75 FR 19272 - Thifensulfuron methyl; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-14

... background exposure level). A short and intermediate-term adverse effect was identified; however... of small renal papillae (only at the highest dose level). Thifensulfuron methyl is classified as... only at the mid-level dose of 177 mg/kg. The lack of response at the high-level dose, the occurrence in...

Cumulative doses analysis in young trauma patients: a single-centre experience.

PubMed

Salerno, Sergio; Marrale, Maurizio; Geraci, Claudia; Caruso, Giuseppe; Lo Re, Giuseppe; Lo Casto, Antonio; Midiri, Massimo

2016-02-01

Multidetector computed tomography (MDCT) represents the main source of radiation exposure in trauma patients. The radiation exposure of young patients is a matter of considerable medical concern due to possible long-term effects. Multiple MDCT studies have been observed in the young trauma population with an increase in radiation exposure. We have identified 249 young adult patients (178 men and 71 women; age range 14-40 years) who had received more than one MDCT study between June 2010 and June 2014. According to the International Commission on Radiological Protection publication, we have calculated the cumulative organ dose tissue-weighting factors by using CT-EXPO software(®). We have observed a mean cumulative dose of about 27 mSv (range from 3 to 297 mSv). The distribution analysis is characterised by low effective dose, below 20 mSv, in the majority of the patients. However, in 29 patients, the effective dose was found to be higher than 20 mSv. Dose distribution for the various organs analysed (breasts, ovaries, testicles, heart and eye lenses) shows an intense peak for lower doses, but in some cases high doses were recorded. Even though cumulative doses may have long-term effects, which are still under debate, high doses are observed in this specific group of young patients.

Furosemide Prescription During the Dry State Is a Predictor of Long-Term Survival of Stable, Optimally Medicated Patients With Systolic Heart Failure.

PubMed

Sargento, Luis; Simões, Andre Vicente; Longo, Susana; Lousada, Nuno; Reis, Roberto Palma Dos

2017-05-01

Furosemide is associated with poor prognosis in patients with heart failure and reduced ejection fraction (HFrEF). To evaluate the association between daily furosemide dose prescribed during the dry state and long-term survival in stable, optimally medicated outpatients with HFrEF. Two hundred sixty-six consecutive outpatients with left ventricular ejection fraction <40%, clinically stable in the dry state and on optimal heart failure therapy, were followed up for 3 years in a heart failure unit. The end point was all-cause death. There were no changes in New York Heart Association class and therapeutics, including diuretics, and no decompensation or hospitalization during 6 months. Furosemide doses were categorized as low or none (0-40 mg/d), intermediate (41-80 mg/d), and high (>80 mg). Cox regression was adjusted for significant confounders. The 3-year mortality rate was 33.8%. Mean dose of furosemide was 57.3 ± 21.4 mg/d. A total of 47.6% of patients received the low dose, 42.1% the intermediate dose, and 2.3% the high dose. Receiver operating characteristics for death associated with furosemide dose showed an area under the curve of 0.74 (95% confidence interval [CI]: 0.68-0.79; P < .001), and the best cutoff was >40 mg/d. An increasing daily dose of furosemide was associated with worse prognosis. Those receiving the intermediate dose (hazard ratio [HR] = 4.1; 95% CI: 2.57-6.64; P < .001) or high dose (HR = 19.8; 95% CI: 7.9-49.6; P < .001) had a higher risk of mortality compared to those receiving a low dose. Patients receiving >40 mg/d, in a propensity score-matched cohort, had a greater risk of mortality than those receiving a low dose (HR = 4.02; 95% CI: 1.8-8.8; P = .001) and those not receiving furosemide (HR = 3.9; 95% CI: 0.07-14.2; P = .039). Furosemide administration during the dry state in stable, optimally medicated outpatients with HFrEF is unfavorably associated with long-term survival. The threshold dose was 40 mg/d.

Immunomodulatory effect of ganoderma lucidum polysaccharides (GLP) on long-term heavy-load exercising mice.

PubMed

Shi, Yali; Cai, Dehua; Wang, Xiaojie; Liu, Xinshen

2012-12-01

Long-term heavy-load exercise can lead to a decrease in the organism's immune response. In this study, we used 100 Kunming (KM) mice to investigate the immune-regulatory effects of Ganoderma lucidum polysaccharides (GLP) on long-term heavy-load exercising mice. Peripheral white blood cells (WBC), the absolute value of neutrophils (NEUT), the phagocytic function of macrophages, serum agglutination valence, and the number of plaque-forming cells (PFC) were evaluated 4 weeks after gavaging long-term heavy-load exercising mice with GLP. After exercise, the WBC count in peripheral blood, absolute neutrophil count, macrophage phagocytic index, serum agglutination valence, and the number of plaque-forming cells were significantly reduced in the mice not fed GLP. Both medium and high doses of GLP drastically increased peripheral WBC, absolute neutrophil count, macrophage phagocytic index, serum agglutination valence, and the number of plaque-forming cells in long-term heavy-load exercising mice. High doses of GLP increased peritoneal macrophage phagocytic rate considerably. With this study, we demonstrate that 4 weeks of heavy-load exercise can lead to exercise-induced immunosuppression in mice. A supplement of GLP fed to these mice improves both non-specific and specific immune responses among these mice. The effect for the high-dose GLP treatment is especially significant.

Sleep architecture in insomniacs with severe benzodiazepine abuse.

PubMed

Manconi, Mauro; Ferri, Raffaele; Miano, Silvia; Maestri, Michelangelo; Bottasini, Valentina; Zucconi, Marco; Ferini-Strambi, Luigi

2017-06-01

Benzodiazepines (BZDs) are the most commonly prescribed compounds in insomnia. A long-term of BZDs use may cause dependence and abuse. The aim of this study was to evaluate sleep architecture and microstructure (in terms of cyclic alternating pattern - CAP - analysis and of sleep EEG power spectral analysis) in a group of long-term users of high doses of BZDs for their primary chronic insomnia. Twenty patients consecutively admitted at the Sleep Centre for drug discontinuation and 13 matched healthy controls underwent a full nocturnal video-polysomnographic recording, after one adaptation night. Significant differences were found in time in bed, REM sleep latency and sleep stage 1% which were increased in patients compared to controls, while CAP rate was dramatically decreased. During NREM sleep, patients showed a clear decrease in the relative power of delta band. Our data demonstrate that in adults with chronic insomnia, long-term use of high doses of BZDs induces a severe disruption of sleep microstructure, while sleep architecture seems to be much less affected. The long term use of high doses of BZDs for chronic insomnia induces a marked depression of slow wave activity and of its physiological instability. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

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.

[Allergology and clinical immunology].

PubMed

Coattrenec, Yann; Harr, Thomas; Chizzolini, Carlo; Jandus, Peter

2018-01-10

Hereditary angioedema (HA) is a disabling and potentially fatal condition. The management of HA includes treatment of acute attacks, short-term prophylaxis to prevent an attack, and long-term prophylaxis to minimize the frequency and severity of recurrent attacks. In this article, we will present new therapeutic alternatives for long term prophylaxis. Glucocorticoids (GC) usage leads to a number of severe side-effects. In giant cell arteritis, the use of tocilizumab in conjunction with low doses of GC reduces the number of relapses. In ANCA-associated vasculitis the use of an anti-C5R (avacopan) alone or in conjunction with low doses of GC results in similar remission rates to those induced by high dose GC.

Tramadol/paracetamol fixed-dose combination in the treatment of moderate to severe pain

PubMed Central

Pergolizzi, Joseph V; van de Laar, Mart; Langford, Richard; Mellinghoff, Hans-Ulrich; Merchante, Ignacio Morón; Nalamachu, Srinivas; O’Brien, Joanne; Perrot, Serge; Raffa, Robert B

2012-01-01

Pain is the most common reason patients seek medical attention and pain relief has been put forward as an ethical obligation of clinicians and a fundamental human right. However, pain management is challenging because the pathophysiology of pain is complex and not completely understood. Widely used analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) have been associated with adverse events. Adverse event rates are of concern, especially in long-term treatment or at high doses. Paracetamol and NSAIDs are available by prescription, over the counter, and in combination preparations. Patients may be unaware of the risk associated with high dosages or long-term use of paracetamol and NSAIDs. Clinicians should encourage patients to disclose all medications they take in a “do ask, do tell” approach that includes patient education about the risks and benefits of common pain relievers. The ideal pain reliever would have few risks and enhanced analgesic efficacy. Fixed-dose combination analgesics with two or more agents may offer additive or synergistic benefits to treat the multiple mechanisms of pain. Therefore, pain may be effectively treated while toxicity is reduced due to lower doses. One recent fixed-dose combination analgesic product combines tramadol, a centrally acting weak opioid analgesic, with low-dose paracetamol. Evidence-based guidelines recognize the potential value of combination analgesics in specific situations. The current guideline-based paradigm for pain treatment recommends NSAIDs for ongoing use with analgesics such as opioids to manage flares. However, the treatment model should evolve how to use low-dose combination products to manage pain with occasional use of NSAIDs for flares to avoid long-term and high-dose treatment with these analgesics. A next step in pain management guidelines should be targeted therapy when possible, or low-dose combination therapy or both, to achieve maximal efficacy with minimal toxicity. PMID:23055775

High-Dose Statin Pretreatment Decreases Periprocedural Myocardial Infarction and Cardiovascular Events in Patients Undergoing Elective Percutaneous Coronary Intervention: A Meta-Analysis of Twenty-Four Randomized Controlled Trials

PubMed Central

Wang, Le; Peng, Pingan; Zhang, Ou; Xu, Xiaohan; Yang, Shiwei; Zhao, Yingxin; Zhou, Yujie

2014-01-01

Background Evidence suggests that high-dose statin pretreatment may reduce the risk of periprocedural myocardial infarction (PMI) and major adverse cardiac events (MACE) for certain patients; however, previous analyses have not considered patients with a history of statin maintenance treatment. In this meta-analysis of randomized controlled trials (RCTs), we reevaluated the efficacy of short-term high-dose statin pretreatment to prevent PMI and MACE in an expanded set of patients undergoing elective percutaneous coronary intervention. Methods We searched the PubMed/Medline database for RCTs that compared high-dose statin pretreatment with no statin or low-dose statin pretreatment as a prevention of PMI and MACE. We evaluated the incidence of PMI and MACE, including death, spontaneous myocardial infarction, and target vessel revascularization at the longest follow-up for each study for subgroups stratified by disease classification and prior low-dose statin treatment. Results Twenty-four RCTs with a total of 5,526 patients were identified. High-dose statin pretreatment was associated with 59% relative reduction in PMI (odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.34–0.49; P<0.00001) and 39% relative reduction in MACE (OR: 0.61; 95% CI: 0.45–0.83; P = 0.002). The benefit of high-dose statin pretreatment on MACE was significant for statin-naive patients (OR: 0.69; 95% CI: 0.50–0.95; P = 0.02) and prior low dose statin-treated patients (OR: 0.28; 95% CI: 0.12–0.65; P = 0.003); and for patients with acute coronary syndrome (OR: 0.52; 95% CI: 0.34–0.79; P = 0.003), but not for patients with stable angina (OR: 0.71; 95% CI 0.45–1.10; P = 0.12). Long-term effects on survival were less obvious. Conclusions High-dose statin pretreatment can result in a significant reduction in PMI and MACE for patients undergoing elective PCI. The positive effect of high-dose statin pretreatment on PMI and MACE is significant for statin-naïve patients and patients with prior treatment. The positive effect of high-dose statin pretreatment on MACE is significant for patients with acute coronary syndrome. PMID:25473831

Dosage effects of histamine-2 receptor antagonist on the primary prophylaxis of non-steroidal anti-inflammatory drug (NSAID)-associated peptic ulcers: a retrospective cohort study.

PubMed

He, Ying; Chan, Esther W; Man, Kenneth K C; Lau, Wallis C Y; Leung, Wai K; Ho, Lai M; Wong, Ian C K

2014-09-01

A histamine-2 receptor antagonist (H2RA) is one of the common gastroprotective co-therapies used with non-steroidal anti-inflammatory drugs (NSAIDs) for the prevention or treatment of peptic ulcers (PUs). To date, no study has directly compared the prophylactic effectiveness between high-dose and low-dose H2RA. Our objective was to compare the effectiveness of high-dose versus low-dose H2RAs in the primary prophylaxis of PUs among short-term NSAID users. A retrospective cohort study was conducted using the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong. Patients aged 18 years or above who received a single prescription of oral NSAID with oral H2RA were identified within the study period (1 January 2009-31 December 2012). Patients with a history of or risk factors for PU in the corresponding 2 years prior to the index date (of the first NSAID prescription) were excluded. Log binomial regression analysis was used to calculate the relative risk of PU among NSAID users with high-dose H2RA versus low-dose H2RA exposure. Among the NSAID cohort (n = 102,042), 77,509 (76 %) were on low-dose H2RA and 24,533 (24 %) were on high-dose H2RA. Of the total 69 PU cases identified during the drug exposure period, 64 (0.08 %) received low-dose-H2RA and five (0.02 %) received high-dose H2RA. The overall absolute risk of PUs for NSAID users whilst on H2RA was approximately 1 per 1,479 patients. The adjusted relative risk for NSAID users receiving high-dose H2RA versus low-dose H2RA was 0.32 (95 % confidence interval [CI] 0.13-0.79). Patients aged ≥65 years, receiving a longer duration of treatment, or with concomitant use of antiplatelet agents were found to be at higher risk of PU. High-dose H2RA showed greater effectiveness than low-dose H2RA in the primary prophylaxis of NSAID-associated PUs in short-term new users.

Characterization and control of EUV scanner dose uniformity and stability

NASA Astrophysics Data System (ADS)

Robinson, Chris; Corliss, Dan; Meli, Luciana; Johnson, Rick

2018-03-01

The EUV source is an impressive feat of engineering that provides 13.5 nm radiation by vaporizing tin droplets with a high power CO2 laser and focusing the photons produced in the resultant plasma into the scanner illumination system. Great strides have been made in addressing the many potential stability challenges, but there are still residual spatial and temporal dose non-uniformity signatures. Since even small dose errors can impact the yieldable process window for the advanced lithography products that are exposed on EUV scanners it is crucial to monitor and control the dose variability. Using on-board metrology, the EUV scanner outputs valuable metrics that provide real time insight into the dose performance. We have supplemented scanner data collection with a wafer based methodology that provides high throughput, high sensitivity, quantitative characterization of the EUV scanner dose delivery. The technique uses open frame EUV exposures, so it is exclusive of lithographic pattern imaging, exclusive of lithographic mask pattern and not limited by placement of metrology features. Processed wafers are inspected rapidly, providing 20,000 pixels of detail per exposure field in approximately one minute. Exposing the wafer on the scanner with a bit less than the resist E0 (open frame clearing dose) results in good sensitivity to small variations in the EUV dose delivered. The nominal exposure dose can be modulated by field to calibrate the inspection results and provide quantitative assessment of variations with < 1% sensitivity. This technique has been used for dose uniformity assessments. It is also being used for long term dose stability monitoring and has proven valuable for short term dose stability follow up investigations.

Short-term, high-dose glucocorticoid treatment does not contribute to reduced bone mineral density in patients with multiple sclerosis.

PubMed

Olsson, A; Oturai, D B; Sørensen, P S; Oturai, P S; Oturai, A B

2015-10-01

Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). The objective of this paper is to assess bone mass in patients with MS and evaluate the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. Osteopenia was present in 38% and osteoporosis in 7% of the study population. Mean Z-score was significantly below zero, indicating a decreased BMD in our MS patients. Multiple linear regression analysis showed no significant association between GCs and BMD. In contrast, age, BMI and disease severity were independently associated with both lumbar and femoral BMD. Reduced BMD was prevalent in patients with MS. GC treatment appears not to be the primary underlying cause of secondary osteoporosis in MS patients. © The Author(s), 2015.

Repeated-dose toxicity of common ragweed on rats

PubMed Central

Kiss, Tivadar; Szabó, Andrea; Oszlánczi, Gábor; Lukács, Anita; Tímár, Zoltán; Tiszlavicz, László

2017-01-01

Ambrosia artemisiifolia L. is an invasive species with highly allergenic pollens. Ragweed originates from North America, but it also occurs and is spreading in Europe, causing seasonal allergic rhinitis for millions of people. Recently, the herb of A. artemisiifolia has gained popularity as medicinal plant and food. The effects of its long-term intake are unknown; there are no toxicological data to support the safe use of this plant. The aim of our study was to assess the repeated dose toxicity of A. artemisiifolia on animals. Ragweed puree was administered in low dose (500 mg/kg b. w.) and high dose (1000 mg/kg b. w.) to male Wistar rats according to 407 OECD Guidelines for the Testing of Chemicals. Clinical symptoms, various blood chemical parameters, body weight and organ weights of the rats were measured. Reduced liver function enzymes (AST, ALT), reduced triglyceride level in the low dose and increased carbamide level in the high dose group were observed. The weight of the liver relative to body weight was significantly reduced in both groups, while the brain weight relative to body weight was significantly elevated in both groups. According to our results, the repeated use of ragweed resulted in toxic effects in rats and these results question the safety of long-term human consumption of common ragweed. PMID:28472131

Radiation tolerance in the tardigrade Milnesium tardigradum.

PubMed

Horikawa, Daiki D; Sakashita, Tetsuya; Katagiri, Chihiro; Watanabe, Masahiko; Kikawada, Takahiro; Nakahara, Yuichi; Hamada, Nobuyuki; Wada, Seiichi; Funayama, Tomoo; Higashi, Seigo; Kobayashi, Yasuhiko; Okuda, Takashi; Kuwabara, Mikinori

2006-12-01

Tardigrades are known to survive high doses of ionizing radiation. However, there have been no reports about radiation effects in tardigrades under culture conditions. In this study, we investigated tolerance of the tardigrade, Milnesium tardigradum, against gamma-rays and heavy ions by determining short-term or long-term survival, and reproductive ability after irradiation. Hydrated and anhydrobiotic animals were exposed to gamma-rays (1000 - 7000 Gy) or heavy ions (1000 - 8000 Gy) to evaluate short-term survival at 2, 24 and 48 h post-irradiation. Long-term survival and reproduction were observed up to 31 days after irradiation with gamma-rays (1000 - 4000 Gy). At 48 h after irradiation, median lethal doses were 5000 Gy (gamma-rays) and 6200 Gy (heavy ions) in hydrated animals, and 4400 Gy (gamma-rays) and 5200 Gy (heavy ions) in anhydrobiotic ones. Gamma-irradiation shortened average life span in a dose-dependent manner both in hydrated and anhydrobiotic groups. No irradiated animals laid eggs with one exception in which a hydrated animal irradiated with 2000 Gy of gamma-rays laid 3 eggs, and those eggs failed to hatch, whereas eggs produced by non-irradiated animals hatched successfully. M. tardigradum survives high doses of ionizing radiation in both hydrated and anhydrobiotic states, but irradiation with >1000 Gy makes them sterile.

High-dose short-term administration of naringin did not alter talinolol pharmacokinetics in humans.

PubMed

Nguyen, M A; Staubach, P; Tamai, I; Langguth, P

2015-02-20

Naringin is considered the major causative ingredient of the inhibition of intestinal drug uptake by grapefruit juice. Moreover, it is contained in highly dosed nutraceuticals available on the market. A controlled, open, randomized, crossover study was performed in 10 healthy volunteers to investigate the effect of high-dose naringin on the bioavailability of talinolol, a substrate of intestinal organic anion-transporting polypeptide (OATP)-mediated uptake. Following 6-day supplementation with 3 capsules of 350 mg naringin daily, 100mg talinolol were administered orally with 3 capsules of the same dietary supplement (1050 mg naringin) on the seventh day. This test treatment was compared to 100mg talinolol only (control). The results showed that short-term high-dose naringin supplementation did not significantly affect talinolol pharmacokinetics. Geometric mean ratios of test versus control ranged between 0.90 and 0.98 for talinolol c(max), AUC(0-48 h), AUC(0-∞), t(1/2) and A(e(0-48 h)). The high dose may provoke inhibition of the efflux transporter P-glycoprotein (P-gp) which counteracts the uptake inhibition. As disintegration and dissolution processes are required for the solid dosage form, dissolved naringin may arrive at the site of interaction after talinolol is already absorbed. In conclusion, the effect of nutraceuticals on drug pharmacokinetics can deviate from that observed when administered as food component due to the different dose and dosage form. Copyright © 2014 Elsevier B.V. All rights reserved.

Efficacy of Low-Dose Corticosteroid Therapy Versus High-Dose Corticosteroid Therapy in Bell's Palsy in Children.

PubMed

Arican, Pinar; Dundar, Nihal Olgac; Gencpinar, Pinar; Cavusoglu, Dilek

2017-01-01

Bell's palsy is the most common cause of acute peripheral facial nerve paralysis, but the optimal dose of corticosteroids in pediatric patients is still unclear. This retrospective study aimed to evaluate the efficacy of low-dose corticosteroid therapy compared with high-dose corticosteroid therapy in children with Bell's palsy. Patients were divided into 2 groups based on the dose of oral prednisolone regimen initiated. The severity of idiopathic facial nerve paralysis was graded according to the House-Brackmann Grading Scale. The patients were re-assessed in terms of recovery rate at the first, third, and sixth months of treatment. There was no significant difference in complete recovery between the 2 groups after 1, 3, and 6 months of treatment. In our study, we concluded that even at a dose of 1 mg/kg/d, oral prednisolone was highly effective in the treatment of Bell's palsy in children.

Patterns of zolpidem use among Iraq and Afghanistan veterans: A retrospective cohort analysis.

PubMed

Shayegani, Ramona; Song, Kangwon; Amuan, Megan E; Jaramillo, Carlos A; Eapen, Blessen C; Pugh, Mary Jo

2018-01-01

Although concern exists regarding the adverse effects and rate of zolpidem use, especially long-term use, limited information is available concerning patterns of zolpidem use. To examine the prevalence and correlates of zolpidem exposure in Iraq and Afghanistan Veterans (IAVs). A retrospective cohort study of zolpidem prescriptions was performed with National Veterans Health Administration (VHA) data. We gathered national VA inpatient, outpatient, and pharmacy data files for IAV's who received VA care between fiscal years (FY) 2013 and 2014. The VA pharmacy database was used to identify the prevalence of long term (>30 days), high-dose zolpidem exposure (>10mg immediate-release; >12.5mg extended-release) and other medications received in FY14. Baseline characteristics (demographics, diagnoses) were identified in FY13. Bivariate and multivariable analyses were used to examine the demographic, clinical, and medication correlates of zolpidem use. Of 493,683 IAVs who received VHA care in FY 2013 and 2014, 7.6% (n = 37,422) were prescribed zolpidem in FY 2014. Women had lower odds of high-dose zolpidem exposure than men. The majority (77.3%) of IAVs who received zolpidem prescriptions had long-term use with an average days' supply of 189.3 days and a minority (0.9%) had high-dose exposure. In multivariable analyses, factors associated with long-term zolpidem exposure included age greater than 29 years old, PTSD, insomnia, Selim Index, physical 2-3 conditions, opioids, antidepressants, benzodiazepines, atypical antipsychotics, and stimulants. High dose exposure was associated with PTSD, depression, substance use disorder, insomnia, benzodiazepines, atypical antipsychotics, and stimulant prescriptions. The current practices of insomnia pharmacotherapy in IAVs fall short of the clinical guidelines and may reflect high-risk zolpidem prescribing practices that put Iraq and Afghanistan Veterans at risk for adverse effects of zolpidem and poor health outcomes.

A case study of the long-term retention of 137Cs after inhalation of high temperature reactor fuel element ash.

PubMed

Froning, M; Kozielewski, T; Schläger, M; Hill, P

2004-01-01

In 1987, a worker was internally contaminated with 137Cs as a result of an accident during the handling of high temperature reactor fuel element ash. In the long-term follow-up monitoring an unusual retention behaviour was found. The observed time dependence of caesium retention does not agree with the standard models of ICRP Publication 30. The present case can be better explained by assuming an intake of a mixture of type F and type S compounds. However, experimental data can be best described by a four-exponential retention function with two long-lived components, which was used as an ad hoc model for dose calculation. The resulting dose is compared with doses calculated on the basis of ICRP Publication 66.

Measurements of the neutron dose equivalent for various radiation qualities, treatment machines and delivery techniques in radiation therapy

NASA Astrophysics Data System (ADS)

Hälg, R. A.; Besserer, J.; Boschung, M.; Mayer, S.; Lomax, A. J.; Schneider, U.

2014-05-01

In radiation therapy, high energy photon and proton beams cause the production of secondary neutrons. This leads to an unwanted dose contribution, which can be considerable for tissues outside of the target volume regarding the long term health of cancer patients. Due to the high biological effectiveness of neutrons in regards to cancer induction, small neutron doses can be important. This study quantified the neutron doses for different radiation therapy modalities. Most of the reports in the literature used neutron dose measurements free in air or on the surface of phantoms to estimate the amount of neutron dose to the patient. In this study, dose measurements were performed in terms of neutron dose equivalent inside an anthropomorphic phantom. The neutron dose equivalent was determined using track etch detectors as a function of the distance to the isocenter, as well as for radiation sensitive organs. The dose distributions were compared with respect to treatment techniques (3D-conformal, volumetric modulated arc therapy and intensity-modulated radiation therapy for photons; spot scanning and passive scattering for protons), therapy machines (Varian, Elekta and Siemens linear accelerators) and radiation quality (photons and protons). The neutron dose equivalent varied between 0.002 and 3 mSv per treatment gray over all measurements. Only small differences were found when comparing treatment techniques, but substantial differences were observed between the linear accelerator models. The neutron dose equivalent for proton therapy was higher than for photons in general and in particular for double-scattered protons. The overall neutron dose equivalent measured in this study was an order of magnitude lower than the stray dose of a treatment using 6 MV photons, suggesting that the contribution of the secondary neutron dose equivalent to the integral dose of a radiotherapy patient is small.

Measurements of the neutron dose equivalent for various radiation qualities, treatment machines and delivery techniques in radiation therapy.

PubMed

Hälg, R A; Besserer, J; Boschung, M; Mayer, S; Lomax, A J; Schneider, U

2014-05-21

In radiation therapy, high energy photon and proton beams cause the production of secondary neutrons. This leads to an unwanted dose contribution, which can be considerable for tissues outside of the target volume regarding the long term health of cancer patients. Due to the high biological effectiveness of neutrons in regards to cancer induction, small neutron doses can be important. This study quantified the neutron doses for different radiation therapy modalities. Most of the reports in the literature used neutron dose measurements free in air or on the surface of phantoms to estimate the amount of neutron dose to the patient. In this study, dose measurements were performed in terms of neutron dose equivalent inside an anthropomorphic phantom. The neutron dose equivalent was determined using track etch detectors as a function of the distance to the isocenter, as well as for radiation sensitive organs. The dose distributions were compared with respect to treatment techniques (3D-conformal, volumetric modulated arc therapy and intensity-modulated radiation therapy for photons; spot scanning and passive scattering for protons), therapy machines (Varian, Elekta and Siemens linear accelerators) and radiation quality (photons and protons). The neutron dose equivalent varied between 0.002 and 3 mSv per treatment gray over all measurements. Only small differences were found when comparing treatment techniques, but substantial differences were observed between the linear accelerator models. The neutron dose equivalent for proton therapy was higher than for photons in general and in particular for double-scattered protons. The overall neutron dose equivalent measured in this study was an order of magnitude lower than the stray dose of a treatment using 6 MV photons, suggesting that the contribution of the secondary neutron dose equivalent to the integral dose of a radiotherapy patient is small.

[Value of early application of different doses of amino acids in parenteral nutrition among preterm infants].

PubMed

Liu, Zhi-Juan; Liu, Guo-Sheng; Chen, Yong-Ge; Zhang, Hui-Li; Wu, Xue-Fen

2015-01-01

To study the short-term response and tolerance of different doses of amino acids in parenteral nutrition among preterm infants. This study included 86 preterm infants who had a birth weight between 1 000 to 2 000 g and were admitted to the hospital within 24 hours of birth between March 2013 and June 2014. According to the early application of different doses of amino acids, they were randomized into low-dose group (n=29, 1.0 g/kg per day with an increase of 1.0 g/kg daily and a maximum of 3.5 g/kg per day), medium-dose group (n=28, 2.0 g/kg per day with an increase of 1.0 g/kg daily and a maximum of 3.7 g/kg per day), and high-dose group (n=29, 3.0 g/kg per day with an increase of 0.5-1.0 g/kg daily and a maximum of 4.0 g/kg per day). Other routine parenteral nutrition and enteral nutrition support were also applied. The maximum weight loss was lower and the growth rate of head circumference was greater in the high-dose group than in the low-dose group (P<0.05). The infants in the medium- and high-dose groups had faster recovery of birth weight, earlier attainment of 100 kcal/(kg·d) of enteral nutrition, shorter duration of hospital stay, and less hospital cost than those in the low-dose group (P<0.05). Blood urea nitrogen (BUN) levels in the high-dose group increased compared with the other two groups 7 days after birth (P<0.05). The levels of creatinine, pH, bicarbonate, bilirubin, and transaminase and the incidence of complications showed no significant differences between groups (P>0.05). Parenteral administration of high-dose amino acids in preterm infants within 24 hours after birth can improve the short-term nutritional status of preterm infants, but there is a transient increase in BUN level.

Lack of Response in an Autistic Population to a Low Dose Clinical Trial of Pyridoxine Plus Magnesium.

ERIC Educational Resources Information Center

Tolbert, Lelland; And Others

1993-01-01

As some therapeutic benefits for autistic persons have been reported from combined high doses of pyridoxine and magnesium, this study evaluated long-term administration of low doses (to minimize adverse effects) to 15 subjects with autism. Findings indicated that, at this dosage level, pyridoxine and magnesium had no effect on the severity of…

Long-term results of high-dose conformal radiotherapy for patients with medically inoperable T1-3N0 non-small-cell lung cancer: is low incidence of regional failure due to incidental nodal irradiation?

PubMed

Chen, Ming; Hayman, James A; Ten Haken, Randall K; Tatro, Daniel; Fernando, Shaneli; Kong, Feng-Ming

2006-01-01

To report the results of high-dose conformal irradiation and examine incidental nodal irradiation and nodal failure in patients with inoperable early-stage non-small-cell lung cancer (NSCLC). This analysis included patients with inoperable CT-staged T1-3N0M0 NSCLC treated on our prospective dose-escalation trial. Patients were treated with radiation alone (total dose, 63-102.9 Gy in 2.1-Gy daily fractions) with a three-dimensional conformal technique without intentional nodal irradiation. Bilateral highest mediastinal and upper/lower paratracheal, prevascular and retrotracheal, sub- and para-aortic, subcarinal, paraesophageal, and ipsilateral hilar regions were delineated individually. Nodal failure and doses of incidental irradiation were studied. The potential median follow-up was 104 months. For patients who completed protocol treatment, median survival was 31 months. The actuarial overall survival rate was 86%, 61%, 43%, and 21% and the cause-specific survival rate was 89%, 70%, 53%, and 35% at 1, 2, 3, and 5 years, respectively. Weight loss (p = 0.008) and radiation dose in Gy (p = 0.013) were significantly associated with overall survival. In only 22% and 13% of patients examined did ipsilateral hilar and paratracheal (and subaortic for left-sided tumor) nodal regions receive a dose of > or = 40 Gy, respectively. Less than 10% of all other nodal regions received a dose of > or = 40 Gy. No patients failed initially at nodal sites. Radiation dose is positively associated with overall survival in patients with medically inoperable T1-3N0 NSCLC, though long-term results remain poor. The nodal failure rate is low and does not seem to be due to high-dose incidental irradiation.

Is Long-Term Low-Dose Aspirin Therapy Associated with Renal Dysfunction in Patients with Type 2 Diabetes? JPAD2 Cohort Study

PubMed Central

Okada, Sadanori; Morimoto, Takeshi; Ogawa, Hisao; Sakuma, Mio; Soejima, Hirofumi; Nakayama, Masafumi; Jinnouchi, Hideaki; Waki, Masako; Akai, Yasuhiro; Ishii, Hitoshi; Saito, Yoshihiko

2016-01-01

Background Low-dose aspirin is widely recommended for patients at high risk for cardiovascular disease (CVD); however, it remains uncertain whether long-term treatment adversely affects renal function in patients with diabetes. We investigated whether long-term low-dose aspirin affects renal dysfunction in patients with diabetes. Methods We conducted a randomized controlled trial (RCT), the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, to evaluate low-dose aspirin as primary prevention for CVD in patients with type 2 diabetes. We followed the patients with negative urine dipstick albumin of the JPAD trial in a cohort study after the RCT period was completed. Patients were randomly allocated to receive aspirin (81 mg or 100 mg daily, aspirin group) or no aspirin (no aspirin group). After the RCT, the treating physician decided whether to administer aspirin. We evaluated the incidence of positive urine dipstick albumin and annual changes in estimated glomerular filtration rate (eGFR). Results Positive urine dipstick albumin developed in 297 patients in the aspirin group (n = 1,075) and 270 patients in the no aspirin group (n = 1,098) during follow-up (median, 8.5 years). Intention-to-treat analysis showed low-dose aspirin did not increase the incidence of positive urine dipstick albumin (hazard ratio [HR], 1.17; 95% confidence interval [CI], 0.995–1.38). On-treatment analysis yielded similar results (HR, 1.08; 95% CI, 0.92–1.28). Multivariable analysis showed the incidence of positive urine dipstick albumin was higher among the elderly and those with elevated serum creatinine, high hemoglobin A1c, or high blood pressure; however, low-dose aspirin did not increase the risk of positive urine dipstick albumin. There were no significant differences in annual changes in eGFR between the groups (aspirin, −0.8 ± 2.9; no aspirin, −0.9 ± 2.5 ml/min/1.73m2/year). Conclusion Long-term low-dose aspirin does not affect eGFR and positive urine dipstick albumin in patients with type 2 diabetes. PMID:26808136

Is Long-Term Low-Dose Aspirin Therapy Associated with Renal Dysfunction in Patients with Type 2 Diabetes? JPAD2 Cohort Study.

PubMed

Okada, Sadanori; Morimoto, Takeshi; Ogawa, Hisao; Sakuma, Mio; Soejima, Hirofumi; Nakayama, Masafumi; Jinnouchi, Hideaki; Waki, Masako; Akai, Yasuhiro; Ishii, Hitoshi; Saito, Yoshihiko

2016-01-01

Low-dose aspirin is widely recommended for patients at high risk for cardiovascular disease (CVD); however, it remains uncertain whether long-term treatment adversely affects renal function in patients with diabetes. We investigated whether long-term low-dose aspirin affects renal dysfunction in patients with diabetes. We conducted a randomized controlled trial (RCT), the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, to evaluate low-dose aspirin as primary prevention for CVD in patients with type 2 diabetes. We followed the patients with negative urine dipstick albumin of the JPAD trial in a cohort study after the RCT period was completed. Patients were randomly allocated to receive aspirin (81 mg or 100 mg daily, aspirin group) or no aspirin (no aspirin group). After the RCT, the treating physician decided whether to administer aspirin. We evaluated the incidence of positive urine dipstick albumin and annual changes in estimated glomerular filtration rate (eGFR). Positive urine dipstick albumin developed in 297 patients in the aspirin group (n = 1,075) and 270 patients in the no aspirin group (n = 1,098) during follow-up (median, 8.5 years). Intention-to-treat analysis showed low-dose aspirin did not increase the incidence of positive urine dipstick albumin (hazard ratio [HR], 1.17; 95% confidence interval [CI], 0.995-1.38). On-treatment analysis yielded similar results (HR, 1.08; 95% CI, 0.92-1.28). Multivariable analysis showed the incidence of positive urine dipstick albumin was higher among the elderly and those with elevated serum creatinine, high hemoglobin A1c, or high blood pressure; however, low-dose aspirin did not increase the risk of positive urine dipstick albumin. There were no significant differences in annual changes in eGFR between the groups (aspirin, -0.8 ± 2.9; no aspirin, -0.9 ± 2.5 ml/min/1.73 m(2)/year). Long-term low-dose aspirin does not affect eGFR and positive urine dipstick albumin in patients with type 2 diabetes.

Influence of long-term, high-dose dexamethasone administration on proliferation and apoptosis in porcine hepatocytes.

PubMed

Mikiewicz, Mateusz; Otrocka-Domagała, Iwona; Paździor-Czapula, Katarzyna; Rotkiewicz, Tadeusz

2017-06-01

The aim of this study was to examine the influence of long-term, high-dose dexamethasone administration on the liver, with particular emphasis on hepatocyte proliferation and apoptosis, using a swine model. The study included 48 large, female Polish breed pigs aged 3months (weighing ca. 30kg) divided into groups I (control; n=24) and II (dexamethasone; n=24) that receiving intra-muscular injections of monosodium phosphate dexamethasone for 29days. The pigs were euthanized on days subsequent to the experiment. Immediately after the euthanasia, the pig livers were sampled, fixed, and processed routinely for histopathology, histochemistry, and immunohistochemistry (for proliferating cell nuclear antigen, Bcl-2, and caspase-3). Apoptosis was visualized by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL). Dexamethasone administration gradually caused hepatocyte glycogen degeneration and finally lipid degeneration, accompanied by sinusoid and central vein dilatation and nuclear chromatin condensation. The proliferating cell nuclear antigen index, mean number of argyrophilic nucleolar organizer regions and proliferation index of argyrophilic nucleolar organizer regions were lower, while Bcl-2 expression was higher in group II compared with group I. The results from this study suggest that safe high-dose dexamethasone administration time is difficult to establish. Long-term, high-dose dexamethasone administration can cause pronounced morphological changes in hepatocytes by diminishing their transcriptional and proliferation activity but also protects them from apoptosis by potentially affecting Bcl-2 expression. Copyright © 2017 Elsevier Ltd. All rights reserved.

Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment.

PubMed

Cryan, John F; Page, Michelle E; Lucki, Irwin

2005-11-01

The forced swim test (FST) is the most widely used model for assessing potential antidepressant activity in rodents following acute or short-term treatment. However, few studies have compared the effects of short- and long-term antidepressant treatment on behaviors in the test, despite the need to treat patients chronically to produce clinical effects. The current studies examined whether antidepressants from different classes produce different behavioral effects following short-term treatment and whether such effects change following administration for a longer duration. The effects of administering short-term (3 days) and long-term (14 days) treatments of antidepressants from three different chemical classes with distinct mechanisms of action via osmotic minipump were examined: the selective norepinephrine reuptake inhibitor reboxetine (10 and 60 mg kg(-1) day(-1)), the selective serotonin reuptake inhibitor fluoxetine (2.5 and 15 mg kg(-1) day(-1)), and the reversible inhibitor of monoamine oxidase moclobemide (2.5 and 15 mg kg(-1) day(-1)). All testing was carried out in a 15-min test with no preswim session in order to negate any confounding aspect of an induction procedure. The majority of antidepressant-sensitive behavioral changes were observed in the first 5 min of the test. The low dose of reboxetine failed to alter behavior in the test after 3 days but significantly decreased immobility and increased climbing behavior following administration for 14 days, whereas the high dose of reboxetine was equally effective following 3 and 14 days of treatment. In a similar fashion, the low dose of fluoxetine failed to alter behavior in the test following 3 days, but showed an augmented response on immobility and increased swimming following administration for 14 days. The high dose of fluoxetine was slightly more effective at reducing immobility following administration for 14 days than 3 days. The low dose of moclobemide decreased immobility and increased climbing behavior following treatment for 3 days, but increases in both swimming and climbing behaviors were measured following treatment for 14 days. Treatment with the high dose of moclobemide for 3 days decreased immobility and increased swimming, whereas treatment for 14 days significantly increased both active behaviors (swimming and climbing). Antidepressants from three different classes produce different effects on active behaviors in the FST. The effects of antidepressants were augmented following chronic administration for 14 days, especially when given at low doses. This suggests that modifications of the FST can be used to examine the onset of action of antidepressant agents produced by long-term administration.

Update on pediatric resuscitation drugs: high dose, low dose, or no dose at all.

PubMed

Sorrentino, Annalise

2005-04-01

Pediatric resuscitation has been a topic of discussion for years. It is difficult to keep abreast of changing recommendations, especially for busy pediatricians who do not regularly use these skills. This review will focus on the most recent guidelines for resuscitation drugs. Three specific questions will be discussed: standard dose versus high-dose epinephrine, amiodarone use, and the future of vasopressin in pediatric resuscitation. The issue of using high-dose epinephrine for cardiopulmonary resuscitation refractory to standard dose epinephrine has been a topic of debate for many years. Recently, a prospective, double-blinded study was performed to help settle the debate. These results will be reviewed and compared with previous studies. Amiodarone is a medication that was added to the pediatric resuscitation algorithms with the most recent recommendations from the American Heart Association in 2000. Its use and safety will also be discussed. Another topic that is resurfacing in resuscitation is the use of vasopressin. Its mechanism and comparisons to other agents will be highlighted, although its use in the pediatric patient has not been thoroughly studied. Pediatric resuscitation is a constantly evolving subject that is on the mind of anyone taking care of sick children. Clinicians are continually searching for the most effective methods to resuscitate children in terms of short- and long-term outcomes. It is important to be familiar with not only the agents being used but also the optimal way to use them.

Characterization of the Exradin W1 scintillator for use in radiotherapy.

PubMed

Carrasco, P; Jornet, N; Jordi, O; Lizondo, M; Latorre-Musoll, A; Eudaldo, T; Ruiz, A; Ribas, M

2015-01-01

To evaluate the main characteristics of the Exradin W1 scintillator as a dosimeter and to estimate measurement uncertainties when used in radiotherapy. We studied the calibration procedure, energy and modality dependence, short-term repeatability, dose-response linearity, angular dependence, temperature dependence, time to reach thermal equilibrium, dose-rate dependence, water-equivalent depth of the effective measurement point, and long-term stability. An uncertainty budget was derived for relative and absolute dose measurements in photon and electron beams. Exradin W1 showed a temperature dependence of -0.225% °C(-1). The loss of sensitivity with accumulated dose decreased with use. The sensitivity of Exradin W1 was energy independent for high-energy photon and electron beams. All remaining dependencies of Exradin W1 were around or below 0.5%, leading to an uncertainty budget of about 1%. When a dual channel electrometer with automatic trigger was not used, timing effects became significant, increasing uncertainties by one order of magnitude. The Exradin W1 response is energy independent for high energy x-rays and electron beams, and only one calibration coefficient is needed. A temperature correction factor should be applied to keep uncertainties around 2% for absolute dose measurements and around 1% for relative measurements in high-energy photon and electron beams. The Exradin W1 scintillator is an excellent alternative to detectors such as diodes for relative dose measurements.

Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study.

PubMed

Marincek, Nicolas; Jörg, Ann-Catherine; Brunner, Philippe; Schindler, Christian; Koller, Michael T; Rochlitz, Christoph; Müller-Brand, Jan; Maecke, Helmut R; Briel, Matthias; Walter, Martin A

2013-01-15

We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1-4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1-158) months, 34 (range: 1-118) months and 29 (range: 1-113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211).

Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study

PubMed Central

2013-01-01

Background We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. Methods In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Results Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1–4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1–158) months, 34 (range: 1–118) months and 29 (range: 1–113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Conclusions Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. Trial registration ClinicalTrials.gov number:NCT00978211 PMID:23320604

High-dose-rate prostate brachytherapy inverse planning on dose-volume criteria by simulated annealing.

PubMed

Deist, T M; Gorissen, B L

2016-02-07

High-dose-rate brachytherapy is a tumor treatment method where a highly radioactive source is brought in close proximity to the tumor. In this paper we develop a simulated annealing algorithm to optimize the dwell times at preselected dwell positions to maximize tumor coverage under dose-volume constraints on the organs at risk. Compared to existing algorithms, our algorithm has advantages in terms of speed and objective value and does not require an expensive general purpose solver. Its success mainly depends on exploiting the efficiency of matrix multiplication and a careful selection of the neighboring states. In this paper we outline its details and make an in-depth comparison with existing methods using real patient data.

Chronic pain treatment with opioid analgesics: benefits versus harms of long-term therapy.

PubMed

Sehgal, Nalini; Colson, James; Smith, Howard S

2013-11-01

Chronic non-cancer pain (CNCP) is a disabling chronic condition with a high prevalence rate around the world. Opioids are routinely prescribed for treatment of chronic pain (CP). In the past two decades there has been a massive increase in the number of opioid prescriptions, prescribed daily opioid doses and overall opioid availability. Many more patients with CNCP receive high doses of long-acting opioids on a long-term basis. Yet CP and related disability rates remain high, and majority of the patients with CNCP are dissatisfied with their treatments. Intersecting with the upward trajectory in opioid use are the increasing trends in opioid related adverse effects, especially prescription drug abuse, addiction and overdose deaths. This complex situation raises questions on the relevance of opioid therapy in the treatment of CNCP. This article reviews current evidence on opioid effectiveness, the benefits and harms of long-term therapy in CNCP.

The influence of a long-term growth hormone treatment on lipid and glucose metabolism: a randomized trial in short Japanese children born small for gestational age.

PubMed

Horikawa, Reiko; Tanaka, Toshiaki; Nishinaga, Hiromi; Ogawa, Yoshihisa; Yokoya, Susumu

2016-01-01

Long-term growth hormone (GH) treatments in short children born small for gestational age (SGA) restore lipid metabolism, but also increase insulin resistance. The aim of this study was to evaluate the influence of long-term GH therapy on lipid and glucose metabolism as well as its dose dependency in short Japanese children born SGA. Eighty Japanese children with a short stature who were born SGA participated in this study; 65 were treated with fixed GH doses of 0.033 (low) or 0.067 (high) mg/kg/day for 260 weeks; 15 were untreated controls in the first year and were randomized to one of the two treatment groups at week 52. Serum cholesterol, glucose and insulin levels were regularly measured. An oral glucose tolerance test (OGTT) was conducted annually. The mean age at the start of GH therapy was approximately 5.3 years. Serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the high dose group significantly decreased over time during GH therapy. In both dose groups for TC, and in the high dose group for LDL-C, the higher the baseline values, the greater the decrease after 260 weeks. The rate of the decrease observed after 260 weeks in patients with high LDL-C levels was greater in the high dose group. Based on the results of OGTT, no patient was classified as being diabetic; however, annual increases were observed in post-OGTT insulin levels. After 260 weeks, the homeostasis model assessment as an index of insulin resistance (HOMA-IR) increased, suggesting that insulin resistance developed over time with the GH treatment, while 36.6 % of the subjects entered puberty. Long-term continuous GH treatment for children born SGA may have a potentially beneficial effect on several parameters in lipid metabolism and does not adversely affect glucose metabolism. GHLIQUID-1516, GHLIQUID-1517, Japan Pharmaceutical Information Center Clinical trial registration: JapicCTI-050132. Registered 13 September 2005. Retrospectively registered. JapicCTI-050137. Registered 13 September 2005. Retrospectively registered. ClinicalTrials.gov trial registration: NCT00184717. Registered 13 September 2005. Retrospectively registered.

Primary central nervous system lymphoma.

PubMed

Ahluwalia, Manmeet S; Peereboom, David M

2010-07-01

Management goals for patients with primary central nervous system lymphoma (PCNSL) include long-term disease control, management of neurologic complications, and preservation of neurocognitive function. Various treatment options can achieve several of these goals. Chemotherapy as monotherapy or as combination therapy has emerged as the cornerstone of therapy for patients with newly diagnosed PCNSL. Outside of a clinical trial, patients with newly diagnosed PCNSL should receive high-dose intravenous methotrexate (MTX) as a single agent or as part of a combination regimen with radiation therapy reserved for relapse. The regimen should have an adequate MTX dose (>3 g/m(2)) to reach cytotoxic concentrations in the cerebrospinal fluid (CSF) to treat occult leptomeningeal disease (LMD). Alternative modes of chemotherapy delivery for selected patients, preferably in the context of a clinical trial, include high-dose chemotherapy with autologous stem cell rescue and intra-arterial chemotherapy with blood-brain barrier disruption. Whole brain radiation therapy (WBRT) in standard doses and fractionation carries an unacceptable rate of long-term neurocognitive toxicity. However, lower doses in daily divided fractions may offer the possibility of adding this modality with preservation of cognition but should be performed only in the context of a clinical trial. The long-term efficacy and toxicity of this approach is currently under investigation. Certain presentations of PCNSL require different strategies. Patients with ocular lymphoma at diagnosis should receive high-dose MTX as this drug can reach cytotoxic intravitreal concentrations. Recurrence in the eyes is managed with intravitreal chemotherapy including MTX or rituximab or with radiation therapy. The field of treatment (eyes vs whole brain) should be individualized. Intrathecal (IT) MTX should be included in the treatment regimen for those patients with a positive CSF cytology, or in regimens in which lower doses of MTX are delivered over longer periods of time. It is probably reasonable to withhold IT chemotherapy in those patients who have no detectable subarachnoid disease and who can receive higher doses of MTX (>3 g/m(2)) over shorter infusion periods (2-4 h). Patients who develop leptomeningeal involvement despite high- dose MTX can be managed with IT chemotherapy such as liposomal cytarabine or MTX or even rituximab. Areas of bulky or symptomatic LMD should probably be treated with radiation therapy as well. Because PCNSL is an uncommon disease, entry into clinical trials must be pursued to advance the state of the art.

Dosimetric feasibility of 4DCT-ventilation imaging guided proton therapy for locally advanced non-small-cell lung cancer.

PubMed

Huang, Qijie; Jabbour, Salma K; Xiao, Zhiyan; Yue, Ning; Wang, Xiao; Cao, Hongbin; Kuang, Yu; Zhang, Yin; Nie, Ke

2018-04-25

The principle aim of this study is to incorporate 4DCT ventilation imaging into functional treatment planning that preserves high-functioning lung with both double scattering and scanning beam techniques in proton therapy. Eight patients with locally advanced non-small-cell lung cancer were included in this study. Deformable image registration was performed for each patient on their planning 4DCTs and the resultant displacement vector field with Jacobian analysis was used to identify the high-, medium- and low-functional lung regions. Five plans were designed for each patient: a regular photon IMRT vs. anatomic proton plans without consideration of functional ventilation information using double scattering proton therapy (DSPT) and intensity modulated proton therapy (IMPT) vs. functional proton plans with avoidance of high-functional lung using both DSPT and IMPT. Dosimetric parameters were compared in terms of tumor coverage, plan heterogeneity, and avoidance of normal tissues. Our results showed that both DSPT and IMPT plans gave superior dose advantage to photon IMRTs in sparing low dose regions of the total lung in terms of V5 (volume receiving 5Gy). The functional DSPT only showed marginal benefit in sparing high-functioning lung in terms of V5 or V20 (volume receiving 20Gy) compared to anatomical plans. Yet, the functional planning in IMPT delivery, can further reduce the low dose in high-functioning lung without degrading the PTV dosimetric coverages, compared to anatomical proton planning. Although the doses to some critical organs might increase during functional planning, the necessary constraints were all met. Incorporating 4DCT ventilation imaging into functional proton therapy is feasible. The functional proton plans, in intensity modulated proton delivery, are effective to further preserve high-functioning lung regions without degrading the PTV coverage.

Efficacy of Short-Term Statin Treatment for the Prevention of Contrast-Induced Acute Kidney Injury in Patients Undergoing Coronary Angiography/Percutaneous Coronary Intervention: A Meta-Analysis of 21 Randomized Controlled Trials.

PubMed

Li, Haixia; Wang, Cailian; Liu, Chuanzhi; Li, Ruifei; Zou, Meijuan; Cheng, Gang

2016-06-01

The results of previous studies have been contradictory in terms of the efficacy of statin treatment in preventing contrast-induced acute kidney injury (CI-AKI) and clinical adverse events (AEs). This meta-analysis was undertaken to assess the role of short-term statin treatment in the prevention of CI-AKI and clinical AEs. We searched the Cochrane Library, EMBASE, and PubMed databases for randomized controlled trials (RCTs) with the development of CI-AKI as a primary outcome. Secondary outcomes were the post-procedural serum creatinine (SCr) level, estimated glomerular filtration rate (eGFR), and development of AEs. We also performed prespecified subgroup analyses. A total of 21 RCTs involving 7746 patients were included. Short-term statin treatment significantly reduced the risk of CI-AKI [risk ratio (RR) 0.57; 95 % confident interval (CI) 0.47-0.69; p < 0.00001) and was associated with a lower post-procedural SCr level and a higher eGFR. High-dose statins resulted in a lower incidence of CI-AKI than the lower-dose statins. In addition, the benefit was seen across various subgroups for patients at risk of CI-AKI, statin-naïve patients, and East Asians, regardless of statin type, definition of CI-AKI, use of N-acetylcysteine (NAC) and hydration, and osmolality of contrast. However, there was no significant difference between the two groups in terms of the incidence of AEs. The meta-analysis suggests that short-term statin treatment can effectively prevent CI-AKI, and the benefit is also observed in high-risk patients, statin-naïve patients, and an East Asian population. However, the effect of simvastatin for the prevention of CI-AKI, of statins for the prevention of AEs, and whether high-dose statins have a better effect than lower-dose statins are all still uncertain.

Dose-Escalated Stereotactic Body Radiation Therapy for Patients With Intermediate- and High-Risk Prostate Cancer: Initial Dosimetry Analysis and Patient Outcomes

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

Kotecha, Rupesh; Djemil, Toufik; Tendulkar, Rahul D.

Purpose: To report the short-term clinical outcomes and acute and late treatment-related genitourinary (GU) and gastrointestinal (GI) toxicities in patients with intermediate- and high-risk prostate cancer treated with dose-escalated stereotactic body radiation therapy (SBRT). Methods and Materials: Between 2011 and 2014, 24 patients with prostate cancer were treated with SBRT to the prostate gland and proximal seminal vesicles. A high-dose avoidance zone (HDAZ) was created by a 3-mm expansion around the rectum, urethra, and bladder. Patients were treated to a minimum dose of 36.25 Gy in 5 fractions, with a simultaneous dose escalation to a dose of 50 Gy to the targetmore » volume away from the HDAZ. Acute and late GU and GI toxicity outcomes were measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 4. Results: The median follow-up was 25 months (range, 18-45 months). Nine patients (38%) experienced an acute grade 2 GU toxicity, which was medically managed, and no patients experienced an acute grade 2 GI toxicity. Two patients (8%) experienced late grade 2 GU toxicity, and 2 patients (8%) experienced late grade 2 GI toxicity. No acute or late grade ≥3 GU or GI toxicities were observed. The 24-month prostate-specific antigen relapse-free survival outcome for all patients was 95.8% (95% confidence interval 75.6%-99.4%), and both biochemical failures occurred in patients with high-risk disease. All patients are currently alive at the time of this analysis and continue to be followed. Conclusions: A heterogeneous prostate SBRT planning technique with differential treatment volumes (low dose: 36.25 Gy; and high dose: 50 Gy) with an HDAZ provides a safe method of dose escalation. Favorable rates of biochemical control and acceptably low rates of acute and long-term GU and GI toxicity can be achieved in patients with intermediate- and high-risk prostate cancer treated with SBRT.« less

Long-term results of high-dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience.

PubMed

Giona, Fiorina; Putti, Maria C; Micalizzi, Concetta; Menna, Giuseppe; Moleti, Maria L; Santoro, Nicola; Iaria, Grazia; Ladogana, Saverio; Burnelli, Roberta; Consarino, Caterina; Varotto, Stefania; Tucci, Francesca; Messina, Chiara; Nanni, Mauro; Diverio, Daniela; Biondi, Andrea; Pession, Andrea; Locatelli, Franco; Piciocchi, Alfonso; Gottardi, Enrico; Saglio, Giuseppe; Foà, Robin

2015-08-01

Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long-term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long-term results of high-dose IM (340 mg/m2 /d) in CML patients in chronic phase (CP-CML) aged <18 years at diagnosis. A total of 47 CP-CML patients with a median age at diagnosis of 11 years 9 months were enrolled in nine Italian centres. Complete cytogenetic response was achieved in 91.5% of the evaluable patients at a median time of 6 months. BCR-ABL1 International Scale ≤ 0.1% (major molecular response; MMR) and ≤0.01% (molecular response; MR) at 12 months were 66.6% and 33%, respectively. During follow-up, MMR and MR were achieved in 78.6% and 61% of children, respectively. IM was safely discontinued in 3 long-term treated children with a durable MR. Twelve patients (eight cytogenetic/molecular responders) underwent stem cell transplantation. The progression-free survival probabilities at 96 months for responding patients who continued IM and for those transplanted were 60% and 50%, respectively. After a median follow-up of 52 months (range 3-146), all patients are alive. High-dose IM is a long-term effective therapy in children and adolescents with CP-CML. © 2015 John Wiley & Sons Ltd.

Effects of Chronic Genistein Treatment in Mammary Gland, Uterus, and Vagina

PubMed Central

Rimoldi, Guillermo; Christoffel, Julie; Seidlova-Wuttke, Dana; Jarry, Hubertus; Wuttke, Wolfgang

2007-01-01

Background The isoflavone genistein (GEN) is found in soy (Glycine max) and red clover (Trifolium pratense). The estrogenic activity of GEN is known, and it is widely advertised as a phytoestrogen useful in alleviating climacteric complaints and other postmenopausal disorders. Knowledge of effects of long-term administration of GEN in laboratory animals is scarce, and effects in the uterus and mammary gland after long-term administration have not been studied. The uterus and mammary gland are known to be negatively influenced by estrogens used in hormone therapy. Objectives We administered two doses of GEN [mean daily uptake 5.4 (low) or 54 mg/kg (high) body weight (bw)] orally over a period of 3 months to ovariectomized (ovx) rats and compared the effects with a treatment with two doses of 17β-estradiol [E2; 0.17 (low) or 0.7 mg/kg bw (high)]. Mammary glands, vaginae, and uteri were investigated morphologically and immunohistochemically. We quantified the expression of proliferating cell nuclear antigen (PCNA) and progesterone receptor (PR) in the mammary gland. Results In rats treated with either of the E2 doses or the high GEN dose, we found increased uterine weight, and histologic analysis showed estrogen-induced features in the uteri. In vaginae, either E2 dose or GEN high induced hyperplastic epithelium compared with the atrophic controls. In the mammary gland, E2 (either dose) or GEN increased proliferation and PR expression. Serum levels of luteinizing hormone were decreased by E2 (both doses) but not by GEN. Conclusions In summary, E2 and GEN share many effects in the studied organs, particularly in the vagina, uterus, and mammary gland but not in the hypothalamo/pituitary unit. PMID:18174952

Defining the "Hostile Pelvis" for Intensity Modulated Radiation Therapy: The Impact of Anatomic Variations in Pelvic Dimensions on Dose Delivered to Target Volumes and Organs at Risk in Patients With High-Risk Prostate Cancer Treated With Whole Pelvic Radiation Therapy.

PubMed

Yirmibeşoğlu Erkal, Eda; Karabey, Sinan; Karabey, Ayşegül; Hayran, Mutlu; Erkal, Haldun Şükrü

2015-07-15

The aim of this study was to evaluate the impact of variations in pelvic dimensions on the dose delivered to the target volumes and the organs at risk (OARs) in patients with high-risk prostate cancer (PCa) to be treated with whole pelvic radiation therapy (WPRT) in an attempt to define the hostile pelvis in terms of intensity modulated radiation therapy (IMRT). In 45 men with high-risk PCa to be treated with WPRT, the target volumes and the OARs were delineated, the dose constraints for the OARs were defined, and treatment plans were generated according to the Radiation Therapy Oncology Group 0924 protocol. Six dimensions to reflect the depth, width, and height of the bony pelvis were measured, and 2 indexes were calculated from the planning computed tomographic scans. The minimum dose (Dmin), maximum dose (Dmax), and mean dose (Dmean) for the target volumes and OARs and the partial volumes of each of these structures receiving a specified dose (VD) were calculated from the dose-volume histograms (DVHs). The data from the DVHs were correlated with the pelvic dimensions and indexes. According to an overall hostility score (OHS) calculation, 25 patients were grouped as having a hospitable pelvis and 20 as having a hostile pelvis. Regarding the OHS grouping, the DVHs for the bladder, bowel bag, left femoral head, and right femoral head differed in favor of the hospitable pelvis group, and the DVHs for the rectum differed for a range of lower doses in favor of the hospitable pelvis group. Pelvimetry might be used as a guide to define the challenging anatomy or the hostile pelvis in terms of treatment planning for IMRT in patients with high-risk PCa to be treated with WPRT. Copyright © 2015 Elsevier Inc. All rights reserved.

The impact of histology and delivered dose on local control of spinal metastases treated with stereotactic radiosurgery.

PubMed

Yamada, Yoshiya; Katsoulakis, Evangelia; Laufer, Ilya; Lovelock, Michael; Barzilai, Ori; McLaughlin, Lily A; Zhang, Zhigang; Schmitt, Adam M; Higginson, Daniel S; Lis, Eric; Zelefsky, Michael J; Mechalakos, James; Bilsky, Mark H

2017-01-01

OBJECTIVE An analysis of factors contributing to durable radiographic control of spinal metastases was undertaken, drawing from a large single-institution database in an attempt to elucidate indications and dose requirements for successful treatment. METHODS All patients treated at a single institution with stereotactic radiosurgery (SRS) of the spine as first-line therapy were assessed for local progression of the treated site, defined as radiographic enlargement of the treated tumor and/or biopsy-proven evidence of active tumor cells. All patients were followed with CT, PET, or MR imaging every 3-6 months until death. Treatment decisions were made by a multidisciplinary team of radiation oncologists, neurosurgeons, and neuroradiologists. Target volumes were defined according to the international consensus guidelines and were reviewed in a multidisciplinary conference. Image-guided techniques and intensity modulation were used for every case. The tumor's histological type, gross tumor volume (GTV), dose that covers 95% of the GTV (GTV D95), percentage of GTV covered by 95% of the prescribed dose (GTV V95), planning target volume (PTV), dose that covers 95% of the PTV (PTV D95), and percentage of PTV covered by 95% of the prescribed dose (PTV V95) were analyzed for significance in relation to local control, based on time to local progression. RESULTS A total of 811 lesions were treated in 657 patients between 2003 and 2015 at a single institution. The mean follow-up and overall survival for the entire cohort was 26.9 months (range 2-141 months). A total of 28 lesions progressed and the mean time to failure was 26 months (range 9.7-57 months). The median prescribed dose was 2400 cGy (range 1600-2600 cGy). Both GTV D95 and PTV D95 were highly significantly associated with local failure in univariate analysis, but GTV and PTV and histological type did not reach statistical significance. The median GTV D95 for the cohort equal to or above the GTV D95 1830 cGy cut point (high dose) was 2356 cGy, and it was 1709 cGy for the cohort of patients who received less than 1830 cGy (low dose). In terms of PTV D95, the median dose for those equal to or above the cut point of 1740 cGy (high dose) was 2233 cGy, versus 1644 cGy for those lesions below the PTV D95 cut point of 1740 cGy (low dose). CONCLUSIONS High-dose single-session SRS provides durable long-term control, regardless of the histological findings or tumor size. In this analysis, the only significant factors predictive of local control were related to the actual dose of radiation given. Although the target volumes were well treated with the intended dose, those lesions irradiated to higher doses (median GTV D95 2356 cGy, minimum 1830 cGy) had a significantly higher probability of durable local control than those treated with lower doses (median PTV D95 2232 cGy, minimum of 1740 cGy) (p < 0.001). Patients in the high-dose cohort had a 2% cumulative rate of local failure. Histological findings were not associated with local failure, suggesting that radioresistant histological types benefit in particular from radiosurgery. For patients with a favorable prognosis, a higher dose of SRS is important for long-term outcomes.

The impact of histology and delivered dose on local control of spinal metastases treated with stereotactic radiosurgery

PubMed Central

Yamada, Yoshiya; Katsoulakis, Evangelia; Laufer, Ilya; Lovelock, Michael; Barzilai, Ori; McLaughlin, Lily A.; Zhang, Zhigang; Schmitt, Adam M.; Higginson, Daniel S.; Lis, Eric; Zelefsky, Michael J.; Mechalakos, James; Bilsky, Mark H.

2017-01-01

Objective An analysis of factors contributing to durable radiographic control of spinal metastases was undertaken, drawing from a large single-institution database in an attempt to elucidate indications and dose requirements for successful treatment. Methods All patients treated at a single institution with stereotactic radiosurgery (SRS) of the spine as first-line therapy were assessed for local progression of the treated site, defined as radiographic enlargement of the treated tumor and/or biopsy-proven evidence of active tumor cells. All patients were followed with CT, PET, or MR imaging every 3–6 months until death. Treatment decisions were made by a multidisciplinary team of radiation oncologists, neurosurgeons, and neuroradiologists. Target volumes were defined according to the international consensus guidelines and were reviewed in a multidisciplinary conference. Image-guided techniques and intensity modulation were used for every case. The tumor’s histological type, gross tumor volume (GTV), dose that covers 95% of the GTV (GTV D95), percentage of GTV covered by 95% of the prescribed dose (GTV V95), planning target volume (PTV), dose that covers 95% of the PTV (PTV D95), and percentage of PTV covered by 95% of the prescribed dose (PTV V95) were analyzed for significance in relation to local control, based on time to local progression. Results A total of 811 lesions were treated in 657 patients between 2003 and 2015 at a single institution. The mean follow-up and overall survival for the entire cohort was 26.9 months (range 2–141 months). A total of 28 lesions progressed and the mean time to failure was 26 months (range 9.7–57 months). The median prescribed dose was 2400 cGy (range 1600–2600 cGy). Both GTV D95 and PTV D95 were highly significantly associated with local failure in univariate analysis, but GTV and PTV and histological type did not reach statistical significance. The median GTV D95 for the cohort equal to or above the GTV D95 1830 cGy cut point (high dose) was 2356 cGy, and it was 1709 cGy for the cohort of patients who received less than 1830 cGy (low dose). In terms of PTV D95, the median dose for those equal to or above the cut point of 1740 cGy (high dose) was 2233 cGy, versus 1644 cGy for those lesions below the PTV D95 cut point of 1740 cGy (low dose). Conclusions High-dose single-session SRS provides durable long-term control, regardless of the histological findings or tumor size. In this analysis, the only significant factors predictive of local control were related to the actual dose of radiation given. Although the target volumes were well treated with the intended dose, those lesions irradiated to higher doses (median GTV D95 2356 cGy, minimum 1830 cGy) had a significantly higher probability of durable local control than those treated with lower doses (median PTV D95 2232 cGy, minimum of 1740 cGy) (p < 0.001). Patients in the high-dose cohort had a 2% cumulative rate of local failure. Histological findings were not associated with local failure, suggesting that radioresistant histological types benefit in particular from radiosurgery. For patients with a favorable prognosis, a higher dose of SRS is important for long-term outcomes. PMID:28041329

Fully Convolutional Architecture for Low-Dose CT Image Noise Reduction

NASA Astrophysics Data System (ADS)

Badretale, S.; Shaker, F.; Babyn, P.; Alirezaie, J.

2017-10-01

One of the critical topics in medical low-dose Computed Tomography (CT) imaging is how best to maintain image quality. As the quality of images decreases with lowering the X-ray radiation dose, improving image quality is extremely important and challenging. We have proposed a novel approach to denoise low-dose CT images. Our algorithm learns directly from an end-to-end mapping from the low-dose Computed Tomography images for denoising the normal-dose CT images. Our method is based on a deep convolutional neural network with rectified linear units. By learning various low-level to high-level features from a low-dose image the proposed algorithm is capable of creating a high-quality denoised image. We demonstrate the superiority of our technique by comparing the results with two other state-of-the-art methods in terms of the peak signal to noise ratio, root mean square error, and a structural similarity index.

Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B

PubMed Central

Nathwani, A.C.; Reiss, U.M.; Tuddenham, E.G.D.; Rosales, C.; Chowdary, P.; McIntosh, J.; Della Peruta, M.; Lheriteau, E.; Patel, N.; Raj, D.; Riddell, A.; Pie, J.; Rangarajan, S.; Bevan, D.; Recht, M.; Shen, Y.-M.; Halka, K.G.; Basner-Tschakarjan, E.; Mingozzi, F.; High, K.A.; Allay, J.; Kay, M.A.; Ng, C.Y.C.; Zhou, J.; Cancio, M.; Morton, C.L.; Gray, J.T.; Srivastava, D.; Nienhuis, A.W.; Davidoff, A.M.

2014-01-01

BACKGROUND In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose–response relationship, and the level of persistent or late toxicity. METHODS We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.) PMID:25409372

Low dosing of gonadotropins in in vitro fertilization cycles for women with poor ovarian reserve: systematic review and meta-analysis.

PubMed

Youssef, Mohamed Abdel-Fattah; van Wely, Madelon; Mochtar, Monique; Fouda, Usama Mohamed; Eldaly, Ashraf; El Abidin, Eman Zein; Elhalwagy, Ahmed; Mageed Abdallah, Ahmed Abdel; Zaki, Sherif Sameh; Abdel Ghafar, Mohamed Sayed; Mohesen, Mohamed Nagi; van der Veen, Fulco

2018-02-01

To evaluate the effectiveness of low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens in terms of ongoing pregnancy per fresh IVF attempt in women with poor ovarian reserve undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment. A systematic review and meta-analysis of randomized controlled studies that evaluate the effectiveness of low dosing of gonadotropins alone or combined with oral compounds compared with high doses of gonadotropins in women with poor ovarian reserve undergoing IVF/ICSI treatment. Not applicable. Subfertile women with poor ovarian reserve undergoing IVF/ICSI treatment. We searched the PubMed, EMBASE, Web of Science, the Cochrane Library, and the Clinical Trials Registry using medical subject headings and free text terms up to June 2016, without language or year restrictions. We included randomized controlled studies (RCTs) enrolling subfertile women with poor ovarian reserve undergoing IVF/ICSI treatment and comparing low doses of gonadotropins and gonadotropins combined with oral compounds versus high doses of gonadotropins. We assessed the risk of bias using the criteria recommended by the Cochrane Collaboration. We pooled the results by meta-analysis using the fixed and random effects model. The primary outcome was ongoing pregnancy rate (PR) per woman randomized. We retrieved 787 records. Fourteen RCTs (N = 2,104 women) were included in the analysis. Five studies (N = 717 women) compared low doses of gonadotropins versus high doses of gonadotropins. There was no evidence of a difference in ongoing PR (2 RCTs: risk rate 0.98, 95% confidence interval 0.62-1.57, I 2 = 0). Nine studies (N = 1,387 women) compared ovarian stimulation using gonadotropins combined with the oral compounds letrozole (n = 6) or clomiphene citrate (CC) (n = 3) versus high doses of gonadotropins. There was no evidence of a difference in ongoing PR (3 RCTs: risk rate 0.90, 95% confidence interval 0.63-1.27, I 2 = 0). We found no evidence of a difference in pregnancy outcomes between low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens. Whether low doses of gonadotropins or gonadotropins combined with oral compounds is to be preferred is unknown, as they have never been compared head to head. A health economic analysis to test the hypothesis that an ovarian stimulation with low dosing is more cost-effective than high doses of gonadotropins is needed. CRD42016041301. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Acute Ethanol Has Biphasic Effects on Short- and Long-Term Memory in Both Foreground and Background Contextual Fear Conditioning in C57BL/6 Mice

PubMed Central

Gulick, Danielle; Gould, Thomas J.

2009-01-01

Background Ethanol is a frequently abused, addictive drug that impairs cognitive function. Ethanol may disrupt cognitive processes by altering attention, short-term memory, and/ or long-term memory. Interestingly, some research suggests that ethanol may enhance cognitive processes at lower doses. The current research examined the dose-dependent effects of ethanol on contextual and cued fear conditioning. In addition, the present studies assessed the importance of stimulus salience in the effects of ethanol and directly compared the effects of ethanol on short-term and long-term memory. Methods This study employed both foreground and background fear conditioning, which differ in the salience of contextual stimuli, and tested conditioning at 4 hours, 24 hours, and 1 week in order to assess the effects of ethanol on short-term and long-term memory. Foreground conditioning consisted of 2 presentations of a foot shock unconditioned stimulus (US) (2 seconds, 0.57 mA). Background conditioning consisted of 2 auditory conditioned stimulus (30 seconds, 85 dB white noise)–foot shock (US; 2 seconds, 0.57 mA) pairings. Results For both foreground and background conditioning, ethanol enhanced short-term and long-term memory for contextual and cued conditioning at a low dose (0.25 g/kg) and impaired short-term and long-term memory for contextual and cued conditioning at a high dose (1.0 g/kg). Conclusions These results suggest that ethanol has long-lasting, biphasic effects on short-term and long-term memory for contextual and cued conditioning. Furthermore, the effects of ethanol on contextual fear conditioning are independent of the salience of the context. PMID:17760787

Long-term changes of renal function in relation to ace inhibitor/angiotensin receptor blocker dosing in patients with heart failure and chronic kidney disease.

PubMed

Fröhlich, Hanna; Nelges, Christoph; Täger, Tobias; Schwenger, Vedat; Cebola, Rita; Schnorbach, Johannes; Goode, Kevin M; Kazmi, Syed; Katus, Hugo A; Cleland, John G F; Clark, Andrew L; Frankenstein, Lutz

2016-08-01

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have become cornerstones of therapy for chronic heart failure (CHF). Guidelines advise high target doses for ACEIs/ARBs, but fear of worsening renal function may limit dose titration in patients with concomitant chronic kidney disease (CKD). In this retrospective observational study, we identified 722 consecutive patients with systolic CHF, stable CKD stage III/IV (estimated glomerular filtration rate [eGFR] 15-60 mL min(-1) 1.73 m(-2)) and chronic ACEI/ARB treatment from the outpatient heart failure clinics at the Universities of Hull, UK, and Heidelberg, Germany. Change of renal function, worsening CHF, and hyperkalemia at 12-month follow-up were analyzed as a function of both baseline ACEI/ARB dose and dose change from baseline. ΔeGFR was not related to baseline dose of ACEI/ARB (P = .58), or to relative (P = .18) or absolute change of ACEI/ARB dose (P = .21) during follow-up. Expressing change of renal function as a categorical variable (improved/stable/decreased) as well as subgroup analyses with respect to age, sex, New York Heart Association functional class, left ventricular ejection fraction, diabetes, concomitant aldosterone antagonists, CKD stage, hypertension, ACEI vs ARB, and congestion status yielded similar results. There was no association of dose/dose change with incidence of either worsening CHF or hyperkalemia. In patients with systolic CHF and stable CKD stage III/IV, neither continuation of high doses of ACEI/ARB nor up-titration was related to adverse changes in longer-term renal function. Conversely, down-titration was not associated with improvement in eGFR. Use of high doses of ACEI/ARB and their up-titration in patients with CHF and CKD III/IV may be appropriate provided that the patient is adequately monitored. Copyright © 2016 Elsevier Inc. All rights reserved.

Patterns of zolpidem use among Iraq and Afghanistan veterans: A retrospective cohort analysis

PubMed Central

Amuan, Megan E.; Jaramillo, Carlos A.; Eapen, Blessen C.

2018-01-01

Background Although concern exists regarding the adverse effects and rate of zolpidem use, especially long-term use, limited information is available concerning patterns of zolpidem use. Objective To examine the prevalence and correlates of zolpidem exposure in Iraq and Afghanistan Veterans (IAVs). Methods A retrospective cohort study of zolpidem prescriptions was performed with National Veterans Health Administration (VHA) data. We gathered national VA inpatient, outpatient, and pharmacy data files for IAV’s who received VA care between fiscal years (FY) 2013 and 2014. The VA pharmacy database was used to identify the prevalence of long term (>30 days), high-dose zolpidem exposure (>10mg immediate-release; >12.5mg extended-release) and other medications received in FY14. Baseline characteristics (demographics, diagnoses) were identified in FY13. Bivariate and multivariable analyses were used to examine the demographic, clinical, and medication correlates of zolpidem use. Results Of 493,683 IAVs who received VHA care in FY 2013 and 2014, 7.6% (n = 37,422) were prescribed zolpidem in FY 2014. Women had lower odds of high-dose zolpidem exposure than men. The majority (77.3%) of IAVs who received zolpidem prescriptions had long-term use with an average days’ supply of 189.3 days and a minority (0.9%) had high-dose exposure. In multivariable analyses, factors associated with long-term zolpidem exposure included age greater than 29 years old, PTSD, insomnia, Selim Index, physical 2–3 conditions, opioids, antidepressants, benzodiazepines, atypical antipsychotics, and stimulants. High dose exposure was associated with PTSD, depression, substance use disorder, insomnia, benzodiazepines, atypical antipsychotics, and stimulant prescriptions. Conclusion The current practices of insomnia pharmacotherapy in IAVs fall short of the clinical guidelines and may reflect high-risk zolpidem prescribing practices that put Iraq and Afghanistan Veterans at risk for adverse effects of zolpidem and poor health outcomes. PMID:29360821

Cancer risk above 1 Gy and the impact for space radiation protection

NASA Astrophysics Data System (ADS)

Schneider, Uwe; Walsh, Linda

2009-07-01

Analyses of the epidemiological data on the Japanese A-bomb survivors, who were exposed to γ-rays and neutrons, provide most current information on the dose-response of radiation-induced cancer. Since the dose span of main interest is usually between 0 and 1 Gy, for radiation protection purposes, the analysis of the A-bomb survivors is often focused on this range. However, estimates of cancer risk for doses larger than 1 Gy are becoming more important for long-term manned space missions. Therefore in this work, emphasis is placed on doses larger than 1 Gy with respect to radiation-induced solid cancer and leukemia mortality. The present analysis of the A-bomb survivors data was extended by including two extra high-dose categories and applying organ-averaged dose instead of the colon-weighted dose. In addition, since there are some recent indications for a high neutron dose contribution, the data were fitted separately for three different values for the relative biological effectiveness (RBE) of the neutrons (10, 35 and 100) and a variable RBE as a function of dose. The data were fitted using a linear and a linear-exponential dose-response relationship using a dose and dose-rate effectiveness factor (DDREF) of both one and two. The work presented here implies that the use of organ-averaged dose, a dose-dependent neutron RBE and the bending-over of the dose-response relationship for radiation-induced cancer could result in a reduction of radiation risk by around 50% above 1 Gy. This could impact radiation risk estimates for space crews on long-term mission above 500 days who might be exposed to doses above 1 Gy. The consequence of using a DDREF of one instead of two increases cancer risk by about 40% and would therefore balance the risk decrease described above.

Predictors of Local Control After Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases

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

Greco, Carlo; Zelefsky, Michael J., E-mail: zelefskm@mskcc.or; Lovelock, Michael

2011-03-15

Purpose: To report tumor local control after treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) to extracranial metastatic sites. Methods and Materials: A total of 126 metastases in 103 patients were treated with SD-IGRT to prescription doses of 18-24 Gy (median, 24 Gy) between 2004 and 2007. Results: The overall actuarial local relapse-free survival (LRFS) rate was 64% at a median follow-up of 18 months (range, 2-45 months). The median time to failure was 9.6 months (range, 1-23 months). On univariate analysis, LRFS was significantly correlated with prescription dose (p = 0.029). Stratification by dose into high (23 to 24 Gy),more » intermediate (21 to 22 Gy), and low (18 to 20 Gy) dose levels revealed highly significant differences in LRFS between high (82%) and low doses (25%) (p < 0.0001). Overall, histology had no significant effect on LRFS (p = 0.16). Renal cell histology displayed a profound dose-response effect, with 80% LRFS at the high dose level (23 to 24 Gy) vs. 37% with low doses ({<=}22 Gy) (p = 0.04). However, for patients who received the high dose level, histology was not a statistically significant predictor of LRFS (p = 0.90). Target organ (bone vs. lymph node vs. soft tissues) (p = 0.5) and planning target volume size (p = 0.55) were not found to be associated with long-term LRFS probability. Multivariate Cox regression analysis confirmed prescription dose to be a significant predictor of LRFS (p = 0.003). Conclusion: High-dose SD-IGRT is a noninvasive procedure resulting in high probability of local tumor control. Single-dose IGRT may be effectively used to locally control metastatic deposits regardless of histology and target organ, provided sufficiently high doses (> 22 Gy) of radiation are delivered.« less

A dose-response curve for biodosimetry from a 6 MV electron linear accelerator

PubMed Central

Lemos-Pinto, M.M.P.; Cadena, M.; Santos, N.; Fernandes, T.S.; Borges, E.; Amaral, A.

2015-01-01

Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. PMID:26445334

Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids

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

Jonasson, Sofia, E-mail: sofia.jonasson@foi.se; Wigenstam, Elisabeth; Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå

Chlorine (Cl{sub 2}) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl{sub 2}-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200 ppm Cl{sub 2} during 15 min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24 h or 14 days post-exposure. A single dose of themore » corticosteroid dexamethasone (10 or 100 mg/kg) was administered intraperitoneally 1, 3, 6, or 12 h following Cl{sub 2} exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6 h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1 h was dose-dependent; high-dose significantly reduced acute airway inflammation (100 mg/kg) but not treatment with the relatively low-dose (10 mg/kg). Both doses reduced AHR 14 days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl{sub 2} exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl{sub 2} exposure. - Highlights: • Inhalation of Cl{sub 2} may lead to a long-standing airway hyperresponsiveness. • The symptoms in Cl{sub 2}-exposed mice are similar to those described for RADS in humans. • Corticosteroids prevent delayed symptoms such as AHR in Cl{sub 2}-induced lung injury. • Early medical intervention of corticosteroids is of importance. • Treatment with corticosteroids alone is insufficient to counteract acute lung injury.« less

University Cooperation Platform (UCP) between Christian-Albrechts-University Kiel (Germany) and Chiang Mai University (Thailand): implementation of image-guided gynecological brachytherapy.

PubMed

Galalae, Razvan; Tharavichitkul, Ekkasit; Wanwilairat, Somsak; Chitapanarux, Imjai; Kimmig, Bernhard; Dunst, Jürgen; Lorvidhaya, Vicharn

2015-02-01

Starting in 1999, the University Cooperation Platform (UCP) implemented an exchange program of researchers and clinicians/physicists between the Christian-Albrechts-University Kiel in Germany and Chiang Mai University in Thailand, to initiate a sustainable base for long-term development of image-guided brachytherapy and in general for high-technology radiotherapy in Chiang Mai. A series of UCP protocols, based constructively on each other, were performed and evaluated at intermediate term follow-up. The first protocol, addressing computed tomography (CT)-optimized brachytherapy for advanced cervical cancer (n = 17), showed a significant reduction of D2cc for the bladder and sigmoid (p < 0.001) while maintaining a very high dose in D90 high-risk clinical target volume (HR-CTV) in comparison with standard point-based planning. In addition, after a follow-up of 19 months no tumor relapse was observed. The second UCP protocol, testing the impact of magnetic resonance imaging (MRI) guidance (n = 15) in patients with cervical cancer, proved significantly smaller D2cc doses for the bladder, rectum, and sigmoid (p = 0.003, p = 0.015, and p = 0.012), and secured highly curative mean doses in D90 HR-CTV of 99.2 Gy. The acute and late toxicity was excellent without any observed grade 3 or higher morbidity. In the third protocol, the combination of image-guided brachytherapy (IGBT) and whole pelvis intensity-modulated external beam radiotherapy (WP-IMRT) (n = 15) reaffirmed the significant reduction of D2cc doses for the bladder, rectum, and sigmoid (p = 0.001 or p < 0.001) along with high equivalent dose at 2 Gy (EQD2) in the HR-CTV, and demonstrated very low acute therapy-related toxicity in absence of grade 3 morbidity. The implementation of transabdominal ultrasound (TAUS) was the focus of the fourth UCP project aiming a more generous potential use of image-guidance on long-term, and enhancing the quality of soft tissue assessment complementary to conventionally planned gynecological brachytherapy. Analyses in 29 patients revealed significantly reduced OARs doses in bladder with a total EQD2 > 80 Gy for bladder in only 17.2% versus 62.1% in conventional planning, and in rectum EQD2 > 75 Gy in 44.8% versus 79.3%, respectively. In conclusion, analyses revealed excellent results for the high-dose-rate IGBT in patients with advanced gynecological cancer both by using CT and MRI, and/or the combination with WP-IMRT. They also define MRI as gold standard for soft tissue assessment and to determine more accurately HR-CTV. The use of TAUS-guidance adds quality aspects to the "classical" conventional X-ray based planning, especially in terms of real-time measures and adequate soft tissue information, and may lower significantly the dose in OARs. The review of all UCP-results reconfirms the importance of the established program that will continue to operate with subsequent projects.

University Cooperation Platform (UCP) between Christian-Albrechts-University Kiel (Germany) and Chiang Mai University (Thailand): implementation of image-guided gynecological brachytherapy

PubMed Central

Tharavichitkul, Ekkasit; Wanwilairat, Somsak; Chitapanarux, Imjai; Kimmig, Bernhard; Dunst, Jürgen; Lorvidhaya, Vicharn

2015-01-01

Starting in 1999, the University Cooperation Platform (UCP) implemented an exchange program of researchers and clinicians/physicists between the Christian-Albrechts-University Kiel in Germany and Chiang Mai University in Thailand, to initiate a sustainable base for long-term development of image-guided brachytherapy and in general for high-technology radiotherapy in Chiang Mai. A series of UCP protocols, based constructively on each other, were performed and evaluated at intermediate term follow-up. The first protocol, addressing computed tomography (CT)-optimized brachytherapy for advanced cervical cancer (n = 17), showed a significant reduction of D2cc for the bladder and sigmoid (p < 0.001) while maintaining a very high dose in D90 high-risk clinical target volume (HR-CTV) in comparison with standard point-based planning. In addition, after a follow-up of 19 months no tumor relapse was observed. The second UCP protocol, testing the impact of magnetic resonance imaging (MRI) guidance (n = 15) in patients with cervical cancer, proved significantly smaller D2cc doses for the bladder, rectum, and sigmoid (p = 0.003, p = 0.015, and p = 0.012), and secured highly curative mean doses in D90 HR-CTV of 99.2 Gy. The acute and late toxicity was excellent without any observed grade 3 or higher morbidity. In the third protocol, the combination of image-guided brachytherapy (IGBT) and whole pelvis intensity-modulated external beam radiotherapy (WP-IMRT) (n = 15) reaffirmed the significant reduction of D2cc doses for the bladder, rectum, and sigmoid (p = 0.001 or p < 0.001) along with high equivalent dose at 2 Gy (EQD2) in the HR-CTV, and demonstrated very low acute therapy-related toxicity in absence of grade 3 morbidity. The implementation of transabdominal ultrasound (TAUS) was the focus of the fourth UCP project aiming a more generous potential use of image-guidance on long-term, and enhancing the quality of soft tissue assessment complementary to conventionally planned gynecological brachytherapy. Analyses in 29 patients revealed significantly reduced OARs doses in bladder with a total EQD2 > 80 Gy for bladder in only 17.2% versus 62.1% in conventional planning, and in rectum EQD2 > 75 Gy in 44.8% versus 79.3%, respectively. In conclusion, analyses revealed excellent results for the high-dose-rate IGBT in patients with advanced gynecological cancer both by using CT and MRI, and/or the combination with WP-IMRT. They also define MRI as gold standard for soft tissue assessment and to determine more accurately HR-CTV. The use of TAUS-guidance adds quality aspects to the “classical” conventional X-ray based planning, especially in terms of real-time measures and adequate soft tissue information, and may lower significantly the dose in OARs. The review of all UCP-results reconfirms the importance of the established program that will continue to operate with subsequent projects. PMID:25829941

Longitudinal associations between changes in physical activity and depressive symptoms in adulthood: the young Finns study.

PubMed

Yang, Xiaolin; Hirvensalo, Mirja; Hintsanen, Mirka; Hintsa, Taina; Pulkki-Råback, Laura; Jokela, Markus; Telama, Risto; Tammelin, Tuija; Hutri-Kähönen, Nina; Viikari, Jorma S A; Raitakari, Olli T

2014-12-01

Although previous studies have associated physical activity (PA) with lower depressive symptoms, the combined effects of the (1) frequency, (2) intensity, and (3) duration of long-term PA have not been examined in detail. We examined the dose-response association between changes in frequency, intensity, and duration of PA and depressive symptoms in men and women over 6 years. Participants comprised 1,959 healthy adults (833 men and 1,126 women), aged 24-39 years in 2001, drawn from the ongoing Young Finns Study. PA was assessed using a self-report questionnaire completed in connection with a medical examination in 2001 and 2007. Depressive symptoms were simultaneously assessed using a modified version of Beck's Depression Inventory in both phases. High doses of PA at baseline were prospectively associated with fewer depressive symptoms in men, while moderate doses of PA at baseline were inversely associated with the prevalence of depressive symptoms in women. Associations between baseline PA and depressive symptom changes were mediated by social and health-related factors which differed between men and women. Long-term participation in regular PA in all dimensions remained remarkably stable (all p < 0.001). Compared to those who remained inactive, the persistently active participants in all dimensions, with the exception of women's intensity group, were more likely to show decreases in depressive symptoms independent of the included confounders. An increase in PA in certain groups was also independently associated with fewer depressive symptoms, particularly in women. Regular and persistent participation in different doses of PA may provide short-term and long-term beneficial effects on depressive symptom changes. The results imply that the moderate to high doses of PA may serve as a buffer against depression in early midlife.

Assessment of diurnal systemic dose of agrochemicals in regulatory toxicity testing--an integrated approach without additional animal use.

PubMed

Saghir, Shakil A; Bartels, Michael J; Rick, David L; McCoy, Alene T; Rasoulpour, Reza J; Ellis-Hutchings, Robert G; Sue Marty, M; Terry, Claire; Bailey, Jason P; Billington, Richard; Bus, James S

2012-07-01

Integrated toxicokinetics (TK) data provide information on the rate, extent and duration of systemic exposure across doses, species, strains, gender, and life stages within a toxicology program. While routine for pharmaceuticals, TK assessments of non-pharmaceuticals are still relatively rare, and have never before been included in a full range of guideline studies for a new agrochemical. In order to better understand the relationship between diurnal systemic dose (AUC(24h)) and toxicity of agrochemicals, TK analyses in the study animals is now included in all short- (excluding acute), medium- and long-term guideline mammalian toxicity studies including reproduction/developmental tests. This paper describes a detailed procedure for the implementation of TK in short-, medium- and long-term regulatory toxicity studies, without the use of satellite animals, conducted on three agrochemicals (X11422208, 2,4-D and X574175). In these studies, kinetically-derived maximum doses (KMD) from short-term studies instead of, or along with, maximum tolerated doses (MTD) were used for the selection of the high dose in subsequent longer-term studies. In addition to leveraging TK data to guide dose level selection, the integrated program was also used to select the most appropriate method of oral administration (i.e., gavage versus dietary) of test materials for rat and rabbit developmental toxicity studies. The integrated TK data obtained across toxicity studies (without the use of additional/satellite animals) provided data critical to understanding differences in response across doses, species, strains, sexes, and life stages. Such data should also be useful in mode of action studies and to improve human risk assessments. Copyright © 2012 Elsevier Inc. All rights reserved.

Long-term outcome of sporadic and FAP-associated desmoid tumors treated with high-dose selective estrogen receptor modulators and sulindac: a single-center long-term observational study in 134 patients.

PubMed

Quast, Daniel Robert; Schneider, Ralph; Burdzik, Emanuel; Hoppe, Steffen; Möslein, Gabriela

2016-01-01

Aim of this study is to evaluate the outcome of long-term conservative treatment with sulindac and high-dose selective estrogen receptor modulators (SERMs) for sporadic and FAP-associated desmoid tumors. Desmoids are very rare tumors in the general population but occur frequently in FAP patients, being encountered in 23-38 %. Treatment of desmoids is still most controversial since response cannot be predicted and they are prone to develop recurrence. This study included all desmoid patients that were treated and followed at our institution and had completed at least 1 year of treatment. Response was defined as stable size or regression of desmoid size between two CT or MRI scans. A total of 134 patients were included. 64 (47.8 %) patients had a confirmed diagnosis of FAP, 69 (51.5 %) patients were sporadic. Overall 114 (85.1 %) patients showed regressive or stable desmoid size. Patients with previous history of multiple desmoid-related surgeries showed less-favorable response. The mean time to reach at least stable size was 14.9 (±9.1) months. After regression or stabilization, medication was tapered in 69 (60.5 %) of the treated patients with only one long-term recurrence after >10 years. The results of this study fortify the role of sulindac and high-dose SERMs as an effective and safe treatment for both, sporadic and FAP-associated desmoid tumors. While invasive treatment frequently results in high recurrence rates, high morbidity and high mortality, this conservative treatment is successful in most patients. The recurrence rate is negligible with no desmoid-related mortality in this large series. Therefore surgical resection, especially for mesenteric desmoids, should be deferred favoring this convincingly effective, well tolerated regimen.

Impact of the Revised 10 CFR 835 on the Neutron Dose Rates at LLNL

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

Radev, R

2009-01-13

In June 2007, 10 CFR 835 [1] was revised to include new radiation weighting factors for neutrons, updated dosimetric models, and dose terms consistent with the newer ICRP recommendations. A significant aspect of the revised 10 CFR 835 is the adoption of the recommendations outlined in ICRP-60 [2]. The recommended new quantities demand a review of much of the basic data used in protection against exposure to sources of ionizing radiation. The International Commission on Radiation Units and Measurements has defined a number of quantities for use in personnel and area monitoring [3,4,5] including the ambient dose equivalent H*(d) tomore » be used for area monitoring and instrument calibrations. These quantities are used in ICRP-60 and ICRP-74. This report deals only with the changes in the ambient dose equivalent and ambient dose rate equivalent for neutrons as a result of the implementation of the revised 10 CFR 835. In the report, the terms neutron dose and neutron dose rate will be used for convenience for ambient neutron dose and ambient neutron dose rate unless otherwise stated. This report provides a qualitative and quantitative estimate of how much the neutron dose rates at LLNL will change with the implementation of the revised 10 CFR 835. Neutron spectra and dose rates from selected locations at the LLNL were measured with a high resolution spectroscopic neutron dose rate system (ROSPEC) as well as with a standard neutron rem meter (a.k.a., a remball). The spectra obtained at these locations compare well with the spectra from the Radiation Calibration Laboratory's (RCL) bare californium source that is currently used to calibrate neutron dose rate instruments. The measurements obtained from the high resolution neutron spectrometer and dose meter ROSPEC and the NRD dose meter compare within the range of {+-}25%. When the new radiation weighting factors are adopted with the implementation of the revised 10 CFR 835, the measured dose rates will increase by up to 22%. The health physicists should consider this increase for any areas that have dose rates near a posting limit, such as near the 100 mrem/hr for a high radiation area, as this increase in measured dose rate may result in some changes to postings and consequent radiological controls.« less

Detection of erythropoietin misuse by the Athlete Biological Passport combined with reticulocyte percentage.

PubMed

Bejder, Jacob; Aachmann-Andersen, Niels Jacob; Bonne, Thomas Christian; Olsen, Niels Vidiendal; Nordsborg, Nikolai Baastrup

2016-10-01

The sensitivity of the adaptive model of the Athlete Biological Passport (ABP) and reticulocyte percentage (ret%) in detection of recombinant human erythropoietin (rHuEPO) misuse was evaluated using both a long-term normal dose and a brief high dose treatment regime. Sixteen subjects received either 65 IU rHuEPO × kg -1 every second day for two weeks (normal-dose), 390 IU rHuEPO × kg -1 on three consecutive days (high-dose), or frequent placebo treatment for 13 days in a randomized, placebo-controlled, double-blind crossover design. Blood variables were measured 4, 11, and 25 days following treatment initiation. The ABP based on haemoglobin concentration ([Hb]) and OFF-hr score ([Hb] - 60 × √ret%) yielded atypical profiles following both normal-dose and high-dose treatment (0 %, 31 %, 13 % vs. 21 %, 33 %, 20 % at days 4, 11, and 25 after normal and high dose, respectively). Including ret% as a stand-alone marker for atypical blood profiles increased (P < 0.05) the sensitivity of the adaptive model at day 11 to 63 % and 67 % for normal-dose and high-dose rHuEPO administration, respectively. In conclusion, ~30 % of subjects injecting a normal-dose rHuEPO for two weeks or a high-dose rHuEPO for three days will present an atypical ABP profile. Including ret% as a stand-alone parameter improves the sensitivity two-fold. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior

PubMed Central

Leclercq, Sophie; Mian, Firoz M.; Stanisz, Andrew M.; Bindels, Laure B.; Cambier, Emmanuel; Ben-Amram, Hila; Koren, Omry; Forsythe, Paul; Bienenstock, John

2017-01-01

There is increasing concern about potential long-term effects of antibiotics on children's health. Epidemiological studies have revealed that early-life antibiotic exposure can increase the risk of developing immune and metabolic diseases, and rodent studies have shown that administration of high doses of antibiotics has long-term effects on brain neurochemistry and behaviour. Here we investigate whether low-dose penicillin in late pregnancy and early postnatal life induces long-term effects in the offspring of mice. We find that penicillin has lasting effects in both sexes on gut microbiota, increases cytokine expression in frontal cortex, modifies blood–brain barrier integrity and alters behaviour. The antibiotic-treated mice exhibit impaired anxiety-like and social behaviours, and display aggression. Concurrent supplementation with Lactobacillus rhamnosus JB-1 prevents some of these alterations. These results warrant further studies on the potential role of early-life antibiotic use in the development of neuropsychiatric disorders, and the possible attenuation of these by beneficial bacteria. PMID:28375200

Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery

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

Moussazadeh, Nelson; Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York; Lis, Eric

Purpose: To characterize local tumor control and toxicity risk in very long-term survivors (>5 years) after high-dose spinal image guided, intensity modulated radiation therapy delivered as single-dose stereotactic radiosurgery (SRS). Previously published spinal SRS outcome analyses have included a heterogeneous population of cancer patients, mostly with short survival. This is the first study reporting the long-term tumor control and toxicity profiles after high-dose single-fraction spinal SRS. Methods and Materials: The study population included all patients treated from June 2004 to July 2009 with single-fraction spinal SRS (dose 24 Gy) who had survived at least 5 years after treatment. The endpoints examined included diseasemore » progression, surgical or radiation retreatment, in-field fracture development, and radiation-associated toxicity, scored using the Radiation Therapy Oncology Group radiation morbidity scoring criteria and the Common Terminology Criteria for Adverse Events, version 4.0. Local control and fracture development were assessed using Kaplan-Meier analysis. Results: Of 278 patients, 31 (11.1%), with 36 segments treated for spinal tumors, survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 6.1 years (maximum 102 months). The histopathologic findings for the 5-year survivors included radiation-resistant metastases in 58%, radiation-sensitive metastases in 22%, and primary bone tumors in 19%. In this selected cohort, 3 treatment failures occurred at a median of 48.6 months, including 2 recurrences in the radiation field and 1 patient with demonstrated progression at the treatment margins. Ten lesions (27.8%) were associated with acute grade 1 cutaneous or gastrointestinal toxicity. Delayed toxicity ≥3 months after treatment included 8 cases (22.2%) of mild neuropathy, 2 (5.6%) of gastrointestinal discomfort, 8 (22.2%) of dermatitides, and 3 (8.3%) of myalgias/myositis. Thirteen treated levels (36.1%) in 12 patients demonstrated progressive vertebral body collapse or endplate fractures at a median of 25.7 months (range 11.6-76.0), of which 5 (14%) became symptomatic and subsequently required percutaneous cement augmentation or surgery. Conclusions: In the longest-term series to date, high-dose single-fraction spinal SRS retained an excellent safety profile among long-term survivors (>5 years)« less

Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial.

PubMed

Beraha, Esther M; Salemink, Elske; Goudriaan, Anna E; Bakker, Abraham; de Jong, David; Smits, Natasha; Zwart, Jan Willem; Geest, Dick van; Bodewits, Pieter; Schiphof, Tom; Defourny, Harma; van Tricht, Mirjam; van den Brink, Wim; Wiers, Reinout W

2016-12-01

Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30-60mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150mg), low-dose baclofen (N=31; 30mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150mg and the mean baclofen dose in this group was 93.6mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ 2 =0.41; p=0.813) or the 16-weeks complete medication period (χ 2 =0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene.

PubMed

Ambrosini, G L; Bremner, A P; Reid, A; Mackerras, D; Alfonso, H; Olsen, N J; Musk, A W; de Klerk, N H

2013-04-01

Uncertainty remains over whether or not high intakes of retinol or vitamin A consumed through food or supplements may increase fracture risk. This intervention study found no increase in fracture risk among 2,322 adults who took a controlled, high-dose retinol supplement (25,000 IU retinyl palmitate/day) for as long as 16 years. There was some evidence that beta-carotene supplementation decreased fracture risk in men. There is conflicting epidemiological evidence regarding high intakes of dietary or supplemental retinol and an increased risk for bone fracture. We examined fracture risk in a study administering high doses of retinol and beta-carotene (BC) between 1990 and 2007. The Vitamin A Program was designed to test the efficacy of retinol and BC supplements in preventing malignancies in persons previously exposed to blue asbestos. Participants were initially randomised to 7.5 mg retinol equivalents (RE)/day as retinyl palmitate, 30 mg/day BC or 0.75 mg/day BC from 1990 to 1996; after which, all participants received 7.5 mg RE/day. Fractures were identified by questionnaire and hospital admission data up until 2006. Risk of any fracture or osteoporotic fracture according to cumulative dose of retinol and BC supplementation was examined using conditional logistic regression models adjusting for age, sex, smoking, body mass index, medication use and previous fracture. Supplementation periods ranged from 1 to 16 years. Of the 2,322 (664 females and 1,658 males) participants, 187 experienced 237 fractures. No associations were observed between cumulative dose of retinol and risk for any fracture (OR per 10 g RE=0.83; 95% CI, 0.63-1.08) or osteoporotic fracture (OR per 10 g RE=0.95; 95% CI 0.64-1.40). Among men, cumulative dose of BC was associated with a slightly reduced risk of any fracture (OR per 10 g=0.89; 95% CI 0.81-0.98) and osteoporotic fracture (OR per 10 g=0.84; 95% CI 0.72-0.97). This study observed no increases in fracture risk after long-term supplementation with high doses of retinol and/or beta-carotene.

High-dose N-acetylcysteine in the prevention of COPD exacerbations: rationale and design of the PANTHEON Study.

PubMed

Zheng, Jin-Ping; Wen, Fu-Qiang; Bai, Chun-Xue; Wan, Huan-Ying; Kang, Jian; Chen, Ping; Yao, Wan-Zhen; Ma, Li-Jun; Xia, Qi-Kui; Gao, Yi; Zhong, Nan-Shan

2013-04-01

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation; from a pathophysiological point of view it involves many components, including mucus hypersecretion, oxidative stress and inflammation. N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. Long-term efficacy of NAC 600mg/d in COPD is controversial; a dose-effect relationship has been demonstrated, but at present it is not known whether a higher dose provides clinical benefits. The PANTHEON Study is a prospective, ICS stratified, randomized, double-blind, placebo-controlled, parallel-group, multi-center trial designed to assess the efficacy and safety of high-dose (1200 mg/daily) NAC treatment for one year in moderate-to-severe COPD patients. The primary endpoint is the annual exacerbation rate. Secondary endpoints include recurrent exacerbations hazard ratio, time to first exacerbation, as well as quality of life and pulmonary function. The hypothesis, design and methodology are described and baseline characteristics of recruited patients are presented. 1006 COPD patients (444 treated with maintenance ICS, 562 ICS naive, aged 66.27±8.76 yrs, average post-bronchodilator FEV1 48.95±11.80 of predicted) have been randomized at 34 hospitals in China. Final results of this study will provide objective data on the effects of high-dose (1200 mg/daily) long-term NAC treatment in the prevention of COPD exacerbations and other outcome variables.

Deterioration of Intellect among Children Surviving Leukemia: IQ Test Changes Modify Estimates of Treatment Toxicity.

ERIC Educational Resources Information Center

Mulhern, Raymond, K; And Others

1992-01-01

Assessed association of young age at treatment, cranial irradiation, and time since treatment with intellectual deterioration among 49 long-term survivors of childhood leukemia. Found no significant effects of treatment group (low-dose cranial irradiation versus high-dose chemotherapy) or age at treatment. Small but statistically significant…

Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer

PubMed Central

Wilcox, Shea W; Aherne, Noel J; Benjamin, Linus C; Wu, Bosco; de Campos Silva, Thomaz; McLachlan, Craig S; McKay, Michael J; Last, Andrew J; Shakespeare, Thomas P

2014-01-01

Purpose Dose-escalated (DE) radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS) in several studies. In the same group of patients, androgen deprivation therapy (ADT) has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT) with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT) and ADT. Methods and materials Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Results Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2.1% and 3.4%, respectively. No grade 3 or 4 late toxicities were reported. Pretreatment prostate specific antigen (P=0.001) and Gleason score (P=0.03) were significant in predicting biochemical failure on multivariate analysis. Conclusion There is a high probability of tumor control with DE IG-IMRT combined with androgen deprivation, and this is a technique with a low probability of significant late toxicity. Our long term results corroborate the safety and efficacy of treating with IG-IMRT to high doses and compares favorably with published series for the treatment of prostate cancer. PMID:25210465

Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer.

PubMed

Wilcox, Shea W; Aherne, Noel J; Benjamin, Linus C; Wu, Bosco; de Campos Silva, Thomaz; McLachlan, Craig S; McKay, Michael J; Last, Andrew J; Shakespeare, Thomas P

2014-01-01

Dose-escalated (DE) radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS) in several studies. In the same group of patients, androgen deprivation therapy (ADT) has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT) with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT) and ADT. Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2.1% and 3.4%, respectively. No grade 3 or 4 late toxicities were reported. Pretreatment prostate specific antigen (P=0.001) and Gleason score (P=0.03) were significant in predicting biochemical failure on multivariate analysis. There is a high probability of tumor control with DE IG-IMRT combined with androgen deprivation, and this is a technique with a low probability of significant late toxicity. Our long term results corroborate the safety and efficacy of treating with IG-IMRT to high doses and compares favorably with published series for the treatment of prostate cancer.

Antipsychotic doses among community-dwelling persons with Alzheimer disease in Finland.

PubMed

Taipale, Heidi; Koponen, Marjaana; Tanskanen, Antti; Tolppanen, Anna-Maija; Tiihonen, Jari; Hartikainen, Sirpa

2014-08-01

Use of antipsychotics for treatment of behavioral and psychological symptoms of dementia is frequent among persons with Alzheimer disease (AD). Doses used in long-term therapy have not been previously reported. We describe antipsychotic doses used among community-dwelling persons with AD and investigate factors associated with high-dose use. The MEDALZ-2005 (Medication use and Alzheimer disease) cohort is a nationwide sample including all persons with clinically diagnosed AD at the end of year 2005 in Finland (n = 28,093). Data including prescriptions, comorbidities, and hospital discharge diagnoses were collected from nationwide registers. Antipsychotic doses in monotherapy were investigated during 2006 to 2009. Among 8920 antipsychotic users, 4% (n = 336) used antipsychotics with high dose. Typical antipsychotics were more often used with high dose than atypical antipsychotics. High-dose use was associated with younger age (<80 years) (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.36-2.15]), male sex (OR, 1.52; CI, 1.21-1.91), history of psychiatric disorder (OR, 3.25; CI, 2.54-4.15), and inversely associated with Charlson Comorbidity Index score (score 1: OR, 0.74; CI, 0.57-0.97; score ≥2: OR, 0.68; CI, 0.47-0.97). In conclusion, the majority of persons with AD used antipsychotics with low or medium dose. Typical antipsychotics were more often used with high dose than atypical antipsychotics, which indicates a need for precise dosing instructions in the treatment of behavioral and psychological symptoms of dementia. Clinicians should regularly assess dosing levels especially among men and those with history of psychiatric disorder.

Mapping of cosmic radiation dose in Croatia.

PubMed

Poje, M; Vuković, B; Radolić, V; Miklavčić, I; Faj, D; Varga Pajtler, M; Planinić, J

2012-01-01

The Earth is continually bombarded by high-energy particles coming from the outer space and the sun. These particles, termed cosmic radiation, interact with nuclei of atmospheric constituents and decrease in intensity with depth in the atmosphere. Measurements of photon and gamma radiation, performed with a Radiameter at 1 m above the ground, indicated dose rates of 50-100 nSv/h. The neutron dose rate was measured with the CR-39 track etch detector calibrated by the CERN-EU high-energy Reference Field (CERF) facility. Correlation between neutron dose rates and altitudes at 36 sites was examined in order to obtain a significant positive correlation coefficient; the resulting linear regression enabled estimation of a neutron dose at particular altitude. The measured neutron dose rate in Osijek (altitude of 89 m, latitude of 45.31° N) was 110 nSv/h. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Radiation therapy for cancer--challenges and opportunities].

PubMed

Specht, Lena

2010-02-01

Radiotherapy for cancer previously employed large treatment fields whereby cures were obtained. However, long-term follow-up documented serious long-term complications due to irradiation of normal tissues. Modern technology makes it possible to very accurately shape the high-dose volume. However, new problems emerge. Organ movement must be managed and the precise definition of the extent of the tumour tissue is crucial. Positron emission tomography and magnetic resonance imaging are increasingly used. Biological imaging may enable us to image tumour biology more accurately and modify radiation doses accordingly.

Comparison of Individual Radiosensitivity to γ-Rays and Carbon Ions.

PubMed

Shim, Grace; Normil, Marie Delna; Testard, Isabelle; Hempel, William M; Ricoul, Michelle; Sabatier, Laure

2016-01-01

Carbon ions are an up-and-coming ion species, currently being used in charged particle radiotherapy. As it is well established that there are considerable interindividual differences in radiosensitivity in the general population that can significantly influence clinical outcomes of radiotherapy, we evaluate the degree of these differences in the context of carbon ion therapy compared with conventional radiotherapy. In this study, we evaluate individual radiosensitivity following exposure to carbon-13 ions or γ-rays in peripheral blood lymphocytes of healthy individuals based on the frequency of ionizing radiation (IR)-induced DNA double strand breaks (DSBs) that was either misrepaired or left unrepaired to form chromosomal aberrations (CAs) (simply referred to here as DSBs for brevity). Levels of DSBs were estimated from the scoring of CAs visualized with telomere/centromere-fluorescence in situ hybridization (TC-FISH). We examine radiosensitivity at the dose of 2 Gy, a routinely administered dose during fractionated radiotherapy, and we determined that a wide range of DSBs were induced by the given dose among healthy individuals, with highly radiosensitive individuals harboring more IR-induced breaks in the genome than radioresistant individuals following exposure to the same dose. Furthermore, we determined the relative effectiveness of carbon irradiation in comparison to γ-irradiation in the induction of DSBs at each studied dose (isodose effect), a quality we term "relative dose effect" (RDE). This ratio is advantageous, as it allows for simple comparison of dose-response curves. At 2 Gy, carbon irradiation was three times more effective in inducing DSBs compared with γ-irradiation (RDE of 3); these results were confirmed using a second cytogenetic technique, multicolor-FISH. We also analyze radiosensitivity at other doses (0.2-15 Gy), to represent hypo- and hyperfractionation doses and determined that RDE is dose dependent: high ratios at low doses, and approaching 1 at high doses. These results could have clinical implications as IR-induced DNA damage and the ensuing CAs and genomic instability can have significant cellular consequences that could potentially have profound implications for long-term human health after IR exposure, such as the emergence of secondary cancers and other pathobiological conditions after radiotherapy.

Carcinogenicity of antioxidants BHA, caffeic acid, sesamol, 4-methoxyphenol and catechol at low doses, either alone or in combination, and modulation of their effects in a rat medium-term multi-organ carcinogenesis model.

PubMed

Hirose, M; Takesada, Y; Tanaka, H; Tamano, S; Kato, T; Shirai, T

1998-01-01

The carcinogenicity of low dietary levels of the antioxidants butylated hydroxyanisole (BHA), caffeic acid, sesamol, 4-methoxyphenol (4-MP) and catechol, known to target the forestomach or glandular stomach, were examined alone or in combination in a 2-year long-term experiment and their modifying effects assessed in a medium-term multiorgan model. In the carcinogenicity study, groups of 30-31 male F344 rats were treated with 0.4% BHA, 0.4% caffeic acid, 0.4% sesamol, 0.4% 4-MP and 0.16% catechol either alone or in combination for up to 104 weeks and then killed. In the medium-term multi-organ model, groups of 10 to 15 male F344 rats were given diethylnitrosamine (DEN), N-methylnitrosourea (MNU), 1,2-dimethylhydrazine (DMH), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) for a total multiple initiation period of 4 weeks (DMBDD treatment). BHA, caffeic acid, sesamol and 4-MP, each at doses of 0.4% or 0.08%, and catechol at doses of 0.16% or 0.032% were administered in the diet either alone or in combination after completion of the initiation regimen. All surviving animals were killed at the end of week 28, and major organs were examined histopathologically. In the carcinogenicity study, slightly increased incidences of forestomach papillomas were found in the sesamol- (15.8%), caffeic acid- (14.8%), catechol- (3%) and 4-MP- (11.5%) treated groups as compared with basal diet (0%), and a significant increase was observed with the five antioxidants in combination (42.9%, P < 0.001). In a medium-term multiorgan carcinogenesis model, incidences of forestomach papillomas and/or carcinomas were increased in each high dose group, but additive or synergistic effects were not found in the combination group. In the low dose case, the incidence of forestomach papillomas was significantly increased only in the combination group. With regard to other organs, the incidence of colon tumors was significantly decreased only in the high dose combination group. The results indicate that even at low dose levels phenolic compounds can exert additive/synergistic effect on carcinogenesis.

Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression

PubMed Central

Brandhorst, Sebastian; Wei, Min; Hwang, Saewon; Morgan, Todd E.; Longo, Valter D.

2013-01-01

Short-term starvation (STS) protects normal cells while simultaneously sensitizing malignant cells to high-dose chemotherapeutic drugs in mice and possibly patients. The fasting-dependent protection of normal cells and sensitization of malignant cells depends, in part, on reduced levels of insulin-like growth factor-1 (IGF-1) and glucose. Calorie restricted diets with defined macronutrient (carbohydrate, protein, fat) ratios were evaluated for the effects on stress sensitization markers and protection in mice treated with high-dose chemotherapy. We show that short-term CR significantly reduced both glucose and IGF-1 levels, but when specific macronutrient deficiencies were tested, only the complete lack of proteins reduced IGF-1 levels. Short-term 50% CR combined with either severe protein-deficiency or ketogenic diets improved chemotoxicity resistance similarly to the standard 50% CR, but did not result in the high protection caused by STS. Notably, a high protein diet reversed the beneficial effects of short-term CR. In a subcutaneous mouse model of glioma, feeding a low protein (4% calories from protein) diet for more than 20 days did not delay tumor progression once the tumor became palpable. Also, cycles of short-term (3 days) 50% CR did not augment the chemotherapy efficacy of cisplatin in a murine breast cancer model. These results indicate that the protection from chemotoxicity and retardation of the progression of certain tumors achieved with fasting is not obtained with short-term calorie and/or macronutrient restriction. PMID:23454633

Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H1 blocker terfenadine-induced torsades de pointes arrhythmias.

PubMed

Takahara, Akira; Sugiyama, Atsushi; Ishida, Yuko; Satoh, Yoshioki; Wang, Kai; Nakamura, Yuji; Hashimoto, Keitaro

2006-03-01

Although a second-generation histamine H(1) blocker terfenadine induced torsades de pointes (TdP) arrhythmias in patients via the blockade of a rapid component of delayed rectifier K(+) current (I(Kr)), such action of terfenadine has not been detected in previous animal models. We analysed the potential of the canine persistent atrioventricular block heart, a new in vivo proarrhythmia model, to detect a torsadogenic effect of terfenadine of an oral dose of 3 or 30 mg kg(-1). The doses can provide therapeutic to supra-therapeutic plasma concentrations as an anti-histamine. In 2 weeks of bradycardiac heart model, there were no significant changes in any of the electrocardiogram parameters after the administration of both doses of terfenadine. In 4-6 weeks of bradycardiac heart model, the low dose of terfenadine hardly affected any of the electrocardiogram parameters except that it induced TdP in one out of six animals. The high dose significantly decreased the atrial rate and ventricular rate, prolonged the QT interval, and induced TdP in five out of six animals. Moreover, temporal variability of repolarization increased after the high-dose administration. These results suggest that long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect terfenadine-induced TdP.

Durable antibody responses following one dose of the bivalent human papillomavirus L1 virus-like particle vaccine in the Costa Rica Vaccine Trial.

PubMed

Safaeian, Mahboobeh; Porras, Carolina; Pan, Yuanji; Kreimer, Aimee; Schiller, John T; Gonzalez, Paula; Lowy, Douglas R; Wacholder, Sholom; Schiffman, Mark; Rodriguez, Ana C; Herrero, Rolando; Kemp, Troy; Shelton, Gloriana; Quint, Wim; van Doorn, Leen-Jan; Hildesheim, Allan; Pinto, Ligia A

2013-11-01

The Costa Rica HPV16/18 Vaccine Trial (CVT) showed that four-year vaccine efficacy against 12-month HPV16/18 persistent infection was similarly high among women who received one, two, or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle (VLP) vaccine. Live-attenuated viral vaccines, but not simple-subunit vaccines, usually induce durable lifelong antibody responses after a single dose. It is unclear whether noninfectious VLP vaccines behave more like live-virus or simple-subunit vaccines in this regard. To explore the likelihood that efficacy will persist longer term, we investigated the magnitude and durability of antibodies to this vaccine by measuring HPV16- and HPV18-specific antibodies by VLP-ELISA using serum from enrollment, vaccination, and annual visits through four years in four vaccinated groups; one-dose (n = 78), two-doses separated by one month (n = 140), two doses separated by six months (n = 52), and three scheduled doses (n = 120, randomly selected). We also tested enrollment sera from n = 113 HPV16- or HPV18 L1-seropositive women prevaccination, presumably from natural infection. At four years, 100% of women in all groups remained HPV16/18 seropositive; both HPV16/18 geometric mean titers (GMT) among the extended two-dose group were non-inferior to the three-dose group, and ELISA titers were highly correlated with neutralization titers in all groups. Compared with the natural infection group, HPV16/18 GMTs were, respectively, at least 24 and 14 times higher among the two-dose and 9 and 5 times higher among one-dose vaccinees. Antibody levels following one-dose remained stable from month 6 through month 48. Results raise the possibility that even a single dose of HPV VLPs will induce long-term protection. ©2013 AACR.

Low-dose-rate or high-dose-rate brachytherapy in treatment of prostate cancer – between options

PubMed Central

2013-01-01

Purpose Permanent low-dose-rate (LDR-BT) and temporary high-dose-rate (HDR-BT) brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never to be conducted comparing these two forms of brachytherapy, a comparative analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. The aim of this paper is to look for possible similarities and differences between both brachytherapy modalities. Indications and contraindications for monotherapy and for brachytherapy as a boost to external beam radiation therapy (EBRT) are presented. It is suggested that each of these techniques has attributes that advocates for one or the other. First, they represent the extreme ends of the spectrum with respect to dose rate and fractionation, and therefore have inherently different radiobiological properties. Low-dose-rate brachytherapy has the great advantage of being practically a one-time procedure, and enjoys a long-term follow-up database supporting its excellent outcomes and low morbidity. Low-dose-rate brachytherapy has been a gold standard for prostate brachytherapy in low risk patients since many years. On the other hand, HDR is a fairly invasive procedure requiring several sessions associated with a brief hospital stay. Although lacking in significant long-term data, it possesses the technical advantage of control over its postimplant dosimetry (by modulating the source dwell time and position), which is absent in LDR brachytherapy. This important difference in dosimetric control allows HDR doses to be escalated safely, a flexibility that does not exist for LDR brachytherapy. Conclusions Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy, using current dose regimens. At present, all available clinical data regarding these two techniques suggests that they are equally effective, stage for stage, in providing high tumor control rates. PMID:23634153

Factors impacting short and long-term kidney graft survival: modification by single intra-operative -high-dose induction with ATG-Fresenius.

PubMed

Kaden, Jürgen; May, Gottfried; Völp, Andreas; Wesslau, Claus

2011-01-01

A majority of recipients benefited from the intra-operative single high-dose induction (HDI) with ATG-Fresenius (ATG-F) still leaving a group of recipients who did not profit from this kind of induction. Therefore the aim of this retrospective analysis was 1st to identify the risk factors impacting short and long-term graft survival, and 2nd to assess the efficacy of this type of induction in kidney graft recipients with or without these risk factors. A total of 606 recipients receiving two different immunosuppressive treatment regimens (1st: Triple drug therapy [TDT, n=196] consisting mainly of steroids, azathioprine and cyclosporine; 2nd: TDT + 9 mg/kg ATG-F intra-operatively [HDI, n=410]) were included in this analysis and grouped according to their kidney graft survival time (short GST: ≤1 yr, n=100 and long GST: >5 yrs, n=506). The main risk factors associated with a shortened graft survival were pre-transplant sensitization, re-transplantation, rejections (in particular vascular or mixed ones) and the necessity of a long-term anti-rejection therapy. Adding ATG-F single high dose induction to TDT was more efficient in prolonging kidney graft survival than TDT alone not only in recipients without any risk factors (p<0.005) but also in recipients with at least one risk factor (p<0.021). Only in 4.6% of recipients having two or more risk factors this effect could not be demonstrated. The intra-operative single high-dose induction with ATG-F significantly improves the kidney graft survival in recipients with or without risk factors and can therefore be recommended.

Long-term sequelae of autologous bone marrow or peripheral stem cell transplantation for lymphoid malignancies.

PubMed

Vose, J M; Kennedy, B C; Bierman, P J; Kessinger, A; Armitage, J O

1992-02-01

The study was made to evaluate the long-term physical and psychosocial changes after high-dose therapy and autologous bone marrow or peripheral stem transplantation for recurrent lymphoid malignancies. Patients who had undergone high dose therapy and autologous bone marrow or peripheral stem cell transplantation for recurrent lymphoid malignancies at least 1 year previously were contacted by phone interview regarding their status after the transplant. The patients' comments were confirmed by checking medical records when possible. Fifty patients who had undergone transplantation at the University of Nebraska Medical Center at least 1 year before the interview were available for interview and willing to answer questions. After transplant, many patients noticed temporary changes in their appearance, which usually returned to normal within 1 year. Few patients reported remarkable cardiovascular, gastrointestinal, or pulmonary changes after transplantation. However, up to one-third of the patients reported changes in sexual function or desire. The most common infectious problem after transplant was Herpes zoster, which occurred in 25% of the patients. Overall, the patients had a positive outlook after high-dose therapy and transplantation, with most being able to return to work and enjoy a normal life style. Ninety-six percent of the patients stated that they would be willing to undergo high-dose therapy and transplantation again under the same circumstances.

Pulse versus continuous peracetic acid applications: effects on Rainbow trout performance, biofilm formation and water quality

USDA-ARS?s Scientific Manuscript database

Peracetic acid (PAA) products are being introduced to aquaculture as sustainable disinfectants. Two strategies are used to apply PAA: short term high dose (1-2 mg L-1 PAA) periodic pulse applications or continuous low dose (< 0.2 mg L-1 PAA) applications. In the present study, these strategies and a...

Latest performance of ArF immersion scanner NSR-S630D for high-volume manufacturing for 7nm node

NASA Astrophysics Data System (ADS)

Funatsu, Takayuki; Uehara, Yusaku; Hikida, Yujiro; Hayakawa, Akira; Ishiyama, Satoshi; Hirayama, Toru; Kono, Hirotaka; Shirata, Yosuke; Shibazaki, Yuichi

2015-03-01

In order to achieve stable operation in cutting-edge semiconductor manufacturing, Nikon has developed NSR-S630D with extremely accurate overlay while maintaining throughput in various conditions resembling a real production environment. In addition, NSR-S630D has been equipped with enhanced capabilities to maintain long-term overlay stability and user interface improvement all due to our newly developed application software platform. In this paper, we describe the most recent S630D performance in various conditions similar to real productions. In a production environment, superior overlay accuracy with high dose conditions and high throughput are often required; therefore, we have performed several experiments with high dose conditions to demonstrate NSR's thermal aberration capabilities in order to achieve world class overlay performance. Furthermore, we will introduce our new software that enables long term overlay performance.

Modelling the effects of booster dose vaccination schedules and recommendations for public health immunization programs: the case of Haemophilus influenzae serotype b.

PubMed

Charania, Nadia A; Moghadas, Seyed M

2017-09-13

Haemophilus influenzae serotype b (Hib) has yet to be eliminated despite the implementation of routine infant immunization programs. There is no consensus regarding the number of primary vaccine doses and an optimal schedule for the booster dose. We sought to evaluate the effect of a booster dose after receiving the primary series on the long-term disease incidence. A stochastic model of Hib transmission dynamics was constructed to compare the long-term impact of a booster vaccination and different booster schedules after receiving the primary series on the incidence of carriage and symptomatic disease. We parameterized the model with available estimates for the efficacy of Hib conjugate vaccine and durations of both vaccine-induced and naturally acquired immunity. We found that administering a booster dose substantially reduced the population burden of Hib disease compared to the scenario of only receiving the primary series. Comparing the schedules, the incidence of carriage for a 2-year delay (on average) in booster vaccination was comparable or lower than that observed for the scenario of booster dose within 1 year after primary series. The temporal reduction of symptomatic disease was similar in the two booster schedules, suggesting no superiority of one schedule over the other in terms of reducing the incidence of symptomatic disease. The findings underscore the importance of a booster vaccination for continued decline of Hib incidence. When the primary series provides a high level of protection temporarily, delaying the booster dose (still within the average duration of protection conferred by the primary series) may be beneficial to maintain longer-term protection levels and decelerate the decline of herd immunity in the population.

Recent skyshine calculations at Jefferson Lab

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

Degtyarenko, P.

1997-12-01

New calculations of the skyshine dose distribution of neutrons and secondary photons have been performed at Jefferson Lab using the Monte Carlo method. The dose dependence on neutron energy, distance to the neutron source, polar angle of a source neutron, and azimuthal angle between the observation point and the momentum direction of a source neutron have been studied. The azimuthally asymmetric term in the skyshine dose distribution is shown to be important in the dose calculations around high-energy accelerator facilities. A parameterization formula and corresponding computer code have been developed which can be used for detailed calculations of the skyshinemore » dose maps.« less

Collagenous colitis: Requirement for high-dose budesonide as maintenance treatment.

PubMed

Fernandez-Bañares, Fernando; Piqueras, Marta; Guagnozzi, Danila; Robles, Virginia; Ruiz-Cerulla, Alexandra; Casanova, María José; Gisbert, Javier P; Busquets, David; Arguedas, Yolanda; Pérez-Aisa, Angeles; Fernández-Salazar, Luis; Lucendo, Alfredo J

2017-09-01

Controlled studies show high efficacy of budesonide in inducing short-term clinical remission in collagenous colitis (CC), but relapses are common after its withdrawal. To evaluate the need for high-dose budesonide (≥6mg/d) to maintain clinical remission in CC. Analysis of a multicentre retrospective cohort of 75 patients with CC (62.3±1.5years; 85% women) treated with budesonide in a clinical practice setting between 2013 and 2015. Frequency of budesonide (9mg/d) refractoriness and safety, and the need for high-dose budesonide to maintain clinical remission, were evaluated. Drugs used as budesonide-sparing, including azathioprine and mercaptopurine, were recorded. Logistic regression analysis was performed to evaluate the risk factors associated with the need for high-dose budesonide (≥6mg/d) to maintain clinical remission. Budesonide induced clinical remission in 92% of patients, with good tolerance. Fourteen of 68 patients (21%; 95% CI, 13-32%) needed high-dose budesonide to maintain remission. Only intake of NSAIDs at diagnosis (OR, 8.6; 95% CI, 1.6-44) was associated with the need for high-dose budesonide in the multivariate analysis. with thiopurines was effective in 5 out of 6 patients (83%; 95% CI, 44-97%), allowing for withdrawal from or a dose decrease of budesonide. One fifth of CC patients, especially those with NSAID intake at diagnosis, require high-dose budesonide (≥6mg/d) to maintain clinical remission. In this setting, thiopurines might be effective as budesonide-sparing drugs. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

SU-E-T-611: Photon and Neutron Peripheral Dose Ratio for Low (6 MV) and High (15 MV) Energy for Treatment Selection

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

Irazola, L; Sanchez-Doblado, F; Servicio de Radiofisica, Hospital Universitario Virgen Macarena, Seville

2015-06-15

Purpose: Differences between radiotherapy techniques and energies, can offer improvements in tumor coverage and organs at risk preservation. However, a more complete decision should include peripheral doses delivered to the patient. The purpose of this work is the balance of photon and neutron peripheral doses for a prostate case solved with 6 different treatment modalities. Methods: Inverse and Forward IMRT and 3D-CRT in 6 and 15 MV for a Siemens Primus linac, using the same CT data set and contours. The methodology described in [1], was used with the TNRD thermal neutron detector [2] for neutron peripheral dose estimation atmore » 7 relevant organs (colon, esophagus, stomach, liver, lung, thyroid and skin). Photon doses were estimated for these organs by terms of the algorithm proposed in [3]. Plans were optimized with the same restrictions and limited to 30 segments in the Inverse case. Results: A similar photon peripheral dose was found comparing 6 and 15 MV cases with slightly higher values of (1.9 ± 1.6) % in mean, for the 6 MV cases. Neutron presence when using 15 MV, represents an increase in peripheral dose of (18 ± 17) % in average. Due to the higher number of MU used in Inverse IMRT, an increasing of (22 ± 3) % in neutron dose is found related to Forward and 3D-CRT plans. This corresponds to photon doses within 44 and 255 mSv along the organs, for a dose prescription of 68 Gy at the isocenter. Conclusion: Neutron and photon peripheral doses for a prostate treatment planified in 6 different techniques have been analyzed. 6 MV plans are slightly more demanding in terms of photon peripheral doses. Inverse technique in 15 MV has Result to be the most demanding one in terms of total peripheral doses, including neutrons and photons.« less

Defining the “Hostile Pelvis” for Intensity Modulated Radiation Therapy: The Impact of Anatomic Variations in Pelvic Dimensions on Dose Delivered to Target Volumes and Organs at Risk in Patients With High-Risk Prostate Cancer Treated With Whole Pelvic Radiation Therapy

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

Yirmibeşoğlu Erkal, Eda, E-mail: eyirmibesoglu@yahoo.com; Karabey, Sinan; Karabey, Ayşegül

2015-07-15

Purpose: The aim of this study was to evaluate the impact of variations in pelvic dimensions on the dose delivered to the target volumes and the organs at risk (OARs) in patients with high-risk prostate cancer (PCa) to be treated with whole pelvic radiation therapy (WPRT) in an attempt to define the hostile pelvis in terms of intensity modulated radiation therapy (IMRT). Methods and Materials: In 45 men with high-risk PCa to be treated with WPRT, the target volumes and the OARs were delineated, the dose constraints for the OARs were defined, and treatment plans were generated according to themore » Radiation Therapy Oncology Group 0924 protocol. Six dimensions to reflect the depth, width, and height of the bony pelvis were measured, and 2 indexes were calculated from the planning computed tomographic scans. The minimum dose (D{sub min}), maximum dose (D{sub max}), and mean dose (D{sub mean}) for the target volumes and OARs and the partial volumes of each of these structures receiving a specified dose (V{sub D}) were calculated from the dose-volume histograms (DVHs). The data from the DVHs were correlated with the pelvic dimensions and indexes. Results: According to an overall hostility score (OHS) calculation, 25 patients were grouped as having a hospitable pelvis and 20 as having a hostile pelvis. Regarding the OHS grouping, the DVHs for the bladder, bowel bag, left femoral head, and right femoral head differed in favor of the hospitable pelvis group, and the DVHs for the rectum differed for a range of lower doses in favor of the hospitable pelvis group. Conclusions: Pelvimetry might be used as a guide to define the challenging anatomy or the hostile pelvis in terms of treatment planning for IMRT in patients with high-risk PCa to be treated with WPRT.« less

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

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated networkmore » (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.« less

The influence of non-DNA-targeted effects on carbon ion–induced low-dose hyper-radiosensitivity in MRC-5 cells

PubMed Central

Ye, Fei; Ning, Jing; Liu, Xinguo; Jin, Xiaodong; Wang, Tieshan; Li, Qiang

2016-01-01

Low-dose hyper-radiosensitivity (LDHRS) is a hot topic in normal tissue radiation protection. However, the primary causes for LDHRS still remain unclear. In this study, the impact of non-DNA-targeted effects (NTEs) on high-LET radiation–induced LDHRS was investigated. Human normal lung fibroblast MRC-5 cells were irradiated with high-LET carbon ions, and low-dose biological effects (in terms of various bio-endpoints, including colony formation, DNA damage and micronuclei formation) were detected under conditions with and without gap junctional intercellular communication (GJIC) inhibition. LDHRS was observed when the radiation dose was <0.2 Gy for all bio-endpoints under investigation, but vanished when the GJIC was suppressed. Based on the probability of cells being hit and micro-dose per cell calculation, we deduced that the LDHRS phenomenon came from the combined action of direct hits and NTEs. We concluded that GJIC definitely plays an important role in cytotoxic substance spreading in high-LET carbon ion–induced LDHRS. PMID:26559335

Evaluation of botulinum toxin type A effectiveness in preventing postoperative intraperitoneal adhesions

PubMed Central

Uysal, Erdal

2017-01-01

Purpose Postoperative intraperitoneal adhesions (PIAs) are one of the most important problems surgeons have to face after laparotomies. In this study, we aimed to evaluate the effectiveness of local application of botulinum toxin type A (BoNT-A) in various dosages on the prevention of intra-abdominal adhesions in rats with experimental intra-abdominal adhesions. Methods Forty Wistar Albino female rats were randomly separated into 4 groups. The 4 groups were determined as follows: Control (group 1, n = 10); Sham (group 2, n = 10); 10-µg/kg low-dose BoNT-A (group 3, n = 10) and 30-µg/kg high-dose BoNT-A (group 4, n = 10). Subserosal injuries were created on the caecum of all rats. Laparotomy was performed on the fifth day. Adhesion scores, histopathological examination, and E-cadherin expression levels were evaluated. Results General adhesion scores for groups 1 and 2 were determined to be significantly high when compared to group 4 (P < 0.001). A significant difference was also determined between groups 3 and 4 in terms of general adhesion scores (P < 0.05). In pair comparisons, a significant decrease in high-dose BoNT-A group (group 4) when compared to groups 1 and 2 in terms of neovascularization, fibroblast density, collagen deposition and inflammatory cell count was determined (P < 0.05). Conclusion A significant decrease was observed only in postoperative PIAs in the high-dose BoNT-A group between all 4 rat-groups with experimentally created postoperative PIAs. In this study, high-dose BoNT-A is determined to be an effective agent in preventing postoperative PIAs. PMID:28706891

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial

PubMed Central

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-01-01

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD. PMID:27552585

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial.

PubMed

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-08-23

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

Comparison of Individual Radiosensitivity to γ-Rays and Carbon Ions

PubMed Central

Shim, Grace; Normil, Marie Delna; Testard, Isabelle; Hempel, William M.; Ricoul, Michelle; Sabatier, Laure

2016-01-01

Carbon ions are an up-and-coming ion species, currently being used in charged particle radiotherapy. As it is well established that there are considerable interindividual differences in radiosensitivity in the general population that can significantly influence clinical outcomes of radiotherapy, we evaluate the degree of these differences in the context of carbon ion therapy compared with conventional radiotherapy. In this study, we evaluate individual radiosensitivity following exposure to carbon-13 ions or γ-rays in peripheral blood lymphocytes of healthy individuals based on the frequency of ionizing radiation (IR)-induced DNA double strand breaks (DSBs) that was either misrepaired or left unrepaired to form chromosomal aberrations (CAs) (simply referred to here as DSBs for brevity). Levels of DSBs were estimated from the scoring of CAs visualized with telomere/centromere-fluorescence in situ hybridization (TC-FISH). We examine radiosensitivity at the dose of 2 Gy, a routinely administered dose during fractionated radiotherapy, and we determined that a wide range of DSBs were induced by the given dose among healthy individuals, with highly radiosensitive individuals harboring more IR-induced breaks in the genome than radioresistant individuals following exposure to the same dose. Furthermore, we determined the relative effectiveness of carbon irradiation in comparison to γ-irradiation in the induction of DSBs at each studied dose (isodose effect), a quality we term “relative dose effect” (RDE). This ratio is advantageous, as it allows for simple comparison of dose–response curves. At 2 Gy, carbon irradiation was three times more effective in inducing DSBs compared with γ-irradiation (RDE of 3); these results were confirmed using a second cytogenetic technique, multicolor-FISH. We also analyze radiosensitivity at other doses (0.2–15 Gy), to represent hypo- and hyperfractionation doses and determined that RDE is dose dependent: high ratios at low doses, and approaching 1 at high doses. These results could have clinical implications as IR-induced DNA damage and the ensuing CAs and genomic instability can have significant cellular consequences that could potentially have profound implications for long-term human health after IR exposure, such as the emergence of secondary cancers and other pathobiological conditions after radiotherapy. PMID:27379201

Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical dose response using different monomers

NASA Astrophysics Data System (ADS)

Senden, R. J.; DeJean, P.; McAuley, K. B.; Schreiner, L. J.

2006-07-01

In this work, three new polymer gel dosimeter recipes were investigated that may be more suitable for widespread applications than polyacrylamide gel dosimeters, since the extremely toxic acrylamide has been replaced with the less harmful monomers N-isopropylacrylamide (NIPAM), diacetone acrylamide and N-vinylformamide. The new gel dosimeters studied contained gelatin (5 wt%), monomer (3 wt%), N,N'-methylene-bis-acrylamide crosslinker (3 wt%) and tetrakis (hydroxymethyl) phosphonium chloride antioxidant (10 mM). The NMR response (R2) of the dosimeters was analysed for conditions of varying dose, dose rate, time post-irradiation, and temperature during irradiation and scanning. It was shown that the dose-response behaviour of the NIPAM/Bis gel dosimeter is comparable to that of normoxic polyacrylamide gel (PAGAT) in terms of high dose-sensitivity and low dependence on dose rate and irradiation temperature, within the ranges considered. The dose-response (R2) of NIPAM/Bis appears to be linear over a greater dose range than the PAGAT gel dosimeter. The effects of time post-irradiation (temporal instability) and temperature during NMR scanning on the R2 response were more significant for NIPAM/Bis dosimeters. Diacetone acrylamide and N-vinylformamide gel dosimeters possessed considerably lower dose-sensitivities. The optical dose-response, measured in terms of the attenuation coefficient for each polymer gel dosimeter, showed potential for the use of optical imaging techniques in future studies.

Patient doses and occupational exposure in a hybrid operating room.

PubMed

Andrés, C; Pérez-García, H; Agulla, M; Torres, R; Miguel, D; Del Castillo, A; Flota, C M; Alonso, D; de Frutos, J; Vaquero, C

2017-05-01

This study aimed to characterize the radiation exposure to patients and workers in a new vascular hybrid operating room during X-ray-guided procedures. During one year, data from 260 interventions performed in a hybrid operating room equipped with a Siemens Artis Zeego angiography system were monitored. The patient doses were analysed using the following parameters: radiation time, kerma-area product, patient entrance reference point dose and peak skin dose. Staff radiation exposure and ambient dose equivalent were also measured using direct reading dosimeters and thermoluminescent dosimeters. The radiation time, kerma-area product, patient entrance reference point dose and peak skin dose were, on average, 19:15min, 67Gy·cm 2 , 0.41Gy and 0.23Gy, respectively. Although the contribution of the acquisition mode was smaller than 5% in terms of the radiation time, this mode accounted for more than 60% of the effective dose per patient. All of the worker dose measurements remained below the limits established by law. The working conditions in the hybrid operating room HOR are safe in terms of patient and staff radiation protection. Nevertheless, doses are highly dependent on the workload; thus, further research is necessary to evaluate any possible radiological deviation of the daily working conditions in the HOR. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Available evidence on re-irradiation with stereotactic ablative radiotherapy following high-dose previous thoracic radiotherapy for lung malignancies.

PubMed

De Bari, Berardino; Filippi, Andrea Riccardo; Mazzola, Rosario; Bonomo, Pierluigi; Trovò, Marco; Livi, Lorenzo; Alongi, Filippo

2015-06-01

Patients affected with intra-thoracic recurrences of primary or secondary lung malignancies after a first course of definitive radiotherapy have limited therapeutic options, and they are often treated with a palliative intent. Re-irradiation with stereotactic ablative radiotherapy (SABR) represents an appealing approach, due to the optimized dose distribution that allows for high-dose delivery with better sparing of organs at risk. This strategy has the goal of long-term control and even cure. Aim of this review is to report and discuss published data on re-irradiation with SABR in terms of efficacy and toxicity. Results indicate that thoracic re-irradiation may offer satisfactory disease control, however the data on outcome and toxicity are derived from low quality retrospective studies, and results should be cautiously interpreted. As SABR may be associated with serious toxicity, attention should be paid for an accurate patients' selection. Copyright © 2015 Elsevier Ltd. All rights reserved.

High- and low-dose oral delayed-release mesalamine in children with mild-to-moderately active ulcerative colitis.

PubMed

Winter, Harland S; Krzeski, Piotr; Heyman, Melvin B; Ibarguen-Secchia, Eduardo; Iwanczak, Barbara; Kaczmarski, Maciej; Kierkus, Jaroslaw; Kolaček, Sanja; Osuntokun, Bankole; Quiros, J Antonio; Shah, Manoj; Yacyshyn, Bruce; Dunnmon, Preston M

2014-12-01

The aim of the study was to assess the safety and efficacy of high- and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild-to-moderately active ulcerative colitis. Patients ages 5 to 17 years, with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score of ≥ 10 to ≤ 55 and a truncated Mayo Score of ≥ 1 for both rectal bleeding and stool frequency, were enrolled. They received body weight-dependent doses of oral, delayed-release mesalamine for 6 weeks in a low- (27-71 mg · g(-1) · day(-1)) or high-dose group (53-118 mg · g(-1) · day(-1)). The primary endpoint was treatment success, defined as the proportion of patients who achieved remission (PUCAI score <10) or partial response (PUCAI score ≥ 10 with a decrease from baseline by ≥ 20 points). Secondary endpoints included truncated Mayo Score and global assessment of change of disease activity. The modified intent-to-treat population included 81 of 83 patients enrolled. Treatment success by PUCAI was achieved by 23 of 41 (56%) and 22 of 40 (55%) patients in the mesalamine low- and high-dose groups, respectively (P = 0.924). Truncated Mayo Score (low-dose 30 [73%] and high-dose 28 [70%] patients) and other efficacy results did not differ between the groups. The type and severity of adverse events were consistent with those reported in previous studies of adults with ulcerative colitis and did not differ between groups. Both low- and high-dose oral, delayed-release mesalamine doses were equally effective as short-term treatment of mild-to-moderately active ulcerative colitis in children, without a specific benefit or risk to using either dose.

Booster and higher antigen doses of inactivated influenza vaccine in HIV-infected patients.

PubMed

Johnston, Jessica A; Tincher, Lindsey B; Lowe, Denise K

2013-12-01

To review the literature regarding booster or higher doses of influenza antigen for increasing immunogenicity of inactivated influenza vaccine (IIV) in HIV-infected patients. MEDLINE (1966 to September 2013) was searched using the terms immunize, influenza, vaccine, and HIV or AIDS in combination with two-dose, booster-dose, increased antigen, or high-dose. One trial of booster dosing with standard doses (SDs) of IIV, trivalent (IIV3); 2 trials of booster dosing with intermediate doses (ID) of H1N1 IIV or IIV3; and 1 trial of high-dose (HD) IIV3 were identified. Trials administering 2-dose, booster-dose, or increased antigen of influenza vaccine to patients with HIV were reviewed. Because adjuvanted IIV is not available and IIV, quadrivalent was recently approved in the United States, studies evaluating these vaccines were excluded. HIV-infected individuals are at high risk for influenza-related complications; however, vaccination with SD IIV may not confer optimal protection. It has been postulated that booster or higher doses of influenza antigen may lead to increased immunogenicity. When ID and SD or ID with boosters were evaluated in HIV-infected patients, significant increases in surrogate markers for influenza protection were not achieved. However, HD IIV3 did result in significant increases in seroprotective antibody levels, though 'clinical' influenza was not evaluated. Currently, evidence is insufficient to reach conclusions about the efficacy of booster dosing, ID, or HD influenza vaccine in HIV-infected patients. Trials evaluating booster or higher-antigen doses of IIV for 'clinical' influenza are necessary before routinely recommending for HIV-infected patients.

Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia.

PubMed

Sun, Bing; Xie, Yuan; Jiang, Jinfa; Wang, Yiping; Xu, Xiaolin; Zhao, Cuimei; Huang, Feifei

2015-04-14

Cardio-protective effect of fibrate therapy is controversial and current research is to evaluate the effect of fenofibrate therapy on rats with hypertriglycemia. Rats with hypertriglycemia were produced by 10% fructose administration (10 ml daily) for 4 weeks. After model has been successfully produced as reflected by increased triglyceride level, different doses of fenofibrate, namely low dose (50 mg/kg body weight) and high dose (100 mg/kg body weight), were orally prescribed for 2 weeks. At baseline, 4 weeks of fructose administration and 2 weeks of fenofibrate therapy, parameters of interest were evaluated and compared. At baseline, no significant differences of parameter were observed between groups. After 4 weeks of fructose prescription, triglyceride level increased in company with high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) decreased. C-reactive protein (CRP) and malondialdehyde (MDA) levels were also elevated. Endothelial function was impaired as reflected by reduced nitric oxide (NO) production and elevated serum asymmetric dimethylarginine (ADMA) level. All these changes were significant as compared to the control group (P<0.05), suggesting that short-term of triglyceride elevation could potently initiate atherosclerosis. With 2 weeks of fenofibrate therapy, in comparison to un-treated group, triglyceride level was significantly reduced in parallel with HDL-C and ApoA1 elevation. Inflammation and oxidation were also profoundly ameliorated as reflected by CRP and MDA reduction. Notably, NO production was enhanced in company with serum ADMA level decrease. Overall, these improvements manifested in a dose-dependent manner, which was supported by multivariate regression analysis showing that after adjusted to other variables, the dose of fenofibrate therapy remained significantly associated with NO production and serum ADMA level, with OR of 1.042 (high-dose versus low-dose, 95% CI 1.028-1.055, P<0.05). Fenofibrate therapy not only could reduce triglyceride level but also confer pleiotropic effects in terms of endothelium-protection and amelioration of inflammation and oxidation in a dose-dependent manner.

Computer model to simulate ionizing radiation effects correlates with experimental data

NASA Astrophysics Data System (ADS)

Perez-Poch, Antoni

Exposure to radiation from high energy protons and particles with ionizing properties is a major challenge for long-term space missions. The specific effect of such radiation on hematopoietic cells is still not fully understood. A number of experiments have been conducted on ground and in space. Those experiments on one hand, measure the extent of damage on blood markers. On the other hand, they intend to quantify the correlation between dose and energy from the radiation particles, with their ability to impair the hematopoietic stem and progenitor function. We present a computer model based on a neural network that intends to assess the relationship between dose, energy and number of hits on a particular cell, to the damage incurred to the human marrow cells. Calibration of the network is performed with the existing experimental data available in bibliography. Different sources of ionizing radiation at different doses (0-90 cGy) and along different patterns of a long-term exposure scenarios are simulated. Results are shown for a continuous variation of doses and are compared with specific data available in the literature. Some predictions are inferred for long-term scenarios of spaceflight, and the risk of jeopardizing a mission due to a major disfunction of the bone marrow is calculated. The method has proved successful in reproducing specific experimental data. We also discuss the significance and validity of the predicted ionizing radiation effects in situations such as long-term missions for a continuous range of dose.

Comparative evaluation of two-dimensional radiography and three dimensional computed tomography based dose-volume parameters for high-dose-rate intracavitary brachytherapy of cervical cancer: a prospective study.

PubMed

Madan, Renu; Pathy, Sushmita; Subramani, Vellaiyan; Sharma, Seema; Mohanti, Bidhu Kalyan; Chander, Subhash; Thulkar, Sanjay; Kumar, Lalit; Dadhwal, Vatsla

2014-01-01

Dosimetric comparison of two dimensional (2D) radiography and three-dimensional computed tomography (3D-CT) based dose distributions with high-dose-rate (HDR) intracavitry radiotherapy (ICRT) for carcinoma cervix, in terms of target coverage and doses to bladder and rectum. Sixty four sessions of HDR ICRT were performed in 22 patients. External beam radiotherapy to pelvis at a dose of 50 Gray in 27 fractions followed by HDR ICRT, 21 Grays to point A in 3 sessions, one week apart was planned . All patients underwent 2D-orthogonal and 3D-CT simulation for each session. Treatment plans were generated using 2D-orthogonal images and dose prescription was made at point A. 3D plans were generated using 3D-CT images after delineating target volume and organs at risk. Comparative evaluation of 2D and 3D treatment planning was made for each session in terms of target coverage (dose received by 90%, 95% and 100% of the target volume: D90, D95 and D100 respectively) and doses to bladder and rectum: ICRU-38 bladder and rectum point dose in 2D planning and dose to 0.1cc, 1cc, 2cc, 5cc, and 10cc of bladder and rectum in 3D planning. Mean doses received by 100% and 90% of the target volume were 4.24 ± 0.63 and 4.9 ± 0.56 Gy respectively. Doses received by 0.1cc, 1cc and 2cc volume of bladder were 2.88 ± 0.72, 2.5 ± 0.65 and 2.2 ± 0.57 times more than the ICRU bladder reference point. Similarly, doses received by 0.1cc, 1cc and 2cc of rectum were 1.80 ± 0.5, 1.48 ± 0.41 and 1.35 ± 0.37 times higher than ICRU rectal reference point. Dosimetric comparative evaluation of 2D and 3D CT based treatment planning for the same brachytherapy session demonstrates underestimation of OAR doses and overestimation of target coverage in 2D treatment planning.

Cycles of Transient High-Dose Cyclophosphamide Administration and Oncolytic Adenovirus Vector Intratumoral Injection for Long Term Tumor Suppression in Syrian Hamsters

PubMed Central

Dhar, Debanjan; Toth, Karoly; Wold, William S.M.

2014-01-01

Immune responses against oncolytic adenovirus (Ad) vectors are thought to limit vector anti-tumor efficacy. In Syrian hamsters, which are immunocompetent and whose tumors and normal tissues are permissive for replication of Ad5-based oncolytic Ad vectors, treating with high-dose cyclophosphamide to suppress the immune system and exert chemotherapeutic effects enhances Ad vector anti-tumor efficacy. However, long term cyclophosphamide treatment and immunosuppression can lead to anemia and vector spread to normal tissues. Here we employed three cycles of transient high-dose cyclophosphamide administration plus intratumoral injection of the oncolytic Ad vector VRX-007 followed by withdrawal from cyclophosphamide. Each cycle lasted 4-6 weeks. This protocol allowed the hamsters to remain healthy so the study could be continued for ~100 days. The tumors were very well suppressed throughout the study. With immunocompetent hamsters, the vector retarded tumor growth initially, but after 3-4 weeks the tumors resumed rapid growth and further injections of vector were ineffective. Preimmunization of the hamsters with Ad5 prevented vector spillover from the tumor to the liver yet still allowed for effective long term anti-tumor efficacy. Our results suggest that a clinical protocol might be developed with cycles of transient chemotherapy plus intratumoral vector injection to achieve significant anti-tumor efficacy while minimizing the side effects of cytostatic treatment. PMID:24722357

Cycles of transient high-dose cyclophosphamide administration and intratumoral oncolytic adenovirus vector injection for long-term tumor suppression in Syrian hamsters.

PubMed

Dhar, D; Toth, K; Wold, W S M

2014-04-01

Immune responses against oncolytic adenovirus (Ad) vectors are thought to limit vector anti-tumor efficacy. With Syrian hamsters, which are immunocompetent and whose tumors and normal tissues are permissive for replication of Ad5-based oncolytic Ad vectors, treating with high-dose cyclophosphamide (CP) to suppress the immune system and exert chemotherapeutic effects enhances Ad vector anti-tumor efficacy. However, long-term CP treatment and immunosuppression can lead to anemia and vector spread to normal tissues. Here, we employed three cycles of transient high-dose CP administration plus intratumoral injection of the oncolytic Ad vector VRX-007 followed by withdrawal of CP. Each cycle lasted 4-6 weeks. This protocol allowed the hamsters to remain healthy so the study could be continued for ~100 days. The tumors were very well suppressed throughout the study. With immunocompetent hamsters, the vector retarded tumor growth initially, but after 3-4 weeks the tumors resumed rapid growth and further injections of vector were ineffective. Preimmunization of the hamsters with Ad5 prevented vector spillover from the tumor to the liver yet still allowed for effective long-term anti-tumor efficacy. Our results suggest that a clinical protocol might be developed with cycles of transient chemotherapy plus intratumoral vector injection to achieve significant anti-tumor efficacy while minimizing the side effects of cytostatic treatment.

Characterizing Potentially Inappropriate Prescribing of Proton Pump Inhibitors in Older People in Primary Care in Ireland from 1997 to 2012.

PubMed

Moriarty, Frank; Bennett, Kathleen; Cahir, Caitriona; Fahey, Tom

2016-12-01

To characterize prescribing of proton pump inhibitors (PPIs) and medicines that increase gastrointestinal bleeding risk (ulcerogenic) in older people from 1997 to 2012 and assess factors associated with maximal-dose prescribing in long-term PPI users. Repeated cross-sectional study of pharmacy claims data. Eastern Health Board region of Ireland. Individuals aged 65 and older from a means-tested health plan in 1997, 2002, 2007, and 2012 (range 78,489-133,884 individuals). PPI prescribing prevalence was determined per study year, categorized according to duration (≤8 or >8 weeks), dosage (maximal or maintenance), and co-prescribed drugs. Logistic regression in long-term PPI users was used to determine whether age, sex, polypharmacy, and ulcerogenic medicine use were associated with being prescribed a maximal dose rather than a maintenance dose. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are presented. Half of this older population received a PPI in 2007 and 2012. Long-term use (>8 weeks) of maximal doses rose from 0.8% of individuals in 1997 to 23.6% in 2012. Although some ulcerogenic medicines and polypharmacy were significantly associated with maximal PPI doses, any nonsteroidal anti-inflammatory drug use was significantly associated with lower odds of maximal PPI dose (adjusted OR = 0.87, 95% CI = 0.85-0.89), as were aspirin use and older age. Adjusting for medication and demographic factors, odds of being prescribed a maximal PPI dose were significantly higher in 2012 than in 1997 (adjusted OR = 6.30, 95% CI = 5.76-6.88). Long-term maximal-dose PPI prescribing is highly prevalent in older adults and is not consistently associated with gastrointestinal bleeding risk factors. Interventions involving prescribers and patients may promote appropriate PPI use, reducing costs and adverse effects of PPI overprescribing. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Characterization of Thymol blue Radiochromic dosimeters for high dose applications

NASA Astrophysics Data System (ADS)

Aldweri, Feras M.; Abuzayed, Manar H.; Al-Ajaleen, Musab S.; Rabaeh, Khalid A.

2018-03-01

Thymol blue (TB) solutions and Thymol blue Polyvinyl Alcohol (TB-PVA) films have been introduced as Radiochromic dosimeter for high dose applications. The dosimeters were irradiated with gamma ray (60Co source) from 5 to 30 kGy for film, and from 0.150 kGy to 4 kGy for solution. The optical density of unirradiated and irradiated TB solution as well as TB-PVA film dosimeters were studied in terms of absorbance at 434 nm using UV/VIS spectrophotometer. The effects of scan temperature, light pre-gamma irradiation, dose rate, relative humidity and stability of the absorbance of solutions and films after irradiation were investigated. We found the dose sensitivity of TB solution and TB-PVA film dosimeters increases significantly with increases of the absorbed dose as well as with the increases of TB dye concentrations. The useful dose range of developed TB solutions and TB-PVA films dosimeters is in the range 0.125-1 kGy and of 5-20 kGy, respectively.

Curative chemotherapy for acute myeloid leukemia: the development of high-dose ara-C from the laboratory to bedside.

PubMed

Capizzi, R L

1996-01-01

In the bench to bedside development of drugs to treat patients with cancer, the common guide to dose and schedule selection is toxicity to normal organs patterned after the preclinical profile of the drug. An understanding of the cellular pharmacology of the drug and specifically the cellular targets linked to the drug's effect is of substantial value in assisting the clinical investigator in selecting the proper dose and schedule of drug administration. The clinical development of ara-C for the treatment of acute myeloid leukemia (AML) provides a useful paradigm for the study of this process. An understanding of the cellular pharmacology, cytokinetics and pharmacokinetics of ara-C in leukemic mice showed substantial schedule-dependency. Exposure to high doses for a short duration (C x t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c x T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c x T approach, has been of limited benefit in terms of long-term disease-free survival. Studies with human leukemia blasts from patients have shown that for the majority of patients, the initial rate-limiting step is membrane transport, the characteristics of which are substantially affected by extracellular drug concentration (dose). This pharmacologic impediment is eliminated with the blood levels attained during the infusion of gram doses (1-3 gm/m2) of the drug (high-dose ara-C, HiDaC) for shorter periods of time, a C x t approach. Clinical confirmation of these pharmacologic observations is evident in the therapeutic efficacy of HiDaC in patients with relapsed or SDaC-refractory acute leukemia. This is further emphasized by the significantly improved leukemia-free survival of patients with AML treated with HiDaC intensification during remission compared to those patients treated with milligram doses typical of SDaC protocols. Thus, the identification and monitoring of important parameters of drug action in tumors during the course of a clinical trial can be of substantial assistance in optimizing drug dose and schedule so as to attain the best therapeutic index.

Development of a high precision dosimetry system for the measurement of surface dose rate distribution for eye applicators.

PubMed

Eichmann, Marion; Flühs, Dirk; Spaan, Bernhard

2009-10-01

The therapeutic outcome of the therapy with ophthalmic applicators is highly dependent on the application of a sufficient dose to the tumor, whereas the dose applied to the surrounding tissue needs to be minimized. The goal for the newly developed apparatus described in this work is the determination of the individual applicator surface dose rate distribution with a high spatial resolution and a high precision in dose rate with respect to time and budget constraints especially important for clinical procedures. Inhomogeneities of the dose rate distribution can be detected and taken into consideration for the treatment planning. In order to achieve this, a dose rate profile as well as a surface profile of the applicator are measured and correlated with each other. An instrumental setup has been developed consisting of a plastic scintillator detector system and a newly designed apparatus for guiding the detector across the applicator surface at a constant small distance. It performs an angular movement of detector and applicator with high precision. The measurements of surface dose rate distributions discussed in this work demonstrate the successful operation of the measuring setup. Measuring the surface dose rate distribution with a small distance between applicator and detector and with a high density of measuring points results in a complete and gapless coverage of the applicator surface, being capable of distinguishing small sized spots with high activities. The dosimetrical accuracy of the measurements and its analysis is sufficient (uncertainty in the dose rate in terms of absorbed dose to water is <7%), especially when taking the surgical techniques in positioning of the applicator on the eyeball into account. The method developed so far allows a fully automated quality assurance of eye applicators even under clinical conditions. These measurements provide the basis for future calculation of a full 3D dose rate distribution, which then can be used as input for a refined clinical treatment planning system. The improved dose rate measurements will facilitate a clinical study, which could correlate the therapeutic outcome of a brachytherapy treatment with an applicator and its individual dose rate distribution.

The impact of low-Z and high-Z metal implants in IMRT: A Monte Carlo study of dose inaccuracies in commercial dose algorithms

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

Spadea, Maria Francesca, E-mail: mfspadea@unicz.it; Verburg, Joost Mathias; Seco, Joao

2014-01-15

Purpose: The aim of the study was to evaluate the dosimetric impact of low-Z and high-Z metallic implants on IMRT plans. Methods: Computed tomography (CT) scans of three patients were analyzed to study effects due to the presence of Titanium (low-Z), Platinum and Gold (high-Z) inserts. To eliminate artifacts in CT images, a sinogram-based metal artifact reduction algorithm was applied. IMRT dose calculations were performed on both the uncorrected and corrected images using a commercial planning system (convolution/superposition algorithm) and an in-house Monte Carlo platform. Dose differences between uncorrected and corrected datasets were computed and analyzed using gamma index (Pγ{submore » <1}) and setting 2 mm and 2% as distance to agreement and dose difference criteria, respectively. Beam specific depth dose profiles across the metal were also examined. Results: Dose discrepancies between corrected and uncorrected datasets were not significant for low-Z material. High-Z materials caused under-dosage of 20%–25% in the region surrounding the metal and over dosage of 10%–15% downstream of the hardware. Gamma index test yielded Pγ{sub <1}>99% for all low-Z cases; while for high-Z cases it returned 91% < Pγ{sub <1}< 99%. Analysis of the depth dose curve of a single beam for low-Z cases revealed that, although the dose attenuation is altered inside the metal, it does not differ downstream of the insert. However, for high-Z metal implants the dose is increased up to 10%–12% around the insert. In addition, Monte Carlo method was more sensitive to the presence of metal inserts than superposition/convolution algorithm. Conclusions: The reduction in terms of dose of metal artifacts in CT images is relevant for high-Z implants. In this case, dose distribution should be calculated using Monte Carlo algorithms, given their superior accuracy in dose modeling in and around the metal. In addition, the knowledge of the composition of metal inserts improves the accuracy of the Monte Carlo dose calculation significantly.« less

Development of a high precision dosimetry system for the measurement of surface dose rate distribution for eye applicators

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

Eichmann, Marion; Fluehs, Dirk; Spaan, Bernhard

2009-10-15

Purpose: The therapeutic outcome of the therapy with ophthalmic applicators is highly dependent on the application of a sufficient dose to the tumor, whereas the dose applied to the surrounding tissue needs to be minimized. The goal for the newly developed apparatus described in this work is the determination of the individual applicator surface dose rate distribution with a high spatial resolution and a high precision in dose rate with respect to time and budget constraints especially important for clinical procedures. Inhomogeneities of the dose rate distribution can be detected and taken into consideration for the treatment planning. Methods: Inmore » order to achieve this, a dose rate profile as well as a surface profile of the applicator are measured and correlated with each other. An instrumental setup has been developed consisting of a plastic scintillator detector system and a newly designed apparatus for guiding the detector across the applicator surface at a constant small distance. It performs an angular movement of detector and applicator with high precision. Results: The measurements of surface dose rate distributions discussed in this work demonstrate the successful operation of the measuring setup. Measuring the surface dose rate distribution with a small distance between applicator and detector and with a high density of measuring points results in a complete and gapless coverage of the applicator surface, being capable of distinguishing small sized spots with high activities. The dosimetrical accuracy of the measurements and its analysis is sufficient (uncertainty in the dose rate in terms of absorbed dose to water is <7%), especially when taking the surgical techniques in positioning of the applicator on the eyeball into account. Conclusions: The method developed so far allows a fully automated quality assurance of eye applicators even under clinical conditions. These measurements provide the basis for future calculation of a full 3D dose rate distribution, which then can be used as input for a refined clinical treatment planning system. The improved dose rate measurements will facilitate a clinical study, which could correlate the therapeutic outcome of a brachytherapy treatment with an applicator and its individual dose rate distribution.« less

The benefit of low dose prophylaxis in the treatment of hemophilia: a focus on China.

PubMed

Wu, Runhui; Luke, Koon Hung

2017-11-01

Currently full dose prophylaxis is the standard of care in the treatment of hemophilia (World Federation of Hemophilia). However, the high costs prevent the use of standard or intermediate dose prophylaxis in China and other developing countries. Low dose prophylaxis would be a viable alternative treatment. At present global research data on the use of low dose prophylaxis is limited. Areas covered: Since 2007, China has been developing low dose prophylaxis as a high priority (90 % of moderate and severe hemophilia boys suffer joint disease by age 6 - 9). 11 studies were successfully conducted and published results showing evidence of the benefits of low dose prophylaxis to reduce joint bleeding. This new knowledge has been implemented into clinical practice in China. However the long-term outcome of arthropathy remains unclear and obstacles in execution exist. Expert commentary: In 2016, the first phenotype-based individualized prophylaxis study using four escalating low dose regimens on severe Chinese hemophilia A boys (China Individualized Prophylaxis Study (CHIP China)) launched. Using the previously published and imminent CHIP data, the goal for China is to establish an effective escalating low dose prophylaxis protocol for use in China as a standard of care.

Long-Term Outcomes of Nasopharyngeal Carcinoma in 148 Children and Adolescents

PubMed Central

Lu, Suying; Chang, Hui; Sun, Xiaofei; Zhen, Zijun; Sun, Feifei; Zhu, Jia; Wang, Juan; Huang, Junting; Liao, Ru; Guo, Xiaofang; Lu, Lixia; Gao, Yuanhong

2016-01-01

Abstract The aim of this study was to investigate the survival and long-term morbidities of nasopharyngeal carcinoma (NPC) in children and adolescents. We retrospectively reviewed children and adolescents with NPC treated at Sun Yat-sen University Cancer Center from February 1991 to October 2010, where the prognostic factors and long-term effects of therapy were analyzed. A total of 148 patients were identified. The median age was 15 years old (range, 5–18 years) and the male to female ratio was 3.6:1. Most of the tumor histopathology was undifferentiated nonkeratinizing carcinoma (97.3%). The number of patients staged with IVa, IVb, IVc, III, and II were 45 (30.4%), 12 (8.1%), 5 (3.4%), 70 (47.3%), and 16 (10.8%), respectively. For the whole series with a median follow-up of 81 months (range, 6–282 months), the 5-year overall survival (OS) and disease-free survival (DFS) ratios were 79.3% and 69.7%, respectively. We observed significant differences in the 5-year OS (81.1% vs 25.0%, P = 0.002) and the DFS rates (72.2% vs 0.0%, P = 0.000) between patients with stage II to IVb disease and stage IVc disease. For patients with stage II, III, IVa, and IVb disease, we found a high radiation dose (dose > 66 Gy to the primary lesion) would not significantly improve the survival compared to the sub-high radiation dose group (dose = 60–66 Gy to the primary lesion), even considering the type of radiation therapy technologies. However, the incidences of sequelae (grades I–IV) in patients with high radiation dose were apparently higher than those in patients with low radiation dose. Considering the late sequelae, a dose of 60 to 66 Gy to the primary lesions seems to be enough for children and adolescents with NPC. PMID:27124036

Postnatal glucocorticoid-induced hypomyelination, gliosis, neurologic deficits are dose-dependent, preparation-specific, and reversible

PubMed Central

Zia, Muhammad TK; Vinukonda, Govindaiah; Vose, Linnea; Bhimavarapu, Bala B.R.; Iacobas, Sanda; Pandey, Nishi K.; Beall, Ann Marie; Dohare, Preeti; LaGamma, Edmund F.; Iacobas, Dumitru A.; Ballabh, Praveen

2014-01-01

Postnatal glucocorticoids (GCs) are widely used in the prevention of chronic lung disease in premature infants. Their pharmacologic use is associated with neurodevelopmental delay and cerebral palsy. However, the effect of GC dose and preparation (dexamethasone versus betamethasone) on short and long-term neurological outcomes remains undetermined, and the mechanisms of GC-induced brain injury are unclear. We hypothesized that postnatal GC would induce hypomyelination and motor impairment in a preparation- and dose-specific manner, and that GC receptor (GR) inhibition might restore myelination and neurological function in GC-treated animals. Additionally, GC-induced hypomyelination and neurological deficit might be transient. To test our hypotheses, we treated prematurely delivered rabbit pups with high (0.5 mg/kg/day) or low (0.2 mg/kg/day) doses of dexamethasone or betamethasone. Myelin basic protein (MBP), oligodendrocyte proliferation and maturation, astrocytes, transcriptomic profile, and neurobehavioral functions were evaluated. We found that high-dose GC treatment, but not low-dose, reduced MBP expression and impaired motor function at postnatal day 14. High-dose dexamethasone induced astrogliosis, betamethasone did not. Mifepristone, a GR antagonist, reversed dexamethasone-induced myelination, but not astrogliosis. Both GCs inhibited oligodendrocyte proliferation and maturation. Moreover, high-dose dexamethasone altered genes associated with myelination, cell-cycle, GR, and Mitogen-activated protein kinase. Importantly, GC-induced hypomyelination, gliosis, and motor-deficit, observed at day 14, completely recovered by day 21. Hence, high-dose, but not low-dose, postnatal GC causes reversible reductions in myelination and motor functions. GC treatment induces hypomyelination by GR-dependent genomic mechanisms, but astrogliosis by non-genomic mechanisms. GC-induced motor impairment and neurodevelopmental delay might be transient and recover spontaneously in premature infants. PMID:25263581

Effects of sublethal fenitrothion ingestion on cholinesterase inhibition, standard metabolism, thermal preference, and prey-capture ability in the Australian central bearded dragon (Pogona vitticeps, Agamidae).

PubMed

Bain, David; Buttemer, William A; Astheimer, Lee; Fildes, Karen; Hooper, Michael J

2004-01-01

The central bearded dragon (Pogona vitticeps) is a medium-sized lizard that is common in semiarid habitats in Australia and that potentially is at risk of fenitrothion exposure from use of the chemical in plague locust control. We examined the effects of single sublethal doses of this organophosphate (OP; low dose = 2.0 mg/kg; high dose = 20 mg/kg; control = vehicle alone) on lizard thermal preference, standard metabolic rate, and prey-capture ability. We also measured activities of plasma total cholinesterase (ChE) and acetylcholinesterase before and at 0, 2, 8, 24, 120, and 504 h after OP dosing. Predose plasma total ChE activity differed significantly between sexes and averaged 0.66 +/- 0.06 and 0.45 +/- 0.06 micromol/min/ml for males and females, respectively. Approximately 75% of total ChE activity was attributable to butyrylcholinesterase. Peak ChE inhibition reached 19% 2 h after OP ingestion in the low-dose group, and 68% 8 h after ingestion in high-dose animals. Neither OP doses significantly affected diurnal body temperature, standard metabolic rate, or feeding rate. Plasma total ChE levels remained substantially depressed up to 21 d after dosing in the high-dose group, making this species a useful long-term biomonitor of OP exposure in its habitat.

Aspirin in polycythemia vera and essential thrombocythemia: current facts and perspectives.

PubMed

Landolfi, R; Patrono, C

1996-09-01

The role of aspirin in the antithrombotic strategy of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is highly controversial. Long considered unsafe on the basis of a single clinical trial testing very high doses in PV patients, aspirin is being increasingly used at lower dosage. The rationale for the use of aspirin in patients with PV and ET is provided by the efficacy of this agent in the treatment of microcirculatory disturbances of thrombocythemic states associated with myeloproliferative disorders and by recent evidence that asymptomatic PV and ET patients have persistently increased thromboxane (TX) A2-biosynthesis. This increase, which most likely reflects enhanced platelet activation in vivo, is independent of the platelet mass and blood viscosity and largely supressed by a short term low-dose aspirin regimen (50 mg/day for 7 days). Since enhanced TXA2 biosynthesis may play a role in transducing the increased thrombotic risk associated with PV and ET, long-term low-dose aspirin administration has been proposed as a possible antithombotic strategy in these subjects. The safety of this treatment in PV patients has been recently reassessed by the Gruppo Italiano per lo Studio della Policitemia Vera (GISP) which has followed for over one year 112 patients randomized to receive 40 mg/day aspirin or placebo. In the same study, serum TXB2 measurements provided evidence that the low-dose aspirin regimen tested was fully effective in inhibiting platelet cyclooxygenase activity. On this basis, a large scale trial aimed at assessing the antithrombotic efficacy of this approach is currently being organized. In patients with ET both the minimal aspirin dose required for complete inhibition of platelet cyclooxygenase and the safety of long-term aspirin administration need to be established prior to extensive clinical evaluation of this strategy.

What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery?

PubMed

Hodgson, Sam; Larvin, Joseph T; Dearman, Charles

2015-09-01

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: what dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Altogether 586 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Current evidence shows clinical benefit of using high-dose tranexamic acid (>80 mg/kg total dose) as opposed to low-dose tranexamic acid (<50 mg/kg total dose) in cardiac surgery with cardiopulmonary bypass. Evidence from a large randomized controlled trial shows that patients receiving high-dose tranexamic acid lose less blood postoperatively than patients receiving low-dose tranexamic acid (590 vs 820 ml, P = 0.01). Patients receiving high-dose tranexamic acid also require fewer units of blood product transfusion (2.5 units vs 4.1 units; P = 0.02) and are less likely to undergo repeat surgery to achieve haemostasis. This effect is larger in those who are at high risk of bleeding. Several prospective studies comparing doses found no difference in clinical outcomes between high- and low-dose regimens, but excluded patients at high risk of bleeding. However, data from numerous observational studies demonstrate that tranexamic acid use is associated with an increased risk of postoperative seizure; one analysis showed tranexamic acid use to be a very strong independent predictor (odds ratio = 14.3, P < 0.001). There is also evidence that this risk of seizure is dose-dependent, with the greatest risk at higher doses of tranexamic acid. We conclude that, in general, patients with a high risk of bleeding should receive high-dose tranexamic acid, while those at low risk of bleeding should receive low-dose tranexamic acid with consideration given to potential dose-related seizure risk. We recommend the regimens of high-dose (30 mg kg(-1) bolus + 16 mg kg(-1) h(-1) + 2 mg kg(-1) priming) and low-dose (10 mg kg(-1) bolus + 1 mg kg(-1) h(-1) + 1 mg kg(-1) priming) tranexamic acid, as these are well established in terms of safety profile and have the strongest evidence for efficacy. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

High-dose phenobarbital or erythropoietin for the treatment of perinatal asphyxia in term newborns.

PubMed

Avasiloaiei, Andreea; Dimitriu, Cristina; Moscalu, Mihaela; Paduraru, Luminita; Stamatin, Maria

2013-10-01

The aim of this study was to compare two neuroprotective strategies to supportive care in the treatment of perinatal asphyxia. A total of 67 term newborns with perinatal asphyxia were included and randomized into three groups: one group received supportive treatment; another group received a single dose of 40 mg/kg phenobarbital; and the third received three daily doses of 1000 IU/kg erythropoietin. The following parameters were analyzed: gestational age, birthweight, Apgar scores, cord blood pH, total serum antioxidant status (TAS), superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). The newborns were included in the follow-up program and examined up to 18 months of age. TAS was higher in the erythropoietin group than in the other groups. SOD and GPx were lower for infants treated with phenobarbital or erythropoietin compared to control infants. MDA was lower in the erythropoietin group compared to the other groups, although the difference was not statistically significant (P > 0.05). The mortality rate was lower in the phenobarbital and erythropoietin groups (both 4.6%) than in the control group (17.4%). Long-term neurologic follow up showed a high incidence of sequelae in the control group compared to the phenobarbital and erythropoietin groups. Follow-up results were better in the phenobarbital group than in the erythropoietin group for motor and cognitive function at 3 and 6 months and worse for expressive language. At 18 months, however, the differences between these two groups were not significant. High-dose phenobarbital or erythropoietin along with supportive treatment has a positive influence on the outcome of newborns with perinatal asphyxia. Phenobarbital has the advantage of low cost and simplicity. © 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.

Metabonomics evaluation of urine from rats administered with phorate under long-term and low-level exposure by ultra-performance liquid chromatography-mass spectrometry.

PubMed

Sun, Xiaowei; Xu, Wei; Zeng, Yan; Hou, Yurong; Guo, Lin; Zhao, Xiujuan; Sun, Changhao

2014-02-01

The purpose of this study was to investigate the toxic effect of long-term and low-level exposure to phorate using a metabonomics approach based on ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Male Wistar rats were given phorate daily in drinking water at low doses of 0.05, 0.15 or 0.45 mg kg⁻¹ body weight (BW) for 24 weeks consecutively. Rats in the control group were given an equivalent volume of drinking water. Compared with the control group, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), urea nitrogen (BUN) and creatinine (CR) were increased in the middle- and high-dose groups whereas albumin (ALB) and cholinesterase (CHE) were decreased. Urine metabonomics profiles were analyzed by UPLC-MS. Compared with the control group, 12 metabolites were significantly changed in phorate-treated groups. In the negative mode, metabolite intensities of uric acid, suberic acid and citric acid were significantly decreased in the middle- and high-dose groups, whereas indoxyl sulfic acid (indican) and cholic acid were increased. In the positive mode, uric acid, creatinine, kynurenic acid and xanthurenic acid were significantly decreased in the middle- and high-dose groups, but 7-methylguanine (N⁷G) was increased. In both negative and positive modes, diethylthiophosphate (DETP) was significantly increased, which was considered as a biomarker of exposure to phorate. In conclusion, long-term and low-level exposure to phorate can cause disturbances in energy-related metabolism, liver and kidney function, the antioxidant system, and DNA damage. Moreover, more information can be provided on the evaluation of toxicity of phorate using metabonomics combined with clinical chemistry. Copyright © 2012 John Wiley & Sons, Ltd.

Toward adaptive radiotherapy for head and neck patients: Uncertainties in dose warping due to the choice of deformable registration algorithm

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

Veiga, Catarina, E-mail: catarina.veiga.11@ucl.ac.uk; Royle, Gary; Lourenço, Ana Mónica

2015-02-15

Purpose: The aims of this work were to evaluate the performance of several deformable image registration (DIR) algorithms implemented in our in-house software (NiftyReg) and the uncertainties inherent to using different algorithms for dose warping. Methods: The authors describe a DIR based adaptive radiotherapy workflow, using CT and cone-beam CT (CBCT) imaging. The transformations that mapped the anatomy between the two time points were obtained using four different DIR approaches available in NiftyReg. These included a standard unidirectional algorithm and more sophisticated bidirectional ones that encourage or ensure inverse consistency. The forward (CT-to-CBCT) deformation vector fields (DVFs) were used tomore » propagate the CT Hounsfield units and structures to the daily geometry for “dose of the day” calculations, while the backward (CBCT-to-CT) DVFs were used to remap the dose of the day onto the planning CT (pCT). Data from five head and neck patients were used to evaluate the performance of each implementation based on geometrical matching, physical properties of the DVFs, and similarity between warped dose distributions. Geometrical matching was verified in terms of dice similarity coefficient (DSC), distance transform, false positives, and false negatives. The physical properties of the DVFs were assessed calculating the harmonic energy, determinant of the Jacobian, and inverse consistency error of the transformations. Dose distributions were displayed on the pCT dose space and compared using dose difference (DD), distance to dose difference, and dose volume histograms. Results: All the DIR algorithms gave similar results in terms of geometrical matching, with an average DSC of 0.85 ± 0.08, but the underlying properties of the DVFs varied in terms of smoothness and inverse consistency. When comparing the doses warped by different algorithms, we found a root mean square DD of 1.9% ± 0.8% of the prescribed dose (pD) and that an average of 9% ± 4% of voxels within the treated volume failed a 2%pD DD-test (DD{sub 2%-pp}). Larger DD{sub 2%-pp} was found within the high dose gradient (21% ± 6%) and regions where the CBCT quality was poorer (28% ± 9%). The differences when estimating the mean and maximum dose delivered to organs-at-risk were up to 2.0%pD and 2.8%pD, respectively. Conclusions: The authors evaluated several DIR algorithms for CT-to-CBCT registrations. In spite of all methods resulting in comparable geometrical matching, the choice of DIR implementation leads to uncertainties in dose warped, particularly in regions of high gradient and/or poor imaging quality.« less

Systematic review and meta-analysis of colon cleansing preparations in patients with inflammatory bowel disease

PubMed Central

Restellini, Sophie; Kherad, Omar; Bessissow, Talat; Ménard, Charles; Martel, Myriam; Taheri Tanjani, Maryam; Lakatos, Peter L; Barkun, Alan N

2017-01-01

AIM To performed a systematic review and meta-analysis to determine any possible differences in terms of effectiveness, safety and tolerability between existing colon-cleansing products in patients with inflammatory bowel disease. METHODS Systematic searches were performed (January 1980-September 2016) using MEDLINE, EMBASE, Scopus, CENTRAL and ISI Web of knowledge for randomized trials assessing preparations with or without adjuvants, given in split and non-split dosing, and in high (> 3 L) or low-volume (2 L or less) regimens. Bowel cleansing quality was the primary outcome. Secondary outcomes included patient willingness-to-repeat the procedure and side effects/complications. RESULTS Out of 439 citations, 4 trials fulfilled our inclusion criteria (n = 449 patients). One trial assessed the impact of adding simethicone to polyethylene glycol (PEG) 4 L with no effect on bowel cleansing quality, but a better tolerance. Another trial compared senna to castor oil, again without any differences in term of bowel cleansing. Two trials compared the efficacy of PEG high-volume vs PEG low-volume associated to an adjuvant in split-dose regimens: PEG low-dose efficacy was not different to PEG high-dose; OR = 0.84 (0.37-1.92). A higher proportion of patients were willing to repeat low-volume preparations vs high-volume; OR = 5.11 (1.31-20.0). CONCLUSION In inflammatory bowel disease population, PEG low-volume regimen seems not inferior to PEG high-volume to clean the colon, and yields improved willingness-to-repeat. Further additional research is urgently required to compare contemporary products in this population. PMID:28932092

Systematic review and meta-analysis of colon cleansing preparations in patients with inflammatory bowel disease.

PubMed

Restellini, Sophie; Kherad, Omar; Bessissow, Talat; Ménard, Charles; Martel, Myriam; Taheri Tanjani, Maryam; Lakatos, Peter L; Barkun, Alan N

2017-08-28

To performed a systematic review and meta-analysis to determine any possible differences in terms of effectiveness, safety and tolerability between existing colon-cleansing products in patients with inflammatory bowel disease. Systematic searches were performed (January 1980-September 2016) using MEDLINE, EMBASE, Scopus, CENTRAL and ISI Web of knowledge for randomized trials assessing preparations with or without adjuvants, given in split and non-split dosing, and in high (> 3 L) or low-volume (2 L or less) regimens. Bowel cleansing quality was the primary outcome. Secondary outcomes included patient willingness-to-repeat the procedure and side effects/complications. Out of 439 citations, 4 trials fulfilled our inclusion criteria ( n = 449 patients). One trial assessed the impact of adding simethicone to polyethylene glycol (PEG) 4 L with no effect on bowel cleansing quality, but a better tolerance. Another trial compared senna to castor oil, again without any differences in term of bowel cleansing. Two trials compared the efficacy of PEG high-volume vs PEG low-volume associated to an adjuvant in split-dose regimens: PEG low-dose efficacy was not different to PEG high-dose; OR = 0.84 (0.37-1.92). A higher proportion of patients were willing to repeat low-volume preparations vs high-volume; OR = 5.11 (1.31-20.0). In inflammatory bowel disease population, PEG low-volume regimen seems not inferior to PEG high-volume to clean the colon, and yields improved willingness-to-repeat. Further additional research is urgently required to compare contemporary products in this population.

Divergent short- and long-term effects of acute stress in object recognition memory are mediated by endogenous opioid system activation.

PubMed

Nava-Mesa, Mauricio O; Lamprea, Marisol R; Múnera, Alejandro

2013-11-01

Acute stress induces short-term object recognition memory impairment and elicits endogenous opioid system activation. The aim of this study was thus to evaluate whether opiate system activation mediates the acute stress-induced object recognition memory changes. Adult male Wistar rats were trained in an object recognition task designed to test both short- and long-term memory. Subjects were randomly assigned to receive an intraperitoneal injection of saline, 1 mg/kg naltrexone or 3 mg/kg naltrexone, four and a half hours before the sample trial. Five minutes after the injection, half the subjects were submitted to movement restraint during four hours while the other half remained in their home cages. Non-stressed subjects receiving saline (control) performed adequately during the short-term memory test, while stressed subjects receiving saline displayed impaired performance. Naltrexone prevented such deleterious effect, in spite of the fact that it had no intrinsic effect on short-term object recognition memory. Stressed subjects receiving saline and non-stressed subjects receiving naltrexone performed adequately during the long-term memory test; however, control subjects as well as stressed subjects receiving a high dose of naltrexone performed poorly. Control subjects' dissociated performance during both memory tests suggests that the short-term memory test induced a retroactive interference effect mediated through light opioid system activation; such effect was prevented either by low dose naltrexone administration or by strongly activating the opioid system through acute stress. Both short-term memory retrieval impairment and long-term memory improvement observed in stressed subjects may have been mediated through strong opioid system activation, since they were prevented by high dose naltrexone administration. Therefore, the activation of the opioid system plays a dual modulating role in object recognition memory. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparison of the effects of dose-dependent zinc chloride on short-term and long-term memory in young male rats.

PubMed

Moazedi, A A; Ghotbeddin, Z; Parham, G H

2007-08-15

The aim of the present study was to evaluate the effects of dose-dependent of zinc chloride on short-term and long-term memory in a shuttle box. Young Wistar rats (94+/-10 g) (age 27-30 days) consumed zinc chloride drinking water in five different doses (20, 30, 50, 70 and 100 mg kg(-1) day(-1)) for two weeks by gavage. After 14 days on experimental diets, a shuttle box used to test short- and long-term memory. Two criteria considering for behavioral test, including latency in entering dark chamber and time spent in the dark chamber. This experiment shows that after 2 weeks oral administration of ZnCl2 with (20, 30 and 50 mg kg(-1) day(-1)) doses, the rat's working (short-term) has been improved (p<0.05). Whereas ZnCl2 with 30 mg kg(-1) day(-1) dose has been more effected than other doses (p<0.001). But rat which received ZnCl2 with 100 mg kg(-1) day(-1), has been shown significant impairment in working memory (p<0.05) and there was no significant difference in reference (long-term) memory for any of groups. In general, this study has demonstrated that zinc chloride consumption with 30 mg kg(-1) day(-1) dose for two weeks was more effective than other doses on short-term memory. But consumption of ZnCl2 with 100 mg kg(-1) day(-1) dose for two week had the negative effect on short-term memory. On the other hand, zinc supplementation did not have an effect on long-term memory.

A single high dose of dexamethasone affects the phosphorylation state of glutamate AMPA receptors in the human limbic system

PubMed Central

Lopes, M W; Leal, R B; Guarnieri, R; Schwarzbold, M L; Hoeller, A; Diaz, A P; Boos, G L; Lin, K; Linhares, M N; Nunes, J C; Quevedo, J; Bortolotto, Z A; Markowitsch, H J; Lightman, S L; Walz, R

2016-01-01

Glucocorticoids (GC) released during stress response exert feedforward effects in the whole brain, but particularly in the limbic circuits that modulates cognition, emotion and behavior. GC are the most commonly prescribed anti-inflammatory and immunosuppressant medication worldwide and pharmacological GC treatment has been paralleled by the high incidence of acute and chronic neuropsychiatric side effects, which reinforces the brain sensitivity for GC. Synapses can be bi-directionally modifiable via potentiation (long-term potentiation, LTP) or depotentiation (long-term depression, LTD) of synaptic transmission efficacy, and the phosphorylation state of Ser831 and Ser845 sites, in the GluA1 subunit of the glutamate AMPA receptors, are a critical event for these synaptic neuroplasticity events. Through a quasi-randomized controlled study, we show that a single high dexamethasone dose significantly reduces in a dose-dependent manner the levels of GluA1-Ser831 phosphorylation in the amygdala resected during surgery for temporal lobe epilepsy. This is the first report demonstrating GC effects on key markers of synaptic neuroplasticity in the human limbic system. The results contribute to understanding how GC affects the human brain under physiologic and pharmacologic conditions. PMID:27959333

Iterative reconstruction for CT perfusion with a prior-image induced hybrid nonlocal means regularization: Phantom studies

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

Li, Bin; Lyu, Qingwen; Ma, Jianhua

2016-04-15

Purpose: In computed tomography perfusion (CTP) imaging, an initial phase CT acquired with a high-dose protocol can be used to improve the image quality of later phase CT acquired with a low-dose protocol. For dynamic regions, signals in the later low-dose CT may not be completely recovered if the initial CT heavily regularizes the iterative reconstruction process. The authors propose a hybrid nonlocal means (hNLM) regularization model for iterative reconstruction of low-dose CTP to overcome the limitation of the conventional prior-image induced penalty. Methods: The hybrid penalty was constructed by combining the NLM of the initial phase high-dose CT inmore » the stationary region and later phase low-dose CT in the dynamic region. The stationary and dynamic regions were determined by the similarity between the initial high-dose scan and later low-dose scan. The similarity was defined as a Gaussian kernel-based distance between the patch-window of the same pixel in the two scans, and its measurement was then used to weigh the influence of the initial high-dose CT. For regions with high similarity (e.g., stationary region), initial high-dose CT played a dominant role for regularizing the solution. For regions with low similarity (e.g., dynamic region), the regularization relied on a low-dose scan itself. This new hNLM penalty was incorporated into the penalized weighted least-squares (PWLS) for CTP reconstruction. Digital and physical phantom studies were performed to evaluate the PWLS-hNLM algorithm. Results: Both phantom studies showed that the PWLS-hNLM algorithm is superior to the conventional prior-image induced penalty term without considering the signal changes within the dynamic region. In the dynamic region of the Catphan phantom, the reconstruction error measured by root mean square error was reduced by 42.9% in PWLS-hNLM reconstructed image. Conclusions: The PWLS-hNLM algorithm can effectively use the initial high-dose CT to reconstruct low-dose CTP in the stationary region while reducing its influence in the dynamic region.« less

Stable and unstable chromosomal aberrations among Finnish nuclear power plant workers.

PubMed

Lindholm, C

2001-01-01

Twenty nuclear power plant workers with relatively high recorded cumulative doses were studied using FISH chromosome painting and dicentric analysis after solid Giemsa staining. The results indicated that chronic exposure to ionising radiation can be detected on the group level using translocation analysis after chromosome painting, although the mean cumulative dose was approximately 100 mSv. A significant association between translocation frequency and cumulative dose was observed. Variability in the translocation yields among workers with similar recorded doses was large, resulting in a poor correlation between translocation frequencies and documented doses on the individual level. The yields of dicentric and acentric chromosomes were not correlated with the cumulative dose, indicating the inability of unstable aberrations to monitor long-term exposures. It was also shown that the unstable aberrations were not correlated with the most recent annual dose.

Consequences of Adolescent Exposure to the Cannabinoid Receptor Agonist WIN55,212-2 on Working Memory in Female Rats.

PubMed

Kirschmann, Erin K; McCalley, Daniel M; Edwards, Caitlyn M; Torregrossa, Mary M

2017-01-01

Marijuana is a prevalent illicit substance used by adolescents, and several studies have indicated that adolescent use can lead to long-term cognitive deficits including problems with attention and memory. However, preclinical animal studies that observe cognitive deficits after cannabinoid exposure during adolescence utilize experimenter administration of doses of cannabinoids that may exceed what an organism would choose to take, suggesting that contingency and dose are critical factors that need to be addressed in translational models of consequences of cannabinoid exposure. Indeed, we recently developed an adolescent cannabinoid self-administration paradigm in male rats, and found that prior adolescent self-administration of the cannabinoid receptor agonist WIN55,212-2 (WIN) resulted in improved working memory performance in adulthood. In addition, the doses self-administered were not as high as those that are found to produce memory deficits. However, given known sex differences in both drug self-administration and learning and memory processes, it is possible that cannabinoid self-administration could have different cognitive consequences in females. Therefore, we aimed to explore the effects of self-administered vs. experimenter-administered WIN in adolescent female rats on adult cognitive function. Female rats were trained to self-administer WIN daily throughout adolescence (postnatal day 34-59). A control group self-administered vehicle solution. The acute effects of adolescent WIN self-administration on memory were determined using a short-term spatial memory test 24 h after final SA session; and the long-term effects on cognitive performance were assessed during protracted abstinence in adulthood using a delayed-match-to-sample working memory task. In a separate experiment, females were given daily intraperitoneal (IP) injections of a low or high dose of WIN, corresponding to self-administered and typical experimenter-administered doses, respectively, or its vehicle during adolescence and working memory was assessed under drug-free conditions in adulthood. While self-administration of WIN in adolescence had no significant effects on short-term spatial memory or adult working memory, experimenter administration of WIN resulted in improved adult working memory performance that was more pronounced in the low dose group. Thus, low-dose adolescent WIN exposure, whether self-administered or experimenter-administered, results in either improvements or no change in adult working memory performance in female rats, similar to previous results found in males.

A comparison of the effects of oral glutamine dipeptide, glutamine, and alanine on blood amino acid availability in rats submitted to insulin-induced hypoglycemia.

PubMed

Minguetti-Câmara, Vania C; Marques, Any de C R; Schiavon, Fabiana P M; Vilela, Vanessa R; Bruschi, Marcos L; Bazotte, Roberto Barbosa

2014-10-21

We compared the effects of oral administration of high-dose or low-dose glutamine dipeptide (GDP), alanine (ALA), glutamine (GLN), and ALA + GLN on the blood availability of amino acids in rats submitted to insulin-induced hypoglycemia (IIH). Insulin detemir (1 U/kg) was intraperitoneally injected to produce IIH; this was followed by oral administration of GDP, GLN + ALA, GLN, or ALA. We observed higher blood levels of GLN, 30 min after oral administration of high-dose GDP (1000 mg/kg) than after administration of ALA (381 mg/kg) + GLN (619 mg/kg), GLN (619 mg/kg), or ALA (381 mg/kg). However, we did not observe the same differences after oral administration of low-dose GDP (100 mg/kg) compared with ALA (38.1 mg/kg) + GLN (61.9 mg/kg), GLN (61.9 mg/kg), or ALA (38.1 mg/kg). We also observed less liver catabolism of GDP compared to ALA and GLN. In conclusion, high-dose GDP promoted higher blood levels of GLN than oral ALA + GLN, GLN, or ALA. Moreover, the lower levels of liver catabolism of GDP, compared to ALA or GLN, contributed to the superior performance of high-dose GDP in terms of blood availability of GLN.

Preoperative steroid administration: effect on morbidity among patients undergoing intestinal bowel resection for Crohńs disease.

PubMed

Bruewer, Matthias; Utech, Markus; Rijcken, Emile J M; Anthoni, Christoph; Laukoetter, Mike G; Kersting, Sabine; Senninger, Norbert; Krieglstein, Christian F

2003-12-01

Long-term steroid therapy may predispose to increased perioperative morbidity in patients undergoing surgery with bowel anastomoses. The aim of our study was to review our data to determine if the steroid dosage is associated with the incidence of early complications after bowel resection in patients with prolonged steroid therapy for Crohńs disease (CD). Altogether, 397 patients underwent bowel resection with primary intestinal anastomoses for CD between 1982 and 2000 in our institution. The mortality and morbidity rates, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and length of postoperative hospitalization in patients who were having high-dose (>/= 20 mg of prednisolone per day, n = 73) and low-dose (< 20 mg prednisolone per day, n = 146) steroid therapy for more than 1 month before surgery were compared with those of patients ( n = 177) who were not receiving steroids. Statistical analysis was performed using Fisher's exact test and Student's t-test, with p < 0.05 considered significant. The three groups were similar in terms of gender, duration since first diagnosis, American Society of Anesthesiologists classification, and obesity. Mortality, morbidity, anastomotic leakage, wound infections, intraabdominal abscesses, reoperation rate, and average postoperative stay were not statistically different in patients with high-dose, low-dose, or no steroid therapy. The only factor associated with increased morbidity was a low preoperative hemoglobin level. Our results demonstrate that, in patients who are undergoing bowel resection for CD, even high-dose prolonged preoperative systemic steroid therapy is not associated with increased postoperative complications.

Retrospective Evaluation Reveals That Long-term Androgen Deprivation Therapy Improves Cause-Specific and Overall Survival in the Setting of Dose-Escalated Radiation for High-Risk Prostate Cancer

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

Feng, Felix Y., E-mail: ffeng@med.umich.edu; Department of Radiation Oncology, Veterans Affairs Medical Center, Ann Arbor, Michigan; Blas, Kevin

2013-05-01

Purpose: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). Methods and Materials: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology. Results: The median follow-up time was 64more » months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. Conclusion: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10.« less

Comparative proteomic analysis of fluoride treated rat bone provides new insights into the molecular mechanisms of fluoride toxicity.

PubMed

Wei, Yan; Zeng, Beibei; Zhang, Hua; Chen, Cheng; Wu, Yanli; Wang, Nanlan; Wu, Yanqiu; Zhao, Danqing; Zhao, Yuxi; Iqbal, Javed; Shen, Liming

2018-07-01

Long-term excessive intake of fluoride (F) could lead to chronic fluorosis. To explore the underlying molecular mechanisms, present study is designed to elucidate the effect of fluoride on proteome expression of bone in sodium fluoride (NaF)-treated SD rats. Hematoxylin and eosin (H&E) staining was used to determine the severity of osteofluorosis, and bone samples were submitted for iTRAQ analysis. The results showed that the cortical thickness and trabecular area of femur bone in medium- and high-dose groups were higher than in control group. Contrary to this, trabecular area was reduced in the low-dose group, indicating that the bone mass was increased in medium- and high-dose groups, and decreased in the low-dose group. Thirteen (13), 35, and 34 differentially expressed proteins were identified in low-, medium-, and high-dose group, respectively. The medium- and high-dose groups shared a more similar protein expression pattern. These proteins were mainly associated with collagen metabolism, proteoglycans (PGs), matrix metalloproteinases (MMPs), etc. The results suggested that the effect of NaF on SD rats is in a dose-dependent manner. Some key proteins found here may be involved in affecting the bone tissues and bone marrow or muscle, and account for the complex pathology and clinical symptoms of fluorosis. Copyright © 2018 Elsevier B.V. All rights reserved.

Bone and bone turnover.

PubMed

Crofton, Patricia M

2009-01-01

Children with cancer are exposed to multiple influences that may adversely affect bone health. Some treatments have direct deleterious effects on bone whilst others may have indirect effects mediated through various endocrine abnormalities. Most clinical outcome studies have concentrated on survivors of acute lymphoblastic leukaemia (ALL). There is now good evidence that earlier treatment protocols that included cranial irradiation with doses of 24 Gy or greater may result in growth hormone deficiency and low bone mineral density (BMD) in the lumbar spine and femoral neck. Under current protocols, BMD decreases during intensive chemotherapy and fracture risk increases. Although total body BMD may eventually return to normal after completion of chemotherapy, lumbar spine trabecular BMD may remain low for many years. The implications for long-term fracture risk are unknown. Risk factors for low BMD include high dose methotrexate, higher cumulative doses of glucocorticoids, male gender and low physical activity. BMD outcome in non-ALL childhood cancers has been less well studied but there is evidence that survivors of childhood brain or bone tumours, and survivors of bone marrow transplants for childhood malignancy, all have a high risk of long-term osteopenia. Long-term follow-up is required, with appropriate treatment of any endocrine abnormalities identified. Copyright (c) 2009 S. Karger AG, Basel.

Consequences of the Chernobyl accident for the natural and human environments

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

Dreicer, M.; Aarkog, A.; Alexakhin, R.

1996-07-01

In the ten years since the Chernobyl accident, an enormous amount of work has been done to assess the consequences to the natural and human environment. Although it is difficult to summarize such a large and varied field, some general conclusions can be drawn. This background paper includes the main findings concerning the direct impacts of radiation on the flora and fauna; the general advances of knowledge in the cycling of radionuclides in natural, seminatural and agricultural environments; some evaluation of countermeasures that were used; and a summary of the human radiation doses resulting from the environmental contamination. although openmore » questions still remain, it can be concluded that: (1) at high radiation levels, the natural environment has shown short term impacts but any significant long term impacts remain to be seen; (2) effective countermeasures can be taken to reduce the transfer of contamination from the environment to humans but these are highly site specific and must be evaluated in terms of practicality as well as population does reduction; (3) the majority of the doses have already been received by the human population. If agricultural countermeasures are appropriately taken, the main source of future doses will be the gathering of food and recreational activities in natural and seminatural ecosystems.« less

Detection and distribution of ostreid herpesvirus 1 in experimentally infected Pacific oyster spat.

PubMed

Segarra, Amélie; Baillon, Laury; Faury, Nicole; Tourbiez, Delphine; Renault, Tristan

2016-01-01

High mortality rates are reported in spat and larvae of Pacific oyster Crassostrea gigas and associated with ostreid herpesvirus 1 (OsHV-1) detection in France. Although the viral infection has been experimentally reproduced in oyster larvae and spat, little knowledge is currently available concerning the viral entry and its distribution in organs and tissues. This study compares OsHV-1 DNA and RNA detection and localization in experimentally infected oysters using two virus doses: a low dose that did not induce any mortality and a high dose inducing high mortality. Real time PCR demonstrated significant differences in terms of viral DNA amounts between the two virus doses. RNA transcripts were detected in oysters receiving the highest dose of viral suspension whereas no transcript was observed in oysters injected with the low dose. This study also allowed observing kinetics of viral DNA and RNA detection in different tissues of oyster spat. Finally, viral detection was significantly different in function of tissues (p<0.005), time (p<0.005) with an interaction between tissues and time (p<0.005) for each probe. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs

NASA Technical Reports Server (NTRS)

Gardier, A. M.; Kaakkola, S.; Erfurth, A.; Wurtman, R. J.

1992-01-01

We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

High-dose benzodiazepine dependence: a qualitative study of patients' perception on cessation and withdrawal.

PubMed

Liebrenz, Michael; Gehring, Marie-Therese; Buadze, Anna; Caflisch, Carlo

2015-05-13

Benzodiazepine withdrawal syndrome has been reported following attempts to withdraw even from low or therapeutic doses and has been compared to barbiturate and alcohol withdrawal. This experience is known to deter patients from future cessation attempts. Research on other psychotropic substances shows that the reasons and motivations for withdrawal attempts - as well as the experiences surrounding those attempts - at least partially predict future efforts at discontinuation as well as relapse. We therefore aimed to qualitatively explore what motivates patients to discontinue this medication as well as to examine their experiences surrounding previous and current withdrawal attempts and treatment interventions in order to positively influence future help-seeking behavior and compliance. To understand these patients better, we conducted a series of 41 unstructured, narrative, in-depth interviews among adult Swiss patients with a long-term dependent use of benzodiazepines in doses equivalent to more than 40 mg diazepam per day and/or otherwise problematic use (mixing benzodiazepines, escalating dosage, recreational use or illegal purchase). Mayring's qualitative content analysis was used to evaluate findings. These high-dose benzodiazepine-dependent patients decision to change consumption patterns were affected by health concerns, the feeling of being addicted and social factors. Discontinuation attempts were frequent and not very successful with fast relapse. Withdrawal was perceived to be a difficult, complicated, and highly unpredictable process. The first attempt at withdrawal occurred at home and typically felt better than at the clinic. Inpatient treatment was believed to be more effective with long term treatment (approaches) than short term. Patients preferred gradual reduction of usage to abrupt cessation (and had experienced both). While no clear preferences for withdrawal were found for benzodiazepines with specific pharmacokinetic properties, participants frequently based their decision to participate in treatment on the availability of their preferred brand name and furthermore discarding equivalent dosage rationales. Our findings provide greater understanding of the factors that motivate high-dose benzodiazepine-dependent individuals to stop taking these medications, and how they experience withdrawal and treatment strategies. They underscore how patients' perceptions of treatment approaches contribute to compliant or non-compliant behavior.

Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation.

PubMed

Yang, Feng; Waters, Katrina M; Miller, John H; Gritsenko, Marina A; Zhao, Rui; Du, Xiuxia; Livesay, Eric A; Purvine, Samuel O; Monroe, Matthew E; Wang, Yingchun; Camp, David G; Smith, Richard D; Stenoien, David L

2010-11-30

High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health.

Phosphoproteomics Profiling of Human Skin Fibroblast Cells Reveals Pathways and Proteins Affected by Low Doses of Ionizing Radiation

PubMed Central

Yang, Feng; Waters, Katrina M.; Miller, John H.; Gritsenko, Marina A.; Zhao, Rui; Du, Xiuxia; Livesay, Eric A.; Purvine, Samuel O.; Monroe, Matthew E.; Wang, Yingchun; Camp, David G.; Smith, Richard D.; Stenoien, David L.

2010-01-01

Background High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. Principal Findings We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conclusions Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health. PMID:21152398

Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into β cells in mice with reversal of diabetes

PubMed Central

Zhang, Mingfeng; Lin, Qing; Qi, Tong; Wang, Tiankun; Chen, Ching-Cheng; Riggs, Arthur D.; Zeng, Defu

2016-01-01

We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments β-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of β-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9+ (Sox9+) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing β cells in an in vitro culture. Whether Sox9+ ductal cells in the adult pancreas can give rise to β cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin- or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9+ ductal cell differentiation into insulin-producing β cells, and medium hyperglycemia (300–450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting β-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9+ ductal cell differentiation into β cells in adult mice. PMID:26733677

Cost-effectiveness of high-dose atorvastatin compared with regular dose simvastatin.

PubMed

Lindgren, Peter; Graff, Jennifer; Olsson, Anders G; Pedersen, Terje J; Jönsson, Bengt

2007-06-01

The aim of the study was to evaluate the long-term cost-effectiveness of high-dose atorvastatin when compared with generic simvastatin for secondary prevention in Denmark, Finland, Norway, and Sweden based on the recently completed IDEAL trial. The IDEAL trial showed that high-dose treatment with atorvastatin was associated with fewer non-fatal myocardial infarctions (MI) or coronary heart disease death (RR 0.89; 95% CI 0.78-1.01) and major cardiovascular events by (RR 0.87; 95% CI 0.77-0.98) or any coronary event (RR 0.84; 95% CI 0.76-0.91) than simvastatin with no significant difference in the number of serious adverse events. Costs during the trial period was estimated based on the trial data and a Markov model was constructed where the risk of MIs and revascularization procedures and the long-term costs, quality of life, and mortality associated with these events was simulated. Costs were based on resource consumptions recorded in the trial multiplied with recent unit costs from each country. Both direct health care costs and indirect costs (costs from lost production due to work absence) were included. Intervention lasted for the duration of the trial (4.8 years) while health-effects and costs are predicted for the lifespan of the patient. The main outcome was quality adjusted life-years (QALY) gained. High-dose treatment was predicted to lead to a mean increase in survival of 0.049 years per patient and 0.033 QALYs gained. The cost to gain one QALY was predicted to 47,197euro (Denmark), 62,639euro (Finland), 35,210euro (Norway), and 43,667euro (Sweden), with cost-effectiveness ratio decreasing with higher risk. In the prevention of cardiovascular events among patients with a previous MI, high-dose atorvastatin appears to be a cost-effective strategy when compared with generic simvastatin 20-40 mg in Denmark, Norway, and Sweden. In Finland, it is cost-effective in high-risk patients. The key driver of the cost-effectiveness is the price-difference between 80 mg atorvastatin and generic simvastatin.

Examination of the suitability of an implementation of the Jette localized heterogeneities fluence term L(1)(x,y,z) in an electron beam treatment planning algorithm

NASA Astrophysics Data System (ADS)

Rodebaugh, Raymond Francis, Jr.

2000-11-01

In this project we applied modifications of the Fermi- Eyges multiple scattering theory to attempt to achieve the goals of a fast, accurate electron dose calculation algorithm. The dose was first calculated for an ``average configuration'' based on the patient's anatomy using a modification of the Hogstrom algorithm. It was split into a measured central axis depth dose component based on the material between the source and the dose calculation point, and an off-axis component based on the physics of multiple coulomb scattering for the average configuration. The former provided the general depth dose characteristics along the beam fan lines, while the latter provided the effects of collimation. The Gaussian localized heterogeneities theory of Jette provided the lateral redistribution of the electron fluence by heterogeneities. Here we terminated Jette's infinite series of fluence redistribution terms after the second term. Experimental comparison data were collected for 1 cm thick x 1 cm diameter air and aluminum pillboxes using the Varian 2100C linear accelerator at Rush-Presbyterian- St. Luke's Medical Center. For an air pillbox, the algorithm results were in reasonable agreement with measured data at both 9 and 20 MeV. For the Aluminum pill box, there were significant discrepancies between the results of this algorithm and experiment. This was particularly apparent for the 9 MeV beam. Of course a one cm thick Aluminum heterogeneity is unlikely to be encountered in a clinical situation; the thickness, linear stopping power, and linear scattering power of Aluminum are all well above what would normally be encountered. We found that the algorithm is highly sensitive to the choice of the average configuration. This is an indication that the series of fluence redistribution terms does not converge fast enough to terminate after the second term. It also makes it difficult to apply the algorithm to cases where there are no a priori means of choosing the best average configuration or where there is a complex geometry containing both lowly and highly scattering heterogeneities. There is some hope of decreasing the sensitivity to the average configuration by including portions of the next term of the localized heterogeneities series.

Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.

PubMed

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J

2009-01-01

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

Low-dose radiosurgery or hypofractionated stereotactic radiotherapy as treatment option in refractory epilepsy due to epileptogenic lesions in eloquent areas - Preliminary report of feasibility and safety.

PubMed

Boström, Jan P; Delev, Daniel; Quesada, Carlos; Widman, Guido; Vatter, Hartmut; Elger, Christian E; Surges, Rainer

2016-03-01

The eradication of epileptogenic lesions (e.g. focal cortical dysplasia) can be used for treatment of drug-resistant focal epilepsy, but in highly eloquent cortex areas it can also lead to a permanent neurological deficit. In such cases the neuromodulation effect of low-dose high-precision irradiation of circumscribed lesions may represent an alternative therapy. A total of 10 patients with eloquent localized lesions causing pharmacoresistant focal epilepsy were prospectively identified. After informed consent, six patients agreed and were treated with risk adapted low-dose radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (hfSRT). Comprehensive data concerning treatment modalities and outcome after short-term follow up (mean=16.3 months) were prospectively collected and evaluated. From the six patients, two patients were treated with hfSRT (marginal dose 36 Gy) and four with SRS (marginal dose 13 Gy). Clinical target volume (CTV) ranged from 0.70 ccm to 4.32 ccm. The short-term follow-up ranged from 6 to 27 months. There were no side effects or neurological deficits after treatment. At last available follow-up two patients were seizure-free, one of them being off antiepileptic drugs. The seizure frequency improved in one and remained unchanged in three patients. Treatment of eloquent localized epileptogenic lesions by SRS and hfSRT showed no adverse events and an acceptable seizure outcome in this small prospective patient series. The relatively short-term follow-up comprises one of the study's drawbacks and therefore a longer follow-up should be awaited in order to evaluate the neuromodulation effect of the treatment. These preliminary results may however justify the initiation of a larger prospective trial investigating whether focused low-dose stereotactic irradiation could be an option for lesions in eloquent brain areas. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Biodosimetric quantification of short-term synchrotron microbeam versus broad-beam radiation damage to mouse skin using a dermatopathological scoring system

PubMed Central

Priyadarshika, R C U; Crosbie, J C; Kumar, B; Rogers, P A W

2011-01-01

Objectives Microbeam radiotherapy (MRT) with wafers of microscopically narrow, synchrotron generated X-rays is being used for pre-clinical cancer trials in animal models. It has been shown that high dose MRT can be effective at destroying tumours in animal models, while causing unexpectedly little damage to normal tissue. The aim of this study was to use a dermatopathological scoring system to quantify and compare the acute biological response of normal mouse skin with microplanar and broad-beam (BB) radiation as a basis for biological dosimetry. Method The skin flaps of three groups of mice were irradiated with high entrance doses (200 Gy, 400 Gy and 800 Gy) of MRT and BB and low dose BB (11 Gy, 22 Gy and 44 Gy). The mice were culled at different time-points post-irradiation. Skin sections were evaluated histologically using the following parameters: epidermal cell death, nuclear enlargement, spongiosis, hair follicle damage and dermal inflammation. The fields of irradiation were identified by γH2AX-positive immunostaining. Results The acute radiation damage in skin from high dose MRT was significantly lower than from high dose BB and, importantly, similar to low dose BB. Conclusion The integrated MRT dose was more relevant than the peak or valley dose when comparing with BB fields. In MRT-treated skin, the apoptotic cells of epidermis and hair follicles were not confined to the microbeam paths. PMID:21849367

Radiation Exposure and Thyroid Cancer Risk After the Fukushima Nuclear Power Plant Accident in Comparison with the Chernobyl Accident.

PubMed

Yamashita, S; Takamura, N; Ohtsuru, A; Suzuki, S

2016-09-01

The actual implementation of the epidemiological study on human health risk from low dose and low-dose rate radiation exposure and the comprehensive long-term radiation health effects survey are important especially after radiological and nuclear accidents because of public fear and concern about the long-term health effects of low-dose radiation exposure have increased considerably. Since the Great East Japan earthquake and the Fukushima Daiichi Nuclear Power Plant accident in Japan, Fukushima Prefecture has started the Fukushima Health Management Survey Project for the purpose of long-term health care administration and medical early diagnosis/treatment for the prefectural residents. Especially on a basis of the lessons learned from the Chernobyl accident, both thyroid examination and mental health care are critically important irrespective of the level of radiation exposure. There are considerable differences between Chernobyl and Fukushima regarding radiation dose to the public, and it is very difficult to estimate retrospectively internal exposure dose from the short-lived radioactive iodines. Therefore, the necessity of thyroid ultrasound examination in Fukushima and the intermediate results of this survey targeting children will be reviewed and discussed in order to avoid any misunderstanding or misinterpretation of the high detection rate of childhood thyroid cancer. © World Health Organisation 2016. All rights reserved. The World Health Organization has granted Oxford University Press permission for the reproduction of this article.

28Si total body irradiation injures bone marrow hematopoietic stem cells via induction of cellular apoptosis

NASA Astrophysics Data System (ADS)

Chang, Jianhui; Feng, Wei; Wang, Yingying; Allen, Antiño R.; Turner, Jennifer; Stewart, Blair; Raber, Jacob; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian

2017-05-01

Long-term space mission exposes astronauts to a radiation environment with potential health hazards. High-energy charged particles (HZE), including 28Si nuclei in space, have deleterious effects on cells due to their characteristics with high linear energy transfer and dense ionization. The influence of 28Si ions contributes more than 10% to the radiation dose equivalent in the space environment. Understanding the biological effects of 28Si irradiation is important to assess the potential health hazards of long-term space missions. The hematopoietic system is highly sensitive to radiation injury and bone marrow (BM) suppression is the primary life-threatening injuries after exposure to a moderate dose of radiation. Therefore, in the present study we investigated the acute effects of low doses of 28Si irradiation on the hematopoietic system in a mouse model. Specifically, 6-month-old C57BL/6 J mice were exposed to 0.3, 0.6 and 0.9 Gy 28Si (600 MeV) total body irradiation (TBI). The effects of 28Si TBI on BM hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were examined four weeks after the exposure. The results showed that exposure to 28Si TBI dramatically reduced the frequencies and numbers of HSCs in irradiated mice, compared to non-irradiated controls, in a radiation dose-dependent manner. In contrast, no significant changes were observed in BM HPCs regardless of radiation doses. Furthermore, irradiated HSCs exhibited a significant impairment in clonogenic ability. These acute effects of 28Si irradiation on HSCs may be attributable to radiation-induced apoptosis of HSCs, because HSCs, but not HPCs, from irradiated mice exhibited a significant increase in apoptosis in a radiation dose-dependent manner. However, exposure to low doses of 28Si did not result in an increased production of reactive oxygen species and DNA damage in HSCs and HPCs. These findings indicate that exposure to 28Si irradiation leads to acute HSC damage.

The effects of crude aqueous and alcohol extracts of Aloe vera on growth and abdominal viscera of suckling rats.

PubMed

Beya, Wabeya; Davidson, Bruce; Erlwanger, Kennedy H

2012-01-01

The gastrointestinal tract of neonates is sensitive to dietary manipulations. When nursing mothers use Aloe vera, their babies are at risk of indirect exposure to Aloe vera via breast feeding or directly as health supplements. The effects of orally administered extracts of Aloe vera in unweaned rats were investigated. Six day old Sprague-Dawley rats were gavaged with aqueous or alcohol extracts of Aloe vera (low dose 50mg. kg⁻¹ or high dose 500mg. kg⁻¹) daily for eight days. All data were expressed as mean ± SD and analyzed by one way ANOVA. Pups receiving high doses of either extract had a significantly higher body mass gain than the group receiving lower dose (p < 0.05). Tibial length was significantly increased in the high dose aqueous extract group (15-26%). The differences in growth could not be attributed to circulating insulin-like growth factor-1 as the levels were not significantly different. The caecum was significantly enlarged in the rats that received the high doses of both extracts. Although, there was no significant difference in the non-fasting plasma concentration of glucose and triglycerides, the hepatic lipid and glycogen content were significantly higher (p < 0.001) for the high dose aqueous extract group. The plasma alanine transaminase was not affected by the treatments, however the high doses of the extracts significantly increased plasma alkaline phosphatase activity. Short term administration of Aloe vera extracts resulted in growth promotion, enhanced hepatic storage of metabolic substrates, increased ALP possibly in relation to bone growth and caused hypertrophy of the caecum of neonatal rats. These effects need to be explored further to enhance animal production and health.

Biomarkers of exposure and dose: state of the art.

PubMed

Brooks, A L

2001-01-01

Biomarkers provide methods to measure changes in biological systems and to relate them to environmental insults and disease processes. Biomarkers can be classified as markers of exposure and dose, markers of sensitivity, and markers of disease. It is important that the differences and applications of the various types of biomarkers be clearly understood. The military is primarily interested in early biomarkers of exposure and dose that do not require high levels of sensitivity but can be used to rapidly triage war fighters under combat or terrorist conditions and determine which, if any, require medical attention. Biomarkers of long-term radiation risk represent the second area of interest for the military. Biomarkers of risk require high sensitivity and specificity for the disease and insult but do not require rapid data turnaround. Biomarkers will help provide information for quick command decisions in the field, characterise long-term troop risks and identify early stages of radiation-induced diseases. This information provides major positive reassurances about individual exposures and risk that will minimise the physical and psychological impact of wartime radiation exposures.

Growth hormone therapy for children born small for gestational age: height gain is less dose dependent over the long term than over the short term.

PubMed

de Zegher, Francis; Hokken-Koelega, Anita

2005-04-01

Approximately 3% of children are born small for gestational age (SGA), and approximately 10% of SGA children maintain a small body size throughout childhood and often into adult life. Among short SGA children, growth hormone (GH) therapy increases short-term growth in a dose-dependent manner; experience with long-term therapy is limited. To delineate the dose dependency of long-term height gain among short SGA children receiving GH therapy. We performed an epianalysis of the first adult height data for SGA children (n = 28) enrolled in 3 randomized trials comparing the growth-promoting efficacy of 2 continuous GH regimens (33 or 67 microg/kg per day for approximately 10 years, starting at approximately 5 years of age); in addition, we performed a meta-analysis of the adult height results published previously and those presented here. Epianalysis outcomes (n = 28) suggested that adult height increased more with a higher-dose regimen than with a lower-dose regimen. In the meta-analysis (n = 82), the higher-dose regimen was found to elicit a long-term height gain superior to that achieved with the lower-dose regimen by a mean of 0.4 SD (approximately 1 inch). Children who were shorter at the start of therapy experienced more long-term height gain. These findings confirm GH therapy as an effective and safe approach to reduce the adult height deficit that short SGA children otherwise face. In addition, the first meta-analysis indicated that height gain is less dose dependent over the long term than over the short term, at least within the dose range explored to date. For SGA children whose stature is not extremely short, current data support the use of a GH dose of approximately 33 microg/kg per day from start to adult height, particularly if treatment starts at a young age; shorter children (for example, height below -3 SD) might benefit from an approach in which short-term catch-up growth is achieved with a higher dose (> or =50 microg/kg per day) and long-term growth to adult height is ensured with a GH dose of approximately 33 mug/kg per day. Because GH-induced accelerations of height and weight gain evolve in parallel, the dose tapering from > or =50 microg/kg to approximately 33 microg/kg can be accomplished by simply maintaining the absolute GH dose (in micrograms) while the child gains weight (in kilograms). With this algorithm, more growth-responsive children taper their GH dose down to approximately 33 microg/kg per day more quickly.

Influence of measurement frequency on the evaluation of short-term dose of sub-micrometric particles during indoor and outdoor generation events

NASA Astrophysics Data System (ADS)

Manigrasso, M.; Stabile, L.; Avino, P.; Buonanno, G.

2013-03-01

Aerosol generation events due to combustion processes are characterized by high particle emissions in the nucleation mode range. Such particles are characterized by very short atmospheric lifetimes, leading to rapid decay in time and space from the emission point. Therefore, the deposited fraction of inhaled particles (dose) also changes. In fact, close to the emission source, high short-term peak exposures occur. The related exposure estimates should therefore rely on measurements of aerosol number-size distributions able to track rapid aerosol dynamics. In order to study the influence of the time resolution on such estimates, simultaneous measurements were carried out via Scanning Mobility Particle Sizer (SMPS) and Fast Mobility Particle Sizer (FMPS) spectrometers during particle generation events in both indoor (cooking activities) and outdoor (airstrip and urban street canyons) microenvironments. Aerosol size distributions in the range 16-520 nm were measured by SMPS and FMPS at frequencies of 0.007 s-1 and 1 s-1, respectively. Based on the two datasets, respiratory dosimetry estimates were made on the basis of the deposition model of the International Commission on Radiological Protection. During cooking activities, SMPS measurements give an approximate representation of aerosol temporal evolution. Consequently, the related instant doses can be approximated to a fair degree. In the two outdoor microenvironments considered, aerosol size distributions change rapidly: the FMPS is able to follow such evolution, whereas the SMPS is not. The high short-term peak concentrations, and the consequent respiratory doses, evidenced by FMPS data are hardly described by SMPS, which is unable to track the fast aerosol changes. The health relevance of such short peak exposures has not been thoroughly investigated in scientific literature, therefore, in the present paper highly time-resolved and size-resolved dosimetry estimates were provided in order to deepen this aspect.

PSA Response to Neoadjuvant Androgen Deprivation Therapy Is a Strong Independent Predictor of Survival in High-Risk Prostate Cancer in the Dose-Escalated Radiation Therapy Era

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

McGuire, Sean E., E-mail: semcguir@mdanderson.org; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; Lee, Andrew K.

2013-01-01

Purpose: The aim of the study was to evaluate the prognostic value of prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer. Methods and Materials: We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long-term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The associations among patient, tumor, and treatment characteristics with biochemical response to neoadjuvant ADT and their effects on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specificmore » mortality (PCSM) and overall survival (OS) were examined. Results: A total of 196 patients met criteria for inclusion. Median follow-up time for patients alive at last contact was 7.0 years (range, 0.5-18.1 years). Multivariate analysis identified the pre-RT PSA concentration (<0.5 vs {>=}0.5 ng/mL) as a significant independent predictor of FFS (P=.021), TDM (P=.009), PCSM (P=.039), and OS (P=.037). On multivariate analysis, pretreatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA of <0.5 ng/mL. Conclusions: For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level {>=}0.5 ng/mL after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and African-American race are associated with increased risk of having a pre-RT PSA level {>=}0.5 ng/mL. These patients should be considered for clinical trials that test newer, more potent androgen-depleting therapies such as abiraterone and MDV3100 in combination with radiation.« less

Managing ‘Bartlett’ pear fruit ripening with 1-methylcyclopropene reapplication during cold storage

USDA-ARS?s Scientific Manuscript database

Repeated low-dose 1-MCP-applications were evaluated during cold storage of ‘Bartlett’ pear fruit to overcome long-term ripening inhibition of a high dose 1-MCP treatment at harvest. Fruit were exposed to 1-MCP at 0, 0.42, 4.2 or 42 umol m-3 at harvest in year one, and to 0, 0.42 or 42 umol m-3 in y...

Concentration-Dependent Effects of Rhodiola Rosea on Long-Term Survival and Stress Resistance of Yeast Saccharomyces Cerevisiae: The Involvement of YAP 1 and MSN2/4 Regulatory Proteins

PubMed Central

Bayliak, Maria M.; Burdyliuk, Nadia I.; Izers’ka, Lilia I.; Lushchak, Volodymyr I.

2014-01-01

Concentration-dependent effects of aqueous extract from R. rosea root on long-term survival and stress resistance of budding yeast Saccharomyces cerevisiae were studied. At low concentrations, R. rosea aqueous extract extended yeast chronological lifespan, enhanced oxidative stress resistance of stationary-phase cells and resistance to number stressors in exponentially growing cultures. At high concentrations, R. rosea extract sensitized yeast cells to stresses and shortened yeast lifespan. These biphasic concentration-responses describe a common hormetic phenomenon characterized by a low-dose stimulation and a high-dose inhibition. Yeast pretreatment with low doses of R. rosea extract enhanced yeast survival and prevented protein oxidation under H2O2-induced oxidative stress. Positive effect of R. rosea extract on yeast survival under heat shock exposure was not accompanied with changes in antioxidant enzyme activities and levels of oxidized proteins. The deficiency in transcriptional regulators, Msn2/Msn4 and Yap1, abolished the positive effect of low doses of R. rosea extract on yeast viability under stress challenges. Potential involvement of Msn2/Msn4 and Yap1 regulatory proteins in realization of R. rosea beneficial effects is discussed. PMID:24659935

Toward reliable and repeatable automated STEM-EDS metrology with high throughput

NASA Astrophysics Data System (ADS)

Zhong, Zhenxin; Donald, Jason; Dutrow, Gavin; Roller, Justin; Ugurlu, Ozan; Verheijen, Martin; Bidiuk, Oleksii

2018-03-01

New materials and designs in complex 3D architectures in logic and memory devices have raised complexity in S/TEM metrology. In this paper, we report about a newly developed, automated, scanning transmission electron microscopy (STEM) based, energy dispersive X-ray spectroscopy (STEM-EDS) metrology method that addresses these challenges. Different methodologies toward repeatable and efficient, automated STEM-EDS metrology with high throughput are presented: we introduce the best known auto-EDS acquisition and quantification methods for robust and reliable metrology and present how electron exposure dose impacts the EDS metrology reproducibility, either due to poor signalto-noise ratio (SNR) at low dose or due to sample modifications at high dose conditions. Finally, we discuss the limitations of the STEM-EDS metrology technique and propose strategies to optimize the process both in terms of throughput and metrology reliability.

Sperm quality and DNA damage in men from Jilin Province, China, who are occupationally exposed to ionizing radiation.

PubMed

Zhou, D D; Hao, J L; Guo, K M; Lu, C W; Liu, X D

2016-03-22

Long-term radiation exposure affects human health. Ionizing radiation has long been known to raise the risk of cancer. In addition to high doses of radiation, low-dose ionizing radiation might increase the risk of cardiovascular disease, lens opacity, and some other non-cancerous diseases. Low- and high-dose exposures to ionizing radiation elicit different signaling events at the molecular level, and may involve different response mechanisms. The health risks arising from exposure to low doses of ionizing radiation should be re-evaluated. Health workers exposed to ionizing radiation experience low-dose radiation and have an increased risk of hematological malignancies. Reproductive function is sensitive to changes in the physical environment, including ionizing radiation. However, data is scarce regarding the association between occupational radiation exposure and risk to human fertility. Sperm DNA integrity is a functional parameter of male fertility evaluation. Hence, we aimed to report sperm quality and DNA damage in men from Jilin Province, China, who were occupationally exposed to ionizing radiation. Sperm motility and normal morphology were significantly lower in the exposed compared with the non-exposed men. There was no statistically significant difference in sperm concentration between exposed and non-exposed men. The sperm DNA fragmentation index was significantly higher in the exposed than the non-exposed men. Chronic long-term exposure to low doses of ionizing radiation could affect sperm motility, normal morphology, and the sperm DNA fragmentation index in the Chinese population. Sperm quality and DNA integrity are functional parameters that could be used to evaluate occupational exposure to ionizing radiation.

High- and Low-Dose Oral Delayed-Release Mesalamine in Children With Mild-to-Moderately Active Ulcerative Colitis

PubMed Central

Winter, Harland S.; Krzeski, Piotr; Heyman, Melvin B.; Ibarguen-Secchia, Eduardo; Iwanczak, Barbara; Kaczmarski, Maciej; Kierkus, Jaroslaw; Kolaček, Sanja; Osuntokun, Bankole; Quiros, J. Antonio; Shah, Manoj; Yacyshyn, Bruce; Dunnmon, Preston M.

2014-01-01

ABSTRACT Objective: The aim of the study was to assess the safety and efficacy of high- and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild-to-moderately active ulcerative colitis. Methods: Patients ages 5 to 17 years, with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score of ≥10 to ≤55 and a truncated Mayo Score of ≥1 for both rectal bleeding and stool frequency, were enrolled. They received body weight–dependent doses of oral, delayed-release mesalamine for 6 weeks in a low- (27–71 mg · g−1 · day−1) or high-dose group (53–118 mg · g−1 · day−1). The primary endpoint was treatment success, defined as the proportion of patients who achieved remission (PUCAI score <10) or partial response (PUCAI score ≥10 with a decrease from baseline by ≥20 points). Secondary endpoints included truncated Mayo Score and global assessment of change of disease activity. Results: The modified intent-to-treat population included 81 of 83 patients enrolled. Treatment success by PUCAI was achieved by 23 of 41 (56%) and 22 of 40 (55%) patients in the mesalamine low- and high-dose groups, respectively (P = 0.924). Truncated Mayo Score (low-dose 30 [73%] and high-dose 28 [70%] patients) and other efficacy results did not differ between the groups. The type and severity of adverse events were consistent with those reported in previous studies of adults with ulcerative colitis and did not differ between groups. Conclusions: Both low- and high-dose oral, delayed-release mesalamine doses were equally effective as short-term treatment of mild-to-moderately active ulcerative colitis in children, without a specific benefit or risk to using either dose. PMID:25419597

Effect of Low (5 mg) vs. High (20-40 mg) Rosuvastatin Dose on 24h Arterial Stiffness, Central Haemodynamics, and Non-Alcoholic Fatty Liver Disease in Patients with Optimally Controlled Arterial Hypertension.

PubMed

Mitsiou, Eudoxia; Boutari, Chrysoula; Kotsis, Vasilios; Georgianou, Eleni; Doumas, Michael; Karagiannis, Asterios; Athyros, Vasilios G

2018-01-01

Arterial Stiffness (AS) and Non-Alcoholic Fatty Liver Diseases (NAFLD) are 2 related, prevalent, risk predictors of Cardiovascular Disease (CVD). We assessed the effect of low dose (5 mg/day) vs. high dose (20-40 mg/day) rosuvastatin on aortic elasticity and central haemodynamics as well as on NAFLD in patients with Arterial Hypertension (AH). Forty patients with optimally controlled AH were randomised to 2 rosuvastatin doses and followed for 6 months. 24h AS was assessed by Mobil-O-Graph, which calculates (adjusted for age and gender) Pulse Wave Velocity (PWV), adjusted for Heart Rate (HR) augmentation index (AIx75%) and central haemodynamics. The diagnosis of NAFLD was based on >5% liver steatosis on ultrasound and moderately elevated serum levels of liver enzymes. Both doses of rosuvastatin reduced Central Pulse Pressure (cPP), PWV and AIx75% (adjusted for HR) to normal values (p = NS adjusted for age, gender and HR). Liver enzymes were reduced in those with NAFLD to normal, but steatosis was reduced more by the 20-40 mg/day rosuvastatin dose (p=0.01) compared with the 5 mg/day dose. Both doses of rosuvastatin had a beneficial effect on AS; the high dose was more efficient in reducing PWVs and central haemodynamics, and also the high dose was more effective in ameliorating NAFLD. Given that AH control was optimal and lipid values attained targets, 4 other CVD predictors were also addressed. Larger and longer term studies are needed to demonstrate the clinical benefit of such treatment preference. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

SR-TXRF analysis of trace elements in whole blood and heart of rats: effects of irradiation with low and high doses

NASA Astrophysics Data System (ADS)

Mota, C. L.; Pickler, A.; Braz, D.; Barroso, R. C.; Mantuano, A.; Salata, C.; Ferreira-Machado, S. C.; Lau, C. C.; de Almeida, C. E.

2018-04-01

In the last decades, studies showed that the exposure to low doses of ionizing radiation of the body could sense and activate the cell signaling pathways needed to respond to any induced cellular damage. This procedure reduces cell killing compared with a single dose of high radiation dose. Damage to the vasculature can affect the function of most body organs by restricting blood flow and oxygen to tissues; however, the heart and brain are of main concern. The precise relationship between long-term health effects and low-dose exposures remain poorly understood. Biological markers are powerful tools that can be used to determine dose- response relationships and to estimate risk, especially when dealing with, the effects of low dose exposures in humans. These markers should be specific, sensitive, as well as easy and fast to quantify. Various types of biologic specimens are potential candidates for identifying biomarkers but blood has the advantage of being minimally invasive to obtain. In this study, we propose to apply total reflection X-ray fluorescence to quantify possible chemical elemental concentration (sulfer, iron, zinc, potassium and calcium) changes in blood and heart tissues of Wistar rats after total body irradiation with low (0.1 Gy) and high (2.5 Gy) doses. The fluorescence measurements were carried out at the X-ray Fluorescence beamline in the Brazilian Synchrotron Light Laboratory. The results showed that the irradiated animals with low doses have significant alterations in blood and cardiac tissue when compared with animals that received high doses of radiation. Taken together the analysis of all the elements, we can observe that the radiation induced oxidative stress may be the leading cause for alteration of the elemental level in the studied samples.

Hydroxychloroquine retinopathy after short-term therapy.

PubMed

Phillips, Brandon N; Chun, Dal W

2014-01-01

To report an unusual case of hydroxychloroquine toxicity after short-term therapy. Observational case report. A 56-year-old woman presented to the Ophthalmology Clinic at Walter Reed Army Medical Center (WRAMC) with a 6-month history of gradually decreasing vision in both eyes. The patient had been taking hydroxychloroquine for the preceding 48 months for the treatment of rheumatoid arthritis. Examination of the posterior segment revealed bilateral "bull's eye" macular lesions. Fundus autofluorescence revealed hyperfluorescence of well-defined bull's eye lesions in both eyes. Optical coherence tomography revealed corresponding parafoveal atrophy with a loss of the retinal inner segment/outer segment junction. Humphrey visual field 10-2 white showed significant central and paracentral defects with a generalized depression. The patient was on a standard dose of 400 mg daily, which was above her ideal dose. The patient had no history of kidney or liver dysfunction. There were no known risk factors but there were several possible confounding factors. The patient was started on high-dose nabumetone, a nonsteroidal antiinflammatory drug, at the same time she was started on hydroxychloroquine. She also reported taking occasional ibuprofen. Retinal toxicity from chloroquine has been recognized for decades with later reports showing retinopathy from long-term hydroxychloroquine (Plaquenil) use for the treatment of antiinflammatory diseases. Hydroxychloroquine is now widely used and retinal toxicity is relatively uncommon. However, it can cause serious vision loss and is usually irreversible. The risk of hydroxychloroquine toxicity rises to nearly 1% with a total cumulative dose of 1,000 g, which is ∼5 years to 7 years of normal use. Toxicity is rare under this dose. For this reason, the American Academy of Ophthalmology has revised its recommendations such that annual screenings begin 5 years after therapy with hydroxychloroquine has begun unless there are known risk factors. This case report confirms the need for a baseline examination and annual ophthalmologic screening for patients taking hydroxychloroquine at a dose higher than the recommended dosage. It is also reasonable to consider annual examinations in patients taking high-dose nonsteroidal antiinflammatory drugs from the initiation of the medication.

Brachytherapy for Prostate Cancer: A Systematic Review

PubMed Central

Koukourakis, Georgios; Kelekis, Nikolaos; Armonis, Vassilios; Kouloulias, Vassilios

2009-01-01

Low-dose rate brachytherapy has become a mainstream treatment option for men diagnosed with prostate cancer because of excellent long-term treatment outcomes in low-, intermediate-, and high-risk patients. To a great extend due to patient lead advocacy for minimally invasive treatment options, high-quality prostate implants have become widely available in the US, Europe, and Japan. High-dose-rate (HDR) afterloading brachytherapy in the management of localised prostate cancer has practical, physical, and biological advantages over low-dose-rate seed brachytherapy. There are no free live sources used, no risk of source loss, and since the implant is a temporary procedure following discharge no issues with regard to radioprotection use of existing facilities exist. Patients with localized prostate cancer may benefit from high-dose-rate brachytherapy, which may be used alone in certain circumstances or in combination with external-beam radiotherapy in other settings. The purpose of this paper is to present the essentials of brachytherapies techniques along with the most important studies that support their effectiveness in the treatment of prostate cancer. PMID:19730753

Neuroprotective potential of high-dose biotin.

PubMed

McCarty, Mark F; DiNicolantonio, James J

2017-11-01

A recent controlled trial has established that high-dose biotin supplementation - 100 mg, three times daily - has a stabilizing effect on progression of multiple sclerosis (MS). Although this effect has been attributed to an optimization of biotin's essential cofactor role in the brain, a case can be made that direct stimulation of soluble guanylate cyclase (sGC) by pharmacological concentrations of biotin plays a key role in this regard. The utility of high-dose biotin in MS might reflect an anti-inflammatory effect of cGMP on the cerebral microvasculature, as well on oligodendrocyte differentiation and on Schwann cell production of neurotrophic factors thought to have potential for managing MS. But biotin's ability to boost cGMP synthesis in the brain may have broader neuroprotective potential. In many types of neurons and neural cells, cGMP exerts neurotrophic-mimetic effects - entailing activation of the PI3K-Akt and Ras-ERK pathways - that promote neuron survival and plasticity. Hippocampal long term potentiation requires nitric oxide synthesis, which in turn promotes an activating phosphorylation of CREB via a pathway involving cGMP and protein kinase G (PKG). In Alzheimer's disease (AD), amyloid beta suppresses this mechanism by inhibiting sGC activity; agents which exert a countervailing effect by boosting cGMP levels tend to restore effective long-term potentiation in rodent models of AD. Moreover, NO/cGMP suppresses amyloid beta production within the brain by inhibiting expression of amyloid precursor protein and BACE1. In conjunction with cGMP's ability to oppose neuron apoptosis, these effects suggest that high-dose biotin might have potential for the prevention and management of AD. cGMP also promotes neurogenesis, and may lessen stroke risk by impeding atherogenesis and hypertrophic remodeling in the cerebral vasculature. The neuroprotective potential of high-dose biotin likely could be boosted by concurrent administration of brain-permeable phosphodiesterase-5 inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Intermediate-term results of image-guided brachytherapy and high-technology external beam radiotherapy in cervical cancer: Chiang Mai University experience.

PubMed

Tharavichitkul, Ekkasit; Chakrabandhu, Somvilai; Wanwilairat, Somsak; Tippanya, Damrongsak; Nobnop, Wannapha; Pukanhaphan, Nantaka; Galalae, Razvan M; Chitapanarux, Imjai

2013-07-01

To evaluate the outcomes of image-guided brachytherapy combined with 3D conformal or intensity modulated external beam radiotherapy (3D CRT/IMRT) in cervical cancer at Chiang Mai University. From 2008 to 2011, forty-seven patients with locally advanced cervical cancer were enrolled in this study. All patients received high-technology (3D CRT/IMRT) whole pelvic radiotherapy with a total dose of 45-46 Gy plus image-guided High-Dose-Rate intracavitary brachytherapy 6.5-7 Gy × 4 fractions to a High-Risk Clinical Target Volume (HR-CTV) according to GEC-ESTRO recommendations. The dose parameters of the HR-CTV for bladder, rectum and sigmoid colon were recorded, as well as toxicity profiles. In addition, the endpoints for local control, disease-free, metastasis-free survival and overall survival were calculated. At the median follow-up time of 26 months, the local control, disease-free survival, and overall survival rates were 97.9%, 85.1%, and 93.6%, respectively. The mean dose of HR-CTV, bladder, rectum and sigmoid were 93.1, 88.2, 69.6, and 72 Gy, respectively. In terms of late toxicity, the incidence of grade 3-4 bladder and rectum morbidity was 2.1% and 2.1%, respectively. A combination of image-guided brachytherapy and IMRT/3D CRT showed very promising results of local control, disease-free survival, metastasis-free survival and overall survival rates. It also caused a low incidence of grade 3-4 toxicity in treated study patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Does perioperative high-dose prednisolone have clinical benefits for generalized myasthenia gravis?

PubMed

Sekine, Yasuo; Kawaguchi, Naoki; Hamada, Chikuma; Sekiguchi, Hiromi; Yasufuku, Kazuhiro; Iyoda, Akira; Shibuya, Kiyoshi; Fujisawa, Takehiko

2006-06-01

The purpose of this study was to clarify the clinical benefits of perioperative administration of high-dose prednisolone (PSL) combined with extended thymectomy on the long-term outcomes of 116 consecutive patients with generalized myasthenia gravis (MG). A retrospective review was conducted on 116 patients diagnosed with generalized MG who received alternate-day oral administration of high-dose PSL (100 mg/alternate days) and had undergone transsternal extended thymectomy. Incidences of postoperative myasthenic crisis, adverse effects of steroid, long-term outcomes, such as complete stable remission (CSR), pharmacologic remission (PR) or improvement (Imp), and disease recurrence after CSR were evaluated. Six patients (5.2%) experienced post-thymectomy myasthenic crisis. Crude cumulative CSR and PR + CSR rates were 44.8 and 62.7%, respectively. Life table analysis showed that 41.8, 52.8 and 63.4% of the patients were in CSR at 3, 5 and 10 years, respectively. Multivariate analysis revealed that age and pretreatment classification according to the Myasthenia Gravis Foundation of America (MGFA) criteria tended to be independent predictors of CSR. There were 6.9% with compressive vertebral fracture, 13.8% with cataract, and 5.2% with steroid-induced diabetes. Life table analysis revealed that recurrence rates after CSR were 36.8 and 46.0% at 3 and 5 years, respectively. Patients with thymoma had a significantly higher rate of recurrence than those without thymoma (p = 0.001). Alternate-day administration of high-dose prednisolone reduced the risk of post-thymectomy myasthenic crisis. Presence of thymoma was a risk factor for MG recurrence after CSR.

Influenza vaccine strategies for solid organ transplant recipients.

PubMed

Hirzel, Cédric; Kumar, Deepali

2018-05-15

The aim of this study was to highlight recent evidence on important aspects of influenza vaccination in solid organ transplant recipients. Influenza vaccine is the most evaluated vaccine in transplant recipients. The immunogenicity of the vaccine is suboptimal after transplantation. Newer formulations such as inactivated unadjuvanted high-dose influenza vaccine and the administration of a booster dose within the same season have shown to increase response rates. Intradermal vaccination and adjuvanted vaccines did not show clear benefit over standard influenza vaccines. Recent studies in transplant recipients do not suggest a higher risk for allograft rejection, neither after vaccination with a standard influenza vaccine nor after the administration of nonstandard formulation (high-dose, adjuvanted vaccines), routes (intradermally) or a booster dose. Nevertheless, influenza vaccine coverage in transplant recipients is still unsatisfactory low, potentially due to misinterpretation of risks and benefits. Annual influenza vaccination is well tolerated and is an important part of long-term care of solid organ transplant recipients.

Short and long term modulation of tissue minerals concentrations following oral administration of black cumin (Nigella sativa L.) seed oil to laboratory rats.

PubMed

Basheer, Irum; Qureshi, Irfan Zia

2018-01-15

Nigella sativa, or commonly called black cumin is a small herb of family Ranunculaceae is a well-known medicinal plant but its effects on tissue mineral concentrations of animal bodies is unknown. To study the effect of oral administration of fixed oil of black cumin seeds on tissues mineral content using laboratory rats as experimental model. Experimental animals were exposed to two oral doses of seed oil (60 and 120 ml kg -1 body weight). Short- and long term experiments lasted 24 h and 60 days respectively, with three replicates each. Oil extracted from black cumin seeds was subjected to GC-MS to identify chemical components. Following the wet digestion in nitric acid, samples of whole blood and organs of rats were subjected to atomic absorption spectrophotometry for determination of elements concentrations. Data were compared statistically at p < .05. Compared to control, Cr, Mn, Ni, Cu, Zn showed decrease, whereas Co, Na, Mg and K demonstrated increase, but Ca showed both increase and decrease in most of the tissues upon short term exposure to low and high doses of black cumin oil. During long term exposure, Cr, Fe, Mn, Cu exhibited decrease; Co, Na, Mg and Ca concentrations demonstrated an upregulation, whereas Ni and Zn showed increase and decrease in most of the tissues. Comparison of short term with long term experiments at low dose revealed increases in Fe, Zn, Cu, Mg, K and Ca, a decrease in Cr, Mn, Ni and Cu in most tissues, but both increase and decrease in Na. At high dose, an increase occurred in Fe, Ni, Zn, K, Ca, Mg, a decrease in Cr, while both increase and decrease in Cu, Co and Na concentrations. Our study demonstrates that oral administration of black cumin seeds oil to laboratory rats significantly alters tissue trace elements and electrolytes concentrations. The study appears beneficial but indicates modulatory role of black cumin oil as regards mineral metabolism with far reaching implications in health and disease. Copyright © 2017. Published by Elsevier GmbH.

Long-term Effect of Pig Slurry Application on Soil Carbon Storage, Quality and Yield Sustainability in Murcia Region, Spain

NASA Astrophysics Data System (ADS)

Büyükkılıç Yanardaǧ, Asuman

2013-04-01

Sustainability of agriculture is now a major global concern, especially since the 1980s. Soil organic matter is very important in the proper functions of the soil, which is also a good indicator of soil quality. This is due to its influence on many of the chemical, physical, and biological processes that control the capacity of a soil to perform properly. Understanding of nutrient supply through organic matter mineralization in agricultural systems is essential for maintaining long-term quality and productivity. The composition of pig manure will have a profound impact on soil properties, quality and crop yield when used in agriculture. We studied the effects of pig slurry (PS) application as an organic fertilizer, trying to determine the optimum amount that can be added to the soil, and the effect on soil properties, quality, and productivity. We applied 3 different doses on silty loam soils: Single (D1), Double (D2), Triple (D3) and unfertilized plots (C) served as controls. Samples were collected at two different levels, surface (0-30 cm) and subsurface (30-60 cm). D1 application dose, which is the agronomic rate of N-requirement (170 kg N/ha/yr) (European Directive 91/676/CEE), is very appropriate in term of sustainable agriculture and also can improve physical, chemical and biological soil properties. Therefore that the long-term use of PS with low dose may necessarily enhance soil quality in the long term. There are many factors to be considered when attempting to assess the overall net impact of a management practice on productivity. Additions of pig manure to soils at agronomic rates (170 kg N ha-1 yr-1) to match crop nutrient requirements are expected to have a positive impact on soil productivity. Therefore, the benefits from the use of application depend on the management of PS, carbon and environmental quality. However, PS have high micronutrient contents, and for this reason the application of high doses can pollute soils and damage human, animal and plant health, which is not suitable in term of sustainable agriculture. Keywords: Management, Pig slurry, Productivity, Quality, Soil.

Effect of high-dose irradiation on the optically stimulated luminescence of Al2O3:C

NASA Technical Reports Server (NTRS)

Yukihara, E. G.; Whitley, V. H.; McKeever, S. W. S.; Akselrod, A. E.; Akselrod, M. S.

2004-01-01

This paper examines the effect of high-dose irradiation on the optically stimulated luminescence (OSL) of Al2O3:C, principally on the shape of the OSL decay curve and on the OSL sensitivity. The effect of the degree of deep trap filling on the OSL was also studied by monitoring the sensitivity changes after doses of beta irradiation and after step-annealing of samples previously irradiated with high doses. The OSL response to dose shows a linear-supralinear-saturation behavior, with a decrease in the response for doses higher than those required for saturation. This behavior correlates with the sensitivity changes observed in the samples annealed only to 773 K, which show sensitization for doses up to 20-50 Gy and desensitization for higher doses. Data from the step-annealing study leads to the suggestion that the sensitization is caused by the filling of deep electron traps, which become thermally unstable at 1100-1200 K, whereas the desensitization is caused by the filling of deep hole traps, which become thermally unstable at 800-875 K, along with a concomitant decrease in the concentration of recombination centers (F+ -centers). Changes in the shape of the OSL decay curves are also observed at high doses, the decay becoming faster as the dose increases. These changes in the OSL decay curves are discussed in terms of multiple overlapping components, each characterized by different photoionization cross-sections. However, using numerical solutions of the rate equations for a simple model consisting of a main trap and a recombination center, it is shown that the kinetics of OSL process may also be partially responsible for the changes in the OSL curves at high doses in Al2O3:C. Finally, the implication of these results for the dosimetry of heavy charged particles is discussed. c2004 Elsevier Ltd. All rights reserved.

NEUROBEHAVIORAL EFFECTS OF CHRONIC DIETARY AND REPEATED HIGH-LEVEL SPIKE EXPOSURE TO CHLORPYRIFOS IN RATS.

EPA Science Inventory

This study aimed to model long-term subtoxic human exposure to an organophosphorus pesticide, chlorpyrifos, and to examine the influence of that exposure on the response to intermittent high-dose acute challenges. Adult rats were maintained on a chlorpyrifos-containing diet to p...

Is heterogeneity in stage 3 non-small cell lung cancer obscuring the potential benefits of dose-escalated concurrent chemo-radiotherapy in clinical trials?

PubMed

Hudson, Andrew; Chan, Clara; Woolf, David; McWilliam, Alan; Hiley, Crispin; O'Connor, James; Bayman, Neil; Blackhall, Fiona; Faivre-Finn, Corinne

2018-04-01

The current standard of care for the management of inoperable stage 3 non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (cCRT) using radiotherapy dose-fractionation and chemotherapy regimens that were established 3 decades ago. In an attempt to improve the chances of long-term control from cCRT, dose-escalation of the radiotherapy dose was assessed in the RTOG 0617 randomised control study comparing the standard 60 Gy in 30 fractions with a high-dose arm receiving 74 Gy in 37 fractions. Following the publication of this trial the thoracic oncology community were surprised to learn that there was worse survival in the dose-escalated arm and that for now the standard of care must remain with the lower dose. In this article we review the RTOG 0617 paper with subsequent analyses and studies to explore why the use of dose-escalated cCRT in stage 3 NSCLC has not shown the benefits that were expected. The overarching theme of this opinion piece is how heterogeneity between stage 3 NSCLC cases in terms of patient, tumour, and clinical factors may obscure the potential benefits of dose-escalation by causing imbalances in the arms of studies such as RTOG 0617. We also examine recent advances in the staging, management, and technological delivery of radiotherapy in NSCLC and how these may be employed to optimise cCRT trials in the future and ensure that any potential benefits of dose-escalation can be detected. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of Pharmacokinetic Processes and Varied Dosing Schedules on the Dynamics of Acquired Resistance to Erlotinib in EGFR-Mutant Lung Cancer

PubMed Central

Foo, Jasmine; Chmielecki, Juliann; Pao, William; Michor, Franziska

2013-01-01

Introduction Erlotinib (Tarceva) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which effectively targets EGFR-mutant driven non–small-cell lung cancer. However, the evolution of acquired resistance because of a second-site mutation (T790M) within EGFR remains an obstacle to successful treatment. Methods We used mathematical modeling and available clinical trial data to predict how different pharmacokinetic parameters (fast versus slow metabolism) and dosing schedules (low dose versus high dose; missed doses with and without make-up doses) might affect the evolution of T790M-mediated resistance in mixed populations of tumor cells. Results We found that high-dose pulses with low-dose continuous therapy impede the development of resistance to the maximum extent, both pre- and post-emergence of resistance. The probability of resistance is greater in fast versus slow drug metabolizers, suggesting a potential mechanism, unappreciated to date, influencing acquired resistance in patients. In case of required dose modifications because of toxicity, little difference is observed in terms of efficacy and resistance dynamics between the standard daily dose (150 mg/d) and 150 mg/d alternating with 100 mg/d. Missed doses are expected to lead to resistance faster, even if make-up doses are attempted. Conclusions For existing and new kinase inhibitors, this novel framework can be used to rationally and rapidly design optimal dosing strategies to minimize the development of acquired resistance. PMID:22982659

High-dose total-body irradiation and autologous marrow reconstitution in dogs: dose-rate-related acute toxicity and fractionation-dependent long-term survival

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

Deeg, H.J.; Storb, R.; Weiden, P.L.

1981-11-01

Beagle dogs treated by total-body irradiation (TBI) were given autologous marrow grafts in order to avoid death from marrow toxicity. Acute and delayed non-marrow toxicities of high single-dose (27 dogs) and fractionated TBI (20 dogs) delivered at 0.05 or 0.1 Gy/min were compared. Fractionated TBI was given in increments of 2 Gy every 6 hr for three increments per day. Acute toxicity and early mortality (<1 month) at identical total irradiation doses were comparable for dogs given fractionated or single-dose TBI. With single-dose TBI, 14, 16, and 18 Gy, respectively, given at 0.05 Gy/min, 0/5, 5/5, and 2/2 dogs diedmore » from acute toxicity; with 10, 12, and 14 Gy, respectively, given at 0.1 Gy/min, 1/5, 4/5, and 5/5 dogs died acutely. With fractionated TBI, 14 and 16 Gy, respectively, given at 0.1 Gy/min, 1/5, 4/5, and 2/2 dogs died auctely. Early deaths were due to radiation enteritis with or without associated septicemia (29 dogs; less than or equal to Day 10). Three dogs given 10 Gy of TBI at 0.1 Gy/min died from bacterial pneumonia; one (Day 18) had been given fractionated and two (Days 14, 22) single-dose TBI. Fifteen dogs survived beyond 1 month; eight of these had single-dose TBI (10-14 Gy) and all died within 7 months of irradiation from a syndrome consisting of hepatic damage, pancreatic fibrosis, malnutrition, wasting, and anemia. Seven of the 15 had fractionated TBI, and only one (14 Gy) died on Day 33 from hepatic failure, whereas 6 (10-14 Gy) are alive and well 250 to 500 days after irradiation. In conclusion, fractionated TBI did not offer advantages over single-dose TBI with regard to acute toxicity and early mortality; rather, these were dependent upon the total dose of TBI. The total acutely tolerated dose was dependent upon the exposure rate; however, only dogs given fractionated TBI became healthy long-term survivors.« less

Radiation streaming and skyshine evaluation for a proposed low-level radioactive waste assured isolation facility.

PubMed

Arno, Matthew; Hamilton, Ian S

2003-10-01

Texas is investigating the idea of building a long term waste storage facility, also known as an Assured Isolation Facility. This is an above-ground, retrievable low-level radioactive waste storage facility. A preliminary, scoping-level analysis has been extended to consider more complex scenarios of radiation streaming and skyshine by using MCNP to model the facility in greater detail. Using bounding source term assumptions, the radiation doses and dose rates are found to exceed applicable limits by an order of magnitude. By altering the facility design to fill in the hollow cores of the prefabricated concrete slabs used in the roof over the "high-gamma" rooms where the waste with greatest gamma radiation intensity is stored, dose rates outside the facility decrease by an order of magnitude. With the modified design, the annual dose at the site fenceline is less than the 1 mSv annual limit for exposure of the public. Within the site perimeter, modifying the roof results in an order of magnitude drop in the dose rate for personnel outside the facility and on the facility roof, as well as a significant drop inside the facility. Radiation streaming inside the facility can be lowered almost two orders of magnitude by placing operational restrictions to keep at least two rows of waste containers in front of the high-gamma room to cut down on the size of the path for streaming.

Modelling evolution of air dose rates in river basins in Fukushima Prefecture affected by sediment-sorbed radiocesium redistribution

NASA Astrophysics Data System (ADS)

Malins, A.; Sakuma, K.; Nakanishi, T.; Kurikami, H.; Machida, M.; Kitamura, A.; Yamada, S.

2015-12-01

The radioactive 134Cs and 137Cs isotopes deposited over Fukushima Prefecture by the Fukushima Daiichi nuclear disaster are the predominant radiological concern for the years following the accident. This is because the energetic gamma radiation they emit on decay constitutes the majority of the elevated air dose rates that now afflict the region. Therefore, we developed a tool for calculating air dose rates from arbitrary radiocesium spatial distributions across the land surface and depth profiles within the ground. As cesium is strongly absorbed by clay soils, its primary redistribution mechanism within Fukushima Prefecture is by soil erosion and water-borne sediment transport. Each year between 0.1~1% of the total radiocesium inventory in the river basins neighboring Fukushima Daiichi is eroded from the land surface and enters into water courses, predominantly during typhoon storms. Although this is a small amount in relative terms, in absolute terms it corresponds to terabecquerels of 134Cs and 137Cs redistribution each year and this can affect the air dose rate at locations of high erosion and sediment deposition. This study inputs the results of sediment redistribution simulations into the dose rate evaluation tool to calculate the locations and magnitude of air dose rate changes due to radiocesium redistribution. The dose rate calculations are supported by handheld survey instrument results taken within the Prefecture.

Factors associated with higher oxytocin requirements in labor.

PubMed

Frey, Heather A; Tuuli, Methodius G; England, Sarah K; Roehl, Kimberly A; Odibo, Anthony O; Macones, George A; Cahill, Alison G

2015-09-01

To identify clinical characteristics associated with high maximum oxytocin doses in women who achieve complete cervical dilation. A retrospective nested case-control study was performed within a cohort of all term women at a single center between 2004 and 2008 who reached the second stage of labor. Cases were defined as women who had a maximum oxytocin dose during labor >20 mu/min, while women in the control group had a maximum oxytocin dose during labor of ≤20 mu/min. Exclusion criteria included no oxytocin administration during labor, multiple gestations, major fetal anomalies, nonvertex presentation, and prior cesarean delivery. Multiple maternal, fetal, and labor factors were evaluated with univariable analysis and multivariable logistic regression. Maximum oxytocin doses >20 mu/min were administered to 108 women (3.6%), while 2864 women received doses ≤20 mu/min. Factors associated with higher maximum oxytocin dose after adjusting for relevant confounders included maternal diabetes, birthweight >4000 g, intrapartum fever, administration of magnesium, and induction of labor. Few women who achieve complete cervical dilation require high doses of oxytocin. We identified maternal, fetal and labor factors that characterize this group of parturients.

Radiation dose reduction in thoracic and lumbar spine instrumentation using navigation based on an intraoperative cone beam CT imaging system: a prospective randomized clinical trial.

PubMed

Pireau, Nathalie; Cordemans, Virginie; Banse, Xavier; Irda, Nadia; Lichtherte, Sébastien; Kaminski, Ludovic

2017-11-01

Spine surgery still remains a challenge for every spine surgeon, aware of the potential serious outcomes of misplaced instrumentation. Though many studies have highlighted that using intraoperative cone beam CT imaging and navigation systems provides higher accuracy than conventional freehand methods for placement of pedicle screws in spine surgery, few studies are concerned about how to reduce radiation exposure for patients with the use of such technology. One of the main focuses of this study is based on the ALARA principle (as low as reasonably achievable). A prospective randomized trial was conducted in the hybrid operating room between December 2015 and December 2016, including 50 patients operated on for posterior instrumented thoracic and/or lumbar spinal fusion. Patients were randomized to intraoperative 3D acquisition high-dose (standard dose) or low-dose protocol, and a total of 216 pedicle screws were analyzed in terms of screw position. Two different methods were used to measure ionizing radiation: the total skin dose (derived from the dose-area product) and the radiation dose evaluated by thermoluminescent dosimeters on the surgical field. According to Gertzbein and Heary classifications, low-dose protocol provided a significant higher accuracy of pedicle screw placement than the high-dose protocol (96.1 versus 92%, respectively). Seven screws (3.2%), all implanted with the high-dose protocol, needed to be revised intraoperatively. The use of low-dose acquisition protocols reduced patient exposure by a factor of five. This study emphasizes the paramount importance of using low-dose protocols for intraoperative cone beam CT imaging coupled with the navigation system, as it at least does not affect the accuracy of pedicle screw placement and irradiates drastically less.

High-Dose Ursodeoxycholic Acid Is Associated With the Development of Colorectal Neoplasia in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis

PubMed Central

Eaton, John E.; Silveira, Marina G.; Pardi, Darrell S.; Sinakos, Emmanouil; Kowdley, Kris V.; Luketic, Velimir A.C.; Harrison, M. Edwyn; McCashland, Timothy; Befeler, Alex S.; Harnois, Denise; Jorgensen, Roberta; Petz, Jan; Lindor, Keith D.

2011-01-01

OBJECTIVES Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28–30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC. METHODS Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer. RESULTS Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30–20.10, P=0.02). CONCLUSIONS Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC. PMID:21556038

Designing Spacecraft and Mission Operations Plans to Meet Flight Crew Radiation Dose Requirements: Why is this an "Epic Challenge" for Long-Term Manned Interplanetary Flight

NASA Technical Reports Server (NTRS)

Koontz, Steven

2012-01-01

Outline of presentation: (1) Radiation Shielding Concepts and Performance - Galactic Cosmic Rays (GCRs) (1a) Some general considerations (1b) Galactic Cosmic Rays (2)GCR Shielding I: What material should I use and how much do I need? (2a) GCR shielding materials design and verification (2b) Spacecraft materials point dose cosmic ray shielding performance - hydrogen content and atomic number (2c) Accelerator point dose materials testing (2d) Material ranking and selection guidelines (2e) Development directions and return on investment (point dose metric) (2f) Secondary particle showers in the human body (2f-1) limited return of investment for low-Z, high-hydrogen content materials (3) GCR shielding II: How much will it cost? (3a) Spacecraft design and verification for mission radiation dose to the crew (3b) Habitat volume, shielding areal density, total weight, and launch cost for two habitat volumes (3c) It's All about the Money - Historical NASA budgets and budget limits (4) So, what can I do about all this? (4a) Program Design Architecture Trade Space (4b) The Vehicle Design Trade Space (4c) Some Near Term Recommendations

Association of High-Dose Ibuprofen Use, Lung Function Decline, and Long-Term Survival in Children with Cystic Fibrosis.

PubMed

Konstan, Michael W; VanDevanter, Donald R; Sawicki, Gregory S; Pasta, David J; Foreman, Aimee J; Neiman, Evgueni A; Morgan, Wayne J

2018-04-01

Cystic fibrosis deaths result primarily from lung function loss, so chronic respiratory therapies, intended to preserve lung function, are cornerstones of cystic fibrosis care. Although treatment-associated reduction in rate of lung function loss should ultimately improve cystic fibrosis survival, no such relationship has been described for any chronic cystic fibrosis therapy. In part, this is because the ages of most rapid lung function decline-early adolescence-precede the median age of cystic fibrosis deaths by more than a decade. To study associations of high-dose ibuprofen treatment with the rate of forced expiratory volume in 1 second decline and mortality among children followed in the Epidemiologic Study of Cystic Fibrosis and subsequently in the U.S. Cystic Fibrosis Foundation Patient Registry. We performed a matched cohort study using data from Epidemiologic Study of Cystic Fibrosis. Exposure was defined as high-dose ibuprofen use reported at ≥80% of encounters over 2 years. Unexposed children were matched to exposed children 5:1 using propensity scores on the basis of demographic, clinical, and treatment covariates. The rate of decline of percent predicted forced expiratory volume in 1 second during the 2-year follow-up period was estimated by mixed-effects modeling with random slopes and intercepts. Survival over 16 follow-up years in the U.S. Cystic Fibrosis Foundation Patient Registry was compared between treatment groups by using proportional hazards modeling controlling for matching and covariates. We included 775 high-dose ibuprofen users and 3,665 nonusers who were well matched on demographic, clinical, and treatment variables. High-dose ibuprofen users declined on average 1.10 percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 0.51, 1.69) during the 2-year treatment period, whereas nonusers declined at a rate of 1.76% percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 1.48, 2.04) during the corresponding 2-year period, a 37.5% slower decline among users compared with nonusers (95% confidence interval; 0.4%, 71.3%; P = 0.046). The users had better subsequent survival (P < 0.001): the unadjusted and adjusted hazard ratios for mortality (high-dose ibuprofen/non-high-dose ibuprofen) (95% confidence interval) were 0.75 (0.64, 0.87) and 0.82 (0.69, 0.96). In a propensity-score matched cohort study of children with cystic fibrosis, we observed an association between high-dose ibuprofen use and both slower lung function decline and improved long-term survival. These results are consistent with the hypothesis that treatment-associated reduction of lung function decline in children with cystic fibrosis leads to improved survival.

DNA Repair Defects and Chromosomal Aberrations

NASA Technical Reports Server (NTRS)

Hada, Megumi; George, K. A.; Huff, J. L.; Pluth, J. M.; Cucinotta, F. A.

2009-01-01

Yields of chromosome aberrations were assessed in cells deficient in DNA doublestrand break (DSB) repair, after exposure to acute or to low-dose-rate (0.018 Gy/hr) gamma rays or acute high LET iron nuclei. We studied several cell lines including fibroblasts deficient in ATM (ataxia telangiectasia mutated; product of the gene that is mutated in ataxia telangiectasia patients) or NBS (nibrin; product of the gene mutated in the Nijmegen breakage syndrome), and gliomablastoma cells that are proficient or lacking in DNA-dependent protein kinase (DNA-PK) activity. Chromosomes were analyzed using the fluorescence in situ hybridization (FISH) chromosome painting method in cells at the first division post irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). Gamma irradiation induced greater yields of both simple and complex exchanges in the DSB repair-defective cells than in the normal cells. The quadratic dose-response terms for both simple and complex chromosome exchanges were significantly higher for the ATM- and NBS-deficient lines than for normal fibroblasts. However, in the NBS cells the linear dose-response term was significantly higher only for simple exchanges. The large increases in the quadratic dose-response terms in these repair-defective cell lines points the importance of the functions of ATM and NBS in chromatin modifications to facilitate correct DSB repair and minimize the formation of aberrations. The differences found between ATM- and NBS-deficient cells at low doses suggest that important questions should with regard to applying observations of radiation sensitivity at high dose to low-dose exposures. For aberrations induced by iron nuclei, regression models preferred purely linear dose responses for simple exchanges and quadratic dose responses for complex exchanges. Relative biological effectiveness (RBE) factors of all of the DNA repair-defective cell lines were smaller than those of normal cells, with the DNA-PK-deficient cells having RBEs near unity. To further investigate the sensitivity differences that were observed in ATM and NBS deficient cells, chromosomal aberrations were analyzed in normal lung fibroblast cells treated with KU-55933 (a specific ATM kinase inhibitor) or Mirin (an Mre11- Rad50-Nbs1 complex inhibitor involved in activation of ATM). We also performed siRNA knockdown of these proteins. Preliminary data indicate that chromosome exchanges increase in cells treated with the specific ATM inhibitor. Possible cytogenetic signatures of acute and low dose-rate gamma irradiation in ATM or nibrin deficient and suppressed cells will be discussed.

Longitudinal in vivo microcomputed tomography of mouse lungs: No evidence for radiotoxicity

PubMed Central

Vande Velde, Greetje; De Langhe, Ellen; Poelmans, Jennifer; Bruyndonckx, Peter; d'Agostino, Emiliano; Verbeken, Erik; Bogaerts, Ria; Himmelreich, Uwe

2015-01-01

Before microcomputed tomography (micro-CT) can be exploited to its full potential for longitudinal monitoring of transgenic and experimental mouse models of lung diseases, radiotoxic side effects such as inflammation or fibrosis must be considered. We evaluated dose and potential radiotoxicity to the lungs for long-term respiratory-gated high-resolution micro-CT protocols. Free-breathing C57Bl/6 mice underwent four different retrospectively respiratory gated micro-CT imaging schedules of repeated scans during 5 or 12 wk, followed by ex vivo micro-CT and detailed histological and biochemical assessment of lung damage. Radiation exposure, dose, and absorbed dose were determined by ionization chamber, thermoluminescent dosimeter measurements and Monte Carlo calculations. Despite the relatively large radiation dose delivered per micro-CT acquisition, mice did not show any signs of radiation-induced lung damage or fibrosis when scanned weekly during 5 and up to 12 wk. Doubling the scanning frequency and once tripling the radiation dose as to mimic the instant repetition of a failed scan also stayed without detectable toxicity after 5 wk of scanning. Histological analyses confirmed the absence of radiotoxic damage to the lungs, thereby demonstrating that long-term monitoring of mouse lungs using high-resolution micro-CT is safe. This opens perspectives for longitudinal monitoring of (transgenic) mouse models of lung diseases and therapeutic response on an individual basis with high spatial and temporal resolution, without concerns for radiation toxicity that could potentially influence the readout of micro-CT-derived lung biomarkers. This work further supports the introduction of micro-CT for routine use in the preclinical pulmonary research field where postmortem histological approaches are still the gold standard. PMID:26024893

Acute Low-Dose Endotoxin Treatment Results in Improved Whole-Body Glucose Homeostasis in Mice

PubMed Central

Stevens, Joseph R.; McMillan, Ryan P.; Resendes, Justin T.; Lloyd, Shannon K.; Ali, Mostafa M.; Frisard, Madlyn I.; Hargett, Stefan; Keller, Susanna R.; Hulver, Matthew W.

2017-01-01

Background Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, a condition known as metabolic endotoxemia. In non-obese and insulin sensitive individuals, circulating endotoxin concentrations fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. Evidence suggests that high-fat feeding alters these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not clearly understood. Purpose/Procedures The goal of this study was to determine the effects of both short-term and long-term increases in endotoxin (lipopolysaccharide, LPS) of a low magnitude on the glucose tolerance and insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis that short-term low-dose endotoxin treatments would augment insulin signaling and glycogen synthesis while long-term treatments would be disruptive in the cell culture model. Second, we examined if these short-term low dose treatments of endotoxin would contribute to similar improvements in whole-body glucose homeostasis in a mouse model. Main Findings Contrary to our initial hypothesis, short-term endotoxin treatment had no effect on insulin signaling or glycogen synthesis, however long-term treatment indeed decreased glycogen synthesis (P<.05). Interestingly, short-term endotoxin treatment resulted in significant improvements in glucose homeostasis in the mouse model (P<.01); which is believed to be at least partly attributed to an inhibitory action of LPS on liver glucose production. Conclusions This research shows that low-magnitude, short-term changes in LPS can have significant effects on whole body glucose metabolism and this likely occurs through its direct actions on the liver. Additional studies are necessary to understand the mechanisms responsible for altered glucose metabolism in response to low magnitude changes in LPS levels. PMID:28183447

Acute low-dose endotoxin treatment results in improved whole-body glucose homeostasis in mice.

PubMed

Stevens, Joseph R; McMillan, Ryan P; Resendes, Justin T; Lloyd, Shannon K; Ali, Mostafa M; Frisard, Madlyn I; Hargett, Stefan; Keller, Susanna R; Hulver, Matthew W

2017-03-01

Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, a condition known as metabolic endotoxemia. In non-obese and insulin sensitive individuals, circulating endotoxin concentrations fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. Evidence suggests that high-fat feeding alters these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not clearly understood. The goal of this study was to determine the effects of both short-term and long-term increases in endotoxin (lipopolysaccharide, LPS) of a low magnitude on the glucose tolerance and insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis that short-term low-dose endotoxin treatments would augment insulin signaling and glycogen synthesis while long-term treatments would be disruptive in the cell culture model. Second, we examined if these short-term low dose treatments of endotoxin would contribute to similar improvements in whole-body glucose homeostasis in a mouse model. Contrary to our initial hypothesis, short-term endotoxin treatment had no effect on insulin signaling or glycogen synthesis, however long-term treatment indeed decreased glycogen synthesis (P<.05). Interestingly, short-term endotoxin treatment resulted in significant improvements in glucose homeostasis in the mouse model (P<.01); which is believed to be at least partly attributed to an inhibitory action of LPS on liver glucose production. This research shows that low-magnitude, short-term changes in LPS can have significant effects on whole body glucose metabolism and this likely occurs through its direct actions on the liver. Additional studies are necessary to understand the mechanisms responsible for altered glucose metabolism in response to low magnitude changes in LPS levels. Copyright © 2016 Elsevier Inc. All rights reserved.

Growth and development after hematopoietic cell transplant in children.

PubMed

Sanders, J E

2008-01-01

Hematopoietic cell transplantation (HCT) following high-dose chemotherapy or chemoradiotherapy for children with malignant or nonmalignant hematologic disorders has resulted in an increasing number of long-term disease-free survivors. The preparative regimens include high doses of alkylating agents, such as CY with or without BU, and may include TBI. These agents impact the neuroendocrine system in growing children and their subsequent growth and development. Children receiving high-dose CY or BUCY have normal thyroid function, but those who receive TBI-containing regimens may develop thyroid function abnormalities. Growth is not impacted by chemotherapy-only preparative regimens, but TBI is likely to result in growth hormone deficiency and decreased growth rates that need to be treated with synthetic growth hormone therapy. Children who receive high-dose CY-only have normal development through puberty, whereas those who receive BUCY have a high incidence of delayed pubertal development. Following fractionated TBI preparative regimens, approximately half of the patients have normal pubertal development. These data demonstrate that the growth and development problems after HCT are dependent upon the preparative regimen received. All children should be followed for years after HCT for detection of growth and development abnormalities that are treatable with appropriate hormone therapy.

The possible mechanism of silver nanoparticle impact on hippocampal synaptic plasticity and spatial cognition in rats.

PubMed

Liu, Ye; Guan, Wei; Ren, Guogang; Yang, Zhuo

2012-03-25

Silver nanoparticles (Ag-np) are very promising engineered nanomaterials which play an important role in the world biomedical, healthcare and in general nanotechnology applications. With the most impressive effect in antibacterial and many other broad-spectrum biotechnological advantages, Ag-np in real applications is still a controversial issue. This study investigated effects of the Ag-np on hippocampal synaptic plasticity and spatial cognition in rats and followed with the research on their possible mechanism. In this study, twenty-four adult male Wister rats were randomly divided into 3 groups: control group, low-dose group (Ag-np, 3 mg/kg) and high-dose group (Ag-np, 30 mg/kg). After two-week exposure to Ag-np through the nasal administration, Morris water maze (MWM) test was performed for the spatial cognition, followed by the long-term potentiation (LTP) recording and reactive oxygen species (ROS) detection in hippocampal homogenate. Results showed that compared with the control group, both LTP and MWM were abnormal in low-dose group and high-dose group. The quantity of ROS in hippocampal homogenate was increased significantly in low-dose group and high-dose group, which may be the reason of the neural damage caused by Ag-np. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Optimizing clinical use of mesalazine (5-aminosalicylic acid) in inflammatory bowel disease

PubMed Central

Williams, Chadwick; Panaccione, Remo; Ghosh, Subrata; Rioux, Kevin

2011-01-01

Mesalazine [5-aminosalicylic acid (5-ASA)] has been used for over 30 years in the treatment of inflammatory bowel disease (IBD). It is a highly effective, safe, and well-tolerated drug for treatment of mild to moderate ulcerative colitis, which represents most patients with this disease. Recent studies of patient adherence to 5-ASA therapies in ulcerative colitis have highlighted the need for regimens that enable long-term compliance to significantly reduce the risk of troublesome and debilitating flares in the short term, and possibly colon cancer in the long term. Indeed, much of the recent innovation in clinical use of 5-ASA in colitis has come from studies of novel delivery mechanisms and simplified oral dosing schedules. These studies have provided much needed clarity on essential matters such as starting dose, dose escalation, and efficacy in terms of the ideal clinical endpoint - mucosal healing. Various manufacturers are re-evaluating their products to determine the safety and efficacy of such dosing regimens. Although once widely employed in the treatment of Crohn’s disease (CD), the accumulated body of evidence now suggests that there is a much more limited role for 5-ASA in this particular form of inflammatory bowel disease. Recent 5-ASA randomized-controlled trials, comparative studies, and outcomes research have led to refined treatment strategies and awareness for practitioners to better inform, engage and facilitate patients in optimal use of 5-ASA in inflammatory bowel disease. PMID:21765868

Characterisation of a plastic scintillation detector to be used in a multicentre stereotactic radiosurgery dosimetry audit

NASA Astrophysics Data System (ADS)

Dimitriadis, A.; Patallo, I. Silvestre; Billas, I.; Duane, S.; Nisbet, A.; Clark, C. H.

2017-11-01

Scintillation detectors are considered highly suitable for dosimetric measurement of small fields in radiotherapy due to their near-tissue equivalence and their small size. A commercially available scintillation detector, the Exradin W1 (Standard Imaging, Middleton, USA), has been previously characterised by two independent studies (Beierholm et al., 2014; Carrasco et al., 2015a, 2015b) but the results from these publications differed in some aspects (e.g. energy dependence, long term stability). The respective authors highlighted the need for more studies to be published (Beierholm et al., 2015; Carrasco et al., 2015a, 2015b). In this work, the Exradin W1 was characterised in terms of dose response, dependence on dose rate, energy, temperature and angle of irradiation, and long-term stability. The observed dose linearity, short-term repeatability and temperature dependence were in good agreement with previously published data. Appropriate corrections should therefore be applied, where possible, in order to achieve measurements with low-uncertainty. The angular dependence was characterised along both the symmetrical and polar axis of the detector for the first time in this work and a dose variation of up to 1% was observed. The response of the detector was observed to decrease at a rate of approximately 1.6% kGy-1 for the first 5 kGy delivered, and then stabilised to 0.2% kGy-1 in the subsequent 20 kGy. The main goal of this work was to assess the suitability of the Exradin W1 for use in dose verification measurements for stereotactic radiosurgery. The results obtained confirm that the detector is suitable for use in such situations. The detector is now utilised in a multi-centre stereotactic radiosurgery dosimetric audit, with the application of appropriate correction factors.

Modeling the long-term persistence of hepatitis A antibody after a two-dose vaccination schedule in Argentinean children.

PubMed

López, Eduardo L; Contrini, María Marta; Mistchenko, Alicia; Kieffer, Alexia; Baggaley, Rebecca F; Di Tanna, Gian Luca; Desai, Kamal; Rasuli, Anvar; Armoni, Judith

2015-04-01

Long-term seroprotection data are essential for decision-making on the need and timing of vaccine boosters. Based on data from longitudinal serological studies, modeling can provide estimates on long-term antibody persistence and inform such decision-making. We examined long-term anti-hepatitis A virus (anti-HAV) antibody persistence in Argentinean children ≤15 years after the initial study where they completed a 2-dose course of inactivated hepatitis A vaccine (Avaxim 80U Pediatric, Sanofi Pasteur, Lyon, France). Blood serum samples were taken at baseline, 2 weeks (post first dose), 6 months (pre-booster), 6.5 months (post-booster), 10 years and 14-15 years after first vaccine dose. We fitted 8 statistical model types, predominantly mixed effects models, to anti-HAV persistence data, to identify the most appropriate and best fitting models for our data set and to predict individuals' anti-HAV levels and seroprotection rates up to 30 years post vaccination. Fifty-four children (mean age at enrollment 30.4 months) were enrolled up to 15 years post first vaccine dose. There were 3 distinct periods of antibody concentration: rapid rise up to peak concentration post-booster, rapid decay from post-booster to 10 years, followed by slower decay. A 3-segmented linear mixed effects model was the most appropriate for the data set. Extrapolating based on the available 14-15-year follow-up, the analysis predicted that 88% of individuals anti-HAV seronegative prior to vaccination would remain seroprotected at 30 years post vaccination and lifelong seroprotection for vaccinees seropositive prior to vaccination. Currently available data demonstrate that Avaxim 80U Pediatric confers to most vaccinees a high level of seroprotection against hepatitis A infection for at least 20-30 years.

Predicting and comparing long-term measles antibody profiles of different immunization policies.

PubMed

Lee, M S; Nokes, D J

2001-01-01

Measles outbreaks are infrequent and localized in areas with high coverage of measles vaccine. The need is to assess long-term effectiveness of coverage. Since 1991, no measles epidemic affecting the whole island has occurred in Taiwan, China. Epidemiological models are developed to predict the long-term measles antibody profiles and compare the merits of different immunization policies on the island. The current measles immunization policy in Taiwan, China, is 1 dose of measles vaccine at 9 months of age and 1 dose of measles, mumps and rubella (MMR) vaccine at 15 months of age, plus a 'mop-up' of MMR-unvaccinated schoolchildren at 6 years of age. Refinements involve a change to a two-dose strategy. Five scenarios based on different vaccination strategies are compared. The models are analysed using Microsoft Excel. First, making the assumption that measles vaccine-induced immunity will not wane, the predicted measles IgG seroprevalences in preschool children range from 81% (lower bound) to 94% (upper bound) and in schoolchildren reach 97-98% in all strategy scenarios. Results are dependent on the association of vaccine coverage between the first and second dose of vaccine. Second, if it is assumed that vaccine-induced antibody titres decay, the long-term measles seroprevalence will depend on the initial titres post vaccination, decay rates of antibody titres and cut-off of seropositivity. If MMR coverage at 12 months of age can reach > 90%, it would be worth changing the current policy to 2 doses at 12 months and 6 years of age to induce higher antibody titres. These epidemiological models could be applied wherever a similar stage of measles elimination has been reached.

High-precision dosimetry for radiotherapy using the optically stimulated luminescence technique and thin Al2O3:C dosimeters.

PubMed

Yukihara, E G; Yoshimura, E M; Lindstrom, T D; Ahmad, S; Taylor, K K; Mardirossian, G

2005-12-07

The potential of using the optically stimulated luminescence (OSL) technique with aluminium oxide (Al(2)O(3):C) dosimeters for a precise and accurate estimation of absorbed doses delivered by high-energy photon beams was investigated. This study demonstrates the high reproducibility of the OSL measurements and presents a preliminary determination of the depth-dose curve in water for a 6 MV photon beam from a linear accelerator. The uncertainty of a single OSL measurement, estimated from the variance of a large sample of dosimeters irradiated with the same dose, was 0.7%. In the depth-dose curve obtained using the OSL technique, the difference between the measured and expected doses was < or =0.7% for depths between 1.5 and 10 cm, and 1.1% for a depth of 15 cm. The readout procedure includes a normalization of the response of the dosimeter with respect to a reference dose in order to eliminate variations in the dosimeter mass, dosimeter sensitivity, and the reader's sensitivity. This may be relevant for quality assurance programmes, since it simplifies the requirements in terms of personnel training to achieve the precision and accuracy necessary for radiotherapy applications. We concluded that the OSL technique has the potential to be reliably incorporated in quality assurance programmes and dose verification.

Long-term follow up of high-dose chemotherapy with autologous stem cell rescue in adults with Ewing tumor.

PubMed

Laurence, Valérie; Pierga, Jean-Yves; Barthier, Sophie; Babinet, Antoine; Alapetite, Claire; Palangié, Thao; de Pinieux, Gonzagues; Anract, Philippe; Pouillart, Pierre

2005-06-01

Ewing tumors remain of poor prognosis, with 5-year overall survival of 55% to 65% in localized patients and not exceeding 25% in primarily metastatic disease. Several reports, mainly in children, have reported that some patients with poor-risk Ewing tumors may benefit from high-dose chemotherapy (HDCT) with autologous stem cell rescue. This retrospective study analyzed 46 patients treated in our institution between 1987 and 2000 for localized or primary metastatic Ewing tumors by HDCT followed by stem cell rescue. Median follow up was 7.1 years. Median age was 21 years (range, 15-46 years). Twenty-two percent of patients had metastases at diagnosis. The tumor site was axial in 56% of patients. Median tumor size was 9.5 cm. The treatment regimen consisted of induction chemotherapy, local treatment, maintenance chemotherapy, and consolidation HDCT based on alkylating agents. No toxic death was observed in the intensive therapy phase. Five-year overall survival and progression-free survival were 63 +/- 7.7% and 47 +/- 7.6%, respectively. Pejorative prognostic factors in this population were metastases at diagnosis (5-year overall survival 34% vs.71%, P = 0.017) and poor pathologic response (5-year overall survival 44% vs.77%, P = 0.03). This retrospective study shows a high long-term survival rate with high-dose chemotherapy in adults.

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

Gorissen, BL; Giantsoudi, D; Unkelbach, J

Purpose: Cell survival experiments suggest that the relative biological effectiveness (RBE) of proton beams depends on linear energy transfer (LET), leading to higher RBE near the end of range. With intensity-modulated proton therapy (IMPT), multiple treatment plans that differ in the dose contribution per field may yield a similar physical dose distribution, but the RBE-weighted dose distribution may be disparate. RBE models currently do not have the required predictive power to be included in an optimization model due to the variations in experimental data. We propose an LET-based planning method that guides IMPT optimization models towards plans with reduced RBE-weightedmore » dose in surrounding organs at risk (OARs) compared to inverse planning based on physical dose alone. Methods: Optimization models for physical dose are extended with a term for dose times LET (doseLET). Monte Carlo code is used to generate the physical dose and doseLET distribution of each individual pencil beam. The method is demonstrated for an atypical meningioma patient where the target volume abuts the brainstem and partially overlaps with the optic nerve. Results: A reference plan optimized based on physical dose alone yields high doseLET values in parts of the brainstem and optic nerve. Minimizing doseLET in these critical structures as an additional planning goal reduces the risk of high RBE-weighted dose. The resulting treatment plan avoids the distal fall-off of the Bragg peaks for shaping the dose distribution in front of critical stuctures. The maximum dose in the OARs evaluated with RBE models from literature is reduced by 8–14\\% with our method compared to conventional planning. Conclusion: LET-based inverse planning for IMPT offers the ability to reduce the RBE-weighted dose in OARs without sacrificing target dose. This project was in part supported by NCI - U19 CA 21239.« less

Neutron dosimetry in low-earth orbit using passive detectors

NASA Technical Reports Server (NTRS)

Benton, E. R.; Benton, E. V.; Frank, A. L.

2001-01-01

This paper summarizes neutron dosimetry measurements made by the USF Physics Research Laboratory aboard US and Russian LEO spacecraft over the past 20 years using two types of passive detector. Thermal/resonance neutron detectors exploiting the 6Li(n,T) alpha reaction were used to measure neutrons of energies <1 MeV. Fission foil neutron detectors were used to measure neutrons of energies above 1 MeV. While originally analysed in terms of dose equivalent using the NCRP-38 definition of quality factor, for the purposes of this paper the measured neutron data have been reanalyzed and are presented in terms of ambient dose equivalent. Dose equivalent rate for neutrons <1 MeV ranged from 0.80 microSv/d on the low altitude, low inclination STS-41B mission to 22.0 microSv/d measured in the Shuttle's cargo bay on the highly inclined STS-51F Spacelab-2 mission. In one particular instance a detector embedded within a large hydrogenous mass on STS-61 (in the ECT experiment) measured 34.6 microSv/d. Dose equivalent rate measurements of neutrons >1 MeV ranged from 4.5 microSv/d on the low altitude STS-3 mission to 172 microSv/d on the 6 year LDEF mission. Thermal neutrons (<0.3 eV) were observed to make a negligible contribution to neutron dose equivalent in all cases. The major fraction of neutron dose equivalent was found to be from neutrons >1 MeV and, on LDEF, neutrons >1 MeV are responsible for over 98% of the total neutron dose equivalent. Estimates of the neutron contribution to the total dose equivalent are somewhat lower than model estimates, ranging from 5.7% at a location under low shielding on LDEF to 18.4% on the highly inclined (82.3 degrees) Biocosmos-2044 mission. c2001 Elsevier Science Ltd. All rights reserved.

Is Parenteral Levothyroxine Therapy Safe in Intractable Hypothyroidism?

PubMed

Peynirci, Hande; Taskiran, Bengur; Erturk, Erdinc; Sisman, Pınar; Ersoy, Canan

2018-06-01

A 32-year old woman was admitted to the hospital due to intractable hypothyroidism refractory to high dose of oral l-thyroxine therapy. She underwent total thyroidectomy and radioactive iodine therapy due to papillary thyroid cancer. After excluding poor adherence to therapy and malabsorption, levothyroxine absorption test was performed. No response was detected. Transient neurologic symptoms developed during the test. She developed 3 attacks consisting of neurologic symptoms during high dose administration. The patient was considered a case of isolated l-thyroxine malabsorption. She became euthyroid after intramuscular twice weekly l-thyroxine therapy. There are a few case reports regarding isolated l-thyroxine. We report successful long term results of twice weekly administered intramuscular l-thyroxine therapy. We also draw attention to neurologic side effects of high dose l-thyroxine therapy. Copyright © 2017 National Medical Association. Published by Elsevier Inc. All rights reserved.

Dose equivalent near the bone-soft tissue interface from nuclear fragments produced by high-energy protons

NASA Technical Reports Server (NTRS)

Shavers, M. R.; Poston, J. W.; Cucinotta, F. A.; Wilson, J. W.

1996-01-01

During manned space missions, high-energy nucleons of cosmic and solar origin collide with atomic nuclei of the human body and produce a broad linear energy transfer spectrum of secondary particles, called target fragments. These nuclear fragments are often more biologically harmful than the direct ionization of the incident nucleon. That these secondary particles increase tissue absorbed dose in regions adjacent to the bone-soft tissue interface was demonstrated in a previous publication. To assess radiological risks to tissue near the bone-soft tissue interface, a computer transport model for nuclear fragments produced by high energy nucleons was used in this study to calculate integral linear energy transfer spectra and dose equivalents resulting from nuclear collisions of 1-GeV protons transversing bone and red bone marrow. In terms of dose equivalent averaged over trabecular bone marrow, target fragments emitted from interactions in both tissues are predicted to be at least as important as the direct ionization of the primary protons-twice as important, if recently recommended radiation weighting factors and "worst-case" geometry are used. The use of conventional dosimetry (absorbed dose weighted by aa linear energy transfer-dependent quality factor) as an appropriate framework for predicting risk from low fluences of high-linear energy transfer target fragments is discussed.

Adaptation and Sensitization to Proteotoxic Stress

PubMed Central

Leak, Rehana K.

2014-01-01

Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons. PMID:24659932

Interactions of NADPH oxidase, renin-angiotensin-aldosterone system and reactive oxygen species in mequindox-mediated aldosterone secretion in Wistar rats.

PubMed

Huang, Xian-Ju; Wang, Xu; Ihsan, Awais; Liu, Qin; Xue, Xi-Juan; Su, Shi-Jia; Yang, Chun-Hui; Zhou, Wen; Yuan, Zong-Hui

2010-10-05

High doses of mequindox (MEQ) are associated with oxidative stress and pathological toxicity in the kidney. In this study, we demonstrated long term effects of MEQ on intra- or extra-adrenal renin-angiotensin-aldosterone system (RAAS) in vivo. RAAS plays a major role in aldosterone secretion. High doses of MEQ in the diet for 180 days in male rats led to inhibition of intra- and extra-adrenal RAAS, concident with down-regulation of Na(+)/K(+)-ATPase (NAKA) and mineralocorticoid receptor (MR), the downstream of aldosterone action. Significant changes of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) in kidney were also observed in the high doses (110, 275mg/kg) groups. The mRNA levels of most subunits of NADPH oxidase were significantly upregulated at low doses (25-110mg/kg) but the upregulation was diminished at higher doses in both kidney and adrenal gland, indicating a complicated and contradictory effect of MEQ on NADPH. These results highlight the complex interactions of drug metabolism, RAAS, NADPH oxidase and oxidative stress in response to MEQ-induced tissue toxicity and aldosterone secretion. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

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

Blanck, Oliver, E-mail: oliver.blanck@uksh.de; CyberKnife Center Northern Germany, Guestrow; Bode, Frank

Purpose: To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. Methods and Materials: Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm{sup 3}). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. Results: Transmural scarringmore » of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. Conclusions: Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.« less

Long-term follow-up study of compensated low-dose /sup 131/I therapy for Graves' disease

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

Sridama, V.; McCormick, M.; Kaplan, E.L.

1984-08-16

We treated 187 patients who had Graves' disease with low-dose radioactive iodide (/sup 131/I), using a protocol that included a compensation for thyroid size. The incidence of early hypothyroidism (12 per cent) was acceptably low in the first year after /sup 131/I treatment, but we found a cumulative high incidence (up to 76 per cent) at the end of the 11th year. In contrast, the incidence of permanent hypothyroidism was relatively stable in 166 surgically treated patients, increasing from 19 to 27 per cent at the end of 11 years. Among 122 medically treated patients, only 40 per cent enteredmore » remission, and hypothyroidism developed in 2 per cent during the same period of follow-up. The long-term incidence of hypothyroidism in our patients treated with low-dose /sup 131/I therapy was much higher than that found in earlier studies using a comparable dose. Our study suggests that it will be difficult to modify therapy with /sup 131/I alone to produce both early control of thyrotoxicosis and a low incidence of hypothyroidism.« less

[Late sequelae of central nervous system prophylaxis in children with acute lymphoblastic leukemia: high doses of intravenous methotrexate versus radiotherapy of the central nervous system--review of literature].

PubMed

Zając-Spychała, Olga; Wachowiak, Jacek

2012-01-01

Acute lymphoblastic leukemia is the most common malignancy in children. All current therapy regimens used in the treatment of childhood acute lymphoblastic leukemia include prophylaxis of the central nervous system. Initially it was thought that the best way of central nervous system prophylaxis is radiotherapy. But despite its effectiveness this method, may cause late sequelae and complications. In the programme currently used in Poland to treat acute lymphoblastic leukemia, prophylactic radiotherapy has been reduced by 50% (12 Gy) and is used only in patients stratified into the high risk group and in patients diagnosed as T-cell ALL (T-ALL). Complementary to radiotherapy, intrathecal methotrexate is given alone or in combination with cytarabine and hydrocortisone is given, as well as systemic chemotherapy with intravenous methotrexate is administered in high or medium doses (depending on risk groups and leukemia immunophenotype). Recent studies have shown that high dose irradiation of the central nervous system impairs cognitive development causing memory loss, visuomotor coordination impairment, attention disorders and reduction in the intelligence quotient. It has been proved that the degree of cognitive impairment depends on the radiation dose directed to the medial temporal lobe structures, particularly in the hippocampus and the surrounding cortex. Also, methotrexate used intravenously in high doses, interferes with the metabolism of folic acid which is necessary for normal development and the optimal functioning of neurons in the central nervous system. It has been proved that patients who have been treated with high doses of methotrexate are characterized by reduced memory skills and a lower intelligence quotient. The literature data concerning long term neuroanatomical abnormalities and neuropsychological deficits are ambiguous, and there is still no data concerning current methods of central nervous system prophylaxis with low doses of irradiation in combination with high doses of intravenous methotrexate.

Comparison of Immunogenicity Between Inactivated and Live Attenuated Hepatitis A Vaccines Among Young Adults: A 3-Year Follow-up Study.

PubMed

Liu, Xue-en; Chen, Hai-ying; Liao, Zheng; Zhou, Yisheng; Wen, Hairong; Peng, Shihui; Liu, Yan; Li, Rui; Li, Jie; Zhuang, Hui

2015-10-15

A randomized clinical trial of hepatitis A vaccines (1 or 2 doses of inactivated vaccine [Healive] or 1 dose of live attenuated vaccine [Biovac]) was conducted among adults to evaluate seroprotection rates and geometric mean concentrations of antibody against hepatitis A virus for 36 months. High rates of seroprotection persisted for at least 36 months among adults who received 1 or 2 doses of inactivated hepatitis A vaccine but not among adults who received 1 dose of live attenuated hepatitis A vaccine. The long-term serial monitoring of immunogenicity induced by 1 dose of inactivated hepatitis A vaccine is needed to determine an effective alternative to a 2-dose schedule. NCT01865968. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Long-term outcome of accelerated partial breast irradiation using a multilumen balloon applicator in a patient with existing breast implants.

PubMed

Akhtari, Mani; Nitsch, Paige L; Bass, Barbara L; Teh, Bin S

2015-01-01

Accelerated partial breast irradiation is now an accepted component of breast-conserving therapy. However, data regarding long-term outcomes of patients treated with multilumen catheter systems who have existing breast implants are limited. We report the treatment and outcome of our patient who had existing bilateral silicone subpectoral implants at the time of presentation. Ultrasound-guided core needle biopsy of the right breast showed infiltrating mucinous carcinoma. Right breast lumpectomy revealed an 8 mm area of infiltrating ductal carcinoma with mucinous features and nuclear grade 1. A 4-5 cm Contura (Bard Biopsy Systems, Tempe, AZ) device was placed, and she was treated over the course of 5 days twice daily to a dose of 34 Gy using a high-dose-rate iridium-192 source. The planning target volume for evaluation was 73.9 cc. The percentage of the planning target volume for evaluation receiving 90%, 95%, and 100% of the prescribed dose was 99.9%, 99.3%, and 97.8%, respectively. The total implant volume was 234.5 cc and received a mean dose of 15.4 Gy and a maximum dose of 72.8 Gy. The percentage of implant volume receiving 50%, 75%, 100%, and 200% of the prescribed dose was 31.1%, 16.5%, 8.6%, 2.0%, and 0%, respectively. Maximum skin dose was 97% of the prescribed dose. With a followup of nearly 5 years, she continues to be cancer free with minimal late toxicities and good to excellent cosmetic outcome. Accelerated partial breast irradiation using a multilumen balloon applicator in patients with existing breast implants can safely be performed with excellent long-term cosmetic outcome. Further studies are needed to establish the absolute dosimetric tolerance of breast implants. Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

NEUROBEHAVIORAL EVALUATION OF RATS EXPOSED TO CHLORPYRIFOS VIA CHRONIC DIETARY AND REPEATED HIGH-LEVEL SPIKE EXPOSURE.

EPA Science Inventory

This study aimed to model long-term subtoxic human exposure to an organophosphorus pesticide, chlorpyrifos (CPF), and to examine the influence of that exposure on the response to intermittent high-dose acute challenges. Adult Long-Evans male rats were maintained at 350g body wei...

NEUROBEHAVIORAL EFFECTS OF CHRONIC DIETARY AND REPEATED HIGH-LEVEL SPIKE EXPOSURE TO CHLORPYRIFOS IN RATS.

EPA Science Inventory

This study aimed to model long-term subtoxic human exposure to an organophosphorus pesticide, chlorpyrifos, and to examine the influence of that exposure on the response to intermittent high-dose acute challenges. Adult Long-Evans male rats were maintained at 350g body weight by...

Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

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

Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya

2009-12-18

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4more » daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.« less

Simultaneous integrated vs. sequential boost in VMAT radiotherapy of high-grade gliomas.

PubMed

Farzin, Mostafa; Molls, Michael; Astner, Sabrina; Rondak, Ina-Christine; Oechsner, Markus

2015-12-01

In 20 patients with high-grade gliomas, we compared two methods of planning for volumetric-modulated arc therapy (VMAT): simultaneous integrated boost (SIB) vs. sequential boost (SEB). The investigation focused on the analysis of dose distributions in the target volumes and the organs at risk (OARs). After contouring the target volumes [planning target volumes (PTVs) and boost volumes (BVs)] and OARs, SIB planning and SEB planning were performed. The SEB method consisted of two plans: in the first plan the PTV received 50 Gy in 25 fractions with a 2-Gy dose per fraction. In the second plan the BV received 10 Gy in 5 fractions with a dose per fraction of 2 Gy. The doses of both plans were summed up to show the total doses delivered. In the SIB method the PTV received 54 Gy in 30 fractions with a dose per fraction of 1.8 Gy, while the BV received 60 Gy in the same fraction number but with a dose per fraction of 2 Gy. All of the OARs showed higher doses (Dmax and Dmean) in the SEB method when compared with the SIB technique. The differences between the two methods were statistically significant in almost all of the OARs. Analysing the total doses of the target volumes we found dose distributions with similar homogeneities and comparable total doses. Our analysis shows that the SIB method offers advantages over the SEB method in terms of sparing OARs.

Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation

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

Yang, Feng; Waters, Katrina M.; Miller, John H.

2010-11-30

Background: High doses of ionizing radiation result in biological damage, however the precise relationships between long term health effects, including cancer, and low dose exposures remain poorly understood and are currently extrapolated using high dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose dependent responses to radiation. Principle Findings: We have identified 6845 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts one hour post-exposure. Dual statistical analyses based on spectral counts and peakmore » intensities identified 287 phosphopeptides (from 231 proteins) and 244 phosphopeptides (from 182 proteins) that varied significantly following exposure to 2 and 50 cGy respectively. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatics analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role of MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conlcusions: Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provides a basis for the systems level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low dose radiation exposure on human health.« less

Tunicamycin impairs olfactory learning and synaptic plasticity in the olfactory bulb.

PubMed

Tong, Jia; Okutani, Fumino; Murata, Yoshihiro; Taniguchi, Mutsuo; Namba, Toshiharu; Wang, Yu-Jie; Kaba, Hideto

2017-03-06

Tunicamycin (TM) induces endoplasmic reticulum (ER) stress and inhibits N-glycosylation in cells. ER stress is associated with neuronal death in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, and most patients complain of the impairment of olfactory recognition. Here we examined the effects of TM on aversive olfactory learning and the underlying synaptic plasticity in the main olfactory bulb (MOB). Behavioral experiments demonstrated that the intrabulbar infusion of TM disabled aversive olfactory learning without affecting short-term memory. Histological analyses revealed that TM infusion upregulated C/EBP homologous protein (CHOP), a marker of ER stress, in the mitral and granule cell layers of MOB. Electrophysiological data indicated that TM inhibited tetanus-induced long-term potentiation (LTP) at the dendrodendritic excitatory synapse from mitral to granule cells. A low dose of TM (250nM) abolished the late phase of LTP, and a high dose (1μM) inhibited the early and late phases of LTP. Further, high-dose, but not low-dose, TM reduced the paired-pulse facilitation ratio, suggesting that the inhibitory effects of TM on LTP are partially mediated through the presynaptic machinery. Thus, our results support the hypothesis that TM-induced ER stress impairs olfactory learning by inhibiting synaptic plasticity via presynaptic and postsynaptic mechanisms in MOB. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus.

PubMed

Miles, Clifford D; Skorupa, Jill Y; Sandoz, John P; Rigley, Theodore H; Nielsen, Kathleen J; Stevens, R Brian

2011-01-01

Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 μg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications. © 2010 John Wiley & Sons A/S.

Safety and long-term humoral immune response in adults after vaccination with an H1N1 2009 pandemic influenza vaccine with or without AS03 adjuvant.

PubMed

Ferguson, Murdo; Risi, George; Davis, Matthew; Sheldon, Eric; Baron, Mira; Li, Ping; Madariaga, Miguel; Fries, Louis; Godeaux, Olivier; Vaughn, David

2012-03-01

In this study (NCT00985088) we evaluated different formulations of an H1N1 2009 pandemic influenza vaccine that deliver various viral hemagglutinin (HA) doses with or without AS03 (a tocopherol-based oil-in-water adjuvant system). A total of 1340 healthy subjects aged ≥18 years were randomized to receive 1 or 2 doses of an adjuvanted (3.75-μg HA/AS03(A) or 1.9-μg HA/AS03(B)) or nonadjuvanted vaccine formulation. Safety and immunogenicity (by hemagglutination-inhibition [HI] assay) after each dose and 6 months after dose 1 are reported here. A single dose of AS03(A)-adjuvanted 3.75-μg HA H1N1 2009 induced the strongest immune responses in subjects aged 18-64 years (seroprotection rate [SPR], 97.2%; seroconversion rate [SCR], 90.1%) as well as in subjects aged >64 years (SPR, 91.1%; SCR, 78.2%) 21 days after vaccination. Six months after dose 1, subjects who received 2 doses of either the adjuvanted formulation or 1 dose of the adjuvanted 3.75-μg HA formulation continued to meet all Center for Biologics Evaluation and Research and Committee for Medicinal Products for Human Use criteria. All formulations had clinically acceptable safety profiles. A single dose of the 3.75-μg HA AS03(A)-adjuvanted H1N1 2009 influenza vaccine was highly immunogenic in both age strata (18-64 and >64 years), inducing long-term persistence of the immune response until at least 6 months after dose 1.

Changes in Mipomersen Dosing Regimen Provide Similar Exposure With Improved Tolerability in Randomized Placebo‐Controlled Study of Healthy Volunteers

PubMed Central

Flaim, JoAnn D.; Grundy, John S.; Baker, Brenda F.; McGowan, Mary P.; Kastelein, John J. P.

2014-01-01

Background Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low‐density lipoprotein (LDL) cholesterol, non‐high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA‐approved subcutaneous dose of 200 mg once weekly. Methods and Results A short‐term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty‐four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable mipomersen post‐distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post‐dose elevation of C‐reactive protein (CRP) in the mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers. Conclusions This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to mipomersen treatment. These results support assessment of alternative dose regimens in longer‐term studies. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01061814. PMID:24627419

Changes in mipomersen dosing regimen provide similar exposure with improved tolerability in randomized placebo-controlled study of healthy volunteers.

PubMed

Flaim, Joann D; Grundy, John S; Baker, Brenda F; McGowan, Mary P; Kastelein, John J P

2014-03-13

Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low-density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA-approved subcutaneous dose of 200 mg once weekly. A short-term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty-four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable mipomersen post-distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post-dose elevation of C-reactive protein (CRP) in the mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers. This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to mipomersen treatment. These results support assessment of alternative dose regimens in longer-term studies. http://www.clinicaltrials.gov. Unique identifier: NCT01061814.

High rate of long-term survival for high-risk lymphoma patients treated with hematopoietic stem cell transplantation as consolidation or salvage therapy.

PubMed

Espigado, I; Ríos, E; Marín-Niebla, A; Carmona, M; Parody, R; Pérez-Hurtado, J M; Márquez, F J; Urbano-Ispizua, A

2008-11-01

Patients with high-relapse-risk lymphomas or those relapsing after initial therapy have a limited probability of cure with conventional treatment. There is recent inconclusive evidence that, in such cases, intensification or salvage treatment with high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT) increases the response rate and may improve survival. Nevertheless, published data on long-term follow-up of high-risk lymphoma patients treated with HSCT are scarce. We analyzed 101 consecutive patients receiving high-dose chemotherapy followed by HSCT after induction with standard chemotherapy. The median age was 38 years (range, 12-63 years). The diagnoses were Hodgkin's disease (n = 32), follicular lymphoma (n = 33), diffuse large B-cell lymphoma (n = 12), mantle cell lymphoma (n = 7), T-cell lymphoma (n = 14), and others (n = 3). Patients received either an autologous graft (n = 72) in first complete remission (1CR; n = 23) or in advanced stages (AS; n = 49), or an allogeneic graft (n = 29) in 1CR (n = 7) or in AS (n = 22). We concluded that transplant-related mortality was 2.7% for patients receiving an autologous HSCT and 27% for patients receiving an allogeneic HSCT. The main etiologies were graft-versus-host disease and infection in the allogeneic setting, and infection in the autologous setting. The probability of long-term (12-year) overall survival was 71%, higher than that described for high-relapse-risk lymphoma patients treated without HSCT and significantly better (P < .05) for patients who received the transplant in 1CR (89%) than in AS (65%). Finally, the probability of long-term survival was significantly better for patients treated with HSCT during the period from 2000-2007 (85%) compared with the period from 1989-1999 (72%).

Efficacy of long-term 4.0 g/day mesalazine (Pentasa) for maintenance therapy in ulcerative colitis.

PubMed

Takeshima, Fuminao; Matsumura, Masato; Makiyama, Kazuya; Ohba, Kazuo; Yamakawa, Masaki; Nishiyama, Hitoshi; Yamao, Takuji; Akazawa, Yuko; Yamaguchi, Naoyuki; Ohnita, Ken; Ichikawa, Tatsuki; Isomoto, Hajime; Nakao, Kazuhiko

2014-07-27

High-dose (4.0 g/day) mesalazine is typically used for induction therapy, but its efficacy as maintenance therapy remains to be determined. We conducted a multicenter retrospective study to investigate the efficacy of continuous treatment with 4.0 g/day of mesalazine. Japanese ulcerative colitis (UC) patients receiving acute induction therapy with 4.0 g/day mesalazine were enrolled and followed. Those who clinically improved or who achieved clinical remission were categorized into 2 sub-groups according to the median duration of treatment with 4.0 g/day of mesalazine. The clinical relapse frequency and the time to relapse were analyzed. We enrolled 180 patients with active UC, and then 115 patients who clinically improved or who achieved clinical remission after treatment with 4.0 g/day mesalazine were categorized into 2 sub-groups according to the median of treatment duration: a short-term treatment group (≤105 days, n=58) and a long-term treatment group (>105 days, n=57). Overall, 45 (39.1%) patients relapsed: 28 (48.3%) in the short-term treatment group and 17 (29.8%) in the long-term treatment group. This difference was statistically significant (p<0.05). The relapse-free rate in the long-term treatment group was significantly higher than that in the short-term treatment group (p<0.05). The mean time to relapse in the long-term treatment group was significantly longer than that in the short-term treatment group (425.6±243.8 days vs. 277.4±224.5 days; p<0.05). Long-term continuous treatment with high-dose mesalazine (4.0 g/day) may be more effective than short-term treatment for maintenance of remission in UC patients.

Low Dose PET Image Reconstruction with Total Variation Using Alternating Direction Method.

PubMed

Yu, Xingjian; Wang, Chenye; Hu, Hongjie; Liu, Huafeng

2016-01-01

In this paper, a total variation (TV) minimization strategy is proposed to overcome the problem of sparse spatial resolution and large amounts of noise in low dose positron emission tomography (PET) imaging reconstruction. Two types of objective function were established based on two statistical models of measured PET data, least-square (LS) TV for the Gaussian distribution and Poisson-TV for the Poisson distribution. To efficiently obtain high quality reconstructed images, the alternating direction method (ADM) is used to solve these objective functions. As compared with the iterative shrinkage/thresholding (IST) based algorithms, the proposed ADM can make full use of the TV constraint and its convergence rate is faster. The performance of the proposed approach is validated through comparisons with the expectation-maximization (EM) method using synthetic and experimental biological data. In the comparisons, the results of both LS-TV and Poisson-TV are taken into consideration to find which models are more suitable for PET imaging, in particular low-dose PET. To evaluate the results quantitatively, we computed bias, variance, and the contrast recovery coefficient (CRC) and drew profiles of the reconstructed images produced by the different methods. The results show that both Poisson-TV and LS-TV can provide a high visual quality at a low dose level. The bias and variance of the proposed LS-TV and Poisson-TV methods are 20% to 74% less at all counting levels than those of the EM method. Poisson-TV gives the best performance in terms of high-accuracy reconstruction with the lowest bias and variance as compared to the ground truth (14.3% less bias and 21.9% less variance). In contrast, LS-TV gives the best performance in terms of the high contrast of the reconstruction with the highest CRC.

Low Dose PET Image Reconstruction with Total Variation Using Alternating Direction Method

PubMed Central

Yu, Xingjian; Wang, Chenye; Hu, Hongjie; Liu, Huafeng

2016-01-01

In this paper, a total variation (TV) minimization strategy is proposed to overcome the problem of sparse spatial resolution and large amounts of noise in low dose positron emission tomography (PET) imaging reconstruction. Two types of objective function were established based on two statistical models of measured PET data, least-square (LS) TV for the Gaussian distribution and Poisson-TV for the Poisson distribution. To efficiently obtain high quality reconstructed images, the alternating direction method (ADM) is used to solve these objective functions. As compared with the iterative shrinkage/thresholding (IST) based algorithms, the proposed ADM can make full use of the TV constraint and its convergence rate is faster. The performance of the proposed approach is validated through comparisons with the expectation-maximization (EM) method using synthetic and experimental biological data. In the comparisons, the results of both LS-TV and Poisson-TV are taken into consideration to find which models are more suitable for PET imaging, in particular low-dose PET. To evaluate the results quantitatively, we computed bias, variance, and the contrast recovery coefficient (CRC) and drew profiles of the reconstructed images produced by the different methods. The results show that both Poisson-TV and LS-TV can provide a high visual quality at a low dose level. The bias and variance of the proposed LS-TV and Poisson-TV methods are 20% to 74% less at all counting levels than those of the EM method. Poisson-TV gives the best performance in terms of high-accuracy reconstruction with the lowest bias and variance as compared to the ground truth (14.3% less bias and 21.9% less variance). In contrast, LS-TV gives the best performance in terms of the high contrast of the reconstruction with the highest CRC. PMID:28005929

Numerical simulation of the radiation environment on Martian surface

NASA Astrophysics Data System (ADS)

Zhao, L.

2015-12-01

The radiation environment on the Martian surface is significantly different from that on earth. Existing observation and studies reveal that the radiation environment on the Martian surface is highly variable regarding to both short- and long-term time scales. For example, its dose rate presents diurnal and seasonal variations associated with atmospheric pressure changes. Moreover, dose rate is also strongly influenced by the modulation from GCR flux. Numerical simulation and theoretical explanations are required to understand the mechanisms behind these features, and to predict the time variation of radiation environment on the Martian surface if aircraft is supposed to land on it in near future. The high energy galactic cosmic rays (GCRs) which are ubiquitous throughout the solar system are highly penetrating and extremely difficult to shield against beyond the Earth's protective atmosphere and magnetosphere. The goal of this article is to evaluate the long term radiation risk on the Martian surface. Therefore, we need to develop a realistic time-dependent GCR model, which will be integrated with Geant4 transport code subsequently to reproduce the observed variation of surface dose rate associated with the changing heliospheric conditions. In general, the propagation of cosmic rays in the interplanetary medium can be described by a Fokker-Planck equation (or Parker equation). In last decade,we witnessed a fast development of GCR transport models within the heliosphere based on accurate gas-dynamic and MHD backgrounds from global models of the heliosphere. The global MHD simulation produces a more realistic pattern of the 3-D heliospheric structure, as well as the interface between the solar system and the surrounding interstellar space. As a consequence, integrating plasma background obtained from global-dependent 3-D MHD simulation and stochastic Parker transport simulation, we expect to produce an accurate global physical-based GCR modulation model. Combined with the Geant4 transport code, this GCR model will provide valuable insight into the long-term dose rates variation on the Martian surface.

External-Beam Radiation Therapy and High-Dose Rate Brachytherapy Combined With Long-Term Androgen Deprivation Therapy in High and Very High Prostate Cancer: Preliminary Data on Clinical Outcome

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

Martinez-Monge, Rafael, E-mail: rmartinezm@unav.es; Moreno, Marta; Ciervide, Raquel

2012-03-01

Purpose: To determine the feasibility of combined long-term androgen deprivation therapy (ADT) and dose escalation with high-dose-rate (HDR) brachytherapy. Methods and Materials: Between 2001 and 2007, 200 patients with high-risk prostate cancer (32.5%) or very high-risk prostate cancer (67.5%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen of 15.2 ng/mL, a clinical stage of T2c, and a Gleason score of 7. Treatment consisted of 54 Gy of external irradiation (three-dimensional conformal radiotherapy [3DCRT]) followed by 19 Gy of HDR brachytherapy in four twice-daily treatments. ADT started 0-3 months before 3DCRT and continuedmore » for 2 years. Results: One hundred and ninety patients (95%) received 2 years of ADT. After a median follow-up of 3.7 years (range, 2-9), late Grade {>=}2 urinary toxicity was observed in 18% of the patients and Grade {>=}3 was observed in 5%. Prior transurethral resection of the prostate (p = 0.013) and bladder D{sub 50} {>=}1.19 Gy (p = 0.014) were associated with increased Grade {>=}2 urinary complications; age {>=}70 (p = 0.05) was associated with Grade {>=}3 urinary complications. Late Grade {>=}2 gastrointestinal toxicity was observed in 9% of the patients and Grade {>=}3 in 1.5%. CTV size {>=}35.8 cc (p = 0.007) and D{sub 100} {>=}3.05 Gy (p = 0.01) were significant for increased Grade {>=}2 complications. The 5-year and 9-year biochemical relapse-free survival (nadir + 2) rates were 85.1% and 75.7%, respectively. Patients with Gleason score of 7-10 had a decreased biochemical relapse-free survival (p = 0.007). Conclusions: Intermediate-term results at the 5-year time point indicate a favorable outcome without an increase in the rate of late complications.« less

Hormesis on life-history traits: is there such thing as a free lunch?

PubMed

Jager, Tjalling; Barsi, Alpar; Ducrot, Virginie

2013-03-01

The term "hormesis" is used to describe dose-response relationships where the response is reversed between low and high doses of a stressor (generally, stimulation at low doses and inhibition at high ones). A mechanistic explanation is needed to interpret the relevance of such responses, but there does not appear to be a single universal mechanism underlying hormesis. When the endpoint is a life-history trait such as growth or reproduction, a stimulation of the response comes with costs in terms of resources. Organisms have to obey the conservation laws for mass and energy; there is no such thing as a free lunch. Based on the principles of Dynamic Energy Budget theory, we introduce three categories of explanations for hormesis that obey the conservation laws: acquisition (i.e., increasing the input of energy into the individual), allocation (i.e., rearranging the energy flows over various traits) and medication (e.g., the stressor is an essential element or acts as a cure for a disease or infection). In this discussion paper, we illustrate these explanations with cases where they might apply, and elaborate on the potential consequences for field populations.

Efficacy of Single-Dose and Triple-Dose Albendazole and Mebendazole against Soil-Transmitted Helminths and Taenia spp.: A Randomized Controlled Trial

PubMed Central

Steinmann, Peter; Utzinger, Jürg; Du, Zun-Wei; Jiang, Jin-Yong; Chen, Jia-Xu; Hattendorf, Jan; Zhou, Hui; Zhou, Xiao-Nong

2011-01-01

Background The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China. Methodology/Principal findings The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3–4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed. Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55–81%) and 29% (95% CI: 20–45%); triple dose: respective CRs 92% (95% CI: 81–98%) and 54% (95% CI: 46–71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole – the most efficacious treatment tested – cured 71% (95% CI: 57–82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93–97%; ERR: all >99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them. Conclusions/Significance Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are warranted. Trial Registration www.controlled-trials.com ISRCTN47375023 PMID:21980373

Low dose radiation hypersensitivity and clustered DNA damages in human fibroblasts exposed to low dose and dose rate protons or 137CS y-rays

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

Bennett P. V.; Bennett, P.V.; Keszenman, D.J.

Effective radioprotection for human space travelers hinges upon understanding the individual properties of charged particles. A significant fraction of particle radiation astronauts will encounter in space exploratory missions will come from high energy protons in galactic cosmic radiation (GCR) and/or possible exposures to lower energy proton flux from solar particle events (SPEs). These potential exposures present major concerns for NASA and others, in planning and executing long term space exploratory missions. We recently reported cell survival and transformation (acquisition of anchorage-independent growth in soft agar) frequencies in apparently normal NFF-28 primary human fibroblasts exposed to 0-30 cGy of 50MeV, 100MeVmore » (SPE-like), or 1000 MeV (GCR-like) monoenergetic protons. These were modeled after 1989 SPE energies at an SPE-like low dose-rate (LDR) of 1.65 cGy/min or high dose rate (HDR) of 33.3 cGy/min delivered at the NASA Space Radiation Laboratory (NSRL) at BNL.« less

Is choline PET useful for identifying intraprostatic tumour lesions? A literature review.

PubMed

Chan, Joachim; Syndikus, Isabel; Mahmood, Shelan; Bell, Lynn; Vinjamuri, Sobhan

2015-09-01

More than 80% of patients with intermediate-risk or high-risk localized prostate cancer are cured with radiation doses of 74-78 Gy, but high doses increase the risk for late bowel and bladder toxicity among long-term survivors. Dose painting, defined as dose escalation to areas in the prostate containing the tumour, rather than to the whole gland, minimizes dose to normal tissues and hence toxicity. It requires accurate identification of the location and size of these lesions, for which functional MRI is the current gold standard. Many studies have assessed the use of choline PET in staging newly diagnosed patients. This review will discuss important imaging variables affecting the accuracy of choline PET scans, how choline PET contributes to tumour identification and is used in radiotherapy planning and how PET can improve the patient pathway involving prostate radiotherapy. In summary, the available literature shows that the accuracy of choline PET improves with higher tracer doses and delayed imaging (although the optimal uptake time is unclear), and tumour identification by MRI is improved by the addition of PET imaging. We propose future research with prolonged choline uptake time and multiphase imaging, which may further improve accuracy.

Enhancement of radiation cytotoxicity by gold nanoparticles in MCF-7 breast cancer cell lines

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

Rosli, Nur Shafawati binti; Rahman, Azhar Abdul; Aziz, Azlan Abdul

2015-04-24

Therapy combined with metallic nanoparticles is a new way to treat cancer, in which gold nanoparticles (AuNPs) are injected through intravenous administration and bound to tumor sites. Radiotherapy aims to deliver a high therapeutic dose of ionizing radiation to the tumor without exceeding normal tissue tolerance. The use of AuNPs which is a high-atomic-number (Z) material in radiotherapy will provide a high probability for photon interaction by photoelectric effect. These provide advantages in terms of radiation dose enhancement. The high linear energy transfer and short range of photoelectric interaction products (photoelectrons, characteristic x-rays, Auger electrons) produce localized dose enhancement ofmore » the tumor. In this work, breast cancer cell lines (MCF-7) are seeded in the 96-well plate and were treated with 13 nm AuNPs before they were irradiated with 6 MV and 10 MV photon beam from a medical linear accelerator at various radiation doses. To validate the enhanced killing effect, both with and without AuNPs MCF-7 cells is irradiated simultaneously. By comparison, the results show that AuNPs significantly enhance cancer killing.« less

Patterns of beta-blocker intensification in ambulatory heart failure patients and short-term association with hospitalization

PubMed Central

2012-01-01

Background In response to the short-term negative inotropic and chronotropic effects of β-blockers, heart failure (HF) guidelines recommend initiating β-blockers at low dose with gradual uptitration as tolerated to doses used in clinical trials. However, patterns and safety of β-blocker intensification in routine practice are poorly described. Methods We described β-blocker intensification among Kaiser Colorado enrollees with a primary discharge diagnosis of HF between 2001–2009. We then assessed β-blocker intensification in the 30 days prior to first hospital readmission for cases compared to the same time period following index hospitalization for non-rehospitalized matched controls. In separate analysis of the subgroup initiated on β-blocker after index hospital discharge, we compared adjusted rates of 30-day hospitalization following initiation of high versus low dose β-blocker. Results Among 3,227 patients, median age was 76 years and 37% had ejection fraction ≤40% (LVSD). During a median follow up of 669 days, 14% were never on β-blocker, 21% were initiated on β-blocker, 43% were discharged on β-blocker but never uptitrated, and 22% had discharge β-blocker uptitrated; 63% were readmitted and 49% died. β-blocker intensification occurred in the 30 days preceding readmission for 39 of 1,674 (2.3%) readmitted cases compared to 27 (1.6%) of matched controls (adjusted OR 1.36, 95% CI 0.81-2.27). Among patients initiated on therapy, readmission over the subsequent 30 days occurred in 6 of 155 (3.9%) prescribed high dose and 9 of 513 (1.8%) prescribed low dose β-blocker (adjusted OR 3.10, 95% CI 1.02-9.40). For the subgroup with LVSD, findings were not significantly different. Conclusion While β-blockers were intensified in nearly half of patients following hospital discharge and high starting dose was associated with increased readmission risk, the prevailing finding was that readmission events were rarely preceded by β-blocker intensification. These data suggest that β-blocker intensification is not a major precipitant of hospitalization, provided recommended dosing is followed. PMID:22709128

High-dose anti-histamine use and risk factors in children with urticaria.

PubMed

Uysal, Pınar; Avcil, Sibelnur; Erge, Duygu

2016-12-01

The drugs of choice in the treatment of urticaria in children are H1-antihistamines. The aim of the study was to evaluate children with urticaria and define risk factors for requirement of high-dose H1-antihistamines in children with urticaria. The medical data of children who were diagnosed as having urticaria admitted to our outpatient clinic between January 2014 and January 2016 were searched. The medical histories, concomitant atopic diseases, parental atopy histories, medications, treatment responses, blood eosinophil and basophil counts, and serum total IgE levels were recorded. In addition, the urticaria activity score for seven days, autoimmune antibody tests, and skin prick test results were evaluated in children with chronic urticaria. The numbers of the children with acute and chronic urticaria were 138 and 92, respectively. The age of the children with chronic urticaria was higher than that of those with acute urticaria (p<0.0001). There was no difference between the two groups in terms of blood eosinophil and basophil counts, and serum total IgE levels (p>0.05). There was a negative correlation between blood eosinophil count and the UAS7 score in children with chronic urticaria (r=-0.276, p=0.011). Chronic urticaria and requirement of high dose H1-antihistamines were significant in children aged ≥10 years (p<0.001, p=0.015). High UAS7 score (OR: 1.09; CI 95%: [1.03-1.15]) and basopenia (OR: 6.77; CI 95%: [2.01-22.75]) were associated with the requirement of high-dose H1-AH in children with chronic urticaria. The requirement of high-dose H1-antihistamines was higher with children's increasing age. Disease severity and basopenia were risk factors for the requirement of high-dose H1-antihistamines.

New era of electronic brachytherapy

PubMed Central

Ramachandran, Prabhakar

2017-01-01

Traditional brachytherapy refers to the placement of radioactive sources on or inside the cancer tissues. Based on the type of sources, brachytherapy can be classified as radionuclide and electronic brachytherapy. Electronic brachytherapy uses miniaturized X-ray sources instead of radionuclides to deliver high doses of radiation. The advantages of electronic brachytherapy include low dose to organs at risk, reduced dose to treating staff, no leakage radiation in off state, less shielding, and no radioactive waste. Most of these systems operate between 50 and 100 kVp and are widely used in the treatment of skin cancer. Intrabeam, Xoft and Papillon systems are also used in the treatment of intra-operative radiotherapy to breast in addition to other treatment sites. The rapid fall-off in the dose due to its low energy is a highly desirable property in brachytherapy and results in a reduced dose to the surrounding normal tissues compared to the Ir-192 source. The Xoft Axxent brachytherapy system uses a 2.25 mm miniaturized X-ray tube and the source almost mimics the high dose rate Ir-192 source in terms of dose rate and it is the only electronic brachytherapy system specifically used in the treatment of cervical cancers. One of the limiting factors that impede the use of electronic brachytherapy for interstitial application is the source dimension. However, it is highly anticipated that the design of miniaturized X-ray tube closer to the dimension of an Ir-192 wire is not too far away, and the new era of electronic brachytherapy has just begun. PMID:28529679

Low or High Fractionation Dose {beta}-Radiotherapy for Pterygium? A Randomized Clinical Trial

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

Viani, Gustavo Arruda, E-mail: gusviani@gmail.com; De Fendi, Ligia Issa; Fonseca, Ellen Carrara

2012-02-01

Purpose: Postoperative adjuvant treatment using {beta}-radiotherapy (RT) is a proven technique for reducing the recurrence of pterygium. A randomized trial was conducted to determine whether a low fractionation dose of 2 Gy within 10 fractions would provide local control similar to that after a high fractionation dose of 5 Gy within 7 fractions for surgically resected pterygium. Methods: A randomized trial was conducted in 200 patients (216 pterygia) between February 2006 and July 2007. Only patients with fresh pterygium resected using a bare sclera method and given RT within 3 days were included. Postoperative RT was delivered using a strontium-90more » eye applicator. The pterygia were randomly treated using either 5 Gy within 7 fractions (Group 1) or 2 Gy within 10 fractions (Group 2). The local control rate was calculated from the date of surgery. Results: Of the 216 pterygia included, 112 were allocated to Group 1 and 104 to Group 2. The 3-year local control rate for Groups 1 and 2 was 93.8% and 92.3%, respectively (p = .616). A statistically significant difference for cosmetic effect (p = .034), photophobia (p = .02), irritation (p = .001), and scleromalacia (p = .017) was noted in favor of Group 2. Conclusions: No better local control rate for postoperative pterygium was obtained using high-dose fractionation vs. low-dose fractionation. However, a low-dose fractionation schedule produced better cosmetic effects and resulted in fewer symptoms than high-dose fractionation. Moreover, pterygia can be safely treated in terms of local recurrence using RT schedules with a biologic effective dose of 24-52.5 Gy{sub 10.}.« less

Joint minimization of uplink and downlink whole-body exposure dose in indoor wireless networks.

PubMed

Plets, D; Joseph, W; Vanhecke, K; Vermeeren, G; Wiart, J; Aerts, S; Varsier, N; Martens, L

2015-01-01

The total whole-body exposure dose in indoor wireless networks is minimized. For the first time, indoor wireless networks are designed and simulated for a minimal exposure dose, where both uplink and downlink are considered. The impact of the minimization is numerically assessed for four scenarios: two WiFi configurations with different throughputs, a Universal Mobile Telecommunications System (UMTS) configuration for phone call traffic, and a Long-Term Evolution (LTE) configuration with a high data rate. Also, the influence of the uplink usage on the total absorbed dose is characterized. Downlink dose reductions of at least 75% are observed when adding more base stations with a lower transmit power. Total dose reductions decrease with increasing uplink usage for WiFi due to the lack of uplink power control but are maintained for LTE and UMTS. Uplink doses become dominant over downlink doses for usages of only a few seconds for WiFi. For UMTS and LTE, an almost continuous uplink usage is required to have a significant effect on the total dose, thanks to the power control mechanism.

Joint Minimization of Uplink and Downlink Whole-Body Exposure Dose in Indoor Wireless Networks

PubMed Central

Plets, D.; Joseph, W.; Vanhecke, K.; Vermeeren, G.; Wiart, J.; Aerts, S.; Varsier, N.; Martens, L.

2015-01-01

The total whole-body exposure dose in indoor wireless networks is minimized. For the first time, indoor wireless networks are designed and simulated for a minimal exposure dose, where both uplink and downlink are considered. The impact of the minimization is numerically assessed for four scenarios: two WiFi configurations with different throughputs, a Universal Mobile Telecommunications System (UMTS) configuration for phone call traffic, and a Long-Term Evolution (LTE) configuration with a high data rate. Also, the influence of the uplink usage on the total absorbed dose is characterized. Downlink dose reductions of at least 75% are observed when adding more base stations with a lower transmit power. Total dose reductions decrease with increasing uplink usage for WiFi due to the lack of uplink power control but are maintained for LTE and UMTS. Uplink doses become dominant over downlink doses for usages of only a few seconds for WiFi. For UMTS and LTE, an almost continuous uplink usage is required to have a significant effect on the total dose, thanks to the power control mechanism. PMID:25793213

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

PubMed Central

Novalic, Zlata; van der Wal, Annemieke M.; Leonhard, Wouter N.; Koehl, Gudrun; Breuning, Martijn H.; Geissler, Edward K.; de Heer, Emile

2012-01-01

Inhibition of the mammalian target of rapamycin (mTOR) shows beneficial effects in animal models of polycystic kidney disease (PKD); however, two clinical trials in patients with autosomal dominant PKD failed to demonstrate a short-term benefit in either the early or progressive stages of disease. The stage of disease during treatment and the dose of mTOR inhibitors may account for these differing results. Here, we studied the effects of a conventional low dose and a higher dose of sirolimus (blood levels of 3 ng/ml and 30–60 ng/ml, respectively) on mTOR activity and renal cystic disease in two Pkd1-mutant mouse models at different stages of the disease. When initiated at early but not late stages of disease, high-dose treatment strongly reduced mTOR signaling in renal tissues, inhibited cystogenesis, accelerated cyst regression, and abrogated fibrosis and the infiltration of immune cells. In contrast, low-dose treatment did not significantly reduce renal cystic disease. Levels of p-S6RpSer240/244, which marks mTOR activity, varied between kidneys; severity of the renal cystic phenotype correlated with the level of mTOR activity. Taken together, these data suggest that long-term treatment with conventional doses of sirolimus is insufficient to inhibit mTOR activity in renal cystic tissue. Mechanisms to increase bioavailability or to target mTOR inhibitors more specifically to kidneys, alone or in combination with other compounds, may improve the potential for these therapies in PKD. PMID:22343118

Animal model of methylphenidate's long-term memory-enhancing effects.

PubMed

Carmack, Stephanie A; Howell, Kristin K; Rasaei, Kleou; Reas, Emilie T; Anagnostaras, Stephan G

2014-01-16

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01-10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1-10 mg/kg, i.p.), bupropion (0.5-20 mg/kg, i.p.), and citalopram (0.01-10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development.

Animal model of methylphenidate's long-term memory-enhancing effects

PubMed Central

Carmack, Stephanie A.; Howell, Kristin K.; Rasaei, Kleou; Reas, Emilie T.; Anagnostaras, Stephan G.

2014-01-01

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01–10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1–10 mg/kg, i.p.), bupropion (0.5–20 mg/kg, i.p.), and citalopram (0.01–10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development. PMID:24434869

Response of Intestinal Bacterial Flora to the Long-term Feeding of Aflatoxin B1 (AFB1) in Mice.

PubMed

Yang, Xiai; Liu, Liangliang; Chen, Jing; Xiao, Aiping

2017-10-12

In order to investigate the influence of aflatoxin B1 (AFB1) on intestinal bacterial flora, 24 Kunming mice (KM mice) were randomly placed into four groups, which were labeled as control, low-dose, medium-dose, and high-dose groups. They were fed intragastrically with 0.4 mL of 0 mg/L, 2.5 mg/L, 4 mg/L, or 10 mg/L of AFB1 solutions, twice a day for 2 months. The hypervariable region V3 + V4 on 16S rDNA of intestinal bacterial flora was sequenced by the use of a high-flux sequencing system on a Miseq Illumina platform; then, the obtained sequences were analyzed. The results showed that, when compared with the control group, both genera and phyla of intestinal bacteria in the three treatment groups decreased. About one third of the total genera and one half of the total phyla remained in the high-dose group. The dominant flora were Lactobacillus and Bacteroides in all groups. There were significant differences in the relative abundance of intestinal bacterial flora among groups. Most bacteria decreased as a whole from the control to the high-dose groups, but several beneficial and pathogenic bacterial species increased significantly with increasing dose of AFB1. Thus, the conclusion was that intragastric feeding with 2.5~10 mg/mL AFB1 for 2 months could decrease the majority of intestinal bacterial flora and induce the proliferation of some intestinal bacteria flora.

Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies.

PubMed

Studerus, Erich; Kometer, Michael; Hasler, Felix; Vollenweider, Franz X

2011-11-01

Psilocybin and related hallucinogenic compounds are increasingly used in human research. However, due to limited information about potential subjective side effects, the controlled medical use of these compounds has remained controversial. We therefore analysed acute, short- and long-term subjective effects of psilocybin in healthy humans by pooling raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008. The analysis included 110 healthy subjects who had received 1-4 oral doses of psilocybin (45-315 µg/kg body weight). Although psilocybin dose-dependently induced profound changes in mood, perception, thought and self-experience, most subjects described the experience as pleasurable, enriching and non-threatening. Acute adverse drug reactions, characterized by strong dysphoria and/or anxiety/panic, occurred only in the two highest dose conditions in a relatively small proportion of subjects. All acute adverse drug reactions were successfully managed by providing interpersonal support and did not need psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long-term impairment of functioning in any of our subjects. The results suggest that the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk.

It's All Relative: A Validation of Radiation Quality Comparison Metrics

NASA Technical Reports Server (NTRS)

Chappell, Lori J.; Milder, Caitlin M.; Elgart, S. Robin; Semones, Edward J.

2017-01-01

The difference between high-LET and low-LET radiation is quantified by a measure called relative biological effectiveness (RBE). RBE is defined as the ratio of the dose of a reference radiation to that of a test radiation to achieve the same effect level, and thus, is described either as an iso-effector dose-to-dose ratio. A single dose point is not sufficient to calculate an RBE value; therefore, studies with only one dose point usually calculate an effect-to-effect ratio. While not formally used in radiation protection, these iso-dose values may still be informative. Shuryak, et al 2017 investigated the use of an iso-dose metric termed "radiation effects ratio" (RER) and used both RBE and RER to estimate high-LET risks. To apply RBE or RER to risk prediction, the selected metric must be uniquely defined. That is, the calculated value must be consistent within a model given a constant set of constraints and assumptions, regardless of how effects are defined using statistical transformations from raw endpoint data. We first test the RBE and the RER to determine whether they are uniquely defined using transformations applied to raw data. Then, we test whether both metrics can predict heavy ion response data after simulated effect size scaling between human populations or when converting animal to human endpoints.

Waning immunity of one-dose measles-mumps-rubella vaccine to mumps in children from kindergarten to early school age: a prospective study.

PubMed

Liu, Yuanbao; Liu, Zhihao; Deng, Xiuying; Hu, Ying; Wang, Zhiguo; Lu, Peishan; Guo, Hongxiong; Sun, Xiang; Xu, Yan; Tang, Fenyang; Zhu, Feng-Cai

2018-05-01

In China, one dose measles-mumps-rubella vaccine (MMR) was administered to children aged 18-24 months. The mumps incidence was still high. Data on the waning immunity to mumps after MMR vaccination are limited. This study aimed to describe the waning immunity to mumps in kindergarten and primary school children to provide a scientific basis for confirming an optimal age for a second dose. An observational, prospective study on one-dose MMR in children in kindergarten and primary school was conducted from 2015 to 2016. Waning immunity to mumps in terms of seropositivity and geometric antibody concentration (GMC) with time was analyzed. In total, 7436 eligible subjects in kindergarten (3435) and primary school (4001) were included in 2015. The overall GMC (201.7 U/ml) and seropositivity (75.4%) to mumps antibodies in 2016 were significantly lower compared to those in 2015 (218.7 U/ml, 78.4%). Asymptomatic infection occurred within one year in 8.8% of children who received one-dose MMR. Children who received one-dose MMR in kindergarten and primary school were at high risk of mumps infection, and waning immunity occurred with time. Determining the optimal age for the second dose of MMR in children should be prioritized to prevent mumps epidemics.

A 14-day repeated-dose oral toxicological evaluation of an isothiocyanate-enriched hydro-alcoholic extract from Moringa oleifera Lam. seeds in rats.

PubMed

Kim, Youjin; Jaja-Chimedza, Asha; Merrill, Daniel; Mendes, Odete; Raskin, Ilya

2018-01-01

A 14-d short-term oral toxicity study in rats evaluated the safety of moringa isothiocyanate-1 (MIC-1)-enriched hydro-alcoholic moringa seeds extract (MSE). Rats (5 males/5 females per group) were gavaged daily for 14 d with the vehicle control or MSE, at 78 (low), 257 (mid-low), 772 (mid-high), or 2571 (high) mg/kg bw/d, standardized to MIC-1 (30, 100, 300, or 1000 mg/kg bw/d, respectively). Toxicological endpoints included body weight and weight gain, food consumption and feed efficiency, clinical observations, hematology, gross necropsy and histopathology, and relative organ weights. Mortality was only observed in the high dose group animals, both male and female, representing decreases in body weight/weight gain and food consumption/feed efficiency. Irregular respiratory patterns and piloerection were major clinical observations found primarily in the mid-high and high dose group animals. In the high dose group, gastrointestinal distention and stomach discoloration were observed in non-surviving males and females, and degeneration and necrosis of the testicular germinal cells and epididymal cells were also observed in a non-surviving male. Increased liver weights were found in females in the mid-high and high dose groups. Animals in the low and mid-low groups did not exhibit adverse effects of MSE (100 mg/kg bw/d MIC-1). A no observed adverse effect level (NOAEL) of the standardized MSE was determined as 257 mg/kg bw/d providing 100 mg/kg bw/d MIC-1.

Novel oral anticoagulants for atrial fibrillation.

PubMed

How, Choon How

2015-12-01

Anticoagulation therapy is effective in preventing primary and secondary thromboembolic events due to atrial fibrillation. Warfarin, which was approved by the United States in 1954, was the only long-term oral anticoagulation therapy till the approval of dabigatran in 2010, and of rivaroxaban and other direct factor Xa inhibitors from 2011, forming a group known as novel oral anticoagulants (NOAC). NOAC have fewer food and drug interactions compared to warfarin; hence, the patient will require fewer clinic visits. However, the short half-life of NOAC means that twice-a-day dosing is needed and there is higher risk of a prothrombotic state when doses are missed. Other disadvantages are the lack of long-term data on NOAC, their high cost and the current lack of locally available antidotes.

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.

SU-F-T-449: Dosimetric Comparison of Acuros XB, Adaptive Convolve in Intensity Modulated Radiotherapy for Head and Neck Cancer

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

Uehara, R; Tachibana, H

Purpose: There have been several publications focusing on dose calculation in lung for a new dose calculation algorithm of Acuros XB (AXB). AXB could contribute to dose calculation for high-density media for bone and dental prosthesis rather than in lung. We compared the dosimetric performance of AXB, Adaptive Convolve (AC) in head and neck IMRT plans. Methods: In a phantom study, the difference in depth profile between AXB and AC was evaluated using Kodak EDR2 film sandwiched with tough water phantoms. 6 MV x-ray using the TrueBeam was irradiated. In a patient study, 20 head and neck IMRT plans hadmore » been clinically approved in Pinnacle3 and were transferred to Eclipse. Dose distribution was recalculated using AXB in Eclipse while maintaining AC-calculated monitor units and MLC sequence planned in Pinnacle. Subsequently, both the dose-volumetric data obtained using the two different calculation algorithms were compared. Results: The results in the phantom evaluation for the shallow area ahead of the build-up region shows over-dose for AXB and under-dose for AC, respectively. In the patient plans, AXB shows more hot spots especially around the high-density media than AC in terms of PTV (Max difference: 4.0%) and OAR (Max. difference: 1.9%). Compared to AC, there were larger dose deviations in steep dose gradient region and higher skin-dose. Conclusion: In head and neck IMRT plans, AXB and AC show different dosimetric performance for the regions inside the target volume around high-density media, steep dose gradient regions and skin-surface. There are limitations in skin-dose and complex anatomic condition using even inhomogeneous anthropomorphic phantom Thus, there is the potential for an increase of hot-spot in AXB, and an underestimation of dose in substance boundaries and skin regions in AC.« less

Anti-radiation vaccine: Immunologically-based Prophylaxis of Acute Toxic Radiation Syndromes Associated with Long-term Space Flight

NASA Technical Reports Server (NTRS)

Popov, Dmitri; Maliev, Vecheslav; Jones, Jeffrey; Casey, Rachael C.

2007-01-01

Protecting crew from ionizing radiation is a key life sciences problem for long-duration space missions. The three major sources/types of radiation are found in space: galactic cosmic rays, trapped Van Allen belt radiation, and solar particle events. All present varying degrees of hazard to crews; however, exposure to high doses of any of these types of radiation ultimately induce both acute and long-term biological effects. High doses of space radiation can lead to the development of toxicity associated with the acute radiation syndrome (ARS) which could have significant mission impact, and even render the crew incapable of performing flight duties. The creation of efficient radiation protection technologies is considered an important target in space radiobiology, immunology, biochemistry and pharmacology. Two major mechanisms of cellular, organelle, and molecular destruction as a result of radiation exposure have been identified: 1) damage induced directly by incident radiation on the macromolecules they encounter and 2) radiolysis of water and generation of secondary free radicals and reactive oxygen species (ROS), which induce chemical bond breakage, molecular substitutions, and damage to biological molecules and membranes. Free-radical scavengers and antioxidants, which neutralize the damaging activities of ROS, are effective in reducing the impact of small to moderate doses of radiation. In the case of high doses of radiation, antioxidants alone may be inadequate as a radioprotective therapy. However, it remains a valuable component of a more holistic strategy of prophylaxis and therapy. High doses of radiation directly damage biological molecules and modify chemical bond, resulting in the main pathological processes that drive the development of acute radiation syndromes (ARS). Which of two types of radiation-induced cellular lethality that ultimately develops, apoptosis or necrosis, depends on the spectrum of incident radiation, dose, dose rate, and functional conditions of impacted cells/organisms. The administration of an experimental anti-radiation vaccine may provide an immunologically based, adjunct method of prevention or prophylaxis against clinical ARS. The administration of experimental anti-radiation serum (ARS) and the use of the blood dialysis methods, such as immune plasma-sorption, may assist in the clearance of radiation-specific toxins and may enhance established strategies for the mitigation of the biological effects leading to ARS, and should be evaluated for use on exploration-class space missions.

Comparative study of two negative CAR resists: EN-024M and NEB 31

NASA Astrophysics Data System (ADS)

Baik, Ki-Ho; Dean, Robert; Lem, Homer Y.; Osborne, Stephen P.; Mueller, Mark A.; Cole, Damon M.

2004-08-01

In this paper, two negative-tone chemically amplified resists (CAR) are evaluated. The methodology and results are compared and discussed. The resists include EN-024M from TOK, and NEB 31 from Sumitomo. Both resists show high contrast, good dry etch selectivity, and high environmental stability. EN-024M showed good coating uniformity while NEB31 showed a coating uniformity problem. This was a round "dimple" approximately one centimeter in diameter of different thickness and density at the center of the plate. We addressed the "dimple" coating problem as described in the paper. Optimum PAB and PEB temperatures and nominal to maximum doses for isolated features were determined by running a matrix of PAB and PEB temperatures along with a dose series. We evaluated the process and compared the lithographic performance in terms of dose sensitivity, dose and bake latitude, resolution, resist profile, OPC (Optical Proximity Correction) pattern fidelity, CD uniformity, environmental stability, Line Edge Roughness (LER) and etching bias and resistance.

Long-term survival in primary CNS lymphoma treated by high-dose methotrexate monochemotherapy: role of STAT6 activation as prognostic determinant.

PubMed

Yang, Seung-Ho; Lee, Kun Soo; Kim, Il Sup; Hong, Jae Taek; Sung, Jae Hoon; Son, Byung Chul; Lee, Sang Won; Hong, Yong-Kil

2009-03-01

We report a single-center experience of 16 immunocompetent patients diagnosed with primary central nervous system lymphoma and treated with monochemotherapy with high-dose methotrexate (MTX) and deferred radiotherapy. MTX was given at a dose of 8.0 g/m2 for induction and at a dose of 3.5-8.0 g/m2 for maintenance. There were eight complete responses (CR), one partial response, one stable disease, and six patients whose tumors progressed in spite of the chemotherapy. At final follow-up, five of five CRs were alive and well without radiotherapy, with median follow-up of 26 months. Overall survival in eight non-CRs treated with the subsequent radiotherapy was 36 months. In the immunohistochemical study, STAT6 was positively expressed in 8 out of 13 cases. They included all non-CRs and two CRs. This observation suggests that STAT6 expression can be used as a prognostic determinant for MTX chemotherapy.

DOSE: an R/Bioconductor package for disease ontology semantic and enrichment analysis.

PubMed

Yu, Guangchuang; Wang, Li-Gen; Yan, Guang-Rong; He, Qing-Yu

2015-02-15

Disease ontology (DO) annotates human genes in the context of disease. DO is important annotation in translating molecular findings from high-throughput data to clinical relevance. DOSE is an R package providing semantic similarity computations among DO terms and genes which allows biologists to explore the similarities of diseases and of gene functions in disease perspective. Enrichment analyses including hypergeometric model and gene set enrichment analysis are also implemented to support discovering disease associations of high-throughput biological data. This allows biologists to verify disease relevance in a biological experiment and identify unexpected disease associations. Comparison among gene clusters is also supported. DOSE is released under Artistic-2.0 License. The source code and documents are freely available through Bioconductor (http://www.bioconductor.org/packages/release/bioc/html/DOSE.html). Supplementary data are available at Bioinformatics online. gcyu@connect.hku.hk or tqyhe@jnu.edu.cn. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Novel oxytocin receptor variants in laboring women requiring high doses of oxytocin.

PubMed

Reinl, Erin L; Goodwin, Zane A; Raghuraman, Nandini; Lee, Grace Y; Jo, Erin Y; Gezahegn, Beakal M; Pillai, Meghan K; Cahill, Alison G; de Guzman Strong, Cristina; England, Sarah K

2017-08-01

Although oxytocin commonly is used to augment or induce labor, it is difficult to predict its effectiveness because oxytocin dose requirements vary significantly among women. One possibility is that women requiring high or low doses of oxytocin have variations in the oxytocin receptor gene. To identify oxytocin receptor gene variants in laboring women with low and high oxytocin dosage requirements. Term, nulliparous women requiring oxytocin doses of ≤4 mU/min (low-dose-requiring, n = 83) or ≥20 mU/min (high-dose-requiring, n = 104) for labor augmentation or induction provided consent to a postpartum blood draw as a source of genomic DNA. Targeted-amplicon sequencing (coverage >30×) with MiSeq (Illumina) was performed to discover variants in the coding exons of the oxytocin receptor gene. Baseline relevant clinical history, outcomes, demographics, and oxytocin receptor gene sequence variants and their allele frequencies were compared between low-dose-requiring and high-dose-requiring women. The Scale-Invariant Feature Transform algorithm was used to predict the effect of variants on oxytocin receptor function. The Fisher exact or χ 2 tests were used for categorical variables, and Student t tests or Wilcoxon rank sum tests were used for continuous variables. A P value < .05 was considered statistically significant. The high-dose-requiring women had greater rates of obesity and diabetes and were more likely to have undergone labor induction and required prostaglandins. High-dose-requiring women were more likely to undergo cesarean delivery for first-stage arrest and less likely to undergo cesarean delivery for nonreassuring fetal status. Targeted sequencing of the oxytocin receptor gene in the total cohort (n = 187) revealed 30 distinct coding variants: 17 nonsynonymous, 11 synonymous, and 2 small structural variants. One novel variant (A243T) was found in both the low- and high-dose-requiring groups. Three novel variants (Y106H, A240_A249del, and P197delfs*206) resulting in an amino acid substitution, loss of 9 amino acids, and a frameshift stop mutation, respectively, were identified only in low-dose-requiring women. Nine nonsynonymous variants were unique to the high-dose-requiring group. These included 3 known variants (R151C, G221S, and W228C) and 6 novel variants (M133V, R150L, H173R, A248V, G253R, and I266V). Of these, R150L, R151C, and H173R were predicted by Scale-Invariant Feature Transform algorithm to damage oxytocin receptor function. There was no statistically significant association between the numbers of synonymous and nonsynonymous substitutions in the patient groups. Obesity, diabetes, and labor induction were associated with the requirement for high doses of oxytocin. We did not identify significant differences in the prevalence of oxytocin receptor variants between low-dose-requiring and high-dose-requiring women, but novel oxytocin receptor variants were enriched in the high-dose-requiring women. We also found 3 oxytocin receptor variants (2 novel, 1 known) that were predicted to damage oxytocin receptor function and would likely increase an individual's risk for requiring a high oxytocin dose. Further investigation of oxytocin receptor variants and their effects on protein function will inform precision medicine in pregnant women. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Long-term Results of Carbon Ion Radiation Therapy for Locally Advanced or Unfavorably Located Choroidal Melanoma: Usefulness of CT-based 2-Port Orthogonal Therapy for Reducing the Incidence of Neovascular Glaucoma

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

Toyama, Shingo; Department of Heavy Particle Therapy and Radiation Oncology, Faculty of Medicine, Saga University, Saga; Tsuji, Hiroshi, E-mail: h_tsuji@nirs.go.jp

2013-06-01

Purpose: To determine the long-term results of carbon ion radiation therapy (C-ion RT) in patients with choroidal melanoma, and to assess the usefulness of CT-based 2-port irradiation in reducing the risk of neovascular glaucoma (NVG). Methods and Materials: Between January 2001 and February 2012, a total of 116 patients with locally advanced or unfavorably located choroidal melanoma received CT-based C-ion RT. Of these patients, 114 were followed up for more than 6 months and their data analyzed. The numbers of T3 and T2 patients (International Union Against Cancer [UICC], 5th edition) were 106 and 8, respectively. The total dose ofmore » C-ion RT varied from 60 to 85 GyE, with each dose given in 5 fractions. Since October 2005, 2-port therapy (51 patients) has been used in an attempt to reduce the risk of NVG. A dose-volume histogram analysis was also performed in 106 patients. Results: The median follow-up was 4.6 years (range, 0.5-10.6 years). The 5-year overall survival, cause-specific survival, local control, distant metastasis-free survival, and eye retention rates were 80.4% (95% confidence interval 89.0%-71.8%), 82.2% (90.6%-73.8%), 92.8% (98.5%-87.1%), 72.1% (81.9%-62.3%), and 92.8% (98.1%-87.5%), respectively. The overall 5-year NVG incidence rate was 35.9% (25.9%-45.9%) and that of 1-port group and 2-port group were 41.6% (29.3%-54.0%) and 13.9% (3.2%-24.6%) with statistically significant difference (P<.001). The dose-volume histogram analysis showed that the average irradiated volume of the iris-ciliary body was significantly lower in the non-NVG group than in the NVG group at all dose levels, and significantly lower in the 2-port group than in the 1-port group at high dose levels. Conclusions: The long-term results of C-ion RT for choroidal melanoma are satisfactory. CT-based 2-port C-ion RT can be used to reduce the high-dose irradiated volume of the iris-ciliary body and the resulting risk of NVG.« less

Metabolites and JAK/STAT pathway were involved in the liver and spleen damage in male Wistar rats fed with mequindox.

PubMed

Wang, Xu; Huang, Xian-Ju; Ihsan, Awais; Liu, Zhao-Ying; Huang, Ling-Li; Zhang, Hua-Hai; Zhang, Hong-Fei; Zhou, Wen; Liu, Qin; Xue, Xi-Juan; Yuan, Zong-Hui

2011-02-27

Mequindox (MEQ) is a novel synthetic quinoxaline 1,4-dioxides antibacterial agent and growth promoter in animal husbandry. This study was to investigate whether reactive oxygen species (ROS), the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, suppressors of cytokine signaling (SOCS) and inflammatory cytokines were involved in toxicities of MEQ. Our data demonstrated that high dose of MEQ (275 mg/kg) apparently led to tissue impairment combined with imbalance of redox in liver. In liver and spleen samples, hydroxylation metabolites and desoxymequindox were detected, directly confirming the potential link of N→O group reduction metabolism with its organ toxicity. Moreover, up-regulation of JAK/STAT, SOCS family, tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) were also observed in the high-dose group. Meanwhile, significant changes of oxidative stress indices in liver were observed in the high-dose group. As for NADPH subunit, the mRNA levels of many subunits were significantly up-regulated at low doses but down-regulated in a dose-dependent manner in liver and spleen, suggesting an involvement of NADPH in MEQ metabolism and ROS generation. In conclusion, we reported the dose-dependent long-term toxicity as well as the discussion of the potential mechanism and pathways of MEQ, which raised further awareness of its toxicity following with the dose change. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Wasabi nose: an underreported complication of cyclophosphamide infusions.

PubMed

Janow, Ginger L; Ilowite, Norman T; Wahezi, Dawn M

2011-07-01

Wasabi nose, a term used to describe the nasopharyngeal discomfort experienced during cyclophosphamide infusions, is a rare phenomenon, previously described in case reports of adult oncology patients typically receiving high-dose chemotherapy regimens. The underlying mechanism by which this phenomenon occurs is unknown. We report four cases of children with rheumatic diseases afflicted by profound nasopharyngeal discomfort secondary to low-dose cyclophosphamide infusions. We additionally review the literature regarding potential medical management of these complications and describe our experience using these interventions.

Inhaled corticosteroids in ventilated preterm neonates: a non-randomized dose-ranging study.

PubMed

Raghuram, Kamini; Dunn, Michael; Jangaard, Krista; Reilly, Maureen; Asztalos, Elizabeth; Kelly, Edmond; Vincer, Michael; Shah, Vibhuti

2018-05-07

Inhaled corticosteroids (ICS) offer targeted treatment for bronchopulmonary dysplasia (BPD) with minimal systemic effects compared to systemic steroids. However, dosing of ICS in the management of infants at high-risk of developing BPD is not well established. The objective of this study was to determine an effective dose of ICS for the treatment of ventilator-dependent infants to facilitate extubation or reduce fractional inspired oxygen concentration. Forty-one infants born at < 32 weeks gestational age (GA) or < 1250 g who were ventilator-dependent at 10-28 days postnatal age were included. A non-randomized dose-ranging trial was performed using aerosolized inhaled beclomethasone with hydrofluoralkane propellant (HFA-BDP). Four dosing groups (200, 400, 600 and 800 μg twice daily for 1 week) with 11, 11, 10 and 9 infants in each group, respectively, were studied. The primary outcome was therapeutic efficacy (successful extubation or reduction in FiO 2 of > 75% from baseline) in ≥60% of infants in the group. Oxygen requirements, complications and long-term neurodevelopmental outcomes were also assessed. The median age at enrollment was 22 (10-28) postnatal days. The primary outcome, therapeutic efficacy as defined above, was not achieved in any group. However, there was a significant reduction in post-treatment FiO 2 at a dose of 800 μg bid. No obvious trends were seen in long-term neurodevelopmental outcomes. Therapeutic efficacy was not achieved with all studied doses of ICS. A significant reduction in oxygen requirements was noted in ventilator-dependent preterm infants at 10-28 days of age when given 800 μg of HFA-BDP bid. Larger randomized trials of ICS are required to determine efficacy for the management of infants at high-risk for development of BPD. This clinical trial was registered retrospectively on clinicaltrials.gov. The registration number is NCT03503994 .

Improvements in dose calculation accuracy for small off-axis targets in high dose per fraction tomotherapy

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

Hardcastle, Nicholas; Bayliss, Adam; Wong, Jeannie Hsiu Ding

2012-08-15

Purpose: A recent field safety notice from TomoTherapy detailed the underdosing of small, off-axis targets when receiving high doses per fraction. This is due to angular undersampling in the dose calculation gantry angles. This study evaluates a correction method to reduce the underdosing, to be implemented in the current version (v4.1) of the TomoTherapy treatment planning software. Methods: The correction method, termed 'Super Sampling' involved the tripling of the number of gantry angles from which the dose is calculated during optimization and dose calculation. Radiochromic film was used to measure the dose to small targets at various off-axis distances receivingmore » a minimum of 21 Gy in one fraction. Measurements were also performed for single small targets at the center of the Lucy phantom, using radiochromic film and the dose magnifying glass (DMG). Results: Without super sampling, the peak dose deficit increased from 0% to 18% for a 10 mm target and 0% to 30% for a 5 mm target as off-axis target distances increased from 0 to 16.5 cm. When super sampling was turned on, the dose deficit trend was removed and all peak doses were within 5% of the planned dose. For measurements in the Lucy phantom at 9.7 cm off-axis, the positional and dose magnitude accuracy using super sampling was verified using radiochromic film and the DMG. Conclusions: A correction method implemented in the TomoTherapy treatment planning system which triples the angular sampling of the gantry angles used during optimization and dose calculation removes the underdosing for targets as small as 5 mm diameter, up to 16.5 cm off-axis receiving up to 21 Gy.« less

Intercoder Reliability of Mapping Between Pharmaceutical Dose Forms in the German Medication Plan and EDQM Standard Terms.

PubMed

Sass, Julian; Becker, Kim; Ludmann, Dominik; Pantazoglou, Elisabeth; Dewenter, Heike; Thun, Sylvia

2018-01-01

A nationally uniform medication plan has recently been part of German legislation. The specification for the German medication plan was developed in cooperation between various stakeholders of the healthcare system. Its' goal is to enhance usability and interoperability while also providing patients and physicians with the necessary information they require for a safe and high-quality therapy. Within the research and development project named Medication Plan PLUS, the specification of the medication plan was tested and reviewed for semantic interoperability in particular. In this study, the list of pharmaceutical dose forms provided in the specification was mapped to the standard terms of the European Directorate for the Quality of Medicines & HealthCare by different coders. The level of agreement between coders was calculated using Cohen's Kappa (κ). Results show that less than half of the dose forms could be coded with EDQM standard terms. In addition to that Kappa was found to be moderate, which means rather unconvincing agreement among coders. In conclusion, there is still vast room for improvement in utilization of standardized international vocabulary and unused potential considering cross-border eHealth implementations in the future.

Dosimetric comparison between 10MV-FFF and 6MV-FFF for lung SBRT

NASA Astrophysics Data System (ADS)

Durmus, I. F.; Atalay, E. D.

2017-02-01

Plans were prepared by using same non-coplanar fields and physical parameters in 6MV-FFF and 10MV-FFF energies for fourteen lung Stereotactic Body Radio Therapy (SBRT) patients. In two plans which have different energies, critic organ doses, PTV doses, quality of plans (Gradient Index (GI), Homogeneity Index (HI), Conformity Index (CI)) and Monitor Unit (MU) values were compared. Quality controls were performed with 2D-Array Iba MatriXX Evolution® dosimetry system for each plans. As a results, plan with 6MV-FFF energy give better results in terms of CI and GI values. In this way, when more conformal dose distributions were provided, there was a rapid dose decrease at out of target volume. Lower MU values were obtained in plans which was prepared with 10MV-FFF energy. In plan with 10MV-FFF energy lower MU values are obtained. Lower values in heart and spinal cord doses are founded and better results are obtained in Body and Ipsa-Lung V5, V10, V20 values with 6MV-FFF energies. When differences were very small in volume which were taken low dose (V5), these differences increased in volume which were taken high dose (V20). High dose rates can be reached by both two unfiltered energies and can be used in lung SBRT.

Variation of mechanical properties and oxidation with radiation dose and source in highly crosslinked remelted UHMWPE.

PubMed

Fung, Mitchell; Bowsher, John G; Van Citters, Douglas W

2018-06-01

Ultra-high molecular weight polyethylene (UHMWPE) is the current gold standard for bearing materials used in total joint arthroplasty. High-dose radiation is commonly used to crosslink UHMWPE, thereby improving its wear resistance. A subsequent remelting step eliminates trapped residual free radicals to promote oxidative stability on the shelf, and to prevent material degradation over the long term. Assessment of clinically retrieved, highly crosslinked UHMWPE devices shows signs of unanticipated oxidation occurring in vivo, despite the absence of free radicals prior to implantation. These findings warrant further investigation into possible factors impacting this phenomenon along with its clinical implications. The overall objective of this work is to quantify the influence of irradiation dose and source on UHMWPE's oxidative stability, along with the effects of oxidation on the ultimate mechanical properties, including strength, ductility, and toughness. The results showed a strong positive correlation between maximum oxidation and initial transvinylene content. Critical oxidation levels in the context of mechanical property loss were determined for e-beam and gamma treatments at various radiation doses. Further, it was shown that critical oxidation was more dependent on radiation dose and less dependent on source. If in vivo oxidation persists in these devices, this can potentially lead to mechanical failure (e.g. fatigue damage) as observed in terminally gamma-sterilized devices. Copyright © 2018 Elsevier Ltd. All rights reserved.

The effects of whole grain high-amylose maize flour as a source of resistant starch on blood glucose, satiety, and food intake in young men.

PubMed

Luhovyy, Bohdan L; Mollard, Rebecca C; Yurchenko, Svitlana; Nunez, Maria Fernanda; Berengut, Shari; Liu, Ting Ting; Smith, Christopher E; Pelkman, Christine L; Anderson, G Harvey

2014-12-01

The objective of this study was to determine the dose response effect of whole grain high-amylose maize (HAM) flour as a source of resistant starch (RS) on blood glucose, appetite and short-term food intake. In a repeated-measures crossover trial, healthy men (n = 30, 22.9 ± 0.6 y, BMI of 22.6 ± 0.3 kg/m(2)) were randomly assigned to consume 1 of 3 cookies once a week for 3 wk. Cookies were control (100% wheat flour), low-dose (63% wheat flour,37% HAM flour), and high-dose (33% wheat flour, 67% HAM flour) providing 53.5, 43.5, and 36.3 g of available carbohydrate, respectively. Ad libitum food intake was measured 120 min at a pizza meal, blood glucose and subjective appetite were measured after consumption of the cookie (0 to 120 min) and after the pizza meal (140 to 200 min). Blood glucose concentrations were lower at 30 and 45 min after high-dose treatment, and at 120 min after both high- and low-dose treatments compared to control (P < 0.05). Blood glucose AUC before the pizza meal (0 to 120 min) was 44% and 14% lower, and higher by 43% and 41% after the pizza meal (140 to 200 min) compared with control. Yet despite the higher response following the meal, cumulative AUC (0 to 200 min) was still 22% lower after the high-dose treatment (P < 0.05). All treatments equally suppressed subjective appetite and there was no effect on food intake. In conclusion, HAM flour as a source of RS and incorporated into a cookie was associated with better glycemic control in young men. © 2014 Institute of Food Technologists®

SU-F-T-429: Craniospinal Irradiation by VMAT Technique: Impact of FFF Beam and High Resolution MLC On Plan Quality

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

Ganesh, T; Sarkar, B; Munshi, A

2016-06-15

Purpose: Objective of this study was to evaluate the impact of using flattening filter free (FFF) beam with 0.5 cm multileaf collimator (MLC) leaves over conventional flattened beam with 1 cm leaf width MLC on the treatment plan quality in cranio-spinal irradiation (CSI). Methods: For five medulloblastoma cases (3 males and 2 females), who were previously treated by volumetric modulated arc therapy (VMAT) technique using conventional flattened beam shaped by 1 cm width MLC leaves, four test plans were generated and compared against the delivered plan. These retrospective plans consisted of four different combinations of flattened and FFF beams frommore » Elekta’s Agility treatment head with 0.5 cm width MLC leaves. Sparing of organs at risks (OAR) in terms of dose to 5%, 50%, 75% and 90% volumes, mean and maximum dose were evaluated. Results: All plans satisfied the planning objective of covering 95% of PTV by at least 95% of prescription dose. Marginal variation of dose spillage was observed between different VMAT plans at very low dose range (1–5 Gy). Variation in dose statistics for PTVs and OARs were within 1% or 1 Gy. Amongst the five plans, the plan with flattened beam with 1 cm MLC had the highest number of MUs, 2.13 times higher than the plan with Agility MLC with FFF beam that had the least number of MUs. No statistically significant difference (p≥0.05) was observed between the reference plan and the retrospectively generated plans in terms of PTV coverage, cold spot, hot spot and organ at risk doses. Conclusion: In the treatment of CSI cases by VMAT technique, FFF beams and/or finer width MLC did not exhibit advantage over the flattened beams or wider MLC in terms of plan quality except for reduction in MUs.« less

X-ray emission reduction and photon dose lowering by energy loss of fast electrons induced by return current during the interaction of a short-pulse high-intensity laser on a metal solid target

NASA Astrophysics Data System (ADS)

Compant La Fontaine, A.

2018-04-01

During the interaction of a short-pulse high-intensity laser with the preplasma produced by the pulse's pedestal in front of a high-Z metal solid target, high-energy electrons are produced, which in turn create an X-ray source by interacting with the atoms of the converter target. The current brought by the hot electrons is almost completely neutralized by a return current j → driven by the background electrons of the conductive target, and the force exerted on the hot electrons by the electric field E → which induces Ohmic heating j → .E → , produced by the background electrons, reduces the energy of the hot electrons and thus lowers the X-ray emission and photon dose. This effect is analyzed here by means of a simple 1-D temperature model which contains the most significant terms of the relativistic Fokker-Planck equation with electron multiple scattering, and the energy equations of ions, hot, and cold electrons are then solved numerically. This Ohmic heating energy loss fraction τOh is introduced as a corrective term in an improved photon dose model. For instance, for a ps laser pulse with 10 μm spot size, the dose obtained with a tantalum target is reduced by less than about 10% to 40% by the Ohmic heating, depending upon the plasma scale length, target thickness, laser parameters, and in particular its spot size. The laser and plasma parameters may be optimized to limit the effect of Ohmic heating, for instance at a small plasma scale length or small laser spot size. Conversely, others regimes not suitable for dose production are identified. For instance, the resistive heating is enhanced in a foam target or at a long plasma scale length and high laser spot size and intensity, as the mean emission angle θ0 of the incident hot electron bunch given by the ponderomotive force is small; thus, the dose produced by a laser interacting in a gas jet may be inhibited under these circumstances. The resistive heating may also be maximized in order to reduce the X-ray emission to lower the radiation level for instance in a safety radiological goal.

Unrestricted Hepatocyte Transduction with Adeno-Associated Virus Serotype 8 Vectors in Mice

PubMed Central

Nakai, Hiroyuki; Fuess, Sally; Storm, Theresa A.; Muramatsu, Shin-ichi; Nara, Yuko; Kay, Mark A.

2005-01-01

Recombinant adeno-associated virus (rAAV) vectors can mediate long-term stable transduction in various target tissues. However, with rAAV serotype 2 (rAAV2) vectors, liver transduction is confined to only a small portion of hepatocytes even after administration of extremely high vector doses. In order to investigate whether rAAV vectors of other serotypes exhibit similar restricted liver transduction, we performed a dose-response study by injecting mice with β-galactosidase-expressing rAAV1 and rAAV8 vectors via the portal vein. The rAAV1 vector showed a blunted dose-response similar to that of rAAV2 at high doses, while the rAAV8 vector dose-response remained unchanged at any dose and ultimately could transduce all the hepatocytes at a dose of 7.2 × 1012 vector genomes/mouse without toxicity. This indicates that all hepatocytes have the ability to process incoming single-stranded vector genomes into duplex DNA. A single tail vein injection of the rAAV8 vector was as efficient as portal vein injection at any dose. In addition, intravascular administration of the rAAV8 vector at a high dose transduced all the skeletal muscles throughout the body, including the diaphragm, the entire cardiac muscle, and substantial numbers of cells in the pancreas, smooth muscles, and brain. Thus, rAAV8 is a robust vector for gene transfer to the liver and provides a promising research tool for delivering genes to various target organs. In addition, the rAAV8 vector may offer a potential therapeutic agent for various diseases affecting nonhepatic tissues, but great caution is required for vector spillover and tight control of tissue-specific gene expression. PMID:15596817

The comparative short-term effectiveness of iron dosing and formulations in US hemodialysis patients.

PubMed

Kshirsagar, Abhijit V; Freburger, Janet K; Ellis, Alan R; Wang, Lily; Winkelmayer, Wolfgang C; Brookhart, M Alan

2013-06-01

Intravenous iron is used widely in hemodialysis, yet there are limited data on the effectiveness of contemporary dosing strategies or formulation type. We conducted a retrospective cohort study using data from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the US Renal Data System to compare the effects of intravenous iron use on anemia management. Dosing comparisons were bolus (consecutive doses ≥100 mg exceeding 600 mg during 1 month) versus maintenance (all other iron doses during the month); and high (>200 mg over 1 month) versus low dose (≤200 mg over 1 month). Formulation comparison was administration of ferric gluconate versus iron sucrose over 1 month. Outcomes were hemoglobin, epoetin dose, transferrin saturation, and serum ferritin during 6 weeks of follow-up. We identified 117,050 patients for the dosing comparison, and 66,207 patients for the formulation comparison. Bolus dosing was associated with higher average adjusted hemoglobin (+0.23 g/dL; 95% confidence interval [CI], 0.21-0.26), transferrin saturation (+3.31%; 95% CI, 2.99-3.63), serum ferritin (+151 μg/L; 95% CI, 134.9-168.7), and lower average epoetin dose (-464 units; 95% CI, -583 to -343) compared with maintenance. Similar trends were observed with high-dose iron versus low-dose. Iron sucrose was associated with higher adjusted average hemoglobin (+0.16 g/dL; 95% CI, 0.12-0.19) versus ferric gluconate. Strategies favoring large doses of intravenous iron or iron sucrose lead to improved measures of anemia management. These potential benefits should be weighed against risks, which currently remain incompletely characterized. Copyright © 2013 Elsevier Inc. All rights reserved.

FZUImageReg: A toolbox for medical image registration and dose fusion in cervical cancer radiotherapy

PubMed Central

Bai, Penggang; Du, Min; Ni, Xiaolei; Ke, Dongzhong; Tong, Tong

2017-01-01

The combination external-beam radiotherapy and high-dose-rate brachytherapy is a standard form of treatment for patients with locally advanced uterine cervical cancer. Personalized radiotherapy in cervical cancer requires efficient and accurate dose planning and assessment across these types of treatment. To achieve radiation dose assessment, accurate mapping of the dose distribution from HDR-BT onto EBRT is extremely important. However, few systems can achieve robust dose fusion and determine the accumulated dose distribution during the entire course of treatment. We have therefore developed a toolbox (FZUImageReg), which is a user-friendly dose fusion system based on hybrid image registration for radiation dose assessment in cervical cancer radiotherapy. The main part of the software consists of a collection of medical image registration algorithms and a modular design with a user-friendly interface, which allows users to quickly configure, test, monitor, and compare different registration methods for a specific application. Owing to the large deformation, the direct application of conventional state-of-the-art image registration methods is not sufficient for the accurate alignment of EBRT and HDR-BT images. To solve this problem, a multi-phase non-rigid registration method using local landmark-based free-form deformation is proposed for locally large deformation between EBRT and HDR-BT images, followed by intensity-based free-form deformation. With the transformation, the software also provides a dose mapping function according to the deformation field. The total dose distribution during the entire course of treatment can then be presented. Experimental results clearly show that the proposed system can achieve accurate registration between EBRT and HDR-BT images and provide radiation dose warping and fusion results for dose assessment in cervical cancer radiotherapy in terms of high accuracy and efficiency. PMID:28388623

Gene Profiling Characteristics of Radioadaptive Response in AG01522 Normal Human Fibroblasts

PubMed Central

Hou, Jue; Wang, Fan; Kong, Peizhong; Yu, Peter K. N.; Wang, Hongzhi; Han, Wei

2015-01-01

Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose. PMID:25886619

Growth Failure in Children with Systemic Juvenile Idiopathic Arthritis and Prolonged Inflammation despite Treatment with Biologicals: Late Normalization of Height by Combined Hormonal Therapies.

PubMed

de Zegher, Francis; Reynaert, Nele; De Somer, Lien; Wouters, Carine; Roelants, Mathieu

2018-06-25

Biologicals targeting the interleukin (IL)-1β or IL-6 pathway are becoming prime choices for the treatment of children with systemic juvenile idiopathic arthritis (sJIA). Up to 1 in 3 sJIA children receiving such treatment continues to have inflammatory activity and to require supra-physiological glucocorticoid doses which may reduce growth velocity for years and may lead to an extremely short stature for age, if not for life. Currently, there is no long-term proposal to normalize the adult height of these children with sJIA. We present long-term (up to 10 years), proof-of-concept evidence that the adult stature and adipose body composition of short sJIA children can be normalized with a hormonal combination strategy: (i) pubertal onset is postponed with a gonadotropin-releasing hormone analog (triptorelin) until a minimum height is reached, or until prepubertal growth is exhausted, and (ii) height gain is promoted with growth hormone (≈50 μg/kg/day), once inflammation is under control and high glucocorticoid doses are no longer needed. The latter treatment takes advantage of the window of relative glucocorticoid deficiency, which is known to open after prolonged glucocorticoid administration, and to be uniquely favorable to height gain. A long-term combination of biological and hormonal treatments for short sJIA children can be guided by a simple concept that involves (i) postponement of pubertal development and (ii) growth-promoting therapy after the episodes of major inflammation and high-dose glucocorticoid treatment. Limited long-term experience in short sJIA children suggests that this strategy leads consistently - albeit late - to a normal adult stature. © 2018 S. Karger AG, Basel.

Alternative chitosan-based EPR dosimeter applicable for a relatively wide range of gamma radiation doses

NASA Astrophysics Data System (ADS)

Piroonpan, Thananchai; Katemake, Pichayada; Panritdam, Eagkapong; Pasanphan, Wanvimol

2017-12-01

Chitosan biopolymer is proposed as an alternative EPR dosimeter. Its ability to be EPR dosimeter was studied in comparison with the conventional alanine, sugars (i.e., glucose and sucrose), formate derivatives (i.e., lithium (Li), magnesium (Mg), and calcium (Ca) formate). Ethylene vinyl acetate (EVA) and paraffin were used as binder for the preparation of composite EPR dosimeter. Dose responses of all materials were investigated in a wide dose range of radiation doses, i.e., low-level (0-1 kGy), medium-level (1-10 kGy) and high-level (10-100 kGy). The EPR dosimeter properties were studied under different parameters, i.e., microwave power, materials contents, absorbed doses, storage conditions and post-irradiation effects. Li-formate showed a simple EPR spectrum and exhibited superior radiation response for low-dose range; whereas chitosan and sucrose exhibited linear dose response in all studied dose ranges. The EPR signals of chitosan exhibited similar stability as glucose, Li-formate and alanine at ambient temperature after irradiation as long as a year. All EPR signals of the studied materials were affected post-irradiation temperature and humidity after gamma irradiation. The EPR signal of chitosan exhibited long-term stability and it was not sensitive to high storage temperatures and humidity values after irradiation. Chitosan has a good merit as the alternative bio-based material for a stable EPR dosimeter in a wide range of radiation-absorbed doses.

Application of TXRF for ion implanter dose matching experiments

NASA Astrophysics Data System (ADS)

Frost, M. R.; French, M.; Harris, W.

2004-06-01

Secondary ion mass spectrometry (SIMS) has been utilized for many years to measure the dose of ion implants in silicon for the purpose of verifying the ability of ion implantation equipment to accurately and reproducibly implant the desired species at the target dose. The development of statistically and instrumentally rigorous protocols has lead to high confidence levels, particularly with regard to accuracy and short-term repeatability. For example, high-dose, high-energy B implant dosimetry can be targeted to within ±1%. However, performing dose determination experiments using SIMS does have undesirable aspects, such as being highly labor intensive and sample destructive. Modern total reflection X-ray fluorescence (TXRF) instruments are equipped with capabilities for full 300 mm wafer handling, automated data acquisition software and intense X-ray sources. These attributes enable the technique to overcome the SIMS disadvantages listed above, as well as provide unique strengths that make it potentially highly amenable to implanter dose matching. In this paper, we report on data collected to date that provides confidence that TXRF is an effective and economical method to perform these measurements within certain limitations. We have investigated a number of ion implanted species that are within the "envelope" of TXRF application. This envelope is defined by a few important parameters. Species: For the anode materials used in the more common X-ray sources on the market, each has its own set of elements that can be detected. We have investigated W and Mo X-ray sources, which are the most common in use in commercial instrumentation. Implant energy: In general, if the energy of the implanted species is too high (or more specifically, the distribution of the implanted species is too deep), the amount of dopant not detected by TXRF may be significant, increasing the error of the measurement. Therefore, for each species investigated, the implant energy cannot exceed a certain level. Dose: Logically, as the implanted dose falls below a certain point, the concentration will be below the TXRF detection limit. In addition to the improved precision of TXRF over SIMS for dose matching, a number of other advantages will be discussed.

Recovery from manual metal arc-stainless steel welding-fume exposure induced lung fibrosis in Sprague-Dawley rats.

PubMed

Yu, Il Je; Song, Kyung Seuk; Chang, Hee Kyung; Han, Jeong Hee; Chung, Yong Hyun; Han, Kuy Tae; Chung, Kyu Hyuck; Chung, Ho Keun

2003-08-28

Welders with radiographic pneumoconiosis abnormalities have exhibited a gradual clearing of the X-ray identified effects following removal from exposure. In some cases, the pulmonary fibrosis associated with welding fumes appears in a more severe form in welders. Accordingly, to investigate the disease and recovery process of pneumoconiosis induced by welding-fume exposure, rats were exposed to welding fumes with concentrations of 63.6+/-4.1 mg/m(3) (low dose) and 107.1+/-6.3 mg/m(3) (high dose) of total suspended particulate for 2 h per day in an inhalation chamber for a total of 2 h or 15, 30, 60 or 90 days. Thereafter, the rats were no longer exposed and allowed to recover from the welding fume-induced lung fibrosis for 90 days. When compared to the unexposed control group, the lung weights significantly increased in both the low- and high-dose rats from day 15 to 90. A histopathological examination combined with fibrosis-specific staining revealed that the lungs from the low-dose rats did not exhibit any significant progressive fibrotic changes. Whereas, the lungs from the high-dose rats exhibited early delicate fibrosis from day 15, which progressed into the perivascular and peribronchiolar regions by day 30. Interstitial fibrosis appeared at day 60 and became prominent by day 90, along with the additional appearance of pleural fibrosis. Recovery, evaluated based on the body and lung weights and a histopathological examination, was observed in both the high and low-dose rats that were exposed up to 30 days. The rats exposed for 60-90 days at the low dose also recovered from the fibrosis, yet the rats exposed for 60-90 days at the high dose did not fully recover. Consequently, recovery from pneumoconiosis induced by welding-fume exposure was observed when the degree of exposure was short-term and moderate.

Metabolic changes in serum steroids induced by total-body irradiation of female C57B/6 mice.

PubMed

Moon, Ju-Yeon; Shin, Hee-June; Son, Hyun-Hwa; Lee, Jeongae; Jung, Uhee; Jo, Sung-Kee; Kim, Hyun Sik; Kwon, Kyung-Hoon; Park, Kyu Hwan; Chung, Bong Chul; Choi, Man Ho

2014-05-01

The short- and long-term effects of a single exposure to gamma radiation on steroid metabolism were investigated in mice. Gas chromatography-mass spectrometry was used to generate quantitative profiles of serum steroid levels in mice that had undergone total-body irradiation (TBI) at doses of 0Gy, 1Gy, and 4Gy. Following TBI, serum samples were collected at the pre-dose time point and 1, 3, 6, and 9 months after TBI. Serum levels of progestins, progesterone, 5β-DHP, 5α-DHP, and 20α-DHP showed a significant down-regulation following short-term exposure to 4Gy, with the exception of 20α-DHP, which was significantly decreased at each of the time points measured. The corticosteroids 5α-THDOC and 5α-DHB were significantly elevated at each of the time points measured after exposure to either 1 or 4Gy. Among the sterols, 24S-OH-cholestoerol showed a dose-related elevation after irradiation that reached significance in the high dose group at the 6- and 9-month time points. Copyright © 2014 Elsevier Ltd. All rights reserved.

Apparatus, Method and Program Storage Device for Determining High-Energy Neutron/Ion Transport to a Target of Interest

NASA Technical Reports Server (NTRS)

Wilson, John W. (Inventor); Tripathi, Ram K. (Inventor); Cucinotta, Francis A. (Inventor); Badavi, Francis F. (Inventor)

2012-01-01

An apparatus, method and program storage device for determining high-energy neutron/ion transport to a target of interest. Boundaries are defined for calculation of a high-energy neutron/ion transport to a target of interest; the high-energy neutron/ion transport to the target of interest is calculated using numerical procedures selected to reduce local truncation error by including higher order terms and to allow absolute control of propagated error by ensuring truncation error is third order in step size, and using scaling procedures for flux coupling terms modified to improve computed results by adding a scaling factor to terms describing production of j-particles from collisions of k-particles; and the calculated high-energy neutron/ion transport is provided to modeling modules to control an effective radiation dose at the target of interest.

Cooperative binding mitigates the high-dose hook effect.

PubMed

Roy, Ranjita Dutta; Rosenmund, Christian; Stefan, Melanie I

2017-08-14

The high-dose hook effect (also called prozone effect) refers to the observation that if a multivalent protein acts as a linker between two parts of a protein complex, then increasing the amount of linker protein in the mixture does not always increase the amount of fully formed complex. On the contrary, at a high enough concentration range the amount of fully formed complex actually decreases. It has been observed that allosterically regulated proteins seem less susceptible to this effect. The aim of this study was two-fold: First, to investigate the mathematical basis of how allostery mitigates the prozone effect. And second, to explore the consequences of allostery and the high-dose hook effect using the example of calmodulin, a calcium-sensing protein that regulates the switch between long-term potentiation and long-term depression in neurons. We use a combinatorial model of a "perfect linker protein" (with infinite binding affinity) to mathematically describe the hook effect and its behaviour under allosteric conditions. We show that allosteric regulation does indeed mitigate the high-dose hook effect. We then turn to calmodulin as a real-life example of an allosteric protein. Using kinetic simulations, we show that calmodulin is indeed subject to a hook effect. We also show that this effect is stronger in the presence of the allosteric activator Ca 2+ /calmodulin-dependent kinase II (CaMKII), because it reduces the overall cooperativity of the calcium-calmodulin system. It follows that, surprisingly, there are conditions where increased amounts of allosteric activator actually decrease the activity of a protein. We show that cooperative binding can indeed act as a protective mechanism against the hook effect. This will have implications in vivo where the extent of cooperativity of a protein can be modulated, for instance, by allosteric activators or inhibitors. This can result in counterintuitive effects of decreased activity with increased concentrations of both the allosteric protein itself and its allosteric activators.

Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure.

PubMed

Teinturier, C; Hartmann, O; Valteau-Couanet, D; Benhamou, E; Bougneres, P F

1998-11-01

We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.

Dose measurements in space by the Hungarian Pille TLD system.

PubMed

Apathy, I; Deme, S; Feher, I; Akatov, Y A; Reitz, G; Arkhanguelski, V V

2002-10-01

Exposure of crew, equipment, and experiments to the ambient space radiation environment in low Earth orbit poses one of the most significant problems to long-term space habitation. Accurate dose measurement has become increasingly important during the assembly (extravehicular activity (EVA)) and operation of space stations such as on Space Station Mir. Passive integrating detector systems such as thermoluminescent dosemeters (TLDs) are commonly used for dosimetry mapping and personal dosimetry on space vehicles. The well-known advantages of passive detector systems are their independence of power supply, small dimensions, high sensitivity, good stability, wide measuring range, resistance to environmental effects, and relatively low cost. Nevertheless, they have the general disadvantage that for evaluation purposes they need a laboratory or large--in mass and power consumption--terrestrial equipment, and consequently they cannot provide time-resolved dose data during long-term space flights. KFKI Atomic Energy Research Institute (KFKI AEKI) has developed and manufactured a series of thermoluminescent dosemeter systems for measuring cosmic radiation doses in the 10 microGy to 10 Gy range, consisting of a set of bulb dosemeters and a compact, self-contained, TLD reader suitable for on-board evaluation of the dosemeters. By means of such a system, highly accurate measurements were carried out on board the Salyut-6, -7 and Mir Space Stations as well as on the Space Shuttle. A detailed description of the system is given and the comprehensive results of these measurements are summarised. c2002 Elsevier Science Ltd. All rights reserved.

Characterization of a microDiamond detector in high-dose-per-pulse electron beams for intra operative radiation therapy.

PubMed

Di Venanzio, C; Marinelli, Marco; Tonnetti, A; Verona-Rinati, G; Falco, M D; Pimpinella, M; Ciccotelli, A; De Stefano, S; Felici, G; Marangoni, F

2015-12-01

To characterize a synthetic diamond dosimeter (PTW Freiburg microDiamond 60019) in high dose-per-pulse electron beams produced by an Intra Operative Radiation Therapy (IORT) dedicated accelerator. The dosimetric properties of the microDiamond were assessed under 6, 8 and 9 MeV electron beams by a NOVAC11 mobile accelerator (Sordina IORT Technologies S.p.A.). The characterization was carried out with dose-per-pulse ranging from 26 to 105 mGy per pulse. The microDiamond performance was compared with an Advanced Markus ionization chamber and a PTW silicon diode E in terms of dose linearity, percentage depth dose (PDD) curves, beam profiles and output factors. A good linearity of the microDiamond response was verified in the dose range from 0.2 Gy to 28 Gy. A sensitivity of 1.29 nC/Gy was measured under IORT electron beams, resulting within 1% with respect to the one obtained in reference condition under (60)Co gamma irradiation. PDD measurements were found in agreement with the ones by the reference dosimeters, with differences in R50 values below 0.3 mm. Profile measurements evidenced a high spatial resolution of the microDiamond, slightly worse than the one of the silicon diode. The penumbra widths measured by the microDiamond resulted approximately 0.5 mm larger than the ones by the Silicon diode. Output factors measured by the microDiamond were found within 2% with those obtained by the Advanced Markus down to 3 cm diameter field sizes. The microDiamond dosimeter was demonstrated to be suitable for precise dosimetry in IORT applications under high dose-per-pulse conditions. Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Decongestion Strategies and Renin-Angiotensin-Aldosterone System Activation in Acute Heart Failure

PubMed Central

Mentz, Robert J.; Stevens, Susanna R.; DeVore, Adam D.; Lala, Anuradha; Vader, Justin M.; AbouEzzeddine, Omar F.; Khazanie, Prateeti; Redfield, Margaret M.; Stevenson, Lynne W.; O'Connor, Christopher M.; Goldsmith, Steven R.; Bart, Bradley A.; Anstrom, Kevin J.; Hernandez, Adrian F.; Braunwald, Eugene; Felker, G. Michael

2014-01-01

Background High dose diuretics in patients with acute heart failure (AHF) are thought to activate the renin-angiotensin-aldosterone system (RAAS), and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation. Methods We analyzed 427 AHF patients enrolled in the DOSE-AHF and CARRESS-HF trials. We assessed the relationship between two markers of RAAS activation (plasma renin activity [PRA] and aldosterone) from baseline to 72-96h and decongestion strategy; high vs. low-dose and continuous infusion vs. bolus furosemide for DOSE-AHF and UF vs. stepped pharmacologic care for CARRESS-HF. We determined the relationship between RAAS biomarkers and 60-day outcomes. Results Patients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium, and higher BUN. Continuous infusion furosemide and UF were associated with greater PRA increases (median +1.66 vs. +0.66 ng/mL/h with continuous vs. bolus, P=0.021; +4.05 vs. +0.56 ng/mL/h with UF vs. stepped care, P=0.014). There was no significant difference in RAAS biomarker change with high vs. low-dose diuretics (both P>0.5). Neither baseline log PRA nor log aldosterone was associated with increased death/HF hospitalization (HR for a doubling 1.05; 95% CI: 0.98-1.13, P=0.18 and HR 1.13; 95% CI: 0.99-1.28, P=0.069, respectively). The change in RAAS biomarkers from baseline to 72-96 h was not associated with outcomes (both P>0.5). Conclusions High-dose loop diuretics did not result in greater RAAS activation than low-dose diuretics. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. PMID:25543972

Review of proton pump inhibitors for the initial treatment of heartburn: is there a dose ceiling effect?

PubMed

Kushner, Pamela R; Peura, David A

2011-05-01

Proton pump inhibitors (PPIs) are widely used in clinical practice. However, concerns have been expressed about their long-term use, particularly with regard to bone health, Clostridium difficile infections, and drug interactions with platelet aggregation inhibitors. There has been limited guidance for clinicians concerning appropriate dose selection of PPIs for the initial treatment of heartburn. This review explored whether published clinical trials provide evidence of a ceiling above which higher PPI doses do not provide additional clinical benefit over the lowest approved dose. All articles of randomized, controlled clinical trials in nonerosive gastroesophageal reflux disease (GERD) in which the effects of two or more doses of the same PPI on symptomatic relief of heartburn were quantified as a study endpoint were identified and analyzed through PubMed searches up to the end of September 2010. The majority of trials evaluated provided no evidence that higher PPI doses were superior to the lowest approved dose for the initial treatment of heartburn. There were no clinically relevant findings with respect to dose dependence and safety outcomes in these studies. Efficacy outcomes from the trials suggest there may be a dose ceiling effect and highlight the need for further research on the use of the lowest effective PPI doses as an appropriate strategy in the initial treatment of uncomplicated heartburn. Observational studies and some meta-analyses have suggested that long-term PPI pharmacotherapy might be associated with safety concerns, which necessitate the periodic evaluation of therapeutic benefit in terms of symptom resolution and regimen tolerability. However, evidence to date suggests that use of the lowest effective dose for the indication is not associated with significant adverse events, particularly in the short term. Clinical practice suggests that patients requiring long-term treatment should be maintained on the lowest dose necessary to control symptoms, and monitored for potentially confounding factors that may lead to safety concerns.

Effects of a new glucocorticoid, oxazacort, on some variables connected with bone metabolism in man: a comparison with prednisone.

PubMed

Caniggia, A; Marchetti, M; Gennari, C; Vattimo, A; Nicolis, F B

1977-03-01

The urinary elimination of calcium, other electrolytes, and hydroxyproline and the oral absorption of 47Ca have been evaluated in three groups of 8 patients before and during a 15-day treatment with prednisone at daily doses of 25 and 50 mg and with oxazacort, a new glucocorticoid, at a daily dose of 50 mg. The results obtained demonstrate that oxazacort in short-term teatment with a high dose has no significant effect on the urinary elimination of calcium and hydroxypyroline in experimental conditions in which prednisone produces statistically significant and clinically relevant increase, both when given at the same dose and when given at half that dose. On the other hand, the oral absorption of 47Ca is decreased by oxazacort, but less than by prednisone at the same dose. As the antirheumatic activity of oxazacort appears to be only slightly lower than that of prednisone (activity ratio of about 0.84: 1), these findings may have interesting therapeutic implications.

Focal exposure of limited lung volumes to high-dose irradiation down-regulated organ development-related functions and up-regulated the immune response in mouse pulmonary tissues.

PubMed

Kim, Bu-Yeo; Jin, Hee; Lee, Yoon-Jin; Kang, Ga-Young; Cho, Jaeho; Lee, Yun-Sil

2016-01-27

Despite the emergence of stereotactic body radiotherapy (SBRT) for treatment of medically inoperable early-stage non-small-cell lung cancer patients, the molecular effects of focal exposure of limited lung volumes to high-dose radiation have not been fully characterized. This study was designed to identify molecular changes induced by focal high-dose irradiation using a mouse model of SBRT. Central areas of the mouse left lung were focally-irradiated (3 mm in diameter) with a single high-dose of radiation (90 Gy). Temporal changes in gene expression in the irradiated and non-irradiated neighboring lung regions were analyzed by microarray. For comparison, the long-term effect (12 months) of 20 Gy radiation on a diffuse region of lung was also measured. The majority of genes were down-regulated in the focally-irradiated lung areas at 2 to 3 weeks after irradiation. This pattern of gene expression was clearly different than gene expression in the diffuse region of lungs exposed to low-dose radiation. Ontological and pathway analyses indicated these down-regulated genes were mainly associated with organ development. Although the number was small, genes that were up-regulated after focal irradiation were associated with immune-related functions. The temporal patterns of gene expression and the associated biological functions were also similar in non-irradiated neighboring lung regions, although statistical significance was greatly reduced when compared with those from focally-irradiated areas of the lung. From network analysis of temporally regulated genes, we identified inter-related modules associated with diverse functions, including organ development and the immune response, in both the focally-irradiated regions and non-irradiated neighboring lung regions. Focal exposure of lung tissue to high-dose radiation induced expression of genes associated with organ development and the immune response. This pattern of gene expression was also observed in non-irradiated neighboring areas of lung tissue, indicating a global lung response to focal high-dose irradiation.

Dose- and Ion-Dependent Effects in the Oxidative Stress Response to Space-Like Radiation Exposure in the Skeletal System

PubMed Central

Alwood, Joshua S.; Tran, Luan H.; Schreurs, Ann-Sofie; Shirazi-Fard, Yasaman; Kumar, Akhilesh; Hilton, Diane; Tahimic, Candice G. T.; Globus, Ruth K.

2017-01-01

Space radiation may pose a risk to skeletal health during subsequent aging. Irradiation acutely stimulates bone remodeling in mice, although the long-term influence of space radiation on bone-forming potential (osteoblastogenesis) and possible adaptive mechanisms are not well understood. We hypothesized that ionizing radiation impairs osteoblastogenesis in an ion-type specific manner, with low doses capable of modulating expression of redox-related genes. 16-weeks old, male, C57BL6/J mice were exposed to low linear-energy-transfer (LET) protons (150 MeV/n) or high-LET 56Fe ions (600 MeV/n) using either low (5 or 10 cGy) or high (50 or 200 cGy) doses at NASA’s Space Radiation Lab. Five weeks or one year after irradiation, tissues were harvested and analyzed by microcomputed tomography for cancellous microarchitecture and cortical geometry. Marrow-derived, adherent cells were grown under osteoblastogenic culture conditions. Cell lysates were analyzed by RT-PCR during the proliferative or mineralizing phase of growth, and differentiation was analyzed by imaging mineralized nodules. As expected, a high dose (200 cGy), but not lower doses, of either 56Fe or protons caused a loss of cancellous bone volume/total volume. Marrow cells produced mineralized nodules ex vivo regardless of radiation type or dose; 56Fe (200 cGy) inhibited osteoblastogenesis by more than 90% (5 weeks and 1 year post-IR). After 5 weeks, irradiation (protons or 56Fe) caused few changes in gene expression levels during osteoblastogenesis, although a high dose 56Fe (200 cGy) increased Catalase and Gadd45. The addition of exogenous superoxide dismutase (SOD) protected marrow-derived osteoprogenitors from the damaging effects of exposure to low-LET (137Cs γ) when irradiated in vitro, but had limited protective effects on high-LET 56Fe-exposed cells. In sum, either protons or 56Fe at a relatively high dose (200 cGy) caused persistent bone loss, whereas only high-LET 56Fe increased redox-related gene expression, albeit to a limited extent, and inhibited osteoblastogenesis. Doses below 50 cGy did not elicit widespread responses in any parameter measured. We conclude that high-LET irradiation at 200 cGy impaired osteoblastogenesis and regulated steady-state gene expression of select redox-related genes during osteoblastogenesis, which may contribute to persistent bone loss. PMID:28994728

Novel oral anticoagulants for atrial fibrillation

PubMed Central

How, Choon How

2015-01-01

Anticoagulation therapy is effective in preventing primary and secondary thromboembolic events due to atrial fibrillation. Warfarin, which was approved by the United States in 1954, was the only long-term oral anticoagulation therapy till the approval of dabigatran in 2010, and of rivaroxaban and other direct factor Xa inhibitors from 2011, forming a group known as novel oral anticoagulants (NOAC). NOAC have fewer food and drug interactions compared to warfarin; hence, the patient will require fewer clinic visits. However, the short half-life of NOAC means that twice-a-day dosing is needed and there is higher risk of a prothrombotic state when doses are missed. Other disadvantages are the lack of long-term data on NOAC, their high cost and the current lack of locally available antidotes. PMID:26702159

Appropriate Use of Effective Dose in Radiation Protection and Risk Assessment.

PubMed

Fisher, Darrell R; Fahey, Frederic H

2017-08-01

Effective dose was introduced by the ICRP for the single, over-arching purpose of setting limits for radiation protection. Effective dose is a derived quantity or mathematical construct and not a physical, measurable quantity. The formula for calculating effective dose to a reference model incorporates terms to account for all radiation types, organ and tissue radiosensitivities, population groups, and multiple biological endpoints. The properties and appropriate applications of effective dose are not well understood by many within and outside the health physics profession; no other quantity in radiation protection has been more confusing or misunderstood. According to ICRP Publication 103, effective dose is to be used for "prospective dose assessment for planning and optimization in radiological protection, and retrospective demonstration of compliance for regulatory purposes." In practice, effective dose has been applied incorrectly to predict cancer risk among exposed persons. The concept of effective dose applies generally to reference models only and not to individual subjects. While conceived to represent a measure of cancer risk or heritable detrimental effects, effective dose is not predictive of future cancer risk. The formula for calculating effective dose incorporates committee-selected weighting factors for radiation quality and organ sensitivity; however, the organ weighting factors are averaged across all ages and both genders and thus do not apply to any specific individual or radiosensitive subpopulations such as children and young women. Further, it is not appropriate to apply effective dose to individual medical patients because patient-specific parameters may vary substantially from the assumptions used in generalized models. Also, effective dose is not applicable to therapeutic uses of radiation, as its mathematical underpinnings pertain only to observed late (stochastic) effects of radiation exposure and do not account for short-term adverse tissue reactions. The weighting factors incorporate substantial uncertainties, and linearity of the dose-response function at low dose is uncertain and highly disputed. Since effective dose is not predictive of future cancer incidence, it follows that effective dose should never be used to estimate future cancer risk from specific sources of radiation exposure. Instead, individual assessments of potential detriment should only be based on organ or tissue radiation absorbed dose, together with best scientific understanding of the corresponding dose-response relationships.

Long-term effectiveness of plasma-derived hepatitis B vaccine 22-28 years after immunization in a hepatitis B virus endemic rural area: is an adult booster dose needed?

PubMed

Li, H; Li, G J; Chen, Q Y; Fang, Z L; Wang, X Y; Tan, C; Yang, Q L; Wang, F Z; Wang, F; Zhang, S; Bi, S L; Shen, L P

2017-04-01

Longan County is considered a highly endemic area for hepatitis B virus (HBV). The plasma-derived vaccine has been used in newborns in this area since 1987. A cross-sectional survey was conducted to evaluate the long-term effectiveness of this vaccine. In total, 1634 participants born during 1987-1993 and who had received a series of plasma-derived HB vaccinations at ages 0, 1, and 6 months were enrolled. Serological HBV markers were detected and compared with previous survey data. Overall the prevalence of hepatitis B surface antigen (HBsAg) in all participants was 3·79%; 3·47% of subjects who had received the first dose within 24 h were HBsAg positive, and 8·41% of subjects who had received a delayed first dose were also HBsAg positive. There were 1527 subjects identified who had received the first dose within 24 h and whose HBsAg and anti-HBc prevalence increased yearly after immunization, while the anti-HBs-positive rate and vaccine effectiveness declined. The geometric mean concentration of antibody in the anti-HB-positive participants was 55·13 mIU/ml and this declined after immunization. Fewer than 2·0% of participants had anti-HB levels ⩾1000 mIU/ml. The data show that the protective efficacy of the plasma-derived vaccinations declined and administration of HB vaccine within 24 h of birth was very important. To reduce the risk of HBV infection in this highly endemic area, a booster dose might be necessary if anti-HBs levels fall below 10 mIU/ml after age 18 years. Furthermore, studies on the immune memory induced by plasma-derived HB vaccine are needed.

Acute development of cortical porosity and endosteal naïve bone formation from the daily but not weekly short-term administration of PTH in rabbit

PubMed Central

Yamane, Hiroshi; Takakura, Aya; Shimadzu, Yukari; Kodama, Toshiyuki; Lee, Ji-Won; Isogai, Yukihiro; Ishizuya, Toshinori; Takao-Kawabata, Ryoko

2017-01-01

Teriparatide [human parathyroid hormone (1–34)], which exerts an anabolic effect on bone, is used for the treatment of osteoporosis in patients who are at a high risk for fracture. That the once-daily administration of teriparatide causes an increase in cortical porosity in animal models and clinical studies has been a matter of concern. However, it is not well documented that the frequency of administration and/or the total dose of teriparatide affect the cortical porosity. The present study developed 4 teriparatide regimens [20 μg/kg/day (D20), 40 μg/kg/day (D40), 140 μg/kg/week (W140) and 280 μg/kg/week (W280)] in the rabbit as a model animal with a well-developed Haversian system and osteons. The total weekly doses were equivalent in the low-dose groups (D20 and W140) and in the high-dose groups (D40 and W280). After the short-term (1 month) administration of TPDT, micro-CT, histomorphometry and three-dimensional second harmonic generation (3D-SHG) imaging to visualize the bone collagen demonstrated that daily regimens but not weekly regimens were associated with the significant development of cortical porosity and endosteal naïve bone formation by marrow fibrosis. We concomitantly monitored the pharmacokinetics of the plasma teriparatide levels as well as the temporal changes in markers of bone formation and resorption. The analyses in the present study suggested that the daily repeated administration of teriparatide causes more deleterious changes in the cortical microarchitecture than the less frequent administration of higher doses. The findings of the present study may have some implications for use of teriparatide in clinical treatment. PMID:28394900

Deleterious Effects of a Low Amount of Ethanol on LTP-Like Plasticity in Human Cortex

PubMed Central

Lücke, Caroline; Heidegger, Tonio; Röhner, Mirjam; Toennes, Stefan W; Krivanekova, Lucia; Müller-Dahlhaus, Florian; Ziemann, Ulf

2014-01-01

Ingesting ethanol (EtOH) at low doses during social drinking is a common human behavior for its facilitating effects on social interactions. However, low-dose EtOH may have also detrimental effects that so far are underexplored. Here we sought to test the effects of low-dose EtOH on long-term potentiation (LTP)-like plasticity in human motor cortex. Previous cellular experiments showed that low-dose EtOH potentiates extrasynaptic GABAAR and reduces NMDAR-mediated currents, processes that would limit the expression of LTP. Paired associative transcranial magnetic stimulation (PASLTP) was employed in nine healthy subjects for induction of LTP-like plasticity, indexed by a long-term increase in motor-evoked potential input–output curves. Synaptic α1-GABAAR function was measured by saccadic peak velocity (SPV). Very low doses of EtOH (resulting in blood concentrations of <5 mM) suppressed LTP-like plasticity but did not affect SPV when compared with a placebo condition. In contrast, 1 mg of alprazolam, a classical benzodiazepine, or 10 mg of zolpidem, a non-benzodiazepine hypnotic, decreased SPV but did not significantly affect LTP-like plasticity when compared with placebo. This double dissociation of low-dose EtOH vs alprazolam/zolpidem effects is best explained by the putatively high affinity of EtOH but not alprazolam/zolpidem to extrasynaptic GABAARs and to NMDARs. Findings suggest that enhancement of extrasynaptic GABAAR-mediated tonic inhibition and/or reduction of NMDAR-mediated neurotransmission by EtOH blocks LTP-like plasticity in human cortex at very low doses that are easily reached during social drinking. Therefore, low-dose EtOH may jeopardize LTP-dependent processes, such as learning and memory formation. PMID:24385131

Radiation dose and subsequent risk for stomach cancer in long-term survivors of cervical cancer

PubMed Central

Kleinerman, Ruth A.; Smith, Susan A.; Holowaty, Eric; Hall, Per; Pukkala, Eero; Vaalavirta, Leila; Stovall, Marilyn; Weathers, Rita; Gilbert, Ethel; Aleman, Berthe M.P.; Kaijser, Magnus; Andersson, Michael; Storm, Hans; Joensuu, Heikki; Lynch, Charles F.; Dores, Graça M.; Travis, Lois B.; Morton, Lindsay M.; Curtis, Rochelle E.

2013-01-01

Purpose To assess the dose-response relationship for stomach cancer following radiotherapy for cervical cancer. Methods and Materials We conducted a nested, matched case-control study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943–1995, from five international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 gray [Gy], range 0.03–46.1 and following parallel opposed pelvic fields, 1.63 Gy, range 0.12–6.3). Results Over 90% of women received radiotherapy, mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was non-significantly increased (odds ratios [ORs] 1.27–2.28) for women receiving between 0.5–4.9 Gy to the stomach cancer site and significantly increased at doses ≥5 Gy (OR=4.20, 95% confidence interval, 1.41–13.4, Ptrend=0.047) compared to non-irradiated women. A highly significant radiation dose-response relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach (Ptrend=0.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach (Ptrend=0.23). Conclusions Our findings showed for the first time a significant linear dose-response relationship for risk of stomach cancer in long-term survivors of cervical cancer. PMID:23707149

Physiological responses and toxin production of Microcystis aeruginosa in short-term exposure to solar UV radiation.

PubMed

Hernando, Marcelo; Minaglia, Melina Celeste Crettaz; Malanga, Gabriela; Houghton, Christian; Andrinolo, Darío; Sedan, Daniela; Rosso, Lorena; Giannuzzi, Leda

2018-01-17

The aim of this study was to evaluate the effects of short-term (hours) exposure to solar UV radiation (UVR, 280-400 nm) on the physiology of Microcystis aeruginosa. Three solar radiation treatments were implemented: (i) PAR (PAR, 400-700 nm), (ii) TUVA (PAR + UVAR, 315-700 nm) and (iii) TUVR (PAR + UVAR + UVBR, 280-700 nm). Differential responses of antioxidant enzymes and the reactive oxygen species (ROS) production to UVR were observed. Antioxidant enzymes were more active at high UVR doses. However, different responses were observed depending on the exposure to UVAR or UVBR and the dose level. No effects were observed on the biomass, ROS production or increased activity of superoxide dismutase (SOD) and catalase (CAT) compared to the control when UVR + PAR doses were lower than 9875 kJ m -2 . For intermediate doses, UVR + PAR doses between 9875 and 10 275 kJ m -2 , oxidative stress increased while resistance was imparted through SOD and CAT in the cells exposed to UVAR. Despite the increased antioxidant activity, biomass decrease and photosynthesis inhibition were observed, but no effects were observed with added exposure to UVBR. At the highest doses (UVR + PAR higher than 10 275 kJ m -2 ), the solar UVR caused decreased photosynthesis and biomass with only activation of CAT by UVBR and SOD and CAT by UVAR. In addition, for such doses, a significant decrease of microcystins (MCs, measured as MC-LR equivalents) was observed as a consequence of UVAR. This study facilitates our understanding of the SOD and CAT protection according to UVAR and UVBR doses and cellular damage and reinforces the importance of UVR as an environmental stressor. In addition, our results support the hypothesized antioxidant function of MCs.

Accelerated Total Lymphoid Irradiation-containing Salvage Regimen for Patients With Refractory and Relapsed Hodgkin Lymphoma: 20 Years of Experience

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

Rimner, Andreas; Lovie, Shona; Hsu, Meier

Purpose: We report the long-term results of integrated accelerated involved field radiation therapy (IFRT) followed by total lymphoid irradiation (TLI) as part of the high-dose salvage regimen followed by autologous bone marrow transplantation or autologous stem cell transplantation in patients with relapsed or refractory Hodgkin lymphoma (HL). Methods and Materials: From November 1985 to July 2008, 186 previously unirradiated patients with relapsed or refractory HL underwent salvage therapy on 4 consecutive institutional review board–approved protocols. All patients had biopsy-proven primary refractory or relapsed HL. After standard-dose salvage chemotherapy (SC), accelerated IFRT (18-20 Gy) was given to relapsed or refractory sites, followedmore » by TLI (15-18 Gy) and high-dose chemotherapy. Overall survival (OS) and event-free survival (EFS) were analyzed by Cox analysis and disease-specific survival (DSS) by competing-risk regression. Results: With a median follow-up period of 57 months among survivors, 5- and 10-year OS rates were 68% and 56%, respectively; 5- and 10-year EFS rates were 62% and 56%, respectively; and 5- and 10-year cumulative incidences of HL-related deaths were 21% and 29%, respectively. On multivariate analysis, complete response to SC was independently associated with improved OS and EFS. Primary refractory disease and extranodal disease were independently associated with poor DSS. Eight patients had grade 3 or higher cardiac toxicity, with 3 deaths. Second malignancies developed in 10 patients, 5 of whom died. Conclusions: Accelerated IFRT followed by TLI and high-dose chemotherapy is an effective, feasible, and safe salvage strategy for patients with relapsed or refractory HL with excellent long-term OS, EFS, and DSS. Complete response to SC is the most important prognostic factor.« less

Analysis of dose-LET distribution in the human body irradiated by high energy hadrons.

PubMed

Sato, T; Tsuda, S; Sakamoto, Y; Yamaguchi, Y; Niita, K

2003-01-01

For the purposes of radiological protection, it is important to analyse profiles of the particle field inside a human body irradiated by high energy hadrons, since they can produce a variety of secondary particles which play an important role in the energy deposition process, and characterise their radiation qualities. Therefore Monte Carlo calculations were performed to evaluate dose distributions in terms of the linear energy transfer of ionising particles (dose-LET distribution) using a newly developed particle transport code (Particle and Heavy Ion Transport code System, PHITS) for incidences of neutrons, protons and pions with energies from 100 MeV to 200 GeV. Based on these calculations, it was found that more than 80% and 90% of the total deposition energies are attributed to ionisation by particles with LET below 10 keV microm(-1) for the irradiations of neutrons and the charged particles, respectively.

Long-Term Quality of Life Outcome After Proton Beam Monotherapy for Localized Prostate Cancer

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

Coen, John J., E-mail: jcoen@partners.org; Paly, Jonathan J.; Niemierko, Andrzej

Objectives: High-dose external radiation for localized prostate cancer results in favorable clinical outcomes and low toxicity rates. Here, we report long-term quality of life (QOL) outcome for men treated with conformal protons. Methods: QOL questionnaires were sent at specified intervals to 95 men who received proton radiation. Of these, 87 men reported 3- and/or 12-month outcomes, whereas 73 also reported long-term outcomes (minimum 2 years). Symptom scores were calculated at baseline, 3 months, 12 months, and long-term follow-up. Generalized estimating equation models were constructed to assess longitudinal outcomes while accounting for correlation among repeated measures in an individual patient. Menmore » were stratified into functional groups from their baseline questionnaires (normal, intermediate, or poor function) for each symptom domain. Long-term QOL changes were assessed overall and within functional groups using the Wilcoxon signed-rank test. Results: Statistically significant changes in all four symptom scores were observed in the longitudinal analysis. For the 73 men reporting long-term outcomes, there were significant change scores for incontinence (ID), bowel (BD) and sexual dysfunction (SD), but not obstructive/irritative voiding dysfunction (OID). When stratified by baseline functional category, only men with normal function had increased scores for ID and BD. For SD, there were significant changes in men with both normal and intermediate function, but not poor function. Conclusions: Patient reported outcomes are sensitive indicators of treatment-related morbidity. These results quantitate the long-term consequences of proton monotherapy for prostate cancer. Analysis by baseline functional category provides an individualized prediction of long-term QOL scores. High dose proton radiation was associated with small increases in bowel dysfunction and incontinence, with more pronounced changes in sexual dysfunction.« less

Effectiveness of intra-articular injection in wrist joints according to triamcinolone hexacetonide dose in rheumatoid arthritis: a randomized controlled double-blind study.

PubMed

Pereira, Daniele Freitas; Natour, Jamil; Machado, Natália Pereira; Furtado, Rita Nely Vilar

2015-02-01

The aim of this study was to compare the effectiveness in the medium term between low and high doses of triamcinolone hexacetonide used in intra-articular injection in medium-sized joints of rheumatoid arthritis (RA) patients. A randomized double-blind study was carried out in rheumatoid arthritis patients with wrist painful refractory synovitis. Sixty wrists were included and randomized to receive low dose (20 mg) or high dose (40 mg). The outcomes assessed in T0, T1, T4, T8, and T12 weeks were visual analog scale for pain and for swelling, chronic disease activity index, goniometry, simplified Stanford Health Assessment Questionnaire, and side effects. Baseline mean (standard deviation) values were pain visual analog scale of 6.1 (1.6) and 6.3 (1.7), P = 0.562; swelling visual analog scale of 5.9 and 6.4, P = 0.466; chronic disease activity index of 17.8 and 16.8, P = 0.366; and Health Assessment Questionnaire of 0.8 and 0.7, P = 0.238, in the high- and low-dose groups, respectively. Both groups improved pain and swelling assessed by the visual analog scale, P < 0.001, in the intragroup analysis. Chronic disease activity index, goniometry, and Health Assessment Questionnaire also improved equally over time in both groups in the intragroup analysis (P < 0.001, 0.001, and 0.002, respectively). No serious side effects were detected. High and low triamcinolone hexacetonide doses had good effectiveness in wrist-blinded intra-articular injection of rheumatoid arthritis patients, without statistical difference between them.

Human response to high-background radiation environments on Earth and in space

NASA Astrophysics Data System (ADS)

Durante, M.; Manti, L.

The main long-term goal of the space exploration program is the colonization of the planets of the Solar System The high cosmic radiation equivalent dose rate represents a major problem for a stable and safe colonization of the planets The dose rate on Mars ranges between 60 and 150 mSv year depending on the Solar cycle and altitude and can reach values as high as 360 mSv year on the Moon The average dose rate on the Earth is about 3 mSv year reduced to about 1 mSv year excluding the internal exposure to Rn daughters However some areas of the Earth have anomalously high levels of background radiation Values 200-400 times higher than the world average are found in regions where monazite sand deposits are abundant Population in Tibet experience a high cosmic radiation background Epidemiological studies did not detect any adverse health effects in the populations living in those high-background radiation areas on Earth Chromosomal aberrations in the peripheral blood lymphocytes from the population living in the high-background radiation areas have been measured in several studies because the chromosomal damage represents an early biomarker of cancer risk Similar cytogenetic studies have been recently performed in cohort of astronauts involved in single or repeated space flights over many years A comparison of the cytogenetic findings in populations exposed at high dose rate on Earth or in space will be described

Intravenous paracetamol with a lower dose is also effective for the treatment of patent ductus arteriosus in pre-term infants.

PubMed

Tekgündüz, Kadir Şerafettin; Ceviz, Naci; Caner, İbrahim; Olgun, Haşim; Demirelli, Yaşar; Yolcu, Canan; Şahin, İrfan Oğuz; Kara, Mustafa

2015-08-01

Haemodynamically significant patent ductus arteriosus is a significant cause of morbidity and mortality in pre-term infants. This retrospective study was conducted to investigate the usefulness of lower-dose paracetamol for the treatment of patent ductus arteriosus in pre-term infants. A total of 13 pre-term infants who received intravenous paracetamol because of contrindications or side effects to oral ibuprofen were retrospectively enrolled. In the first patient, the dose regimen was 15 mg/kg/dose, every 6 hours. As the patient developed significant elevation in transaminase levels, the dose was decreased to 10 mg/kg/dose, every 8 hours in the following 12 patients. Echocardiographic examination was conducted daily. In case of closure, it was repeated after 2 days and when needed thereafter in terms of reopening. A total of 13 patients received intravenous paracetamol. Median gestational age was 29 weeks ranging from 24 to 31 weeks and birth weight was 950 g ranging from 470 to 1390 g. The median postnatal age at the first intravenous paracetamol dose was 3 days ranging from 2 to 9 days. In 10 of the 13 patients (76.9%), patent ductus arteriosus was closed at the median 2nd day of intravenous paracetamol ranging from 1 to 4 days. When the patient who developed hepatotoxicity was eliminated, the closure rate was found to be 83.3% (10/12). Intravenous paracetamol may be a useful treatment option for the treatment of patent ductus arteriosus in pre-term infants with contrindication to ibuprofen. In our experience, lower-dose paracetamol is effective in closing the patent ductus arteriosus in 83.3% of the cases.

MODELING THE VARIATIONS OF DOSE RATE MEASURED BY RAD DURING THE FIRST MSL MARTIAN YEAR: 2012–2014

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

Guo, Jingnan; Wimmer-Schweingruber, Robert F.; Heber, Bernd

2015-09-01

The Radiation Assessment Detector (RAD), on board Mars Science Laboratory’s (MSL) rover Curiosity, measures the energy spectra of both energetic charged and neutral particles along with the radiation dose rate at the surface of Mars. With these first-ever measurements on the Martian surface, RAD observed several effects influencing the galactic cosmic-ray (GCR) induced surface radiation dose concurrently: (a) short-term diurnal variations of the Martian atmospheric pressure caused by daily thermal tides, (b) long-term seasonal pressure changes in the Martian atmosphere, and (c) the modulation of the primary GCR flux by the heliospheric magnetic field, which correlates with long-term solar activitymore » and the rotation of the Sun. The RAD surface dose measurements, along with the surface pressure data and the solar modulation factor, are analyzed and fitted to empirical models that quantitatively demonstrate how the long-term influences ((b) and (c)) are related to the measured dose rates. Correspondingly, we can estimate dose rate and dose equivalents under different solar modulations and different atmospheric conditions, thus allowing empirical predictions of the Martian surface radiation environment.« less

Choosing the optimal dose in sublingual immunotherapy: Rationale for the 300 index of reactivity dose.

PubMed

Demoly, Pascal; Passalacqua, Gianni; Calderon, Moises A; Yalaoui, Tarik

2015-01-01

Sublingual immunotherapy (SLIT) is an effective and well-tolerated method of treating allergic respiratory diseases associated with seasonal and perennial allergens. In contrast to the subcutaneous route, SLIT requires a much greater amount of antigen to achieve a clinical effect. Many studies have shown that SLIT involves a dose-response relationship, and therefore it is important to use a proven clinically effective dose from the onset of treatment, because low doses are ineffective and very high doses may increase the risk of side effects. A well-defined standardization of allergen content is also crucial to ensure consistent quality, potency and appropriate immunomodulatory action of the SLIT product. Several methods of measuring antigenicity are used by manufacturers of SLIT products, including the index of reactivity (IR), standardized quality tablet unit, and bioequivalent allergy unit. A large body of evidence has established the 300 IR dose of SLIT as offering optimal efficacy and tolerability for allergic rhinitis due to grass and birch pollen and HDM, and HDM-induced moderate, persistent allergic asthma. The 300 IR dose also offers consistency of dosing across a variety of different allergens, and is associated with higher rates of adherence and patient satisfaction. Studies in patients with grass pollen allergies showed that the 300 IR dose has a rapid onset of action, is effective in both adults and children in the short term and, when administered pre-coseasonally in the long term, and maintains the clinical benefit, even after cessation of treatment. In patients with HDM-associated AR and/or asthma, the 300 IR dose also demonstrated significant improvements in symptoms and quality of life, and significantly decreased use of symptomatic medication. The 300 IR dose is well tolerated, with adverse events generally being of mild or moderate severity, declining in frequency and severity over time and in the subsequent courses. We discuss herein the most important factors that affect the selection of the optimal dose of SLIT with natural allergens, and review the rationale and evidence supporting the use of the 300 IR dose.

An Interlaboratory Comparison of Dosimetry for a Multi-institutional Radiobiological

PubMed Central

Seed, TM; Xiao, S; Manley, N; Nikolich-Zugich, J; Pugh, J; van den Brink, M; Hirabayashi, Y; Yasutomo, K; Iwama, A; Koyasu, S; Shterev, I; Sempowski, G; Macchiarini, F; Nakachi, K; Kunugi, KC; Hammer, CG; DeWerd, LA

2016-01-01

Purpose An interlaboratory comparison of radiation dosimetry was conducted to determine the accuracy of doses being used experimentally for animal exposures within a large multi-institutional research project. The background and approach to this effort are described and discussed in terms of basic findings, problems and solutions. Methods Dosimetry tests were carried out utilizing optically stimulated luminescence (OSL) dosimeters embedded midline into mouse carcasses and thermal luminescence dosimeters (TLD) embedded midline into acrylic phantoms. Results The effort demonstrated that the majority (4/7) of the laboratories was able to deliver sufficiently accurate exposures having maximum dosing errors of ≤ 5%. Comparable rates of ‘dosimetric compliance’ were noted between OSL- and TLD-based tests. Data analysis showed a highly linear relationship between ‘measured’ and ‘target’ doses, with errors falling largely between 0–20%. Outliers were most notable for OSL-based tests, while multiple tests by ‘non-compliant’ laboratories using orthovoltage x-rays contributed heavily to the wide variation in dosing errors. Conclusions For the dosimetrically non-compliant laboratories, the relatively high rates of dosing errors were problematic, potentially compromising the quality of ongoing radiobiological research. This dosimetry effort proved to be instructive in establishing rigorous reviews of basic dosimetry protocols ensuring that dosing errors were minimized. PMID:26857121

An interlaboratory comparison of dosimetry for a multi-institutional radiobiological research project: Observations, problems, solutions and lessons learned.

PubMed

Seed, Thomas M; Xiao, Shiyun; Manley, Nancy; Nikolich-Zugich, Janko; Pugh, Jason; Van den Brink, Marcel; Hirabayashi, Yoko; Yasutomo, Koji; Iwama, Atsushi; Koyasu, Shigeo; Shterev, Ivo; Sempowski, Gregory; Macchiarini, Francesca; Nakachi, Kei; Kunugi, Keith C; Hammer, Clifford G; Dewerd, Lawrence A

2016-01-01

An interlaboratory comparison of radiation dosimetry was conducted to determine the accuracy of doses being used experimentally for animal exposures within a large multi-institutional research project. The background and approach to this effort are described and discussed in terms of basic findings, problems and solutions. Dosimetry tests were carried out utilizing optically stimulated luminescence (OSL) dosimeters embedded midline into mouse carcasses and thermal luminescence dosimeters (TLD) embedded midline into acrylic phantoms. The effort demonstrated that the majority (4/7) of the laboratories was able to deliver sufficiently accurate exposures having maximum dosing errors of ≤5%. Comparable rates of 'dosimetric compliance' were noted between OSL- and TLD-based tests. Data analysis showed a highly linear relationship between 'measured' and 'target' doses, with errors falling largely between 0 and 20%. Outliers were most notable for OSL-based tests, while multiple tests by 'non-compliant' laboratories using orthovoltage X-rays contributed heavily to the wide variation in dosing errors. For the dosimetrically non-compliant laboratories, the relatively high rates of dosing errors were problematic, potentially compromising the quality of ongoing radiobiological research. This dosimetry effort proved to be instructive in establishing rigorous reviews of basic dosimetry protocols ensuring that dosing errors were minimized.

Genomic instability, bystander effect, cytoplasmic irradiation and other phenomena that may achieve fame without fortune.

PubMed

Hall, E J

2001-01-01

The possible risk of induced malignancies in astronauts, as a consequence of the radiation environment in space, is a factor of concern for long term missions. Cancer risk estimates for high doses of low LET radiation are available from the epidemiological studies of the A-bomb survivors. Cancer risks at lower doses cannot be detected in epidemiological studies and must be inferred by extrapolation from the high dose risks. The standard setting bodies, such as the ICRP recommend a linear, no-threshold extrapolation of risks from high to low doses, but this is controversial. A study of mechanisms of carcinogenesis may shed some light on the validity of a linear extrapolation. The multi-step nature of carcinogenesis suggests that the role of radiation may be to induce a mutation leading to a mutator phenotype. High energy Fe ions, such as those encountered in space are highly effective in inducing genomic instability. Experiments involving the single particle microbeam have demonstrated a "bystander effect", ie a biological effect in cells not themselves hit, but in close proximity to those that are, as well as the induction of mutations in cells where only the cytoplasm, and not the nucleus, have been traversed by a charged particle. These recent experiments cast doubt on the validity of a simple linear extrapolation, but the data are so far fragmentary and conflicting. More studies are necessary. While mechanistic studies cannot replace epidemiology as a source of quantitative risk estimates, they may shed some light on the shape of the dose response relationship and therefore on the limitations of a linear extrapolation to low doses.

Genomic instability, bystander effect, cytoplasmic irradiation and other phenomena that may achieve fame without fortune

NASA Technical Reports Server (NTRS)

Hall, E. J.

2001-01-01

The possible risk of induced malignancies in astronauts, as a consequence of the radiation environment in space, is a factor of concern for long term missions. Cancer risk estimates for high doses of low LET radiation are available from the epidemiological studies of the A-bomb survivors. Cancer risks at lower doses cannot be detected in epidemiological studies and must be inferred by extrapolation from the high dose risks. The standard setting bodies, such as the ICRP recommend a linear, no-threshold extrapolation of risks from high to low doses, but this is controversial. A study of mechanisms of carcinogenesis may shed some light on the validity of a linear extrapolation. The multi-step nature of carcinogenesis suggests that the role of radiation may be to induce a mutation leading to a mutator phenotype. High energy Fe ions, such as those encountered in space are highly effective in inducing genomic instability. Experiments involving the single particle microbeam have demonstrated a "bystander effect", ie a biological effect in cells not themselves hit, but in close proximity to those that are, as well as the induction of mutations in cells where only the cytoplasm, and not the nucleus, have been traversed by a charged particle. These recent experiments cast doubt on the validity of a simple linear extrapolation, but the data are so far fragmentary and conflicting. More studies are necessary. While mechanistic studies cannot replace epidemiology as a source of quantitative risk estimates, they may shed some light on the shape of the dose response relationship and therefore on the limitations of a linear extrapolation to low doses.

The Fukushima releases: an inverse modelling approach to assess the source term by using gamma dose rate observations

NASA Astrophysics Data System (ADS)

Saunier, Olivier; Mathieu, Anne; Didier, Damien; Tombette, Marilyne; Quélo, Denis; Winiarek, Victor; Bocquet, Marc

2013-04-01

The Chernobyl nuclear accident and more recently the Fukushima accident highlighted that the largest source of error on consequences assessment is the source term estimation including the time evolution of the release rate and its distribution between radioisotopes. Inverse modelling methods have proved to be efficient to assess the source term due to accidental situation (Gudiksen, 1989, Krysta and Bocquet, 2007, Stohl et al 2011, Winiarek et al 2012). These methods combine environmental measurements and atmospheric dispersion models. They have been recently applied to the Fukushima accident. Most existing approaches are designed to use air sampling measurements (Winiarek et al, 2012) and some of them use also deposition measurements (Stohl et al, 2012, Winiarek et al, 2013). During the Fukushima accident, such measurements are far less numerous and not as well distributed within Japan than the dose rate measurements. To efficiently document the evolution of the contamination, gamma dose rate measurements were numerous, well distributed within Japan and they offered a high temporal frequency. However, dose rate data are not as easy to use as air sampling measurements and until now they were not used in inverse modelling approach. Indeed, dose rate data results from all the gamma emitters present in the ground and in the atmosphere in the vicinity of the receptor. They do not allow one to determine the isotopic composition or to distinguish the plume contribution from wet deposition. The presented approach proposes a way to use dose rate measurement in inverse modeling approach without the need of a-priori information on emissions. The method proved to be efficient and reliable when applied on the Fukushima accident. The emissions for the 8 main isotopes Xe-133, Cs-134, Cs-136, Cs-137, Ba-137m, I-131, I-132 and Te-132 have been assessed. The Daiichi power plant events (such as ventings, explosions…) known to have caused atmospheric releases are well identified in the retrieved source term, except for unit 3 explosion where no measurement was available. The comparisons between the simulations of atmospheric dispersion and deposition of the retrieved source term show a good agreement with environmental observations. Moreover, an important outcome of this study is that the method proved to be perfectly suited to crisis management and should contribute to improve our response in case of a nuclear accident.

On the Formation and Seasonal Properties of Topical Cirrus Clouds over Amazon Basin (2.89ºS, 59.97ºW): Observations from Lidar, Radiosonde and Satellite instruments.

NASA Astrophysics Data System (ADS)

Blagev, D. P.; Mendoza, D. L.; Rea, S.; Sorensen, J.

2014-12-01

Adverse health effects have been associated with urban pollutant exposure arising from close proximity to highly-emitting sources and atmospheric mixing. The relative air pollution exposure dose and time effects on various diseases remains unknown. This study compares the increased risk of health complications when patients are exposed to short term high-levels of air pollution vs. longer term exposure to lower levels of air pollution. We used the electronic medical record of an integrated hospital system based in Utah, Intermountain Healthcare, to identify a cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) who were seen between 2009-2014. We determined patient demographics as well as comorbidity data and healthcare utilization. To determine the approximate air pollution dose and time exposure, we used the Hestia highly-resolved emissions inventory for Salt Lake County, Utah in conjunction with emissions based on the National Emissions Inventory (NEI). Hourly emissions of CO2 and criteria air pollutants were gridded at a 0.002o x 0.002o resolution for the study years. The resulting emissions were transported using the CALPUFF and AERMOD dispersion models to estimate air pollutant concentrations at an hourly 0.002o x 0.002oresolution. Additionally, pollutant concentrations were estimated at each patient's home and work address to estimate exposure. Multivariate analysis adjusting for patient demographics, comorbidities and severity of COPD was performed to determine association between air pollution exposure and the risk of hospitalization or emergency department (ED) visit for COPD exacerbation and an equivalency estimate for air pollution exposure was developed. We noted associations with air pollution levels for each pollutant and hospitalizations and ED visits for COPD and other patient comorbidities. We also present an equivalency estimate for dose of air pollution exposure and health outcomes. This analysis compares the increased risk of health complications when patients are exposed to short term high-levels of air pollution vs. longer term exposure to lower levels of air pollution. These findings highlight pollutant emissions and exposures spatial and temporal heterogeneity and associated health effects.

Interaction between Chronic Obstructive Pulmonary Disease (COPD) and other important health conditions and measurable air pollution

NASA Astrophysics Data System (ADS)

Blagev, D. P.; Mendoza, D. L.; Rea, S.; Sorensen, J.

2015-12-01

Adverse health effects have been associated with urban pollutant exposure arising from close proximity to highly-emitting sources and atmospheric mixing. The relative air pollution exposure dose and time effects on various diseases remains unknown. This study compares the increased risk of health complications when patients are exposed to short term high-levels of air pollution vs. longer term exposure to lower levels of air pollution. We used the electronic medical record of an integrated hospital system based in Utah, Intermountain Healthcare, to identify a cohort of patients with Chronic Obstructive Pulmonary Disease (COPD) who were seen between 2009-2014. We determined patient demographics as well as comorbidity data and healthcare utilization. To determine the approximate air pollution dose and time exposure, we used the Hestia highly-resolved emissions inventory for Salt Lake County, Utah in conjunction with emissions based on the National Emissions Inventory (NEI). Hourly emissions of CO2 and criteria air pollutants were gridded at a 0.002o x 0.002o resolution for the study years. The resulting emissions were transported using the CALPUFF and AERMOD dispersion models to estimate air pollutant concentrations at an hourly 0.002o x 0.002oresolution. Additionally, pollutant concentrations were estimated at each patient's home and work address to estimate exposure. Multivariate analysis adjusting for patient demographics, comorbidities and severity of COPD was performed to determine association between air pollution exposure and the risk of hospitalization or emergency department (ED) visit for COPD exacerbation and an equivalency estimate for air pollution exposure was developed. We noted associations with air pollution levels for each pollutant and hospitalizations and ED visits for COPD and other patient comorbidities. We also present an equivalency estimate for dose of air pollution exposure and health outcomes. This analysis compares the increased risk of health complications when patients are exposed to short term high-levels of air pollution vs. longer term exposure to lower levels of air pollution. These findings highlight pollutant emissions and exposures spatial and temporal heterogeneity and associated health effects.

SU-E-T-625: Robustness Evaluation and Robust Optimization of IMPT Plans Based on Per-Voxel Standard Deviation of Dose Distributions.

PubMed

Liu, W; Mohan, R

2012-06-01

Proton dose distributions, IMPT in particular, are highly sensitive to setup and range uncertainties. We report a novel method, based on per-voxel standard deviation (SD) of dose distributions, to evaluate the robustness of proton plans and to robustly optimize IMPT plans to render them less sensitive to uncertainties. For each optimization iteration, nine dose distributions are computed - the nominal one, and one each for ± setup uncertainties along x, y and z axes and for ± range uncertainty. SD of dose in each voxel is used to create SD-volume histogram (SVH) for each structure. SVH may be considered a quantitative representation of the robustness of the dose distribution. For optimization, the desired robustness may be specified in terms of an SD-volume (SV) constraint on the CTV and incorporated as a term in the objective function. Results of optimization with and without this constraint were compared in terms of plan optimality and robustness using the so called'worst case' dose distributions; which are obtained by assigning the lowest among the nine doses to each voxel in the clinical target volume (CTV) and the highest to normal tissue voxels outside the CTV. The SVH curve and the area under it for each structure were used as quantitative measures of robustness. Penalty parameter of SV constraint may be varied to control the tradeoff between robustness and plan optimality. We applied these methods to one case each of H&N and lung. In both cases, we found that imposing SV constraint improved plan robustness but at the cost of normal tissue sparing. SVH-based optimization and evaluation is an effective tool for robustness evaluation and robust optimization of IMPT plans. Studies need to be conducted to test the methods for larger cohorts of patients and for other sites. This research is supported by National Cancer Institute (NCI) grant P01CA021239, the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center, and MD Anderson’s cancer center support grant CA016672. © 2012 American Association of Physicists in Medicine.

Impact of ozonation on naphthenic acids speciation and toxicity of oil sands process-affected water to Vibrio fischeri and mammalian immune system.

PubMed

Wang, Nan; Chelme-Ayala, Pamela; Perez-Estrada, Leonidas; Garcia-Garcia, Erick; Pun, Jonathan; Martin, Jonathan W; Belosevic, Miodrag; Gamal El-Din, Mohamed

2013-06-18

Oil sands process-affected water (OSPW) is the water contained in tailings impoundment structures in oil sands operations. There are concerns about the environmental impacts of the release of OSPW because of its toxicity. In this study, ozonation followed by biodegradation was used to remediate OSPW. The impacts of the ozone process evolution on the naphthenic acids (NAs) speciation and acute toxicity were evaluated. Ion-mobility spectrometry (IMS) was used to preliminarily separate isomeric and homologous species. The results showed limited effects of the ozone reactor size on the treatment performance in terms of contaminant removal. In terms of NAs speciation, high reactivity of NAs with higher number of carbons and rings was only observed in a region of high reactivity (i.e., utilized ozone dose lower than 50 mg/L). It was also found that nearly 0.5 mg/L total NAs was oxidized per mg/L of utilized ozone dose, at utilized ozone doses lower than 50 mg/L. IMS showed that ozonation was able to degrade NAs, oxidized NAs, and sulfur/nitrogenated NAs. Complete removal of toxicity toward Vibrio fischeri was achieved after ozonation followed by 28-day biodegradation period. In vitro and in vivo assays indicated that ozonation reduced the OSPW toxicity to mice.

A versatile indirect detector design for hard X-ray microimaging

NASA Astrophysics Data System (ADS)

Douissard, P.-A.; Cecilia, A.; Rochet, X.; Chapel, X.; Martin, T.; van de Kamp, T.; Helfen, L.; Baumbach, T.; Luquot, L.; Xiao, X.; Meinhardt, J.; Rack, A.

2012-09-01

Indirect X-ray detectors are of outstanding importance for high resolution imaging, especially at synchrotron light sources: while consisting mostly of components which are widely commercially available, they allow for a broad range of applications in terms of the X-ray energy employed, radiation dose to the detector, data acquisition rate and spatial resolving power. Frequently, an indirect detector consists of a thin-film single crystal scintillator and a high-resolution visible light microscope as well as a camera. In this article, a novel modular-based indirect design is introduced, which offers several advantages: it can be adapted for different cameras, i.e. different sensor sizes, and can be trimmed to work either with (quasi-)monochromatic illumination and the correspondingly lower absorbed dose or with intense white beam irradiation. In addition, it allows for a motorized quick exchange between different magnifications / spatial resolutions. Developed within the European project SCINTAX, it is now commercially available. The characteristics of the detector in its different configurations (i.e. for low dose or for high dose irradiation) as measured within the SCINTAX project will be outlined. Together with selected applications from materials research, non-destructive evaluation and life sciences they underline the potential of this design to make high resolution X-ray imaging widely available.

Maximum likelihood analysis of bioassay data from long-term follow-up of two refractory PuO2 inhalation cases.

PubMed

Avtandilashvili, Maia; Brey, Richard; James, Anthony C

2012-07-01

The U.S. Transuranium and Uranium Registries' tissue donors 0202 and 0407 are the two most highly exposed of the 18 registrants who were involved in the 1965 plutonium fire accident at a defense nuclear facility. Material released during the fire was well characterized as "high fired" refractory plutonium dioxide with 0.32-μm mass median diameter. The extensive bioassay data from long-term follow-up of these two cases were used to evaluate the applicability of the Human Respiratory Tract Model presented by International Commission on Radiological Protection in Publication 66 and its revision proposed by Gregoratto et al. in order to account for the observed long-term retention of insoluble material in the lungs. The maximum likelihood method was used to calculate the point estimates of intake and tissue doses and to examine the effect of different lung clearance, blood absorption, and systemic models on the goodness-of-fit and estimated dose values. With appropriate adjustments, Gregoratto et al. particle transport model coupled with the customized blood absorption parameters yielded a credible fit to the bioassay data for both cases and predicted the Case 0202 liver and skeletal activities measured postmortem. PuO2 particles produced by the plutonium fire are extremely insoluble. About 1% of this material is absorbed from the respiratory tract relatively rapidly, at a rate of about 1 to 2 d (half-time about 8 to 16 h). The remainder (99%) is absorbed extremely slowly, at a rate of about 5 × 10(-6) d (half-time about 400 y). When considering this situation, it appears that doses to other body organs are negligible in comparison to those to tissues of the respiratory tract. About 96% of the total committed weighted dose equivalent is contributed by the lungs. Doses absorbed by these workers' lungs were high: 3.2 Gy to AI and 6.5 Gy to LNTH for Case 0202 (18 y post-intake) and 3.2 Gy to AI and 55.5 Gy to LNTH for Case 0407 (43 y post-intake). This evaluation supports the Gregoratto et al. proposed revision to the ICRP 66 model when considering situations of extremely insoluble particles.

Methamphetamine blood concentrations in human abusers: application to pharmacokinetic modeling.

PubMed

Melega, William P; Cho, Arthur K; Harvey, Dennis; Laćan, Goran

2007-04-01

Characterization of methamphetamine's (METH) dose-dependent effects on brain neurochemistry may represent a critical component for better understanding the range of resultant behavioral pathologies. Most human studies, however, have assessed only the effects of long term, high dose METH abuse (e.g., greater than 1000 mg/day) in individuals meeting DSM-IV criteria for METH dependence. Yet, for the majority of METH abusers, their patterns of METH exposure that consist of lower doses remain less well-characterized. In this study, blood samples were obtained from 105 individuals detained by police for possible criminal activity and testing positive for stimulants by EMIT assay. METH blood concentrations were subsequently quantified by GC-MS and were predominantly in the low micromolar range (0.1-11.1 microM), with median and mean values of 1.3 microM (0.19 mg/l) and 2 microM (0.3 mg/l), respectively. Pharmacokinetic calculations based on these measured values were used to estimate initial METH body burdens, the median value being 52 mg. Modeling a 52 mg dose for a 4 day-METH maintenance exposure pattern of 4 doses/day at 4 h intervals showed that blood concentrations remained between 1 and 4 microM during this period. Collectively, these data present evidence for a METH exposure pattern distinct from high dose-METH abuse and provide the rationale for assessing potential brain pathology associated with such lower dose-METH exposure.

[Clinical experience of carbon ion radiotherapy for malignant tumors].

PubMed

Ishikawa, Hitoshi; Tsuji, Hiroshi; Tsujii, Hirohiko

2006-04-01

The carbon ion (C-ion) beams provide unique advantageous biological and physical properties in radiotherapy (RT) for malignant tumors. C-ion beams have a high relative biological effectiveness (RBE) resulting from the high linear energy transfer (LET). In terms of their physical characteristics, C-ion beams exhibit a spread-out Bragg peak (SOBP) and make for a better dose distribution of the target volume by specified beam modulations. Between June 1994 and August 2005, a total of 2,371 patients with malignant tumors were registered in phase I/II dose-escalation studies and clinical phase II trials using C-ion beams generated at Heavy Ion Medical Accelerator in Chiba (HIMAC). In the initial dose-escalation studies, grade 3 or more late rectal complications had developed in some patients. However, the adverse effects were resolved because of the use of appropriate dose levels and modification of the radiation technique. C-ion beams can carry out hypofractionated radiotherapy with a large fraction dose and reduce the overall treatment times compared with conventional radiotherapy. They can also achieve better local tumor control even for radio-resistant tumors such as malignant melanoma, hepatocellular carcinoma and bone and soft tissue sarcomas with minimal morbidity to the normal surrounding tissues.

Radiation exposure and lung disease in today's nuclear world.

PubMed

Deas, Steven D; Huprikar, Nikhil; Skabelund, Andrew

2017-03-01

Ionizing radiation poses important health risks. The per capita annual dose rate has increased in the United States and there is increasing concern for the risks posed by low-dose occupational exposure among workers in nuclear industries and healthcare. Recent nuclear accidents and concern for terrorism have heightened concern for catastrophic, high-dose ionizing radiation exposure. This review will highlight recent research into the risks to lung health posed by ionizing radiation exposure and into potential treatments. Angiotensin-converting enzyme inhibitors and some antioxidants have shown promise as mitigators, to decrease pneumonitis and fibrosis when given after exposure. Studies of survivors of nuclear catastrophes have shown increased risk for lung cancer, especially in nonsmokers. There is evidence for increased lung cancer risk in industrial radiation workers, especially those who process plutonium and may inhale radioactive particles. There does not seem to be an increased risk of lung cancer in healthcare workers who perform fluoroscopic procedures. High-dose ionizing radiation exposure causes pneumonitis and fibrosis, and more research is needed to develop mitigators to improve outcomes in nuclear catastrophes. Long-term, low-dose occupational radiation may increase lung cancer risk. More research to better define this risk could lead to improved safety protocols and screening programs.

Cumulative trauma and posttraumatic stress disorder among children exposed to the 9/11 World Trade Center attack.

PubMed

Mullett-Hume, Elizabeth; Anshel, Daphne; Guevara, Vivianne; Cloitre, Marylene

2008-01-01

Two and one-half years after the September 11, 2001 World Trade Center attack, 204 middle school students in an immigrant community located near Ground Zero were assessed for posttraumatic stress disorder (PTSD) symptoms as influenced by "dose" of exposure to the attack and accumulated lifetime traumas. Ninety percent of students reported at least one traumatic event other than 9/11 (e.g., community violence) with an average of 4 lifetime events reported. An interaction was obtained such that the dose-response effect depended on presence of other traumas. Among students with the lowest number of additional traumas, the usual dose-response pattern of increasing PTSD symptoms with increasing 9/11 exposure was observed; among those with medium to high cumulative life trauma, PTSD symptoms were substantially higher and uniformly so regardless of 9/11 exposure dose. Results suggest that traumas that precede or follow mass violence often have as much as if not greater impact on long-term symptom severity than high-dose exposure to the event. Implications regarding the presence of continuing or previous trauma exposure for postdisaster and early intervention policies are discussed. (c) 2008 APA, all rights reserved

Radiation-induced genomic instability: radiation quality and dose response

NASA Technical Reports Server (NTRS)

Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

2003-01-01

Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

Neutron dose measurements of Varian and Elekta linacs by TLD600 and TLD700 dosimeters and comparison with MCNP calculations

PubMed Central

Nedaie, Hassan Ali; Darestani, Hoda; Banaee, Nooshin; Shagholi, Negin; Mohammadi, Kheirollah; Shahvar, Arjang; Bayat, Esmaeel

2014-01-01

High-energy linacs produce secondary particles such as neutrons (photoneutron production). The neutrons have the important role during treatment with high energy photons in terms of protection and dose escalation. In this work, neutron dose equivalents of 18 MV Varian and Elekta accelerators are measured by thermoluminescent dosimeter (TLD) 600 and TLD700 detectors and compared with the Monte Carlo calculations. For neutron and photon dose discrimination, first TLDs were calibrated separately by gamma and neutron doses. Gamma calibration was carried out in two procedures; by standard 60Co source and by 18 MV linac photon beam. For neutron calibration by 241Am-Be source, irradiations were performed in several different time intervals. The Varian and Elekta linac heads and the phantom were simulated by the MCNPX code (v. 2.5). Neutron dose equivalent was calculated in the central axis, on the phantom surface and depths of 1, 2, 3.3, 4, 5, and 6 cm. The maximum photoneutron dose equivalents which calculated by the MCNPX code were 7.06 and 2.37 mSv.Gy-1 for Varian and Elekta accelerators, respectively, in comparison with 50 and 44 mSv.Gy-1 achieved by TLDs. All the results showed more photoneutron production in Varian accelerator compared to Elekta. According to the results, it seems that TLD600 and TLD700 pairs are not suitable dosimeters for neutron dosimetry inside the linac field due to high photon flux, while MCNPX code is an appropriate alternative for studying photoneutron production. PMID:24600167

Neutron dose measurements of Varian and Elekta linacs by TLD600 and TLD700 dosimeters and comparison with MCNP calculations.

PubMed

Nedaie, Hassan Ali; Darestani, Hoda; Banaee, Nooshin; Shagholi, Negin; Mohammadi, Kheirollah; Shahvar, Arjang; Bayat, Esmaeel

2014-01-01

High-energy linacs produce secondary particles such as neutrons (photoneutron production). The neutrons have the important role during treatment with high energy photons in terms of protection and dose escalation. In this work, neutron dose equivalents of 18 MV Varian and Elekta accelerators are measured by thermoluminescent dosimeter (TLD) 600 and TLD700 detectors and compared with the Monte Carlo calculations. For neutron and photon dose discrimination, first TLDs were calibrated separately by gamma and neutron doses. Gamma calibration was carried out in two procedures; by standard 60Co source and by 18 MV linac photon beam. For neutron calibration by (241)Am-Be source, irradiations were performed in several different time intervals. The Varian and Elekta linac heads and the phantom were simulated by the MCNPX code (v. 2.5). Neutron dose equivalent was calculated in the central axis, on the phantom surface and depths of 1, 2, 3.3, 4, 5, and 6 cm. The maximum photoneutron dose equivalents which calculated by the MCNPX code were 7.06 and 2.37 mSv.Gy(-1) for Varian and Elekta accelerators, respectively, in comparison with 50 and 44 mSv.Gy(-1) achieved by TLDs. All the results showed more photoneutron production in Varian accelerator compared to Elekta. According to the results, it seems that TLD600 and TLD700 pairs are not suitable dosimeters for neutron dosimetry inside the linac field due to high photon flux, while MCNPX code is an appropriate alternative for studying photoneutron production.

Streptozotocin-induced hippocampal astrogliosis and insulin signaling malfunction as experimental scales for subclinical sporadic Alzheimer model.

PubMed

Rostami, Farzaneh; Javan, Mohammad; Moghimi, Ali; Haddad-Mashadrizeh, Aliakbar; Fereidoni, Masoud

2017-11-01

Insulin signaling malfunction has recently been suggested as a preliminary event involved in the etiology of Sporadic Alzheimer's disease (SAD). In order to develop insulin resistance-related SAD model, rats were treated with streptozotocin, intracerebroventricularly (icv-STZ). Nevertheless, given the lack of knowledge regarding sub-clinical stages of SAD, the current challenging issue is establishing a practical pre-clinical SAD model. Despite some proposed mechanisms, such as insulin malfunction, neuroinflammation, and gliosis, icv-STZ mechanism of action is not fully understood yet and Streptozotocin-induced rat model of Alzheimer has still major shortcomings. Using three STZ doses (0.5, 1, and 3mg/kg) and three testing time (short-term, medium-term and long-term), we sought the best dose of STZ in order to mimic the characteristic feature of sAD in rats. So, we conducted a series of fifteen-week follow-up cognitive and non-cognitive studies. Besides, IR, tau and ChAT mRNA levels were measured, along with histological analysis of astrocyte, dark neuron numbers, and pyramidal layer thickness, in order to compare the effects of different doses of icv-STZ. STZ 3mg/kg caused cognitive and insulin signaling disturbance from the very first testing-time. STZ1-injected animals, however, showed an augmented hippocampal astrocyte numbers in a short time; they, also, were diagnosed with disturbed insulin signaling in medium-term post icv-STZ-injection. Moreover, behavioral, molecular and histological impairments induced by 0.5mg/kg icv-STZ were slowly progressing in comparison to high doses of STZ. STZ1 and 0.5mg/kg-treated animals are, respectively, suggested as a suitable experimental model of MCI, and sub-clinical stage. Copyright © 2017 Elsevier Inc. All rights reserved.

A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice

PubMed Central

Pellegrini, Giovanni; Siwowska, Klaudia; Haller, Stephanie; Antoine, Daniel J.; Schibli, Roger; Kipar, Anja; Müller, Cristina

2017-01-01

Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage. PMID:28635637

High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse

PubMed Central

Somparn, Poorichaya; Bootprapan, Tanabodee; Tu, Hongbin; Tangtanatakul, Pattarin; Nuengjumnong, Ratchanok; Worasilchai, Navaporn; Tiranathanagul, Khajohn; Eiam-ong, Somchai; Levine, Mark; Chinampon, Ariya; Srisawat, Nattachai

2015-01-01

Amphotericin B (Ampho B) is a fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically. We tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression in patients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with <11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage, liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans. PMID:25994956

Evaluation and optimization of occupational eye lens dosimetry during positron emission tomography (PET) procedures.

PubMed

Guiu-Souto, Jacobo; Sánchez-García, Manuel; Vázquez-Vázquez, Rubén; Otero, Carlos; Luna, Victor; Mosquera, Javier; Busto, Ramón Lobato; Aguiar, Pablo; Ruibal, Álvaro; Pardo-Montero, Juan; Pombar-Cameán, Miguel

2016-06-01

The last recommendations of the International Commission on Radiological Protection for eye lens dose suggest an important reduction on the radiation limits associated with early and late tissue reactions. The aim of this work is to quantify and optimize the eye lens dose associated to nurse staff during positron emission tomography (PET) procedures. PET is one of the most important diagnostic methods of oncological and neurological cancer disease involving an important number of workers exposed to the high energy isotope F-18. We characterize the relevant stages as preparation and administration of monodose syringes in terms of occupational dose. A direct reading silicon dosimeter was used to measure the lens dose to staff. The highest dose of radiation was observed during preparation of the fluorodesoxyglucose (FDG) syringes. By optimizing a suitable vials' distribution of FDG we find an important reduction in occupational doses. Extrapolation of our data to other clinical scenarios indicates that, depending on the work load and/or syringes activity, safety limits of the dose might be exceeded.

Radiological dose in Muria peninsula from SB-LOCA event

NASA Astrophysics Data System (ADS)

Sunarko; Suud, Zaki

2017-01-01

Dose assessment for accident condition is performed for Muria Peninsula region using source-term from Three-Mile Island unit 2 SB-LOCA accident. Xe-133, Kr-88, 1-131 and Cs-137 isotopes are considered in the calculation. The effluent is assumed to be released from a 50 m stack. Lagrangian particle dispersion method (LPDM) employing non-Gaussian dispersion coefficient in 3-dimensional mass-consistent wind-field is employed to obtain periodic surface-level concentration which is then time-integrated to obtain spatial distribution of ground-level dose. In 1-hour simulation, segmented plumes with 60 seconds duration with a total of 18.000 particles involved. Simulations using 6-hour worst-case meteorological data from Muria peninsula results in a peak external dose of around 1.668 mSv for low scenario and 6.892 mSv for high scenario in dry condition. In wet condition with 5 mm/hour and 10 mm/hour rain for the whole duration of the simulation provides only minor effect to dose. The peak external dose is below the regulatory limit of 50 mSv for effective skin dose from external gamma exposure.

SU-E-P-51: Dosimetric Comparison to Organs at Risk Sparing Using Volumetric-Modulated Arc Therapy Versus Intensity-Modulated Radiotherapy in Postoperative Radiotherapy of Left-Sided Breast Cancer

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

Qiao, L; Deng, G; Xie, J

2015-06-15

Purpose: To compare the dosimetric characteristics of volumetric-modulated arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) techniques in treatment planning for left-sided breast cancer patients with modified radical mastectomy. Methods: Twenty-four left-sided breast cancer patients treated with modified radical mastectomy were selected in this study. The planning target volume (PTV) was generated by using 7-mm uniform expansion of the clinical target volume (CTV) in all direction except the skin surface. The organs at risk (OARs) included heart, left lung, right lung, and right breast. Dose volume histograms (DVHs) were utilized to evaluate the dose distribution in PTV and OARs. Results: Bothmore » VMAT and IMRT plans met the requirement of PTV coverage. VMAT was superior to IMRT in terms of conformity, with a statistically significant difference (p=0.024). Mean doses, V5 and V10 of heart and both lungs in VMAT plans were significantly decreased compared to IMRT plans (P<0.05), but in terms of heart volume irradiated by high doses (V30 and V45), no significant differences were observed (P>0.05). For right breast, VMAT showed the reduction of V5 in comparison with IMRT (P<0.05). Additionally, the mean number of monitor units (MU) and treatment time in VMAT (357.21, 3.62 min) were significantly less than those in IMRT (1132.85, 8.74 min). Conclusion: VMAT showed similar PTV coverage and significant advantage in OARs sparing compared with IMRT, especially in terms of decreased volumes irradiated by low doses, while significantly reducing the treatment time and MU number.« less

What we need to know about the effect of lithium on the kidney.

PubMed

Gong, Rujun; Wang, Pei; Dworkin, Lance

2016-12-01

Lithium has been a valuable treatment for bipolar affective disorders for decades. Clinical use of lithium, however, has been problematic due to its narrow therapeutic index and concerns for its toxicity in various organ systems. Renal side effects associated with lithium include polyuria, nephrogenic diabetes insipidus, proteinuria, distal renal tubular acidosis, and reduction in glomerular filtration rate. Histologically, chronic lithium nephrotoxicity is characterized by interstitial nephritis with microcyst formation and occasional focal segmental glomerulosclerosis. Nevertheless, this type of toxicity is uncommon, with the strongest risk factors being high serum levels of lithium and longer time on lithium therapy. In contrast, in experimental models of acute kidney injury and glomerular disease, lithium has antiproteinuric, kidney protective, and reparative effects. This paradox may be partially explained by lower lithium doses and short duration of therapy. While long-term exposure to higher psychiatric doses of lithium may be nephrotoxic, short-term low dose of lithium may be beneficial and ameliorate kidney and podocyte injury. Mechanistically, lithium targets glycogen synthase kinase-3β, a ubiquitously expressed serine/threonine protein kinase implicated in the processes of tissue injury, repair, and regeneration in multiple organ systems, including the kidney. Future studies are warranted to discover the exact "kidney-protective dose" of lithium and test the effects of low-dose lithium on acute and chronic kidney disease in humans. Copyright © 2016 the American Physiological Society.

Preliminary calculation of solar cosmic ray dose to the female breast in space mission

NASA Technical Reports Server (NTRS)

Shavers, Mark; Poston, John W.; Atwell, William; Hardy, Alva C.; Wilson, John W.

1991-01-01

No regulatory dose limits are specifically assigned for the radiation exposure of female breasts during manned space flight. However, the relatively high radiosensitivity of the glandular tissue of the breasts and its potential exposure to solar flare protons on short- and long-term missions mandate a priori estimation of the associated risks. A model for estimating exposure within the breast is developed for use in future NASA missions. The female breast and torso geometry is represented by a simple interim model. A recently developed proton dose-buildup procedure is used for estimating doses. The model considers geomagnetic shielding, magnetic-storm conditions, spacecraft shielding, and body self-shielding. Inputs to the model include proton energy spectra, spacecraft orbital parameters, STS orbiter-shielding distribution at a given position, and a single parameter allowing for variation in breast size.

A compact in vivo neutron activation analysis system to quantify manganese in human hand bone

NASA Astrophysics Data System (ADS)

Liu, Yingzi

As an urgent issue of correlating cumulative manganese (Mn) exposure to neurotoxicity, bone has emerged as an attractive biomarker for long-term Mn deposition and storage. A novel Deuterium-Deuterium (DD) neutron generator irradiation system has been simulated and constructed, incorporating moderator, reflector and shielding. This neutron activation analysis (NAA) irradiation assembly presents several desirable features, including high neutron flux, improved detection limit and acceptable neutron & photon dose, which would allow it be ready for clinical measurement. Key steps include simulation modeling and verifying, irradiation system design, detector characterization, and neutron flux and dose assessment. Activation foils were also analyzed to reveal the accurate neutron spectrum in the irradiation cave. The detection limit with this system is 0.428 ppm with 36 mSv equivalent hand dose and 52 microSv whole body effective dose.

Inhaled corticosteroids and asthma control in adult-onset asthma: 12-year follow-up study.

PubMed

Vähätalo, Iida; Ilmarinen, Pinja; Tuomisto, Leena E; Niemelä, Onni; Kankaanranta, Hannu

2018-04-01

Prescribed inhaled corticosteroid (ICS) doses in asthma have been studied in cross-sectional settings whereas long-term follow-up studies have not been carried out. To evaluate prescribed medication longitudinally by calculating cumulative ICS doses and dose changes in a cohort of new-onset adult asthma during 12 years and in different groups of asthma control. A total of 203 patients were followed for 12 years as part of Seinäjoki Adult Asthma Study (SAAS). All asthma-related visits and prescribed medication over the study period were collected from medical records. Total cumulative ICS dose for the 12-year follow-up period was 3.4g (±SEM 0.1) per patient. Both respiratory specialists and GPs prescribed step-ups and step-downs in ICS treatment and in total 649 dose changes were noted during the follow-up (median 3(1-5) per patient). Patients with uncontrolled asthma received higher ICS doses throughout the follow-up period, and therefore, cumulative 12-year ICS dose (3.8g ± SEM 0.2) in this group was higher than that in those with partially controlled (3.4g ± SEM 0.2) or controlled disease (2.9g ± SEM 0.2) (p = 0.0001). Patients with uncontrolled asthma were also prescribed a higher number of ICS dose changes than patients with controlled disease. Despite frequent dose changes and high ICS doses during the 12-year follow-up, the level of asthma control remained poor in patients with uncontrolled asthma. This suggests that high ICS doses may not be effective enough for management of disease in patients with uncontrolled adult-onset asthma and novel targeted treatments are required. Copyright © 2018 Elsevier Ltd. All rights reserved.

Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age.

PubMed

Leuchter, Russia Ha-Vinh; Gui, Laura; Poncet, Antoine; Hagmann, Cornelia; Lodygensky, Gregory Anton; Martin, Ernst; Koller, Brigitte; Darqué, Alexandra; Bucher, Hans Ulrich; Hüppi, Petra Susan

2014-08-27

Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies. To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age. A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age. Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome. At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89). In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes. clinicaltrials.gov Identifier: NCT00413946.

The Fukushima nuclear accident and the pale grass blue butterfly: evaluating biological effects of long-term low-dose exposures.

PubMed

Hiyama, Atsuki; Nohara, Chiyo; Taira, Wataru; Kinjo, Seira; Iwata, Masaki; Otaki, Joji M

2013-08-12

On August 9th 2012, we published an original research article in Scientific Reports, concluding that artificial radionuclides released from the Fukushima Dai-ichi Nuclear Power Plant exerted genetically and physiologically adverse effects on the pale grass blue butterfly Zizeeria maha in the Fukushima area. Immediately following publication, many questions and comments were generated from all over the world. Here, we have clarified points made in the original paper and answered questions posed by the readers. The following points were clarified. (1) There are many advantages to using the pale grass blue butterfly as an indicator species. (2) The forewings of the individuals collected in Fukushima were significantly smaller than in the northern and southern localities. (3) We observed growth retardation in the butterflies from the Fukushima area. (4) The aberrant colour patterns in the butterflies obtained in the Fukushima area were different from the colour patterns induced by temperature and sibling crosses but similar to those induced by external and internal exposures to the artificial radionuclides and by a chemical mutagen, suggesting that genetic mutations caused the aberrations. (5) This species of butterfly has been plentiful in Fukushima area for at least half a century. We here present specimens collected from Fukushima Prefecture before the accident. (6) Mutation accumulation was detected by the increase in the abnormality rates from May 2011 to September 2011. (7) The abnormal traits were heritable. (8) Our sampling localities were not affected by the tsunami. (9) We used a high enough number of samples to obtain statistically significant results. (10) The standard rearing method was followed, producing normal adults in the control groups. (11) The exposure experiments successfully reproduced the results of the field work. This species of butterfly is vulnerable to long-term low-dose internal and external exposures; however, insect cells are known to be resistant to short-term high-dose irradiation. This discrepancy is reconcilable based on the differences in the experimental conditions. We are just beginning to understand the biological effects of long-term low-dose exposures in animals. Further research is necessary to accurately assess the possible biological effects of the accident.

Low dose radiation interactions with the transformation growth factor (TFG)-beta pathway

NASA Astrophysics Data System (ADS)

Maslowski, Amy Jesse

A major limiting factor for long-term, deep-space missions is the radiation dose to astronauts. Because the dose to the astronauts is a mixed field of low- and high-LET radiation, there is a need to understand the effects of both radiation types on whole tissue; however, there are limited published data on the effects of high-LET (linear-energy-transfer) radiation on tissue. Thus, we designed a perfusion chamber system for rat trachea in order to mimic in vivo respiratory tissue. We successfully maintained the perfused tracheal tissue ex vivo in a healthy and viable condition for up to three days. In addition, this project studied the effects of high-LET Fe particles on the overall transformation growth factor (TGF)-beta response after TGF-beta inactivation and compared the results to the TGF-beta response post x-ray irradiation. It was found that a TGF-beta response could be measured in the perfused tracheal tissue, for x-ray and Fe particle irradiations, despite the high autofluorescent background intrinsic to tissue. However, after comparing the TGF-beta response of x-ray irradiation to High-Z-High-energy (HZE) irradiation, there was not a significant difference in radiation types. The TGF-beta response in x-ray and HZE irradiated perfusion chambers was also measured over time post irradiation. It was found that for 6 hour and 8 hour post irradiation, the TGF-beta response was higher for lower doses of radiation than for higher doses. This is in contrast to the 0 hour fixation which found the TGF-beta response to increase with increased dose. The inverse relationship found for 6 hour and 8 hour fixation times may indicate a threshold response for TGF-beta response; i.e., for low doses, a threshold of dose must be reached for an immediate TGF-beta response, otherwise the tissue responds more slowly to the irradiation damage. This result was unexpected and will require further investigation to determine if the threshold can be determined for the 250 kVp x-rays and 1 Gev Fe particles.

Long-Term Effects of Exposure to Ionizing Irradiation on Periodontal Health Status – The Tinea capitis Cohort Study

PubMed Central

Sadetzki, Siegal; Chetrit, Angela; Sgan-Cohen, Harold D.; Mann, Jonathan; Amitai, Tova; Even-Nir, Hadas; Vered, Yuval

2015-01-01

Studies among long-term survivors of childhood cancer who had received high-dose irradiation therapy of 4–60 Gy, demonstrated acute and chronic dental effects, including periodontal diseases. However, the possible effects of low to moderate doses of radiation on dental health are sparse. The aim of this study is to investigate the association between childhood exposure to low–moderate doses of ionizing radiation and periodontal health following 50 years since exposure. The study population included 253 irradiated subjects (treated for Tinea capitis in the 1950s) and, 162 non-irradiated subjects. The estimated dose to the teeth was 0.2–0.4 Gy. Dental examination was performed according to the community periodontal index (CPI). Socioeconomic and health behavior variables were obtained through a personal questionnaire. Periodontal disease was operationally defined as “deep periodontal pockets.” A multivariate logistic regression model was used for the association of irradiation status and other independent variables with periodontal status. The results showed that among the irradiated subjects, 23%, (95% CI 18–28%) demonstrated complete edentulousness or insufficient teeth for CPI scoring as compared to 13% (95% CI 8–19%) among the non-irradiated subjects (p = 0.01). Periodontal disease was detected among 54% of the irradiated subjects as compared to 40% of the non-irradiated (p = 0.008). Controlling for education and smoking, the ORs for the association between radiation and periodontal disease were 1.61 (95% CI 1.01–2.57) and 1.95 (95% CI 1.1–3.5) for ever never and per 1 Gy absorbed in the salivary gland, respectively. In line with other studies, a protective effect for periodontal diseases among those with high education and an increased risk for ever smokers were observed. In conclusion, childhood exposure to low-moderate doses of ionizing radiation might be associated with later outcomes of dental health. The results add valuable data on the long-term health effects of exposure to ionizing radiation and support the implementation of the ALARA principle in childhood exposure to diagnostic procedure involving radiation. PMID:26539423

High-dose versus low-dose local anaesthetic for transversus abdominis plane block post-Caesarean delivery analgesia: a meta-analysis.

PubMed

Ng, S C; Habib, A S; Sodha, S; Carvalho, B; Sultan, P

2018-02-01

The optimal local-anaesthetic (LA) dose for transversus-abdominis-plane (TAP) block is unclear. In this meta-analysis, we aimed to determine whether TAP blocks for Caesarean delivery (CD) with low-dose (LD) LA demonstrated non-inferiority in terms of analgesic efficacy, compared with high-dose (HD) LA. A literature search was performed for randomised controlled trials examining the analgesic efficacy of TAP blocks vs control after CD. The different dosing used in these studies was classified as HD or LD (bupivacaine equivalents >50 or ≤50 mg per block side, respectively). The pooled results of each dose group vs control were indirectly compared using the Q test. The primary outcome was 24 h opioid consumption. Secondary outcomes included 6 and 24 h postoperative pain scores, time to first analgesia, 6 h opioid consumption, opioid-related side-effects, and maternal satisfaction. Fourteen studies consisting of 770 women (389 TAP and 381 control) were included. Compared with controls, the 24 h opioid consumption (milligram morphine equivalents) was lower in HD [mean difference (MD) 95% confidence interval (CI) -22.41 (-38.56, -6.26); P=0.007; I 2 =93%] and LD [MD 95% CI -16.29 (-29.74, -2.84); P=0.02; I 2 =98%] TAP groups. However, no differences were demonstrated between the HD and LD groups (P=0.57). There were also no differences between the HD and LD groups for the 6 h opioid consumption, time to first analgesia, 6 and 24 h pain scores, postoperative nausea and vomiting, pruritus, and maternal satisfaction. Low-dose TAP blocks for Caesarean delivery provide analgesia and opioid-sparing effects comparable with the high-dose blocks. This suggests that lower doses can be used to reduce local anaesthetic toxicity risk without compromising the analgesic efficacy. Copyright © 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Management of venous thromboembolism in patients with advanced cancer: a systematic review and meta-analysis.

PubMed

Noble, Simon I R; Shelley, Mike D; Coles, Bernadette; Williams, Susan M; Wilcock, Andrew; Johnson, Miriam J

2008-06-01

Venous thromboembolism is common in patients with cancer. However, no management guidelines exist for venous thromboembolism specific to patients with advanced progressive cancer. To help develop recommendations for practice, we have done a comprehensive review of anticoagulation treatment in patients with cancer, with particular focus on studies that included patients with advanced disease. Data from 19 publications, including randomised, prospective, and retrospective studies suggest that: long-term full-dose low-molecular-weight heparin (LMWH) is more effective than warfarin in the secondary prophylaxis of venous thromboembolism in patients with cancer of any stage, performance status, or prognosis; warfarin should not be used in patients with advancing progressive disease; and in patients at high risk of bleeding, full-dose LMWH for 7 days followed by a long-term decreased fixed dose long term can be considered. The optimum treatment duration is unclear, but because the prothrombotic tendency will persist in patients with advanced cancer, indefinite treatment is generally recommended. For patients with contraindications to anticoagulation, inferior-vena-caval filters can be considered, but their use needs careful patient selection. Ultimately, the decision to initiate, continue, and stop anticoagulation will need to be made on an individual basis, guided by the available evidence, the patient's circumstances, and their informed preferences.

Oxidative stress and myocardial dysfunction in young rabbits after short term anabolic steroids administration.

PubMed

Germanakis, Ioannis; Tsarouhas, Konstantinos; Fragkiadaki, Persefoni; Tsitsimpikou, Christina; Goutzourelas, Nikolaos; Champsas, Maria Christakis; Stagos, Demetrios; Rentoukas, Elias; Tsatsakis, Aristidis M

2013-11-01

The present study focuses on the short term effects of repeated low level administration of turinabol and methanabol on cardiac function in young rabbits (4 months-old). The experimental scheme consisted of two oral administration periods, lasting 1 month each, interrupted by 1-month wash-out period. Serial echocardiographic evaluation at the end of all three experimental periods was performed in all animals. Oxidative stress markers have also been monitored at the end of each administration period. Treated animals originally showed significantly increased myocardial mass and systolic cardiac output, which normalized at the end of the wash out period. Re-administration led to increased cardiac output, at the cost though of a progressive myocardial mass reduction. A dose-dependent trend towards impaired longitudinal systolic, diastolic and global myocardial function was also observed. The adverse effects were more pronounced in the methanabol group. For both anabolic steroids studied, the low dose had no significant effects on oxidative stress markers monitored, while the high dose created a hostile oxidative environment. In conclusion, anabolic administration has been found to create a possible deleterious long term effect on the growth of the immature heart and should be strongly discouraged especially in young human subjects. Copyright © 2013 Elsevier Ltd. All rights reserved.

Determining the Critical Dose Threshold of Electron-Induced Electron Yield for Minimally Charged Highly Insulating Materials

NASA Astrophysics Data System (ADS)

Hoffmann, Ryan; Dennison, J. R.; Abbott, Jonathan

2006-03-01

When incident energetic electrons interact with a material, they excite electrons within the material to escape energies. The electron emission is quantified as the ratio of emitted electrons to incident particle flux, termed electron yield. Measuring the electron yield of insulators is difficult due to dynamic surface charge accumulation which directly affects landing energies and the potential barrier that emitted electrons must overcome. Our recent measurements of highly insulating materials have demonstrated significant changes in total yield curves and yield decay curves for very small electron doses equivalent to a trapped charge density of <10^10 electrons /cm^3. The Chung-Everhart theory provides a basic model for the behavior of the electron emission spectra which we relate to yield decay curves as charge is allowed to accumulate. Yield measurements as a function of dose for polyimide (Kapton^TM) and microcrystalline SiO2 will be presented. We use our data and model to address the question of whether there is a minimal dose threshold at which the accumulated charge no longer affects the yield.

Duration of protection against hepatitis A for the current two-dose vaccine compared to a three-dose vaccine schedule in children

PubMed Central

Raczniak, Gregory A.; Thomas, Timothy K.; Bulkow, Lisa R.; Negus, Susan E.; Zanis, Carolyn L.; Bruce, Michael G.; Spradling, Philip R.; Teshale, Eyasu H.; McMahon, Brian J.

2015-01-01

Background Hepatitis A is mostly a self-limiting disease but causes substantial economic burden. Consequently, United States Advisory Committee for Immunization Practices recommends inactivated hepatitis A vaccination for all children beginning at age 1 year and for high risk adults. The hepatitis A vaccine is highly effective but the duration of protection is unknown. Methods We examined the proportion of children with protective hepatitis A antibody levels (anti-HAV ≥20 mIU/mL) as well as the geometric mean concentration (GMC) of anti-HAV in a cross sectional convenience sample of individuals aged 12–24 years, who had been vaccinated with a two-dose schedule in childhood, with the initial dose at least 5 years ago. We compared a subset of data from persons vaccinated with two-doses (720 EL.U.) at age 3–6 years with a demographically similar prospective cohort that received a three-dose (360 EL.U.) schedule and have been followed for 17 years. Results No significant differences were observed when comparing GMC between the two cohorts at 10 (P = 0.467), 12 (P = 0.496), and 14 (P = 0.175) years post-immunization. For the three-dose cohort, protective antibody levels remain for 17 years and have leveled-off over the past 7 years. Conclusion The two- and three-dose schedules provide similar protection >14 years after vaccination, indicating a booster dose is not needed at this time. Plateauing anti-HAV GMC levels suggest protective antibody levels may persist long-term. PMID:23470239

High-dose anti-histamine use and risk factors in children with urticaria

PubMed Central

Uysal, Pınar; Avcil, Sibelnur; Erge, Duygu

2016-01-01

Aim The drugs of choice in the treatment of urticaria in children are H1-antihistamines. The aim of the study was to evaluate children with urticaria and define risk factors for requirement of high-dose H1-antihistamines in children with urticaria. Material and Methods The medical data of children who were diagnosed as having urticaria admitted to our outpatient clinic between January 2014 and January 2016 were searched. The medical histories, concomitant atopic diseases, parental atopy histories, medications, treatment responses, blood eosinophil and basophil counts, and serum total IgE levels were recorded. In addition, the urticaria activity score for seven days, autoimmune antibody tests, and skin prick test results were evaluated in children with chronic urticaria. Results The numbers of the children with acute and chronic urticaria were 138 and 92, respectively. The age of the children with chronic urticaria was higher than that of those with acute urticaria (p<0.0001). There was no difference between the two groups in terms of blood eosinophil and basophil counts, and serum total IgE levels (p>0.05). There was a negative correlation between blood eosinophil count and the UAS7 score in children with chronic urticaria (r=−0.276, p=0.011). Chronic urticaria and requirement of high dose H1-antihistamines were significant in children aged ≥10 years (p<0.001, p=0.015). High UAS7 score (OR: 1.09; CI 95%: [1.03–1.15]) and basopenia (OR: 6.77; CI 95%: [2.01–22.75]) were associated with the requirement of high-dose H1-AH in children with chronic urticaria. Conclusion The requirement of high-dose H1-antihistamines was higher with children’s increasing age. Disease severity and basopenia were risk factors for the requirement of high-dose H1-antihistamines. PMID:28123332

Long-Term Outcomes Among Adult Survivors of Childhood Central Nervous System Malignancies in the Childhood Cancer Survivor Study

PubMed Central

Liu, Qi; Yasui, Yutaka; Huang, Sujuan; Ness, Kirsten K.; Leisenring, Wendy; Hudson, Melissa M.; Donaldson, Sarah S.; King, Allison A.; Stovall, Marilyn; Krull, Kevin R.; Robison, Leslie L.; Packer, Roger J.

2009-01-01

Background Adult survivors of childhood central nervous system (CNS) malignancies are at high risk for long-term morbidity and late mortality. However, patterns of late mortality, the long-term risks of subsequent neoplasms and debilitating medical conditions, and sociodemographic outcomes have not been comprehensively characterized for individual diagnostic and treatment groups. Methods We collected information on treatment, mortality, chronic medical conditions, and neurocognitive functioning of adult 5-year survivors of CNS malignancies diagnosed between 1970 and 1986 within the Childhood Cancer Survivor Study. Using competing risk framework, we calculated cumulative mortality according to cause of death and cumulative incidence of subsequent neoplasms according to exposure and dose of cranial radiation therapy (RT). Neurocognitive impairment and socioeconomic outcomes were assessed with respect to dose of CNS radiotherapy to specific brain regions. Cumulative incidence of chronic medical conditions was compared between survivors and siblings using Cox regression models. All tests of statistical significance were two-sided. Results Among all eligible 5-year survivors (n = 2821), cumulative late mortality at 30 years was 25.8% (95% confidence interval [CI] = 23.4% to 28.3%), due primarily to recurrence and/or progression of primary disease. Patients who received cranial RT of 50 Gy or more (n = 813) had a cumulative incidence of a subsequent neoplasm within the CNS of 7.1% (95% CI = 4.5% to 9.6%) at 25 years from diagnosis compared with 1.0% (95% CI = 0% to 2.3%) for patients who had no RT. Survivors had higher risk than siblings of developing new endocrine, neurological, or sensory complications 5 or more years after diagnosis. Neurocognitive impairment was high and proportional to radiation dose for specific tumor types. There was a dose-dependent association between RT to the frontal and/or temporal lobes and lower rates of employment, and marriage. Conclusions Survivors of childhood CNS malignancies are at high risk for late mortality and for developing subsequent neoplasms and chronic medical conditions. Care providers should be informed of these risks so they can provide risk-directed care and develop screening guidelines. PMID:19535780

Epigenetic effects of prenatal estradiol-17β exposure on the reproductive system of pigs.

PubMed

Kradolfer, David; Flöter, Veronika L; Bick, Jochen T; Fürst, Rainer W; Rode, Kristina; Brehm, Ralph; Henning, Heiko; Waberski, Dagmar; Bauersachs, Stefan; Ulbrich, Susanne E

2016-07-15

There is growing evidence that early life exposure to endocrine disrupting chemicals might increase the risk for certain adult onset diseases, in particular reproductive health problems and hormone dependent cancers. Studies in rodents suggest that perinatal exposure to even low doses of estrogenic substances can cause adverse effects, including epigenetic reprogramming of the prostate and increased formation of precancerous lesions. We analyzed the effects of an in utero exposure to the strongest natural estrogen, estradiol-17β, in a pig model. Two different low and one high dose of estradiol-17β (0.05, 10 and 1000 μg/kg body weight/day) were orally applied to gilts during pregnancy and potential effects on the reproductive system of the offspring were analyzed. No significant effects on sperm vitality parameters and testes size were observed in adult boars. However, prenatal exposure to the high dose decreased absolute, but not relative weight of the testes in prepubertal piglets. RNA sequencing revealed significantly regulated genes of the prepubertal prostate, while testes and uteri were not affected. Notably, we found an increased prostate expression of CCDC80 and a decreased ADH1C expression in the low dose treatment groups. BGN and SPARC, two genes associated with prostate tumor progression, were as well more abundant in exposed animals. Strikingly, the gene body DNA methylation level of BGN was accordingly increased in the high dose group. Thus, while only prenatal exposure to a high dose of estrogen altered testes development and local DNA methylation of the prostate, even low dose exposure had significant effects on gene expression in the prostate of prepubertal piglet offspring. The relevance of these distinct, but subtle transcriptional changes following low dose treatment lacking a clear phenotype calls for further long-term investigations. An epigenetic reprogramming of the pig prostate due to prenatal estrogen cannot be neglected. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Monitoring the eye lens: which dose quantity is adequate?

NASA Astrophysics Data System (ADS)

Behrens, R.; Dietze, G.

2010-07-01

Recent epidemiological studies suggest a rather low dose threshold (below 0.5 Gy) for the induction of a cataract of the eye lens. Some other studies even assume that there is no threshold at all. Therefore, protection measures have to be optimized and current dose limits for the eye lens may be reduced in the future. The question of which personal dose equivalent quantity is appropriate for monitoring the dose to the eye lens arises from this situation. While in many countries dosemeters calibrated in terms of the dose equivalent quantity Hp(0.07) have been seen as being adequate for monitoring the dose to the eye lens, this might be questionable in the case of reduced dose limits and, thus, it may become necessary to use the dose equivalent quantity Hp(3) for this purpose. To discuss this question, the dose conversion coefficients for the equivalent dose of the eye lens (in the following eye lens dose) were determined for realistic photon and beta radiation fields and compared with the values of the corresponding conversion coefficients for the different operational quantities. The values obtained lead to the following conclusions: in radiation fields where most of the dose comes from photons, especially x-rays, it is appropriate to use dosemeters calibrated in terms of Hp(0.07) on a slab phantom, while in other radiation fields (dominated by beta radiation or unknown contributions of photon and beta radiation) dosemeters calibrated in terms of Hp(3) on a slab phantom should be used. As an alternative, dosemeters calibrated in terms of Hp(0.07) on a slab phantom could also be used; however, in radiation fields containing beta radiation with the end point energy near 1 MeV, an overestimation of the eye lens dose by up to a factor of 550 is possible.

Monitoring the eye lens: which dose quantity is adequate?

PubMed

Behrens, R; Dietze, G

2010-07-21

Recent epidemiological studies suggest a rather low dose threshold (below 0.5 Gy) for the induction of a cataract of the eye lens. Some other studies even assume that there is no threshold at all. Therefore, protection measures have to be optimized and current dose limits for the eye lens may be reduced in the future. The question of which personal dose equivalent quantity is appropriate for monitoring the dose to the eye lens arises from this situation. While in many countries dosemeters calibrated in terms of the dose equivalent quantity H(p)(0.07) have been seen as being adequate for monitoring the dose to the eye lens, this might be questionable in the case of reduced dose limits and, thus, it may become necessary to use the dose equivalent quantity H(p)(3) for this purpose. To discuss this question, the dose conversion coefficients for the equivalent dose of the eye lens (in the following eye lens dose) were determined for realistic photon and beta radiation fields and compared with the values of the corresponding conversion coefficients for the different operational quantities. The values obtained lead to the following conclusions: in radiation fields where most of the dose comes from photons, especially x-rays, it is appropriate to use dosemeters calibrated in terms of H(p)(0.07) on a slab phantom, while in other radiation fields (dominated by beta radiation or unknown contributions of photon and beta radiation) dosemeters calibrated in terms of H(p)(3) on a slab phantom should be used. As an alternative, dosemeters calibrated in terms of H(p)(0.07) on a slab phantom could also be used; however, in radiation fields containing beta radiation with the end point energy near 1 MeV, an overestimation of the eye lens dose by up to a factor of 550 is possible.

A water extract of Mucuna pruriens provides long-term amelioration of parkinsonism with reduced risk for dyskinesias.

PubMed

Lieu, Christopher A; Kunselman, Allen R; Manyam, Bala V; Venkiteswaran, Kala; Subramanian, Thyagarajan

2010-08-01

Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinson's disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of M. pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE+BZ), LD+BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD+BZ or MPE+BZ at high (6mg/kg) and medium (4mg/kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD+BZ at low doses (2mg/kg) did not provide significant alleviation of parkinsonism. In contrast, MPE+BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12mg/kg and 20mg/kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD+BZ or MPE+BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD+BZ. These findings suggest that M. pruriens contains water-soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term anti-parkinsonian effects of a parenterally administered water extract of M. pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD.

A Water Extract of Mucuna pruriens Provides Long-Term Amelioration of Parkinsonism with Reduced Risk for Dyskinesias

PubMed Central

Lieu, Christopher A.; Kunselman, Allen R.; Manyam, Bala V.; Venkiteswaran, Kala; Subramanian, Thyagarajan

2010-01-01

Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinson's disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of Mucuna pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE+BZ), LD+BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD+BZ or MPE+BZ at high (6mg/Kg) and medium (4mg/Kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD+BZ at low doses (2mg/Kg) did not provide significant alleviation of parkinsonism. In contrast, MPE+BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12mg/Kg and 20mg/Kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD+BZ or MPE+BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD+BZ. These findings suggest that Mucuna pruriens contains water soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term antiparkinsonian effects of a parenterally administered water extract of Mucuna pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD. PMID:20570206

CURRENT USE AND FUTURE NEEDS OF BIODOSIMETRY IN STUDIES OF LONG-TERM HEALTH RISK FOLLOWING RADIATION EXPOSURE

PubMed Central

Simon, Steven L.; Bouville, André; Kleinerman, Ruth

2009-01-01

Biodosimetry measurements can potentially be an important and integral part of the dosimetric methods used in long-term studies of health risk following radiation exposure. Such studies rely on accurate estimation of doses to the whole body or to specific organs of individuals in order to derive reliable estimates of cancer risk. However, dose estimates based on analytical dose reconstruction (i.e., models) or personnel monitoring measurements, e.g., film-badges, can have substantial uncertainty. Biodosimetry can potentially reduce uncertainty in health risk studies by corroboration of model-based dose estimates or by using them to assess bias in dose models. While biodosimetry has begun to play a more significant role in long-term health risk studies, its use is still generally limited in that context due to one or more factors including, inadequate limits of detection, large inter-individual variability of the signal measured, high per-sample cost, and invasiveness. Presently, the most suitable biodosimetry methods for epidemiologic studies are chromosome aberration frequencies from fluorescence in situ hybridization (FISH) of peripheral blood lymphocytes and electron paramagnetic resonance (EPR) measurements made on tooth enamel. Both types of measurements, however, are usually invasive and require difficult to obtain biological samples. Moreover, doses derived from these methods are not always directly relevant to the tissues of interest. To increase the value of biodosimetry to epidemiologic studies, a number of issues need to be considered including limits of detection, effects of inhomogenous exposure of the body, how to extrapolate from the tissue sampled to the tissues of interest, and how to adjust dosimetry models applied to large populations based on sparse biodosimetry measurements. The requirements of health risk studies suggest a set of characteristics that, if satisfied by new biodosimetry methods, would increase the overall usefulness of biodosimetry to determining radiation health risks. PMID:20065672

Proton pump inhibitors and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals.

PubMed

Maggio, Marcello; Corsonello, Andrea; Ceda, Gian Paolo; Cattabiani, Chiara; Lauretani, Fulvio; Buttò, Valeria; Ferrucci, Luigi; Bandinelli, Stefania; Abbatecola, Angela Marie; Spazzafumo, Liana; Lattanzio, Fabrizia

2013-04-08

The use of proton pump inhibitors (PPIs) has rapidly increased during the past several years. However, concern remains about risks associated with their long-term use in older populations. To investigate the relationship between the use of PPIs and the risk of death or the combined end point of death or rehospitalization in older patients discharged from acute care hospitals. We investigated the relationship between PPI use and study outcomes using time-dependent Cox proportional hazards regression in patients 65 years or older discharged from acute care medical wards from April 1 to June 30, 2007. Eleven acute care medical wards. Four hundred ninety-one patients (mean [SD] age, 80.0 [5.9] years). Mortality and the combined end point of death or rehospitalization. RESULTS The use of PPIs was independently associated with mortality (hazard ratio, 1.51 [95% CI, 1.03-2.77]) but not with the combined end point (1.49 [0.98-2.17]). An increased risk of mortality was observed among patients exposed to high-dose PPIs vs none (hazard ratio, 2.59 [95% CI, 1.22-7.16]). In older patients discharged from acute care hospitals, the use of high-dose PPIs is associated with increased 1-year mortality. Randomized controlled studies including older frail patients are needed. In the meantime, physicians need to use caution and balance benefits and harms in long-term prescription of high-dose PPIs.

High Energy Resolution Hyperspectral X-Ray Imaging for Low-Dose Contrast-Enhanced Digital Mammography.

PubMed

Pani, Silvia; Saifuddin, Sarene C; Ferreira, Filipa I M; Henthorn, Nicholas; Seller, Paul; Sellin, Paul J; Stratmann, Philipp; Veale, Matthew C; Wilson, Matthew D; Cernik, Robert J

2017-09-01

Contrast-enhanced digital mammography (CEDM) is an alternative to conventional X-ray mammography for imaging dense breasts. However, conventional approaches to CEDM require a double exposure of the patient, implying higher dose, and risk of incorrect image registration due to motion artifacts. A novel approach is presented, based on hyperspectral imaging, where a detector combining positional and high-resolution spectral information (in this case based on Cadmium Telluride) is used. This allows simultaneous acquisition of the two images required for CEDM. The approach was tested on a custom breast-equivalent phantom containing iodinated contrast agent (Niopam 150®). Two algorithms were used to obtain images of the contrast agent distribution: K-edge subtraction (KES), providing images of the distribution of the contrast agent with the background structures removed, and a dual-energy (DE) algorithm, providing an iodine-equivalent image and a water-equivalent image. The high energy resolution of the detector allowed the selection of two close-by energies, maximising the signal in KES images, and enhancing the visibility of details with the low surface concentration of contrast agent. DE performed consistently better than KES in terms of contrast-to-noise ratio of the details; moreover, it allowed a correct reconstruction of the surface concentration of the contrast agent in the iodine image. Comparison with CEDM with a conventional detector proved the superior performance of hyperspectral CEDM in terms of the image quality/dose tradeoff.

Comparing photon and proton-based hypofractioned SBRT for prostate cancer accounting for robustness and realistic treatment deliverability.

PubMed

Goddard, Lee C; Brodin, N Patrik; Bodner, William R; Garg, Madhur K; Tomé, Wolfgang A

2018-05-01

To investigate whether photon or proton-based stereotactic body radiation therapy (SBRT is the preferred modality for high dose hypofractionation prostate cancer treatment. Achievable dose distributions were compared when uncertainties in target positioning and range uncertainties were appropriately accounted for. 10 patients with prostate cancer previously treated at our institution (Montefiore Medical Center) with photon SBRT using volumetric modulated arc therapy (VMAT) were identified. MRI images fused to the treatment planning CT allowed for accurate target and organ at risk (OAR) delineation. The clinical target volume was defined as the prostate gland plus the proximal seminal vesicles. Critical OARs include the bladder wall, bowel, femoral heads, neurovascular bundle, penile bulb, rectal wall, urethra and urogenital diaphragm. Photon plan robustness was evaluated by simulating 2 mm isotropic setup variations. Comparative proton SBRT plans employing intensity modulated proton therapy (IMPT) were generated using robust optimization. Plan robustness was evaluated by simulating 2 mm setup variations and 3% or 1% Hounsfield unit (HU) calibration uncertainties. Comparable maximum OAR doses are achievable between photon and proton SBRT, however, robust optimization results in higher maximum doses for proton SBRT. Rectal maximum doses are significantly higher for Robust proton SBRT with 1% HU uncertainty compared to photon SBRT (p = 0.03), whereas maximum doses were comparable for bladder wall (p = 0.43), urethra (p = 0.82) and urogenital diaphragm (p = 0.50). Mean doses to bladder and rectal wall are lower for proton SBRT, but higher for neurovascular bundle, urethra and urogenital diaphragm due to increased lateral scatter. Similar target conformality is achieved, albeit with slightly larger treated volume ratios for proton SBRT, >1.4 compared to 1.2 for photon SBRT. Similar treatment plans can be generated with IMPT compared to VMAT in terms of target coverage, target conformality, and OAR sparing when range and HU uncertainties are neglected. However, when accounting for these uncertainties during robust optimization, VMAT outperforms IMPT in terms of achievable target conformity and OAR sparing. Advances in knowledge: Comparison between achievable dose distributions using modern, robust optimization of IMPT for high dose per fraction SBRT regimens for the prostate has not been previously investigated.

Increased Transcription of Immune and Metabolic Pathways in Naive and Allergic Mice Exposed to Diesel Exhaust

EPA Science Inventory

Diesel exhaust (DE) has been shown to enhance allergic sensitization in animals following high dose instillation or chronic inhalation exposure scenarios. The purpose of this study was to determine if short term exposures to diluted DE enhance allergic immune responses to antigen...

21 CFR 522.960c - Flumethasone solution.

Code of Federal Regulations, 2012 CFR

2012-04-01

... dose. A protein-rich diet is useful in dogs and cats on long-term therapy to counteract nitrogen loss if it should occur. A small amount of potassium chloride daily in the diet will counteract excessive potassium loss if this is present. (c) It has been demonstrated that corticosteroids, especially at high...

21 CFR 522.960c - Flumethasone solution.

Code of Federal Regulations, 2010 CFR

2010-04-01

... dose. A protein-rich diet is useful in dogs and cats on long-term therapy to counteract nitrogen loss if it should occur. A small amount of potassium chloride daily in the diet will counteract excessive potassium loss if this is present. (c) It has been demonstrated that corticosteroids, especially at high...

21 CFR 522.960c - Flumethasone solution.

Code of Federal Regulations, 2013 CFR

2013-04-01

... dose. A protein-rich diet is useful in dogs and cats on long-term therapy to counteract nitrogen loss if it should occur. A small amount of potassium chloride daily in the diet will counteract excessive potassium loss if this is present. (c) It has been demonstrated that corticosteroids, especially at high...

21 CFR 522.960c - Flumethasone solution.

Code of Federal Regulations, 2011 CFR

2011-04-01

... dose. A protein-rich diet is useful in dogs and cats on long-term therapy to counteract nitrogen loss if it should occur. A small amount of potassium chloride daily in the diet will counteract excessive potassium loss if this is present. (c) It has been demonstrated that corticosteroids, especially at high...

Longitudinal study of alcohol consumption and high-density lipoprotein concentrations: A community-based study

USDA-ARS?s Scientific Manuscript database

Background: In cross-sectional studies and short-term clinical trials, it has been suggested that there is a positive dose-response relation between alcohol consumption and HDL concentrations. However, prospective data have been limited. Objective: We sought to determine the association between tota...

High-Dose Benzodiazepine Dependence: A Qualitative Study of Patients’ Perceptions on Initiation, Reasons for Use, and Obtainment

PubMed Central

Liebrenz, Michael; Schneider, Marcel; Buadze, Anna; Gehring, Marie-Therese; Dube, Anish; Caflisch, Carlo

2015-01-01

Background High-dose benzodiazepine (BZD) dependence is associated with a wide variety of negative health consequences. Affected individuals are reported to suffer from severe mental disorders and are often unable to achieve long-term abstinence via recommended discontinuation strategies. Although it is increasingly understood that treatment interventions should take subjective experiences and beliefs into account, the perceptions of this group of individuals remain under-investigated. Methods We conducted an exploratory qualitative study with 41 adult subjects meeting criteria for (high-dose) BZD-dependence, as defined by ICD-10. One-on-one in-depth interviews allowed for an exploration of this group’s views on the reasons behind their initial and then continued use of BZDs, as well as their procurement strategies. Mayring’s qualitative content analysis was used to evaluate our data. Results In this sample, all participants had developed explanatory models for why they began using BZDs. We identified a multitude of reasons that we grouped into four broad categories, as explaining continued BZD use: (1) to cope with symptoms of psychological distress or mental disorder other than substance use, (2) to manage symptoms of physical or psychological discomfort associated with somatic disorder, (3) to alleviate symptoms of substance-related disorders, and (4) for recreational purposes, that is, sensation-seeking and other social reasons. Subjects often considered BZDs less dangerous than other substances and associated their use more often with harm reduction than as recreational. Specific obtainment strategies varied widely: the majority of participants oscillated between legal and illegal methods, often relying on the black market when faced with treatment termination. Conclusions Irrespective of comorbidity, participants expressed a clear preference for medically related explanatory models for their BZD use. We therefore suggest that clinicians consider patients’ motives for long-term, high-dose BZD use when formulating treatment plans for this patient group, especially since it is known that individuals are more compliant with approaches they perceive to be manageable, tolerable, and effective. PMID:26556055

Evaluation of radiotherapy techniques for radical treatment of lateralised oropharyngeal cancers : Dosimetry and NTCP.

PubMed

McQuaid, D; Dunlop, A; Nill, S; Franzese, C; Nutting, C M; Harrington, K J; Newbold, K L; Bhide, S A

2016-08-01

The aim of this study was to investigate potential advantages and disadvantages of three-dimensional conformal radiotherapy (3DCRT), multiple fixed-field intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) in terms of dose to the planning target volume (PTV), organs at risk (OARs) and normal tissue complication probability (NTCP) for delivering ipsilateral radiotherapy. 3DCRT, IMRT and VMAT were compared in patients with well-lateralised primary tonsillar cancers who underwent primary radical ipsilateral radiotherapy. The following parameters were compared: conformity index (CI); homogeneity index (HI); dose-volume histograms (DVHs) of PTVs and OARs; NTCP, risk of radiation-induced cancer and dose accumulation during treatment. IMRT and VMAT were superior to 3DCRT in terms of CI, HI and dose to the target volumes, as well as mandible and dose accumulation robustness. The techniques were equivalent in terms of dose and NTCP for the contralateral oral cavity, contralateral submandibular gland and mandible, when specific dose constraint objectives were used on the oral cavity volume. Although the volume of normal tissue exposed to low-dose radiation was significantly higher with IMRT and VMAT, the risk of radiation-induced secondary malignancy was dependant on the mathematical model used. This study demonstrates the superiority of IMRT/VMAT techniques over 3DCRT in terms of dose homogeneity, conformity and consistent dose delivery to the PTV throughout the course of treatment in patients with lateralised oropharyngeal cancers. Dosimetry and NTCP calculations show that these techniques are equivalent to 3DCRT with regard to the risk of acute mucositis when specific dose constraint objectives were used on the contralateral oral cavity OAR.

Lorcaserin, a 5-HT2C Agonist, Decreases Nicotine Self-Administration in Female Rats

PubMed Central

Johnson, Joshua E.; Slade, Susan; Wells, Corinne; Cauley, Marty; Petro, Ann; Rose, Jed E.

2011-01-01

Lorcaserin, a selective 5-hydroxytryptamine2C (5-HT2C) agonist, has been shown to facilitate weight loss in obese populations. It was assessed for its efficacy in reducing nicotine self-administration in young adult female Sprague-Dawley rats. The effect of short-term doses (subcutaneous) on nicotine self-administration (0.03 mg/kg per infusion) with a fixed ratio 1 schedule was assessed in 3-h sessions. Short-term lorcaserin doses (0.3125–20 mg/kg) were administered in a counterbalanced order. Significant reduction of nicotine self-administration was achieved with all of the short-term doses in this range. Tests of lorcaserin on locomotor activity detected prominent sedative effects at doses greater than 1.25 mg/kg with more modest transient effects seen at 0.625 to 1.25 mg/kg. Long-term effects of lorcaserin on locomotor activity were tested with repeated injections with 0.625 mg/kg lorcaserin 10 times over 2 weeks. This low lorcaserin dose did not cause an overall change in locomotor activity relative to that of saline-injected controls. Long-term lorcaserin (0.625 mg/kg) significantly reduced nicotine self-administration over a 2-week period of repeated injections. Long-term lorcaserin at this same dose had no significant effects on food self-administration over the same 2-week period of repeated injections. These studies support development of the 5-HT2C agonist lorcaserin to aid tobacco smoking cessation. PMID:21636655

Lorcaserin, a 5-HT2C agonist, decreases nicotine self-administration in female rats.

PubMed

Levin, Edward D; Johnson, Joshua E; Slade, Susan; Wells, Corinne; Cauley, Marty; Petro, Ann; Rose, Jed E

2011-09-01

Lorcaserin, a selective 5-hydroxytryptamine(2C) (5-HT(2C)) agonist, has been shown to facilitate weight loss in obese populations. It was assessed for its efficacy in reducing nicotine self-administration in young adult female Sprague-Dawley rats. The effect of short-term doses (subcutaneous) on nicotine self-administration (0.03 mg/kg per infusion) with a fixed ratio 1 schedule was assessed in 3-h sessions. Short-term lorcaserin doses (0.3125-20 mg/kg) were administered in a counterbalanced order. Significant reduction of nicotine self-administration was achieved with all of the short-term doses in this range. Tests of lorcaserin on locomotor activity detected prominent sedative effects at doses greater than 1.25 mg/kg with more modest transient effects seen at 0.625 to 1.25 mg/kg. Long-term effects of lorcaserin on locomotor activity were tested with repeated injections with 0.625 mg/kg lorcaserin 10 times over 2 weeks. This low lorcaserin dose did not cause an overall change in locomotor activity relative to that of saline-injected controls. Long-term lorcaserin (0.625 mg/kg) significantly reduced nicotine self-administration over a 2-week period of repeated injections. Long-term lorcaserin at this same dose had no significant effects on food self-administration over the same 2-week period of repeated injections. These studies support development of the 5-HT(2C) agonist lorcaserin to aid tobacco smoking cessation.

Eye lens dosimetry in interventional cardiology: results of staff dose measurements and link to patient dose levels.

PubMed

Antic, V; Ciraj-Bjelac, O; Rehani, M; Aleksandric, S; Arandjic, D; Ostojic, M

2013-01-01

Workers involved in interventional cardiology procedures receive high eye lens dose if protection is not used. Currently, there is no suitable method for routine use for the measurement of eye dose. Since most angiography machines are equipped with suitable patient dosemeters, deriving factors linking staff eye doses to the patient doses can be helpful. In this study the patient kerma-area product, cumulative dose at an interventional reference point and eye dose in terms of Hp(3) of the cardiologists, nurses and radiographers for interventional cardiology procedures have been measured. Correlations between the patient dose and the staff eye dose were obtained. The mean eye dose was 121 µSv for the first operator, 33 µSv for the second operator/nurse and 12 µSv for radiographer. Normalised eye lens doses per unit kerma-area product were 0.94 µSv Gy⁻¹ cm⁻² for the first operator, 0.33 µSv Gy⁻¹ cm⁻² for the second operator/nurse and 0.16 µSv Gy⁻¹ cm⁻² for radiographers. Statistical analysis indicated that there is a weak but significant (p < 0.01) correlation between the eye dose and the kerma-area product for all three staff categories. These values are based on a local practice and may provide useful reference for other studies for validation and for wider utilisation in assessing the eye dose using patient dose values.

The similia principle: results obtained in a cellular model system.

PubMed

Wiegant, Fred; Van Wijk, Roeland

2010-01-01

This paper describes the results of a research program focused on the beneficial effect of low dose stress conditions that were applied according to the similia principle to cells previously disturbed by more severe stress conditions. In first instance, we discuss criteria for research on the similia principle at the cellular level. Then, the homologous ('isopathic') approach is reviewed, in which the initial (high dose) stress used to disturb cellular physiology and the subsequent (low dose) stress are identical. Beneficial effects of low dose stress are described in terms of increased cellular survival capacity and at the molecular level as an increase in the synthesis of heat shock proteins (hsps). Both phenomena reflect a stimulation of the endogenous cellular self-recovery capacity. Low dose stress conditions applied in a homologous approach stimulate the synthesis of hsps and enhance survival in comparison with stressed cells that were incubated in the absence of low dose stress conditions. Thirdly, the specificity of the low dose stress condition is described where the initial (high dose) stress is different in nature from the subsequently applied (low dose) stress; the heterologous or 'heteropathic' approach. The results support the similia principle at the cellular level and add to understanding of how low dose stress conditions influence the regulatory processes underlying self-recovery. In addition, the phenomenon of 'symptom aggravation' which is also observed at the cellular level, is discussed in the context of self-recovery. Finally, the difference in efficiency between the homologous and the heterologous approach is discussed; a perspective is indicated for further research; and the relationship between studies on the similia principle and the recently introduced concept of 'postconditioning hormesis' is emphasized. Copyright 2009 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.

Successful pregnancy following very high-dose total body irradiation (1575 cGy) and bone marrow transplantation in a woman with acute myeloid leukemia.

PubMed

Wang, W S; Tzeng, C H; Hsieh, R K; Chiou, T J; Liu, J H; Yen, C C; Chen, P M

1998-02-01

A 22-year-old woman had a normal full-term delivery 6 years after a successful allogeneic bone marrow transplantation (BMT) for acute myeloid leukemia (AML). Conditioning therapy consisted of cyclophosphamide (120 mg/kg) and total body irradiation (TBI) to a total of 1575 cGy in seven fractions (225 cGy x 7, at a dose rate of 3.5 cGy/min). Graft-versus-host disease prophylaxis was with methotrexate and cyclosporin A. Grade I acute GVHD developed after BMT but there was no chronic GVHD. She became amenorrhoeic after BMT and serial gonadal testing indicated hypergonadotrophic hypogonadism. She became pregnant and delivered a full-term, healthy baby 6 years after BMT. Successful pregnancy after TBI of more than 1200 cGy is extremely rare. This case, to the best of our knowledge, is the second patient who received a higher dose of TBI (1575 cGy) to have a successful pregnancy. This and previous reports indicate that normal pregnancy is possible after BMT with TBI in excess of 1200 cGy.

Ultra-low power high temperature and radiation hard complementary metal-oxide-semiconductor (CMOS) silicon-on-insulator (SOI) voltage reference.

PubMed

Boufouss, El Hafed; Francis, Laurent A; Kilchytska, Valeriya; Gérard, Pierre; Simon, Pascal; Flandre, Denis

2013-12-13

This paper presents an ultra-low power CMOS voltage reference circuit which is robust under biomedical extreme conditions, such as high temperature and high total ionized dose (TID) radiation. To achieve such performances, the voltage reference is designed in a suitable 130 nm Silicon-on-Insulator (SOI) industrial technology and is optimized to work in the subthreshold regime of the transistors. The design simulations have been performed over the temperature range of -40-200 °C and for different process corners. Robustness to radiation was simulated using custom model parameters including TID effects, such as mobilities and threshold voltages degradation. The proposed circuit has been tested up to high total radiation dose, i.e., 1 Mrad (Si) performed at three different temperatures (room temperature, 100 °C and 200 °C). The maximum drift of the reference voltage V(REF) depends on the considered temperature and on radiation dose; however, it remains lower than 10% of the mean value of 1.5 V. The typical power dissipation at 2.5 V supply voltage is about 20 μW at room temperature and only 75 μW at a high temperature of 200 °C. To understand the effects caused by the combination of high total ionizing dose and temperature on such voltage reference, the threshold voltages of the used SOI MOSFETs were extracted under different conditions. The evolution of V(REF) and power consumption with temperature and radiation dose can then be explained in terms of the different balance between fixed oxide charge and interface states build-up. The total occupied area including pad-ring is less than 0.09 mm2.

Comparison Between Prospectively Electrocardiogram-Gated High-Pitch Mode and Retrospectively Electrocardiogram-Gated Mode for Dual-Source CT Coronary Angiography.

PubMed

Koplay, Mustafa; Celik, Mahmut; Avcı, Ahmet; Erdogan, Hasan; Demir, Kenan; Sivri, Mesut; Nayman, Alaaddin

2015-01-01

We aimed to report the image quality, relationship between heart rate and image quality, amount of contrast agent given to the patients and radiation doses in coronary CT angiography (CTA) obtained by using high-pitch prospectively ECG-gated "Flash Spiral" technique (method A) or retrospectively ECG-gated technique (method B) using 128×2-slice dual-source CT. A total of 110 patients who were evaluated with method A and method B technique with a 128×2-detector dual-source CT device were included in the study. Patients were divided into three groups based on their heart rates during the procedure, and a relationship between heart rate and image quality were evaluated. The relationship between heart rate, gender and radiation dose received by the patients was compared. A total of 1760 segments were evaluated in terms of image quality. Comparison of the relationship between heart rate and image quality revealed a significant difference between heart rate <60 beats/min group and >75 beats/min group whereas <60 beats/min and 60-75 beats/min groups did not differ significantly. The average effective dose for coronary CTA was calculated as 1.11 mSv (0.47-2.01 mSv) for method A and 8.22 mSv (2.19-12.88 mSv) for method B. Method A provided high quality images with doses as low as <1 mSv in selected patients who have low heart rates with a high negative predictive value to rule out coronary artery disease. Although method B increases the amount of effective dose, it provides high diagnostic quality images for patients who have a high heart rate and arrhythmia which makes it is difficult to obtain images.

3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings.

PubMed

Baumann, Michael H; Wang, Xiaoying; Rothman, Richard B

2007-01-01

3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been interpreted as neurotoxicity. Whether such 5-HT deficits reflect neuronal damage is a matter of ongoing debate. The present paper reviews four specific issues related to the hypothesis of MDMA neurotoxicity in rats: (1) the effects of MDMA on monoamine neurons, (2) the use of "interspecies scaling" to adjust MDMA doses across species, (3) the effects of MDMA on established markers of neuronal damage, and (4) functional impairments associated with MDMA-induced 5-HT depletions. MDMA is a substrate for monoamine transporters, and stimulated release of 5-HT, NE, and DA mediates effects of the drug. MDMA produces neurochemical, endocrine, and behavioral actions in rats and humans at equivalent doses (e.g., 1-2 mg/kg), suggesting that there is no reason to adjust doses between these species. Typical doses of MDMA causing long-term 5-HT depletions in rats (e.g., 10-20 mg/kg) do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA-induced 5-HT depletions are accompanied by a number of functional consequences including reductions in evoked 5-HT release and changes in hormone secretion. Perhaps more importantly, administration of MDMA to rats induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits. MDMA-induced 5-HT depletions are not necessarily synonymous with neurotoxic damage. However, doses of MDMA which do not cause long-term 5-HT depletions can have protracted effects on behavior, suggesting even moderate doses of the drug may pose risks.

Stochastic Predictions of Cell Kill During Stereotactic Ablative Radiation Therapy: Do Hypoxia and Reoxygenation Really Matter?

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

Harriss-Phillips, Wendy M., E-mail: wharrphil@gmail.com; School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia; Bezak, Eva

Purpose: To simulate stereotactic ablative radiation therapy on hypoxic and well-oxygenated in silico tumors, incorporating probabilistic parameter distributions and linear-quadratic versus linear-quadratic-cubic methodology and the evaluation of optimal fractionation schemes using biological effective dose (BED{sub α/β=10} {sub or} {sub 3}) comparisons. Methods and Materials: A temporal tumor growth and radiation therapy algorithm simulated high-dose external beam radiation therapy using stochastic methods. Realistic biological proliferative cellular hierarchy and pO{sub 2} histograms were incorporated into the 10{sup 8}-cell tumor model, with randomized radiation therapy applied during continual cell proliferation and volume-based gradual tumor reoxygenation. Dose fractions ranged from 6-35 Gy, with predictive outcomes presentedmore » in terms of the total doses (converted to BED) required to eliminate all cells that could potentially regenerate the tumor. Results: Well-oxygenated tumor control BED{sub 10} outcomes were not significantly different for high-dose versus conventional radiation therapy (BED{sub 10}: 79-84 Gy; Equivalent Dose in 2 Gy fractions with α/β of 10: 66-70 Gy); however, total treatment times decreased from 7 down to 1-3 weeks. For hypoxic tumors, an additional 28 Gy (51 Gy BED{sub 10}) was required, with BED{sub 10} increasing with dose per fraction due to wasted dose in the final fraction. Fractions of 9 Gy compromised well for total treatment time and BED, with BED{sub 10}:BED{sub 3} of 84:176 Gy for oxic and 132:278 Gy for non-reoxygenating hypoxic tumors. Initial doses of 12 Gy followed by 6 Gy further increased the therapeutic ratio. When delivering ≥9 Gy per fraction, applying reoxygenation and/or linear-quadratic-cubic cell survival both affected tumor control doses by a significant 1-2 fractions. Conclusions: The complex temporal dynamics of tumor oxygenation combined with probabilistic cell kinetics in the modeling of radiation therapy requires sophisticated stochastic modeling to predict tumor cell kill. For stereotactic ablative radiation therapy, high doses in the first week followed by doses that are more moderate may be beneficial because a high percentage of hypoxic cells could be eradicated early while keeping the required BED{sub 10} relatively low and BED{sub 3} toxicity to tolerable levels.« less

Very low-dose fluvastatin-valsartan combination decreases parameters of inflammation and oxidative stress in patients with type 1 diabetes mellitus.

PubMed

Lunder, Mojca; Janić, Miodrag; Savić, Vedran; Janež, Andrej; Kanc, Karin; Šabovič, Mišo

2017-05-01

Previously we revealed the effectiveness of a new therapeutic approach with a short-term, very-low dose fluvastatin-valsartan combination on the improvement of arterial function in type 1 diabetes mellitus patients (T1DM). In this study we explored whether this approach influences inflammation and oxidative stress and explored any association of these effects with arterial function improvement. This was a supplementary analysis of the two previous double blind randomized studies (included 44 T1DM patients). Treatment group received very-low dose fluvastatin-valsartan, the control group received placebo. Blood samples were collected and inflammation parameters: high-sensitivity CRP (hsCRP), interleukin 6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1) and oxidative stress parameter total antioxidant status (TAS) were measured. Treatment decreased hsCRP values (by 56.5%, P<0.05) and IL-6 values (by 33.6%, P<0.05) and increased TAS values (by 21.1%; P<0.05) after 30days of treatment. High sensitivity CRP and TAS remained decreased 3months after treatment discontinuation. Importantly, the anti-inflammatory and anti-oxidative action significantly correlated with arterial function improvement. The approach consisting of short-term (30days) treatment with a very low-dose fluvastatin-valsartan combination acts anti-inflammatory and anti-oxidative in T1DM patients. These observations along with the improvement of arterial function support the assumption that this approach could have an important clinical benefit in T1DM patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Optimizing home dialysis: role of hemodiafiltration.

PubMed

Vilar, Enric; Farrington, Ken; Bates, Chris; Mumford, Carol; Greenwood, Roger

2011-01-01

Over the last 40 years the technical obstacles which prevented a convective contribution to diffusive dialysis have been overcome. Hemodiafiltration represents a natural evolution of intermittent extracorporeal blood purification and the technology is now available to offer this as standard treatment in-center. The first randomized control trial of dialysis dose (National Cooperative Dialysis Study) showed that for three times weekly dialysis a critical level of urea clearance was necessary to ensure complication-free survival, the effect being noticeable by 3 months. Following this, observational studies suggested that higher doses improved longer term outcome. In a second large randomized controlled study (HEMO), higher small molecule clearance did not further improve outcome, but high-flux membranes, which permitted enhanced clearance of middle molecules, appeared to confer survival benefit in patients who had already been on dialysis > 3.7 years. Recently, outcomes from the Membrane Permeability Outcome study confirmed a survival benefit of high-flux membranes in high-risk patients. These studies indicate that in the medium term survival is critically dependent on achieving a minimum level of small solute removal. However, longer term survival (measured in years or decades) not only requires better small solute clearance but also enhanced clearance of middle molecules, the toxicity of which manifest over longer time scales. The rationale for convective treatment is strongest, therefore in those patients who have the greatest potential for long-term survival. Patients who opt for self-care at home to allow frequent dialysis generally are constituents of this group. Hemodiafiltration is likely to become standard therapy in-center and in the home. Copyright © 2011 S. Karger AG, Basel.

Short- and long-term physiological responses of grapevine leaves to UV-B radiation.

PubMed

Martínez-Lüscher, J; Morales, F; Delrot, S; Sánchez-Díaz, M; Gomés, E; Aguirreolea, J; Pascual, I

2013-12-01

The present study aimed at evaluating the short- and long-term effects of UV-B radiation on leaves of grapevine Vitis vinifera (cv. Tempranillo). Grapevine fruit-bearing cuttings were exposed to two doses of supplemental biologically effective UV-B radiation (UV-BBE) under glasshouse-controlled conditions: 5.98 and 9.66kJm(-2)d(-1). The treatments were applied either for 20d (from mid-veraison to ripeness) or 75d (from fruit set to ripeness). A 0kJm(-2)d(-1) UV-B treatment was included as control. The main effects of UV-B were observed after the short-term exposure (20d) to 9.66kJm(-2)d(-1). Significant decreases in net photosynthesis, stomatal conductance, sub-stomatal CO2 concentration, the actual photosystem II (PSII) efficiency, total soluble proteins and de-epoxidation state of the VAZ cycle were observed, whereas the activities of several antioxidant enzymes increased significantly. UV-B did not markedly affect dark respiration, photorespiration, the maximum potential PSII efficiency (Fv/Fm), non-photochemical quenching (NPQ), as well as the intrinsic PSII efficiency. However, after 75d of exposure to 5.98and 9.66kJm(-2)d(-1) UV-B most photosynthetic and biochemical variables were unaffected and there were no sign of oxidative damage in leaves. The results suggest a high long-term acclimation capacity of grapevine to high UV-B levels, associated with a high accumulation of UV-B absorbing compounds in leaves, whereas plants seemed to be tolerant to moderate doses of UV-B. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Bitemporal v. high-dose right unilateral electroconvulsive therapy for depression: a systematic review and meta-analysis of randomized controlled trials.

PubMed

Kolshus, E; Jelovac, A; McLoughlin, D M

2017-02-01

Brief-pulse electroconvulsive therapy (ECT) is the most acutely effective treatment for severe depression though concerns persist about cognitive side-effects. While bitemporal electrode placement is the most commonly used form worldwide, right unilateral ECT causes less cognitive side-effects though historically it has been deemed less effective. Several randomized trials have now compared high-dose (>5× seizure threshold) unilateral ECT with moderate-dose (1.0-2.5× seizure threshold) bitemporal ECT to investigate if it is as effective as bitemporal ECT but still has less cognitive side-effects. We aimed to systematically review these trials and meta-analyse clinical and cognitive outcomes where appropriate. We searched PubMed, PsycINFO, Web of Science, Cochrane Library and EMBASE for randomized trials comparing these forms of ECT using the terms 'electroconvulsive' OR 'electroshock' AND 'trial'. Seven trials (n = 792) met inclusion criteria. Bitemporal ECT did not differ from high-dose unilateral ECT on depression rating change scores [Hedges's g = -0.03, 95% confidence interval (CI) -0.17 to 0.11], remission (RR 1.06, 95% CI 0.93-1.20), or relapse at 12 months (RR 1.42, 95% CI 0.90-2.23). There was an advantage for unilateral ECT on reorientation time after individual ECT sessions (mean difference in minutes = -8.28, 95% CI -12.86 to -3.70) and retrograde autobiographical memory (Hedges's g = -0.46, 95% CI -0.87 to -0.04) after completing an ECT course. There were no differences for general cognition, category fluency and delayed visual and verbal memory. High-dose unilateral ECT does not differ from moderate-dose bitemporal ECT in antidepressant efficacy but has some cognitive advantages.

Coronary calcium score in 12-year breast cancer survivors after adjuvant radiotherapy with low to moderate heart exposure - Relationship to cardiac radiation dose and cardiovascular risk factors.

PubMed

Tjessem, Kristin Holm; Bosse, Gerhard; Fosså, Kristian; Reinertsen, Kristin V; Fosså, Sophie D; Johansen, Safora; Fosså, Alexander

2015-03-01

We explored the relation between coronary artery calcium (CAC) and cardiac radiation doses in breast cancer survivors (BCS) treated with radiotherapy (RT). Additionally, we examined the impact of other risk factors and biomarkers of coronary artery disease (CAD). 236 BCS (median age 51years [range 30-70], median observation time 12years [9.2-15.7]), treated with 4-field RT of 50GY, were included and examined in 2004 (T1), 2007 (T2) and 2011 (T3) with clinical examination, blood tests and questionnaires. At T3, cardiac computed tomography was performed with quantification of CAC using Agatston score (AS). For 106 patients cardiac dose volume histograms were available. The cohort-based median of the mean cardiac dose was 2.5 (range 0.5-7.0) Gy. There was no correlation between measures of cardiac dose and AS. AS was correlated with high cholesterol at T1/T2 (p=0.022), high proBNP at T1/T2 (p<0.022) and T3 (p<0.022) and high HbA1c at T3 (p=0.022). In addition, a high AS was significantly associated with hypertension (p=0.022). Age (p<0.001) and cholesterol at T1/T2 (p=0.001) retained significant associations in multivariate analysis. Traditional, modifiable risk factors of CAD correlate with CAC and may be important for the long term risk of CAD after RT. With low to moderate cardiac radiation exposure, a contribution of radiation dose to CAC could not be demonstrated. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Discriminative feature representation: an effective postprocessing solution to low dose CT imaging

NASA Astrophysics Data System (ADS)

Chen, Yang; Liu, Jin; Hu, Yining; Yang, Jian; Shi, Luyao; Shu, Huazhong; Gui, Zhiguo; Coatrieux, Gouenou; Luo, Limin

2017-03-01

This paper proposes a concise and effective approach termed discriminative feature representation (DFR) for low dose computerized tomography (LDCT) image processing, which is currently a challenging problem in medical imaging field. This DFR method assumes LDCT images as the superposition of desirable high dose CT (HDCT) 3D features and undesirable noise-artifact 3D features (the combined term of noise and artifact features induced by low dose scan protocols), and the decomposed HDCT features are used to provide the processed LDCT images with higher quality. The target HDCT features are solved via the DFR algorithm using a featured dictionary composed by atoms representing HDCT features and noise-artifact features. In this study, the featured dictionary is efficiently built using physical phantom images collected from the same CT scanner as the target clinical LDCT images to process. The proposed DFR method also has good robustness in parameter setting for different CT scanner types. This DFR method can be directly applied to process DICOM formatted LDCT images, and has good applicability to current CT systems. Comparative experiments with abdomen LDCT data validate the good performance of the proposed approach. This research was supported by National Natural Science Foundation under grants (81370040, 81530060), the Fundamental Research Funds for the Central Universities, and the Qing Lan Project in Jiangsu Province.

Quantifying the Combined Effect of Radiation Therapy and Hyperthermia in Terms of Equivalent Dose Distributions

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

Kok, H. Petra, E-mail: H.P.Kok@amc.uva.nl; Crezee, Johannes; Franken, Nicolaas A.P.

2014-03-01

Purpose: To develop a method to quantify the therapeutic effect of radiosensitization by hyperthermia; to this end, a numerical method was proposed to convert radiation therapy dose distributions with hyperthermia to equivalent dose distributions without hyperthermia. Methods and Materials: Clinical intensity modulated radiation therapy plans were created for 15 prostate cancer cases. To simulate a clinically relevant heterogeneous temperature distribution, hyperthermia treatment planning was performed for heating with the AMC-8 system. The temperature-dependent parameters α (Gy{sup −1}) and β (Gy{sup −2}) of the linear–quadratic model for prostate cancer were estimated from the literature. No thermal enhancement was assumed for normalmore » tissue. The intensity modulated radiation therapy plans and temperature distributions were exported to our in-house-developed radiation therapy treatment planning system, APlan, and equivalent dose distributions without hyperthermia were calculated voxel by voxel using the linear–quadratic model. Results: The planned average tumor temperatures T90, T50, and T10 in the planning target volume were 40.5°C, 41.6°C, and 42.4°C, respectively. The planned minimum, mean, and maximum radiation therapy doses were 62.9 Gy, 76.0 Gy, and 81.0 Gy, respectively. Adding hyperthermia yielded an equivalent dose distribution with an extended 95% isodose level. The equivalent minimum, mean, and maximum doses reflecting the radiosensitization by hyperthermia were 70.3 Gy, 86.3 Gy, and 93.6 Gy, respectively, for a linear increase of α with temperature. This can be considered similar to a dose escalation with a substantial increase in tumor control probability for high-risk prostate carcinoma. Conclusion: A model to quantify the effect of combined radiation therapy and hyperthermia in terms of equivalent dose distributions was presented. This model is particularly instructive to estimate the potential effects of interaction from different treatment modalities.« less

Six steps to a successful dose-reduction strategy

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

Bennett, M.

1995-03-01

The increased importance of demonstrating achievement of the ALARA principle has helped produce a proliferation of dose-reduction ideas. Across a company there may be many dose-reduction items being pursued in a variety of areas. However, companies have a limited amount of resource and, therefore, to ensure funding is directed to those items which will produce the most benefit and that all areas apply a common policy, requires the presence of a dose-reduction strategy. Six steps were identified in formulating the dose-reduction strategy for Rolls-Royce and Associates (RRA): (1) collating the ideas; (2) quantitatively evaluating them on a common basis; (3)more » prioritizing the ideas in terms of cost benefit, (4) implementation of the highest priority items; (5) monitoring their success; (6) periodically reviewing the strategy. Inherent in producing the dose-reduction strategy has been a comprehensive dose database and the RRA-developed dose management computer code DOMAIN, which allows prediction of dose rates and dose. The database enabled high task dose items to be identified, assisted in evaluating dose benefits, and monitored dose trends once items had been implemented. The DOMAIN code was used both in quantifying some of the project dose benefits and its results, such as dose contours, used in some of the dose-reduction items themselves. In all, over fifty dose-reduction items were evaluated in the strategy process and the items which will give greatest benefit are being implemented. The strategy has been successful in giving renewed impetus and direction to dose-reduction management.« less

Lung dosimetry for inhaled radon progeny in smokers.

PubMed

Baias, Paul F; Hofmann, Werner; Winkler-Heil, Renate; Cosma, Constantin; Duliu, Octavian G

2010-02-01

Cigarette smoking may change the morphological and physiological parameters of the lung. Thus the primary objective of the present study was to investigate to what extent these smoke-induced changes can modify deposition, clearance and resulting doses of inhaled radon progeny relative to healthy non-smokers (NSs). Doses to sensitive bronchial target cells were computed for four categories of smokers: (1) Light, short-term (LST) smokers, (2) light, long-term (LLT) smokers, (3) heavy, short-term (HST) smokers and (4) heavy, long-term (HLT) smokers. Because of only small changes of morphological and physiological parameters, doses for the LST smokers hardly differed from those for NSs. For LLT and HST smokers, even a protective effect could be observed, caused by a thicker mucus layer and increased mucus velocities. Only in the case of HLT smokers were doses higher by about a factor of 2 than those for NSs, caused primarily by impaired mucociliary clearance, higher breathing frequency, reduced lung volume and airway obstructions. These higher doses suggest that the contribution of inhaled radon progeny to the risk of lung cancer in smokers may be higher than currently assumed on the basis of NS doses.

History of dose specification in Brachytherapy: From Threshold Erythema Dose to Computational Dosimetry

NASA Astrophysics Data System (ADS)

Williamson, Jeffrey F.

2006-09-01

This paper briefly reviews the evolution of brachytherapy dosimetry from 1900 to the present. Dosimetric practices in brachytherapy fall into three distinct eras: During the era of biological dosimetry (1900-1938), radium pioneers could only specify Ra-226 and Rn-222 implants in terms of the mass of radium encapsulated within the implanted sources. Due to the high energy of its emitted gamma rays and the long range of its secondary electrons in air, free-air chambers could not be used to quantify the output of Ra-226 sources in terms of exposure. Biological dosimetry, most prominently the threshold erythema dose, gained currency as a means of intercomparing radium treatments with exposure-calibrated orthovoltage x-ray units. The classical dosimetry era (1940-1980) began with successful exposure standardization of Ra-226 sources by Bragg-Gray cavity chambers. Classical dose-computation algorithms, based upon 1-D buildup factor measurements and point-source superposition computational algorithms, were able to accommodate artificial radionuclides such as Co-60, Ir-192, and Cs-137. The quantitative dosimetry era (1980- ) arose in response to the increasing utilization of low energy K-capture radionuclides such as I-125 and Pd-103 for which classical approaches could not be expected to estimate accurate correct doses. This led to intensive development of both experimental (largely TLD-100 dosimetry) and Monte Carlo dosimetry techniques along with more accurate air-kerma strength standards. As a result of extensive benchmarking and intercomparison of these different methods, single-seed low-energy radionuclide dose distributions are now known with a total uncertainty of 3%-5%.

Acute kidney injury after primary angioplasty: effect of different hydration treatments.

PubMed

Manari, Antonio; Magnavacchi, Paolo; Puggioni, Enrico; Vignali, Luigi; Fiaccadori, Enrico; Menozzi, Mila; Tondi, Stefano; Robotti, Stefano; Ferrari, Duilio; Valgimigli, Marco

2014-01-01

We evaluated the effect of different dose hydration protocols, with normal saline or bicarbonate, on the incidence of contrast-induced acute kidney injury (CI-AKI) in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PPCI). We considered 592 STEMI patients treated with PPCI in 5 Italian centers. Patients were randomized to receive standard or high-dose infusions of normal saline or sodium bicarbonate started immediately before contrast medium administration and continued for the following 12 h. The cumulative incidence of CI-AKI was 18.1% without any difference among treatment groups. Shock, age, ejection fraction 35% or less, and basal serum creatinine were significantly associated with an increased risk of CI-AKI. Follow-up at 12 months was complete in 573 patients. Overall, 25 out of 573 patients died (4.3%). We observed higher short-term mortality rates in patients receiving high-volume hydration. Otherwise, only age, shock and CI-AKI were significantly associated with 1-year mortality. In patients with STEMI undergoing PPCI, high-volume hydration with normal saline or sodium bicarbonate administrated at the time of contrast media administration was not associated with any significant advantage in terms of CI-AKI prevention.

Avacopan in the treatment of ANCA-associated vasculitis.

PubMed

Tesar, Vladimir; Hruskova, Zdenka

2018-05-08

ANCA-associated vasculitis (AAV) is a rare but potentially life-threatening disease. Currently used induction treatment (cyclophosphamide or rituximab with high-dose corticosteroids) has significantly improved outcome of AAV, but is associated with high toxicity. Alternative complement pathway activation was shown to play a role in the pathogenesis of AAV, thus providing rationale for the use of avacopan, a selective inhibitor of C5a receptor, in the treatment of AAV. Areas covered: Pharmacokinetic and pharmocodynamic properties of avacopan, clinical efficacy and safety and tolerability of avacopan in so far performed clinical trials in patients with AAV are reviewed and discussed. Expert opinion: Avacopan was shown to have at least similar efficacy compared to high dose corticosteroids in patients with active AAV with renal involvement, while there were no major safety issues reported. Replacement of corticosteroids should decrease the corticosteroid-related toxicity and improve long-term outcome of patients with AAV even though this still needs to be confirmed in a larger trial. Data on long-term outcome of avacopan-treated patients are currently lacking and will be eagerly awaited. In the future, avacopan could replace corticosteroids not only in the induction phase, but also in the maintenance treatment of AAV.

Reviewing long-term antidepressants can reduce drug burden: a prospective observational cohort study

PubMed Central

Johnson, Chris F; Macdonald, Hector J; Atkinson, Pauline; Buchanan, Alasdair I; Downes, Noreen; Dougall, Nadine

2012-01-01

Background Antidepressant prescribing continues to rise. Contributing factors are increased long-term prescribing and possibly the use of higher selective serotonin re-uptake inhibitor (SSRI) doses. Aim To review general practice patients prescribed the same antidepressant long-term (≥2 years) and evaluate prescribing and management pre and post-review. Design and setting Prospective observational cohort study using routine data from 78 urban general practices, Scotland. Method All patients prescribed antidepressants (excluding amitriptyline) for ≥2 years were identified from records November 2009 to March 2010. GPs selected patients for face-to-face review of clinical condition and medication, December 2009 to September 2010. Pre- and post-review data were collected; average antidepressant doses and changes in prescribed daily doses were calculated. Onward referral to support services was recorded. Results 8.6% (33 312/388 656) of all registered patients were prescribed an antidepressant, 47.1% (15 689) were defined as long-term users and 2849 (18.2%) were reviewed. 811 (28.5%) patients reviewed had a change in antidepressant therapy: 7.0% stopped, 12.8% reduced dose, 5.3% increased dose, and 3.4% changed antidepressant, resulting in 9.5% (95% CI = 9.1% to 9.8% P<0.001) reduction in prescribed daily dose and 8.1% reduction in prescribing costs. 6.3% were referred onwards, half to NHS Mental Health Services. Pre-review SSRI doses were 10–30% higher than previously reported. Conclusion Almost half of all people prescribed antidepressants were long-term users. Appropriate reductions in prescribing can be achieved by reviewing patients. Higher SSRI doses may be contributing to current antidepressant growth. PMID:23211181

HDRK-Woman: whole-body voxel model based on high-resolution color slice images of Korean adult female cadaver

NASA Astrophysics Data System (ADS)

Yeom, Yeon Soo; Jeong, Jong Hwi; Kim, Chan Hyeong; Han, Min Cheol; Ham, Bo Kyoung; Cho, Kun Woo; Hwang, Sung Bae

2014-07-01

In a previous study, we constructed a male reference Korean phantom; HDRK-Man (High-Definition Reference Korean-Man), to represent Korean adult males for radiation protection purposes. In the present study, a female phantom; HDRK-Woman (High-Definition Reference Korean-Woman), was constructed to represent Korean adult females. High-resolution color photographic images obtained by serial sectioning of a 26 year-old Korean adult female cadaver were utilized. The body height and weight, the skeletal mass, and the dimensions of the individual organs and tissues were adjusted to the reference Korean data. The phantom was then compared with the International Commission on Radiological Protection (ICRP) female reference phantom in terms of calculated organ doses and organ-depth distributions. Additionally, the effective doses were calculated using both the HDRK-Man and HDRK-Woman phantoms, and the values were compared with those of the ICRP reference phantoms.

HDRK-Woman: whole-body voxel model based on high-resolution color slice images of Korean adult female cadaver.

PubMed

Yeom, Yeon Soo; Jeong, Jong Hwi; Kim, Chan Hyeong; Han, Min Cheol; Ham, Bo Kyoung; Cho, Kun Woo; Hwang, Sung Bae

2014-07-21

In a previous study, we constructed a male reference Korean phantom; HDRK-Man (High-Definition Reference Korean-Man), to represent Korean adult males for radiation protection purposes. In the present study, a female phantom; HDRK-Woman (High-Definition Reference Korean-Woman), was constructed to represent Korean adult females. High-resolution color photographic images obtained by serial sectioning of a 26 year-old Korean adult female cadaver were utilized. The body height and weight, the skeletal mass, and the dimensions of the individual organs and tissues were adjusted to the reference Korean data. The phantom was then compared with the International Commission on Radiological Protection (ICRP) female reference phantom in terms of calculated organ doses and organ-depth distributions. Additionally, the effective doses were calculated using both the HDRK-Man and HDRK-Woman phantoms, and the values were compared with those of the ICRP reference phantoms.

Human response to high-background radiation environments on Earth and in space

NASA Astrophysics Data System (ADS)

Durante, M.; Manti, L.

2008-09-01

The main long-term objective of the space exploration program is the colonization of the planets of the Solar System. The high cosmic radiation equivalent dose rate represents an inescapable problem for the safe establishment of permanent human settlements on these planets. The unshielded equivalent dose rate on Mars ranges between 100 and 200 mSv/year, depending on the Solar cycle and altitude, and can reach values as high as 360 mSv/year on the Moon. The average annual effective dose on Earth is about 3 mSv, nearly 85% of which comes from natural background radiation, reduced to less than 1 mSv if man-made sources and the internal exposure to Rn daughters are excluded. However, some areas on Earth display anomalously high levels of background radiation, as is the case with thorium-rich monazite bearing sand deposits where values 200 400 times higher than the world average can be found. About 2% of the world’s population live above 3 km and receive a disproportionate 10% of the annual effective collective dose due to cosmic radiation, with a net contribution to effective dose by the neutron component which is 3 4 fold that at sea level. Thus far, epidemiological studies have failed to show any adverse health effects in the populations living in these terrestrial high-background radiation areas (HBRA), which provide an unique opportunity to study the health implications of an environment that, as closely as possibly achievable on Earth, resembles the chronic exposure of future space colonists to higher-than-normal levels of ionizing radiation. Chromosomal aberrations in the peripheral blood lymphocytes from the HBRA residents have been measured in several studies because chromosomal damage represents an early biomarker of cancer risk. Similar cytogenetic studies have been recently performed in a cohort of astronauts involved in single or repeated space flights over many years. The cytogenetic findings in populations exposed to high dose-rate background radiation on Earth or in space will be discussed.

Near infrared radio-luminescence of O{sub 2} loaded radiation hardened silica optical fibers: A candidate dosimeter for harsh environments

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

Di Francesca, D., E-mail: diego.di.francesca@univ-st-etienne.fr; Dipartimento di Fisica e Chimica, Università degli Studi di Palermo, I-90123 Palermo; Girard, S.

2014-11-03

We report on an experimental investigation of the infrared Radio-Luminescence (iRL) emission of interstitial O{sub 2} molecules loaded in radiation hardened pure-silica-core and fluorine-doped silica-based optical fibers (OFs). The O{sub 2} loading treatment successfully dissolved high concentrations of oxygen molecules into the silica matrix. A sharp luminescence at 1272 nm was detected when 2.5 cm of the treated OFs were irradiated with 10 keV X-rays. This emission originates from the radiative decay of the first excited singlet state of the embedded O{sub 2} molecules. The dose, dose-rate, and temperature dependencies of the infrared emission are studied through in situ optical measurements. The resultsmore » show that the iRL is quite stable in doses of up to 1 MGy(SiO{sub 2}) and is linearly dependent on the dose-rate up to the maximum investigated dose-rate of ∼200 kGy(SiO{sub 2})/h. The temperature dependency of the iRL shows a decrease in efficiency above 200 °C, which is attributed to the non-radiative decay of the excited O{sub 2} molecules. The results obtained and the long-term stability of the O{sub 2}-loading treatment (no out-gassing effect) strongly suggest the applicability of these components to real-time remote dosimetry in environments characterized by high radiation doses and dose-rates.« less

Comparison of selected dose calculation algorithms in radiotherapy treatment planning for tissues with inhomogeneities

NASA Astrophysics Data System (ADS)

Woon, Y. L.; Heng, S. P.; Wong, J. H. D.; Ung, N. M.

2016-03-01

Inhomogeneity correction is recommended for accurate dose calculation in radiotherapy treatment planning since human body are highly inhomogeneous with the presence of bones and air cavities. However, each dose calculation algorithm has its own limitations. This study is to assess the accuracy of five algorithms that are currently implemented for treatment planning, including pencil beam convolution (PBC), superposition (SP), anisotropic analytical algorithm (AAA), Monte Carlo (MC) and Acuros XB (AXB). The calculated dose was compared with the measured dose using radiochromic film (Gafchromic EBT2) in inhomogeneous phantoms. In addition, the dosimetric impact of different algorithms on intensity modulated radiotherapy (IMRT) was studied for head and neck region. MC had the best agreement with the measured percentage depth dose (PDD) within the inhomogeneous region. This was followed by AXB, AAA, SP and PBC. For IMRT planning, MC algorithm is recommended for treatment planning in preference to PBC and SP. The MC and AXB algorithms were found to have better accuracy in terms of inhomogeneity correction and should be used for tumour volume within the proximity of inhomogeneous structures.

Oral and inhaled glucocorticoid use and risk of Achilles or biceps tendon rupture: a population-based case-control study.

PubMed

Spoendlin, Julia; Meier, Christian; Jick, Susan S; Meier, Christoph R

2015-01-01

Tendinotoxicity of glucocorticoids (GC) has been shown, but evidence on how this translates into clinical practice remains scarce. To explore the association between oral or inhaled GC use and the risk of Achilles or biceps tendon rupture (ATR/BTR). We identified patients aged 18 to 89 years with incident ATR or BTR (1995-2013) for a matched (1:4) case-control analysis using the UK-based Clinical Practice Research Datalink. We stratified oral GC use by indication, timing and duration of use, continuous versus intermittent use, cumulative dose, and average daily dose. We stratified inhaled GC use by timing and number of prescriptions. Among 8,202 cases, we observed increased odds ratios (ORs) around 3.0 for continuous oral GC use, which declined shortly after therapy cessation (similarly across indications). Odds ratios increased with average daily dose (≥ 10 mg/day, OR 4.05, 95% CI 2.32-7.08) and were elevated after one cycle of high-dose oral GC (≥ 20 mg/day). There was no effect of inhaled GC at any level of exposure. Our results provide evidence that oral GC therapy increases the risk of tendon rupture in a dose-response relationship. A single short-term high-dose GC treatment course may be sufficient transiently to increase the risk of tendon rupture.

Cosmic Radiation Exposure of Future Hypersonic Flight Missions.

PubMed

Koops, L

2017-06-15

Cosmic radiation exposure in air traffic grows with flight altitude, geographical latitude and flight time. For future high-speed intercontinental point-to-point travel, the trade-off between reduced flight time and enhanced dose rate at higher flight altitudes is investigated. Various representative (partly) hypersonic cruise missions are considered and in dependence on solar activity the integral route dose is calculated for envisaged flight profiles and trajectories. Our results are compared to those for corresponding air connections served by present day subsonic airliners. During solar maximum, we find a significant reduction in route dose for all considered high-speed missions compared to the subsonic reference. However, during solar minimum, comparable or somewhat larger doses result on transpolar trajectories with (partly) hypersonic cruise at Mach 5. Both solar activity and routing are hence found to determine, whether passengers can profit from shorter flight times in terms of radiation exposure, despite of altitude-induced higher dose rates. Yet, aircrews with fixed number of block hours are always subject to larger annual doses, which in the considered cases take values up to five times the reference. We comment on the implications of our results for route planning and aviation decision-making in the absence of radiation shielding solutions. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

NEURAL AND CARDIAC TOXICITIES ASSOCIATED WITH 3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA)

PubMed Central

Baumann, Michael H.; Rothman, Richard B.

2011-01-01

(±)-3,4-Methylenedioxymethamphetamine (MDMA) is a commonly abused illicit drug which affects multiple organ systems. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been viewed as neurotoxicity. Recent data implicate MDMA in the development of valvular heart disease (VHD). The present paper reviews several issues related to MDMA-associated neural and cardiac toxicities. The hypothesis of MDMA neurotoxicity in rats is evaluated in terms of the effects of MDMA on monoamine neurons, the use of scaling methods to extrapolate MDMA doses across species, and functional consequences of MDMA exposure. A potential treatment regimen (l-5-hydroxytryptophan plus carbidopa) for MDMA-associated neural deficits is discussed. The pathogenesis of MDMA-associated VHD is reviewed with specific reference to the role of valvular 5-HT2B receptors. We conclude that pharmacological effects of MDMA occur at the same doses in rats and humans. High doses of MDMA that produce 5-HT depletions in rats are associated with tolerance and impaired 5-HT release. Doses of MDMA that fail to deplete 5-HT in rats can cause persistent behavioral dysfunction, suggesting even moderate doses may pose risks. Finally, the MDMA metabolite, 3,4-methylenedioxyamphetamine (MDA), is a potent 5-HT2B agonist which could contribute to the increased risk of VHD observed in heavy MDMA users. PMID:19897081

Dose-dependent valproate-induced alopecia in patients with mental disorders.

PubMed

Tomita, Takashi; Goto, Hidekazu; Yoshida, Tadashi; Tanaka, Katsuya; Sumiya, Kenji; Kohda, Yukinao

2015-01-01

Drug-induced hair loss may occur as a side effect in patients treated with valproate. However, few studies have reported a relationship between the blood levels of valproate and the occurrence of hair loss. We report three cases of alopecia that occurred in patients who received sodium valproate for mental disorders. In all three cases, alopecia appeared after long-term valproate exposure with a plasma concentration of 100 µg/ml approximately. However, the alopecia resolved in all cases after dose reduction or treatment discontinuation. Therefore, alopecia may develop in patients with chronic exposure to high plasma concentrations of valproate. Based on these findings, we believe that patients with high plasma concentrations of valproate should be closely monitored for the occurrence of side effects, particularly alopecia.

Adverse effects of antioxidative vitamins.

PubMed

Rutkowski, Maciej; Grzegorczyk, Krzysztof

2012-06-01

High doses of synthetic antioxidative vitamins: A, E, C and β-carotene are often used on long-term basis in numerous preventive and therapeutic medical applications. Instead of expected health effects, the use of those vitamins may however lead to cases of hypervitaminosis and even to intoxication. The article points out main principles of safety which are to be observed during supplementation with antioxidative vitamins. Toxic effects resulting from erroneous administration of high doses of those substances on organs and systems of the organism are also discussed. Attention is drawn to interactions of antioxidative vitamins with concomitantly used drugs, as well as intensification of adverse effects caused by various exogenous chemical factors. Moreover, the article presents the evaluation of supplementation with these vitamins, which was performed in large studies.

Medical intelligence in Sweden. Vitamin B12: oral compared with parenteral?

PubMed

Nilsson, M; Norberg, B; Hultdin, J; Sandström, H; Westman, G; Lökk, J

2005-03-01

Sweden is the only country in which oral high dose vitamin B12 has gained widespread use in the treatment of deficiency states. The aim of the study was to describe prescribing patterns and sales statistics of vitamin B12 tablets and injections in Sweden 1990-2000.Design, setting, and sources: Official statistics of cobalamin prescriptions and sales were used. The use of vitamin B12 increased in Sweden 1990-2000, mainly because of an increase in the use of oral high dose vitamin B12 therapy. The experience, in statistical terms a "total investigation", comprised 1,000,000 patient years for tablets and 750,000 patient years for injections. During 2000, 13% of residents aged 70 and over were treated with vitamin B12, two of three with the tablet preparation. Most patients in Sweden requiring vitamin B12 therapy have transferred from parenteral to oral high dose vitamin B12 since 1964, when the oral preparation was introduced. The findings suggest that many patients in other post-industrial societies may also be suitable for oral vitamin B12 treatment.

Emergence of a daptomycin-non-susceptible Enterococcus faecium strain that encodes mutations in DNA repair genes after high-dose daptomycin therapy.

PubMed

Matono, Takashi; Hayakawa, Kayoko; Hirai, Risen; Tanimura, Akira; Yamamoto, Kei; Fujiya, Yoshihiro; Mawatari, Momoko; Kutsuna, Satoshi; Takeshita, Nozomi; Mezaki, Kazuhisa; Ohmagari, Norio; Miyoshi-Akiyama, Tohru

2016-04-01

An increasing number of reports have documented the emergence of daptomycin-nonsusceptible Enterococcus in patients during daptomycin therapy. Even though several mechanisms for daptomycin-nonsusceptibility have been suggested, the potential genetic mutations which might contribute to the daptomycin-nonsusceptibility are not fully understood. We isolated a vancomycin-susceptible, daptomycin nonsusceptible Enterococcus faecium strain from a patient with acute lymphocytic leukemia who received high-dose daptomycin therapy for E. faecium endocarditis. Whole-genome sequencing analysis revealed mutations within genes encoding DNA repair proteins MutL and RecJ of the daptomycin-nonsusceptible Enterococcus strain which might have facilitated its emergence. We identified the mutations of DNA mismatch repair genes in a clinical isolate of daptomycin nonsusceptible E. faecium which emerged in spite of high-dose daptomycin therapy. The finding implicates the possible association of DNA repair mechanism and daptomycin resistance. Careful monitoring is necessary to avoid the emergence of daptomycin non-susceptible isolates of E. faecium and particularly in cases of long-term daptomycin use or in immunocompromised patients.

Short-Term Effect of Vermicompost Application on Biological Properties of an Alkaline Soil with High Lime Content from Mediterranean Region of Turkey

PubMed Central

Uz, Ilker; Tavali, Ismail Emrah

2014-01-01

This study was conducted to investigate direct short-term impact of vermicompost on some soil biological properties by monitoring changes after addition of vermicompost as compared to farmyard manure in an alkaline soil with high lime content from semiarid Mediterranean region of Turkey. For this purpose, mixtures of soil and organic fertilizers in different doses were incubated under greenhouse condition. Soil samples collected in regular intervals were analyzed for biological parameters including dehydrogenase, β-glucosidase, urease, alkaline phosphatase activities, and total number of aerobic mesophilic bacteria. Even though soil dehydrogenase activity appeared to be dose-independent based on overall evaluation, organic amendments were found to elevate dehydrogenase activity when sampling periods are evaluated individually. β-glucosidase, urease, alkaline phosphatase activity, and aerobic mesophilic bacterial numbers in vermicompost treatments fluctuated but remained significantly above the control. A slight but statistically significant difference was detected between organic amendments in terms of urease activity. Vermicompost appeared to more significantly increase bacterial number in soil. Clearly, vermicompost has a potential to be used as an alternative to farmyard manure to improve and maintain soil biological activity in alkaline calcareous soils from the Mediterranean region of Turkey. Further studies are needed to assess its full potential for these soils. PMID:25254238

mRNA levels of circadian clock components Bmal1 and Per2 alter independently from dosing time-dependent efficacy of combination treatment with valsartan and amlodipine in spontaneously hypertensive rats.

PubMed

Potucek, Peter; Radik, Michal; Doka, Gabriel; Kralova, Eva; Krenek, Peter; Klimas, Jan

2017-01-01

Chronopharmacological effects of antihypertensives play a role in the outcome of hypertension therapy. However, studies produce contradictory findings when combination of valsartan plus amlodipine (VA) is applied. Here, we hypothesized different efficacy of morning versus evening dosing of VA in spontaneously hypertensive rats (SHR) and the involvement of circadian clock genes Bmal1 and Per2. We tested the therapy outcome in short-term and also long-term settings. SHRs aged between 8 and 10 weeks were treated with 10 mg/kg of valsartan and 4 mg/kg of amlodipine, either in the morning or in the evening with treatment duration 1 or 6 weeks and compared with parallel placebo groups. After short-term treatment, only morning dosing resulted in significant blood pressure (BP) control (measured by tail-cuff method) when compared to placebo, while after long-term treatment, both dosing groups gained similar superior results in BP control against placebo. However, mRNA levels of Bmal1 and Per2 (measured by RT-PCR) exhibited an independent pattern, with similar alterations in left and right ventricle, kidney as well as in aorta predominantly in groups with evening dosing in both, short-term and also long-term settings. This was accompanied by increased cardiac mRNA expression of plasminogen activator inhibitor-1. In summary, morning dosing proved to be advantageous due to earlier onset of antihypertensive action; however, long-term treatment was demonstrated to be effective regardless of administration time. Our findings also suggest that combination of VA may serve as an independent modulator of circadian clock and might influence disease progression beyond the primary BP lowering effect.

The Effect of Dose Rate on Composite Durability When Exposed to a Simulated Long-Term Lunar Radiation Environment

NASA Technical Reports Server (NTRS)

Rojdev, Kristina; O'Rourke, Mary Jane; Hill, Charles; Nutt, Steven; Atwell, William

2011-01-01

Human exploration of space beyond low Earth orbit (LEO) requires a safe living and working environment for crew. Composite materials are one type of material being investigated by NASA as a multi-functional structural approach to habitats for long-term use in space or on planetary surfaces with limited magnetic fields and atmosphere. These materials provide high strength with the potential for decreased weight and increased radiation protection of crew and electronics when compared with conventional aluminum structures. However, these materials have not been evaluated in a harsh radiation environment, as would be experienced outside of LEO or on a planetary surface. Thus, NASA has been investigating the durability of select composite materials in a long-term radiation environment. Previously, NASA exposed composite samples to a simulated, accelerated 30-year radiation treatment and tensile stresses similar to those of a habitat pressure vessel. The results showed evidence of potential surface oxidation and enhanced cross-linking of the matrix. As a follow-on study, we performed the same accelerated exposure alongside an exposure with a decreased dose rate. The slower dose ]rate is comparable to a realistic scenario, although still accelerated. Strain measurements were collected during exposure and showed that with a fastdose rate, the strain decreased with time, but with a slow ]dose rate, the strain increased with time. After the radiation exposures, samples were characterized via tensile tests, flexure tests, Fourier Transform Infrared Spectroscopy (FTIR), and Differential Scanning Calorimetry (DSC). The results of these tests will be discussed.

Long-term safety of PEG 4000 in children with chronic functional constipation: A biochemical perspective

PubMed Central

2010-01-01

Purpose To evaluate the long-term safety of polyethylene glycol (PEG) 4000 in children with constipation, particularly the biochemical aspects of safety. Methods Medical records were evaluated, and 100 children, who had been taking PEG 4000 for more than 6 months, and who had been under clinical and biochemical monitoring, were enrolled. Ages; 6.11±3.12 years, Duration of therapy; 16.93±7.02 months, dose of PEG 4000; 0.72±0.21 g/kg/d. Results None of the children complained of clinical adverse effect. The first biochemical test was performed at 8.05 months after beginning of PEG 4000. Serum phosphate (SP) value was high in 10 children, and leucopenia was noted in one child. The second test was performed in 44 children at 7.57 months after the first test. The SP value was high in four children, including the three children whose initial SP value was high and one new child. Six out of 10 children with high initial SP value became normal and one was lost. Hypernatremia was noted in one child. The third test was done in 15 children at 7.5 months after the second test. The SP value of the new child from the second test was high, but became normal after finishing treatment. Two out of 3 children with high SP value at the second test became normal and one was lost. The fourth test was done in 2 children few months after the third test. All of the results were normal. There were no relation between duration of therapy and hyperphosphatemia, or between dose of PEG 4000 and hyperphosphatemia. Conclusions PEG 4000 is safe for long-term therapy in children with constipation with respect to biochemical parameters. PMID:21189949

Human exposure to high natural background radiation: what can it teach us about radiation risks?

PubMed Central

Hendry, Jolyon H; Simon, Steven L; Wojcik, Andrzej; Sohrabi, Mehdi; Burkart, Werner; Cardis, Elisabeth; Laurier, Dominique; Tirmarche, Margot; Hayata, Isamu

2014-01-01

Natural radiation is the major source of human exposure to ionising radiation, and its largest contributing component to effective dose arises from inhalation of 222Rn and its radioactive progeny. However, despite extensive knowledge of radiation risks gained through epidemiologic investigations and mechanistic considerations, the health effects of chronic low-level radiation exposure are still poorly understood. The present paper reviews the possible contribution of studies of populations living in high natural background radiation (HNBR) areas (Guarapari, Brazil; Kerala, India; Ramsar, Iran; Yangjiang, China), including radon-prone areas, to low dose risk estimation. Much of the direct information about risk related to HNBR comes from case–control studies of radon and lung cancer, which provide convincing evidence of an association between long-term protracted radiation exposures in the general population and disease incidence. The success of these studies is mainly due to the careful organ dose reconstruction (with relatively high doses to the lung), and to the fact that large-scale collaborative studies have been conducted to maximise the statistical power and to ensure the systematic collection of information on potential confounding factors. In contrast, studies in other (non-radon) HNBR areas have provided little information, relying mainly on ecological designs and very rough effective dose categorisations. Recent steps taken in China and India to establish cohorts for follow-up and to conduct nested case–control studies may provide useful information about risks in the future, provided that careful organ dose reconstruction is possible and information is collected on potential confounding factors. PMID:19454802

Effects of dietary calcium fructoborate supplementation on joint comfort and flexibility and serum inflammatory markers in dogs with osteoarthritis.

PubMed

Price, A K; de Godoy, M R C; Harper, T A; Knap, K E; Joslyn, S; Pietrzkowski, Z; Cross, B K; Detweiler, K B; Swanson, K S

2017-07-01

Our objective was to evaluate the short-term effects of calcium fructoborate (CFB) on gait, joint range of motion, serum inflammatory markers, and owner perception of pain in client-owned dogs. We used 59 osteoarthritic dogs with impairment, with dogs being randomly assigned to 4 treatments: placebo (60 mg fructose; = 15), low dose (69 mg CFB; = 14), high dose (127 mg CFB; = 14), or combination (69 mg CFB, 500 mg glucosamine hydrochloride and 200 mg chondroitin sulfate; = 16). Dogs up to 22.9 kg received 1 capsule/d, while dogs weighing 23 to 50 kg received 2 capsules/d. A physical examination, radiographs, goniometry measurements, gait analysis, blood sample collection, and a canine brief pain inventory questionnaire were performed on d 0 and 28. Change from baseline values were statistically analyzed among groups. After 28 d, dogs fed the low and high doses had an improved ( < 0.05) ability to rise from a lying position compared to placebo. Dogs fed the high dose also had a greater ( = 0.05) increase in soluble receptor for advanced glycation end products concentration than dogs fed the placebo. Sub-analysis of only large dogs (> 23 kg) showed that dogs fed the low dose had decreased ( < 0.05) pain severity score and pain at its worst compared to dogs fed the placebo. Large dogs fed the low dose also were shown to improve ( < 0.05) in their ability to rise from a lying position compared to dogs fed the placebo. Overall, CFB supplementation was well-tolerated and may aid in mitigating joint discomfort in dogs.

How does exercise dose affect patients with long-term osteoarthritis of the knee? A study protocol of a randomised controlled trial in Sweden and Norway: the SWENOR Study

PubMed Central

Grooten, Wilhelmus J A; Østerås, Håvard; Heijne, Annette; Harms-Ringdahl, Karin; Äng, Björn Olov

2018-01-01

Introduction Osteoarthritis (OA) of the knee is characterised by knee pain, disability and degenerative changes, and places a burden on societies all over the world. Exercise therapy is an often-used modality, but there is little evidence of what type of exercise dose is the most effective, indicating a need for controlled studies of the effect of different dosages. Thus, the aim of the study described in this protocol is to evaluate the effects of high-dose versus low-dose medical exercise therapy (MET) in patients with knee OA. Methods and analysis This is a multicentre prospective randomised two-arm trial with blinded assessment and data analysis. We are planning to include 200 patients aged 45–85 years with symptomatic (pain and decreased functioning) and X-ray verified diagnosis of knee OA. Those eligible for participation will be randomly allocated to either high-dose (n=100) or low-dose (n=100) MET. All patients receive three supervised treatments each week for 12 weeks, giving a total of 36 MET sessions. The high-dose group exercises for 70–90 min compared with 20–30 min for the low-dose group. The high-dose group exercises for a longer time, and receives a greater number of exercises with more repetitions and sets. Background and outcome variables are recorded at inclusion, and outcome measures are collected after every sixth treatment, at the end of treatment, and at 6-month and 12-month follow-ups. Primary outcome is self-rated knee functioning and pain using the Knee Injury and Osteoarthritis Outcome Score (KOOS). The primary end point is at the end of treatment after 3 months, and secondary end points are at 6 months and 12 months after the end of treatment. Ethics and dissemination This project has been approved by the Regional Research Ethics Committees in Stockholm, Sweden, and in Norway. Our results will be submitted to peer-reviewed journals and presented at national and international conferences. Trial registration number NCT02024126; Pre-results. PMID:29730615

Impact of Dose to the Bladder Trigone on Long-Term Urinary Function After High-Dose Intensity Modulated Radiation Therapy for Localized Prostate Cancer

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

Ghadjar, Pirus; Zelefsky, Michael J.; Spratt, Daniel E.

2014-02-01

Purpose: To determine the potential association between genitourinary (GU) toxicity and planning dose–volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients. Methods and Materials: A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose–volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analysesmore » were done by the Kaplan-Meier method and Cox proportional hazard models, respectively. Results: Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19). Conclusions: The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the bladder trigone seems to be associated with a reduction in late GU toxicity.« less

New approach for food allergy management using low-dose oral food challenges and low-dose oral immunotherapies.

PubMed

Yanagida, Noriyuki; Okada, Yu; Sato, Sakura; Ebisawa, Motohiro

2016-04-01

A number of studies have suggested that a large subset of children (approximately 70%) who react to unheated milk or egg can tolerate extensively heated forms of these foods. A diet that includes baked milk or egg is well tolerated and appears to accelerate the development of regular milk or egg tolerance when compared with strict avoidance. However, the indications for an oral food challenge (OFC) using baked products are limited for patients with high specific IgE values or large skin prick test diameters. Oral immunotherapies (OITs) are becoming increasingly popular for the management of food allergies. However, the reported efficacy of OIT is not satisfactory, given the high frequency of symptoms and requirement for long-term therapy. With food allergies, removing the need to eliminate a food that could be consumed in low doses could significantly improve quality of life. This review discusses the importance of an OFC and OIT that use low doses of causative foods as the target volumes. Utilizing an OFC or OIT with a low dose as the target volume could be a novel approach for accelerating the tolerance to causative foods. Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

Fundamental Flaws of Hormesis for Public Health Decisions

PubMed Central

Thayer, Kristina A.; Melnick, Ronald; Burns, Kathy; Davis, Devra; Huff, James

2005-01-01

Hormesis (defined operationally as low-dose stimulation, high-dose inhibition) is often used to promote the notion that while high-level exposures to toxic chemicals could be detrimental to human health, low-level exposures would be beneficial. Some proponents claim hormesis is an adaptive, generalizable phenomenon and argue that the default assumption for risk assessments should be that toxic chemicals induce stimulatory (i.e., “beneficial”) effects at low exposures. In many cases, nonmonotonic dose–response curves are called hormetic responses even in the absence of any mechanistic characterization of that response. Use of the term “hormesis,” with its associated descriptors, distracts from the broader and more important questions regarding the frequency and interpretation of nonmonotonic dose responses in biological systems. A better understanding of the biological basis and consequences of nonmonotonic dose–response curves is warranted for evaluating human health risks. The assumption that hormesis is generally adaptive is an oversimplification of complex biological processes. Even if certain low-dose effects were sometimes considered beneficial, this should not influence regulatory decisions to allow increased environmental exposures to toxic and carcinogenic agents, given factors such as interindividual differences in susceptibility and multiplicity in exposures. In this commentary we evaluate the hormesis hypothesis and potential adverse consequences of incorporating low-dose beneficial effects into public health decisions. PMID:16203233

Treatment of androgen excess in adolescent girls: ethinylestradiol-cyproteroneacetate versus low-dose pioglitazone-flutamide-metformin.

PubMed

Ibáñez, Lourdes; Diaz, Marta; Sebastiani, Giorgia; Sánchez-Infantes, David; Salvador, Cristina; Lopez-Bermejo, Abel; de Zegher, Francis

2011-11-01

The aim was to perform a first comparison between the effects of a classic therapy and those of a novel treatment for androgen excess in adolescent girls. We conducted a randomized, open-labeled trial at a university hospital. Thirty-four adolescents with hyperinsulinemic androgen excess and without risk of pregnancy participated in the study. Ethinyl estradiol-cyproterone acetate (EE-CA) vs. a low-dose combination of pioglitazone, flutamide, and metformin (PioFluMet) was administered for 6 months. We assessed hirsutism and acne scores; androgen excess; fasting insulin, lipid profile, C-reactive protein, high molecular-weight adiponectin, leptin, follistatin; carotid intima-media thickness; body composition (absorptiometry); and abdominal fat partitioning (magnetic resonance imaging). EE-CA and PioFluMet attenuated the androgen excess comparably but had divergent effects on fasting insulinemia; on circulating cholesterol, triglycerides, C-reactive protein, high molecular-weight adiponectin, leptin, and follistatin; on carotid intima-media thickness; on lean mass; and on abdominal, visceral, and hepatic fat, with all these divergences pointing to a healthier condition on low-dose PioFluMet. Low-dose PioFluMet compared favorably to EE-CA in adolescents with androgen excess and without pregnancy risk. The efficacy and safety of low-dose PioFluMet remain to be studied over a longer term and in larger cohorts.

Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects?

PubMed

Gilissen, L P L; Derijks, L J J; Driessen, A; Bos, L P; Hooymans, P M; Stockbrügger, R W; Engels, L G J B

2007-02-01

6-Thioguanine is used in inflammatory bowel disease since 2001, with promising short-term results. In 2003, liver histology of some 6-thioguanine treated patients showed nodular regenerative hyperplasia. Recently, magnetic resonance imaging revealed nodular regenerative hyperplasia in patients with normal histology. Investigating the presence of nodular regenerative hyperplasia in long-term 6-thioguanine treated patients. Inflammatory bowel disease patients, using 6-thioguanine minimally 24 months, were asked to undergo liver biopsy and magnetic resonance imaging. Fourteen patients used 6-thioguanine minimally 24 months, 13 participated. Mean 6-thioguanine therapy duration, daily dose and 6-thioguanine nucleotide levels were: 36 months, 18.8 mg (0.28 mg/kg) and 705 pmol/8x10(8) erythrocytes, respectively. Liver histology and magnetic resonance imaging showed no nodular regenerative hyperplasia. Liver biopsy and magnetic resonance imaging showed no nodular regenerative hyperplasia in these long-term 6-thioguanine treated inflammatory bowel disease patients. 6-thioguanine dose and metabolite levels were lower compared with previous nodular regenerative hyperplasia reports, suggesting dose or metabolite level-dependent effects. Otherwise, nodular regenerative hyperplasia is related with inflammatory bowel disease itself and immunosuppressives, including azathioprine and 6-mercaptopurine. 6-Thioguanine is debated due to nodular regenerative hyperplasia. We found no nodular regenerative hyperplasia in inflammatory bowel disease patients with long-term, low dosed 6-thioguanine, suggesting metabolite level-dependent effects. Therefore, 6-thioguanine still seems useful, but in selected patients, intolerant for other immunosuppressives, low dosed and under close surveillance of metabolite levels and hepatotoxity.

Long-Term Anabolic Androgenic Steroid Use Is Associated with Increased Atrial Electromechanical Delay in Male Bodybuilders

PubMed Central

Akçakoyun, Mustafa; Gündoğdu, Recep; Bulut, Mustafa; Tabakcı, Mehmet Mustafa; Açar, Göksel; Avcı, Anıl; Şimşek, Zeki; Demir, Serdar; Kargın, Ramazan; Emiroğlu, Mehmet Yunus

2014-01-01

We investigated the effect of long-term supraphysiologic doses of anabolic androgenic steroids (AAS) on atrial electromechanical delay (AEMD) in male bodybuilders. We clearly demonstrated that long-term consumption of supraphysiologic doses of AAS is associated with higher values of inter- and intra-AEMD in healthy young bodybuilders. PMID:24883314

Effect of electron beam irradiation and microencapsulation on the flame retardancy of ethylene-vinyl acetate copolymer materials during hot water ageing test

NASA Astrophysics Data System (ADS)

Sheng, Haibo; Zhang, Yan; Wang, Bibo; Yu, Bin; Shi, Yongqian; Song, Lei; Kundu, Chanchal Kumar; Tao, Youji; Jie, Ganxin; Feng, Hao; Hu, Yuan

2017-04-01

Microencapsulated ammonium polyphosphate (MCAPP) in combination with polyester polyurethane (TPU) was used to flame retardant ethylene-vinyl acetate copolymer (EVA). The EVA composites with different irradiation doses were immersed in hot water (80 °C) to accelerate ageing process. The microencapsulation and irradiation dose ensured positive impacts on the properties of the EVA composites in terms of better dimensional stability and flame retardant performance. The microencapsulation of APP could lower its solubility in water and the higher irradiation dose led to the more MCAPP immobilized in three dimensional crosslinked structure of the EVA matrix which could jointly enhance the flame retardant and electrical insulation properties of the EVA composites. So, the EVA composites with 180 kGy irradiation dose exhibited better dimensional stability than the EVA composites with 120 kGy due to the higher crosslinking degree. Moreover, the higher irradiation dose lead to the more MCAPP immobilizated in crosslinked three-dimensional structure of EVA, enhancing the flame retardancy and electrical insulation properties of the EVA composites. After ageing test in hot water at 80 °C for 2 weeks, the EVA/TPU/MCAPP composite with 180 kGy could still maintain the UL-94 V-0 rating and the limiting oxygen index (LOI) value was as high as 30%. This investigation indicated the flame retardant EVA cable containing MCAPP could achieve stable properties and lower electrical fire hazard risk during long-term hot water ageing test.

Amphetamine modulation of long-term potentiation in the prefrontal cortex: dose dependency, monoaminergic contributions, and paradoxical rescue in hyperdopaminergic mutant.

PubMed

Xu, Tai-Xiang; Ma, Qi; Spealman, Roger D; Yao, Wei-Dong

2010-12-01

Amphetamine can improve cognition in healthy subjects and patients with schizophrenia, attention-deficit hyperactivity disorder, and other neuropsychiatric diseases; higher doses, however, can impair cognitive function, especially those mediated by the prefrontal cortex. We investigated how amphetamine affects prefrontal cortex long-term potentiation (LTP), a cellular correlate of learning and memory, in normal and hyperdopaminergic mice lacking the dopamine transporter. Acute amphetamine treatment in wild-type mice produced a biphasic dose-response modulation of LTP, with a low dose enhancing LTP and a high dose impairing it. Amphetamine-induced LTP enhancement was prevented by pharmacological blockade of D(1) - (but not D(2)-) class dopamine receptors, by blockade of β-adrenergic receptors, or by inhibition of cAMP-PKA signaling. In contrast, amphetamine-induced LTP impairment was prevented by inhibition of post-synaptic protein phosphatase-1, a downstream target of PKA signaling, or by blockade of either D(1) - or D(2)-class dopamine, but not noradrenergic, receptors. Thus, amphetamine biphasically modulates LTP via cAMP-PKA signaling orchestrated mainly through dopamine receptors. Unexpectedly, amphetamine restored the loss of LTP in dopamine transporter-knockout mice primarily by activation of the noradrenergic system. Our results mirror the biphasic effectiveness of amphetamine in humans and provide new mechanistic insights into its effects on cognition under normal and hyperdopaminergic conditions. © 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.

Why Is Parkinsonism Not a Feature of Human Methamphetamine Users?

ERIC Educational Resources Information Center

Moszczynska, Anna; Fitzmaurice, Paul; Ang, Lee; Kalasinsky, Kathryn S.; Schmunk, Gregory A.; Peretti, Frank J.; Aiken, Sally S.; Wickham, Dennis J.; Kish, Stephen J.

2004-01-01

For more than 50 years, methamphetamine has been a widely used stimulant drug taken to maintain wakefulness and performance and, in high doses, to cause intense euphoria. Animal studies show that methamphetamine can cause short-term and even persistent depletion of brain levels of the neurotransmitter dopamine. However, the clinical features of…

The big bang of hemofiltration: the beginning of a new era in the third millennium for extra-corporeal blood purification!

PubMed

Honore', P M; Joannes-Boyau, O; Merson, L; Boer, W; Piette, V; Galloy, A-C; Janvier, G

2006-07-01

Since the last decade, hemofiltration and especially high volume hemofiltration has rapidly evolved from a somewhat experimental treatment towards a potentially effective 'adjunctive' therapy in severe septic shock and especially refractory or catecholamine resistant hypodynamic septic shock. Nevertheless, this approach lacks prospective randomized studies (PRT'S) evaluating the critical role of early hemofiltration in sepsis. An important step forward which could be called the 'big bang' in term of hemofiltration was the publication of a PRT in patients with acute renal failure (ARF) (1). Before this study (2), nobody believed that hemofiltration could change the survival rate in intensive care. Since that big bang, many physicians consider that hemofiltration at a certain dose can change the survival rate in intensive care. So the world of hemofiltration in ICU is not a definitive world, it is still in expansion. Indeed, we now have to try to define what will be the exact dose we need in septic acute renal failure. This dose might well be 'higher' than 35 ml/kg/hour in the septic acute renal failure 'group' as suggested by many studies (2-5). At present, it is the issue of continuous dose of high volume hemofiltration that has to be tested in future randomized studies. Since the Vicenza study (2) has shown that 35 ml/kg/h is the best dose in terms of survival, dealing with non septic acute renal failure in ICU, several studies from different groups have shown that, in septic acute renal failure, a higher dose might correlate with better survival. This has also been shown in some way by the study of the 'Vicenza group' but not with a statistically significant value (2). New PRT'S have just started in Europe like the IVOIRE study (hIgh VOlume in Intensive caRE) (6) and the RENAL study. Another large study is looking more basically at dose in non septic acute renal failure in Australasia and is led by the group of Rinaldo Bellomo in Melbourne (7) as well as the ATN study (8) led by Palevsky and colleagues in the USA, also testing the importance of dose in the treatment for ARF. Nevertheless, 'early goal-directed hemofiltration therapy' like early goal directed therapy (9) has to be studied in our critical ill patients. Regarding this issue, fewer studies, mainly retrospective exist, but again the IVOIRE study (6) will address this issue by studying septic patients with acute renal injury according to the Rifle classification (10). So, this review focuses on the early application and on the adequate dose of continuous high volume hemofiltration in septic shock in order to improve not only hemodynamics, but survival in this very severely ill cohort of patients. This could well be called the 'big bang of hemofiltration' as one could never have anticipated that an adequate dose of hemofiltration could markedly influence the survival rate of ICU-septic acute renal failure patients. On top of the use of early and adequate dose of hemofiltration in sepsis, a higher dose could also provide better renal recovery rate and reduce the risk of associate chronic dialysis in these patients. Furthermore, this paper also reviews 'brand' new theories regarding the rationale for hemofiltration in sepsis. Finally, this paper also addresses the so-called negative studies as well anticipated side effects.

Correlation of Noncancer Benchmark Doses in Short- and Long-Term Rodent Bioassays.

PubMed

Kratchman, Jessica; Wang, Bing; Fox, John; Gray, George

2018-05-01

This study investigated whether, in the absence of chronic noncancer toxicity data, short-term noncancer toxicity data can be used to predict chronic toxicity effect levels by focusing on the dose-response relationship instead of a critical effect. Data from National Toxicology Program (NTP) technical reports have been extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Best-fit, minimum benchmark dose (BMD), and benchmark dose lower limits (BMDLs) have been modeled for all NTP pathologist identified significant nonneoplastic lesions, final mean body weight, and mean organ weight of 41 chemicals tested by NTP between 2000 and 2012. Models were then developed at the chemical level using orthogonal regression techniques to predict chronic (two years) noncancer health effect levels using the results of the short-term (three months) toxicity data. The findings indicate that short-term animal studies may reasonably provide a quantitative estimate of a chronic BMD or BMDL. This can allow for faster development of human health toxicity values for risk assessment for chemicals that lack chronic toxicity data. © 2017 Society for Risk Analysis.

High-dose therapy and autologous hematopoietic stem cell transplant in T-cell lymphoma: a single center experience.

PubMed

Cairoli, Anne; Ketterer, Nicolas; Barelli, Stefano; Duchosal, Michel A

2014-08-01

We report here the long-term outcome of autologous stem cell transplant in peripheral T-cell lymphoma (PTCL). Forty-three consecutive patients with PTCL diagnosed between 2000 and 2011 were treated with high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) in our center. Diagnoses included PTCL-not otherwise specified (n = 19), anaplastic large cell lymphoma (n = 11), angioimmunoblastic T-cell lymphoma (n = 5), enteropathy-associated T-cell lymphoma (n = 5) and other rare subtypes (n = 3). Thirty-six patients with a median age of 50 years (range 22-65) were transplanted in first response and seven after relapse. After a median follow-up of 63 months, estimated overall survival at 12 years was 40%, progression-free survival at 12 years was 34% and event-free survival at 12 years was 30%. On univariate analysis, age less than 50 years and no B symptoms at diagnosis were significantly associated with prolonged overall and progression-free-survival. HDCT/ASCT for peripheral T-cell lymphoma can lead to long-term survival for patients responding to induction chemotherapy.

Effects of short-term niacin treatment on plasma lipoprotein concentrations in African green monkeys (Chlorocebus aethiops).

PubMed

Chauke, Chesa G; Arieff, Zainunisha; Kaur, Mandeep; Seier, Jurgen V

2014-02-01

Niacin is the most effective drug available for raising levels of high-density lipoprotein (HDL) cholesterol. To evaluate its effects on plasma lipid concentrations, the authors administered a low dose of niacin to healthy, adult, female African green monkeys for 3 months. In the treated monkeys, low-density lipoprotein cholesterol concentrations decreased by 43% from baseline, whereas concentrations of HDL cholesterol and apolipoprotein A-I increased by 49% and 34%, respectively. The results suggest that in this primate model, a low dose of niacin can effectively increase concentrations of HDL cholesterol.

Diagnostic radiation exposure in pediatric trauma patients.

PubMed

Brunetti, Marissa A; Mahesh, Mahadevappa; Nabaweesi, Rosemary; Locke, Paul; Ziegfeld, Susan; Brown, Robert

2011-02-01

The amount of imaging studies performed for disease diagnosis has been rapidly increasing. We examined the amount of radiation exposure that pediatric trauma patients receive because they are an at-risk population. Our hypothesis was that pediatric trauma patients are exposed to high levels of radiation during a single hospital visit. Retrospective review of children who presented to Johns Hopkins Pediatric Trauma Center from July 1, 2004, to June 30, 2005. Radiographic studies were recorded for each patient and doses were calculated to give a total effective dose of radiation. All radiographic studies that each child received during evaluation, including any associated hospital admission, were included. A total of 945 children were evaluated during the study year. A total of 719 children were included in the analysis. Mean age was 7.8 (±4.6) years. Four thousand six hundred three radiographic studies were performed; 1,457 were computed tomography (CT) studies (31.7%). Average radiation dose was 12.8 (±12) mSv. We found that while CT accounted for only 31.7% of the radiologic studies performed, it accounted for 91% of the total radiation dose. Mean dose for admitted children was 17.9 (±13.8) mSv. Mean dose for discharged children was 8.4 (±7.8) mSv (p<0.0001). Burn injuries had the lowest radiation dose [1.2 (±2.6) mSv], whereas motor vehicle collision victims had the highest dose [18.8 (±14.7) mSv]. When the use of radiologic imaging is considered essential, cumulative radiation exposure can be high. In young children with relatively long life spans, the benefit of each imaging study and the cumulative radiation dose should be weighed against the long-term risks of increased exposure.

Prenatal tolerance induction: relationship between cell dose, marrow T-cells, chimerism, and tolerance.

PubMed

Chen, Jeng-Chang; Chang, Ming-Ling; Huang, Shiu-Feng; Chang, Pei-Yeh; Muench, Marcus O; Fu, Ren-Huei; Ou, Liang-Shiou; Kuo, Ming-Ling

2008-01-01

It was reported that the dose of self-antigens can determine the consequence of deletional tolerance and donor T cells are critical for tolerance induction in mixed chimeras. This study aimed at assessing the effect of cell doses and marrow T cells on engraftment and tolerance induction after prenatal bone marrow transplantation. Intraperitoneal cell transplantation was performed in FVB/N (H-2K(q)) mice at gestational day 14 with escalating doses of adult C57BL/6 (H-2K(b)) marrows. Peripheral chimerism was examined postnatally by flow cytometry and tolerance was tested by skin transplantation. Transplantation of light-density marrow cells showed a dose response. High-level chimerism emerged with a threshold dose of 5.0 x 10(6) and host leukocytes could be nearly replaced at a dose of 7.5-10.0 x 10(6). High-dose transplants conferred a steady long-lasting donor-specific tolerance but were accompanied by >50% incidence of graft-versus-host disease. Depletion of marrow T cells lessened graft-versus-host disease to the detriment of engraftment. With low-level chimerism, tolerance was a graded phenomenon dependent upon the level of chimerism. Durable chimerism within 6 months required a threshold of > or = 2% chimerism at 1 month of age and predicted a 50% chance of long-term tolerance, whereas transient chimerism (<2%) only caused hyporesponsiveness to the donor. Tolerance induction did not succeed without peripheral chimerism even if a large amount of injected donor cells persisted in the peritoneum. Neither did an increase in cell doses or donor T-cell contents benefit skin graft survivals unless it had substantially improved peripheral chimerism. Thus, peripheral chimerism level can be a simple and straightforward test to predict the degree of prenatal immune tolerance.

SLI381 (Adderall XR), a two-component, extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparison of fasted, fed, and sprinkled administration.

PubMed

Tulloch, Simon J; Zhang, Yuxin; McLean, Angus; Wolf, Kathleen N

2002-11-01

To assess the bioavailability of three test formulations of a single dose of extended-release Adderall 20-mg capsules compared with two doses of immediate-release Adderall 10-mg tablets, and to assess the bioequivalence of a single 30-mg dose of the chosen extended-release Adderall formulation (designated as SLI381) administered in applesauce (sprinkled) and the same dose administered as an intact capsule with or without food. Randomized, open-label, crossover study. Clinical research unit. Forty-one healthy adults. Study A had four treatment sequences: three test formulations (A, B, and C) of a single dose of extended-release Adderall 20 mg, and two 10-mg doses of Adderall given 4 hours apart. Study B had three treatment sequences: a single dose of SLI381 30 mg as an intact capsule after overnight fast, an intact capsule after a high-fat breakfast, and the contents of a capsule sprinkled in 1 tablespoon of applesauce. The 20-mg test formulation A had comparable pharmacokinetic profiles and bioequivalence in rate and extent of drug absorption to Adderall 10 mg twice/day for both d- and l-amphetamine. Formulations B and C had statistically significant differences from the reference drug in some pharmacokinetic parameters. A 30-mg dose of SLI381 showed no significant differences in rate and extent of absorption of d- and l-amphetamine for fasted or sprinkled conditions compared with the high-fat meal condition. SLI381 20 mg/day is bioequivalent to Adderall 10 mg twice/day. SLI381 30 mg administered in applesauce is bioequivalent in terms of both rate and extent of absorption to the same dose administered as an intact capsule in both fasted and fed states.

Ten-year oral toxicity study with Norlestrin in rhesus monkeys.

PubMed

Fitzgerald, J; de la Iglesia, F; Goldenthal, E I

1982-12-01

The long term effects of the oral contraceptive, Norlestrin, were evaluated in sexually mature female rhesus (Macaca mulatta) monkeys over a 10 year period. Norlestrin, a combination of norethindrone acetate and ethinylestradiol (50:1) was given orally on a continuous cyclic regimen of 21 d of dosing followed by 7 d without treatment. Groups of 16 monkeys each received the drug at dose levels of 0.05, 0.51, and 2.55 mg/kg representing multiples of 1, 10, and 50 times the human dose, respectively. A comparable group of 16 animals remained untreated and served as controls. Selected clinical and laboratory parameters were monitored throughout the study and all animals were necropsied and evaluated for gross and histopathologic changes. All dose levels were well tolerated and survival was not affected. There were no consistent treatment-related alterations in coagulation or other clinical laboratory parameters. Ophthalmologically, macular pigmentary anomalies were observed in all groups. Treatment-associated pathologic findings, representing exaggerated pharmacological responses with superimposed senile changes, including ovarian and uterine atrophy and dilatation of acini and ducts in the mammary gland. Periodic vaginal cytologic examination and mammary gland palpation did not demonstrate drug related changes. A small number of neoplasms was seen in all groups and a granulosa cell carcinoma of the ovary occurred in a control animal. The benign tumors consisted of three cutaneous papillomas: one in a low dose and one in a high dose animal, a uterine leiomyoma in one high dose animal, and a pancreatic duct adenoma in one low dose animal. The results of this study indicate that Norlestrin had no significant toxic manifestations or tumorigenic potential when administered on a cyclic regimen to female rhesus monkeys at levels up to 50 times the human dose for ten yr.

GENERAL CONSIDERATIONS OF DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS

EPA Science Inventory

ABSTRACT In 2003, the International Union of Pure and Applied chemistry (IUPAC) issued a glossary of terms that included the defi nition of dose-effect and doseresponse relationships (Nordberg et al., 2004). Dose effect relationship is defined as an association between dose and...

Prospective memory deficits in illicit polydrug users are associated with the average long-term typical dose of ecstasy typically consumed in a single session.

PubMed

Gallagher, Denis T; Hadjiefthyvoulou, Florentia; Fisk, John E; Montgomery, Catharine; Robinson, Sarita J; Judge, Jeannie

2014-01-01

Neuroimaging evidence suggests that ecstasy-related reductions in SERT densities relate more closely to the number of tablets typically consumed per session rather than estimated total lifetime use. To better understand the basis of drug related deficits in prospective memory (p.m.) we explored the association between p.m. and average long-term typical dose and long-term frequency of use. Study 1: Sixty-five ecstasy/polydrug users and 85 nonecstasy users completed an event-based, a short-term and a long-term time-based p.m. task. Study 2: Study 1 data were merged with outcomes on the same p.m. measures from a previous study creating a combined sample of 103 ecstasy/polydrug users, 38 cannabis-only users, and 65 nonusers of illicit drugs. Study 1: Ecstasy/polydrug users had significant impairments on all p.m. outcomes compared with nonecstasy users. Study 2: Ecstasy/polydrug users were impaired in event-based p.m. compared with both other groups and in long-term time-based p.m. compared with nonillicit drug users. Both drug using groups did worse on the short-term time-based p.m. task compared with nonusers. Higher long-term average typical dose of ecstasy was associated with poorer performance on the event and short-term time-based p.m. tasks and accounted for unique variance in the two p.m. measures over and above the variance associated with cannabis and cocaine use. The typical ecstasy dose consumed in a single session is an important predictor of p.m. impairments with higher doses reflecting increasing tolerance giving rise to greater p.m. impairment.

42 CFR 81.4 - Definition of terms used in this part.

Code of Federal Regulations, 2011 CFR

2011-10-01

...]. (e) Equivalent dose means the absorbed dose in a tissue or organ multiplied by a radiation weighting... dose means the portion of the equivalent dose that is received from radiation sources outside of the... pattern and level of radiation exposure. (h) Internal dose means the portion of the equivalent dose that...

Activation-specific metabolic requirements for NK cell IFN-γ production1

PubMed Central

Keppel, Molly P.; Topcagic, Nermina; Mah, Annelise Y.; Vogel, Tiphanie P.; Cooper, Megan A.

2014-01-01

There has been increasing recognition of the importance of cellular metabolism and metabolic substrates for the function and differentiation of immune cells. Here, for the first time, we investigate the metabolic requirements for production of IFN-γ by freshly isolated NK cells. Primary murine NK cells mainly utilize mitochondrial oxidative phosphorylation at rest and with short-term activation. Remarkably, we discovered significant differences in the metabolic requirements of murine NK cell IFN-γ production depending upon the activation signal. Stimulation of NK cell IFN-γ production was independent of glycolysis or mitochondrial oxidative phosphorylation when cells were activated with IL-12+IL-18. By contrast, stimulation via activating NK receptors required glucose-driven oxidative phosphorylation. Prolonged treatment with high-dose, but not low dose, IL-15 eliminated the metabolic requirement for receptor stimulation. In summary, this study demonstrates that metabolism provides an essential second signal for induction of IFN-γ production by activating NK cell receptors that can be reversed with prolonged high-dose IL-15 treatment. PMID:25595780

Long-term Survival and Toxicity in Patients Treated With High-Dose Intensity Modulated Radiation Therapy for Localized Prostate Cancer

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

Spratt, Daniel E.; Pei, Xin; Yamada, Josh

2013-03-01

Purpose: To report long-term survival and toxicity outcomes with the use of high-dose intensity modulated radiation therapy (IMRT) to 86.4 Gy for patients with localized prostate cancer. Methods and Materials: Between August 1997 and December 2008, 1002 patients were treated to a dose of 86.4 Gy using a 5-7 field IMRT technique. Patients were stratified by prognostic risk group based on National Comprehensive Cancer Network risk classification criteria. A total of 587 patients (59%) were treated with neoadjuvant and concurrent androgen deprivation therapy. The median follow-up for the entire cohort was 5.5 years (range, 1-14 years). Results: For low-, intermediate-,more » and high-risk groups, 7-year biochemical relapse-free survival outcomes were 98.8%, 85.6%, and 67.9%, respectively (P<.001), and distant metastasis-free survival rates were 99.4%, 94.1%, and 82.0% (P<.001), respectively. On multivariate analysis, T stage (P<.001), Gleason score (P<.001), and >50% of initial biopsy positive core (P=.001) were predictive for distant mestastases. No prostate cancer-related deaths were observed in the low-risk group. The 7-year prostate cancer-specific mortality (PCSM) rates, using competing risk analysis for intermediate- and high-risk groups, were 3.3% and 8.1%, respectively (P=.008). On multivariate analysis, Gleason score (P=.004), percentage of biopsy core positivity (P=.003), and T-stage (P=.033) were predictive for PCSM. Actuarial 7-year grade 2 or higher late gastrointestinal and genitourinary toxicities were 4.4% and 21.1%, respectively. Late grade 3 gastrointestinal and genitourinary toxicity was experienced by 7 patients (0.7%) and 22 patients (2.2%), respectively. Of the 427 men with full potency at baseline, 317 men (74%) retained sexual function at time of last follow-up. Conclusions: This study represents the largest cohort of patients treated with high-dose radiation to 86.4 Gy, using IMRT for localized prostate cancer, with the longest follow-up to date. Our findings indicate that this treatment results in excellent clinical outcomes with acceptable toxicity.« less

Infrastructure to Support Ultra High Throughput Biodosimetry Screening after a Radiological Event

PubMed Central

Garty, G.; Karam, P.A.; Brenner, D. J.

2011-01-01

Purpose After a large-scale radiological event, there will be a pressing need to assess, within a few days, the radiation doses received by tens or hundreds of thousands of individuals. This is for triage, to prevent treatment locations from being overwhelmed, in what is sure to be a resource limited scenario, as well as to facilitate dose-dependent treatment decisions. In addition there are psychosocial considerations, in that active reassurance of minimal exposure is a potentially effective antidote to mass panic, as well as long-term considerations, to facilitate later studies of cancer and other long-term disease risks. Materials and Methods As described elsewhere in this issue, we are developing a Rapid Automated Biodosimetry Tool (RABiT). The RABiT allows high throughput analysis of thousands of blood samples per day, providing a dose estimate that can be used to support clinical triage and treatment decisions. Results Development of the RABiT has motivated us to consider the logistics of incorporating such a system into the existing emergency response scenarios of a large metropolitan area. We present here a view of how one or more centralized biodosimetry readout devices might be incorporated into an infrastructure in which fingerstick blood samples are taken at many distributed locations within an affected city or region and transported to centralized locations. Conclusions High throughput biodosimetry systems offer the opportunity to perform biodosimetric assessments on a large number of persons. As such systems reach a high level of maturity, emergency response scenarios will need to be tweaked to make use of these powerful tools. This can be done relatively easily within the framework of current scenarios. PMID:21675819

The long-term decrease of 90Sr availability in the environment and its transfer to man after a nuclear fallout.

PubMed

Mück, K; Sinojmeri, M; Whilidal, H; Steger, F

2001-01-01

Due to its long physical half-life, and the fact that its long-term mobility in the environment as well as its radiotoxicity is higher than that of 137Cs, the long-term bio-availability of 90Sr in the environment is of importance with regard to the long-term population exposure after fallout from nuclear weapons detonations or a severe reactor accident. It will also substantially influence the time-span required until re-utilisation of highly contaminated territory is possible again. An assessment of the long-term decrease of the activity concentration in all foodstuffs relevant for internal exposure after severe 90Sr fallout was performed. The observed effective half-lives were approximately 1.8-2.1 years in the first 2-3 years after the end of fallout and 8-10 years in the following three decades. This is equivalent to a biological half-life of about 13.2 years and results in a total 50 year dose of 6.2 times the first year exposure. Due to this decline in 90Sr-availability, the average annual activity intake of 90Sr in Austria has decreased from 840 Bq at the climax of the nuclear weapons tests to about 42 Bq in 1997 for adults, and from 500 Bq to about 35 Bq for 1 year old infants. This is equivalent to a 90Sr ingestion dose of 1.2 microSv for adults and 2.5 microSv for 1 year old infants in 1997 or less than 0.4% of the ingestion dose by natural radionuclides in the diet.

A unique role of the cholera toxin A1-DD adjuvant for long-term plasma and memory B cell development.

PubMed

Bemark, Mats; Bergqvist, Peter; Stensson, Anneli; Holmberg, Anna; Mattsson, Johan; Lycke, Nils Y

2011-02-01

Adjuvants have traditionally been appreciated for their immunoenhancing effects, whereas their impact on immunological memory has largely been neglected. In this paper, we have compared three mechanistically distinct adjuvants: aluminum salts (Alum), Ribi (monophosphoryl lipid A), and the cholera toxin A1 fusion protein CTA1-DD. Their influence on long-term memory development was dramatically different. Whereas a single immunization i.p. with 4-hydroxy-3-nitrophenyl acetyl (NP)-chicken γ-globulin and adjuvant stimulated serum anti-NP IgG titers that were comparable at 5 wk, CTA1-DD-adjuvanted responses were maintained for >16 mo with a half-life of anti-NP IgG ∼36 wk, but <15 wk after Ribi or Alum. A CTA1-DD dose-dependent increase in germinal center (GC) size and numbers was found, with >60% of splenic B cell follicles hosting GC at an optimal CTA1-DD dose. Roughly 7% of these GC were NP specific. This GC-promoting effect correlated well with the persistence of long-term plasma cells in the bone marrow and memory B cells in the spleen. CTA1-DD also facilitated increased somatic hypermutation and affinity maturation of NP-specific IgG Abs in a dose-dependent fashion, hence arguing that large GC not only promotes higher Ab titers but also high-quality Ab production. Adoptive transfer of splenic CD80(+), but not CD80(-), B cells, at 1 y after immunization demonstrated functional long-term anti-NP IgG and IgM memory cells. To our knowledge, this is the first report to specifically compare and document that adjuvants can differ considerably in their support of long-term immune responses. Differential effects on the GC reaction appear to be the basis for these differences.

Methylxanthines during pregnancy and early postnatal life.

PubMed

Adén, Ulrika

2011-01-01

World-wide, many fetuses and infants are exposed to methylxanthines via maternal consumption of coffee and other beverages containing these substances. Methylxanthines (caffeine, theophylline and aminophylline) are also commonly used as a medication for apnea of prematurity.The metabolism of methylxanthines is impaired in pregnant women, fetuses and neonates, leading to accumulating levels thereof. Methylxanthines readily passes the placenta barrier and enters all tissues and thus may affect the fetus/newborn at any time during pregnancy or postnatal life, given that the effector systems are mature.At clinically relevant doses, the major effector system for methylxanthines is adenosine receptors. Animal studies suggest that adenosine receptors in the cardiovascular, respiratory and immune system are developed at birth, but that cerebral adenosine receptors are not fully functional. Furthermore animal studies have shown protective positive effects of methylxanthines in situations of hypoxia/ischemia in neonates. Similarly, a positive long-term effect on lung function and CNS development was found in human preterm infants treated with high doses of caffeine for apneas. There is now evidence that the overall benefits from methylxanthine therapy for apnea of prematurity outweigh potential short-term risks.On the other hand it is important to note that experimental studies have indicated that long-term effects of caffeine during pregnancy and postnatally may include altered behavior and altered respiratory control in the offspring, although there is currently no human data to support this.Some epidemiology studies have reported negative effects on pregnancy and perinatal outcomes related to maternal ingestion of high doses of caffeine, but the results are inconclusive. The evidence base for adverse effects of caffeine in first third of pregnancy are stronger than for later parts of pregnancy and there is currently insufficient evidence to advise women to restrict caffeine intake after the first trimester.

Hair cortisol measurement in mitotane-treated adrenocortical cancer patients.

PubMed

Manenschijn, L; Quinkler, M; van Rossum, E F C

2014-04-01

The only approved drug for the treatment of adrenocortical cancer (ACC) is mitotane. Mitotane is adrenolytic and therefore, hydrocortisone replacement therapy is necessary. Since mitotane increases cortisol binding globulin (CBG) and induces CYP3A4 activity, high doses of hydrocortisone are thought to be required. Evaluation of hydrocortisone therapy in mitotane-treated patients has been difficult since there is no good marker to evaluate hydrocortisone therapy. Measurement of cortisol in scalp hair is a novel method that offers the opportunity to measure long-term cortisol levels. Our aim was to evaluate whether hair cortisol measurements could be useful in evaluating recent hydrocortisone treatment in mitotane-treated ACC patients. Hair cortisol levels were measured in 15 mitotane-treated ACC patients on hydrocortisone substitution and 96 healthy individuals. Cortisol levels were measured in 3 cm hair segments, corresponding to a period of 3 months. Hair cortisol levels were higher in ACC patients compared to healthy individuals (p<0.0001). Seven ACC patients (47%) had hair cortisol levels above the reference range. None of the patients had hair cortisol levels below normal. In contrast to hydrocortisone doses (β=0.03, p=0.93), hair cortisol levels were associated with BMI (β=0.53, p=0.042). There was no correlation between hair cortisol levels and hydrocortisone doses (β=0.41, p=0.13). Almost half of the ACC patients had high hair cortisol levels, suggesting long-term over-substitution of hydrocortisone in some of the patients, whereas none of the patients was under-substituted. Hair cortisol measurements might be useful in long-term monitoring hydrocortisone treatment in mitotane-treated ACC patients. © Georg Thieme Verlag KG Stuttgart · New York.

Fluence-to-dose conversion coefficients for heavy ions calculated using the PHITS code and the ICRP/ICRU adult reference computational phantoms.

PubMed

Sato, Tatsuhiko; Endo, Akira; Niita, Koji

2010-04-21

The fluence to organ-absorbed-dose and effective-dose conversion coefficients for heavy ions with atomic numbers up to 28 and energies from 1 MeV/nucleon to 100 GeV/nucleon were calculated using the PHITS code coupled to the ICRP/ICRU adult reference computational phantoms, following the instruction given in ICRP Publication 103 (2007 (Oxford: Pergamon)). The conversion coefficients for effective dose equivalents derived using the radiation quality factors of both Q(L) and Q(y) relationships were also estimated, utilizing the functions for calculating the probability densities of absorbed dose in terms of LET (L) and lineal energy (y), respectively, implemented in PHITS. The calculation results indicate that the effective dose can generally give a conservative estimation of the effective dose equivalent for heavy-ion exposure, although it is occasionally too conservative especially for high-energy lighter-ion irradiations. It is also found from the calculation that the conversion coefficients for the Q(y)-based effective dose equivalents are generally smaller than the corresponding Q(L)-based values because of the conceptual difference between LET and y as well as the numerical incompatibility between the Q(L) and Q(y) relationships. The calculated data of these dose conversion coefficients are very useful for the dose estimation of astronauts due to cosmic-ray exposure.

[Hypofractionation and radiotherapy: "the eternal return"].

PubMed

Cosset, J-M; Mornex, F; Eschwège, F

2013-10-01

Hypofractionation is not a new idea in radiotherapy. The use of a few high-dose fractions has been proposed by some pioneers of our specialty in the early years of the 20th century. Hypofractionation then reappeared several times in the next decades, based on successive radiobiological concepts, a number of them having been shown to be wrong. The nominal single dose (NSD), for example, so fashionable in the 1970's, dramatically underestimated the late toxicity of the high-dose fractions. Consequently, the NSD was directly responsible for a significant increase of the incidence and of the severity of late complications in large cohorts of patients. The linear-quadratic model (LQ) unequivocally improved our understanding of fractionation sensitivity, but one has to keep in mind its limitations, both in the areas of low and high doses per fraction. For more than a decade, prostate cancer has been the subject of fierce discussions about its sensitivity to fractionation. A number of studies have suggested an unusually low (for a malignant tumor) alpha/beta ratio. However, the available data do not allow a precise evaluation of this ratio; "very low" (1.5 Gy), with an advantage of hypofractionation in terms of local control? Or simply "low" (3-4 Gy), only allowing a reduction of the total number of fractions (with a dose adequately reduced)? While waiting for complementary data, it is advised to remain very careful when modifying the classical schemes towards hypofractionation. Copyright © 2013. Published by Elsevier SAS.

Non-steroidal anti-inflammatory drug related upper gastrointestinal bleeding: types of drug use and patient profiles in real clinical practice.

PubMed

Sostres, Carlos; Carrera-Lasfuentes, Patrica; Lanas, Angel

2017-10-01

The best available evidence regarding non-steroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) bleeding comes from randomized controlled trials including patients who use NSAIDs to manage chronic rheumatic diseases; however, patients with varying background profiles commonly take NSAIDs for many other reasons, often without prescription, and such usage has not been well studied. To define the characteristics of patients hospitalized for upper GI bleeding in clinical practice, we conducted a case-control study among patients with endoscopy-proven major upper GI bleeding due to gastroduodenal peptic lesions and control subjects. We used adjusted logistic regression models to estimate bleeding risks. Data analysis was performed using SPSS 22.0. Our analysis included 3785 cases and 6540 controls, including 1270 cases (33.55%) and 834 controls (12.75%) reporting recent use (<30 days) of NSAIDs including high-dose acetylsalicylic acid (ASA). NSAID use was associated with increased risk of upper GI bleeding, with an adjusted relative risk of 4.86 (95% CI, 4.32-5.46). Acute musculoskeletal pain (36.1%), chronic osteoarthritis (13.5%), and headache (13.6%) were the most common reasons for NSAID use. Among cases, only 17.31% took NSAIDs and 6.38% took high dose ASA due to chronic osteoarthritis. Demographic characteristics significantly differed between subjects with chronic vs. acute musculoskeletal pain. Proton pump inhibitor use was significantly higher in patients who used NSAIDs due to chronic osteoarthritis compared to patients with acute musculoskeletal pain. NSAID (65.15%) or high-dose ASA use (65.83%) preceding upper GI bleeding was most often short-term. In over half of cases (63.62%), the upper GI bleeding event was not preceded by dyspeptic warning symptoms. The majority of patients hospitalized due to NSAID-related upper GI bleeding reported short-term NSAID use for reasons other than chronic rheumatic disease. These findings suggest that current prevention strategies may not reach a wide population of short-term NSAID users.

SU-E-T-766: Treatment Planning Comparison Study On Two Different Multileaf Collimators Delivered with Volumetric Modulated Arc Therapy

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

Zhang, R; Xiaomei, F; Bai, W

2015-06-15

Purpose: To compare and evaluate the performance of two different multileaf collimators(MLCi2 and Agility) delivery with volumetric modulated arc therapy techniques. Methods: Treatment plans were graded four (Low, Moderate, Moderate-High and High complexity) accorrding to the complexity. This includes 1 Low complexity(brain metastasis), 2 Moderate complexity(Lung and Liver), 1 Moderate-High complexity(prostate) and 1 High complexity ( head and neck) cases. Total dose of 60 Gy was given for all the plans. All cases were desigined two VMAT plans, one with MLCi2(group A) and the other with Agility(group B). All plans were done on Elekta VMAT with Monaco treatment planning system.more » All plans were generated with 6 MV X-rays for both Plan A and Plan B. Plans were evaluated based on the ability to meet the dose volume histogram, radiation conformity index, estimated radiation delivery time, dose homogeneity index(HI) and monitor units(MU) needed to deliver the prescribed dose. Results: Plans of group B achieved the best HI (HI = 1.05 Vs. 1.06) at the Low complexity cases while plans of group A were slightly better at the high complexity cases (HI = 1.12 Vs. 1.14). Faster VMAT plan delivery with Agility than with MLCi2 as plan complexity increased (Low complexity:52s Vs.52s, Moderate complexity:58s Vs. 55s, Moderate-High complexity: 171s Vs.152s, High complexity : 326s Vs. 202s ), especially for the most complex paradigms delivered time can be decresed 38%. No Significant changes were observed between the group B and group A plans in terms of the healthy tissue mean dose and MU. Both plans respected the planning objective for all organs at risk. Conclusion: The study concludes that VMAT plans with the novel Agility MLC can significant decrease the delivering time at the high complexity cases, while a slight compromise in the dose homogeneity index should be noted. This work was supported by The Medical Science Foundation of The health department of Hebei Province (No. 20130253)« less

Congenital hypothyroidism from complete iodide transport defect: long-term evolution with iodide treatment.

PubMed Central

Albero, R.; Cerdan, A.; Sanchez Franco, F.

1987-01-01

Hypothyroidism from iodide transport deficiency is a rare disease, especially when found in two affected siblings. Treatment with high doses of iodide has been recommended, but no long term results have been reported. Two siblings with congenital hypothyroidism due to total failure to transport iodide have been followed up during twelve and a half years of treatment with oral potassium iodide. Iodine doses varied between 10.3 and 22 mg/day, and serum total iodine concentrations between 100 and 210 micrograms/dl. Total triiodothyronine (T3), thyroxine (T4) and free T4 were in the normal range during the time of study. Basal thyroid stimulating hormones (TSH) and maximum TSH response to thyrotrophin releasing hormone (TRH) were also in the range of normal values. These data along with clinical findings confirmed the potential usefulness of iodine in hypothyroidism due to complete iodide transport defect. PMID:3451231

Whole-Body Exposure to 28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term.

PubMed

Whoolery, Cody W; Walker, Angela K; Richardson, Devon R; Lucero, Melanie J; Reynolds, Ryan P; Beddow, David H; Clark, K Lyles; Shih, Hung-Ying; LeBlanc, Junie A; Cole, Mara G; Amaral, Wellington Z; Mukherjee, Shibani; Zhang, Shichuan; Ahn, Francisca; Bulin, Sarah E; DeCarolis, Nathan A; Rivera, Phillip D; Chen, Benjamin P C; Yun, Sanghee; Eisch, Amelia J

2017-11-01

Astronauts traveling to Mars will be exposed to chronic low doses of galactic cosmic space radiation, which contains highly charged, high-energy (HZE) particles. 56 Fe-HZE-particle exposure decreases hippocampal dentate gyrus (DG) neurogenesis and disrupts hippocampal function in young adult rodents, raising the possibility of impaired astronaut cognition and risk of mission failure. However, far less is known about how exposure to other HZE particles, such as 28 Si, influences hippocampal neurogenesis and function. To compare the influence of 28 Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56 Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice (NGFP; made and maintained for 10 or more generations on a C57BL/6J background) received whole-body 28 Si-particle-radiation exposure (0, 0.2 and 1 Gy, 300 MeV/n, LET 67 KeV/μ, dose rate 1 Gy/min). For neurogenesis assessment, the NGFP mice were injected with the mitotic marker BrdU at 22 h postirradiation and brains were examined for indices of hippocampal proliferation and neurogenesis, including Ki67 + , BrdU + , BrdU + NeuN + and DCX + cell numbers at short- and long-term time points (24 h and 3 months postirradiation, respectively). In the short-term group, stereology revealed fewer Ki67 + , BrdU + and DCX + cells in 1-Gy-irradiated group relative to nonirradiated control mice, fewer Ki67 + and DCX + cells in 0.2 Gy group relative to control group and fewer BrdU + and DCX + cells in 1 Gy group relative to 0.2 Gy group. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Notably, there were fewer surviving BrdU + cells in the 1 Gy group relative to 0- and 0.2-Gy-irradiated mice in the long-term group. When the short- and long-term groups were analyzed by sex, exposure to radiation had a similar effect on neurogenesis indices in male and female mice, although only male mice showed fewer surviving BrdU + cells in the long-term group. Fluorescent immunolabeling and confocal phenotypic analysis revealed that most surviving BrdU + cells in the long-term group expressed the neuronal marker NeuN, definitively confirming that exposure to 1 Gy 28 Si radiation decreased the number of surviving adult-generated neurons in male mice relative to both 0- and 0.2-Gy-irradiated mice. For hippocampal function assessment, 9-week-old male C57BL/6J mice received whole-body 28 Si-particle exposure and were then assessed long-term for performance on contextual and cued fear conditioning. In the context test the animals that received 0.2 Gy froze less relative to control animals, suggesting decreased hippocampal-dependent function. However, in the cued fear conditioning test, animals that received 1 Gy froze more during the pretone portion of the test, relative to controls and 0.2-Gy-irradiated mice, suggesting enhanced anxiety. Compared to previously reported studies, these data suggest that 28 Si-radiation exposure damages neurogenesis, but to a lesser extent than 56 Fe radiation and that low-dose 28 Si exposure induces abnormalities in hippocampal function, disrupting fear memory but also inducing anxiety-like behavior. Furthermore, exposure to 28 Si radiation decreased new neuron survival in long-term male groups but not females suggests that sex may be an important factor when performing brain health risk assessment for astronauts traveling in space.

Estimating the Effects of Astronaut Career Ionizing Radiation Dose Limits on Manned Interplanetary Flight Programs

NASA Technical Reports Server (NTRS)

Koontz, Steven L.; Rojdev, Kristina; Valle, Gerard D.; Zipay, John J.; Atwell, William S.

2013-01-01

The Hybrid Inflatable DSH combined with electric propulsion and high power solar-electric power systems offer a near TRL-now solution to the space radiation crew dose problem that is an inevitable aspect of long term manned interplanetary flight. Spreading program development and launch costs over several years can lead to a spending plan that fits with NASA's current and future budgetary limitations, enabling early manned interplanetary operations with space radiation dose control, in the near future while biomedical research, nuclear electric propulsion and active shielding research and development proceed in parallel. Furthermore, future work should encompass laboratory validation of HZETRN calculations, as previous laboratory investigations have not considered large shielding thicknesses and the calculations presented at these thicknesses are currently performed via extrapolation.

Radiation-Induced Noncancer Risks in Interventional Cardiology: Optimisation of Procedures and Staff and Patient Dose Reduction

PubMed Central

Khairuddin Md Yusof, Ahmad

2013-01-01

Concerns about ionizing radiation during interventional cardiology have been increased in recent years as a result of rapid growth in interventional procedure volumes and the high radiation doses associated with some procedures. Noncancer radiation risks to cardiologists and medical staff in terms of radiation-induced cataracts and skin injuries for patients appear clear potential consequences of interventional cardiology procedures, while radiation-induced potential risk of developing cardiovascular effects remains less clear. This paper provides an overview of the evidence-based reviews of concerns about noncancer risks of radiation exposure in interventional cardiology. Strategies commonly undertaken to reduce radiation doses to both medical staff and patients during interventional cardiology procedures are discussed; optimisation of interventional cardiology procedures is highlighted. PMID:24027768

Single Event Effects and Total Dose Testing of the Intersil ISL 70003SEH Integrated Point of Load Converter

NASA Astrophysics Data System (ADS)

van Vonno, N. W.; White, J. D.; Pearce, L. G.; Thomson, E. J.; Gill, J. S.; Mansilla, O. E.

2014-08-01

Single-event transient (SET) phenomena in power management applications has evolved into a key issue, particularly in point of load (POL) buck regulators, as the loads driven by these devices are sensitive to even short-term overvoltage conditions. We preface this paper by a discussion of earlier destructive and nondestructive SEE testing of Intersil integrated point of load regulators, with emphasis on SET phenomena and some of the lessons learned in this work. We then report recent results of SET and destructive SEE testing of the ISL70003SEH POL converter, together with a brief discussion of the part's electrical and radiation hardness specifications. We conclude with a brief overview of low and high dose rate total dose testing of the part.

Dyshidrotic eczema associated with the use of IVIg

PubMed Central

Kotan, Dilcan; Erdem, Teoman; Acar, Bilgehan Atilgan; Boluk, Ayhan

2013-01-01

Intravenous immunoglobulin (IVIg) treatment is highly effective for autoimmune diseases including myasthenia gravis. Recovery is observed at approximately. 75% of myasthenia gravis patients through IVIg treatment. As a result of many clinical studies, the recommended dose is determined as 0.4 g/kg for 5 days (maximum total dose at 2 g/kg body weight). If an additional immunomodulatory treatment is not administered, IVIg maintenance treatment is needed mostly. However, some side effects may inhibit long-term treatment. For this reason, it is important to know the effect profile well and when the treatment should be discontinued. A female myasthenia gravis patient case is presented here, where dyshidrotic eczema has occurred after the second dose of  intravenous Ig medication and whose treatment is despite further IVIg therapy. PMID:23417935

A review of immunogenicity and tolerability of live attenuated Hepatitis A vaccine in children.

PubMed

Rao, Sameer; Mao, J S; Motlekar, Salman; Fangcheng, Zhuang; Kadhe, Ganesh

2016-12-01

Changing epidemiology of Hepatitis A virus (HAV) has led to an increased susceptibility of adolescents and adults to the infection. Vaccination can remarkably reduce the incidence and associated morbidity of HAV infection. This review is focused on the safety and efficacy of H2 strain derived live attenuated Hepatitis A vaccine. We found the vaccine to be highly immunogenic with minimal or negligible safety issues. Moreover, a single dose of live attenuated vaccine persists a long term immune response and can be a preferred option for developing countries. In 2014, Indian Academy of Paediatrics (IAP) also updated their recommendations for H2 vaccine as a single dose as against the previous 2 dose schedule. A focused approach to include the vaccine in national immunization program should be explored.

Long-Term, Low-Dose Exposure to Microcystin-LR Does not Cause or Increase the Severity of Liver Disease in Rodents.

PubMed

Labine, Meaghan; Gong, Yuewen; Minuk, Gerald Y

Acute exposure to high concentrations of microcystin-LR (MC-LR) can cause significant hepatocyte injury. To document the effects of long-term, low-dose MC-LR exposure on hepatic inflammation and fibrosis in mice with healthy and diseased livers. Male CD1 mice (N = 20/group) were exposed to 1.0 μg/L of MC-LR in drinking water; 1.0 μg/L MC-LR plus 300 mg/L of the hepatotoxin thioacetamide (MC-LR/TAA); or 300 mg/L TAA alone for 28 weeks. Liver biochemistry and histology were documented at the end of the study period. In addition, hepatic stellate cells (HSCs), were exposed in vitro to MC-LR (0.1-10,000 μg/L) and monitored for changes in cell metabolism, proliferation and activation. Liver biochemistry and histology were essentially normal in MC-LR alone exposed mice. MC-LR/TAA and TAA alone exposed mice had significant hepatic inflammation and fibrosis but the extent of the changes were similar in the two groups. In vitro, MC-LR had no effect on HSC metabolism, proliferation or activation. Long-term, low-dose exposure to MC-LR is unlikely to lead to chronic liver disease in the setting of a normal liver or exacerbate existing liver disease in the setting of ongoing hepatitis.

SU-E-T-37: A GPU-Based Pencil Beam Algorithm for Dose Calculations in Proton Radiation Therapy

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

Kalantzis, G; Leventouri, T; Tachibana, H

Purpose: Recent developments in radiation therapy have been focused on applications of charged particles, especially protons. Over the years several dose calculation methods have been proposed in proton therapy. A common characteristic of all these methods is their extensive computational burden. In the current study we present for the first time, to our best knowledge, a GPU-based PBA for proton dose calculations in Matlab. Methods: In the current study we employed an analytical expression for the protons depth dose distribution. The central-axis term is taken from the broad-beam central-axis depth dose in water modified by an inverse square correction whilemore » the distribution of the off-axis term was considered Gaussian. The serial code was implemented in MATLAB and was launched on a desktop with a quad core Intel Xeon X5550 at 2.67GHz with 8 GB of RAM. For the parallelization on the GPU, the parallel computing toolbox was employed and the code was launched on a GTX 770 with Kepler architecture. The performance comparison was established on the speedup factors. Results: The performance of the GPU code was evaluated for three different energies: low (50 MeV), medium (100 MeV) and high (150 MeV). Four square fields were selected for each energy, and the dose calculations were performed with both the serial and parallel codes for a homogeneous water phantom with size 300×300×300 mm3. The resolution of the PBs was set to 1.0 mm. The maximum speedup of ∼127 was achieved for the highest energy and the largest field size. Conclusion: A GPU-based PB algorithm for proton dose calculations in Matlab was presented. A maximum speedup of ∼127 was achieved. Future directions of the current work include extension of our method for dose calculation in heterogeneous phantoms.« less

A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease.

PubMed

Farlow, Martin R; Grossberg, George T; Sadowsky, Carl H; Meng, Xiangyi; Velting, Drew M

2015-01-01

The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open-label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (-4.6; SD=8.7) and SIB (-7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (-3.9; SD=8.0 and -4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch.

Rapid expansion of T cells: Effects of culture and cryopreservation and importance of short-term cell recovery.

PubMed

Sadeghi, Arian; Ullenhag, Gustav; Wagenius, Gunnar; Tötterman, Thomas H; Eriksson, Fredrik

2013-06-01

Successful cell therapy relies on the identification and mass expansion of functional cells for infusion. Cryopreservation of cells is an inevitable step in most cell therapies which also entails consequences for the frozen cells. This study assessed the impact of cryopreservation and the widely used protocol for rapid expansion of T lymphocytes. The effects on cell viability, immunocompetence and the impact on apoptotic and immunosuppressive marker expression were analyzed using validated assays. Cryopreservation of lymphocytes during the rapid expansion protocol did not affect cell viability. Lymphocytes that underwent mass expansion or culture in high dose IL-2 were unable to respond to PHA stimulation by intracellular ATP production immediately after thawing (ATP = 16 ± 11 ng/ml). However, their reactivity to PHA was regained within 48 hours of recovery (ATP = 356 ± 61 ng/ml). Analysis of mRNA levels revealed downregulation of TGF-β and IL-10 at all time points. Culture in high dose IL-2 led to upregulation of p73 and BCL-2 mRNA levels while FoxP3 expression was elevated after culture in IL-2 and artificial TCR stimuli. FoxP3 levels decreased after short-term recovery without IL-2 or stimulation. Antigen specificity, as determined by IFNγ secretion, was unaffected by cryopreservation but was completely lost after addition of high dose IL-2 and artificial TCR stimuli. In conclusion, allowing short-time recovery of mass expanded and cryopreserved cells before reinfusion could enhance the outcome of adoptive cell therapy as the cells regain immune competence and specificity.

Mean Absorbed Dose to the Anal-Sphincter Region and Fecal Leakage among Irradiated Prostate Cancer Survivors

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

Alsadius, David, E-mail: david.alsadius@oncology.gu.se; Hedelin, Maria; Division of Clinical Cancer Epidemiology, Department of Oncology-Pathology, Karolinska Institute, Stockholm

2012-10-01

Purpose: To supplement previous findings that the absorbed dose of ionizing radiation to the anal sphincter or lower rectum affects the occurrence of fecal leakage among irradiated prostate-cancer survivors. We also wanted to determine whether anatomically defining the anal-sphincter region as the organ at risk could increase the degree of evidence underlying clinical guidelines for restriction doses to eliminate this excess risk. Methods and Materials: We identified 985 men irradiated for prostate cancer between 1993 and 2006. In 2008, we assessed long-term gastrointestinal symptoms among these men using a study-specific questionnaire. We restrict the analysis to the 414 men whomore » had been treated with external beam radiation therapy only (no brachytherapy) to a total dose of 70 Gy in 2-Gy daily fractions to the prostate or postoperative prostatic region. On reconstructed original radiation therapy dose plans, we delineated the anal-sphincter region as an organ at risk. Results: We found that the prevalence of long-term fecal leakage at least once per month was strongly correlated with the mean dose to the anal-sphincter region. Examining different dose intervals, we found a large increase at 40 Gy; {>=}40 Gy compared with <40 Gy gave a prevalence ratio of 3.8 (95% confidence interval 1.6-8.6). Conclusions: This long-term study shows that mean absorbed dose to the anal-sphincter region is associated with the occurrence of long-term fecal leakage among irradiated prostate-cancer survivors; delineating the anal-sphincter region separately from the rectum and applying a restriction of a mean dose <40 Gy will, according to our data, reduce the risk considerably.« less

Improved long-term survival after intra-operative single high-dose ATG-Fresenius induction in renal transplantation: a single centre experience.

PubMed

Kaden, Jürgen; May, Gottfried; Völp, Andreas; Wesslau, Claus

2009-01-01

In organ grafts donor-specific sensitization is initiated immediately after revascularization. Therefore, in 1990 we introduced the intra-operative single high-dose ATG-Fresenius (ATG-F) induction in addition to standard triple drug therapy (TDT) consisting of steroids, azathioprine and cyclosporin. A total of 778 first renal transplantations from deceased donors, performed between 1987 and 1998, were included in this evaluation. This retrospective analysis of clinic records and electronic databases presents data of all recipients of first kidney grafts who received two different ATG-F inductions (1(st) group: 9 mg/kg body weight as single high-dose intra-operatively, n=484; 2(nd) group: 3 mg/kg body weight on 7 or 8 consecutive days as multiple-dose starting also intra-operatively, n=78) and standard TDT alone (3(rd) group: TDT alone, n=216). The 10-year patient survival rates were 72.6+/-2.6% (TDT + ATG-F single high-dose), 79.5+/-5.1% (TDT + ATG-F multiple-dose) and 67.2+/-3.7%% (TDT alone; Kaplan-Meier estimates with standard errors; ATG-F vs TDT alone, p=0.001). The 10-year graft survival rates with censoring of patients that died with a functioning graft were 73.8+/-2.4%, 57.7+/-5.8% and 58.4+/-3.6% (Kaplan-Meier estimates with standard errors; 1(st) vs 2(nd )and 3(rd) group, respectively, p<0.001) and the 10-year graft survival rates with patient death counted as graft failure were 58.3+/-2.7%, 55.7+/-5.8% and 48.2+/-3.5% (Kaplan-Meier estimates with standard errors; ATG-F single high-dose vs TDT, p=0.023). In pre-sensitized recipients there were also significant differences in favour of ATG-F, more notably in the single high-dose ATG-F induction. A total of 69% of the patients in the two cohorts receiving ATG-F did not experience any transplant rejections compared to 56% in patients undergoing TDT alone (p=0.018). The incidence of infectious complications was comparable across all groups. According to evidence obtained from the routine documentation of 778 renal transplantations, ATG-F induction therapy administered as a part of immunosuppressive therapy significantly improves patient survival and reduces the risk of graft failure and transplant rejections.

Long-term therapy in COPD: any evidence of adverse effect on bone?

PubMed Central

Langhammer, Arnulf; Forsmo, Siri; Syversen, Unni

2009-01-01

Patients with COPD have high risk for osteoporosis and fractures. Hip and vertebral fractures might impair mobility, and vertebral fractures further reduce lung function. This review discusses the evidence of bone loss due to medical treatment opposed to disease severity and risk factors for COPD, and therapeutic options for the prevention and treatment of osteoporosis in these patients. A review of the English-language literature was conducted using the MEDLINE database until June 2009. Currently used bronchodilators probably lack adverse effect on bone. Oral corticosteroids (OCS) increase bone resorption and decrease bone formation in a dose response relationship, but the fracture risk is increased more than reflected by bone densitometry. Inhaled corticosteroids (ICS) have been associated with both increased bone loss and fracture risk. This might be a result of confounding by disease severity, but high doses of ICS have similar effects as equipotent doses of OCS. The life-style factors should be modified, use of regular OCS avoided and use of ICS restricted to those with evidenced effect and probably kept at moderate doses. The health care should actively reveal risk factors, include bone densitometry in fracture risk evaluation, and give adequate prevention and treatment for osteoporosis. PMID:19888355

Equally sloped X-ray microtomography of living insects with low radiation dose and improved resolution capability

NASA Astrophysics Data System (ADS)

Yao, Shengkun; Fan, Jiadong; Zong, Yunbing; He, You; Zhou, Guangzhao; Sun, Zhibin; Zhang, Jianhua; Huang, Qingjie; Xiao, Tiqiao; Jiang, Huaidong

2016-03-01

Three-dimensional X-ray imaging of living specimens is challenging due to the limited resolution of conventional absorption contrast X-ray imaging and potential irradiation damage of biological specimens. In this letter, we present microtomography of a living specimen combining phase-contrast imaging and a Fourier-based iterative algorithm termed equally sloped tomography. Non-destructive 3D imaging of an anesthetized living yellow mealworm Tenebrio molitor was demonstrated with a relatively low dose using synchrotron generated X-rays. Based on the high-quality 3D images, branching tracheoles and different tissues of the insect in a natural state were identified and analyzed, demonstrating a significant advantage of the technique over conventional X-ray radiography or histotomy. Additionally, the insect survived without problem after a 1.92-s X-ray exposure and subsequent absorbed radiation dose of ˜1.2 Gy. No notable physiological effects were observed after reviving the insect from anesthesia. The improved static tomographic method demonstrated in this letter shows advantage in the non-destructive structural investigation of living insects in three dimensions due to the low radiation dose and high resolution capability, and offers many potential applications in biological science.

Equally sloped X-ray microtomography of living insects with low radiation dose and improved resolution capability

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

Yao, Shengkun; Fan, Jiadong; Zong, Yunbing

Three-dimensional X-ray imaging of living specimens is challenging due to the limited resolution of conventional absorption contrast X-ray imaging and potential irradiation damage of biological specimens. In this letter, we present microtomography of a living specimen combining phase-contrast imaging and a Fourier-based iterative algorithm termed equally sloped tomography. Non-destructive 3D imaging of an anesthetized living yellow mealworm Tenebrio molitor was demonstrated with a relatively low dose using synchrotron generated X-rays. Based on the high-quality 3D images, branching tracheoles and different tissues of the insect in a natural state were identified and analyzed, demonstrating a significant advantage of the technique overmore » conventional X-ray radiography or histotomy. Additionally, the insect survived without problem after a 1.92-s X-ray exposure and subsequent absorbed radiation dose of ∼1.2 Gy. No notable physiological effects were observed after reviving the insect from anesthesia. The improved static tomographic method demonstrated in this letter shows advantage in the non-destructive structural investigation of living insects in three dimensions due to the low radiation dose and high resolution capability, and offers many potential applications in biological science.« less

Valbenazine for Tardive Dyskinesia.

PubMed

Freudenreich, Oliver; Remington, Gary

Tardive dyskinesia (TD) remains a clinical concern for any patient who receives an antipsychotic. While the overall risk of developing TD is lower with newer antipsychotics compared to older agents, a significant number of patients who require long-term treatment will develop TD. Recently, valbenazine (brand name Ingrezza) became the first drug to be approved by the FDA specifically for the treatment of TD. In this New Drug Review, we summarize the basic pharmacology and clinical trial results for valbenazine. Valbenazine is a modified metabolite of the vesicular monoamine transporter 2 (VMAT-2) inhibitor tetrabenazine, which is approved for the treatment of the hyperkinetic movement disorder, Huntington's disease. In short-term clinical trials, valbenazine at a dose of 80 mg/day improved TD, with an effect size that is clinically significant (d=0.90). The effect size for the 40-mg/day dose was lower (d=0.52). Compared to tetrabenazine, valbenazine has better clinical characteristics (i.e., once-a-day dosing, better short-term side effect profile). However, only long-term experience in routine clinical populations can delineate valbenazine's full benefits, optimal dosing, and risks not identified during short-term registration trials.

Probabilistic dose assessment of normal operations and accident conditions for an assured isolation facility in Texas

NASA Astrophysics Data System (ADS)

Arno, Matthew Gordon

Texas is investigating building a long-term waste storage facility, also known as an Assured Isolation Facility. This is an above-ground low-level radioactive waste storage facility that is actively maintained and from which waste may be retrieved. A preliminary, scoping-level analysis has been extended to consider more complex scenarios of radiation streaming and skyshine by using the computer code Monte Carlo N-Particle (MCNP) to model the facility in greater detail. Accidental release scenarios have been studied in more depth to better assess the potential dose to off-site individuals. Using bounding source term assumptions, the projected radiation doses and dose rates are estimated to exceed applicable limits by an order of magnitude. By altering the facility design to fill in the hollow cores of the prefabricated concrete slabs used in the roof over the "high-gamma rooms," where the waste with the highest concentration of gamma emitting radioactive material is stored, dose rates outside the facility decrease by an order of magnitude. With the modified design, the annual dose at the site fenceline is estimated at 86 mrem, below the 100 mrem annual limit for exposure of the public. Within the site perimeter, the dose rates are lowered sufficiently such that it is not necessary to categorize many workers and contractor personnel as radiation workers, saving on costs as well as being advisable under ALARA principles. A detailed analysis of bounding accidents incorporating information on the local meteorological conditions indicate that the maximum committed effective dose equivalent from the passage of a plume of material released in an accident at any of the cities near the facility is 59 :rem in the city of Eunice, NM based on the combined day and night meteorological conditions. Using the daytime meteorological conditions, the maximum dose at any city is 7 :rem, also in the city of Eunice. The maximum dose at the site boundary was determined to be 230 mrem using the combined day and night meteorological conditions and 33 mrem using the daytime conditions.

Heart failure treated with low-dose milrinone in a full-term newborn.

PubMed

Sebková, S; Tomek, V; Zemanová, P; Janota, J

2012-01-01

A term newborn with a hypocontractile myocardium complicating persistent pulmonary hypertension of the newborn was successfully treated with a low-dose phosphodiesterase III inhibitor milrinone. Echocardiography diagnosed heart failure with a left ventricular ejection fraction of 35% and a left ventricular shortening fraction of 18% and severe persistent pulmonary hypertension of the newborn with oxygenation index of 28. Milrinone was started at an initial dose of 50 mcg/kg, followed by continuous infusion of 0.20 mcg/kg/min. With lowdose milrinone oxygenation index decreased to 3 within 6 hours, left ventricular ejection fraction and left ventricular shortening fraction increased to 57%, and 30%, respectively. Low doses of milrinone might be promising in the treatment of heart failure and persistent pulmonary hypertension of the newborn in term newborns.

Efficacy of Low-dose (2 millicurie) versus Standard-dose (4 millicurie) Radioiodine Treatment for Cats with Mild-to-Moderate Hyperthyroidism.

PubMed

Lucy, J M; Peterson, M E; Randolph, J F; Scrivani, P V; Rishniw, M; Davignon, D L; Thompson, M S; Scarlett, J M

2017-03-01

Radioiodine ( 131 I) is effective treatment for hyperthyroidism in cats, but optimal dose to restore euthyroidism without inducing hypothyroidism is unclear. Treatment-induced hypothyroidism can lead to azotemia and reduced duration of survival. To compare efficacy and short-term outcomes of low-dose 131 I versus higher, standard-dose 131 I as treatment for hyperthyroidism. A total of 189 client-owned cats undergoing 131 I treatment for mild-to-moderate hyperthyroidism (serum T 4 ≥ 4.0 μg/dL and <13.0 μg/dL). Prospective, nonrandomized, cohort study comparing treatment with either low-dose (2 mCi, n = 150) or standard-dose (4 mCi, n = 39) 131 I. Serum T 4 , thyroid-stimulating hormone (TSH), and creatinine concentrations were measured after 1, 3, and 6 months to determine persistent hyperthyroidism, overt hypothyroidism (low T 4 , high TSH), subclinical hypothyroidism (normal T 4 , high TSH), and azotemia. There was no significant difference in prevalence of cats with persistent hyperthyroidism between standard- and low-dose treatment groups at 3 (0% versus 5.3%; P = .34) and 6 (0% versus 3.3%; P = .51) months. Overt (18% versus 1%; P = .0005) or subclinical (46% versus 21%; P = .004) hypothyroidism was more common in cats at 6 months after standard-dose 131 I. No difference in incidence of azotemia existed between groups, but cats treated with standard-dose 131 I had higher creatinine concentrations (P < .05) and higher percent rises in creatinine (P < .0001). Low-dose 131 I is safe and effective for cats with mild-to-moderate hyperthyroidism, as evidenced by a cure rate of >95% with reduced frequency of iatrogenic hypothyroidism and azotemia. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Monte Carlo dose calculations for high-dose-rate brachytherapy using GPU-accelerated processing.

PubMed

Tian, Z; Zhang, M; Hrycushko, B; Albuquerque, K; Jiang, S B; Jia, X

2016-01-01

Current clinical brachytherapy dose calculations are typically based on the Association of American Physicists in Medicine Task Group report 43 (TG-43) guidelines, which approximate patient geometry as an infinitely large water phantom. This ignores patient and applicator geometries and heterogeneities, causing dosimetric errors. Although Monte Carlo (MC) dose calculation is commonly recognized as the most accurate method, its associated long computational time is a major bottleneck for routine clinical applications. This article presents our recent developments of a fast MC dose calculation package for high-dose-rate (HDR) brachytherapy, gBMC, built on a graphics processing unit (GPU) platform. gBMC-simulated photon transport in voxelized geometry with physics in (192)Ir HDR brachytherapy energy range considered. A phase-space file was used as a source model. GPU-based parallel computation was used to simultaneously transport multiple photons, one on a GPU thread. We validated gBMC by comparing the dose calculation results in water with that computed TG-43. We also studied heterogeneous phantom cases and a patient case and compared gBMC results with Acuros BV results. Radial dose function in water calculated by gBMC showed <0.6% relative difference from that of the TG-43 data. Difference in anisotropy function was <1%. In two heterogeneous slab phantoms and one shielded cylinder applicator case, average dose discrepancy between gBMC and Acuros BV was <0.87%. For a tandem and ovoid patient case, good agreement between gBMC and Acruos BV results was observed in both isodose lines and dose-volume histograms. In terms of the efficiency, it took ∼47.5 seconds for gBMC to reach 0.15% statistical uncertainty within the 5% isodose line for the patient case. The accuracy and efficiency of a new GPU-based MC dose calculation package, gBMC, for HDR brachytherapy make it attractive for clinical applications. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Hepatitis B virus-related mortality in rheumatoid arthritis patients undergoing long-term low-dose glucocorticoid treatment: A population-based study.

PubMed

Yang, Sheng-Shun; Hung, Chin-Tun; Li, Shu-Fen; Lee, Horng-Mo; Chung, Yueh-Chin; Chen, Hsin-Hua; Chang, Shu-Chuan

2017-09-04

Glucocorticoids (GC) are commonly used in rheumatoid arthritis (RA) patients which bears a risk of hepatitis B virus (HBV) reactivation. The purpose of this study was to investigate the risk of HBV-related mortality under long-term low-dose GCs in Taiwanese RA patients. We retrospectively analyzed 45,423 RA patients using National Health Insurance Research Database from January 1999 to December 2011. Of them, 2204 patients had the diagnosis of HBV and were classified into four groups according to GCs regimens. Outcome comparison by Cox model analysis for liver-related mortality was performed. In this cohort, 90.5% were older than 40. One hundred and five patients had been treated with short-term large-dose GCs (Group A); 862 patients received GCs ≥20 mg/day for ≥3 days or a variable dose but did not meet Group C criteria (Group B); 689 patients were continuously treated with low-dose (<20 mg/day) GCs for ≥3 months for at least one session (Group C); and 548 patients had never been exposed to GCs (Group D). Two hundred and sixty-one patients had been exposed to antiviral agents, which was significantly higher in Group C. Fifty-eight patients (2.63%) died of acute hepatic failure, while no statistically significant difference between each groups (p = 0.074). Groups C and D comparison by two-sample test showed that long-term low-dose GC treatment was not associated with liver-related death after adjusting for malignancy. Long-term low-dose GC treatment was not associated with liver-related mortality in RA with concomitant HBV patients probably due to commonly applied antiviral therapy by rheumatologists. Copyright © 2017. Published by Elsevier B.V.

Repairable-conditionally repairable damage model based on dual Poisson processes.

PubMed

Lind, B K; Persson, L M; Edgren, M R; Hedlöf, I; Brahme, A

2003-09-01

The advent of intensity-modulated radiation therapy makes it increasingly important to model the response accurately when large volumes of normal tissues are irradiated by controlled graded dose distributions aimed at maximizing tumor cure and minimizing normal tissue toxicity. The cell survival model proposed here is very useful and flexible for accurate description of the response of healthy tissues as well as tumors in classical and truly radiobiologically optimized radiation therapy. The repairable-conditionally repairable (RCR) model distinguishes between two different types of damage, namely the potentially repairable, which may also be lethal, i.e. if unrepaired or misrepaired, and the conditionally repairable, which may be repaired or may lead to apoptosis if it has not been repaired correctly. When potentially repairable damage is being repaired, for example by nonhomologous end joining, conditionally repairable damage may require in addition a high-fidelity correction by homologous repair. The induction of both types of damage is assumed to be described by Poisson statistics. The resultant cell survival expression has the unique ability to fit most experimental data well at low doses (the initial hypersensitive range), intermediate doses (on the shoulder of the survival curve), and high doses (on the quasi-exponential region of the survival curve). The complete Poisson expression can be approximated well by a simple bi-exponential cell survival expression, S(D) = e(-aD) + bDe(-cD), where the first term describes the survival of undamaged cells and the last term represents survival after complete repair of sublethal damage. The bi-exponential expression makes it easy to derive D(0), D(q), n and alpha, beta values to facilitate comparison with classical cell survival models.

Use of GnRH agonist implants for long-term suppression of fertility in extensively managed heifers and cows.

PubMed

D'Occhio, Michael J; Fordyce, Geoffry; Whyte, Tim R; Jubb, Tristan F; Fitzpatrick, Lee A; Cooper, Neil J; Aspden, William J; Bolam, Matt J; Trigg, Timothy E

2002-12-16

The ability of gonadotrophin releasing hormone (GnRH) agonist implants to suppress ovarian activity and prevent pregnancies, long-term, was examined in heifers and cows maintained under extensive management. At three cattle stations, heifers (2-year-old) and older cows (3- to 16-year-old) were assigned to a control group that received no treatment, or were treated with high-dose (12 mg, Station A) or low-dose (8 mg, Station B and Station C) GnRH agonist implants. The respective numbers of control and GnRH agonist-treated animals (heifers + cows) at each station were: Station A, 20 and 99; Station B, 19 and 89; Station C, 20 and 76. Animals were maintained with 4% bulls and monitored for pregnancy at 2-monthly intervals for approximately 12 months. Pregnancy rates for control heifers and control cows ranged from 60-90% and 80-100%, respectively, depending on the study site. The respective number of animals (heifers + cows) treated with GnRH agonist that conceived, and days to first conception, were: Station A, 9 (9%) and 336 +/- 3 days; Station B, 8 (10%) and 244 +/- 13 days; Station C, 20 (26%) and 231 +/- 3 days. Treatment with high-dose GnRH agonist prevented pregnancies for longer (approximately 300 days) than treatment with low-dose GnRH agonist (approximately 200 days). In the majority of heifers and cows treated with GnRH agonist, ovarian follicular growth was restricted to early antral follicles (2-4mm). The findings indicate that GnRH agonist implants have considerable potential as a practical technology to suppress ovarian activity and control reproduction in female cattle maintained in extensive rangelands environments. The technology also has broader applications in diverse cattle production systems. Copyright 2002 Elsevier Science B.V.

Simultaneous integrated protection : A new concept for high-precision radiation therapy.

PubMed

Brunner, Thomas B; Nestle, Ursula; Adebahr, Sonja; Gkika, Eleni; Wiehle, Rolf; Baltas, Dimos; Grosu, Anca-Ligia

2016-12-01

Stereotactic radiotherapy near serial organs at risk (OAR) requires special caution. A novel intensity-modulated radiotherapy (IMRT) prescription concept termed simultaneous integrated protection (SIP) for quantifiable and comparable dose prescription to targets very close to OAR is described. An intersection volume of a planning risk volume (PRV) with the total planning target volume (PTV) defined the protection volume (PTV SIP ). The remainder of the PTV represented the dominant PTV (PTV dom ). Planning was performed using IMRT. Dose was prescribed to PTV dom according to ICRU in 3, 5, 8, or 12 fractions. Constraints to OARs were expressed as absolute and as equieffective doses at 2 Gy (EQD2). Dose to the gross risk volume of an OAR was to respect constraints. Violation of constraints to OAR triggered a planning iteration at increased fractionation. Dose to PTV SIP was required to be as high as possible within the constraints to avoid local relapse. SIP was applied in 6 patients with OAR being large airways (n = 2) or bowel (n = 4) in 3, 5, 8, and 12 fractions in 1, 3, 1, and 1 patients, respectively. PTVs were 14.5-84.9 ml and PTV SIP 1.8-3.9 ml (2.9-13.4 % of PTV). Safety of the plans was analyzed from the absolute dose-volume histogram (dose to ml). The steepness of dose fall-off could be determined by comparing the dose constraints to the PRVs with those to the OARs (Wilcoxon test p = 0.001). Constraints were respected for the corresponding OARs. All patients had local control at a median 9 month follow-up and toxicity was low. SIP results in a median dose of ≥100 % to PTV, to achieve high local control and low toxicity. Longer follow-up is required to verify results and a prospective clinical trial is currently testing this new approach in chest and abdomen stereotactic body radiotherapy.

Metabolic Profile as a Potential Modifier of Long-Term Radiation Effects on Peripheral Lymphocyte Subsets in Atomic Bomb Survivors.

PubMed

Yoshida, Kengo; Nakashima, Eiji; Kyoizumi, Seishi; Hakoda, Masayuki; Hayashi, Tomonori; Hida, Ayumi; Ohishi, Waka; Kusunoki, Yoichiro

2016-09-01

Immune system impairments reflected by the composition and function of circulating lymphocytes are still observed in atomic bomb survivors, and metabolic abnormalities including altered blood triglyceride and cholesterol levels have also been detected in such survivors. Based on closely related features of immune and metabolic profiles of individuals, we investigated the hypothesis that long-term effects of radiation exposure on lymphocyte subsets might be modified by metabolic profiles in 3,113 atomic bomb survivors who participated in health examinations at the Radiation Effect Research Foundation, Hiroshima and Nagasaki, in 2000-2002. The lymphocyte subsets analyzed involved T-, B- and NK-cell subsets, and their percentages in the lymphocyte fraction were assessed using flow cytometry. Health examinations included metabolic indicators, body mass index, serum levels of total cholesterol, high-density lipoprotein cholesterol, C-reactive protein and hemoglobin A1c, as well as diabetes and fatty liver diagnoses. Standard regression analyses indicated that several metabolic indicators of obesity/related disease, particularly high-density lipoprotein cholesterol levels, were positively associated with type-1 helper T- and B-cell percentages but were inversely associated with naïve CD4 T and NK cells. A regression analysis adjusted for high-density lipoprotein cholesterol revealed a radiation dose relationship with increasing NK-cell percentage. Additionally, an interaction effect was suggested between radiation dose and C-reactive protein on B-cell percentage with a negative coefficient of the interaction term. Collectively, these findings suggest that radiation exposure and subsequent metabolic profile changes, potentially in relationship to obesity-related inflammation, lead to such long-term alterations in lymphocyte subset composition. Because this study is based on cross-sectional and exploratory analyses, the implications regarding radiation exposure, metabolic profiles and circulating lymphocytes warrant future longitudinal and molecular mechanistic studies.

Low Dose CT Reconstruction via Edge-preserving Total Variation Regularization

PubMed Central

Tian, Zhen; Jia, Xun; Yuan, Kehong; Pan, Tinsu; Jiang, Steve B.

2014-01-01

High radiation dose in CT scans increases a lifetime risk of cancer and has become a major clinical concern. Recently, iterative reconstruction algorithms with Total Variation (TV) regularization have been developed to reconstruct CT images from highly undersampled data acquired at low mAs levels in order to reduce the imaging dose. Nonetheless, the low contrast structures tend to be smoothed out by the TV regularization, posing a great challenge for the TV method. To solve this problem, in this work we develop an iterative CT reconstruction algorithm with edge-preserving TV regularization to reconstruct CT images from highly undersampled data obtained at low mAs levels. The CT image is reconstructed by minimizing an energy consisting of an edge-preserving TV norm and a data fidelity term posed by the x-ray projections. The edge-preserving TV term is proposed to preferentially perform smoothing only on non-edge part of the image in order to better preserve the edges, which is realized by introducing a penalty weight to the original total variation norm. During the reconstruction process, the pixels at edges would be gradually identified and given small penalty weight. Our iterative algorithm is implemented on GPU to improve its speed. We test our reconstruction algorithm on a digital NCAT phantom, a physical chest phantom, and a Catphan phantom. Reconstruction results from a conventional FBP algorithm and a TV regularization method without edge preserving penalty are also presented for comparison purpose. The experimental results illustrate that both TV-based algorithm and our edge-preserving TV algorithm outperform the conventional FBP algorithm in suppressing the streaking artifacts and image noise under the low dose context. Our edge-preserving algorithm is superior to the TV-based algorithm in that it can preserve more information of low contrast structures and therefore maintain acceptable spatial resolution. PMID:21860076

Fabrication of 4H-SiC PiN diodes without bipolar degradation by improved device processes

NASA Astrophysics Data System (ADS)

Bu, Yuan; Yoshimoto, Hiroyuki; Watanabe, Naoki; Shima, Akio

2017-12-01

We developed a simple technology for fabricating bipolar degradation-free 6.5 kV SiC PiN diodes on the basal plane dislocation (BPD)-free areas of commercially available 4H-SiC wafers. In order to suppress process-induced basal plane dislocation, we first investigated the causes of BPD generation during fabrication and then improved the processes. We found that no BPD was induced on a flat Si-face, but a large number of BPDs were concentrated in the mesa edge after high-dose Al ions were implanted [p++ ion implantation (I. I.)] at room temperature (RT) followed by activation annealing. Therefore, we examined new technologies in device processes including (I) long-term high-temperature oxidation after the mesa process to remove etching damage in the mesa edge and (II) reducing the Al dose (p+ I. I.) in the mesa edge to suppress BPD generation. We investigated the effect of the Al dose in the mesa edge on BPD generation and bipolar degradation. The results indicated that no BPD appeared when the dose was lower than 1 × 1015 atoms/cm2 and when long-term high-temperature oxidation was applied after the mesa process. As a result, we successfully fabricated 6.5 kV PiN diodes without bipolar degradation on BPD-free areas. Moreover, the diodes are very stable when applying 270 A/cm2 for over 100 h. Photoluminescence (PL) observation indicated that no BPD was generated during the improved fabrication processes. Besides, the Ir-Vr measurements showed that the breakdown voltage was over 8 kV at RT. The leakage currents are as low as 7.6 × 10-5 mA/cm2 (25 °C) and 6.3 × 10-4 mA/cm2 (150 °C) at 6.5 kV. Moreover, this result is applicable not only for PiN diodes but also for MOSFETs (body diode), IGBTs, thyristors, etc.

Short-term treatment with transdermal nicotine affects the function of canine saphenous veins.

PubMed

Clouse, W D; Rud, K S; Hurt, R D; Miller, V M

2000-01-01

Experiments were designed to determine the effects of nicotine treatment on the functions of saphenous veins used for coronary artery bypass grafts in dogs. Dogs received either no treatment or transdermal nicotine for 5 weeks at doses of 11 mg, 22 mg or 44 mg/day. Saphenous veins were removed and suspended for the measurement of isometric force in organ chambers. Endothelium was removed mechanically from some rings. N(G)-mono-methyl-L-arginine (L-NMMA; 10(-4) M) was used to inhibit the production of nitric oxide. Contractions to alpha2-adrenergic stimulation were decreased in veins from dogs treated with a 22-mg/day dose of transdermal nicotine. In addition, endothelium-dependent relaxations to adenosine-diphosphate (10(-8)-10(-4) M) and the calcium ionophore A23,187 (10(-8)-10(-6) M) were decreased in veins from dogs with a 22-mg/day dose and increased in veins from dogs treated with a 44-mg/day dose. These relaxations were inhibited by L-NMMA. Plasma concentrations of oxidized products of nitric oxide were decreased only in dogs treated with 22 mg/day of nicotine. The relaxation of rings without endothelium (direct response on the smooth muscle) to nitric oxide were not altered by nicotine treatment. These results suggest that the short-term treatment of dogs with intermediate (22 mg/day) but not low (11 mg/day) or high (44 mg/day) doses of transdermal nicotine decreases the endothelial function of veins used for coronary artery bypass grafts. Therefore, changes in plasma products of nitric oxide and endothelium-dependent relaxations mediated by nitric oxide are related to the dose of nicotine treatment.

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

Symptomatic radiation-induced cardiac disease in long-term survivors of esophageal cancer.

PubMed

Ogino, Ichiro; Watanabe, Shigenobu; Iwahashi, Noriaki; Kosuge, Masami; Sakamaki, Kentaro; Kunisaki, Chikara; Kimura, Kazuo

2016-06-01

To evaluate clinical and dosimetric factors retrospectively affecting the risk of symptomatic cardiac disease (SCD) in esophageal cancer patients treated with radiotherapy. A total of 343 patients with newly diagnosed esophageal cancer were managed with concurrent chemoradiotherapy or radiotherapy alone. Of these, 58 patients were followed at our hospital for at least 4 years. Median clinical follow-up was 79 months. Cardiac toxicity was determined by Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0. The maximum and mean doses to the heart and percentage of the volume were calculated from the dose-volume histograms. SCD manifested in 11 patients. The heart diseases included three pericardial effusions, one pericardial effusion with valvular disease and paroxysmal atrial tachycardia, three atrial fibrillations, one sinus tachycardia, one coronary artery disease, one chest pain with strongly suspected coronary artery disease, and one congestive heart failure. The actual incidence of SCD was 13.8 % at 5 years. Univariate and multivariate analyses of continuous variables revealed that the risk of developing an SCD depended on the volume of the heart receiving a dose greater than 45 Gy (V45), 50 Gy (V50), and 55 Gy (V55). No other clinical factors were found to influence the risk of SCD. For V45, V50, and V55, the lowest significant cutoff values were 15, 10, and 5 %, respectively. High-dose and large-volume irradiation of the heart increased the risk of SCD in long-term survivors. Using modern radiotherapy techniques, it is important to minimize the heart dose-volume parameters without reducing the tumor dose.

Low dose dynamic CT myocardial perfusion imaging using a statistical iterative reconstruction method

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

Tao, Yinghua; Chen, Guang-Hong; Hacker, Timothy A.

Purpose: Dynamic CT myocardial perfusion imaging has the potential to provide both functional and anatomical information regarding coronary artery stenosis. However, radiation dose can be potentially high due to repeated scanning of the same region. The purpose of this study is to investigate the use of statistical iterative reconstruction to improve parametric maps of myocardial perfusion derived from a low tube current dynamic CT acquisition. Methods: Four pigs underwent high (500 mA) and low (25 mA) dose dynamic CT myocardial perfusion scans with and without coronary occlusion. To delineate the affected myocardial territory, an N-13 ammonia PET perfusion scan wasmore » performed for each animal in each occlusion state. Filtered backprojection (FBP) reconstruction was first applied to all CT data sets. Then, a statistical iterative reconstruction (SIR) method was applied to data sets acquired at low dose. Image voxel noise was matched between the low dose SIR and high dose FBP reconstructions. CT perfusion maps were compared among the low dose FBP, low dose SIR and high dose FBP reconstructions. Numerical simulations of a dynamic CT scan at high and low dose (20:1 ratio) were performed to quantitatively evaluate SIR and FBP performance in terms of flow map accuracy, precision, dose efficiency, and spatial resolution. Results: Forin vivo studies, the 500 mA FBP maps gave −88.4%, −96.0%, −76.7%, and −65.8% flow change in the occluded anterior region compared to the open-coronary scans (four animals). The percent changes in the 25 mA SIR maps were in good agreement, measuring −94.7%, −81.6%, −84.0%, and −72.2%. The 25 mA FBP maps gave unreliable flow measurements due to streaks caused by photon starvation (percent changes of +137.4%, +71.0%, −11.8%, and −3.5%). Agreement between 25 mA SIR and 500 mA FBP global flow was −9.7%, 8.8%, −3.1%, and 26.4%. The average variability of flow measurements in a nonoccluded region was 16.3%, 24.1%, and 937.9% for the 500 mA FBP, 25 mA SIR, and 25 mA FBP, respectively. In numerical simulations, SIR mitigated streak artifacts in the low dose data and yielded flow maps with mean error <7% and standard deviation <9% of mean, for 30×30 pixel ROIs (12.9 × 12.9 mm{sup 2}). In comparison, low dose FBP flow errors were −38% to +258%, and standard deviation was 6%–93%. Additionally, low dose SIR achieved 4.6 times improvement in flow map CNR{sup 2} per unit input dose compared to low dose FBP. Conclusions: SIR reconstruction can reduce image noise and mitigate streaking artifacts caused by photon starvation in dynamic CT myocardial perfusion data sets acquired at low dose (low tube current), and improve perfusion map quality in comparison to FBP reconstruction at the same dose.« less

Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases

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

Balajee, A.S.; Meador, J.A.; Su, Y.

It is increasingly realized that human exposure either to an acute low dose or multiple chronic low doses of low LET radiation has the potential to cause different types of cancer. Therefore, the central theme of research for DOE and NASA is focused on understanding the molecular mechanisms and pathways responsible for the cellular response to low dose radiation which would not only improve the accuracy of estimating health risks but also help in the development of predictive assays for low dose radiation risks associated with tissue degeneration and cancer. The working hypothesis for this proposal is that the cellularmore » mechanisms in terms of DNA damage signaling, repair and cell cycle checkpoint regulation are different for low and high doses of low LET radiation and that the mode of action of phosphatidylinositol-3 kinase like kinases (PIKK: ATM, ATR and DNA-PK) determines the dose dependent cellular responses. The hypothesis will be tested at two levels: (I) Evaluation of the role of ATM, ATR and DNA-PK in cellular response to low and high doses of low LET radiation in simple in vitro human cell systems and (II) Determination of radiation responses in complex cell microenvironments such as human EpiDerm tissue constructs. Cellular responses to low and high doses of low LET radiation will be assessed from the view points of DNA damage signaling, DNA double strand break repair and cell cycle checkpoint regulation by analyzing the activities (i.e. post-translational modifications and kinetics of protein-protein interactions) of the key target proteins for PI-3 kinase like kinases both at the intra-cellular and molecular levels. The proteins chosen for this proposal are placed under three categories: (I) sensors/initiators include ATM ser1981, ATR, 53BP1, gamma-H2AX, MDC1, MRE11, Rad50 and Nbs1; (II) signal transducers include Chk1, Chk2, FANCD2 and SMC1; and (III) effectors include p53, CDC25A and CDC25C. The primary goal of this proposal is to elucidate the differences in cellular defense mechanisms between low and high doses of low LET radiation and to define the radiation doses where the cellular DNA damage signaling and repair mechanisms tend to shift. This information is critically important to address and advance some of the low dose research program objectives of DOE. The results of this proposed study will lead to a better understanding of the mechanisms for the cellular responses to low and high doses of low LET radiation. Further, systematic analysis of the role of PIKK signaling pathways as a function of radiation dose in tissue microenvironment will provide useful mechanistic information for improving the accuracy of radiation risk assessment for low doses. Knowledge of radiation responses in tissue microenvironment is important for the accurate prediction of ionizing radiation risks associated with cancer and tissue degeneration in humans.« less

Polyethylene glycol 3350 without electrolytes for the treatment of functional constipation in infants and toddlers.

PubMed

Loening-Baucke, Vera; Krishna, Rachana; Pashankar, Dinesh S

2004-11-01

We have recently reported the safety and efficacy of polyethylene glycol 3350 without electrolytes (PEG) for the daily treatment of constipation in older children. Because there are very few data available on the use of PEG in infants and toddlers, we evaluated the efficacy and safety of PEG for the treatment of constipation in children <2 years of age. This is a retrospective chart review of 75 constipated children <2 years of age at start of PEG therapy. PEG was started at an average dose of 1 g/kg body weight/d and parents were asked to adjust the dose to yield 1 to 2 soft painless stools/d. Data from the history and physical examination were collected initially and at short-term (or=6 months) follow-up. 75 otherwise healthy children received PEG for functional constipation. The mean age was 17 months (range, 1 to 24 months) and the mean duration of constipation was 10 months (range, 0.5 to 23 months). The mean duration of short-term follow-up was 2 months and mean duration of long-term follow-up was 11 months. The mean effective short-term PEG dose was 1.1 g/kg body weight/d and the mean long-term dose was 0.8 g/kg body weight/d. Constipation was relieved in 85% with short-term and in 91% with long-term PEG therapy. Adverse effects were mild and included diarrhea, which disappeared with lowering the dose. No subjects stopped PEG because of adverse effects. PEG is effective, well tolerated and appeared safe for the treatment of functional constipation in children <2 years of age.

SU-F-T-686: Considerations About Dose Protraction Factor in TCP Calculations for Prostate VMAT Treatments

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

Clemente, F; Perez-Vara, C; Clavo, M

2016-06-15

Purpose: Dose protraction factor should be considered in order to model the TCP calculations. Nevertheless, this study describes a brief discussion showing that the lack of its inclusion should not invalidate these calculations for prostate VMAT treatments. Methods: Dose protraction factor (G) modifies the quadratic term of the linear-quadratic expression in order to take into account the sublethal damage repair of protracting the dose delivery. If the delivery takes a short time (instantaneous), G = 1. For any other dose delivery pattern, G < 1. The Lea-Catcheside dose protraction factor for external beam radiotherapy contains terms depending of on themore » tissue specific repair parameter (λ) and the irradiation time (T). Expanding the exponential term using a Taylor’s series and neglecting terms of order (λT){sup 3}, the approximation leads to G = 1. The described situation occurs for 3DCRT techniques, where treatment times are about few minutes. For IMRT techniques, fraction times are prolonged compared to 3DCRT times. Wang et al. (2003) and Fowler et al. (2004) investigated the protraction effect with respect to IMRT treatments, reporting clinically significant loss in biological effect associated with IMRT delivery times. Results: Treatment times are noticeably reduced for prostate treatments using VMAT techniques. These times are comparable to 3DCRT times, leading to consider the previous approximation. Conclusion: Dose protraction factor can be approximated by G = 1 in TCP calculations for prostate treatments using VMAT techniques.« less

Moving Toward Bioadjuvant Approaches to Head and Neck Cancer Prevention

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

Saba, Nabil F.; Hammond, Anthea; Shin, Dong M.

2007-10-01

Head and neck squamous cell carcinoma affects >45,000 Americans annually. Patients who are successfully treated for their primary tumor are at high risk of developing a second primary tumor, making effective preventive strategies highly desirable for this disease. Although a landmark study in 1990 suggested some benefit of high-dose retinoids in head and neck cancer prevention, subsequent trials using more tolerable doses have shown limited clinical success. Newer preventive strategies have included bioadjuvant therapy combining retinoids with interferon and {alpha}-tocopherol, combinations of molecularly targeted agents, and oncolytic viruses. Furthermore, considerable evidence has supported a cancer protective role for several nutrients,more » including green tea and curcumin analogs. Natural compounds such as these with favorable long-term safety profiles might be particularly suited to the cancer prevention setting, in which patients will usually tolerate only moderate risk and toxicity.« less

Evaluation of optimum room entry times for radiation therapists after high energy whole pelvic photon treatments.

PubMed

Ho, Lavine; White, Peter; Chan, Edward; Chan, Kim; Ng, Janet; Tam, Timothy

2012-01-01

Linear accelerators operating at or above 10 MV produce neutrons by photonuclear reactions and induce activation in machine components, which are a source of potential exposure for radiation therapists. This study estimated gamma dose contributions to radiation therapists during high energy, whole pelvic, photon beam treatments and determined the optimum room entry times, in terms of safety of radiation therapists. Two types of technique (anterior-posterior opposing and 3-field technique) were studied. An Elekta Precise treatment system, operating up to 18 MV, was investigated. Measurements with an area monitoring device (a Mini 900R radiation monitor) were performed, to calculate gamma dose rates around the radiotherapy facility. Measurements inside the treatment room were performed when the linear accelerator was in use. The doses received by radiation therapists were estimated, and optimum room entry times were determined. The highest gamma dose rates were approximately 7 μSv/h inside the treatment room, while the doses in the control room were close to background (~0 μSv/h) for all techniques. The highest personal dose received by radiation therapists was estimated at 5 mSv/yr. To optimize protection, radiation therapists should wait for up to11 min after beam-off prior to room entry. The potential risks to radiation therapists with standard safety procedures were well below internationally recommended values, but risks could be further decreased by delaying room entry times. Dependent on the technique used, optimum entry times ranged between 7 to 11 min. A balance between moderate treatment times versus reduction in measured equivalent doses should be considered.

[Effects of control-releasing arsenic trioxide-eluting stent on intimal smooth muscle cells and type III collagen in canine coronary artery post-stent model].

PubMed

Zhao, Jun-Li; Sun, Bao-Gui; Wen, Qin-Zhu

2010-06-01

To study the safety and efficacy of control-releasing arsenic trioxide (As2O3)-eluting stent on intimal smooth muscle cells (SMC) and type III collagen (CIII) in canine coronary artery post-stent model. Twenty-four experimental canines were equally divided into 4 groups, the three tested groups were deployed by stents with different dosage of As2O3 (1.6 microg/mm2, 2.4 microg/mm2 and 3.2 microg/mm2 in low, median and high dose groups, respectively) and coated with polybutyl methacrylate/nano silica and poly-lactide-coglycolide in mild oversizing (stent/vessel ratio of 1.3:1) in left anterior descending (LAD) or circumflex coronary arteries (LCX), while the control group only by simple coated stent without As2O3. The effect was assessed 4 weeks after stent implantation in terms of vascular histomorphology, and changes of SMC and C III expressions were detected using immunohistochemical analysis. Subintimal hemorrhage, medial/adventitial necrosis, thrombosis and inflammatory cell infiltration were not found and integral endothelium could be seen under screening electron microscopy in all groups. Positive expression of SMC and CIII in the tested groups, especial in the high dose As2O3 group, was more weaker than that in control group. Histo-morphological analysis showed that the neo-genetic intimal area and vascular stenosis were lower, but the mean luminal diameter was larger in the three tested groups than that in the control group (P < 0.01). Comparisons of various indices between tested groups treated by different doses of As2O3 showed that the difference between high/median dose vs. low dose was significant (P < 0.01), but that between high dose vs. median dose was insignificant (P > 0.05). Control-releasing As2O3-eluting stent shows a reliable and safe effect in preventing and treating post-stent restenosis by its dose-dependent inhibition on expressions of SMC and CIII to suppress the neo-genesis of intimal hyperplasia.

The Fukushima nuclear accident and the pale grass blue butterfly: evaluating biological effects of long-term low-dose exposures

PubMed Central

2013-01-01

Background On August 9th 2012, we published an original research article in Scientific Reports, concluding that artificial radionuclides released from the Fukushima Dai-ichi Nuclear Power Plant exerted genetically and physiologically adverse effects on the pale grass blue butterfly Zizeeria maha in the Fukushima area. Immediately following publication, many questions and comments were generated from all over the world. Here, we have clarified points made in the original paper and answered questions posed by the readers. Results The following points were clarified. (1) There are many advantages to using the pale grass blue butterfly as an indicator species. (2) The forewings of the individuals collected in Fukushima were significantly smaller than in the northern and southern localities. (3) We observed growth retardation in the butterflies from the Fukushima area. (4) The aberrant colour patterns in the butterflies obtained in the Fukushima area were different from the colour patterns induced by temperature and sibling crosses but similar to those induced by external and internal exposures to the artificial radionuclides and by a chemical mutagen, suggesting that genetic mutations caused the aberrations. (5) This species of butterfly has been plentiful in Fukushima area for at least half a century. We here present specimens collected from Fukushima Prefecture before the accident. (6) Mutation accumulation was detected by the increase in the abnormality rates from May 2011 to September 2011. (7) The abnormal traits were heritable. (8) Our sampling localities were not affected by the tsunami. (9) We used a high enough number of samples to obtain statistically significant results. (10) The standard rearing method was followed, producing normal adults in the control groups. (11) The exposure experiments successfully reproduced the results of the field work. This species of butterfly is vulnerable to long-term low-dose internal and external exposures; however, insect cells are known to be resistant to short-term high-dose irradiation. This discrepancy is reconcilable based on the differences in the experimental conditions. Conclusions We are just beginning to understand the biological effects of long-term low-dose exposures in animals. Further research is necessary to accurately assess the possible biological effects of the accident. PMID:23937355

Hypoglycemic and Antidiabetic Effect of Pleurotus sajor-caju Aqueous Extract in Normal and Streptozotocin-Induced Diabetic Rats

PubMed Central

Ng, Sze Han; Mohd Zain, Mohd Shazwan; Zakaria, Fatariah; Wan Ishak, Wan Rosli; Wan Ahmad, Wan Amir Nizam

2015-01-01

Introduction. Pleurotus sajor-caju (PSC) is an edible oyster mushroom featuring high nutritional values and pharmacological properties. Objective. To investigate the hypoglycemic and antidiabetic effects of single and repeated oral administration of PSC aqueous extract in normal and diabetic rats. Materials and Methods. A single dose of 500, 750, or 1000 mg/kg of the PSC extract was given to experimental rats to determine the effects on blood glucose (BG) and oral glucose tolerance test (OGTT). The effective dose (750 mg/kg) of PSC extract was repeatedly administrated daily for 21 days in diabetic rats to examine its antidiabetic effects in terms of BG control, body weight, urine sugar, HbA1c, and several serum profiles. Results. The dose of 750 mg/kg showed the most significant BG reduction (23.5%) in normal rats 6 hours after administration in BG study (p < 0.05). In OGTT study, the same dose produced a maximum BG fall of 41.3% in normal rats and 36.5% in diabetic rats 3 hours after glucose administration. In 21-day study, treated diabetic rats showed significant improvement in terms of fasting BG, body weight, and urine sugar as compared to control diabetic rats. Conclusion. The study evidenced scientifically the beneficial use of PSC as an alternative medicine in diabetes management. PMID:26682215

What we need to know about the effect of lithium on the kidney

PubMed Central

Gong, Rujun; Wang, Pei

2016-01-01

Lithium has been a valuable treatment for bipolar affective disorders for decades. Clinical use of lithium, however, has been problematic due to its narrow therapeutic index and concerns for its toxicity in various organ systems. Renal side effects associated with lithium include polyuria, nephrogenic diabetes insipidus, proteinuria, distal renal tubular acidosis, and reduction in glomerular filtration rate. Histologically, chronic lithium nephrotoxicity is characterized by interstitial nephritis with microcyst formation and occasional focal segmental glomerulosclerosis. Nevertheless, this type of toxicity is uncommon, with the strongest risk factors being high serum levels of lithium and longer time on lithium therapy. In contrast, in experimental models of acute kidney injury and glomerular disease, lithium has antiproteinuric, kidney protective, and reparative effects. This paradox may be partially explained by lower lithium doses and short duration of therapy. While long-term exposure to higher psychiatric doses of lithium may be nephrotoxic, short-term low dose of lithium may be beneficial and ameliorate kidney and podocyte injury. Mechanistically, lithium targets glycogen synthase kinase-3β, a ubiquitously expressed serine/threonine protein kinase implicated in the processes of tissue injury, repair, and regeneration in multiple organ systems, including the kidney. Future studies are warranted to discover the exact “kidney-protective dose” of lithium and test the effects of low-dose lithium on acute and chronic kidney disease in humans. PMID:27122541

[The role of bemitil pharmacokinetics in realizing its therapeutic efficacy].

PubMed

Boĭko, S S; Zherdev, V P; Neznamov, G G

1991-01-01

The pharmacokinetics of a new psychotropic drug bemithil was studied after single and long-term administrations under monotherapy and in combination with phenazepam in patients with asthenoneurotic disturbances. A high degree of correlation for some pharmacokinetic parameters of bemithil following the administration of the drug test dose and its global therapeutic effect was established.

The Johns Hopkins RTR Consortium: A Collaborative Approach to Advance Translational Science and Standardize Clinical Monitoring of Restorative Transplantation

DTIC Science & Technology

2016-10-01

received non-myeloablative conditioning with 50cGy total body and 350cGy thymic irradiation for induction. Aim1: Group I was treated with high-dose...regimen of non-myeloablative irradiation and peritransplant tacrolimus. The long-term graft survival off of immunosuppression for animals treated

Doses effects of zoledronic acid on mineral apatite and collagen quality of newly-formed bone in the rat's calvaria defect.

PubMed

Olejnik, Cécile; Falgayrac, Guillaume; During, Alexandrine; Cortet, Bernard; Penel, Guillaume

2016-08-01

Due to their inhibitory effects on resorption, bisphosphonates are widely used in the treatment of diseases associated to an extensive bone loss. Yet, little is known about bisphosphonates effects on newly-formed bone quality. In the present study, adult male Sprague-Dawley rats (n=80) with a bone defect calvaria area were used and short-term effects of zoledronic acid (ZA) were studied on the healing bone area. Three ZA treatments were tested by using either: 1°) a low single dose (120μgZA/kg, n=10; equivalent to human osteoporosis treatment), 2°) a low fractionated doses (20μgZA/kg daily for 6days either a total of 120μg/kg, n=15), and 3°) a high fractionated doses, (100μgZA/kg weekly for 6weeks, n=15; equivalent to 6months of human bone metastasis treatment). For each treatment, a control "vehicle" treatment was performed (with an identical number of rats). After ZA administration, the intrinsic bone material properties were evaluated by quantitative backscattered electron imaging (qBEI) and Raman microspectroscopy. Neither single nor fractionated low ZA doses modify the intrinsic bone material properties of the newly-formed bone compared to their respective control animals. On the opposite, the high ZA treatment resulted in a significant decrease of the crystallinity (-25%, P< 0.05) and of the hydroxyproline-to-proline ratio (-30%, P<0.05) in newly-formed bones. Moreover, with the high ZA treatment, the crystallinity was positively correlated with the hydroxyproline-to-proline ratio (ρ=0.78, P<0.0001). The present data highlight new properties for ZA on bone formation in a craniofacial defect model. As such, ZA at high doses disrupted the apatite crystal organization. In addition, we report here for the first time that high ZA doses decreased the hydroxyproline-to-proline ratio suggesting that ZA may affect the early collagen organization during the bone healing. Copyright © 2016 Elsevier Inc. All rights reserved.

Review of clinical brachytherapy uncertainties: Analysis guidelines of GEC-ESTRO and the AAPM☆

PubMed Central

Kirisits, Christian; Rivard, Mark J.; Baltas, Dimos; Ballester, Facundo; De Brabandere, Marisol; van der Laarse, Rob; Niatsetski, Yury; Papagiannis, Panagiotis; Hellebust, Taran Paulsen; Perez-Calatayud, Jose; Tanderup, Kari; Venselaar, Jack L.M.; Siebert, Frank-André

2014-01-01

Background and purpose A substantial reduction of uncertainties in clinical brachytherapy should result in improved outcome in terms of increased local control and reduced side effects. Types of uncertainties have to be identified, grouped, and quantified. Methods A detailed literature review was performed to identify uncertainty components and their relative importance to the combined overall uncertainty. Results Very few components (e.g., source strength and afterloader timer) are independent of clinical disease site and location of administered dose. While the influence of medium on dose calculation can be substantial for low energy sources or non-deeply seated implants, the influence of medium is of minor importance for high-energy sources in the pelvic region. The level of uncertainties due to target, organ, applicator, and/or source movement in relation to the geometry assumed for treatment planning is highly dependent on fractionation and the level of image guided adaptive treatment. Most studies to date report the results in a manner that allows no direct reproduction and further comparison with other studies. Often, no distinction is made between variations, uncertainties, and errors or mistakes. The literature review facilitated the drafting of recommendations for uniform uncertainty reporting in clinical BT, which are also provided. The recommended comprehensive uncertainty investigations are key to obtain a general impression of uncertainties, and may help to identify elements of the brachytherapy treatment process that need improvement in terms of diminishing their dosimetric uncertainties. It is recommended to present data on the analyzed parameters (distance shifts, volume changes, source or applicator position, etc.), and also their influence on absorbed dose for clinically-relevant dose parameters (e.g., target parameters such as D90 or OAR doses). Publications on brachytherapy should include a statement of total dose uncertainty for the entire treatment course, taking into account the fractionation schedule and level of image guidance for adaptation. Conclusions This report on brachytherapy clinical uncertainties represents a working project developed by the Brachytherapy Physics Quality Assurances System (BRAPHYQS) subcommittee to the Physics Committee within GEC-ESTRO. Further, this report has been reviewed and approved by the American Association of Physicists in Medicine. PMID:24299968

Review and state of the art on radiation sterilization of medical devices

NASA Astrophysics Data System (ADS)

Dorpema, J. W.

Review and state of art of radiation sterilization Radiation as a sterilization method was designed in the years 1950-1960. The decade afterwards the application for sterilization of medical products and devices was developped. Extensive studies performed on both the physical, chemical and (micro) biological aspects revealed the requirements for safety and efficacy. These efforts were highly stimulated by the IAEA and resulted in a elegant sterilization method. In product manufacturing, where sterilization represents a final step in the production sequence, radiation has eversince reached its widest application in the field of medical devices. As a spin off it initiated new ideas and approaches towards sterilization in general. Consequently sterility was redefined in terms of a probabilistic concept (10-6) and the bioburden determination method was introduced as a tool for both quality control and potential instrument for dose setting. However these refinements also created controversies, whereby the dose requirements became divided for Europe and North America. Moreover studies recently performed in Europe suggest even a further extension of this opinion gap. Detailed studies, on the clinical effects of low dose treated products (12.5 - 17.5 kGy) are needed to counterbalance the dose suggestions extracted from statistically based dose determinations (> 28 kGy ) and the microbiological resistance determinations ( > 28 - 30 kGy). Dose setting based on risk classification could be considered for distinct product categories. In the mean time a general acceptance of the originally, in the early seventhies, established minimum dose of 25 kGy would seem a reasonable compromise. As the interest for radiation sterilization as the favourable, non polluting and simple method is increasing rapidly over the last five years, both gamma- and beta driven sterilization plants will be needed. Harmonization on sterilization dose therfore requires high priority.

Phase I/II trial of single-fraction high-dose-rate brachytherapy-boosted hypofractionated intensity-modulated radiation therapy for localized adenocarcinoma of the prostate.

PubMed

Myers, Michael A; Hagan, Michael P; Todor, Dorin; Gilbert, Lynn; Mukhopadhyay, Nitai; Randolf, Jessica; Heimiller, Jeffrey; Anscher, Mitchell S

2012-01-01

A Phase I/II protocol was conducted to examine the toxicity and efficacy of the combination of intensity-modulated radiation therapy (IMRT) with a single-fraction high-dose-rate (HDR) brachytherapy implant. From 2001 through 2006, 26 consecutive patients were treated on the trial. The primary objective was to demonstrate a high rate of completion without experiencing a treatment-limiting toxicity. Eligibility was limited to patients with T stage ≤2b, prostate-specific antigen (PSA) ≤20, and Gleason score ≤7. Treatment began with a single HDR fraction of 6Gy to the entire prostate and 9Gy to the peripheral zone, followed by IMRT optimized to deliver in 28 fractions with a normalized total dose of 70Gy. Patients received 50.4Gy to the pelvic lymph node. The prostate dose (IMRT and HDR) resulted in an average biologic equivalent dose >128Gy (α/β=3). Patients whose pretreatment PSA was ≥10ng/mL, Gleason score 7, or stage ≥T2b received short-term androgen ablation. Median followup was 53 months (9-68 months). There were no biochemical failures by either the American Society of Therapeutic Radiology and Oncology or the Phoenix definitions. The median nadir PSA was 0.32ng/mL. All the 26 patients completed the treatment as prescribed. The rate of Grade 3 late genitourinary toxicity was 3.8% consisting of a urethral stricture. There was no other Grade 3 or 4 genitourinary or gastrointestinal toxicities. Single-fraction HDR-boosted IMRT is a safe effective method of dose escalation for localized prostate cancer. Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

[Directions for use of corticosteroids and calcineurin inhibitors against generalized myasthenia gravis: therapeutic strategies that can lead to early improvements and veer away from high-dose oral corticosteroids].

PubMed

Utsugisawa, Kimiaki; Nagane, Yuriko; Suzuki, Shigeaki; Suzuki, Norihiro

2012-01-01

The advent of effective immune treatment has meant that myasthenia gravis (MG) is most often not lethal. However, many MG patients still find it difficult to maintain daily activities due to chronic residual fatigability and long-term side effects of medication, since full remission without immune treatment is not common. Our analysis demonstrated that disease severity, dose of oral corticosteroids, and depressive state are the major independent factors negatively associated with self-reported QOL (MG-QOL15-J score). It is noteworthy that oral corticosteroid, the first-line agent for MG, is negatively associated with patients' QOL. When the analysis took into account MGFA postintervention status and dose of oral prednisolne (PSL), the MG-QOL15-J score of MM status patients taking ≤ 5 mg PSL per day is identically low (i.e., just as good QOL) as that seen in CSR and is a target of treatment. In order to veer away from high-dose oral corticosteroids and to achieve early MM or better status with PSL ≤ 5 mg/day, we advocate the early aggressive treatment strategy that can achieve early improvement by performing an aggressive therapy using combined treatment with plasmapheresis and high-dose intravenous methylprednisolone and then maintain an improved clinical status using low-dose oral corticosteroids and calcineurin inhibitors (cyclosporine microemulsion and tacrolimus). The early stages of MG are susceptible to treatment with calcineurin inhibitors. When using cyclosporine microemulsion for MG, blood concentrations 2 h after administration (C2) correlate with clinical improvement and immediately before administration (C0) with side effects (increased serum creatinine and/or hypertension). Monitoring of C2 and C0 levels is useful to estimate efficacy and safety of the drug.

Effects of Gamma Irradiation and Pasteurization on the Nutritive Composition of Commercially Available Animal Diets

PubMed Central

Caulfield, Catherine D; Cassidy, Joseph P; Kelly, John P

2008-01-01

Gamma radiation is used to sterilize diets for specific pathogen-free (SPF) animals. Because a gamma-irradiated diet was linked to leukoencephalomyelopathy in SPF cats, we investigated the effects of ‘typical’ (28.9–34.3 kGy) and ‘high-end’ (38.4–48.7 kGy) doses of gamma irradiation and of pasteurization (at 107 °C for 15 min) on the amounts of fat; protein; carbohydrate (and taurine in cat diet); vitamins A, E, B1, B2, B6, and B12; and peroxide in commercially available dry cat, dog, and rodent diets. The only treatment-related changes occurred with vitamin A and peroxide. The typical and high-end doses of gamma irradiation reduced the vitamin A level of the cat diet to 42% and 30% of the untreated value, respectively—levels below recommended allowances for growth and reproduction. Only the higher irradiation dose reduced vitamin A in the rodent diet, and neither dose altered the canine diet. Pasteurization reduced the vitamin A content of the cat diet to 50% of its original level, which was within the recommended level for this species. Irradiation increased the peroxide content of all 3 animal diets: by approximately 11-fold with the typical dose and by 14- to 25-fold with the high-end dose. Therefore gamma irradiation can have profound, selective effects on the vitamin A and peroxide contents of dry diets, and caution is advised when feeding such diets long-term and exclusively to SPF animals, particularly cats. Furthermore, pasteurization (with its fewer deleterious effects) may represent an alternative method of decontaminating diets for rodents, dogs, and cats. PMID:19049256

Hepatosplenic γδ T-cell lymphoma of two adolescents: Case report and retrospective literature review in children, adolescents, and young adults.

PubMed

McThenia, Sheila S; Rawwas, Jawhar; Oliveira, Jennifer L; Khan, Shakila P; Rodriguez, Vilmarie

2018-06-19

HSTCL is a highly aggressive malignancy with a poor prognosis. Case series and accounts have reported the use of different chemotherapy regimens with diverse patient outcomes. Most long-term survivors had undergone high-dose chemotherapy with autologous or allogeneic HCT. We describe two pediatric patients with HSTCL who were treated with chemotherapy followed by allogeneic HCT. Both patients are alive and in complete remission 2 and 8 years after therapy. Multiagent chemotherapy followed with allogeneic HCT seems to provide patients who have chemotherapy-sensitive disease a long-term disease-free survival. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Low-dose dynamic myocardial perfusion CT image reconstruction using pre-contrast normal-dose CT scan induced structure tensor total variation regularization

NASA Astrophysics Data System (ADS)

Gong, Changfei; Han, Ce; Gan, Guanghui; Deng, Zhenxiang; Zhou, Yongqiang; Yi, Jinling; Zheng, Xiaomin; Xie, Congying; Jin, Xiance

2017-04-01

Dynamic myocardial perfusion CT (DMP-CT) imaging provides quantitative functional information for diagnosis and risk stratification of coronary artery disease by calculating myocardial perfusion hemodynamic parameter (MPHP) maps. However, the level of radiation delivered by dynamic sequential scan protocol can be potentially high. The purpose of this work is to develop a pre-contrast normal-dose scan induced structure tensor total variation regularization based on the penalized weighted least-squares (PWLS) criteria to improve the image quality of DMP-CT with a low-mAs CT acquisition. For simplicity, the present approach was termed as ‘PWLS-ndiSTV’. Specifically, the ndiSTV regularization takes into account the spatial-temporal structure information of DMP-CT data and further exploits the higher order derivatives of the objective images to enhance denoising performance. Subsequently, an effective optimization algorithm based on the split-Bregman approach was adopted to minimize the associative objective function. Evaluations with modified dynamic XCAT phantom and preclinical porcine datasets have demonstrated that the proposed PWLS-ndiSTV approach can achieve promising gains over other existing approaches in terms of noise-induced artifacts mitigation, edge details preservation, and accurate MPHP maps calculation.

Low-dose X-ray computed tomography image reconstruction with a combined low-mAs and sparse-view protocol.

PubMed

Gao, Yang; Bian, Zhaoying; Huang, Jing; Zhang, Yunwan; Niu, Shanzhou; Feng, Qianjin; Chen, Wufan; Liang, Zhengrong; Ma, Jianhua

2014-06-16

To realize low-dose imaging in X-ray computed tomography (CT) examination, lowering milliampere-seconds (low-mAs) or reducing the required number of projection views (sparse-view) per rotation around the body has been widely studied as an easy and effective approach. In this study, we are focusing on low-dose CT image reconstruction from the sinograms acquired with a combined low-mAs and sparse-view protocol and propose a two-step image reconstruction strategy. Specifically, to suppress significant statistical noise in the noisy and insufficient sinograms, an adaptive sinogram restoration (ASR) method is first proposed with consideration of the statistical property of sinogram data, and then to further acquire a high-quality image, a total variation based projection onto convex sets (TV-POCS) method is adopted with a slight modification. For simplicity, the present reconstruction strategy was termed as "ASR-TV-POCS." To evaluate the present ASR-TV-POCS method, both qualitative and quantitative studies were performed on a physical phantom. Experimental results have demonstrated that the present ASR-TV-POCS method can achieve promising gains over other existing methods in terms of the noise reduction, contrast-to-noise ratio, and edge detail preservation.

Candidate Dosimetric Predictors of Long-Term Swallowing Dysfunction After Oropharyngeal Intensity-Modulated Radiotherapy

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

Schwartz, David L., E-mail: docdls@mdanderson.or; Department of Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, TX; Hutcheson, Katherine

2010-12-01

Purpose: To investigate long-term swallowing function in oropharyngeal cancer patients treated with intensity-modulated radiotherapy (IMRT), and to identify novel dose-limiting criteria predictive for dysphagia. Methods and Materials: Thirty-one patients with Stage IV oropharyngeal squamous carcinoma enrolled on a Phase II trial were prospectively evaluated by modified barium swallow studies at baseline, and 6, 12, and 24 months post-IMRT treatment. Candidate dysphagia-associated organs at risk were retrospectively contoured into original treatment plans. Twenty-one (68%) cases were base of tongue and 10 (32%) were tonsil. Stage distribution was T1 (12 patients), T2 (10), T3 (4), T4 (2), and TX (3), and N2more » (24), N3 (5), and NX (2). Median age was 52.8 years (range, 42-78 years). Thirteen patients (42%) received concurrent chemotherapy during IMRT. Thirteen (42%) were former smokers. Mean dose to glottic larynx for the cohort was limited to 18 Gy (range, 6-39 Gy) by matching IMRT to conventional low-neck fields. Results: Dose-volume constraints (V30 < 65% and V35 < 35% for anterior oral cavity and V55 < 80% and V65 < 30% for high superior pharyngeal constrictors) predictive for objective swallowing dysfunction were identified by univariate and multivariate analyses. Aspiration and feeding tube dependence were observed in only 1 patient at 24 months. Conclusions: In the context of glottic laryngeal shielding, we describe candidate oral cavity and superior pharyngeal constrictor organs at risk and dose-volume constraints associated with preserved long-term swallowing function; these constraints are currently undergoing prospective validation. Strict protection of the glottic larynx via beam-split IMRT techniques promises to make chronic aspiration an uncommon outcome.« less

[Urine metabonomic study on long-term use of total ginsenosides in rats].

PubMed

Xie, Xie; Chen, Shao-Qiu; Lv, Ying-Fang; Wang, Xiao-Yan; Jia, Wei

2014-12-01

Due to its effect of systems regulation and promotion on body, Ginseng is always referred to be long-term used as a dietary supplement. But it was still unclear about its target of the tonic effects and also the side-effects long-term use may bring. Urine metabolomic method is suitable for long-term studies of pharmaco-dynamics, pharmacology and toxicology of traditional Chinese medicine because of its characteristics of non-invasive and monitoring the whole-body metabolism. This study was designed to detect the dynamic variation of rat urine metabolome along with a long-term administration of total ginsenosides using GC-TOF based metabolomic technology. Our result showed that either short-term or chronic administration of ginsenosides did not impact the rat urine metabolome significantly (as the PCA subgroup was not successful). By comparison, the short-term (1-3 w) dose of ginsenosides had the biggest metabolic influence including TCA cycle, catecholamines and neurotransmitter amino acids. Medium-term (6-10 w) dose had a gradually lower effect and long-term (27 w) dose almost had no effect. Our study indicates that both short and long-term administration of ginsenosides showed almost no obvious side-effect on the experimental animals.

Ultrafast treatment plan optimization for volumetric modulated arc therapy (VMAT)

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

Men Chunhua; Romeijn, H. Edwin; Jia Xun

2010-11-15

Purpose: To develop a novel aperture-based algorithm for volumetric modulated arc therapy (VMAT) treatment plan optimization with high quality and high efficiency. Methods: The VMAT optimization problem is formulated as a large-scale convex programming problem solved by a column generation approach. The authors consider a cost function consisting two terms, the first enforcing a desired dose distribution and the second guaranteeing a smooth dose rate variation between successive gantry angles. A gantry rotation is discretized into 180 beam angles and for each beam angle, only one MLC aperture is allowed. The apertures are generated one by one in a sequentialmore » way. At each iteration of the column generation method, a deliverable MLC aperture is generated for one of the unoccupied beam angles by solving a subproblem with the consideration of MLC mechanic constraints. A subsequent master problem is then solved to determine the dose rate at all currently generated apertures by minimizing the cost function. When all 180 beam angles are occupied, the optimization completes, yielding a set of deliverable apertures and associated dose rates that produce a high quality plan. Results: The algorithm was preliminarily tested on five prostate and five head-and-neck clinical cases, each with one full gantry rotation without any couch/collimator rotations. High quality VMAT plans have been generated for all ten cases with extremely high efficiency. It takes only 5-8 min on CPU (MATLAB code on an Intel Xeon 2.27 GHz CPU) and 18-31 s on GPU (CUDA code on an NVIDIA Tesla C1060 GPU card) to generate such plans. Conclusions: The authors have developed an aperture-based VMAT optimization algorithm which can generate clinically deliverable high quality treatment plans at very high efficiency.« less

Ultrafast treatment plan optimization for volumetric modulated arc therapy (VMAT).

PubMed

Men, Chunhua; Romeijn, H Edwin; Jia, Xun; Jiang, Steve B

2010-11-01

To develop a novel aperture-based algorithm for volumetric modulated are therapy (VMAT) treatment plan optimization with high quality and high efficiency. The VMAT optimization problem is formulated as a large-scale convex programming problem solved by a column generation approach. The authors consider a cost function consisting two terms, the first enforcing a desired dose distribution and the second guaranteeing a smooth dose rate variation between successive gantry angles. A gantry rotation is discretized into 180 beam angles and for each beam angle, only one MLC aperture is allowed. The apertures are generated one by one in a sequential way. At each iteration of the column generation method, a deliverable MLC aperture is generated for one of the unoccupied beam angles by solving a subproblem with the consideration of MLC mechanic constraints. A subsequent master problem is then solved to determine the dose rate at all currently generated apertures by minimizing the cost function. When all 180 beam angles are occupied, the optimization completes, yielding a set of deliverable apertures and associated dose rates that produce a high quality plan. The algorithm was preliminarily tested on five prostate and five head-and-neck clinical cases, each with one full gantry rotation without any couch/collimator rotations. High quality VMAT plans have been generated for all ten cases with extremely high efficiency. It takes only 5-8 min on CPU (MATLAB code on an Intel Xeon 2.27 GHz CPU) and 18-31 s on GPU (CUDA code on an NVIDIA Tesla C1060 GPU card) to generate such plans. The authors have developed an aperture-based VMAT optimization algorithm which can generate clinically deliverable high quality treatment plans at very high efficiency.

Use of rivastigmine transdermal patch in the treatment of Alzheimer's disease.

PubMed

Winblad, Bengt; Machado, João Carlos

2008-12-01

Cholinesterase inhibitors such as rivastigmine and donepezil exhibit a dose-response relationship, with higher doses of the drugs demonstrating greater efficacy. Transdermal patches provide smooth continuous drug delivery, with the potential to offer efficacious levels of drug exposure while avoiding the peaks and troughs associated with side effects. As a small, lipophilic and hydrophilic molecule, rivastigmine (C14H22N2O2) is chemically well-suited to transdermal delivery. The technology underlying the rivastigmine patch allows it to be discreetly small and thin. The target dose 9.5 mg/24 h rivastigmine patch has a diameter of just 3.5 cm and a surface area of 10 cm2. A large randomized controlled trial has demonstrated that the target dose 9.5 mg/24 h rivastigmine patch provided similar efficacy to the highest rivastigmine capsule doses, yet with three times fewer reports of nausea and vomiting. Thus, the rivastigmine patch enables quick and easy access to high dose efficacy. The skin tolerability profile is good, and the patch has demonstrated excellent adhesion. The apparent success of rivastigmine patch, in terms of clinical utility and patient acceptability, suggests that it may mark the next generation of dementia treatment.

Paediatric x-ray examinations in Rio de Janeiro

NASA Astrophysics Data System (ADS)

Azevedo, A. C. P.; Osibote, O. A.; Boechat, M. C. B.

2006-08-01

This work presents the results of a dose survey performed for paediatric patients and carried out in two large paediatric public hospitals in Rio de Janeiro city. The entrance surface dose (ESD) and the effective dose (ED) were evaluated for chest, skull, abdomen, lumbar spine, cervical spine and pelvis in antero-posterior (AP), postero-anterior (PA) and lateral (LAT) projections. For each examination, four age groups 0-1, 1-5, 5-10 and 10-15 years were studied. The DoseCal software was used to calculate these doses. Wide variations for the same type of examination and projection have been detected. These variations were evident, in Brazil, from previous work. In spite of the present results being still preliminary, they can give an idea of what paediatric ESDs are like in Brazil. Also, with respect to the entrance surface dose, some of the results are above the reference levels, which cause high ED, as well. On the other hand, the wide range of ESD reflects the disparity of radiographic techniques and demonstrates that the ALARA principle is not being applied in Brazilian hospitals and becomes a concern in terms of public health.

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.

Isolation, antigenicity and immunogenicity of Lleida bat lyssavirus.

PubMed

Banyard, Ashley C; Selden, David; Wu, Guanghui; Thorne, Leigh; Jennings, Daisy; Marston, Denise; Finke, Stefan; Freuling, Conrad M; Müller, Thomas; Echevarría, Juan E; Fooks, Anthony R

2018-05-10

The lyssaviruses are an important group of viruses that cause a fatal encephalitis termed rabies. The prototypic lyssavirus, rabies virus, is predicted to cause more than 60 000 human fatalities annually. The burden of disease for the other lyssaviruses is undefined. The original reports for the recently described highly divergent Lleida bat lyssavirus were based on the detection of virus sequence alone. The successful isolation of live Lleida bat lyssavirus from the carcass of the original bat and in vitro characterization of this novel lyssavirus are described here. In addition, the ability of a human rabies vaccine to confer protective immunity following challenge with this divergent lyssavirus was assessed. Two different doses of Lleida bat lyssavirus were used to challenge vaccinated or naïve mice: a high dose of 100 focus-forming units (f.f.u.) 30 µl -1 and a 100-fold dilution of this dose, 1 f.f.u. 30 µl -1 . Although all naïve control mice succumbed to the 100 f.f.u. 30 µl -1 challenge, 42 % (n=5/12) of those infected intracerebrally with 1 f.f.u. 30 µl -1 survived the challenge. In the high-challenge-dose group, 42 % of the vaccinated mice survived the challenge (n=5/12), whilst at the lower challenge dose, 33 % (n=4/12) survived to the end of the experiment. Interestingly, a high proportion of mice demonstrated a measurable virus-neutralizing antibody response, demonstrating that neutralizing antibody titres do not necessarily correlate with the outcome of infection via the intracerebral route. Assessing the ability of existing rabies vaccines to protect against novel divergent lyssaviruses is important for the development of future public health strategies.

Vitamin C revisited.

PubMed

Oudemans-van Straaten, Heleen M; Spoelstra-de Man, Angelique Me; de Waard, Monique C

2014-08-06

This narrative review summarizes the role of vitamin C in mitigating oxidative injury-induced microcirculatory impairment and associated organ failure in ischemia/reperfusion or sepsis. Preclinical studies show that high-dose vitamin C can prevent or restore microcirculatory flow impairment by inhibiting activation of nicotinamide adenine dinucleotide phosphate-oxidase and inducible nitric oxide synthase, augmenting tetrahydrobiopterin, preventing uncoupling of oxidative phosphorylation, and decreasing the formation of superoxide and peroxynitrite, and by directly scavenging superoxide. Vitamin C can additionally restore vascular responsiveness to vasoconstrictors, preserve endothelial barrier by maintaining cyclic guanylate phosphatase and occludin phosphorylation and preventing apoptosis. Finally, high-dose vitamin C can augment antibacterial defense. These protective effects against overwhelming oxidative stress due to ischemia/reperfusion, sepsis or burn seems to mitigate organ injury and dysfunction, and promote recovery after cardiac revascularization and in critically ill patients, in the latter partially in combination with other antioxidants. Of note, several questions remain to be solved, including optimal dose, timing and combination of vitamin C with other antioxidants. The combination obviously offers a synergistic effect and seems reasonable during sustained critical illness. High-dose vitamin C, however, provides a cheap, strong and multifaceted antioxidant, especially robust for resuscitation of the circulation. Vitamin C given as early as possible after the injurious event, or before if feasible, seems most effective. The latter could be considered at the start of cardiac surgery, organ transplant or major gastrointestinal surgery. Preoperative supplementation should consider the inhibiting effect of vitamin C on ischemic preconditioning. In critically ill patients, future research should focus on the use of short-term high-dose intravenous vitamin C as a resuscitation drug, to intervene as early as possible in the oxidant cascade in order to optimize macrocirculation and microcirculation and limit cellular injury.

Haloperidol dose combined with dexamethasone for PONV prophylaxis in high-risk patients undergoing gynecological laparoscopic surgery: a prospective, randomized, double-blind, dose-response and placebo-controlled study.

PubMed

Joo, Jin; Park, Yong Gyu; Baek, Jungwon; Moon, Young Eun

2015-07-08

Low-dose haloperidol is known to be effective for the prevention of postoperative nausea and vomiting (PONV). However, precise dose-response studies have not been completed, especially in patients at high risk for PONV who require combination therapy. This study sought to identify which dose of haloperidol 1mg or 2mg could be combined with dexamethasone without adverse effects in high-risk patients undergoing gynecological laparoscopic surgery. Female adults (n = 150) with three established PONV risk factors based on Apfel's score were randomized into one of three study groups. At the end of anesthesia, groups H0, H1, and H2 were given intravenous (IV) saline, haloperidol 1 mg, and haloperidol 2 mg, respectively. All patients were given dexamethasone 5 mg during the induction of anesthesia. The overall early (0-2 h) and late (2-24 h) incidences of nausea, vomiting, rescue anti-emetic administration, pain, and adverse effects (cardiac arrhythmias and extrapyramidal effects) were assessed postoperatively. The sedation score was recorded in the postanesthesia care unit (PACU). The total incidence of PONV over 24 h was significantly lower in groups H1 (29 %) and H2 (24 %) than in group H0 (54 %; P = 0.003), but there was no significant difference between groups H1 and H2. In the PACU, group H2 had a higher sedation score than groups H1 and H0 (P < 0.001). For high-risk PONV patients undergoing gynecological laparoscopic surgery, when used with dexamethasone, 1-mg haloperidol was equally effective as 2 mg in terms of preventing PONV with the less sedative effect. ClinicalTrials.gov ( NCT01639599 ).

Dietary intake of high-dose biotin inhibits spermatogenesis in young rats.

PubMed

Sawamura, Hiromi; Ikeda, Chieko; Shimada, Ryoko; Yoshii, Yui; Watanabe, Toshiaki

2015-02-01

To characterize a new function of the water-soluble vitamin, biotin, in reproduction and early growth in mammals, the effects of high dietary doses of biotin on early spermatogenesis were biochemically and histologically investigated in male rats. Weaned rats were fed a CE-2 (control) diet containing 0.00004% biotin, or a control diet supplemented with 0.01%, 0.1%, or 1.0% biotin. Pair-fed rats were fed a control diet that was equal in calories to the amount ingested by the 1.0% biotin group, because food intake was decreased in the 1.0% biotin group. Food intake and body weight gain were lower in the 1.0% biotin group than in the control group. The kidney, brain and testis weights were significantly lower in the 1.0% biotin group than in the pair-fed group after 6 weeks of feeding. The accumulation of biotin in the liver and testis increased in a dose-dependent manner. In the 1.0% biotin group, the number of mature sperm was markedly lower, that of sperm with morphologically abnormal heads, mainly consisting of round heads, had increased. In addition, the development of seminiferous tubules was inhibited, and few spermatogonia and no spermatocytes were histologically observed. These results demonstrated that the long-term intake of high-dose biotin inhibited spermatogenesis in young male rats. © 2014 Japanese Teratology Society.

Short-term evaluation of captopril in patients with chronic left sided valvular regurgitations.

PubMed

Jirasirirojanakorn, K; Mahanonda, N; Jootar, P; Chaithiraphan, S; Wansanit, K; Watanaprakarnchai, W

1998-01-01

To evaluate the clinical effects and the changes in cardiac performance of high- and low-dose captopril compared to placebo in patients with chronic symptomatic aortic regurgitation (AR), and/or mitral regurgitation (MR). We randomized patients into three groups, placebo (Group 1), incremental daily doses of 50 mg (Group 2), and 100 mg captopril (Group 3). We compared exercise capacity before and after four-week of treatment. Treatment was well tolerated with no serious side effects including blood chemistry. There were no significant effects of treatment on left ventricular dimensions nor calculated left ventricular ejection fraction (LVEF) between groups (LVEF change -0.6%, -2.6%, 2.4%, in group 1, 2 and 3 respectively; p > 0.05). No difference of exercise duration between treatment and placebo arms (change by 13%, 12.8%, 16.4%, respectively; p > 0.05). However, there were trends in the number of the patients who improved in left ventricular performance (absolute LVEF change > 5% unit = 15%, 16%, and 42% respectively; p > 0.05) and exercise performance (exercise time improvement > 75 sec = 50%, 47%, and 68% respectively; p > 0.05) in high dose captopril treatment group. There was no significant improvement of left ventricular performance and exercise capacity after four-weeks' treatment of low and high dose captopril. Further study with a larger sample size, and longer follow-up period may be required.