could quickly and accurately predict the patient-specific benefits of PBT for skull-base tumors. Similar models could be developed for other tumor sites. Such models will be useful when an estimation of the feasible benefits of PBT is desired but the experience and/or resources required for treatment planning are unavailable.« less

SU-E-T-572: Normal Lung Tissue Sparing in Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, C; Ju, S; Ahn, Y

2015-06-15

Purpose: To compare normal lung-sparing capabilities of three advanced radiation therapy techniques for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: Four-dimensional computed tomography (4DCT) was performed in 10 patients with stage IIIb LA-NSCLC. The internal target volume (ITV); planning target volume (PTV); and organs at risks (OARs) such as spinal cord, total normal lung, heart, and esophagus were delineated for each CT data set. Intensity-modulated radiation therapy (IMRT), Tomohelical-IMRT (TH-IMRT), and TomoDirect-IMRT (TD-IMRT) plans were generated (total prescribed dose, 66 Gy in 33 fractions to the PTV) for each patient. To reduce the normal lung dose, complete and directionalmore » block function was applied outside the normal lung far from the target for both TH-IMRT and TD-IMRT, while pseudo- OAR was set in the same region for IMRT. Dosimetric characteristics of the three plans were compared in terms of target coverage, the sparing capability for the OAR, and the normal tissue complication probability (NTCP). Beam delivery efficiency was also compared. Results: TH-IMRT and TD-IMRT provided better target coverage than IMRT plans. Lung volume receiving ≥–30 Gy, mean dose, and NTCP were significant with TH-IMRT than with IMRT (p=0.006), and volume receiving ≥20–30 Gy was lower in TD-IMRT than in IMRT (p<0.05). Compared with IMRT, TH-IMRT had better sparing effect on the spinal cord (Dmax, NTCP) and heart (V45) (p<0.05). NTCP for the spinal cord, V45 and V60 for the heart, and Dmax for the esophagus were significantly lower in TD-IMRT than in IMRT. The monitor units per fraction were clearly smaller for IMRT than for TH-IMRT and TD-IMRT (p=0.006). Conclusion: In LA-NSCLC, TH-IMRT gave superior PTV coverage and OAR sparing compared to IMRT. TH-IMRT provided better control of the lung volume receiving ≥5–30 Gy. The delivery time and monitor units were lower in TD-IMRT than in TH-IMRT.« less

Efficiency gains for spinal radiosurgery using multicriteria optimization intensity modulated radiation therapy guided volumetric modulated arc therapy planning.

PubMed

Chen, Huixiao; Winey, Brian A; Daartz, Juliane; Oh, Kevin S; Shin, John H; Gierga, David P

2015-01-01

To evaluate plan quality and delivery efficiency gains of volumetric modulated arc therapy (VMAT) versus a multicriteria optimization-based intensity modulated radiation therapy (MCO-IMRT) for stereotactic radiosurgery of spinal metastases. MCO-IMRT plans (RayStation V2.5; RaySearch Laboratories, Stockholm, Sweden) of 10 spinal radiosurgery cases using 7-9 beams were developed for clinical delivery, and patients were replanned using VMAT with partial arcs. The prescribed dose was 18 Gy, and target coverage was maximized such that the maximum dose to the planning organ-at-risk volume (PRV) of the spinal cord was 10 or 12 Gy. Dose-volume histogram (DVH) constraints from the clinically acceptable MCO-IMRT plans were utilized for VMAT optimization. Plan quality and delivery efficiency with and without collimator rotation for MCO-IMRT and VMAT were compared and analyzed based upon DVH, planning target volume coverage, homogeneity index, conformity number, cord PRV sparing, total monitor units (MU), and delivery time. The VMAT plans were capable of matching most DVH constraints from the MCO-IMRT plans. The ranges of MU were 4808-7193 for MCO-IMRT without collimator rotation, 3509-5907 for MCO-IMRT with collimator rotation, 4444-7309 for VMAT without collimator rotation, and 3277-5643 for VMAT with collimator of 90 degrees. The MU for the VMAT plans were similar to their corresponding MCO-IMRT plans, depending upon the complexity of the target and PRV geometries, but had a larger range. The delivery times of the MCO-IMRT and VMAT plans, both with collimator rotation, were 18.3 ± 2.5 minutes and 14.2 ± 2.0 minutes, respectively (P < .05). The MCO-IMRT and VMAT can create clinically acceptable plans for spinal radiosurgery. The MU for MCO-IMRT and VMAT can be reduced significantly by utilizing a collimator rotation following the orientation of the spinal cord. Plan quality for VMAT is similar to MCO-IMRT, with similar MU for both modalities. Delivery times can be reduced by nominally 25% with VMAT. Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Olfactory ensheathing cells but not fibroblasts reduce the duration of autonomic dysreflexia in spinal cord injured rats.

PubMed

Cloutier, Frank; Kalincik, Tomas; Lauschke, Jenny; Tuxworth, Gervase; Cavanagh, Brenton; Meedeniya, Adrian; Mackay-Sim, Alan; Carrive, Pascal; Waite, Phil

2016-12-01

Autonomic dysreflexia is a common complication after high level spinal cord injury and can be life-threatening. We have previously shown that the acute transplantation of olfactory ensheathing cells into the lesion site of rats transected at the fourth thoracic spinal cord level reduced autonomic dysreflexia up to 8weeks after spinal cord injury. This beneficial effect was correlated with changes in the morphology of sympathetic preganglionic neurons despite the olfactory cells surviving no longer than 3weeks. Thus the transitory presence of olfactory ensheathing cells at the injury site initiated long-term functional as well as morphological changes in the sympathetic preganglionic neurons. The primary aim of the present study was to evaluate whether olfactory ensheathing cells survive after transplantation within the parenchyma close to sympathetic preganglionic neurons and whether, in this position, they still reduce the duration of autonomic dysreflexia and modulate sympathetic preganglionic neuron morphology. The second aim was to quantify the density of synapses on the somata of sympathetic preganglionic neurons with the hypothesis that the reduction of autonomic dysreflexia requires synaptic changes. As a third aim, we evaluated the cell type-specificity of olfactory ensheathing cells by comparing their effects with a control group transplanted with fibroblasts. Animals transplanted with OECs had a faster recovery from hypertension induced by colorectal distension at 6 and 7weeks but not at 8weeks after T4 spinal cord transection. Olfactory ensheathing cells survived for at least 8weeks and were observed adjacent to sympathetic preganglionic neurons whose overall number of primary dendrites was reduced and the synaptic density on the somata increased, both caudal to the lesion site. Our results showed a long term cell type-specific effects of olfactory ensheathing cells on sympathetic preganglionic neurons morphology and on the synaptic density on their somata, and a transient cell type-specific reduction of autonomic dysreflexia. Copyright © 2016 Elsevier B.V. All rights reserved.

Important Clinical Rehabilitation Principles Unique to People with Non-traumatic Spinal Cord Dysfunction.

PubMed

New, Peter Wayne; Eriks-Hoogland, Inge; Scivoletto, Giorgio; Reeves, Ronald K; Townson, Andrea; Marshall, Ruth; Rathore, Farooq A

2017-01-01

Background: Non-traumatic spinal cord dysfunction (SCDys) is caused by a large range of heterogeneous etiologies. Although most aspects of rehabilitation for traumatic spinal cord injury and SCDys are the same, people with SCDys have some unique rehabilitation issues. Purpose: This article presents an overview of important clinical rehabilitation principles unique to SCDys. Methods: Electronic literature search conducted (January 2017) using MEDLINE and Embase (1990-2016) databases for publications regarding SCDys. The focus of the literature search was on identifying publications that present suggestions regarding the clinical rehabilitation of SCDys. Results: The electronic search of MEDLINE and Embase identified no relevant publications, and the publications included were from the authors' libraries. A number of important clinical rehabilitation principles unique to people with SCDys were identified, including classification issues, general rehabilitation issues, etiology-specific issues, and a role for the rehabilitation physician as a diagnostic clinician. The classification issues were regarding the etiology of SCDys and the International Standards for Neurological Classification of Spinal Cord Injury. The general rehabilitation issues were predicting survival, improvement, and rehabilitation outcomes; admission to spinal rehabilitation units, including selection decision issues; participation in rehabilitation; and secondary health conditions. The etiology-specific issues were for SCDys due to spinal cord degeneration, tumors, and infections. Conclusions: Although there are special considerations regarding the rehabilitation of people with SCDys, such as the potential for progression of the underlying condition, functional improvement is typically significant with adequate planning of rehabilitation programs and special attention regarding the clinical condition of patients with SCDys.

CRISPR-mediated genomic deletion of Sox2 in the axolotl shows a requirement in spinal cord neural stem cell amplification during tail regeneration.

PubMed

Fei, Ji-Feng; Schuez, Maritta; Tazaki, Akira; Taniguchi, Yuka; Roensch, Kathleen; Tanaka, Elly M

2014-09-09

The salamander is the only tetrapod that functionally regenerates all cell types of the limb and spinal cord (SC) and thus represents an important regeneration model, but the lack of gene-knockout technology has limited molecular analysis. We compared transcriptional activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPRs) in the knockout of three loci in the axolotl and find that CRISPRs show highly penetrant knockout with less toxic effects compared to TALENs. Deletion of Sox2 in up to 100% of cells yielded viable F0 larvae with normal SC organization and ependymoglial cell marker expression such as GFAP and ZO-1. However, upon tail amputation, neural stem cell proliferation was inhibited, resulting in spinal-cord-specific regeneration failure. In contrast, the mesodermal blastema formed normally. Sox3 expression during development, but not regeneration, most likely allowed embryonic survival and the regeneration-specific phenotype. This analysis represents the first tissue-specific regeneration phenotype from the genomic deletion of a gene in the axolotl. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

The impact of male burials on the construction of Corded Ware identity: Reconstructing networks of information in the 3rd millennium BC.

PubMed

Bourgeois, Quentin; Kroon, Erik

2017-01-01

The emergence of Corded Ware Groups throughout Europe in the 3rd millennium BC is one of the most defining events in European history. From the Wolga to the Rhine communities start to speak Indo-European languages and bury their dead in an extremely similar fashion. Recent ancient DNA-analyses identify a massive migration from the Eurasian steppe as the prime cause for this event. However, there is a fundamental difference between expressing a Corded Ware identity-the sharing of world views and ideas-and having a specific DNA-profile. Therefore, we argue that investigating the exchange of cultural information on burial rites between these communities serves as a crucial complement to the exchange of biological information. By adopting a practice perspective to 1161 Corded Ware burials throughout north-western Europe, combined with similarity indexes and network representations, we demonstrate a high degree of information sharing on the burial ritual between different regions. Moreover, we show that male burials are much more international in character than female burials and as such can be considered as the vector along which cultural information and Corded Ware identity was transmitted. This finding highlights an underlying complex societal organization of Corded Ware burial rites in which gender roles had a significant impact on the composition and transmission of cultural information. Our findings corroborate recent studies that suggest the Corded Ware was a male focused society.

Planning comparison between intensity modulated radiation therapy and intensity modulated proton therapy in a case of head and neck cancer

NASA Astrophysics Data System (ADS)

Nguyen, T. T. C.; Nguyen, B. T.; Mai, N. V.

2018-03-01

In this work, we made the comparison between IMRT plan and IMPT plan for a head and neck case. We used Prowess Panther to perform IMRT plan and LAP- CERR for IMPT plan. The result showed that IMPT plan had better coverage than IMRT plan. In the IMRT plan, normal structures received higher dose with higher volume. Especially, the maximum dose of spinal cord is 31.5 Gy (RBE) using IMRT technique compared to 13.5 Gy (RBE) using IMPT technique. These results showed that IMPT is beneficial for head and neck cancer compared to IMRT technique.

SU-E-T-503: Intensity Modulated Proton Therapy (IMPT) Versus Intensity Modulated X-Ray Therapy (IMRT) for Patient with Hepatocellular Carcinoma: A Dosimetric Comparison

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, H; Zhao, L; Prabhu, K

2015-06-15

Purpose This study compares the dosimetric parameters in treatment of unresectable hepatocellular carcinoma between intensity modulated proton therapy (IMPT) and intensity modulated x-ray radiation therapy (IMRT). Methods and Materials: We studied four patients treated at our institution. All patients were simulated supine with 4D-CT using a GE light speed simulator with a maximum slice thickness of 3mm. The average CT and an internal target volume to account for respiration motion were used for planning. Both IMRT and IMPT plans were created using Elekta’s CMSXiO treatment planning system (TPS). The prescription dose was 58.05 CGE in 15 fractions. The IMRT plansmore » had five beams with combination of co-planar and non-co-planar. The IMPT plans had 2 to 3 beams. Dose comparison was performed based on the averaged results of the four patients. Results The mean dose and V95% to PTV were 58.24CGE, 98.57% for IMPT, versus 57.34CGE and 96.68% for IMRT, respectively. The V10, V20, V30 and mean dose of the normal liver for IMPT were 23.10%, 18.61%, 13.75% and 9.78 CGE; and 47.19%, 37.55%, 22.73% and 17.12CGE for IMRT. The spinal cord didn’t receive any dose in IMPT technique, but received a maximum of 18.77CGE for IMRT. The IMPT gave lower maximum dose to the stomach as compared to IMRT (19.26 vs 26.35CGE). V14 for left and right kidney was 0% and 2.32% for IMPT and 3.89% and 29.54% for IMRT. The mean dose, V35, V40 and V45 for small bowl were similar in both techniques, 0.74CGE, 6.27cc, 4.85cc and 3.53 cc for IMPT, 3.47CGE, 9.73cc, 7.61cc 5.35cc for IMRT. Conclusion Based on this study, IMPT plans gave less dose to the critical structures such as normal liver, kidney, stomach and spinal cord as compared to IMRT plans, potentially leading to less toxicity and providing better quality of life for patients.« less

Primary Intramedullary Malignant Lymphoma in the Cervical Cord with a Presyrinx State

PubMed Central

Sugawara, Atsushi; Koji, Takahiro; Beppu, Takaaki; Mue, Yoshiharu; Sugai, Tamotsu; Ogasawara, Knuaki

2017-01-01

A 79-year-old man presented with primary intramedullary malignant lymphoma with a presyrinx state in the cervical cord manifesting as left hemiparesis and hemidysesthesia. The magnetic resonance imaging (MRI) scan showed an intramedullary mass in the cervical spinal cord at the level of C1 and T2-weighted image prolongation from the medulla to the level of C5. According to the progression of hemiparesis, he underwent an emergency removal of the tumor under general anesthesia. The tumor was totally removed, and the peritumoral signal abnormality was not present in the postoperative MRI. Histological examination revealed diffuse large B cell lymphoma. While brain MRI, bone marrow puncture, and 18F-fluorodeoxy-glucose positron emission tomography (18FDG-PET) of the whole body were performed to find out a primary lesion, there were no abnormalities. He underwent a high-dose methotrexate-based chemotherapy and a local irradiation therapy (40Gy). He has been alive for more than two years since the symptom onset, and without any evidence of recurrence. This case suggests that malignant lymphoma, as an infiltrating and rapidly progressive tumor, may be accompanied by syrinx. PMID:29507854

Effects of intrathecal ketorolac on human experimental pain

PubMed Central

Eisenach, James C.; Curry, Regina; Tong, Chuanyao; Houle, Timothy T.; Yaksh, Tony L.

2010-01-01

Background Nonsteroidal antiinflammatory drugs, the most commonly used analgesics, reduce pain by inhibiting cyclooxygenase at peripheral sites of inflammation, but potentially also by inhibiting cyclooxygenase in the central nervous system, especially the spinal cord. Animal studies suggest that products of cyclooxygenase in the spinal cord do not alter pain responses to acute noxious stimuli, but reduce pain and sensitization following peripheral inflammation. We used spinal injection of small doses of the cyclooxygenase inhibitor, ketorolac, to survey the role of spinal cyclooxygenase in human experimental pain and hypersensitivity states. Methods Following regulatory agency approval and informed consent, we examined the effect of 2.0 mg intrathecal ketorolac in 41 healthy volunteers to acute noxious thermal stimuli in normal skin and to mechanical stimuli in skin sensitized by topical capsaicin or ultraviolet burn. We also examined the effect of intravenous ketorolac, Results Intrathecal ketorolac reduced hypersensitivity when it was induced by a combination of ultraviolet burn plus intermittent heat and, according to one of two analytical strategies, when it was induced by ultraviolet burn alone. Conclusions These data suggest a more limited role for spinal cord cyclooxygenase in human pain states than predicted by studies in animals. PMID:20395821

Irradiation of Pediatric High-Grade Spinal Cord Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tendulkar, Rahul D.; Pai Panandiker, Atmaram S., E-mail: atmaram.pai-panandiker@stjude.or; Wu Shengjie

2010-12-01

Purpose: To report the outcome using radiation therapy (RT) for pediatric patients with high-grade spinal cord tumors. Methods and Materials: A retrospective chart review was conducted that included 17 children with high-grade spinal cord tumors treated with RT at St. Jude Children's Research Hospital between 1981 and 2007. Three patients had gross total resection, 11 had subtotal resection, and 3 underwent biopsy. The tumor diagnosis was glioblastoma multiforme (n = 7), anaplastic astrocytoma (n = 8), or anaplastic oligodendroglioma (n = 2). Seven patients received craniospinal irradiation (34.2-48.6 Gy). The median dose to the primary site was 52.2 Gy (range,more » 38-66 Gy). Results: The median progression-free and overall survivals were 10.8 and 13.8 months, respectively. Local tumor progression at 12 months (79% vs. 30%, p = 0.02) and median survival (13.1 vs. 27.2 months, p = 0.09) were worse for patients with glioblastoma multiforme compared with anaplastic astrocytoma or oligodendroglioma. The median overall survival was shorter for patients when failure included neuraxis dissemination (n = 8) compared with local failure alone (n = 5), 9.6 vs. 13.8 months, p = 0.08. Three long-term survivors with World Health Organization Grade III tumors were alive with follow-up, ranging from 88-239 months. Conclusions: High-grade spinal cord primary tumors in children have a poor prognosis. The propensity for neuraxis metastases as a component of progression after RT suggests the need for more aggressive therapy.« less

M-ficolin concentrations in cord blood are related to circulating phagocytes and to early-onset sepsis.

PubMed

Schlapbach, Luregn J; Kjaer, Troels R; Thiel, Steffen; Mattmann, Maika; Nelle, Mathias; Wagner, Bendicht P; Ammann, Roland A; Aebi, Christoph; Jensenius, Jens C

2012-04-01

The pattern-recognition molecule M-ficolin is synthesized by monocytes and neutrophils. M-ficolin activates the complement system in a manner similar to mannan-binding lectin (MBL), but little is known about its role in host defense. Neonates are highly vulnerable to bacterial sepsis, in particular, due to their decreased phagocytic function. M-ficolin cord blood concentration was positively correlated with the absolute phagocyte count (ρ 0.51, P < 0.001) and with immature/total neutrophil ratio (ρ 0.34, P < 0.001). When comparing infants with sepsis and controls, a high M-ficolin cord blood concentration (>1,000 ng/ml) was associated with early-onset sepsis (EOS) (multivariate odds ratio 10.92, 95% confidence interval 2.21-54.02, P = 0.003). Experimental exposure of phagocytes isolated from adult donors to Escherichia coli resulted in a significant time- and dose-dependent release of M-ficolin. In conclusion, M-ficolin concentrations were related to circulating phagocytes and EOS. Our results indicate that bacterial sepsis can trigger M-ficolin release by phagocytes. Future studies should investigate whether M-ficolin may be used as a marker of neutrophil activation during invasive infections. We investigated M-ficolin in 47 infants with culture-positive sepsis during the first 30 days of life (13 with EOS and in 94 matched controls. M-ficolin was measured in cord blood using time-resolved immunofluorometric assay (TRIFMA). Multivariate logistic regression was performed.

The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice.

PubMed

Almad, Akshata; Lash, A Todd; Wei, Ping; Lovett-Racke, Amy E; McTigue, Dana M

2011-12-01

Peroxisome Proliferator Activated Receptor (PPAR)-α is a key regulator of lipid metabolism and recent studies reveal it also regulates inflammation in several different disease models. Gemfibrozil, an agonist of PPAR-α, is a FDA approved drug for hyperlipidemia and has been shown to inhibit clinical signs in a rodent model of multiple sclerosis. Since many studies have shown improved outcome from spinal cord injury (SCI) by anti-inflammatory and neuroprotective agents, we tested the efficacy of oral gemfibrozil given before or after SCI for promoting tissue preservation and behavioral recovery after spinal contusion injury in mice. Unfortunately, the results were contrary to our hypothesis; in our first attempt, gemfibrozil treatment exacerbated locomotor deficits and increased tissue pathology after SCI. In subsequent experiments, the behavioral effects were not replicated but histological outcomes again were worse. We also tested the efficacy of a different PPAR-α agonist, fenofibrate, which also modulates immune responses and is beneficial in several neurodegenerative disease models. Fenofibrate treatment did not improve recovery, although there was a slight trend for a modest increase in histological tissue sparing. Based on our results, we conclude that PPAR-α agonists yield either no effect or worsen recovery from spinal cord injury, at least at the doses and the time points of drug delivery tested here. Further, patients sustaining spinal cord injury while taking gemfibrozil might be prone to exacerbated tissue damage. Copyright © 2011 Elsevier Inc. All rights reserved.

A sea urchin Na(+)K(+)2Cl(-) cotransporter is involved in the maintenance of calcification-relevant cytoplasmic cords in Strongylocentrotus droebachiensis larvae.

PubMed

Basse, Wiebke C; Gutowska, Magdalena A; Findeisen, Ulrike; Stumpp, Meike; Dupont, Sam; Jackson, Daniel J; Himmerkus, Nina; Melzner, Frank; Bleich, Markus

2015-09-01

The cellular mechanisms of calcification in sea urchin larvae are still not well understood. Primary mesenchyme cells within the larval body cavity form a syncytium to secrete CaCO3 spicules from intracellular amorphous CaCO3 (ACC) stores. We studied the role of Na(+)K(+)2Cl(-) cotransporter (NKCC) in intracellular ACC accumulation and larval spicule formation of Strongylocentrotus droebachiensis. First, we incubated growing larvae with three different loop diuretics (azosemide, bumetanide, and furosemide) and established concentration-response curves. All loop diuretics were able to inhibit calcification already at concentrations that specifically inhibit NKCC. Calcification was most effectively inhibited by azosemide (IC50=6.5 μM), while larval mortality and swimming ability were not negatively impacted by the treatment. The inhibition by bumetanide (IC50=26.4 μM) and furosemide (IC50=315.4 μM) resembled the pharmacological fingerprint of the mammalian NKCC1 isoform. We further examined the effect of azosemide on the maintenance of cytoplasmic cords and on the occurrence of calcification vesicles using fluorescent dyes (calcein, FM1-43). Fifty micromolars of azosemide inhibited the maintenance of cytoplasmic cords and resulted in increased calcein fluorescence within calcification vesicles. The expression of NKCC in S. droebachiensis was verified by PCR and Western blot with a specific NKCC antibody. In summary, the pharmacological profile of loop diuretics and their specific effects on calcification in sea urchin larvae suggest that they act by inhibition of NKCC via repression of cytoplasmic cord formation and maintenance. Copyright © 2015 Elsevier Inc. All rights reserved.

Multimodal intraoperative monitoring: an overview and proposal of methodology based on 1,017 cases

PubMed Central

Eggspuehler, Andreas; Muller, Alfred; Dvorak, Jiri

2007-01-01

To describe different currently available tests of multimodal intraoperative monitoring (MIOM) used in spine and spinal cord surgery indicating the technical parameters, application and interpretation as an easy understanding systematic overview to help implementation of MIOM and improve communication between neurophysiologists and spine surgeons. This article aims to give an overview and proposal of the different MIOM-techniques as used daily in spine and spinal cord surgery at our institution. Intensive research in neurophysiology over the past decades has lead to a profound understanding of the spinal cord, nerve functions and their intraoperative functional evaluation in anaesthetised patients. At present, spine surgeons and neurophysiologist are faced with 1,883 publications in PubMed on spinal cord monitoring. The value and the limitations of single monitoring methods are well documented. The diagnostic power of the multimodal approach in a larger study population in spine surgery, as measured with sensitivity and specificity, is dealt with elsewhere in this supplement (Sutter et al. in Eur Spine J Suppl, 2007). This paper aims to give a detailed description of the different modalities used in this study. Description of monitoring techniques of the descending and ascending spinal cord and nerve root pathways by motor evoked potentials of the spinal cord and muscles elicited after transcranial electrical motor cortex, spinal cord, cauda equina and nerve root stimulation, continuous EMG, sensory cortical and spinal evoked potentials, as well as direct spinal cord evoked potentials applied on 1,017 patients. The method of MIOM, continuously adapted according to the site, stage of surgery and potential danger to nerve tissues, proved to be applicable with online results, reliable and furthermore teachable. PMID:17653777

Evaluating a switch from meconium to umbilical cord tissue for newborn drug testing: A retrospective study at an academic medical center.

PubMed

Palmer, Kendra L; Wood, Kelly E; Krasowski, Matthew D

2017-04-01

The objective of this study was to compare detection rates of newborn drug exposure at an academic medical center transitioning from meconium to umbilical cord tissue toxicology testing. We performed an Institutional Review Board-approved retrospective chart review on all newborns (n=2072) for whom newborn drug testing was ordered at our academic medical center between June 2012 and August 2015 (in August 2013, umbilical cord tissue became the preferred specimen). Meconium toxicology testing was positive for at least one compound in 221 cases (21.3% of 1037 total specimens), with non-medical drug use identified in 85 cases (8.2%). Umbilical cord tissue toxicology testing was positive for at least one compound in 302 cases (29.2%), with non-medical drug use identified in 107 cases (10.3%). Of the cases involving non-medical drug use, the most common compounds detected were tetrahydrocannabinol and amphetamines. Non-medical drug use did not differ significantly between meconium and umbilical cord tissue, either as a total or for classes of drugs such as amphetamines, cannabinoids, and opiates. Maternal non-medical use of tramadol (not tested for in meconium) was identified in 5 cases (0.4%). There were significant differences in rate of detection of iatrogenic medications. Specifically, morphine, lorazepam, phenobarbital, and codeine were more commonly detected in meconium, while oxycodone was more commonly detected in umbilical cord tissue. Umbilical cord tissue toxicology testing yielded a similar detection rate compared to meconium testing. The use of umbilical cord tissue avoids detection of medications given to the neonate prior to meconium collection. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Evaluation Overview for the Massachusetts Childhood Obesity Research Demonstration (MA-CORD) Project

PubMed Central

Falbe, Jennifer; Taveras, Elsie M.; Gortmaker, Steve; Kulldorff, Martin; Perkins, Meghan; Blaine, Rachel E.; Franckle, Rebecca L.; Ganter, Claudia; Woo Baidal, Jennifer; Kwass, Jo-Ann; Buszkiewicz, James; Smith, Lauren; Land, Thomas

2015-01-01

Abstract Background: The Massachusetts Childhood Obesity Research Demonstration (MA-CORD) project is a 2-year, multilevel, multisector community intervention to prevent and control obesity among children 2–12 years of age from two predominantly low-income communities in Massachusetts. MA-CORD includes evidence-based interventions in multiple sectors, including community health centers, early care and education centers, schools, afterschool programs, the Special Supplemental Nutrition Program for Women, Infants and Children, and the broader community. Currently, implementation of MA-CORD is complete and the final year of data collection is in progress. Here, the MA-CORD evaluation plan is described and baseline data are presented. Methods/Design: The impact of MA-CORD on children's BMI, lifestyle behaviors, obesity-related care, and quality of life will be assessed using sector-specific, pre/post, time-series, and quasi-experimental designs. Change in the primary outcomes will be compared for intervention and comparison communities. Additionally, change in mean BMI and obesity prevalence in intervention school districts will be compared to similar districts throughout the state. Results: At baseline in 2012, approximately 16% of preschool-aged and 25% of school-aged children were obese. Moreover, 15–40% of children consumed no vegetables on the previous day, 25–75% drank a sugar-sweetened beverage on the previous day, up to 87% had insufficient physical activity, 50–75% had a television in the room where they slept, and 50–80% obtained insufficient sleep. Conclusions: There is ample room for improvement in BMI and health behaviors in children in MA-CORD communities. If successful, MA-CORD may serve as a model for multilevel, multisector approaches to childhood obesity prevention and control. PMID:25575095

Use Dose Bricks Concept to Implement Nasopharyngeal Carcinoma Treatment Planning

PubMed Central

Wu, Jia-Ming; Yu, Tsan-Jung; Yeh, Shyh-An; Chao, Pei-Ju; Huang, Chih-Jou

2014-01-01

Purpose. A “dose bricks” concept has been used to implement nasopharyngeal carcinoma treatment plan; this method specializes particularly in the case with bell shape nasopharyngeal carcinoma case. Materials and Methods. Five noncoplanar fields were used to accomplish the dose bricks technique treatment plan. These five fields include (a) right superior anterior oblique (RSAO), (b) left superior anterior oblique (LSAO), (c) right anterior oblique (RAO), (d) left anterior oblique (LAO), and (e) superior inferior vertex (SIV). Nondivergence collimator central axis planes were used to create different abutting field edge while normal organs were blocked by multileaf collimators in this technique. Results. The resulting 92% isodose curves encompassed the CTV, while maximum dose was about 115%. Approximately 50% volume of parotid glands obtained 10–15% of total dose and 50% volume of brain obtained less than 20% of total dose. Spinal cord receives only 5% from the scatter dose. Conclusions. Compared with IMRT, the expenditure of planning time and costing, “dose bricks” may after all be accepted as an optional implementation in nasopharyngeal carcinoma conformal treatment plan; furthermore, this method also fits the need of other nonhead and neck lesions if organ sparing and noncoplanar technique can be executed. PMID:24967395

Dietary and supplemental maternal methyl-group donor intake and cord blood DNA methylation.

PubMed

Pauwels, Sara; Ghosh, Manosij; Duca, Radu Corneliu; Bekaert, Bram; Freson, Kathleen; Huybrechts, Inge; A S Langie, Sabine; Koppen, Gudrun; Devlieger, Roland; Godderis, Lode

2017-01-02

Maternal nutrition is critically involved in the development and health of the fetus. We evaluated maternal methyl-group donor intake through diet (methionine, betaine, choline, folate) and supplementation (folic acid) before and during pregnancy in relation to global DNA methylation and hydroxymethylation and gene specific (IGF2 DMR, DNMT1, LEP, RXRA) cord blood methylation. A total of 115 mother-infant pairs were enrolled in the MAternal Nutrition and Offspring's Epigenome (MANOE) study. The intake of methyl-group donors was assessed using a food-frequency questionnaire. LC-MS/MS and pyrosequencing were used to measure global and gene specific methylation, respectively. Dietary intake of methyl-groups before and during pregnancy was associated with changes in LEP, DNMT1, and RXRA cord blood methylation. Statistically significant higher cord blood LEP methylation was observed when mothers started folic acid supplementation more than 6 months before conception compared with 3-6 months before conception (34.6 ± 6.3% vs. 30.1 ± 3.6%, P = 0.011, LEP CpG1) or no folic acid used before conception (16.2 ± 4.4% vs. 13.9 ± 3%, P = 0.036 for LEP CpG3 and 24.5 ± 3.5% vs. 22.2 ± 3.5%, P = 0.045 for LEP mean CpG). Taking folic acid supplements during the entire pregnancy resulted in statistically significantly higher cord blood RXRA methylation as compared with stopping supplementation in the second trimester (12.3 ± 1.9% vs. 11.1 ± 2%, P = 0.008 for RXRA mean CpG). To conclude, long-term folic acid use before and during pregnancy was associated with higher LEP and RXRA cord blood methylation, respectively. To date, pregnant women are advised to take a folic acid supplement of 400 µg/day from 4 weeks before until 12 weeks of pregnancy. Our results suggest significant epigenetic modifications when taking a folic acid supplement beyond the current advice.

Dosimetric evaluation of the feasibility of stereotactic body radiotherapy for primary lung cancer with lobe-specific selective elective nodal irradiation

PubMed Central

Komatsu, Tetsuya; Kunieda, Etsuo; Kitahara, Tadashi; Akiba, Takeshi; Nagao, Ryuta; Fukuzawa, Tsuyoshi

2016-01-01

More than 10% of all patients treated with stereotactic body radiotherapy (SBRT) for primary lung cancer develop regional lymph node recurrence. We evaluated the dosimetric feasibility of SBRT with lobe-specific selective elective nodal irradiation (ENI) on dose–volume histograms. A total of 21 patients were treated with SBRT for Stage I primary lung cancer between January 2010 and June 2012 at our institution. The extents of lobe-specific selective ENI fields were determined with reference to prior surgical reports. The ENI fields included lymph node stations (LNS) 3 + 4 + 11 for the right upper lobe tumors, LNS 7 + 11 for the right middle or lower lobe tumors, LNS 5 + 11 for the left upper lobe tumors, and LNS 7 + 11 for the left lower lobe tumors. A composite plan was generated by combining the ENI plan and the SBRT plan and recalculating for biologically equivalent doses of 2 Gy per fraction, using a linear quadratic model. The V20 of the lung, D1cm3 of the spinal cord, D1cm3 and D10cm3 of the esophagus and D10cm3 of the tracheobronchial wall were evaluated. Of the 21 patients, nine patients (43%) could not fulfill the dose constraints. In all these patients, the distance between the planning target volume (PTV) of ENI (PTVeni) and the PTV of SBRT (PTVsrt) was ≤2.0 cm. Of the three patients who developed regional metastasis, two patients had isolated lymph node failure, and the lymph node metastasis was included within the ENI field. When the distance between the PTVeni and PTVsrt is >2.0 cm, SBRT with selective ENI may therefore dosimetrically feasible. PMID:26566656

Effect of atelectasis changes on tissue mass and dose during lung radiotherapy.

PubMed

Guy, Christopher L; Weiss, Elisabeth; Jan, Nuzhat; Reshko, Leonid B; Christensen, Gary E; Hugo, Geoffrey D

2016-11-01

To characterize mass and density changes of lung parenchyma in non-small cell lung cancer (NSCLC) patients following midtreatment resolution of atelectasis and to quantify the impact this large geometric change has on normal tissue dose. Baseline and midtreatment CT images and contours were obtained for 18 NSCLC patients with atelectasis. Patients were classified based on atelectasis volume reduction between the two scans as having either full, partial, or no resolution. Relative mass and density changes from baseline to midtreatment were calculated based on voxel intensity and volume for each lung lobe. Patients also had clinical treatment plans available which were used to assess changes in normal tissue dose constraints from baseline to midtreatment. The midtreatment image was rigidly aligned with the baseline scan in two ways: (1) bony anatomy and (2) carina. Treatment parameters (beam apertures, weights, angles, monitor units, etc.) were transferred to each image. Then, dose was recalculated. Typical IMRT dose constraints were evaluated on all images, and the changes from baseline to each midtreatment image were investigated. Atelectatic lobes experienced mean (stdev) mass changes of -2.8% (36.6%), -24.4% (33.0%), and -9.2% (17.5%) and density changes of -66.0% (6.4%), -25.6% (13.6%), and -17.0% (21.1%) for full, partial, and no resolution, respectively. Means (stdev) of dose changes to spinal cord D max , esophagus D mean , and lungs D mean were 0.67 (2.99), 0.99 (2.69), and 0.50 Gy (2.05 Gy), respectively, for bone alignment and 0.14 (1.80), 0.77 (2.95), and 0.06 Gy (1.71 Gy) for carina alignment. Dose increases with bone alignment up to 10.93, 7.92, and 5.69 Gy were found for maximum spinal cord, mean esophagus, and mean lung doses, respectively, with carina alignment yielding similar values. 44% and 22% of patients had at least one metric change by at least 5 Gy (dose metrics) or 5% (volume metrics) for bone and carina alignments, respectively. Investigation of GTV coverage showed mean (stdev) changes in V Rx , D max , and D min of -5.5% (13.5%), 2.5% (4.2%), and 0.8% (8.9%), respectively, for bone alignment with similar results for carina alignment. Resolution of atelectasis caused mass and density decreases, on average, and introduced substantial changes in normal tissue dose metrics in a subset of the patient cohort.

Effect of atelectasis changes on tissue mass and dose during lung radiotherapy

PubMed Central

Guy, Christopher L.; Weiss, Elisabeth; Jan, Nuzhat; Reshko, Leonid B.; Christensen, Gary E.; Hugo, Geoffrey D.

2016-01-01

Purpose: To characterize mass and density changes of lung parenchyma in non-small cell lung cancer (NSCLC) patients following midtreatment resolution of atelectasis and to quantify the impact this large geometric change has on normal tissue dose. Methods: Baseline and midtreatment CT images and contours were obtained for 18 NSCLC patients with atelectasis. Patients were classified based on atelectasis volume reduction between the two scans as having either full, partial, or no resolution. Relative mass and density changes from baseline to midtreatment were calculated based on voxel intensity and volume for each lung lobe. Patients also had clinical treatment plans available which were used to assess changes in normal tissue dose constraints from baseline to midtreatment. The midtreatment image was rigidly aligned with the baseline scan in two ways: (1) bony anatomy and (2) carina. Treatment parameters (beam apertures, weights, angles, monitor units, etc.) were transferred to each image. Then, dose was recalculated. Typical IMRT dose constraints were evaluated on all images, and the changes from baseline to each midtreatment image were investigated. Results: Atelectatic lobes experienced mean (stdev) mass changes of −2.8% (36.6%), −24.4% (33.0%), and −9.2% (17.5%) and density changes of −66.0% (6.4%), −25.6% (13.6%), and −17.0% (21.1%) for full, partial, and no resolution, respectively. Means (stdev) of dose changes to spinal cord Dmax, esophagus Dmean, and lungs Dmean were 0.67 (2.99), 0.99 (2.69), and 0.50 Gy (2.05 Gy), respectively, for bone alignment and 0.14 (1.80), 0.77 (2.95), and 0.06 Gy (1.71 Gy) for carina alignment. Dose increases with bone alignment up to 10.93, 7.92, and 5.69 Gy were found for maximum spinal cord, mean esophagus, and mean lung doses, respectively, with carina alignment yielding similar values. 44% and 22% of patients had at least one metric change by at least 5 Gy (dose metrics) or 5% (volume metrics) for bone and carina alignments, respectively. Investigation of GTV coverage showed mean (stdev) changes in VRx, Dmax, and Dmin of −5.5% (13.5%), 2.5% (4.2%), and 0.8% (8.9%), respectively, for bone alignment with similar results for carina alignment. Conclusions: Resolution of atelectasis caused mass and density decreases, on average, and introduced substantial changes in normal tissue dose metrics in a subset of the patient cohort. PMID:27806593

SU-D-201-07: Exploring the Utility of 4D FDG-PET/CT Scans in Design of Radiation Therapy Planning Compared with 3D PET/CT: A Prospective Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, C; Yin, Y

2015-06-15

Purpose: A method using four-dimensional(4D) PET/CT in design of radiation treatment planning was proposed and the target volume and radiation dose distribution changes relative to standard three-dimensional (3D) PET/CT were examined. Methods: A target deformable registration method was used by which the whole patient’s respiration process was considered and the effect of respiration motion was minimized when designing radiotherapy planning. The gross tumor volume of a non-small-cell lung cancer was contoured on the 4D FDG-PET/CT and 3D PET/CT scans by use of two different techniques: manual contouring by an experienced radiation oncologist using a predetermined protocol; another technique using amore » constant threshold of standardized uptake value (SUV) greater than 2.5. The target volume and radiotherapy dose distribution between VOL3D and VOL4D were analyzed. Results: For all phases, the average automatic and manually GTV volume was 18.61 cm3 (range, 16.39–22.03 cm3) and 31.29 cm3 (range, 30.11–35.55 cm3), respectively. The automatic and manually volume of merged IGTV were 27.82 cm3 and 49.37 cm3, respectively. For the manual contour, compared to 3D plan the mean dose for the left, right, and total lung of 4D plan have an average decrease 21.55%, 15.17% and 15.86%, respectively. The maximum dose of spinal cord has an average decrease 2.35%. For the automatic contour, the mean dose for the left, right, and total lung have an average decrease 23.48%, 16.84% and 17.44%, respectively. The maximum dose of spinal cord has an average decrease 1.68%. Conclusion: In comparison to 3D PET/CT, 4D PET/CT may better define the extent of moving tumors and reduce the contouring tumor volume thereby optimize radiation treatment planning for lung tumors.« less

WE-AB-207B-01: Dose Tolerance for SBRT/SABR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grimm, J

Purpose: Stereotactic body radiation therapy (SBRT) / stereotactic ablative body radiotherapy (SABR) is gaining popularity, but quantitative dose tolerance has still been lacking. To improve this, the April 2016 issue of Seminars in Radiation Oncology will have normal tissue complication probability (NTCP) models for 10 critical structures: optic pathway, cochlea, oral mucosa, esophagus, chestwall, aorta, bronchi, duodenum, small bowel, and spinal cord. Methods: The project included more than 1500 treatments in 1–5 fractions using CyberKnife, Gamma Knife, or LINAC, with 60 authors from 15 institutions. NTCP models were constructed from the 97 grade 2–3 complications, predominantly scored using the commonmore » terminology criteria for adverse events (CTCAEv4). Dose volume histogram (DVH) data from each institutional dataset was loaded into the DVH Evaluator software (DiversiLabs, LLC, Huntingdon Valley, Pa) for modeling. The current state of the literature for the critical structures was depicted using DVH Risk Maps: comparative graphs of dose tolerance limits that can include estimated risk levels, reported complications, DVH data for study patients, as well as high- and low-risk dose tolerance limits. Results: For relatively acceptable toxicity like grade 1–3 rib fractures and chestwall pain, the high-risk limits have 50% risk and the low-risk limits have 5% risk. Emami et al (IJROBP 1991 May 15;21(1):109–22) used 50% and 5% risk levels for all structures, whereas this effort used clinically acceptable ranges for each: in structures like aorta or spinal cord where complications must be avoided, the high- and low-risk limits have about 3% and 1% risk, respectively, in this issue of Seminars. These statistically based guidelines can help ensure plan quality for each patient. Conclusion: NTCP for SBRT is now becoming available. Hypofractionated dose tolerance can be dramatically different than extrapolations of conventional fractionation so NTCP analysis of the SBRT/SBRT data is important to ensure safe clinical practice. Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and was used to analyze the data.« less

Screening for glucose-6-phosphate dehydrogenase deficiency in neonates: a comparison between cord and peripheral blood samples.

PubMed

AlSaif, Saif; Ponferrada, Ma Bella; AlKhairy, Khalid; AlTawil, Khalil; Sallam, Adel; Ahmed, Ibrahim; Khawaji, Mohammed; AlHathlol, Khalid; Baylon, Beverly; AlSuhaibani, Ahmed; AlBalwi, Mohammed

2017-07-11

The use of cord blood in the neonatal screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency is being done with increasing frequency but has yet to be adequately evaluated against the use of peripheral blood sample which is usually employed for confirmation. We sought to determine the incidence and gender distribution of G6PD deficiency, and compare the results of cord against peripheral blood in identifying G6PD DEFICIENCY neonates using quantitative enzyme activity assay. We carried out a retrospective and cross-sectional study employing review of primary hospital data of neonates born in a tertiary care center from January to December 2008. Among the 8139 neonates with cord blood G6PD assays, an overall incidence of 2% for G6PD deficiency was computed. 79% of these were males and 21% were females with significantly more deficient males (p < .001). Gender-specific incidence was 3.06% for males and 0.85% for females. A subgroup analysis comparing cord and peripheral blood samples (n = 1253) showed a significantly higher mean G6PD value for peripheral than cord blood (15.12 ± 4.52 U/g and 14.52 ± 4.43 U/g, respectively, p = 0.0008). However, the proportion of G6PD deficient neonates did not significantly differ in the two groups (p = 0.79). Sensitivity of cord blood in screening for G6PD deficiency, using peripheral G6PD assay as a gold standard was 98.6% with a NPV of 99.5%. There was no difference between cord and peripheral blood samples in discriminating between G6PD deficient and non-deficient neonates. A significantly higher mean peripheral G6PD assay reinforces the use of cord blood for neonatal screening since it has substantially low false negative results.

Umbilical cord blood banking: implications for perinatal care providers.

PubMed

Armson, B Anthony

2005-03-01

To evaluate the risks and benefits of umbilical cord blood banking for future stem cell transplantation and to provide guidelines for Canadian perinatal care providers regarding the counselling, procedural, and ethical implications of this potential therapeutic option. Selective or routine collection and storage of umbilical cord blood for future autologous (self) or allogenic (related or unrelated) transplantation of hematopoietic stem cells to treat malignant and nonmalignant disorders in children and adults. Maternal and perinatal morbidity, indications for umbilical cord blood transplantation, short- and long-term risks and benefits of umbilical cord blood transplantation, burden of umbilical cord blood collection on perinatal care providers, parental satisfaction, and health care costs. MEDLINE and PubMed searches were conducted from January 1970 to October 2003 for English-language articles related to umbilical cord blood collection, banking, and transplantation; the Cochrane library was searched; and committee opinions of the Royal College of Obstetricians and Gynaecologists, the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists were obtained. The evidence collected was reviewed and evaluated by the Maternal/Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC), and recommendations were made using the evaluation of evidence guidelines developed by the Canadian Task Force on the Periodic Health Exam. Umbilical cord blood is a readily available source of hematopoietic stem cells used with increasing frequency as an alternative to bone marrow or peripheral stem cells for transplantation in the treatment of malignant and nonmalignant conditions in children and adults. Umbilical cord blood transplantation provides a rich source of hematopoietic stem cells with several advantages, including prompt availability, decreased risk of transmissible viral infections and graft-versus-host disease (GVHD) in both human leukocyte antigen(HLA)-matched and HLA-mismatched stem cell transplants, and ease of collection with little risk to the mother or newborn. Potential limitations of umbilical cord blood transplantation include insufficient stem cell dose to reliably treat larger children and adult recipients, slower rate of engraftment, and the potential for transfer of genetically abnormal hematopoietic stem cells. The optimum method of umbilical cord blood transplantation is not yet clear, though available evidence would favour collection before delivery of the placenta. There are many unresolved ethical issues related to umbilical cord blood banking, particularly related to the rapid growth of private, for-profit, cord blood banks offering long-term storage for potential future autologous or related allogenic transplantation. The financial burden to the health care system for public cord blood banking and to families for private cord blood collection and storage is considerable. 1. Perinatal care providers should be informed about the promising clinical potential of hematopoietic stem cells in umbilical cord blood and about current indications for its collection, storage, and use, based on sound scientific evidence (II-3B). 2. Umbilical cord blood collection should be considered for a sibling or parent in need of stem cell transplantation when an HLA-identical bone marrow cell or peripheral stem cell donation from a sibling or parent is unavailable for transplantation (II-2B). 3. Umbilical cord blood should be considered when allogeneic transplantation is the treatment of choice for a child who does not have an HLA-identical sibling or a well-matched, unrelated adult bone marrow donor (II-2B). 4. Umbilical cord blood should be considered for allogeneic transplantation in adolescents and young adults with hematologic malignancies who have no suitable bone marrow donor and who require urgent transplantation (II-3B). 5. Altruistic donation of cord blood for public banking and subsequent allogeneic transplantation should be encouraged when umbilical cord blood banking is being considered by childbearing women, prenatal care providers, and(or) obstetric facilities (II-2B). 6. Collection and long-term storage of umbilical cord blood for autologous donation is not recommended because of the limited indications and lack of scientific evidence to support the practice (III-D). 7. Birth unit staff should receive training in standardized cord blood unit volume and reduce the rejection rate owing to labelling problems, bacterial contamination, and clotting (II-3B). 8. The safe management of obstetric delivery should never be compromised to facilitate cord blood collection. Manoeuvres to optimize cord blood unit volume, such as early clamping of the umbilical cord, may be employed at the discretion of the perinatal care team, provided the safety of the mother and newborn remains the major priority (III-A). 9. Collection of cord blood should be performed after the delivery of the infant but before delivery of the placenta, using a closed collection system and procedures that minimize risk of bacterial and maternal fluid contamination (see Figures 1a-1c) (I-B). 10. Public and private cord blood banks should strictly adhere to standardized policies and procedures for transportation, safety testing, HLA typing, cryopreservation, and long-term storage of umbilical cord blood units to prevent harm to the recipient, to eliminate the risk of transmitting communicable diseases, and thus to maximize the effectiveness of umbilical cord blood stem cell transplantation (II-1A). 11. Canada should establish registration, regulation, and accreditation of cord blood collection centres and banks (III-B). 12. Recruitment of cord blood donors should be fair and noncoercive. Criteria to ensure an equitable recruitment process include the following: (a) adequate supply to meet population transplantation needs; (b) fair distribution of the burdens and benefits of cord blood collection; (c) optimal timing of recruitment; (d) appropriately trained personnel; and (e) accurate recruitment message (III-A). 13. Informed consent for umbilical cord blood collection and banking should be obtained during prenatal care, before the onset of labour, with confirmation of consent after delivery (III-B). 14. Linkage of cord blood units and donors is recommended for public safety. Policies regarding the disclosure of abnormal test results to donor parents should be developed. Donor privacy and confidentiality of test results must be respected (III-C). 15. Commercial cord blood banks should be carefully regulated to ensure that promotion and pricing practices are fair, financial relationships are transparent, banked cord blood is stored and used according to approved standards, and parents and care providers understand the differences between autologous versus allogenic donations and private versus public banks (III-B). 16. Policies and procedures need to be developed by perinatal facilities and national health authorities to respond to prenatal requests for public and private cord blood banking (III-C).

Photons, protons or carbon ions for stage I non-small cell lung cancer - Results of the multicentric ROCOCO in silico study.

PubMed

Wink, Krista C J; Roelofs, Erik; Simone, Charles B; Dechambre, David; Santiago, Alina; van der Stoep, Judith; Dries, Wim; Smits, Julia; Avery, Stephen; Ammazzalorso, Filippo; Jansen, Nicolas; Jelen, Urszula; Solberg, Timothy; de Ruysscher, Dirk; Troost, Esther G C

2018-03-12

To compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial. For each patient, 3 photon plans [Intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and CyberKnife], a double scattered proton (DSP) and an intensity-modulated carbon-ion (IMIT) therapy plan were created. Dose prescription was 60 Gy (equivalent) in 8 fractions. The mean dose and dose to 2% of the clinical target volume (CTV) were lower for protons and ions compared with IMRT (p < 0.01). Doses to the lungs, heart, and mediastinal structures were lowest with IMIT (p < 0.01), doses to the spinal cord were lowest with DSP (p < 0.01). VMAT and CyberKnife allowed for reduced doses to most OARs compared with IMRT. Dose escalation was possible for 8 patients. Generally, the mediastinum was the primary dose-limiting organ. On average, the doses to the OARs were lowest using particles, with more homogenous CTV doses. Given the ability of VMAT and CyberKnife to limit doses to OARs compared with IMRT, the additional benefit of particles may only be clinically relevant in selected patients and thus should be carefully weighed for every individual patient. Copyright © 2018 Elsevier B.V. All rights reserved.

Contributions of identifiable neurons and neuron classes to lamprey vertebrate neurobiology.

PubMed

Buchanan, J T

2001-03-01

Among the advantages offered by the lamprey brainstem and spinal cord for studies of the structure and function of the nervous system is the unique identifiability of several pairs of reticulospinal neurons in the brainstem. These neurons have been exploited in investigations of the patterns of sensory input to these cells and the patterns of their outputs to spinal neurons, but no doubt these cells could be used much more effectively in exploring their roles in descending control of the spinal cord. The variability of cell positions of neurons in the spinal cord has precluded the recognition of unique spinal neurons. However, classes of nerve cells can be readily defined and characterized within the lamprey spinal cord and this has led to progress in understanding the cellular and synaptic mechanisms of locomotor activity. In addition, both the identifiable reticulospinal cells and the various spinal nerve cell classes and their known synaptic interactions have been used to demonstrate the degree and specificity of regeneration within the lamprey nervous system. The lack of uniquely identifiable cells within the lamprey spinal cord has hampered progress in these areas, especially in gaining a full understanding of the locomotor network and how neuromodulation of the network is accomplished.

Engraftment, neuroglial transdifferentiation and behavioral recovery after complete spinal cord transection in rats.

PubMed

Sabino, Luzzi; Maria, Crovace Alberto; Luca, Lacitignola; Valerio, Valentini; Edda, Francioso; Giacomo, Rossi; Gloria, Invernici; Juan, Galzio Renato; Antonio, Crovace

2018-01-01

Proof of the efficacy and safety of a xenogeneic mesenchymal stem cell (MSCs) transplant for spinal cord injury (SCI) may theoretically widen the spectrum of possible grafts for neuroregeneration. Twenty rats were submitted to complete spinal cord transection. Ovine bone marrow MSCs, retrovirally transfected with red fluorescent protein and not previously induced for neuroglial differentiation, were applied in 10 study rats (MSCG). Fibrin glue was injected in 10 control rats (FGG). All rats were evaluated on a weekly basis and scored using the Basso-Beattie-Bresnahan (BBB) locomotor scale for 10 weeks, when the collected data were statistically analyzed. The spinal cords were then harvested and analyzed with light microscopy, immunohistochemistry, and immunofluorescence. Ovine MSCs culture showed positivity for Nestin. MSCG had a significant and durable recovery of motor functions ( P <.001). Red fluorescence was found at the injury sites in MSCG. Positivity for Nestin, tubulin βIII, NG2 glia, neuron-specific enolase, vimentin, and 200 kD neurofilament were also found at the same sites. Xenogeneic ovine bone marrow MSCs proved capable of engrafting into the injured rat spinal cord. Transdifferentiation into a neuroglial phenotype was able to support partial functional recovery.

Engraftment, neuroglial transdifferentiation and behavioral recovery after complete spinal cord transection in rats

PubMed Central

Sabino, Luzzi; Maria, Crovace Alberto; Luca, Lacitignola; Valerio, Valentini; Edda, Francioso; Giacomo, Rossi; Gloria, Invernici; Juan, Galzio Renato; Antonio, Crovace

2018-01-01

Background: Proof of the efficacy and safety of a xenogeneic mesenchymal stem cell (MSCs) transplant for spinal cord injury (SCI) may theoretically widen the spectrum of possible grafts for neuroregeneration. Methods: Twenty rats were submitted to complete spinal cord transection. Ovine bone marrow MSCs, retrovirally transfected with red fluorescent protein and not previously induced for neuroglial differentiation, were applied in 10 study rats (MSCG). Fibrin glue was injected in 10 control rats (FGG). All rats were evaluated on a weekly basis and scored using the Basso–Beattie–Bresnahan (BBB) locomotor scale for 10 weeks, when the collected data were statistically analyzed. The spinal cords were then harvested and analyzed with light microscopy, immunohistochemistry, and immunofluorescence. Results: Ovine MSCs culture showed positivity for Nestin. MSCG had a significant and durable recovery of motor functions (P <.001). Red fluorescence was found at the injury sites in MSCG. Positivity for Nestin, tubulin βIII, NG2 glia, neuron-specific enolase, vimentin, and 200 kD neurofilament were also found at the same sites. Conclusions: Xenogeneic ovine bone marrow MSCs proved capable of engrafting into the injured rat spinal cord. Transdifferentiation into a neuroglial phenotype was able to support partial functional recovery. PMID:29497572

Exploration of a Novel Persistent Reversal of Pathological Pain: Mechanisms and Mediators

DTIC Science & Technology

2015-04-01

ability of a single IT ATL313 dose to reverse neuropathic pain from traumatic peripheral neuropathy . Milestone 2 is complete. We determined that 1 pmol...cord injury; to prevent and reverse neuropathic pain from inflammatory peripheral neuropathy following either IT or peri-sciatic nerve ( peripheral ...ATL313 can reverse neuropathic pain from inflammatory peripheral neuropathy following either IT or peri-sciatic nerve ( peripheral ) injections. We also

Aspergillus epidural abscess and cord compression in a patient with aspergilloma and empyema. Survival and response to high dose systemic amphotericin therapy.

PubMed

Hendrix, W C; Arruda, L K; Platts-Mills, T A; Haworth, C S; Jabour, R; Ward, G W

1992-06-01

A 57-yr-old man with a chronic lung cavity presumed to be related to ankylosing spondylitis and/or old cavitary tuberculosis presented with hemoptysis and rapidly developed lower extremity paresis and hypoesthesia. On chest radiograph he had a left upper lobe lesion suggestive of aspergilloma combined with a large left empyema with bronchopleural fistula. Serologic analysis demonstrated precipitins and very high titer IgG antibodies to Aspergillus fumigatus antigens. Decompressive laminectomy from T1 to T5 was performed, with drainage of A. fumigatus culture-positive material from an epidural abscess compressing the spinal cord. Chest drainage was required for control of the empyema. With a total course of 3 g of intravenously administered amphotericin B, rehabilitative therapy, and chronic empyema drainage, he is now at home and ambulatory with assistance. He is also being followed by regular serum assays of IgG antibodies to Aspergillus proteins. We report the case of an apparent long-term survivor of a formerly lethal and/or nonreversible paraplegic condition. The critical factors compared with previous cases with a poor outcome would appear to be prompt neurosurgical intervention, restoration of a normal number of T-cells, effective long-term chest drainage, and high dose amphotericin treatment.

[Silymarin Protects Umbilical Cord-Derived Mesenchymal Stem Cells against Apoptosis Induced by Serum-Deprivation].

PubMed

Wei, Xiao-Juan; Zhang, Hong-Chao; Guo, Zi-Kuan; Zheng, Hai-Bin; Yang, Lei-Lei; Liu, Chao-Zhong

2015-10-01

To investigate the protection of silymarin against the human mesenchymal stem cell (MSC) apoptosis induced by serum deprivation and its underlying mechanism. Human umbilical cord MSCs were cultured in the absence of serum, and the silymain of different concentration (1-10 µg/ml) was added into the medium. MTT test was performed to observe the cell proliferation status. After being cultured for 72 hours, the cells were collected, and flow cytometry with Annexin-V-PI double-staining was used to detect the apoptotic cells from the control and silymarin-treated groups. Furthermore, the intracellular contents of BAX and BCL-2 were detected by Western blot for exploring the potential mechanism. The silymarin promoted the proliferation of human UC-MSCs in a dose-dependent manner, reaching its maximal at a dose of 5 µg/ml. Moreover, silymarin could inhibit the serum deprivation-induced apoptosis of MSCs and, the inhibitory rate reached up to 30% when it was added at a concentration of 5 µg/ml. The content of intracellular BAX was obviously elevated after serum-deprivation treatment, and this increase could be blunted by the addition of silymarin. Meanwhile, the content of BCL-2 was not obviously changed. The silymarin can stimulate MSC growth and inhibit the apoptosis of MSCs probably by the mitochondria pathway.

[Pharmacokinetic and clinical studies of flomoxef in the perinatal period].

PubMed

Matsuda, S; Hirayama, H; Oh, K; Tamate, K; Sengoku, K; Ishikawa, M; Shimizu, T; Haga, H; Hasegawa, T; Takada, H

1993-07-01

Pharmacokinetic and clinical studies on flomoxef (FMOX) in the perinatal period were carried out and following results were obtained 1. The pharmacokinetic parameter T1/2's of FMOX in maternal serum, umbilical cord serum and amniotic fluid in mothers after single intravenous injection of 1 g (n = 46) and 2 g (n = 34) were 1.11, 9.24, 9.24 hours and 2.54, 12.49, 12.49 hours, respectively. Cmax's and Tmax's of umbilical cord serum and amniotic fluid were 12.71, 11.77 micrograms/ml and 0.57, 3.35 hours upon single dose of 1 g i.v., and 35.17, 12.37 micrograms/ml and 0.32, 3.42 hours upon single dose of 2 g i.v., respectively. 2. Clinical usefulness were evaluated in 93 cases including were various infections in pregnancy and puerperal period. In pregnancy cases, clinical efficacy rate was 95.5% (21/22), and 100% in puerperal period. Bacteriological response rate was 84.6% (eradicated: 29, decreased: 4, unchanged: 2, replaced: 4 and unknown: 8 cases). No severe side effects nor clinical laboratory test results were observed in any cases. From above basic and clinical results, we conclude that FMOX is a useful and safe agent for various infections in pregnancy and puerperal period.

Descending pathways to the cutaneus trunci muscle motoneuronal cell group in the cat

NASA Technical Reports Server (NTRS)

Holstege, Gert; Blok, Bertil F.

1989-01-01

The descending pathways to the motoneuronal cell group of the cutaneous trunci muscle (CTM) of the cat were investigated by injecting H-3-labeled lucine into the brain stem, the diencephalon, or the C1, C2, C6, and C8 segments of the spinal cord, and examining fixed autoradiographic sections of the spinal cord and brain regions. Results demonstrate presence of specific supraspinal projectons to the CTM motor nucleus originating in the contralateral nucleus retroambiguous and the ipsilateral dorsolateral pontine tegmentum. Results also suggest that propriospinal pathways to the CTM motor nucleus originating in the cervical cord do not exist, although these propriospinal projections to all other motoneuronal cell groups surrounding the CTM nucleus are very strong.

Clearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis.

PubMed

Brown, Julia A; Stevenson, Kristen; Kim, Haesook T; Cutler, Corey; Ballen, Karen; McDonough, Sean; Reynolds, Carol; Herrera, Maria; Liney, Deborah; Ho, Vincent; Kao, Grace; Armand, Philippe; Koreth, John; Alyea, Edwin; McAfee, Steve; Attar, Eyal; Dey, Bimalangshu; Spitzer, Thomas; Soiffer, Robert; Ritz, Jerome; Antin, Joseph H; Boussiotis, Vassiliki A

2010-05-20

Umbilical cord blood grafts are increasingly used as sources of hematopoietic stem cells in adults. Data regarding the outcome of this approach in adults are consistent with delayed and insufficient immune reconstitution resulting in high infection-related morbidity and mortality. Using cytomegalovirus (CMV)-specific immunity as a paradigm, we evaluated the status, mechanism, and clinical implications of immune reconstitution in adults with hematologic malignancies undergoing unrelated double unit cord blood transplantation. Our data indicate that CD8(+) T cells capable of secreting interferon-gamma (IFN-gamma) in a CMV-specific enzyme-linked immunosorbent spot (ELISpot) assay are detectable at 8 weeks after transplantation, before reconstitution of thymopoiesis, but fail to clear CMV viremia. Clearance of CMV viremia occurs later and depends on the recovery of CD4(+)CD45RA(+) T cells, reconstitution of thymopoiesis, and attainment of T-cell receptor rearrangement excision circle (TREC) levels of 2000 or more copies/mug DNA. In addition, overall survival was significantly higher in patients who displayed thymic regeneration and attainment of TREC levels of 2000 or more copies/mug DNA (P = .005). These results indicate that reconstitution of thymopoiesis is critical for long-term clinical outcome in adult recipients of umbilical cord blood transplant. The trial was prospectively registered at http://www.clinicaltrials.gov (NCT00133367).

Predicting onset of chronic lung disease using cord blood cytokines.

PubMed

Takao, Daishi; Ibara, Satoshi; Tokuhisa, Takuya; Ishihara, Chie; Maede, Yoshinobu; Matsui, Takako; Tokumasu, Hironobu; Sato, Kyoko; Hirakawa, Eiji; Kabayama, Chika; Yamamoto, Masakatu

2014-08-01

Applicability of cord blood interleukin-6 (IL-6) and interleukin-8 (IL-8) as markers for early prediction of the onset of chronic lung disease (CLD) due to intrauterine infection was investigated in the present study. Eighty very low-birthweight infants with chorioamnionitis were divided into two groups: the CLD group (42 patients) and the non-CLD group (38 patients), according to the presence or absence of CLD, and the clinical background and cord blood IL-6 and IL-8 levels in each group were compared and investigated. The CLD group had significantly longer duration of mechanical ventilation and hospitalization (P < 0.05) and significantly higher IL-6 and IL-8 (P < 0.01) than the non-CLD group. Using the receiver operating characteristic curves of CLD onset for both IL-6 and IL-8, the cut-off value of IL-6 for predicting onset of CLD was 48.0 pg/mL, and its sensitivity and specificity were 76% and 96%, respectively. The cut-off value for IL-8 was 66.0 pg/mL, and its sensitivity and specificity were 71% and 82%, respectively. The cord blood levels of both IL-6 and IL-8 were significantly higher in the CLD group, indicating that both IL-6 and IL-8 are useful predictors of onset of CLD. © 2014 Japan Pediatric Society.

Changes in Locomotor Muscle Activity After Treadmill Training in Subjects With Incomplete Spinal Cord Injury

PubMed Central

Gorassini, Monica A.; Norton, Jonathan A.; Nevett-Duchcherer, Jennifer; Roy, Francois D.; Yang, Jaynie F.

2009-01-01

Intensive treadmill training after incomplete spinal cord injury can improve functional walking abilities. To determine the changes in muscle activation patterns that are associated with improvements in walking, we measured the electromyography (EMG) of leg muscles in 17 individuals with incomplete spinal cord injury during similar walking conditions both before and after training. Specific differences were observed between subjects that eventually gained functional improvements in overground walking (responders), compared with subjects where treadmill training was ineffective (nonresponders). Although both groups developed a more regular and less clonic EMG pattern on the treadmill, it was only the tibialis anterior and hamstring muscles in the responders that displayed increases in EMG activation. Likewise, only the responders demonstrated decreases in burst duration and cocontraction of proximal (hamstrings and quadriceps) muscle activity. Surprisingly, the proximal muscle activity in the responders, unlike nonresponders, was three- to fourfold greater than that in uninjured control subjects walking at similar speeds and level of body weight support, suggesting that the ability to modify muscle activation patterns after injury may predict the ability of subjects to further compensate in response to motor training. In summary, increases in the amount and decreases in the duration of EMG activity of specific muscles are associated with functional recovery of walking skills after treadmill training in subjects that are able to modify muscle activity patterns following incomplete spinal cord injury. PMID:19073799

Ultrasonography assessment of vocal cords mobility in children after cardiac surgery.

PubMed

Shaath, Ghassan A; Jijeh, Abdulraouf; Alkurdi, Ahmad; Ismail, Sameh; Elbarbary, Mahmoud; Kabbani, Mohamed S

2012-07-01

Upper airway obstruction after pediatric cardiac surgery is not uncommon. In the cardiac surgical population, an important etiology is vocal cord paresis or paralysis following extubation. In this study, we aimed to evaluate the feasibility and accuracy of ultrasonography (US) assessment of the vocal cords mobility and compare it to fiber-optic laryngoscope (FL). A prospective pilot study has been conducted in Pediatric Cardiac ICU (PCICU) at King Abdulaziz Cardiac Center (KACC) from the 1st of June 2009 till the end of July 2010. Patients who had cardiac surgery manifested with significant signs of upper airway obstruction were included. Each procedure was performed by different operators who were blinded to each other report. Results of invasive (FL) and non-invasive ultrasonography (US) investigations were compared. Ten patients developed persistent significant upper airway obstruction after cardiac surgery were included in the study. Their mean ± SEM of weight and age were 4.6 ± 0.4 kg and 126.4 ± 51.4 days, respectively. All patients were referred to bedside US screening for vocal cord mobility. The results of US were compared subsequently with FL findings. Results were identical in nine (90%) patients and partially different in one (10%). Six patients showed abnormal glottal movement while the other four patients demonstrated normal vocal cords mobility by FL. Sensitivity of US was 100% and specificity of 80%. US assessment of vocal cord is simple, non-invasive and reliable tool to assess vocal cords mobility in the critical care settings. This screening tool requires skills that can be easily obtained.

Gross umbilical cord complications are associated with placental lesions of circulatory stasis and fetal hypoxia.

PubMed

Chan, Joanna S Y; Baergen, Rebecca N

2012-01-01

Umbilical cord complications (UCC), such as true knots (TK), velamentous (VEL) insertion, marginal umbilical cord (MUC) insertion, umbilical cord entanglement (UCE) (both nuchal and non-nuchal), excessively long umbilical cord (ELUC), and excessively twisted umbilical cord (ETUC), can lead to decreased UC blood flow and have been associated with adverse fetal outcome and intrauterine fetal demise (IUFD). Few large series exist that correlate UCC with specific pathologic findings of the placenta. We present the largest series of UCC at this time. Eight hundred forty-one 3rd-trimester placentas with UCC were identified, as well as 858 randomly selected gestational age-matched placentas with grossly unremarkable UC. Lesions associated with circulatory stasis and thrombosis, including villous capillary congestion (VC), umbilical vessel distension (UVD), chorionic plate vessel distension (CPD), umbilical vessel thrombosis (UVT), fetal vascular thrombosis (FVT), intimal fibrin cushions (IFC), and avascular villi (AV), were noted, as well as other pathologic lesions. Data were analyzed by analysis of variance and Fisher exact tests, with P < 0.05 statistically significant. Umbilical cord complications as a group was associated with a significant increase in placental circulatory stasis lesions. Lesions associated with hypoxia, namely nucleated red blood cells and chorangiosis, were also increased. Finally, the presence of any UCC was significantly associated with IUFD. We also found that multiple UCC are associated with nonreassuring fetal heart rate and chorangiosis but that the presence of a single UCC was not. This indicates that UCC may lead to intrauterine hypoxia and subsequent adverse fetal outcome and that multiple UCC may be cumulative in effect.

The pathway of subarachnoid CSF moving into the spinal parenchyma and the role of astrocytic aquaporin-4 in this process.

PubMed

Wei, Fang; Zhang, Cui; Xue, Rong; Shan, Lidong; Gong, Shan; Wang, Guoqing; Tao, Jin; Xu, Guangyin; Zhang, Guoxing; Wang, Linhui

2017-08-01

It has been proved that cerebrospinal fluid (CSF) in the subarachnoid space could reenter the brain parenchyma via the perivascular space. The present study was designed to explore the pathway of subarachnoid CSF flux into the spinal cord and the potential role of aquaporin-4 (AQP4) in this process. Fluorescently tagged cadaverine, for the first time, was used to study CSF movement in mice. Following intracisternal infusion of CSF tracers, the cervical spinal cord was sliced and prepared for fluorescence imaging. Some sections were subject with immunostaining in order to observe tracer distribution and AQP4 expression. Fluorescently tagged cadaverine rapidly entered the spinal cord. Tracer influx into the spinal parenchyma was time dependent. At 10min post-infusion, cadaverine was largely distributed in the superficial tissue adjacent to the pial surface. At 70min post-infusion, cadaverine was distributed in the whole cord and especially concentrated in the gray matter. Furthermore, fluorescent tracer could enter the spinal parenchyma either along the perivascular space or across the pial surface. AQP4 was observed highly expressed in the astrocytic endfeet surrounding blood vessels and the pial surface. Blocking AQP4 by its specific inhibitor TGN-020 strikingly reduced the inflow of CSF tracers into the spinal cord. Subarachnoid CSF could flow into the spinal cord along the perivascular space or across the pial surface, in which AQP4 is involved. Our observation provides a basis for the study on CSF movement in the spinal cord when some neurological diseases occur. Copyright © 2017 Elsevier Inc. All rights reserved.