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Sample records for submucosa reduces stimulated

  1. Generating elastin-rich small intestinal submucosa-based smooth muscle constructs utilizing exogenous growth factors and cyclic mechanical stimulation.

    PubMed

    Heise, Rebecca Long; Ivanova, Julia; Parekh, Aron; Sacks, Michael S

    2009-12-01

    Successful approaches to tissue engineering smooth muscle tissues utilize biodegradable scaffolds seeded with autologous cells. One common problem in using biological scaffolds specifically is the difficulty of inducing cellular penetration and controlling de novo extracellular matrix deposition/remodeling in vitro. Our hypothesis was that small intestinal submucosa (SIS) exposed to specific mechanical stimulation regimes would modulate the synthesis of de novo collagen and elastin by bladder smooth muscle cells (BSMC) within the SIS matrix. We further hypothesized that the cytokines vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), two key growth factors involved in epithelial mesenchymal signaling, will promote the cellular penetration into SIS necessary for mechanical stimulation. BSMC were seeded at 0.5 x 10(6) cells/cm(2) onto the luminal side of SIS specimens. VEGF (10 ng/mL) and FGF-2 (5 ng/mL) were added to each insert in the media every other day for up to 7 days in static culture. Following static culture, specimens were stretched strip-biaxially under 15% peak strain at either 0.5 or 0.1 Hz for an additional 7 days. Following the culture period, specimens were assayed histologically and biochemically for cellular penetration, proliferation, elastin, collagen, and protease activity. Histological analyses demonstrated that in standard culture media, BSMC remained on the surface of the SIS while both FGF-2 and VEGF profoundly promoted ingrowth of the BSMC into the SIS. The penetration of the cells in response to these cytokines was confirmed using a Transwell assay. Following cellular penetration, BSMC produced significant amounts of elastic fibers under cyclic mechanical stretching at 0.1 Hz under 15% stretch, as evidenced by colorimetric assay and histology using a Verhoeff-Van Gieson stain. Protease activity was assessed in the media and found to be statistically increased in static culture following FGF-2 treatment. These

  2. Reduced urothelial regeneration in rat bladders augmented with permeable porcine small intestinal submucosa assessed by magnetic resonance imaging.

    PubMed

    Yang, Qing; Xia, Ding; Towner, Rheal A; Smith, Nataliya; Saunders, Debra; Fung, Kar-Ming; Aston, Christopher E; Greenwood-Van Meerveld, Beverley; Hurst, Robert E; Madihally, Sundararajan V; Kropp, Bradley P; Lin, Hsueh-Kung

    2017-09-13

    Augmentation enterocystoplasty remains the gold standard surgical bladder reconstruction procedure to increase the capacity and compliance of dysfunctional bladders. Since the use of the patient's intestine has severe risks of complications, alternative biodegradable matrices have been explored. Porcine small intestinal submucosa (SIS) has gained immense interests in bladder reconstruction due to its favorable properties. However, trials have shown inconsistent regeneration with SIS, attributed to the heterogeneity in microstructures and mechanical properties. We hypothesize that uneven SIS permeability to urine is a factor responsible for the inconsistency. We measured permeability to urine in situ using a contrast enhanced-magnetic resonance imaging (MRI), and evaluated urothelium regeneration using immunohistochemical staining of urothelial cell markers in SIS-augmented rat bladders. Results showed significant differences in permeability among SIS-augmented rat bladders. Commercial SIS scaffolds were then categorized into nonleaky and leaky groups based on MRI results. Hematoxylin and eosin staining showed higher numbers of inflammatory cells in leaky SIS on day 14 relative to nonleaky SIS. In addition, trichrome staining showed major changes in the distribution of collagen on day 28 between SIS-augmented bladder groups. Furthermore, expressions of urothelium-associated markers (cytokeratins AE1/AE3, claudin 4, and uroplakin III) were completed in bladders augmented with nonleaky SIS, whereas limited urothelial differentiation was noticed in leaky SIS-augmented bladders at post-augmentative day 14. These results show that scaffold permeability to urine may be responsible for variations in regenerative capacity of porcine SIS. Applications of MRI technique will be helpful to understand a relationship between biomaterial property and regenerative capacity. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2017. © 2017 Wiley Periodicals

  3. Deep brain stimulation to reduce sexual drive

    PubMed Central

    Fuss, Johannes; Auer, Matthias K.; Biedermann, Sarah V.; Briken, Peer; Hacke, Werner

    2015-01-01

    To date there are few treatment options to reduce high sexual drive or sexual urges in paraphilic patients with a risk for sexual offending. Pharmacological therapy aims to reduce sexual drive by lowering testosterone at the cost of severe side effects. We hypothesize that high sexual drive could also be reduced with deep brain stimulation (DBS) of circuits that generate sexual drive. This approach would help to avoid systemic side effects of antiandrogenic drug therapies. So far the best investigated target to reduce sexual drive is the ventromedial hypothalamus, which was lesioned unilaterally and bilaterally by stereotaxic interventions in paraphilic patients in the 1970s. Here, we discuss DBS as a treatment strategy in patients with severe paraphilic disorders with a serious risk of sexual offending. There are profound ethical and practical issues associated with DBS treatment of paraphilic patients that must be solved before considering such a treatment approach. PMID:26057198

  4. Label-free visualization of collagen in submucosa as a potential diagnostic marker for early detection of colorectal cancer

    NASA Astrophysics Data System (ADS)

    Qiu, Jingting; Yang, Yinghong; Jiang, Weizhong; Feng, Changyin; Chen, Zhifen; Guan, Guoxian; Zhu, Xiaoqin; Zhuo, Shuangmu; Chen, Jianxin

    2014-09-01

    The collagen signature in colorectal submucosa is changed due to remodeling of the extracellular matrix during the malignant process and plays an important role in noninvasive early detection of human colorectal cancer. In this work, multiphoton microscopy (MPM) was used to monitor the changes of collagen in normal colorectal submucosa (NCS) and cancerous colorectal submucosa (CCS). What's more, the collagen content was quantitatively measured. It was found that in CCS the morphology of collagen becomes much looser and the collagen content is significantly reduced compared to NCS. These results suggest that MPM has the ability to provide collagen signature as a potential diagnostic marker for early detection of colorectal cancer.

  5. Reducing interaction in simultaneous paired stimulation with CI.

    PubMed

    Vellinga, Dirk; Bruijn, Saskia; Briaire, Jeroen J; Kalkman, Randy K; Frijns, Johan H M

    2017-01-01

    In this study simultaneous paired stimulation of electrodes in cochlear implants is investigated by psychophysical experiments in 8 post-lingually deaf subjects (and one extra subject who only participated in part of the experiments). Simultaneous and sequential monopolar stimulation modes are used as references and are compared to channel interaction compensation, partial tripolar stimulation and a novel sequential stimulation strategy named phased array compensation. Psychophysical experiments are performed to investigate both the loudness integration during paired stimulation at the main electrodes as well as the interaction with the electrode contact located halfway between the stimulating pair. The study shows that simultaneous monopolar stimulation has more loudness integration on the main electrodes and more interaction in between the electrodes than sequential stimulation. Channel interaction compensation works to reduce the loudness integration at the main electrodes, but does not reduce the interaction in between the electrodes caused by paired stimulation. Partial tripolar stimulation uses much more current to reach the needed loudness, but shows the same interaction in between the electrodes as sequential monopolar stimulation. In phased array compensation we have used the individual impedance matrix of each subject to calculate the current needed on each electrode to exactly match the stimulation voltage along the array to that of sequential stimulation. The results show that the interaction in between the electrodes is the same as monopolar stimulation. The strategy uses less current than partial tripolar stimulation, but more than monopolar stimulation. In conclusion, the paper shows that paired stimulation is possible if the interaction is compensated.

  6. Reducing interaction in simultaneous paired stimulation with CI

    PubMed Central

    Vellinga, Dirk; Briaire, Jeroen J.; Kalkman, Randy K.; Frijns, Johan H. M.

    2017-01-01

    In this study simultaneous paired stimulation of electrodes in cochlear implants is investigated by psychophysical experiments in 8 post-lingually deaf subjects (and one extra subject who only participated in part of the experiments). Simultaneous and sequential monopolar stimulation modes are used as references and are compared to channel interaction compensation, partial tripolar stimulation and a novel sequential stimulation strategy named phased array compensation. Psychophysical experiments are performed to investigate both the loudness integration during paired stimulation at the main electrodes as well as the interaction with the electrode contact located halfway between the stimulating pair. The study shows that simultaneous monopolar stimulation has more loudness integration on the main electrodes and more interaction in between the electrodes than sequential stimulation. Channel interaction compensation works to reduce the loudness integration at the main electrodes, but does not reduce the interaction in between the electrodes caused by paired stimulation. Partial tripolar stimulation uses much more current to reach the needed loudness, but shows the same interaction in between the electrodes as sequential monopolar stimulation. In phased array compensation we have used the individual impedance matrix of each subject to calculate the current needed on each electrode to exactly match the stimulation voltage along the array to that of sequential stimulation. The results show that the interaction in between the electrodes is the same as monopolar stimulation. The strategy uses less current than partial tripolar stimulation, but more than monopolar stimulation. In conclusion, the paper shows that paired stimulation is possible if the interaction is compensated. PMID:28182685

  7. Actions of Angeli's salt, a nitroxyl (HNO) donor, on ion transport across mucosa-submucosa preparations from rat distal colon.

    PubMed

    Pouokam, Ervice; Bell, Anna; Diener, Martin

    2013-09-05

    The aim of this study was to investigate whether nitroxyl (HNO), a redox variant of the radical gasotransmitter nitric oxide (NO) with therapeutically promising properties, affects colonic ion transport. Changes in short-circuit current (Isc) induced by the HNO donor Angeli's salt were recorded in Ussing chambers. Cytosolic Ca(2+) concentration was measured with fura-2. The nitroxyl donor induced a concentration-dependent increase in Isc across rat distal colon which was due to a stimulation of chloride secretion. The secretion induced by Angeli's salt (5×10(-4)mol/l) was not altered by the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO), but was abolished by the HNO scavenger l-cysteine. The response was not dependent on the activity of soluble guanylate cyclase or enteric neurons, but was inhibited by indomethacin. Experiments with apically permeabilized epithelia revealed the activation of basolateral K(+) channels and a stimulation of the current carried by the basolateral Na(+)-K(+)-pump by Angeli's salt. The secretion induced by Angeli's salt was reduced in the absence of extracellular Ca(2+). A prominent increase in the cytosolic Ca(2+) concentration was evoked by Angeli's salt predominantly in subepithelial cells within the submucosa, which had the same dependence on extracellular Ca(2+) as the Angeli's salt-induced Cl(-) secretion. Consequently, Angeli's salt induces a soluble guanylate cyclase-independent, Ca(2+)-dependent Cl(-) secretion via activation of the Na(+)-K(+)-ATPase and of basolateral K(+) channels. Cyclooxygenase metabolites produced within the submucosa seem to be involved in this response.

  8. Tactile stimulation reduces fear in fish

    PubMed Central

    Schirmer, Annett; Jesuthasan, Suresh; Mathuru, Ajay S.

    2013-01-01

    Being groomed or touched can counter stress and negative affect in mammals. In two experiments we explored whether a similar phenomenon exists in non-mammals like zebrafish. In Experiment 1, we exposed zebrafish to a natural stressor, a chemical alarm signal released by injured conspecifics. Before moving them into an observation tank, one group of fish was washed and then subjected to a water current that served as the tactile stimulus. The other group was simply washed. Fish with tactile treatment demonstrated fewer fear behaviors (e.g., bottom dwelling) and lower cortisol levels than fish without. In Experiment 2, we ascertained a role of somatosensation in these effects. Using a similar paradigm as in Experiment 1, we recorded fear behaviors of intact fish and fish with damaged lateral line hair cells. Relative to the former, the latter benefited less from the tactile stimulus during fear recovery. Together these findings show that tactile stimulation can calm fish and that tactile receptors, evolutionarily older than those present in mammals, contribute to this phenomenon. PMID:24319415

  9. Spatially distributed sequential stimulation reduces muscle fatigue during neuromuscular electrical stimulation.

    PubMed

    Sayenko, Dimitry G; Popovic, Milos R; Masani, Kei

    2013-01-01

    A critical limitation with neuromuscular electrical stimulation (NMES) approach is the rapid onset of muscle fatigue during repeated contractions, which results in the muscle force decay and slowing of muscle contractile properties. In our previous study, we demonstrated that spatially distributed sequential stimulation (SDSS) show a drastically greater fatigue-reducing ability compared to a conventional, single active electrode stimulation (SES) with an individual with spinal cord injury when applied for plantar flexors. The purpose of the present study is to explore the fatigue-reducing ability of SDSS for major lower limb muscle groups in the able-bodied population as well as individuals with spinal cord injury (SCI). SDSS was delivered through four active electrodes applied to the muscle of interest, sending a stimulation pulse to each electrode one after another with 90° phase shift between successive electrodes. For comparison, SES was delivered through one active electrode. For both modes of stimulation, the resultant frequency to the muscle as a whole was 40 Hz. Using corresponding protocols for the fatiguing stimulation, we demonstrated the fatigue-reducing ability of SDSS by higher fatigue indices as compared with single active electrode setup for major leg muscles in both subject groups. The present work verifies and extends reported findings on the effectiveness of using spatially distributed sequential stimulation in the leg muscles to reduce muscle fatigue. Application of this technique can improve the usefulness of NMES during functional movements in the clinical setup.

  10. Repetitive electric brain stimulation reduces food intake in humans.

    PubMed

    Jauch-Chara, Kamila; Kistenmacher, Alina; Herzog, Nina; Schwarz, Marianka; Schweiger, Ulrich; Oltmanns, Kerstin M

    2014-10-01

    The dorsolateral prefrontal cortex (DLPFC) plays an important role in appetite and food intake regulation. Because previous data revealed that transcranial direct current stimulation (tDCS) of the DLPFC reduces food cravings, we hypothesized that repetitive electric stimulation of the right DLPFC would lower food intake behavior in humans. In a single-blind, code-based, placebo-controlled, counterbalanced, randomized crossover experiment, 14 healthy young men with body mass index (in kg/m(2)) from 20 to 25 were examined during 8 d of daily tDCS or a sham stimulation. After tDCS or sham stimulation on the first and the last day of both experimental conditions, participants consumed food ad libitum from a standardized test buffet. One week of daily anodal tDCS reduced overall caloric intake by 14% in comparison with sham stimulation. Moreover, repetitive tDCS diminished self-reported appetite scores. Our study implies that the application of anodal direct currents to the right DLPFC represents a promising option for reducing both caloric intake and appetite in humans. This trial was registered at the German Clinical Trials Register (www.germanctr.de) as DRKS00005811. © 2014 American Society for Nutrition.

  11. Reduced Environmental Stimulation Techniques and Control of Psychological Dependencies.

    ERIC Educational Resources Information Center

    Cooper, G. David

    Three areas of research have supported the conceptual relevance of Reduced Environmental Stimulation (RES) techniques in the management of psychological dependencies. First, preliminary studies through the late l960's indicated that relatively short periods of RES had a facilitative effect on the type of subject who might be most vulnerable to…

  12. Immune stimulation reduces sleep and memory ability in Drosophila melanogaster.

    PubMed

    Mallon, Eamonn B; Alghamdi, Akram; Holdbrook, Robert T K; Rosato, Ezio

    2014-01-01

    Psychoneuroimmunology studies the increasing number of connections between neurobiology, immunology and behaviour. We demonstrate the effects of the immune response on two fundamental behaviours: sleep and memory ability in Drosophila melanogaster. We used the Geneswitch system to upregulate peptidoglycan receptor protein (PGRP) expression, thereby stimulating the immune system in the absence of infection. Geneswitch was activated by feeding the steroid RU486, to the flies. We used an aversive classical conditioning paradigm to quantify memory and measures of activity to infer sleep. Immune stimulated flies exhibited reduced levels of sleep, which could not be explained by a generalised increase in waking activity. Immune stimulated flies also showed a reduction in memory abilities. These results lend support to Drosophila as a model for immune-neural interactions and provide a possible role for sleep in the interplay between the immune response and memory.

  13. Reducing proactive aggression through non-invasive brain stimulation.

    PubMed

    Dambacher, Franziska; Schuhmann, Teresa; Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T

    2015-10-01

    Aggressive behavior poses a threat to human collaboration and social safety. It is of utmost importance to identify the functional mechanisms underlying aggression and to develop potential interventions capable of reducing dysfunctional aggressive behavior already at a brain level. We here experimentally shifted fronto-cortical asymmetry to manipulate the underlying motivational emotional states in both male and female participants while assessing the behavioral effects on proactive and reactive aggression. Thirty-two healthy volunteers received either anodal transcranial direct current stimulation to increase neural activity within right dorsolateral prefrontal cortex, or sham stimulation. Aggressive behavior was measured with the Taylor Aggression Paradigm. We revealed a general gender effect, showing that men displayed more behavioral aggression than women. After the induction of right fronto-hemispheric dominance, proactive aggression was reduced in men. This study demonstrates that non-invasive brain stimulation can reduce aggression in men. This is a relevant and promising step to better understand how cortical brain states connect to impulsive actions and to examine the causal role of the prefrontal cortex in aggression. Ultimately, such findings could help to examine whether the brain can be a direct target for potential supportive interventions in clinical settings dealing with overly aggressive patients and/or violent offenders.

  14. Reducing proactive aggression through non-invasive brain stimulation

    PubMed Central

    Schuhmann, Teresa; Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T.

    2015-01-01

    Aggressive behavior poses a threat to human collaboration and social safety. It is of utmost importance to identify the functional mechanisms underlying aggression and to develop potential interventions capable of reducing dysfunctional aggressive behavior already at a brain level. We here experimentally shifted fronto-cortical asymmetry to manipulate the underlying motivational emotional states in both male and female participants while assessing the behavioral effects on proactive and reactive aggression. Thirty-two healthy volunteers received either anodal transcranial direct current stimulation to increase neural activity within right dorsolateral prefrontal cortex, or sham stimulation. Aggressive behavior was measured with the Taylor Aggression Paradigm. We revealed a general gender effect, showing that men displayed more behavioral aggression than women. After the induction of right fronto-hemispheric dominance, proactive aggression was reduced in men. This study demonstrates that non-invasive brain stimulation can reduce aggression in men. This is a relevant and promising step to better understand how cortical brain states connect to impulsive actions and to examine the causal role of the prefrontal cortex in aggression. Ultimately, such findings could help to examine whether the brain can be a direct target for potential supportive interventions in clinical settings dealing with overly aggressive patients and/or violent offenders. PMID:25680991

  15. Median nerve stimulation reduces ventricular arrhythmias induced by dorsomedial hypothalamic stimulation.

    PubMed

    Zhao, Shuang; Tang, Min; Yuan, Kexin; Gu, Jingli; Yu, Jun; Long, Xiaoyang; Liu, Miaomiao; Cao, Ji-Min; Zhang, Shu

    2016-12-01

    This study tested the hypothesis that median nerve stimulation (MNS) prevents ventricular arrhythmias (VAs) induced by dorsomedial hypothalamus stimulation (DMHS) and investigated the electrophysiological mechanisms underlying the anti-arrhythmic effects of MNS by recording left stellate ganglion activity (LSGA). Eighteen rabbits were anesthetized, the median nerve was anchored by stimulating electrodes, and a bipolar electrode was implanted into the LSG to record nerve activity. The DMH was stimulated to induce arrhythmia. All animals underwent six repetitions of DMHS (30 s). The 18 rabbits were divided into the following 3 groups: a control group, which underwent only DMHS (n = 6); an MNS group, which underwent MNS during both the third and fourth DMHS repetitions (n = 6); and an LSGA-recording group, for which LSGA was recorded at baseline, immediately following DMHS and again immediately following MNS and DMHS (n = 6). Repeated DMHS-induced multiple VAs, in the rabbits. Compared with the DMHS-only group, the concurrent administration of MNS during DMHS significantly reduced the incidence of VAs (7 ± 3 and 9 ± 2 beats for the third and fourth DMHS + MNS repetitions vs. 29 ± 8 and 27 ± 9 beats for the first two DMHS repetitions, p < 0.05). The total duration of the abnormal discharges of the LSG (ADLSG) following MNS and DMHS was significantly reduced compared with that of the DMHS-only group (40 ± 18 vs. 14 ± 6 s, p < 0.05). MNS reduced VAs induced by DMHS, which is thought to be mediated through suppressing of ADLSG. Median nerve electrical stimulation prevented ventricular arrhythmias induced by DMHS through the mechanism of suppressing abnormal discharges of left stellate ganglion.

  16. Stimulant Treatment Reduces Lapses in Attention among Children with ADHD

    PubMed Central

    Spencer, Sarah V.; Hawk, Larry W.; Richards, Jerry B.; Shiels, Keri; Pelham, William E.; Waxmonsky, James G.

    2009-01-01

    Recent research has suggested that intra-individual variability in reaction time (RT) distributions of children with ADHD is characterized by a particularly large rightward skew that may reflect lapses in attention. The purpose of the study was to provide the first randomized, placebo-controlled test of the effects of the stimulant methylphenidate (MPH) on this tail and other RT distribution characteristics. Participants were 49 9- to 12-year-old children with ADHD. Children participated in a 3-day double-blind, placebo-controlled medication assessment during which they received long-acting MPH (Concerta®), with the nearest equivalents of .3 and .6 mg/kg t.i.d. immediate-release MPH. Children completed a simple two-choice speeded discrimination task on and off of medication. Mode RT and deviation from the mode were used to examine the peak and skew, respectively, of RT distributions. MPH significantly reduced the peak and skew of RT distributions. Importantly, the two medication effects were uncorrelated suggesting that MPH works to improve both the speed and variability in responding. The improvement in variability with stimulant treatment is interpreted as a reduction in lapses in attention. This, in turn, may reflect stimulant enhancement of self-regulatory processes theorized to be at the core of ADHD. PMID:19291387

  17. Reducing muscle fatigue due to functional electrical stimulation using random modulation of stimulation parameters.

    PubMed

    Thrasher, Adam; Graham, Geoffrey M; Popovic, Milos R

    2005-06-01

    A major limitation of many functional electrical stimulation (FES) applications is that muscles tend to fatigue very rapidly. It was hypothesized that FES-induced muscle fatigue could be reduced by randomly modulating the pulse frequency, amplitude, and pulse width in a range of +/-15%. Seven subjects with spinal-cord injuries participated in this study. FES was applied to quadriceps and tibialis anterior muscles using surface electrodes. Isometric force was measured, and the time for the force to drop by 3 dB (fatigue time) was compared between trials. Four different modes of FES were applied in random order: constant stimulation, randomized frequency, randomized amplitude, and randomized pulse width. There was no significant difference between the fatigue-time measurements for the four modes of stimulation (P=0.329). Therefore, random modulation appeared to have no effect. Based on an observed correlation between maximum force measurements and trial order, we concluded that having 10-min rest periods between trials was insufficient.

  18. Laparoscopic Herniorrhaphy with Porcine Small Intestinal Submucosa: A Preliminary Study

    PubMed Central

    2002-01-01

    Introduction: Using mesh or a synthetic prosthesis during the laparoscopic repair of inguinal hernias has been demonstrated to be safe and effective. A new material, porcine small intestinal submucosa (SIS mesh), has been successfully used in canine and rodent animal models with excellent results. This mesh is degradable and resorbable with a marked decrease in the possibility of becoming infected. However, the amount of fibroblast ingrowth is equal to that with polypropylene mesh. Methods: A comparison was made between this new SIS mesh to repair 15 inguinal hernias in 12 patients and polypropylene mesh used in 12 similar patients. A preperitoneal approach with balloon dissection was used in all patients. Results: Demographics were similar in both groups. The results were excellent and compared equally. Complications (seroma, discomfort) were minimal in both groups and were similar. Conclusions: Porcine small intestinal submucosa, SIS mesh, can be used for laparoscopic repair of inguinal hernias. Long-term follow-up will be necessary to confirm these preliminary results. PMID:12166756

  19. Biochemical and biomechanical characterization of porcine small intestinal submucosa (SIS): a mini review

    PubMed Central

    Shi, Lei; Ronfard, Vincent

    2013-01-01

    Porcine small intestinal submucosa (SIS [Oasis®]) is an acellular, biological extracellular matrix (ECM) that has been found to significantly improve the healing of difficult-to-heal or chronic wounds in humans. Like dermal ECM, SIS contains collagen, elastin, glycosaminoglycans, proteoglycans, and growth factors that play important roles in healing. Preclinical studies have shown that numerous cell types attach to SIS, proliferate and migrate into the matrix, and differentiate. In addition, SIS can reduce the activity of matrix metalloproteinases (MMPs)—endogenous proteolytic enzymes whose levels and activities are increased in chronic wounds. Compared to the original single-layer SIS, multi-layer SIS has stronger mechanical properties and is more slowly degraded in wounds. Together, these SIS products provide flexibility in the selection of biologically-active ECMs that may be useful for the repair of diverse wound types. PMID:24273692

  20. Small intestinal submucosa as a graft to increase rectum diameter.

    PubMed

    Greca, Fernando Hintz; de Noronha, Lucia; Marcolini, Fayrus Rodrigo Nastally; Verona, Alessandro; Pereira, Ian Arantes; Bier, Rodrigo Shueda

    2013-08-01

    The purpose of our study was to assess the biocompatibility of the porcine small bowel submucosa and its ability to increase the rectal diameter compared with a formal transverse coloplasty. We assigned 36 New Zealand male rabbits to four experimental groups: groups C1 and C2 were treated with transverse coloplasty and groups S1 and S2 were treated with a patch of a porcine small intestine submucosa. We killed the animals in the C1 and S1 groups on the 7th postoperative day, and the animals in the C2 and S2 groups on the 30th postoperative day. We evaluated outcomes on the basis of animal survival, clinical course, anastomosis bursting pressures, morphometric examination, and histologic and immunohistochemical assessment. Morphometric examination showed a significant increase in colonic diameter in animals in the S2 group. We found no statistical difference regarding anastomosis bursting pressure between the C1 and S1 groups, and the C2 and S2 groups. On the 30th postoperative day, histologic examination showed total epithelium coverage of the grafts, and the immunohistochemical study showed an organized smooth muscular layer covering the graft. The higher concentration of collagen ticker fiber, type I, was seen in the S2 and C2 groups, but there was no statistical difference between them. The implanted graft proved superior to transverse coloplasty regarding the increase in distal colon diameter. Remarkable regeneration, marked fibroplasia, and epithelium coverage occurred throughout the graft on the 30th postoperative day. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Transcranial magnetic stimulation reduces nociceptive threshold in rats.

    PubMed

    Ambriz-Tututi, Mónica; Sánchez-González, Violeta; Drucker-Colín, René

    2012-05-01

    Transcranial magnetic stimulation (TMS) is a procedure that uses magnetic fields to stimulate or inhibit nerve cells in the brain noninvasively. TMS induces an electromagnetic current in the underlying cortical neurons. Varying frequencies and intensities of TMS increase or decrease excitability in the cortical area directly targeted. It has been suggested that TMS has potential in the treatment of some neurological disorders such as Parkinson's disease, stroke, and depression. Initial case reports and open label trials reported by several groups support the use of TMS in pain treatment. In the present study, we evaluated the effect of TMS on the nociceptive threshold in the rat. The parameters used were a frequency of 60 Hz and an intensity of 2 and 6 mT for 2 hr twice per day. After 5 days of TMS treatment, rats were evaluated for mechanical, chemical, and cold stimulation. We observed a significant reduction in the nociceptive threshold in TMS-treated rats but not in sham-treated rats in all behavioral tests evaluated. When TMS treatment was stopped, a slow recovery to normal mechanic threshold was observed. Interestingly, i.c.v. MK-801 or CNQX administration reverted the TMS-induced pronociception. The results suggest that high-frequency TMS can alter the nociceptive threshold and produce allodynia in the rats; results suggest the involvement of NMDA and AMPA/KA receptors on TMS-induced allodynia in the rat.

  2. [Dentification ability of inbred strain mice tooth germs homologically transplanted into oral submucosa].

    PubMed

    Li, Heng; Que, Guoying; Zhang, Lei

    2010-05-01

    To establish a suitable environment for the bioengineered teeth in vivo by observing the dentification ability of BALB/C mice tooth germs homologically implanted into the oral submucosa. The first molar tooth germs of BALB/C mice 4 days after birth were transplanted into the oral submucosa of BALB/C male mice, and then recycled for regular histological observation after 1, 2, 3, and 6 week transplantation. The tooth germs in the oral submucosa grew well with continuing developing enamelum and pulpodentinal complex, and the dentinal tubules were clear. The environment of the BALB/C male mice oral submucosa is favorable for the growth of tooth germs in inbred strain BALB/C mice, and it can provide a new environment for the development of bioengineered teeth in vivo.

  3. Efficacy and safety of small intestinal submucosa in dural defect repair in a canine model.

    PubMed

    He, Shu-Kun; Guo, Jin-Hai; Wang, Zhu-le; Zhang, Yi; Tu, Yun-Hu; Wu, Shi-Zhou; Huang, Fu-Guo; Xie, Hui-Qi

    2017-04-01

    Dural defects are a common problem, and inadequate dural closure can lead to complications. Several types of dural substitute materials have recently been discarded or modified owing to poor biocompatibility or mechanical properties and adverse reactions. The small intestinal submucosa (SIS) is a promising material used in a variety of applications. Based on the limitations of previous studies, we conducted an animal study to evaluate the efficacy and safety of the SIS in preclinical trials. Twenty-four male beagle dogs were subjected to surgical resection to produce dural defects. SIS or autologous dural mater was patched on the dural defect. Gross and histological evaluations were carried out to evaluate the efficacy and safety of the therapy. Our findings demonstrated that the SIS, which stimulated connective and epithelial tissue responses for dural regeneration and functional recovery without immunological rejection, could provide prolonged defect repair and prevent complications. The mechanical properties of the SIS could be adjusted by application of multiple layers, and the biocompatibility of the material was appropriate. Thus, our data suggested that this material may represent an alternative option for clinical treatment of dural defects.

  4. EGCG stimulates autophagy and reduces cytoplasmic HMGB1 levels in endotoxin-stimulated macrophages.

    PubMed

    Li, Wei; Zhu, Shu; Li, Jianhua; Assa, Andrei; Jundoria, Arvin; Xu, Jianying; Fan, Saijun; Eissa, N Tony; Tracey, Kevin J; Sama, Andrew E; Wang, Haichao

    2011-05-01

    Historically, consumption of Green tea (Camellia sinensis) has been associated with health benefits against multiple diseases including cancer, atherosclerosis and cardiovascular disorders. Emerging evidence has suggested a pathogenic role for HMGB1, a newly identified "late" mediator of lethal systemic inflammation, in the aforementioned diseases. Here we demonstrated that a major ingredient of Green tea, EGCG, was internalized into HMGB1-containing LC3-positive cytoplasmic vesicles (likely autophagosomes) in macrophages, and induced HMGB1 aggregation in a time-dependent manner. Furthermore, EGCG stimulated LC3-II production and autophagosome formation, and inhibited LPS-induced HMGB1 up-regulation and extracellular release. The EGCG-mediated HMGB1 inhibitory effects were diminished by inhibition of class III phosphatidylinositol-3 kinase (with 3-methyladenine) or knockdown of an essential autophagy-regulating protein, beclin-1. Moreover, the EGCG-mediated protection against lethal sepsis was partly impaired by co-administration of an autophagy inhibitor, chloroquine. Taken together, the present study has suggested a possibility that EGCG inhibits HMGB1 release by stimulating its autophagic degradation.

  5. Use of small intestine submucosa as ureteral allograft in pigs.

    PubMed

    Greca, Fernando H; Noronha, Lucia; Bendhack, Marcelo; Feres, André; Soccol, Andréa; Duda, João R

    2004-01-01

    The aim of the present study was to evaluate the biocompatibility of small intestine submucosa (SIS) in the reconstruction of the ureter in swine. An experimental study was performed in 10 half-breed pigs weighing between 20 and 30 K, in which a previously prepared segment of SIS measuring approximately 2.0 cm was implanted in the upper third part of the right ureter. Of the 10 operated animals, one died 14 days after the surgery due to a dehiscence on the suture line of the implanted graft. The remaining 9 animals were submitted to ultrasound examination of the urinary tract and were sacrificed on the 40th postoperative day. The macroscopic evaluation showed no calculus, incrustation, fistula, abscesses or adhesions in the ureters with the graft. Microscopic evaluation with hematoxylin-eosin and Sirius red showed in the experimental area (graft) the presence of urothelium in 100% of the cases, collagen in 100% of the cases, and smooth muscle layer in 87.5% of the animals. In the area adjacent to the graft (proximal and distal), we observed 92.86% of urothelium, 42.86% of collagen and 71.43% of smooth muscle. In the contralateral ureter, it was found 100% of urothelium and smooth muscle and just 11.11% of collagen. The microscopic analysis of the kidneys whose ureters received the graft of SIS evidenced congestion in 55.55%, pelvic edema in 66.66% and interstitial nephritis in 77.78%. Hydronephrosis was present in 33.33% and chronic pyelonephritis in 44%. Only 1 animal presented total absence of glomerulus in the renal parenchyma. The SIS graft behaved as a biological tissue support, allowing the regeneration of the urothelium and smooth muscle grow, despite of chronic inflammatory process.

  6. Spatially distributed sequential stimulation reduces fatigue in paralyzed triceps surae muscles: a case study.

    PubMed

    Nguyen, Robert; Masani, Kei; Micera, Silvestro; Morari, Manfred; Popovic, Milos R

    2011-12-01

    Functional electrical stimulation (FES) is limited by the rapid onset of muscle fatigue caused by localized nerve excitation repeatedly activating only a subset of motor units. The purpose of this study was to investigate reducing fatigue by sequentially changing, pulse by pulse, the area of stimulation using multiple surface electrodes that cover the same area as one electrode during conventional stimulation. Paralyzed triceps surae muscles of an individual with complete spinal cord injury were stimulated, via the tibial nerve, through four active electrodes using spatially distributed sequential stimulation (SDSS) that was delivered by sending a stimulation pulse to each electrode one after another with 90° phase shift between successive electrodes. For comparison, single electrode stimulation was delivered through one active electrode. For both modes of stimulation, the resultant frequency to the muscle as a whole was 40 Hz. Isometric ankle torque was measured during fatiguing stimulations lasting 2 min. Each mode of stimulation was delivered a total of six times over 12 separate days. Three fatigue measures were used for comparison: fatigue index (final torque normalized to maximum torque), fatigue time (time for torque to drop by 3 dB), and torque-time integral (over the entire trial). The measures were all higher during SDSS (P < 0.001), by 234, 280, and 171%, respectively. The results are an encouraging first step toward addressing muscle fatigue, which is one of the greatest problems for FES.

  7. Motor cortex stimulation reduces hyperalgesia in an animal model of central pain.

    PubMed

    Lucas, Jessica M; Ji, Yadong; Masri, Radi

    2011-06-01

    Electrical stimulation of the primary motor cortex has been used since 1991 to treat chronic neuropathic pain. Since its inception, motor cortex stimulation (MCS) treatment has had varied clinical outcomes. Until this point, there has not been a systematic study of the stimulation parameters that most effectively treat chronic pain, or of the mechanisms by which MCS relieves pain. Here, using a rodent model of central pain, we perform a systematic study of stimulation parameters used for MCS and investigate the mechanisms by which MCS reduces hyperalgesia. Specifically, we study the role of the inhibitory nucleus zona incerta (ZI) in mediating the analgesic effects of MCS. In animals with mechanical and thermal hyperalgesia, we find that stimulation at 50 μA, 50 Hz, and 300 μs square pulses for 30 minutes is sufficient to reverse mechanical and thermal hyperalgesia. We also find that stimulation of the ZI mimics the effects of MCS and that reversible inactivation of ZI blocks the effects of MCS. These findings suggest that the reduction of hyperalgesia may be due to MCS effects on ZI. In an animal model of central pain syndrome, motor cortex stimulation reduces hyperalgesia by activating zona incerta and therefore restoring inhibition in the thalamus.

  8. Influence of mesenchymal stem cells on stomach tissue engineering using small intestinal submucosa.

    PubMed

    Nakatsu, Hiroki; Ueno, Tomio; Oga, Atsunori; Nakao, Mitsuhiro; Nishimura, Taku; Kobayashi, Sei; Oka, Masaaki

    2015-03-01

    Small intestinal submucosa (SIS) is a biodegradable collagen-rich matrix containing functional growth factors. We have previously reported encouraging outcomes for regeneration of an artificial defect in the rodent stomach using SIS grafts, although the muscular layer was diminutive. In this study, we investigated the feasibility of SIS in conjunction with mesenchymal stem cells (MSCs) for regeneration of the gastrointestinal tract. MSCs from the bone marrow of green fluorescence protein (GFP)-transgenic Sprague-Dawley (SD) rats were isolated and expanded ex vivo. A 1 cm whole-layer stomach defect in SD rats was repaired using: a plain SIS graft without MSCs (group 1, control); a plain SIS graft followed by intravenous injection of MSCs (group 2); a SIS graft co-cultured with MSCs (group 3); or a SIS sandwich containing an MSC sheet (group 4). Pharmacological, electrophysiological and immunohistochemical examination was performed to evaluate the regenerated stomach tissue. Contractility in response to a muscarinic receptor agonist, a nitric oxide precursor or electrical field stimulation was observed in all groups. SIS grafts seeded with MSCs (groups 3 and 4) appeared to support improved regeneration compared with SIS grafts not seeded with MSCs (groups 1 and 2), by enabling the development of well-structured smooth muscle layers of significantly increased length. GFP expression was detected in the regenerated interstitial tissue, with fibroblast-like cells in the seeded-SIS groups. SIS potently induced pharmacological and electrophysiological regeneration of the digestive tract, and seeded MSCs provided an enriched environment that supported tissue regeneration by the SIS graft in the engineered stomach. © 2013 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd.

  9. Simultaneous osseous metaplasia nodules of the submucosa and mesosalpinx after first trimester abortion: a case report.

    PubMed

    Feng, Zhou; Jiale, Qin; Xiaofei, Zhang; Qingyun, Guo; Lili, Huang

    2013-11-19

    Here, we report a case of simultaneous osseous metaplasia nodules of the submucosa and mesosalpinx after a first trimester abortion. A 36-year-old woman presented to the Women's Hospital, School of Medicine, Zhejiang University with vaginal bleeding and infertility resulting from osseous metaplasia nodules of the submucosa and mesosalpinx after a first trimester abortion. Diagnostic and operative hysteroscopy and laparoscope procedures were performed. The osseous metaplasia nodules disappeared after hysteroscopy and laparoscope interventions; 2 weeks postoperatively, the patient underwent a transvaginal ultrasound examination and the abnormal ultrasound appearance had resolved. Osseous metaplasia nodules in the submucosa and mesosalpinx can be a rare cause of vaginal bleeding and infertility. Autologous tissue, not persistent heterologous tissue, may be the true reason for metaplasia. Treatment is by ultrasound-guided curettage or by hysteroscopic and laparoscope removal.

  10. Simultaneous osseous metaplasia nodules of the submucosa and mesosalpinx after first trimester abortion: a case report

    PubMed Central

    2013-01-01

    Objectives Here, we report a case of simultaneous osseous metaplasia nodules of the submucosa and mesosalpinx after a first trimester abortion. Case presentation A 36-year-old woman presented to the Women’s Hospital, School of Medicine, Zhejiang University with vaginal bleeding and infertility resulting from osseous metaplasia nodules of the submucosa and mesosalpinx after a first trimester abortion. Diagnostic and operative hysteroscopy and laparoscope procedures were performed. The osseous metaplasia nodules disappeared after hysteroscopy and laparoscope interventions; 2 weeks postoperatively, the patient underwent a transvaginal ultrasound examination and the abnormal ultrasound appearance had resolved. Conclusions Osseous metaplasia nodules in the submucosa and mesosalpinx can be a rare cause of vaginal bleeding and infertility. Autologous tissue, not persistent heterologous tissue, may be the true reason for metaplasia. Treatment is by ultrasound-guided curettage or by hysteroscopic and laparoscope removal. PMID:24245923

  11. Reduced discomfort during high-definition transcutaneous stimulation using 6% benzocaine.

    PubMed

    Guleyupoglu, Berkan; Febles, Nicole; Minhas, Preet; Hahn, Christoph; Bikson, Marom

    2014-01-01

    High-Definition transcranial Direct Current Stimulation (HD-tDCS) allows for non-invasive neuromodulation using an array of compact (approximately 1 cm(2) contact area) "High-Definition" (HD) electrodes, as compared to conventional tDCS (which uses two large pads that are approximately 35 cm(2)). In a previous transcutaneous study, we developed and validated designs for HD electrodes that reduce discomfort over >20 min session with 2 mA electrode current. The purpose of this study was to investigate the use of a chemical pretreatment with 6% benzocaine (topical numbing agent) to further reduce subjective discomfort during transcutaneous stimulation and to allow for better sham controlled studies. Pre-treatment with 6% benzocaine was compared with control (no pretreatment) for 22 min 2 mA of stimulation, with either CCNY-4 or Lectron II electroconductive gel, for both cathodal and anodal transcutaneous (forearm) stimulation (eight different combinations). RESULTS show that for all conditions and polarities tested, stimulation with HD electrodes is safe and well tolerated and that pretreatment further reduced subjective discomfort. Pretreatment with a mild analgesic reduces discomfort during HD-tDCS.

  12. Subthreshold electrical stimulation reduces motor unit discharge variability and decreases the force fluctuations of plantar flexion.

    PubMed

    Kouzaki, Motoki; Kimura, Tetsuya; Yoshitake, Yasuhide; Hayashi, Tatsuya; Moritani, Toshio

    2012-04-04

    The purpose of this study was to examine the influence of subthreshold electrical stimulation on the force fluctuations and motor-unit discharge variability during low-level, steady contraction of the plantar flexor muscles. Seven subjects performed a force-matching task of isometric plantar flexion at 5% of maximal voluntary contraction with and without random electrical stimulation applied to the tibial nerve. During the task, the motor unit action potential was continuously recorded with fine-wire electrodes, and the inter-spike intervals of a single motor unit were calculated. The coefficient of variation (CV) of the force fluctuations and the inter-spike intervals of the motor unit discharge were significantly decreased by the intervention of subthreshold electrical stimulation, although there were no changes in the mean values. These results suggest that subthreshold stimulation reduced the motor-unit discharge variability, which in turn, increased the steadiness of the force.

  13. Adding simultaneous stimulating channels to reduce power consumption in cochlear implants.

    PubMed

    Langner, Florian; Saoji, Aniket A; Büchner, Andreas; Nogueira, Waldo

    2017-03-01

    Sound coding strategies for Cochlear Implant (CI) listeners can be used to control the trade-off between speech performance and power consumption. Most commercial CI strategies use non-simultaneous channel stimulation, stimulating only one electrode at a time. One could add parallel simultaneous stimulating channels such that the electrical interaction between channels is increased. This would produce spectral smearing, because the electrical fields of the simultaneous stimulated channels interact, but also power savings. The parallel channels produce a louder sensation than sequential stimulation. To test this hypothesis we implemented different sound coding strategies using a research interface from Advanced Bionics: the commercial F120 strategy using sequential channel stimulation (one channel equals two electrodes with current steering) and the Paired strategy, consisting of simultaneous stimulation with two channels. Here, the electrical field of both channels will interact, requiring less current on each channel to perceive the same loudness as with F120. However, channel interaction between the independent channels may reduce speech recognition or understanding. This can be diminished by adding an inverse-polarity stimulation channel between both channels. This strategy is termed Paired with Flanks. Additionally, Triplet with three channels and an adjacent Flank style was investigated. For each strategy we measured speech intelligibility with the Hochmair-Schulz-Moser sentence test. Spectral resolution was assessed using a spectral modulation depth detection task. Results show that Paired without Flanks obtains similar performance while reducing the current by 20% on average compared to F120. Triplet with and without Flanks shows overall poorer performance when compared to F120. All strategies inhibit the option to increase the pulse width which would result in even further decreased power consumption.

  14. Frontal Cortex Stimulation Reduces Vigilance to Threat: Implications for the Treatment of Depression and Anxiety.

    PubMed

    Ironside, Maria; O'Shea, Jacinta; Cowen, Philip J; Harmer, Catherine J

    2016-05-15

    The difficulty in treating mood disorders has brought about clinical interest in alternative treatments, such as transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). However, the optimal parameters for stimulation and underlying mechanisms of action are unclear. Psychiatric treatments have acute effects on emotional processing that predict later therapeutic action. Such effects have been proposed as cognitive biomarkers for screening novel treatments for depression and anxiety. This study assessed the effect of tDCS on a battery of emotional processing measures sensitive to antidepressant action. To refine optimal stimulation parameters, DLPFC stimulation using two common electrode montages was compared with sham. Sixty healthy volunteers received 20 minutes of active or sham DLPFC stimulation before completing computerized emotional processing tasks, including a dot-probe measure of vigilance to threat. Relative to sham stimulation, participants receiving simultaneous anodal stimulation of left DLPFC and cathodal stimulation of right DLPFC (bipolar-balanced montage) showed reduced vigilance to threatening stimuli. There was no such significant effect when the cathode was placed on the supraorbital ridge (bipolar-unbalanced montage). There were no effects of tDCS on other measures of emotional processing. Our findings provide the first experimental evidence that modulating activity in the DLPFC reduces vigilance to threatening stimuli. This significant reduction in fear vigilance is similar to that seen with anxiolytic treatments in the same cognitive paradigm. The finding that DLPFC tDCS acutely alters the processing of threatening information suggests a potential cognitive mechanism that could underwrite treatment effects in clinical populations. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  15. Vagus Nerve Stimulation Reduces Cocaine Seeking and Alters Plasticity in the Extinction Network

    ERIC Educational Resources Information Center

    Childs, Jessica E.; DeLeon, Jaime; Nickel, Emily; Kroener, Sven

    2017-01-01

    Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic…

  16. Vagus Nerve Stimulation Reduces Cocaine Seeking and Alters Plasticity in the Extinction Network

    ERIC Educational Resources Information Center

    Childs, Jessica E.; DeLeon, Jaime; Nickel, Emily; Kroener, Sven

    2017-01-01

    Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic…

  17. Reducing aggressive responses to social exclusion using transcranial direct current stimulation.

    PubMed

    Riva, Paolo; Romero Lauro, Leonor J; DeWall, C Nathan; Chester, David S; Bushman, Brad J

    2015-03-01

    A vast body of research showed that social exclusion can trigger aggression. However, the neural mechanisms involved in regulating aggressive responses to social exclusion are still largely unknown. Transcranial direct current stimulation (tDCS) modulates the excitability of a target region. Building on studies suggesting that activity in the right ventrolateral pre-frontal cortex (rVLPFC) might aid the regulation or inhibition of social exclusion-related distress, we hypothesized that non-invasive brain polarization through tDCS over the rVLPFC would reduce behavioral aggression following social exclusion. Participants were socially excluded or included while they received tDCS or sham stimulation to the rVLPFC. Next, they received an opportunity to aggress. Excluded participants demonstrated cognitive awareness of their inclusionary status, yet tDCS (but not sham stimulation) reduced their behavioral aggression. Excluded participants who received tDCS stimulation were no more aggressive than included participants. tDCS stimulation did not influence socially included participants' aggression. Our findings provide the first causal test for the role of rVLPFC in modulating aggressive responses to social exclusion. Our findings suggest that modulating activity in a brain area (i.e. the rVLPFC) implicated in self-control and emotion regulation can break the link between social exclusion and aggression.

  18. Interphase gap as a means to reduce electrical stimulation thresholds for epiretinal prostheses

    NASA Astrophysics Data System (ADS)

    Weitz, Andrew C.; Behrend, Matthew R.; Ahuja, Ashish K.; Christopher, Punita; Wei, Jianing; Wuyyuru, Varalakshmi; Patel, Uday; Greenberg, Robert J.; Humayun, Mark S.; Chow, Robert H.; Weiland, James D.

    2014-02-01

    Objective. Epiretinal prostheses are designed to restore functional vision to the blind by electrically stimulating surviving retinal neurons. These devices have classically employed symmetric biphasic current pulses in order to maintain a balance of charge. Prior electrophysiological and psychophysical studies in peripheral nerve show that adding an interphase gap (IPG) between the two phases makes stimulation more efficient than pulses with no gap. This led us to investigate the effect of IPG duration on retinal stimulation thresholds. Approach. We measured retinal ganglion cell (RGC) electrical thresholds in salamander retina and phosphene perceptual thresholds in epiretinal prosthesis patients during stimulation with different IPG lengths. We also built Hodgkin-Huxley-type models of RGCs to further study how IPG affects thresholds. Main results. In general, there was a negative exponential correlation between threshold and IPG duration. Durations greater than or equal to ˜0.5 ms reduced salamander RGC thresholds by 20-25%. Psychophysical testing in five retinal prosthesis patients indicated that stimulating with IPGs can decrease perceptual thresholds by 10-15%. Results from computational models of RGCs corroborated the observed behavior. Significance. Incorporating interphase gaps can reduce the power consumption of epiretinal prostheses and increase the available dynamic range of phosphene size and brightness.

  19. Reducing aggressive responses to social exclusion using transcranial direct current stimulation

    PubMed Central

    Romero Lauro, Leonor J.; DeWall, C. Nathan; Chester, David S.; Bushman, Brad J.

    2015-01-01

    A vast body of research showed that social exclusion can trigger aggression. However, the neural mechanisms involved in regulating aggressive responses to social exclusion are still largely unknown. Transcranial direct current stimulation (tDCS) modulates the excitability of a target region. Building on studies suggesting that activity in the right ventrolateral pre-frontal cortex (rVLPFC) might aid the regulation or inhibition of social exclusion-related distress, we hypothesized that non-invasive brain polarization through tDCS over the rVLPFC would reduce behavioral aggression following social exclusion. Participants were socially excluded or included while they received tDCS or sham stimulation to the rVLPFC. Next, they received an opportunity to aggress. Excluded participants demonstrated cognitive awareness of their inclusionary status, yet tDCS (but not sham stimulation) reduced their behavioral aggression. Excluded participants who received tDCS stimulation were no more aggressive than included participants. tDCS stimulation did not influence socially included participants’ aggression. Our findings provide the first causal test for the role of rVLPFC in modulating aggressive responses to social exclusion. Our findings suggest that modulating activity in a brain area (i.e. the rVLPFC) implicated in self-control and emotion regulation can break the link between social exclusion and aggression. PMID:24748546

  20. Bronchoscopic findings of extramural lung cancer invading the subepithelium or submucosa.

    PubMed

    Gemma, A; Takenaka, K; Andou, M; Yamada, K; Hasegawa, K; Tachibana, M; Iwanami, H; Sakonji, M; Tsuboi, E; Kudoh, S

    1995-03-01

    Bronchoscopic findings from the main to segmental bronchi were compared with the histopathological findings in 185 resected cases of lung cancer, in order to determine which bronchoscopic features are associated with lung cancer invading the subepithelium or submucosa from beyond the bronchial wall. Carcinoma invaded the subepithelium or submucosa from beyond the bronchial wall in 43 cases (22.9%) out of the total of 185 cases. Bronchoscopic findings were evaluated in these 43 cases, and were summarized as follows: (1) The bronchoscopic findings in cases of subepithelial invasion consisted of vascular engorgement, bleeding, subepithelial tumor, and emphasized longitudinal relief; (2) irregularity of the mucosa was observed in cases of epithelial or muscular invasion; (3) indistinct bronchial cartilage was observed in cases of invasion proximal to the extramuscular layer; (4) accentuated irregular folds were observed in cases of invasion of the extramuscular or cartilage layers; and (5) edema and redness were not specific for malignancy. In addition, the occurrence of mediastinal lymph node metastasis was higher in cases of invasion to main or lobar bronchi. This result indicates that recognition of invasion of the subepithelium or submucosa of the central bronchus may be helpful in indicating the probability of mediastinal lymph node metastasis. Accordingly, there may be specific bronchoscopic findings which correlate with invasion of the bronchial subepithelium or submucosa. Accurate recognition of these findings may be useful in determining appropriate biopsy sites and may provide more information concerning selection of therapeutic strategy.

  1. A case of gastric lipoma resected by endoscopic submucosa dissection with difficulty in preoperative diagnosis.

    PubMed

    Ichinose, Mizue; Hikichi, Takuto; Kanno, Yukiko; Gunji, Naohiko; Fujita, Masashi; Kuroda, Masahito; Terashima, Kumiko; Sato, Yoshinori; Kawana, Satoshi; Hashimoto, Yuko; Ohira, Hiromasa; Miyata, Masayuki

    2017-09-14

    A 66-year-old man was referred to our hospital with an increasing subepithelial lesion in the gastric antrum. Using esophagogastroduodenoscopy, a tumor with a steep, 20-mm-high rise protruding in the lumen was observed. The mucosal surface of the tumor was reddish, with ulcers forming at the base. Moreover, the tumor was mobile and soft. A biopsy specimen was taken from the ulcer, but tumor tissue was not collected from the submucosa. Endoscopic ultrasonography (EUS) showed a high echoic mass in the submucosa. However, because the mucosal surface of the ulceration was red, the mesenchymal tumor with internal bleeding was inferred to be lipoma. Additionally, because the tumor was small, flexible, and soft, collecting tumor tissue under EUS-guided fine-needle aspiration was inferred as difficult. We were unable to make a final diagnosis because the lesion showed a small tumor with atypical macroscopic morphology. Therefore, endoscopic submucosa dissection (ESD) was chosen for the diagnostic treatment. Sodium hyaluronate sufficient for separation from the muscular layer was injected into the submucosa. Then submucosal dissection was performed just above the muscle layer. Results demonstrate the possibility of removing the tumor reliably without perforation. Pathological evaluation of the ESD specimen indicated a diagnosis of gastric lipoma.

  2. Characterization of human normal and cancerous gastric submucosa based on multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Zhong, Jiazhao; Chen, G.; Liu, Y. C.; Zhuo, S. M.; Chen, J. X.; Yan, J.

    2012-03-01

    Gastric cancer is one of the most frequent cancers in the world; almost two-thirds of gastric cancer cases and deaths occur in less developed regions. The initial diagnosis of gastric cancer often is delayed because up to 80 percent of patients are asymptomatic during the early stages of stomach cancer. So the ability to perform real-time in vivo histological diagnosis for early gastric cancer at the cellular level during ongoing endoscopy is a long-standing goal of endoscopists. In this paper, using multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG), MPM images of human normal and cancerous gastric submucosa were obtained at excitation wavelength of 800 nm. The features such as the appearance of abnormal cells and the large loss of collagen in cancerous gastric submucosa were extracted to be as significant indicators to distinguish cancerous submucosa from normal submucosa. With the implementation of multiphoton microscopy concept in endoscopy applications, multiphoton endoscopy might realize in vivo histological diagnosis goal of endoscopists.

  3. Characterization of human normal and cancerous gastric submucosa based on multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Zhong, Jiazhao; Chen, G.; Liu, Y. C.; Zhuo, S. M.; Chen, J. X.; Yan, J.

    2011-11-01

    Gastric cancer is one of the most frequent cancers in the world; almost two-thirds of gastric cancer cases and deaths occur in less developed regions. The initial diagnosis of gastric cancer often is delayed because up to 80 percent of patients are asymptomatic during the early stages of stomach cancer. So the ability to perform real-time in vivo histological diagnosis for early gastric cancer at the cellular level during ongoing endoscopy is a long-standing goal of endoscopists. In this paper, using multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG), MPM images of human normal and cancerous gastric submucosa were obtained at excitation wavelength of 800 nm. The features such as the appearance of abnormal cells and the large loss of collagen in cancerous gastric submucosa were extracted to be as significant indicators to distinguish cancerous submucosa from normal submucosa. With the implementation of multiphoton microscopy concept in endoscopy applications, multiphoton endoscopy might realize in vivo histological diagnosis goal of endoscopists.

  4. Ablation of the sphenopalatine ganglion does not attenuate the infarct reducing effect of vagus nerve stimulation

    PubMed Central

    Ay, Ilknur; Ay, Hakan

    2013-01-01

    Electrical stimulation of the cervical vagus nerve reduces infarct size by approximately 50% after cerebral ischemia in rats. The mechanism of ischemic protection by vagus nerve stimulation (VNS) is not known. In this study, we investigated whether the infarct reducing effect of VNS was mediated by activation of the parasympathetic vasodilator fibers that originate from the sphenopalatine ganglion (SPG) and innervate the anterior cerebral circulation. We examined the effects of electrical stimulation of the cervical vagus nerve in two groups of rats: one with and one without SPG ablation. Electrical stimulation was initiated 30 min after induction of ischemia, and lasted for 1h. Measurement of infarct size 24h later revealed that the volume of ischemic damage was smaller in those animals that received VNS treatment (41.32 ± 2.07% vs. 24.19 ± 2.62% of the contralateral hemispheric volume, n=6 in both; p<0.05). SPG ablation did not abolish this effect; the reduction in infarct volume following VNS was 58% in SPG-damaged animals, 41% in SPG-intact animals (p>0.05). In both SPG-intact and SPG-damaged animals VNS treatment resulted in better motor outcome (p<0.05 vs. corresponding controls for both). Our findings show that VNS can protect the brain against acute ischemic injury, and that this effect is not mediated by SPG projections. PMID:23273773

  5. Composite elastomeric polyurethane scaffolds incorporating small intestinal submucosa for soft tissue engineering.

    PubMed

    Da, Lincui; Gong, Mei; Chen, Anjing; Zhang, Yi; Huang, Yizhou; Guo, Zhijun; Li, Shengfu; Li-Ling, Jesse; Zhang, Li; Xie, Huiqi

    2017-09-01

    Although soft tissue replacement has been clinically successful in many cases, the corresponding procedure has many limitations including the lack of resilience and mechanical integrity, significant donor-site morbidity, volume loss with time, and fibrous capsular contracture. These disadvantages can be alleviated by utilizing bio-absorbable scaffolds with high resilience and large strain, which are capable of stimulating natural tissue regeneration. Hence, the chemically crosslinked tridimensional scaffolds obtained by incorporating water-based polyurethane (PU) (which was synthesized from polytetramethylene ether glycol, isophorone diisocyanate, and 2,2-bis(hydroxymethyl) butyric acid) into a bioactive extracellular matrix consisting of small intestinal submucosa (SIS) have been tested in this study to develop a new approach for soft tissue engineering. After characterizing the structure and properties of the produced PU/SIS composites, the strength, Young's modulus, and resilience of wet PU/SIS samples were compared with those of crosslinked PU. In addition, the fabricated specimens were investigated using human umbilical vein endothelial cells to evaluate their ability to enhance cell attachment and proliferation. As a result, the synthesized PU/SIS samples exhibited high resilience and were capable of enhancing cell viability with no evidence of cytotoxicity. Subcutaneous implantation in animals and the subsequent testing conducted after 2, 4, and 8weeks indicated that sound implant integration and vascularization occurred inside the PU/SIS composites, while the presence of SIS promoted cell infiltration, angiogenesis, and ultimately tissue regeneration. The obtained results revealed that the produced PU/SIS composites were characterized by high bioactivity and resilience, and, therefore, could be used for soft tissue engineering applications. Hybrid composites containing synthetic polymers with high mechanical strength and naturally derived components, which

  6. Hypothalamic paraventricular nucleus stimulation reduces intestinal injury in rats with ulcerative colitis

    PubMed Central

    Deng, Quan-Jun; Deng, Ding-Jing; Che, Jin; Zhao, Hai-Rong; Yu, Jun-Jie; Lu, Yong-Yu

    2016-01-01

    AIM: To investigate the effect and mechanism of stimulation of the hypothalamic paraventricular nucleus with glutamate acid in rats with ulcerative colitis (UC). METHODS: The rats were anesthetized with 10% chloral hydrate via abdominal injection and treated with an equal volume of TNBS + 50% ethanol enema, injected into the upper section of the anus with the tail facing up. Colonic damage scores were calculated after injecting a certain dose of glutamic acid into the paraventricular nucleus (PVN), and the effect of the nucleus tractus solitarius (NTS) and vagus nerve in alleviating UC injury through chemical stimulation of the PVN was observed in rats. Expression changes of C-myc, Apaf-1, caspase-3, interleukin (IL)-6, and IL-17 during the protection against UC injury through chemical stimulation of the PVN in rats were detected by Western blot. Malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in colon tissues of rats were measured by colorimetric methods. RESULTS: Chemical stimulation of the PVN significantly reduced UC in rats in a dose-dependent manner. The protective effects of the chemical stimulation of the PVN on rats with UC were eliminated after chemical damage to the PVN. After glutamate receptor antagonist kynurenic acid was injected into the PVN, the protective effects of the chemical stimulation of the PVN were eliminated in rats with UC. After AVP-Vl receptor antagonist ([Deamino-penl, val4, D-Arg8]-vasopressin) was injected into NTS or bilateral chemical damage to NTS, the protective effect of the chemical stimulation of PVN on UC was also eliminated. After chemical stimulation of the PVN, SOD activity increased, MDA content decreased, C-myc protein expression significantly increased, caspase-3 and Apaf-1 protein expression significantly decreased, and IL-6 and IL-17 expression decreased in colon tissues in rats with UC. CONCLUSION: Chemical stimulation of the hypothalamic PVN provides a protective effect against UC injury in

  7. Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation

    PubMed Central

    Birdno, Merrill J.; Kuncel, Alexis M.; Dorval, Alan D.; Turner, Dennis A.; Gross, Robert E.

    2012-01-01

    Deep brain stimulation (DBS) provides dramatic tremor relief when delivered at high-stimulation frequencies (more than ∼100 Hz), but its mechanisms of action are not well-understood. Previous studies indicate that high-frequency stimulation is less effective when the stimulation train is temporally irregular. The purpose of this study was to determine the specific characteristics of temporally irregular stimulus trains that reduce their effectiveness: long pauses, bursts, or irregularity per se. We isolated these characteristics in stimulus trains and conducted intraoperative measurements of postural tremor in eight volunteers. Tremor varied significantly across stimulus conditions (P < 0.015), and stimulus trains with pauses were significantly less effective than stimulus trains without (P < 0.002). There were no significant differences in tremor between trains with or without bursts or between trains that were irregular or periodic. Thus the decreased effectiveness of temporally irregular DBS trains is due to long pauses in the stimulus trains, not the degree of temporal irregularity alone. We also conducted computer simulations of neuronal responses to the experimental stimulus trains using a biophysical model of the thalamic network. Trains that suppressed tremor in volunteers also suppressed fluctuations in thalamic transmembrane potential at the frequency associated with cerebellar burst-driver inputs. Clinical and computational findings indicate that DBS suppresses tremor by masking burst-driver inputs to the thalamus and that pauses in stimulation prevent such masking. Although stimulation of other anatomic targets may provide tremor suppression, we propose that the most relevant neuronal targets for effective tremor suppression are the afferent cerebellar fibers that terminate in the thalamus. PMID:21994263

  8. Fiber Tract Stimulation Can Reduce Epileptiform Activity in an in-vitro Bilateral Hippocampal Slice Preparation

    PubMed Central

    Toprani, Sheela; Durand, Dominique

    2012-01-01

    Mesial temporal lobe epilepsy (MTLE) is a common medically refractory neurological disease that has been treated with electrical stimulation of gray matter with limited success. However, stimulation of a white matter tract connecting the hippocampi could maximize treatment efficacy and extent. We tested low-frequency stimulation (LFS) of a novel target that enables simultaneous targeting of bilateral hippocampi: the ventral hippocampal commissure (VHC) with a novel in-vitro slice preparation containing bilateral hippocampi connected by the VHC. The goal of this study is to understand the role of hippocampal interplay in seizure propagation and reduction by commissural fiber tract stimulation. LFS is applied to the VHC as extracellular and intracellular recording techniques are combined with signal processing to estimate several metrics of epilepsy including: (1) total time occupied by seizure activity (%); (2) seizure duration (s); (3) seizures per minute (#); and (4) power in the ictal (V2Hz−1); as well as (5) interictal spectra (V2Hz−1). Bilateral epileptiform activity in this preparation is highly correlated between hippocampi. Application of LFS to the VHC reduces all metrics of epilepsy during treatment in an amplitude and frequency dependent manner. This study lends several insights into the mechanisms of bilateral seizure reduction by LFS of the VHC, including that depolarization blocking, LTD/LTP and GABAA are not involved. Importantly, enhanced post-stimulation 1-Hz spiking correlates with long-lasting seizure reduction and both are heightened by targeting bilateral hippocampi via the VHC. Therefore, stimulating bilateral hippocampi via a single electrode in the VHC may provide an effective MTLE treatment. PMID:23123405

  9. Interphase gap as a means to reduce electrical stimulation thresholds for epiretinal prostheses

    PubMed Central

    Weitz, Andrew C; Behrend, Matthew R; Ahuja, Ashish K; Christopher, Punita; Wei, Jianing; Wuyyuru, Varalakshmi; Patel, Uday; Greenberg, Robert J; Humayun, Mark S; Chow, Robert H; Weiland, James D

    2014-01-01

    Epiretinal prostheses are designed to restore functional vision to the blind by electrically stimulating surviving retinal neurons. These devices have classically employed symmetric biphasic current pulses in order to maintain a balance of charge. Prior electrophysiological and psychophysical studies in peripheral nerve show that adding an interphase gap (IPG) between the two phases makes stimulation more efficient than pulses with no gap. We investigated the effect of IPG duration on retinal ganglion cell (RGC) electrical thresholds in salamander retina, as well as phosphene perceptual thresholds in epiretinal prosthesis patients. In general, there was a negative exponential correlation between threshold and IPG duration. Durations greater than or equal to ~0.5 ms reduced salamander RGC thresholds by 20–25%. Psychophysical testing in five retinal prosthesis patients indicated that stimulating with IPGs can decrease phosphene perceptual thresholds by 10–15%. Results from Hodgkin-Huxley-type simulations of RGC behavior corroborated the observed behavior. Incorporating interphase gaps can reduce the power consumption of epiretinal prostheses and increase the available dynamic range of phosphene size and brightness. PMID:24654269

  10. High-Frequency Repetitive Transcranial Magnetic Stimulation Reduces Pain in Postherpetic Neuralgia.

    PubMed

    Ma, Shu-Min; Ni, Jia-Xiang; Li, Xuan-Ying; Yang, Li-Qiang; Guo, Yu-Na; Tang, Yuan-Zhang

    2015-11-01

    Postherpetic neuralgia (PHN) is one of the most intractable pain disorders, especially in elderly patients. There is evidence that repetitive transcranial magnetic stimulation (rTMS) reduces neuropathic pain; however, its effectiveness for PHN is unknown. This study investigated the efficacy of high-frequency rTMS in patients with PHN. A total of 40 patients were randomly assigned to receive 10 sessions of real or sham rTMS of the primary motor cortex. Each stimulation session consisted of a series of 300 five-second pulses with a frequency of 10 Hz and an interval of 3 seconds between each train, giving a total of 1500 pulses per session. The primary outcome was pain intensity measured before stimulation from first intervention (T0) to the final stimulation (T10), and 1 and 3 months after final stimulation (T11 and T12). Other outcomes measured included scores on the short form McGill pain questionnaire, self-rating depression scale, quality of life (QOL), sleep quality, the patient global impression of change, medication regulation, and reported adverse events. The real rTMS group demonstrated greater reduction of visual analogue scale (VAS) than the sham group at each time point except for T0 (P = 0.399) and T1 (P = 0.091). Mean VAS reduction in the real rTMS group was 16.89% for duration of disease longer than 6 months. These analgesic effects were associated with long-term improvement in rating-scale items related to QOL. The results suggest that rTMS is an effective and safe therapy in patients with PHN. Wiley Periodicals, Inc.

  11. Pedophilia is linked to reduced activation in hypothalamus and lateral prefrontal cortex during visual erotic stimulation.

    PubMed

    Walter, Martin; Witzel, Joachim; Wiebking, Christine; Gubka, Udo; Rotte, Michael; Schiltz, Kolja; Bermpohl, Felix; Tempelmann, Claus; Bogerts, Bernhard; Heinze, Hans Jochen; Northoff, Georg

    2007-09-15

    Although pedophilia is of high public concern, little is known about underlying neural mechanisms. Although pedophilic patients are sexually attracted to prepubescent children, they show no sexual interest toward adults. This study aimed to investigate the neural correlates of deficits of sexual and emotional arousal in pedophiles. Thirteen pedophilic patients and 14 healthy control subjects were tested for differential neural activity during visual stimulation with emotional and erotic pictures with functional magnetic resonance imaging. Regions showing differential activations during the erotic condition comprised the hypothalamus, the periaqueductal gray, and dorsolateral prefrontal cortex, the latter correlating with a clinical measure. Alterations of emotional processing concerned the amygdala-hippocampus and dorsomedial prefrontal cortex. Hypothesized regions relevant for processing of erotic stimuli in healthy individuals showed reduced activations during visual erotic stimulation in pedophilic patients. This suggests an impaired recruitment of key structures that might contribute to an altered sexual interest of these patients toward adults.

  12. Adipose tissue-derived stem cell-seeded small intestinal submucosa for tunica albuginea grafting and reconstruction.

    PubMed

    Ma, Limin; Yang, Yijun; Sikka, Suresh C; Kadowitz, Philip J; Ignarro, Louis J; Abdel-Mageed, Asim B; Hellstrom, Wayne J G

    2012-02-07

    Porcine small intestinal submucosa (SIS) has been widely used in tunica albuginea (TA) reconstructive surgery. Adipose tissue-derived stem cells (ADSCs) can repair damaged tissue, augment cellular differentiation, and stimulate release of multiple growth factors. The aim of this rat study was to assess the feasibility of seeding ADSCs onto SIS grafts for TA reconstruction. Here, we demonstrate that seeding syngeneic ADSCs onto SIS grafts (SIS-ADSC) resulted in significant cavernosal tissue preservation and maintained erectile responses, similar to controls, in a rat model of bilateral incision of TA, compared with sham-operated animals and rats grafted with SIS graft (SIS) alone. In addition to increased TGF-β1 and FGF-2 expression levels, cross-sectional studies of the rat penis with SIS and SIS-ADSC revealed mild to moderate fibrosis and an increase of 30% and 40% in mean diameter in flaccid and erectile states, respectively. SIS grafting induced transcriptional up-regulation of iNOS and down-regulation of endothelial NOS, neuronal NOS, and VEGF, an effect that was restored by seeding ADCSs on the SIS graft. Taken together, these data show that rats undergoing TA incision with autologous SIS-ADSC grafts maintained better erectile function compared with animals grafted with SIS alone. This study suggests that SIS-ADSC grafting can be successfully used for TA reconstruction procedures and can restore erectile function.

  13. Adipose tissue-derived stem cell-seeded small intestinal submucosa for tunica albuginea grafting and reconstruction

    PubMed Central

    Ma, Limin; Yang, Yijun; Sikka, Suresh C.; Kadowitz, Philip J.; Ignarro, Louis J.; Abdel-Mageed, Asim B.; Hellstrom, Wayne J. G.

    2012-01-01

    Porcine small intestinal submucosa (SIS) has been widely used in tunica albuginea (TA) reconstructive surgery. Adipose tissue-derived stem cells (ADSCs) can repair damaged tissue, augment cellular differentiation, and stimulate release of multiple growth factors. The aim of this rat study was to assess the feasibility of seeding ADSCs onto SIS grafts for TA reconstruction. Here, we demonstrate that seeding syngeneic ADSCs onto SIS grafts (SIS-ADSC) resulted in significant cavernosal tissue preservation and maintained erectile responses, similar to controls, in a rat model of bilateral incision of TA, compared with sham-operated animals and rats grafted with SIS graft (SIS) alone. In addition to increased TGF-β1 and FGF-2 expression levels, cross-sectional studies of the rat penis with SIS and SIS-ADSC revealed mild to moderate fibrosis and an increase of 30% and 40% in mean diameter in flaccid and erectile states, respectively. SIS grafting induced transcriptional up-regulation of iNOS and down-regulation of endothelial NOS, neuronal NOS, and VEGF, an effect that was restored by seeding ADCSs on the SIS graft. Taken together, these data show that rats undergoing TA incision with autologous SIS-ADSC grafts maintained better erectile function compared with animals grafted with SIS alone. This study suggests that SIS-ADSC grafting can be successfully used for TA reconstruction procedures and can restore erectile function. PMID:22308363

  14. Method to Reduce Muscle Fatigue During Transcutaneous Neuromuscular Electrical Stimulation in Major Knee and Ankle Muscle Groups.

    PubMed

    Sayenko, Dimitry G; Nguyen, Robert; Hirabayashi, Tomoyo; Popovic, Milos R; Masani, Kei

    2015-09-01

    A critical limitation with transcutaneous neuromuscular electrical stimulation as a rehabilitative approach is the rapid onset of muscle fatigue during repeated contractions. We have developed a method called spatially distributed sequential stimulation (SDSS) to reduce muscle fatigue by distributing the center of electrical field over a wide area within a single stimulation site, using an array of surface electrodes. To extend the previous findings and to prove feasibility of the method by exploring the fatigue-reducing ability of SDSS for lower limb muscle groups in the able-bodied population, as well as in individuals with spinal cord injury (SCI). SDSS was delivered through 4 active electrodes applied to the knee extensors and flexors, plantarflexors, and dorsiflexors, sending a stimulation pulse to each electrode one after another with 90° phase shift between successive electrodes. Isometric ankle torque was measured during fatiguing stimulations using SDSS and conventional single active electrode stimulation lasting 2 minutes. We demonstrated greater fatigue-reducing ability of SDSS compared with the conventional protocol, as revealed by larger values of fatigue index and/or torque peak mean in all muscles except knee flexors of able-bodied individuals, and in all muscles tested in individuals with SCI. Our study has revealed improvements in fatigue tolerance during transcutaneous neuromuscular electrical stimulation using SDSS, a stimulation strategy that alternates activation of subcompartments of muscles. The SDSS protocol can provide greater stimulation times with less decrement in mechanical output compared with the conventional protocol. © The Author(s) 2014.

  15. Reduced WIF-1 expression stimulates skin hyperpigmentation in patients with melasma.

    PubMed

    Kim, Ji-Young; Lee, Tae-Ryong; Lee, Ai-Young

    2013-01-01

    The expression of Wnt inhibitory factor-1 (WIF-1) gene, which was detected by a microarray analysis of hyperpigmented and normally pigmented skin sets of melasma patients, was significantly reduced in the hyperpigmented skin from melasma patients, but not in healthy controls, regardless of UV irradiation. Wnt signals regulate skin pigmentation; however, WIF-1 is expressed in cultured skin keratinocytes and fibroblasts, but not in melanocytes. Therefore, we examined whether WIF-1 knockdown in neighboring keratinocytes and fibroblasts plays a role in melasma. Additionally, the effect of WIF-1 overexpression on the amelioration of hyperpigmentation was examined. WIF-1 knockdown, either in fibroblasts or in keratinocytes, significantly stimulated tyrosinase expression and melanosome transfer, whereas melanocytes with WIF-1 overexpression significantly reduced those parameters. The WIF-1 knockdown decreased glycogen synthase kinase-3β (GSK-3β), β-catenin, and NFATc2 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 2) phosphorylation and increased microphthalmia-associated transcription factor (MITF) expression as in melanocytes with Wnt-1 overexpression, whereas the WIF-1 overexpression reversed the results. Expression of Wnts, both canonical and noncanonical, was increased in the hyperpigmented skin of melasma patients. Collectively, WIF-1 downregulation, which may occur in epidermal keratinocytes and in dermal fibroblasts, is involved in melasma development because of the stimulation of melanogenesis and melanosome transfer through upregulation of the canonical and the noncanonical Wnt signaling pathway.

  16. High Frequency Electrical Stimulation of Lateral Habenula Reduces Voluntary Ethanol Consumption in Rats

    PubMed Central

    Li, Jing; Zuo, Wanhong; Fu, Rao; Xie, Guiqin; Kaur, Amandeep; Bekker, Alex

    2016-01-01

    Background: Development of new strategies that can effectively prevent and/or treat alcohol use disorders is of paramount importance, because the currently available treatments are inadequate. Increasing evidence indicates that the lateral habenula (LHb) plays an important role in aversion, drug abuse, and depression. In light of the success of high-frequency stimulation (HFS) of the LHb in improving helplessness behavior in rodents, we assessed the effects of LHb HFS on ethanol-drinking behavior in rats. Methods: We trained rats to drink ethanol under an intermittent access two-bottle choice procedure. We used c-Fos immunohistochemistry and electrophysiological approaches to examine LHb activity. We applied a HFS protocol that has proven effective for reducing helplessness behavior in rats via a bipolar electrode implanted into the LHb. Results: c-Fos protein expression and the frequency of both spontaneous action potential firings and spontaneous excitatory postsynaptic currents were higher in LHb neurons of ethanol-withdrawn rats compared to their ethanol-naïve counterparts. HFS to the LHb produced long-term reduction of intake and preference for ethanol, without altering locomotor activity. Conversely, low-frequency electrical stimulation to the LHb or HFS applied to the nearby nucleus did not affect drinking behavior. Conclusions: Our results suggest that withdrawal from chronic ethanol exposure increases glutamate release and the activity of LHb neurons, and that functional inhibition of the LHb via HFS reduces ethanol consumption. Thus, LHb HFS could be a potential new therapeutic option for alcoholics. PMID:27234303

  17. Leucine supplementation stimulates protein synthesis and reduces degradation signal activation in muscle of newborn pigs during acute endotoxemia

    USDA-ARS?s Scientific Manuscript database

    Sepsis disrupts skeletal muscle proteostasis and mitigates the anabolic response to leucine (Leu) in muscle of mature animals. We have shown that Leu stimulates muscle protein synthesis (PS) in healthy neonatal piglets. To determine if supplemental Leu can stimulate PS and reduce protein degradation...

  18. Breastfeeding or nipple stimulation for reducing postpartum haemorrhage in the third stage of labour.

    PubMed

    Abedi, Parvin; Jahanfar, Shayesteh; Namvar, Farideh; Lee, Jasmine

    2016-01-27

    Oxytocin and prostaglandin are hormones responsible for uterine contraction during the third stage of labour. Receptors in the uterine muscles are stimulated by exogenous or endogenous oxytocin leading to uterine contractions. Nipple stimulation or breastfeeding are stimuli that can lead to the secretion of oxytocin and consequent uterine contractions. Consequently, uterine contractions can reduce bleeding during the third stage of labour. To investigate the effects of breastfeeding or nipple stimulation on postpartum haemorrhage (PPH) during the third stage of labour. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 July 2015) and reference lists of retrieved studies. Randomised and quasi-randomised controlled trials comparing breast stimulation, breastfeeding or suckling for PPH in the third stage of labour were selected for this review. Two review authors independently assessed studies for inclusion in terms of risk of bias and independently extracted data. Disagreements were resolved by a third review author. We included four trials (4608 women), but only two studies contributed data to the review's analyses (n = 4472). The studies contributing data were assessed as of high risk of bias overall. One of these studies was cluster-randomised and conducted in a low-income country and the other study was carried out in a high-income country. All four included studies assessed blood loss in the third stage of labour. Birth attendants estimated blood loss in two trials. The third trial assessed the hematocrit level on the second day postpartum to determine the effect of the bleeding. The fourth study measured PPH ≥ 500 mL. Nipple stimulation versus no treatmentOne study (4385 women) compared the effect of suckling versus no treatment. Blood loss was not measured in 114 women (59 in control group and 55 in suckling group). After excluding twin pregnancies, stillbirths and neonatal deaths, the main analyses for this trial were performed on

  19. Noninvasive stimulation of prefrontal cortex strengthens existing episodic memories and reduces forgetting in the elderly

    PubMed Central

    Sandrini, Marco; Brambilla, Michela; Manenti, Rosa; Rosini, Sandra; Cohen, Leonardo G.; Cotelli, Maria

    2014-01-01

    Memory consolidation is a dynamic process. Reactivation of consolidated memories by a reminder triggers reconsolidation, a time-limited period during which existing memories can be modified (i.e., weakened or strengthened). Episodic memory refers to our ability to recall specific past events about what happened, including where and when. Difficulties in this form of long-term memory commonly occur in healthy aging. Because episodic memory is critical for daily life functioning, the development of effective interventions to reduce memory loss in elderly individuals is of great importance. Previous studies in young adults showed that the dorsolateral prefrontal cortex (DLPFC) plays a causal role in strengthening of verbal episodic memories through reconsolidation. The aim of the present study was to explore the extent to which facilitatory transcranial direct current stimulation (anodal tDCS) over the left DLPFC would strengthen existing episodic memories through reconsolidation in elderly individuals. On Day 1, older adults learned a list of 20 words. On Day 2 (24 h later), they received a reminder or not, and after 10 min tDCS was applied over the left DLPFC. Memory recall was tested on Day 3 (48 h later) and Day 30 (1 month later). Surprisingly, anodal tDCS over the left DLPFC (i.e., with or without the reminder) strengthened existing verbal episodic memories and reduced forgetting compared to sham stimulation. These results provide a framework for testing the hypothesis that facilitatory tDCS of left DLPFC might strengthen existing episodic memories and reduce memory loss in older adults with amnestic mild cognitive impairment. PMID:25368577

  20. Gastric electrical stimulation optimized to inhibit gastric motility reduces food intake in dogs.

    PubMed

    Song, Geng-Qing; Zhu, Hongbing; Lei, Yong; Yuan, Charlene; Starkebaum, Warren; Yin, Jieyun; Chen, Jiande D Z

    2015-06-01

    The aim of this study was to test the hypothesis that that a method of gastric electrical stimulation (GES) optimized to inhibit gastric motility was effective in reducing food intake in dogs. Female dogs with a gastric cannula and gastric serosal electrodes were studied in three experiments: (1) to determine the best parameters and locations of GES in inhibiting gastric tone, slow waves, and contractions in dogs;( 2) to investigate the reproducibility of the inhibitory effects of GES; and (3) to study the effect of the GES method on food intake in dogs. (1) For GES to exert significant effects on gastric motility, a pulse width of ≥2 ms was required, and with other appropriate inhibitory parameters, GES was able to increase gastric volume by 190.4 %, reduce antral contractions by 39.7 %, and decrease the percentage of normal slow waves by 47.6 %. In addition, the inhibitory effect of GES was more potent with the stimulation electrodes placed along the lesser or greater curvature than placed in the middle, and more potent with the electrodes placed in the distal stomach than in the proximal stomach; (2) the inhibitory effects of GES on gastric motility were reproducible; (3) the GES method optimized to inhibit gastric motility produced a 20 % reduction in food intakes in non-obese dogs. GES with appropriate parameters inhibits gastric motility, and the effects are reproducible. The GES method optimized to inhibit gastric motility reduces food intake in healthy dogs and may have a therapeutic potential for treating obesity.

  1. Transcutaneous electrical nerve stimulation reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia.

    PubMed

    Dailey, Dana L; Rakel, Barbara A; Vance, Carol G T; Liebano, Richard E; Amrit, Anand S; Bush, Heather M; Lee, Kyoung S; Lee, Jennifer E; Sluka, Kathleen A

    2013-11-01

    Because transcutaneous electrical nerve stimulation (TENS) works by reducing central excitability and activating central inhibition pathways, we tested the hypothesis that TENS would reduce pain and fatigue and improve function and hyperalgesia in people with fibromyalgia who have enhanced central excitability and reduced inhibition. The current study used a double-blinded randomized, placebo-controlled cross-over design to test the effects of a single treatment of TENS with people with fibromyalgia. Three treatments were assessed in random order: active TENS, placebo TENS and no TENS. The following measures were assessed before and after each TENS treatment: pain and fatigue at rest and in movement; pressure pain thresholds, 6-m walk test, range of motion; 5-time sit-to-stand test, and single-leg stance. Conditioned pain modulation was completed at the end of testing. There was a significant decrease in pain and fatigue with movement for active TENS compared to placebo and no TENS. Pressure pain thresholds increased at the site of TENS (spine) and outside the site of TENS (leg) when compared to placebo TENS or no TENS. During active TENS, conditioned pain modulation was significantly stronger compared to placebo TENS and no TENS. No changes in functional tasks were observed with TENS. Thus, the current study suggests TENS has short-term efficacy in relieving symptoms of fibromyalgia while the stimulator is active. Future clinical trials should examine the effects of repeated daily delivery of TENS, similar to the way in which TENS is used clinically on pain, fatigue, function, and quality of life in individuals with fibromyalgia.

  2. Does electrical stimulation reduce spasticity after stroke? A randomized controlled study.

    PubMed

    Bakhtiary, Amir H; Fatemy, Elham

    2008-05-01

    To investigate the therapeutic effect of electrical stimulation on plantarflexor spasticity in stroke patients. A randomized controlled clinical trial study. Rehabilitation clinic of Semnan University of Medical Sciences. Forty stroke patients (aged from 42 to 65 years) with ankle plantarflexor spasticity. Fifteen minutes of inhibitory Bobath techniques were applied to one experimental group and a combination of 9 minutes of electrical stimulation on the dorsiflexor muscles and inhibitory Bobath techniques was applied to another group for 20 sessions daily. Passive ankle joint dorsiflexion range of motion, dorsiflexion strength test, plantarflexor muscle tone by Modified Ashworth Scale and soleus muscle H-reflex. The mean change of passive ankle joint dorsiflexion in the combination therapy group was 11.4 (SD 4.79) degrees versus 6.1 (SD 3.09) degrees, which was significantly higher (P = 0.001). The mean change of plantarflexor muscle tonicity measured by the Modified Ashworth Scale in the combination therapy group was -1.6 (SD 0.5) versus -1.1 (SD 0.31) in the Bobath group (P = 0.001). Dorsiflexor muscle strength was also increased significantly (P = 0.04) in the combination therapy group (0.7 +/- 0.37) compared with the Bobath group (0.4 +/- 0.23). However, no significant change in the amplitude of H-reflex was found between combination therapy (-0.41 +/- 0.29) and Bobath (-0.3 +/- 0.28) groups. Therapy combining Bobath inhibitory technique and electrical stimulation may help to reduce spasticity effectively in stroke patients.

  3. Adenosine reduces reactive oxygen species and interleukin-8 production by Trichomonas vaginalis-stimulated neutrophils.

    PubMed

    Frasson, Amanda Piccoli; Menezes, Camila Braz; Goelzer, Gustavo Krumel; Gnoatto, Simone Cristina Baggio; Garcia, Solange Cristina; Tasca, Tiana

    2017-09-06

    Trichomonas vaginalis is a flagellated protozoan that affects the human urogenital tract causing 276.4 million new infections a year. The parasite elicits a vaginal mucosal infiltration of immune cells, especially neutrophils which are considered to be primarily responsible for cytological change observed at the infection site as well as the major contributor in the inflammatory response against the parasite. Extracellular nucleotides and their nucleosides are signaling compounds involved in several biological processes, including inflammation and immune responses. Once in the extracellular space, the nucleotides and nucleosides can directly activate the purinergic receptors. Herein, we investigated the involvement of purinergic signaling on the production of reactive oxygen species (ROS) and cytokines by T. vaginalis-stimulated neutrophils. Parasites were able to induce an increase in ROS and IL-8 levels while they did not promote IL-6 secretion or neutrophil elastase activity. Adenine and guanine nucleotides or nucleosides were not able to modulate ROS and cytokine production; however, when T. vaginalis-stimulated neutrophils were incubated with adenosine and adenosine deaminase inhibitor, the levels of ROS and IL-8 were significantly reduced. These immunosuppressive effects were probably a response to the higher bioavailability of adenosine found in the supernatant as result of inhibition of enzyme activity. The involvement of P1 receptors was investigated by immunofluorescence and A1 receptor was the most abundant. Our data show that the influence of purinergic signaling, specifically those effects associated with adenosine accumulation, on the modulation of production of proinflammatory mediators by T. vaginalis-stimulated neutrophils contribute to the understanding of immunological aspects of trichomoniasis.

  4. Reduced postactivation depression of soleus H reflex and root evoked potential after transcranial magnetic stimulation

    PubMed Central

    Andrews, Jennifer C.; Stein, Richard B.

    2015-01-01

    Postactivation depression of the Hoffmann (H) reflex is associated with a transient period of suppression following activation of the reflex pathway. In soleus, the depression lasts for 100–200 ms during voluntary contraction and up to 10 s at rest. A reflex root evoked potential (REP), elicited after a single pulse of transcutaneous stimulation to the thoracolumbar spine, has been shown to exhibit similar suppression. The present study systematically characterized the effect of transcranial magnetic stimulation (TMS) on postactivation depression using double-pulse H reflexes and REPs. A TMS pulse reduced the period of depression to 10–15 ms for both reflexes. TMS could even produce postactivation facilitation of the H reflex, as the second reflex response was increased to 243 ± 51% of control values at the 75-ms interval. The time course was qualitatively similar for the REP, yet the overall increase was less. While recovery of the H reflex was slower in the relaxed muscle, the profile exhibited a distinct bimodal shape characterized by an early peak at the 25-ms interval, reaching 72 ± 23% of control values, followed by a trough at 50 ms, and then a gradual recovery at intervals > 50 ms. The rapid recovery of two successively depressed H reflexes, ∼25 ms apart, was also possible with double-pulse TMS. The effect of the TMS-induced corticospinal excitation on postactivation depression may be explained by a combination of pre- and postsynaptic mechanisms, although further investigation is required to distinguish between them. PMID:25995355

  5. Prefrontal Electrical Stimulation in Non-depressed Reduces Levels of Reported Negative Affects from Daily Stressors

    PubMed Central

    Austin, Adelaide; Jiga-Boy, Gabriela M.; Rea, Sara; Newstead, Simon A.; Roderick, Sian; Davis, Nick J.; Clement, R. Marc; Boy, Frédéric

    2016-01-01

    Negative emotional responses to the daily life stresses have cumulative effects which, in turn, impose wide-ranging negative constraints on emotional well being and neurocognitive performance (Kalueff and Nutt, 2007; Nadler et al., 2010; Charles et al., 2013). Crucial cognitive functions such as memory and problem solving, as well more short term emotional responses (e.g., anticipation of- and response to- monetary rewards or losses) are influenced by mood. The negative impact of these behavioral responses is felt at the individual level, but it also imposes major economic burden on modern healthcare systems. Although much research has been undertaken to understand the underlying mechanisms of depressed mood and design efficient treatment pathways, comparatively little was done to characterize mood modulations that remain within the boundaries of a healthy mental functioning. In one placebo-controlled experiment, we applied daily prefrontal transcranial Direct Current Stimulation (tDCS) at five points in time, and found reliable improvements on self-reported mood evaluation. Using a new team of experimenters, we replicated this finding in an independent double-blinded placebo-controlled experiment and showed that stimulation over a shorter period of time (3 days) is sufficient to create detectable mood improvements. Taken together, our data show that repeated bilateral prefrontal tDCS can reduce psychological distress in non-depressed individuals. PMID:26973591

  6. Reconstruction of a large diaphragmatic defect in a kitten using small intestinal submucosa (SIS).

    PubMed

    Andreoni, Angelo A; Voss, Katja

    2009-12-01

    A double-layer sheet of small intestinal submucosa (SIS) was used to reconstruct a large chronic diaphragmatic defect in a 4-month-old kitten. The SIS graft was easy to use, postoperative recovery was uneventful, no side effects of the SIS implant were observed, and the SIS graft resulted in restoration of normal clinical function while allowing growth of the kitten without restriction of chest wall development. Herniation of fat through the caval hiatus was diagnosed 29 months postoperatively on a CT scan. The cat was free of clinical signs.

  7. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease

    PubMed Central

    de Hemptinne, Coralie; Swann, Nicole; Ostrem, Jill L.; Ryapolova-Webb, Elena S.; Luciano, Marta San; Galifianakis, Nicholas; Starr, Philip A.

    2015-01-01

    Deep brain stimulation (DBS) is increasingly applied to the treatment of brain disorders, but its mechanism of action remains unknown. Here, we evaluate the effect of basal ganglia DBS on cortical function using invasive cortical recordings in Parkinson's disease (PD) patients undergoing DBS implantation surgery. In the primary motor cortex of PD patients neuronal population spiking is excessively synchronized to the phase of network oscillations. This manifests in brain surface recordings as exaggerated coupling between the phase of the β rhythm and the amplitude of broadband activity. We show that acute therapeutic DBS reversibly reduces phase-amplitude interactions over a similar time course as reduction in parkinsonian motor signs. We propose that DBS of the basal ganglia improves cortical function by alleviating excessive β phase locking of motor cortex neurons. PMID:25867121

  8. Interpersonal multisensory stimulation reduces the overwhelming distracting power of self-gaze: psychophysical evidence for 'engazement'.

    PubMed

    Porciello, Giuseppina; Holmes, Brittany Serra; Liuzza, Marco Tullio; Crostella, Filippo; Aglioti, Salvatore Maria; Bufalari, Ilaria

    2014-10-20

    One's own face and gaze are never seen directly but only in a mirror. Yet, these stimuli capture attention more powerfully than others' face and gaze, suggesting the self is special for brain and behavior. Synchronous touches felt on one's own and seen on the face of others induce the sensation of including others in one's own face (enfacement). We demonstrate that enfacement may also reduce the overwhelming distracting power of self-gaze. This effect, hereafter called 'engazement', depends on the perceived physical attractiveness and inner beauty of the pair partner. Thus, we highlight for the first time the close link between enfacement and engazement by showing that changes of the self-face representation induced by facial visuo-tactile stimulation extend to gaze following, a separate process likely underpinned by different neural substrates. Moreover, although gaze following is a largely automatic, engazement is penetrable to the influence of social variables, such as positive interpersonal perception.

  9. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease.

    PubMed

    de Hemptinne, Coralie; Swann, Nicole C; Ostrem, Jill L; Ryapolova-Webb, Elena S; San Luciano, Marta; Galifianakis, Nicholas B; Starr, Philip A

    2015-05-01

    Deep brain stimulation (DBS) is increasingly applied for the treatment of brain disorders, but its mechanism of action remains unknown. Here we evaluate the effect of basal ganglia DBS on cortical function using invasive cortical recordings in Parkinson's disease (PD) patients undergoing DBS implantation surgery. In the primary motor cortex of PD patients, neuronal population spiking is excessively synchronized to the phase of network oscillations. This manifests in brain surface recordings as exaggerated coupling between the phase of the beta rhythm and the amplitude of broadband activity. We show that acute therapeutic DBS reversibly reduces phase-amplitude interactions over a similar time course as that of the reduction in parkinsonian motor signs. We propose that DBS of the basal ganglia improves cortical function by alleviating excessive beta phase locking of motor cortex neurons.

  10. Environmental Stimulation Does Not Reduce Impulsive Choice in ADHD: A "Pink Noise" Study.

    PubMed

    Metin, Baris; Roeyers, Herbert; Wiersema, Jan R; van der Meere, Jaap J; Gasthuys, Roos; Sonuga-Barke, Edmund

    2016-01-01

    The preference for sooner smaller over larger later rewards is a prominent manifestation of impulsivity in ADHD. According to the State Regulation Deficit (SRD) model, this impulsive choice is the result of impaired regulation of arousal level and can be alleviated by adding environmental stimulation to increase levels of arousal. To test this prediction, we studied the effects of adding background "pink noise" on impulsive choice using a classical and new adjusting choice delay task in a sample of 25 children with ADHD and 28 controls. Children with ADHD made more impulsive choices than controls. Adding noise did not reduce impulsive choice in ADHD. The findings add to the existing evidence on impulsive choice in ADHD, but no evidence is found for the SRD model's explanation of this behavioral style. Alternative explanations for impulsive choice in ADHD are discussed. © The Author(s) 2013.

  11. Aging Reduces the Stimulating Effect of Blue Light on Cognitive Brain Functions

    PubMed Central

    Daneault, Véronique; Hébert, Marc; Albouy, Geneviève; Doyon, Julien; Dumont, Marie; Carrier, Julie; Vandewalle, Gilles

    2014-01-01

    Study Objectives: Light exposure, particularly blue light, is being recognized as a potent mean to stimulate alertness and cognition in young individuals. Aging is associated with changes in alertness regulation and cognition. Whether the effect of light on cognitive brain function changes with aging is unknown, however. Design: Cross-sectional study. Setting: Functional Neuroimaging Unit, University of Montreal Geriatric Institute. Participants: Sixteen younger (23 ± 4.1 y) and 14 older (61 ± 4.5 y) healthy participants were recruited in the current study. Intervention: Blue light administration. Measurements: We used functional magnetic resonance imaging to record brain responses to an auditory working memory task in young and older healthy individuals, alternatively maintained in darkness or exposed to blue light. Results: Results show that the older brain remains capable of showing sustained responses to light in several brain areas. However, compared to young individuals, the effect of blue light is decreased in the pulvinar, amygdala, and tegmentum as well as in the insular, prefrontal, and occipital cortices in elderly individuals. Conclusion: The effect of blue light on brain responses diminishes with aging in areas typically involved in visual functions and in key regions for alertness regulation and higher executive processes. Our findings provide the first indications that the effect of light on cognition may be reduced in healthy aging. Citation: Daneault V; Hébert M; Albouy G; Doyon J; Dumont M; Carrier J; Vandewalle G. Aging reduces the stimulating effect of blue light on cognitive brain functions. SLEEP 2014;37(1):85-96. PMID:24381372

  12. Defoliation reduces soil biota - and modifies stimulating effects of elevated CO2.

    PubMed

    Dam, Marie; Christensen, Søren

    2015-11-01

    To understand the responses to external disturbance such as defoliation and possible feedback mechanisms at global change in terrestrial ecosystems, it is necessary to examine the extent and nature of effects on aboveground-belowground interactions. We studied a temperate heathland system subjected to experimental climate and atmospheric factors based on prognoses for year 2075 and further exposed to defoliation. By defoliating plants, we were able to study how global change modifies the interactions of the plant-soil system. Shoot production, root biomass, microbial biomass, and nematode abundance were assessed in the rhizosphere of manually defoliated patches of Deschampsia flexuosa in June in a full-factorial FACE experiment with the treatments: increased atmospheric CO 2, increased nighttime temperatures, summer droughts, and all of their combinations. We found a negative effect of defoliation on microbial biomass that was not apparently affected by global change. The negative effect of defoliation cascades through to soil nematodes as dependent on CO 2 and drought. At ambient CO 2, drought and defoliation each reduced nematodes. In contrast, at elevated CO 2, a combination of drought and defoliation was needed to reduce nematodes. We found positive effects of CO 2 on root density and microbial biomass. Defoliation affected soil biota negatively, whereas elevated CO 2 stimulated the plant-soil system. This effect seen in June is contrasted by the effects seen in September at the same site. Late season defoliation increased activity and biomass of soil biota and more so at elevated CO 2. Based on soil biota responses, plants defoliated in active growth therefore conserve resources, whereas defoliation after termination of growth results in release of resources. This result challenges the idea that plants via exudation of organic carbon stimulate their rhizosphere biota when in apparent need of nutrients for growth.

  13. Low Frequency Stimulation of Hippocampal Commissures Reduces Seizures in Chronic Rat Model of Temporal Lobe Epilepsy

    PubMed Central

    Rashid, Saifur; Pho, Gerald; Czigler, Michael; Werz, Mary Ann; Durand, Dominique M.

    2013-01-01

    SUMMARY Purpose To investigate the effects of low frequency stimulation (LFS) of a fiber track for the suppression of spontaneous seizures described by Nissinen in a rat model of human temporal lobe epilepsy. Methods Stimulation electrodes were implanted into the ventral hippocampal commissure (VHC) in a rat post-status epilepticus (SE) model of human temporal lobe epilepsy (n = 7). Two recordings electrodes were placed in the CA3 regions bilaterally and neural data was recorded for a minimum of six weeks. LFS (60 minute train of 1Hz biphasic square wave pulses, each 0.1ms in duration and 200μA in amplitude, followed by 15 minutes of rest) was applied to the VHC for, two weeks, 24 hours a day. Key Findings The baseline mean seizure frequency of the study animals was 3.7 seizures per day. The seizures were significantly reduced by the application of LFS in every animal (n=7). By the end of the two-week period of stimulation, there was a significant 90% (<1 seizure/day) reduction of seizure frequencies (p < 0.05) and a 57% reduction during the period following LFS (p < 0.05) when compared to baseline. LFS also resulted in a significant reduction of hippocampal interictal spike frequency (71%, p < 0.05), during two weeks LFS session. The hippocampal histological analysis showed no significant difference between rats that received LFS and SE-induction and those that had only received SE-induction. None of the animals showed any symptomatic hemorrhage, infection or complication. Significance LFS applied at a frequency of 1Hz significantly reduced both the excitability of the neural tissue as well as the seizure frequency in a rat model of human temporal lobe epilepsy. The results support the hypothesis that LFS of fiber tracts can be an effective method for the suppression of spontaneous seizures in a temporal lobe model of epilepsy in rats and could be lead to the development of the new therapeutic modality for human patients with temporal lobe epilepsy. PMID:22150779

  14. Stimulation of 5-HT(1B) receptors enhances cocaine reinforcement yet reduces cocaine-seeking behavior.

    PubMed

    Pentkowski, Nathan S; Acosta, Jazmin I; Browning, Jenny R; Hamilton, Elizabeth C; Neisewander, Janet L

    2009-09-01

    Paradoxically, stimulation of 5-HT(1B) receptors (5-HT(1B)Rs) enhances sensitivity to the reinforcing effects of cocaine but attenuates incentive motivation for cocaine as measured using the extinction/reinstatement model. We revisited this issue by examining the effects of a 5-HT(1B)R agonist, CP94253, on cocaine reinforcement and cocaine-primed reinstatement, predicting that CP94253 would enhance cocaine-seeking behavior reinstated by a low priming dose, similar to its effect on cocaine reinforcement. Rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. For reinstatement experiments, they then underwent daily extinction training to reduce cocaine-seeking behavior (operant responses without cocaine reinforcement). Next, they were pre-treated with CP94253 (3-10 mg/kg, s.c.) and either tested for cocaine-primed (10 or 2.5 mg/kg, i.p.) or cue-elicited reinstatement of extinguished cocaine-seeking behavior. For reinforcement, effects of CP94253 (5.6 mg/kg) across a range of self-administered cocaine doses (0-1.5 mg/kg, i.v.) were examined. Cocaine dose-dependently reinstated cocaine-seeking behavior, but contrary to our prediction, CP94253 reduced reinstatement with both priming doses. Similarly, CP94253 reduced cue-elicited reinstatement. In contrast, CP94253 shifted the self-administration dose-effect curve leftward, consistent with enhanced cocaine reinforcement. When saline was substituted for cocaine, CP94253 reduced response rates (i.e. cocaine-seeking behavior). In subsequent control experiments, CP94253 decreased open-arm exploration in an elevated plus-maze suggesting an anxiogenic effect, but had no effect on locomotion or sucrose reinforcement. These results provide strong evidence that stimulation of 5-HT(1B)Rs produces opposite effects on cocaine reinforcement and cocaine-seeking behavior, and further suggest that 5-HT(1B)Rs may be a novel target for developing medications for cocaine dependence.

  15. Transcutaneous electrical nerve stimulation reduces exercise-induced perceived pain and improves endurance exercise performance.

    PubMed

    Astokorki, Ali H Y; Mauger, Alexis R

    2017-03-01

    Muscle pain is a natural consequence of intense and prolonged exercise and has been suggested to be a limiter of performance. Transcutaneous electrical nerve stimulation (TENS) and interferential current (IFC) have been shown to reduce both chronic and acute pain in a variety of conditions. This study sought to ascertain whether TENS and IFC could reduce exercise-induced pain (EIP) and whether this would affect exercise performance. It was hypothesised that TENS and IFC would reduce EIP and result in an improved exercise performance. In two parts, 18 (Part I) and 22 (Part II) healthy male and female participants completed an isometric contraction of the dominant bicep until exhaustion (Part I) and a 16.1 km cycling time trial as quickly as they could (Part II) whilst receiving TENS, IFC, and a SHAM placebo in a repeated measures, randomised cross-over, and placebo-controlled design. Perceived EIP was recorded in both tasks using a validated subjective scale. In Part I, TENS significantly reduced perceived EIP (mean reduction of 12%) during the isometric contraction (P = 0.006) and significantly improved participants' time to exhaustion by a mean of 38% (P = 0.02). In Part II, TENS significantly improved (P = 0.003) participants' time trial completion time (~2% improvement) through an increased mean power output. These findings demonstrate that TENS can attenuate perceived EIP in a healthy population and that doing so significantly improves endurance performance in both submaximal isometric single limb exercise and whole-body dynamic exercise.

  16. Myocardial regeneration after implantation of porcine small intestinal submucosa in the left ventricle

    PubMed Central

    Ramos, Cassiana Maria Garcez; Francisco, Julio César; Olandoski, Marcia; de Carvalho, Katherine Athayde Teixeira; Cunha, Ricardo; Erbano, Bruna Olandoski; Jorge, Lianna Ferrari; Baena, Cristina Pellegrino; do Amaral, Vivian Ferreira; Noronha, Lucia; de Macedo, Rafael Michel; Faria-Neto, José Rocha; Guarita-Souza, Luiz César

    2014-01-01

    Introduction Most cardiomyocytes do not regenerate after myocardial infarction. Porcine small intestinal submucosa has been shown to be effective in tissue repair. Objective To evaluate myocardial tissue regeneration and functional effects of SIS implantation in pigs after left ventriculotomy. Methods Fifteen pigs were assigned to two groups: porcine small intestinal submucosa (SIS) (N=10) and control (N=5). The SIS group underwent a mini sternotomy, left ventriculotomy and placement of a SIS patch. The control group underwent a sham procedure. Echocardiography was performed before and 60 days after the surgical procedure. Histological analysis was performed with hematoxylin-eosin stain and markers for actin 1A4, anti sarcomeric actin, connexin43 and factor VIII. Results Weight gain was similar in both groups. Echocardiography analysis revealed no difference between groups regarding end diastolic and systolic diameters and left ventricular ejection fraction, both pre (P=0.118, P=0.313, P=0.944) and post procedure (P=0.333, P=0.522, P=0.628). Both groups showed an increase in end diastolic (P<0,001 for both) and systolic diameter 60 days after surgery (P=0.005, SIS group and P=0.004, control group). New cardiomyocytes, blood vessels and inflammatory reactions were histologically identified in the SIS group. Conclusion SIS implantation in pigs after left ventriculotomy was associated with angiomuscular regeneration and no damage in cardiac function. PMID:25140470

  17. Wheel running reduces high-fat diet intake, preference and mu-opioid agonist stimulated intake.

    PubMed

    Liang, Nu-Chu; Bello, Nicholas T; Moran, Timothy H

    2015-05-01

    The ranges of mechanisms by which exercise affects energy balance remain unclear. One potential mechanism may be that exercise reduces intake and preference for highly palatable, energy dense fatty foods. The current study used a rodent wheel running model to determine whether and how physical activity affects HF diet intake/preference and reward signaling. Experiment 1 examined whether wheel running affected the ability of intracerebroventricular (ICV) μ opioid receptor agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO) to increase HF diet intake. Experiment 2 examined the effects of wheel running on the intake of and preference for a previously preferred HF diet. We also assessed the effects of wheel running and diet choice on mesolimbic dopaminergic and opioidergic gene expression. Experiment 1 revealed that wheel running decreased the ability of ICV DAMGO administration to stimulate HF diet intake. Experiment 2 showed that wheel running suppressed weight gain and reduced intake and preference for a previously preferred HF diet. Furthermore, the mesolimbic gene expression profile of wheel running rats was different from that of their sedentary paired-fed controls but similar to that of sedentary rats with large HF diet consumption. These data suggest that alterations in preference for palatable, energy dense foods play a role in the effects of exercise on energy homeostasis. The gene expression results also suggest that the hedonic effects of exercise may substitute for food reward to limit food intake and suppress weight gain. Published by Elsevier B.V.

  18. Wheel running reduces high-fat diet intake, preference and mu-opioid agonist stimulated intake

    PubMed Central

    Liang, Nu-Chu; Bello, Nicholas T.; Moran, Timothy H.

    2015-01-01

    The ranges of mechanisms by which exercise affects energy balance remain unclear. One potential mechanism may be that exercise reduces intake and preference for highly palatable, energy dense fatty foods. The current study used a rodent wheel running model to determine whether and how physical activity affects HF diet intake/preference and reward signaling. Experiment 1 examined whether wheel running affected the ability of intracerebroventricular (ICV) µ opioid receptor agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO) to increase HF diet intake. Experiment 2 examined the effects of wheel running on the intake of and preference for a previously preferred HF diet. We also assessed the effects of wheel running and diet choice on mesolimbic dopaminergic and opioidergic gene expression. Experiment 1 revealed that wheel running decreased the ability of ICV DAMGO administration to stimulate HF diet intake. Experiment 2 showed that wheel running suppressed weight gain and reduced intake and preference for a previously preferred HF diet. Furthermore, the mesolimbic gene expression profile of wheel running rats was different from that of their sedentary paired-fed controls but similar to that of sedentary rats with large HF diet consumption. These data suggest that alterations in preference for palatable, energy dense foods play a role in the effects of exercise on energy homeostasis. The gene expression results also suggest that the hedonic effects of exercise may substitute for food reward to limit food intake and suppress weight gain. PMID:25668514

  19. The mismatch repair system reduces meiotic homeologous recombination and stimulates recombination-dependent chromosome loss.

    PubMed Central

    Chambers, S R; Hunter, N; Louis, E J; Borts, R H

    1996-01-01

    Efficient genetic recombination requires near-perfect homology between participating molecules. Sequence divergence reduces the frequency of recombination, a process that is dependent on the activity of the mismatch repair system. The effects of chromosomal divergence in diploids of Saccharomyces cerevisiae in which one copy of chromosome III is derived from a closely related species, Saccharomyces paradoxus, have been examined. Meiotic recombination between the diverged chromosomes is decreased by 25-fold. Spore viability is reduced with an observable increase in the number of tetrads with only two or three viable spores. Asci with only two viable spores are disomic for chromosome III, consistent with meiosis I nondisjunction of the homeologs. Asci with three viable spores are highly enriched for recombinants relative to tetrads with four viable spores. In 96% of the class with three viable spores, only one spore possesses a recombinant chromosome III, suggesting that the recombination process itself contributes to meiotic death. This phenomenon is dependent on the activities of the mismatch repair genes PMS1 and MSH2. A model of mismatch-stimulated chromosome loss is proposed to account for this observation. As expected, crossing over is increased in pms1 and msh2 mutants. Furthermore, genetic exchange in pms1 msh2 double mutants is affected to a greater extent than in either mutant alone, suggesting that the two proteins act independently to inhibit homeologous recombination. All mismatch repair-deficient strains exhibited reductions in the rate of chromosome III nondisjunction. PMID:8887641

  20. Nitrate stimulation of indigenous nitrate-reducing, sulfide-oxidising bacterial community in wastewater anaerobic biofilms.

    PubMed

    Garcia-de-Lomas, Juan; Corzo, Alfonso; Carmen Portillo, M; Gonzalez, Juan M; Andrades, Jose A; Saiz-Jimenez, Cesáreo; Garcia-Robledo, Emilio

    2007-07-01

    The role of the nitrate-reducing, sulfide-oxidising bacteria (NR-SOB) in the nitrate-mediated inhibition of sulfide net production by anaerobic wastewater biofilms was analyzed in two experimental bioreactors, continuously fed with the primary effluent of a wastewater treatment plant, one used as control (BRC) and the other one supplemented with nitrate (BRN). This study integrated information from H(2)S and pH microelectrodes, RNA-based molecular techniques, and the time course of biofilm growth and bioreactors water phase. Biofilms were a net source of sulfide for the water phase (2.01 micromol S(2-)(tot)m(-2)s(-1)) in the absence of nitrate dosing. Nitrate addition effectively led to the cessation of sulfide release from biofilms despite which a low rate of net sulfate reduction activity (0.26 micromol S(2-)(tot)m(-2)s(-1)) persisted at a deep layer within the biofilm. Indigenous NR-SOB including Thiomicrospira denitrificans, Arcobacter sp., and Thiobacillus denitrificans were stimulated by nitrate addition resulting in the elimination of most sulfide from the biofilms. Active sulfate reducing bacteria (SRB) represented comparable fractions of total metabolically active bacteria in the libraries obtained from BRN and BRC. However, we detected changes in the taxonomic composition of the SRB community suggesting its adaptation to a higher level of NR-SOB activity in the presence of nitrate.

  1. High salt reduces the activation of IL-4– and IL-13–stimulated macrophages

    PubMed Central

    Binger, Katrina J.; Gebhardt, Matthias; Heinig, Matthias; Rintisch, Carola; Schroeder, Agnes; Neuhofer, Wolfgang; Hilgers, Karl; Manzel, Arndt; Schwartz, Christian; Kleinewietfeld, Markus; Voelkl, Jakob; Schatz, Valentin; Linker, Ralf A.; Lang, Florian; Voehringer, David; Wright, Mark D.; Hubner, Norbert; Dechend, Ralf; Jantsch, Jonathan; Titze, Jens; Müller, Dominik N.

    2015-01-01

    A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt–induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis. PMID:26485286

  2. Preconditioning somatothermal stimulation on Qimen (LR14) reduces hepatic ischemia/reperfusion injury in rats

    PubMed Central

    2014-01-01

    Background In human beings or animals, ischemia/reperfusion (I/R) injury of the liver may occur in many clinical conditions, such as circulating shock, liver transplantation and surgery and several other pathological conditions. I/R injury has a complex pathophysiology resulting from a number of contributing factors. Therefore, it is difficult to achieve effective treatment or protection by individually targeting the mediators. This study aimed at studying the effects of local somatothermal stimulation preconditioning on the right Qimen (LR14) on hepatic I/R injury in rats. Methods Eighteen male Sprague-Dawley rats were randomly divided into three groups. The rats were preconditioned with thermal tolerance study, which included one dose of local somatothermal stimulation (LSTS) on right Qimen (LR14) at an interval of 12 h, followed by hepatic ischemia for 60 min and then reperfusion for 60 min. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been used to assess the liver functions, and liver tissues were taken for the measurements such as malondialdehyde (MDA), glutathione (GSH), catalase (CAT), superoxidase dismutase (SOD), and myeloperoxidase (MPO). Results The results show that the plasma ALT and AST activities were higher in the I/R group than in the control group. In addition, the plasma ALT and AST activities decreased in the groups that received LSTS. The hepatic SOD levels reduced significantly by I/R injury. Moreover, the hepatic MPO activity significantly increased by I/R injury while it decreased in the groups given LSTS. Conclusions Our findings show that LSTS provides a protective effects on the liver from the I/R injury. Therefore, LSTS might offer an easy and inexpensive intervention for patients who have suffered from I/R of the liver especially in the process of hepatotomy and hepatic transplantation. PMID:24417801

  3. Histomorphometric analysis of early epithelialization and dermal changes in mid-partial-thickness burn wounds in humans treated with porcine small intestinal submucosa and silver-containing hydrofiber.

    PubMed

    Salgado, Rosa M; Bravo, Leonardo; García, Mario; Melchor, Juan M; Krötzsch, Edgar

    2014-01-01

    The objective of this study was to determine the healing rates of mid-partial-thickness burns treated with a porcine intestinal submucosa (SIS) vs. silver-containing cellulose hydrofiber (AgH) dressings. This was done by comparing healing response of burn wounds treated with SIS vs that of burns treated with AgH dressings. Five patients with mid-partial-thickness burns ≤10% of body surface were treated simultaneously, but in different areas, with SIS and AgH dressings; full-thickness biopsies were taken at days 0 and 7. Tissues treated with SIS presented higher epithelial maturation index (6.2 ± 0.84 vs. 3.2 ± 3.28; [mean ± standard deviation], P = .029), better orientation and differentiation of epithelial cells, as well as an appropriate basal lamina structure, collagen deposition, and higher transforming growth factor-β3 expression (7.4 ± 8.1 vs. 2.1 ± 2.6; P = .055) than tissues treated with AgH dressings. Importantly, after the treatment SIS was not integrated in healed tissues. After 3 months of treatment, SIS produced a lower score according to Vancouver Scar Scale (3.6 ± 2.6 vs. 7.2 ± 2.5, P = .025).The submucosa dressing does not simply act as scaffolding for the wound, it provides stimulation in the healing area, probably via growth factors initially present in SIS or matrikines derived from its digestion in the wound site. In conclusion, the present study demonstrated that biological matrices favor the wound-healing process.

  4. Electrical stimulation over bilateral occipito-temporal regions reduces N170 in the right hemisphere and the composite face effect.

    PubMed

    Yang, Li-Zhuang; Zhang, Wei; Shi, Bin; Yang, Zhiyu; Wei, Zhengde; Gu, Feng; Zhang, Jing; Cui, Guanbao; Liu, Ying; Zhou, Yifeng; Zhang, Xiaochu; Rao, Hengyi

    2014-01-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that can modulate cortical excitability. Although the clinical value of tDCS has been advocated, the potential of tDCS in cognitive rehabilitation of face processing deficits is less understood. Face processing has been associated with the occipito-temporal cortex (OT). The present study investigated whether face processing in healthy adults can be modulated by applying tDCS over the OT. Experiment 1 investigated whether tDCS can affect N170, a face-sensitive ERP component, with a face orientation judgment task. The N170 in the right hemisphere was reduced in active stimulation conditions compared with the sham stimulation condition for both upright faces and inverted faces. Experiment 2 further demonstrated that tDCS can modulate the composite face effect, a type of holistic processing that reflects the obligatory attention to all parts of a face. The composite face effect was reduced in active stimulation conditions compared with the sham stimulation condition. Additionally, the current polarity did not modulate the effect of tDCS in the two experiments. The present study demonstrates that N170 can be causally manipulated by stimulating the OT with weak currents. Furthermore, our study provides evidence that obligatory attention to all parts of a face can be affected by the commonly used tDCS parameter setting.

  5. Electrical Stimulation over Bilateral Occipito-Temporal Regions Reduces N170 in the Right Hemisphere and the Composite Face Effect

    PubMed Central

    Yang, Li-Zhuang; Zhang, Wei; Shi, Bin; Yang, Zhiyu; Wei, Zhengde; Gu, Feng; Zhang, Jing; Cui, Guanbao; Liu, Ying; Zhou, Yifeng; Zhang, Xiaochu; Rao, Hengyi

    2014-01-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that can modulate cortical excitability. Although the clinical value of tDCS has been advocated, the potential of tDCS in cognitive rehabilitation of face processing deficits is less understood. Face processing has been associated with the occipito-temporal cortex (OT). The present study investigated whether face processing in healthy adults can be modulated by applying tDCS over the OT. Experiment 1 investigated whether tDCS can affect N170, a face-sensitive ERP component, with a face orientation judgment task. The N170 in the right hemisphere was reduced in active stimulation conditions compared with the sham stimulation condition for both upright faces and inverted faces. Experiment 2 further demonstrated that tDCS can modulate the composite face effect, a type of holistic processing that reflects the obligatory attention to all parts of a face. The composite face effect was reduced in active stimulation conditions compared with the sham stimulation condition. Additionally, the current polarity did not modulate the effect of tDCS in the two experiments. The present study demonstrates that N170 can be causally manipulated by stimulating the OT with weak currents. Furthermore, our study provides evidence that obligatory attention to all parts of a face can be affected by the commonly used tDCS parameter setting. PMID:25531112

  6. Electrical stimulation of primary afferent A fibres does not reduce substance P release in the dorsal horn of the cat.

    PubMed

    Hutchison, W D; Morton, C R

    1989-06-01

    Antibody microprobes were used to measure the release of immunoreactive substance P in the dorsal horn of anaesthetised cats during noxious mechanical or thermal stimulation of the hind limb. Concomitant electrical stimulation of the ipsilateral tibial or sural nerve at intensities sufficient to excite only A alpha beta or additionally A delta primary afferent fibres did not reduce the release of substance P evoked by noxious stimuli. The results suggest that segmental inhibition produced in the dorsal horn by electrical stimulation of peripheral nerves is not mediated by presynaptic inhibition of substance P release from nociceptive primary afferent fibres.

  7. Electric stimulation of the vagus nerve reduced mouse neuroinflammation induced by lipopolysaccharide.

    PubMed

    Meneses, G; Bautista, M; Florentino, A; Díaz, G; Acero, G; Besedovsky, H; Meneses, D; Fleury, A; Del Rey, A; Gevorkian, G; Fragoso, G; Sciutto, E

    2016-01-01

    Neuroinflammation (NI) is a key feature in the pathogenesis and progression of infectious and non-infectious neuropathologies, and its amelioration usually improves the patient outcome. Peripheral inflammation may promote NI through microglia and astrocytes activation, an increased expression of inflammatory mediators and vascular permeability that may lead to neurodegeneration. Several anti-inflammatory strategies have been proposed to control peripheral inflammation. Among them, electrical stimulation of the vagus nerve (VNS) recently emerged as an alternative to effectively attenuate peripheral inflammation in a variety of pathological conditions with few side effects. Considering that NI underlies several neurologic pathologies we explored herein the possibility that electrically VNS can also exert anti-inflammatory effects in the brain. NI was experimentally induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS) in C57BL/6 male mice; VNS with constant voltage (5 Hz, 0.75 mA, 2 ms) was applied for 30 s, 48 or 72 h after lipopolysaccharide injection. Twenty four hours later, pro-inflammatory cytokines (IL-1β, IL-6, TNFα) levels were measured by ELISA in brain and spleen extracts and total brain cells were isolated and microglia and macrophage proliferation and activation was assessed by flow cytometry. The level of ionized calcium binding adaptor molecule (Iba-1) and glial fibrillary acidic protein (GFAP) were estimated in whole brain extracts and in histologic slides by Western blot and immunohistochemistry, respectively. VNS significantly reduced the central levels of pro-inflammatory cytokines and the percentage of microglia (CD11b/CD45(low)) and macrophages (CD11b/CD45(high)), 24 h after the electrical stimulus in LPS stimulated mice. A significantly reduced level of Iba-1 expression was also observed in whole brain extracts and in the hippocampus, suggesting a reduction in activated microglia. VNS is a feasible therapeutic tool

  8. Reduced graphene oxide-coated hydroxyapatite composites stimulate spontaneous osteogenic differentiation of human mesenchymal stem cells

    NASA Astrophysics Data System (ADS)

    Lee, Jong Ho; Shin, Yong Cheol; Jin, Oh Seong; Kang, Seok Hee; Hwang, Yu-Shik; Park, Jong-Chul; Hong, Suck Won; Han, Dong-Wook

    2015-07-01

    Human mesenchymal stem cells (hMSCs) have great potential as cell sources for bone tissue engineering and regeneration, but the control and induction of their specific differentiation into bone cells remain challenging. Graphene-based nanomaterials are considered attractive candidates for biomedical applications such as scaffolds in tissue engineering, substrates for SC differentiation and components of implantable devices, due to their biocompatible and bioactive properties. Despite the potential biomedical applications of graphene and its derivatives, only limited information is available regarding their osteogenic activity. This study concentrates upon the effects of reduced graphene oxide (rGO)-coated hydroxyapatite (HAp) composites on osteogenic differentiation of hMSCs. The average particle sizes of HAp and rGO were 1270 +/- 476 nm and 438 +/- 180 nm, respectively. When coated on HAp particulates, rGO synergistically enhanced spontaneous osteogenic differentiation of hMSCs, without hampering their proliferation. This result was confirmed by determining alkaline phosphatase activity and mineralization of calcium and phosphate as early and late stage markers of osteogenic differentiation. It is suggested that rGO-coated HAp composites can be effectively utilized as dental and orthopedic bone fillers since these graphene-based particulate materials have potent effects on stimulating the spontaneous differentiation of MSCs and show superior bioactivity and osteoinductive potential.Human mesenchymal stem cells (hMSCs) have great potential as cell sources for bone tissue engineering and regeneration, but the control and induction of their specific differentiation into bone cells remain challenging. Graphene-based nanomaterials are considered attractive candidates for biomedical applications such as scaffolds in tissue engineering, substrates for SC differentiation and components of implantable devices, due to their biocompatible and bioactive properties. Despite

  9. Cytokine refacing effect reduces granulocyte macrophage colony-stimulating factor susceptibility to antibody neutralization.

    PubMed

    Heinzelman, Pete; Carlson, Sharon J; Cox, George N

    2015-10-01

    Crohn's Disease (CD) afflicts over half a million Americans with an annual economic impact exceeding $10 billion. Granulocyte macrophage colony-stimulating factor (GM-CSF) can increase patient immune responses against intestinal microbes that promote CD and has been effective for some patients in clinical trials. We have made important progress toward developing GM-CSF variants that could be more effective CD therapeutics by virtue of being less prone to neutralization by the endogenous GM-CSF autoantibodies that are highly expressed in CD patients. Yeast display engineering revealed mutations that increase GM-CSF variant binding affinity by up to ∼3-fold toward both GM-CSF receptor alpha and beta subunits in surface plasmon resonance experiments. Increased binding affinity did not reduce GM-CSF half-maximum effective concentration (EC50) values in conventional in vitro human leukocyte proliferation assays. Affinity-enhancing mutations did, however, promote a 'refacing effect' that imparted all five evaluated GM-CSF variants with increased in vitro bioactivity in the presence of GM-CSF-neutralizing polyclonal antisera. The most improved variant, H15L/R23L, was 6-fold more active than wild-type GM-CSF. Incorporation of additional known affinity-increasing mutations could augment the refacing effect and concomitant bioactivity improvements described here. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Aging reduces the stimulating effect of blue light on cognitive brain functions.

    PubMed

    Daneault, Véronique; Hébert, Marc; Albouy, Geneviève; Doyon, Julien; Dumont, Marie; Carrier, Julie; Vandewalle, Gilles

    2014-01-01

    Light exposure, particularly blue light, is being recognized as a potent mean to stimulate alertness and cognition in young individuals. Aging is associated with changes in alertness regulation and cognition. Whether the effect of light on cognitive brain function changes with aging is unknown, however. Cross-sectional study. Functional Neuroimaging Unit, University of Montreal Geriatric Institute. Sixteen younger (23 ± 4.1 y) and 14 older (61 ± 4.5 y) healthy participants were recruited in the current study. Blue light administration. We used functional magnetic resonance imaging to record brain responses to an auditory working memory task in young and older healthy individuals, alternatively maintained in darkness or exposed to blue light. Results show that the older brain remains capable of showing sustained responses to light in several brain areas. However, compared to young individuals, the effect of blue light is decreased in the pulvinar, amygdala, and tegmentum as well as in the insular, prefrontal, and occipital cortices in elderly individuals. The effect of blue light on brain responses diminishes with aging in areas typically involved in visual functions and in key regions for alertness regulation and higher executive processes. Our findings provide the first indications that the effect of light on cognition may be reduced in healthy aging.

  11. Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy.

    PubMed

    Schaeffer, Véronique; Lavenir, Isabelle; Ozcelik, Sefika; Tolnay, Markus; Winkler, David T; Goedert, Michel

    2012-07-01

    The accumulation of insoluble proteins is a pathological hallmark of several neurodegenerative disorders. Tauopathies are caused by the dysfunction and aggregation of tau protein and an impairment of cellular protein degradation pathways may contribute to their pathogenesis. Thus, a deficiency in autophagy can cause neurodegeneration, while activation of autophagy is protective against some proteinopathies. Little is known about the role of autophagy in animal models of human tauopathy. In the present report, we assessed the effects of autophagy stimulation by trehalose in a transgenic mouse model of tauopathy, the human mutant P301S tau mouse, using biochemical and immunohistochemical analyses. Neuronal survival was evaluated by stereology. Autophagy was activated in the brain, where the number of neurons containing tau inclusions was significantly reduced, as was the amount of insoluble tau protein. This reduction in tau aggregates was associated with improved neuronal survival in the cerebral cortex and the brainstem. We also observed a decrease of p62 protein, suggesting that it may contribute to the removal of tau inclusions. Trehalose failed to activate autophagy in the spinal cord, where it had no impact on the level of sarkosyl-insoluble tau. Accordingly, trehalose had no effect on the motor impairment of human mutant P301S tau transgenic mice. Our findings provide direct evidence in favour of the degradation of tau aggregates by autophagy. Activation of autophagy may be worth investigating in the context of therapies for human tauopathies.

  12. Transcutaneous electric acupoint stimulation at Jiaji points reduce abdominal pain after colonoscopy: a randomized controlled trial

    PubMed Central

    Chen, Yanqing; Wu, Weilan; Yao, Yusheng; Yang, Yang; Zhao, Qiuyan; Qiu, Liangcheng

    2015-01-01

    Background: Transcutaneous electric acupoint stimulation (TEAS) at Jiaji acupuncture points has therapeutic potential for relieving viscera pain and opioid-related side effects. This prospective, randomized, triple-blinded, placebo-controlled trial was to investigate the efficacy of TEAS on abdominal pain after colonoscopy. Methods: Consecutive outpatients with American Society of Anesthesiologists (ASA) physical status I or II underwent selective colonoscopy were randomly assigned into two groups for either TEAS or sham pretreatment. The primary outcomes were the incidence of abdominal pain after colonoscopy. The secondary outcomes included the incidence of abdominal distension, postoperative nausea and vomiting (PONV), duration of PACU stay, and patient’s satisfaction and acceptance. Results: Among the 229 patients analyzed, fewer occurrence of post-procedural abdominal pain (11.4% vs 25.2%, P = 0.007) and distension (1.8% vs 7.8%, P = 0.032) were observed in TEAS group, when compared with the sham group. The duration of PACU stay was significant shortened in TEAS group (P < 0.001). Meanwhile, patients’ satisfaction score to medical service was higher (P < 0.001), and their acceptance to colonoscopy was improved (P = 0.011). Conclusion: Pretreatment with TEAS can reduce post-procedural discomfort, provide more efficient medical resources utilization, and improved patient’s satisfaction and colonoscopy acceptance. PMID:26131193

  13. Reduced graphene oxide-coated hydroxyapatite composites stimulate spontaneous osteogenic differentiation of human mesenchymal stem cells.

    PubMed

    Lee, Jong Ho; Shin, Yong Cheol; Jin, Oh Seong; Kang, Seok Hee; Hwang, Yu-Shik; Park, Jong-Chul; Hong, Suck Won; Han, Dong-Wook

    2015-07-21

    Human mesenchymal stem cells (hMSCs) have great potential as cell sources for bone tissue engineering and regeneration, but the control and induction of their specific differentiation into bone cells remain challenging. Graphene-based nanomaterials are considered attractive candidates for biomedical applications such as scaffolds in tissue engineering, substrates for SC differentiation and components of implantable devices, due to their biocompatible and bioactive properties. Despite the potential biomedical applications of graphene and its derivatives, only limited information is available regarding their osteogenic activity. This study concentrates upon the effects of reduced graphene oxide (rGO)-coated hydroxyapatite (HAp) composites on osteogenic differentiation of hMSCs. The average particle sizes of HAp and rGO were 1270 ± 476 nm and 438 ± 180 nm, respectively. When coated on HAp particulates, rGO synergistically enhanced spontaneous osteogenic differentiation of hMSCs, without hampering their proliferation. This result was confirmed by determining alkaline phosphatase activity and mineralization of calcium and phosphate as early and late stage markers of osteogenic differentiation. It is suggested that rGO-coated HAp composites can be effectively utilized as dental and orthopedic bone fillers since these graphene-based particulate materials have potent effects on stimulating the spontaneous differentiation of MSCs and show superior bioactivity and osteoinductive potential.

  14. Subthalamic Nucleus Deep Brain Stimulation May Reduce Medication Costs in Early Stage Parkinson's Disease.

    PubMed

    Hacker, Mallory L; Currie, Amanda D; Molinari, Anna L; Turchan, Maxim; Millan, Sarah M; Heusinkveld, Lauren E; Roach, Jonathon; Konrad, Peter E; Davis, Thomas L; Neimat, Joseph S; Phibbs, Fenna T; Hedera, Peter; Byrne, Daniel W; Charles, David

    2016-01-01

    Subthalamic nucleus deep brain stimulation (STN-DBS) is well-known to reduce medication burden in advanced stage Parkinson's disease (PD). Preliminary data from a prospective, single blind, controlled pilot trial demonstrated that early stage PD subjects treated with STN-DBS also required less medication than those treated with optimal drug therapy (ODT). The purpose of this study was to analyze medication cost and utilization from the pilot trial of DBS in early stage PD and to project 10 year medication costs. Medication data collected at each visit were used to calculate medication costs. Medications were converted to levodopa equivalent daily dose, categorized by medication class, and compared. Medication costs were projected to advanced stage PD, the time when a typical patient may be offered DBS. Medication costs increased 72% in the ODT group and decreased 16% in the DBS+ODT group from baseline to 24 months. This cost difference translates into a cumulative savings for the DBS+ODT group of $7,150 over the study period. Projected medication cost savings over 10 years reach $64,590. Additionally, DBS+ODT subjects were 80% less likely to require polypharmacy compared with ODT subjects at 24 months (p <  0.05; OR = 0.2; 95% CI: 0.04-0.97). STN-DBS in early PD reduced medication cost over the two-year study period. DBS may offer substantial long-term reduction in medication cost by maintaining a simplified, low dose medication regimen. Further study is needed to confirm these findings, and the FDA has approved a pivotal, multicenter clinical trial evaluating STN-DBS in early PD.

  15. Transcutaneous electrical nerve stimulation reduces acute low back pain during emergency transport.

    PubMed

    Bertalanffy, Alexander; Kober, Alexander; Bertalanffy, Petra; Gustorff, Burkhard; Gore, Odette; Adel, Sharam; Hoerauf, Klaus

    2005-07-01

    Patients with acute low back pain may require emergency transport because of pain and immobilization. Transcutaneous electrical nerve stimulation (TENS) is a nonpharmaceutical therapy for patients with low back pain. To evaluate the efficacy of paramedic-administered TENS in patients with acute low back pain during emergency transport. This was a prospective, randomized study involving 74 patients transported to hospital. The patients were randomly assigned to two groups: group 1 (n = 36) was treated with true TENS, while group 2 (n = 36) was treated with sham TENS. The authors recorded pain and anxiety as the main outcome variables using a visual analog scale (VAS). The authors recorded a significant (p < 0.01) pain reduction (mean +/- standard deviation) during transport in group 1 (79.2 +/- 6.5 mm VAS to 48.9 +/- 8.2 mm VAS), whereas pain scores remained unchanged in group 2 (75.9 +/- 16.4 mm VAS and 77.1 +/- 11.2 mm VAS). Similarly, the scores for anxiety were significantly reduced (p < 0.01) in group 1 (81.7 +/- 7.9 mm VAS to 69.2 +/- 12.1 mm VAS) after treatment. No significant change was noted (84.5 +/- 5.8 mm VAS and 83.5 +/- 8.9 mm VAS, respectively) in group 2. TENS was found to be effective and rapid in reducing pain during emergency transport of patients with acute low back pain and should be considered due to its ease of use and lack of side effects in the study population.

  16. Diabetes reduces right atrial beta-adrenergic signaling but not agonist stimulation of heart rate in swine.

    PubMed

    Stanley, W C; Dore, J J; Hall, J L; Hamilton, C D; Pizzurro, R D; Roth, D A

    2001-04-01

    This study assessed the effects of streptozotocin diabetes in swine on the heart rate response to beta-adrenergic stimulation the adenylyl cyclase signal transduction pathway. Diabetic animals (n = 9) were hyperglycemic compared to the control group (n = 10) (12.6 +/- 1.0 vs. 3.53 +/- 0.29 mM). There were no significant differences between the diabetic and nondiabetic groups in the heart rate response to isoproterenol, however, there was a significant reduction (14%) in beta-adrenergic receptor density in the right atrium in the diabetic (61 +/- 3 fmol/mg protein) versus the nondiabetic group (71 +/- 3) (P < 0.05). The content of guanosine triphosphate binding regulatory proteins (Gs and Gi) in the right atrium was not affected by diabetes, nor was adenylyl cyclase activity under unstimulated conditions or with receptor-dependent stimulation with isoproterenol. On the other hand, adenylyl cyclase activity was 34% lower when directly stimulated with forskolin, and it was reduced by 23% when stimulated through Gs with Gpp(NH)p. In conclusion, beta-adrenergic stimulation of heart rate with isoproteronol and the receptor-dependent signal transduction pathway remained intact in the right atrium of diabetic swine despite reduced beta-adrenergic receptor density, G-protein content, and direct stimulation of adenylyl cyclase activity.

  17. High-amplitude electrical stimulation can reduce elicited neuronal activity in visual prosthesis

    PubMed Central

    Barriga-Rivera, Alejandro; Guo, Tianruo; Yang, Chih-Yu; Abed, Amr Al; Dokos, Socrates; Lovell, Nigel H.; Morley, John W.; Suaning, Gregg J.

    2017-01-01

    Retinal electrostimulation is promising a successful therapy to restore functional vision. However, a narrow stimulating current range exists between retinal neuron excitation and inhibition which may lead to misperformance of visual prostheses. As the conveyance of representation of complex visual scenes may require neighbouring electrodes to be activated simultaneously, electric field summation may contribute to reach this inhibitory threshold. This study used three approaches to assess the implications of relatively high stimulating conditions in visual prostheses: (1) in vivo, using a suprachoroidal prosthesis implanted in a feline model, (2) in vitro through electrostimulation of murine retinal preparations, and (3) in silico by computing the response of a population of retinal ganglion cells. Inhibitory stimulating conditions led to diminished cortical activity in the cat. Stimulus-response relationships showed non-monotonic profiles to increasing stimulating current. This was observed in vitro and in silico as the combined response of groups of neurons (close to the stimulating electrode) being inhibited at certain stimulating amplitudes, whilst other groups (far from the stimulating electrode) being recruited. These findings may explain the halo-like phosphene shapes reported in clinical trials and suggest that simultaneous stimulation in retinal prostheses is limited by the inhibitory threshold of the retinal ganglion cells. PMID:28209965

  18. Small Intestinal Submucosa Plug for Closure of Dilated Nephrostomy Tracts: A Pilot Study in Swine

    SciTech Connect

    Kakizawa, Hideyaki; Conlin, M. J.; Pavcnik, Dusan Uchida, Barry T.; Loriaux, Marc; Kim, Young Hwan; Keller, Frederick S.; Roesch, Josef

    2010-06-15

    The aim of this study was to evaluate efficacy of a plug made of small intestinal submucosa (SIS) for closure of dilated nephrostomy tract in the kidney after nephroscopy. Ten kidneys in 5 swine had nephrostomy tracts dilated up to 8 mm. The SIS plug was placed into the dilated renal cortex under nephroscopic control. Follow-up arteriograms, retrograde pyelograms, and macroscopic and histologic studies at 24 h (n = 4), 6 weeks (n = 2), and 3 months (n = 4) were performed to evaluate the efficacy of the plug. The SIS plug effectively closed the dilated nephrostomy tract. Follow-up studies showed minimal changes of the kidneys, except for 1 small infarction, regarding inflammatory and foreign-body reactions and progressive scarring of the SIS. SIS plug is effective for occlusion of dilated nephrostomy tract after nephroscopy. Its efficacy should be compared with other therapeutic options.

  19. Blood sinuses in the submucosa of the large airways of the sheep.

    PubMed Central

    Hill, P; Goulding, D; Webber, S E; Widdicombe, J G

    1989-01-01

    We have studied the airway vasculature in sheep using light and transmission electron microscopy, as well as arterial and venous (retrograde) injections of anatomical corrosion compound and latex. Vascular casts were viewed by scanning electron microscopy. There is a complex network of blood sinuses of large diameter (up to 500 microns) in the submucosa of the large airways. The vessels have thin walls formed by a single layer of flattened endothelium with tight junctions and without pericytes or smooth muscle cells. Characteristically the sinuses lie between the cartilage and lamina propria of the trachea or between cartilage and smooth muscle in the bronchi. Sinuses of greater than 50 microns transverse diameter are not found in airways less than 1.0 mm across. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 7 PMID:2808119

  20. Background matters: Minor vibratory stimulation during motor skill acquisition selectively reduces off-line memory consolidation.

    PubMed

    Korman, Maria; Herling, Zohar; Levy, Ishay; Egbarieh, Nebal; Engel-Yeger, Batya; Karni, Avi

    2017-04-01

    Although a ubiquitous situation, it is not clear how effective is a learning experience when task-irrelevant, sensory noise occurs in the background. Here, young adults were trained on the finger opposition sequence task, in a well-established training and testing protocol affording measures for online as well as off-line learning. During the training session, one group experienced a minor background vibratory stimulation to the trunk by the means of vibrating cushion, while the second group experienced recorded sound vibrations. A control group was trained with no extra sensory stimulation. Sensory stimulation during training had no effect on the online within-session gains, but dampened the expression of the off-line, consolidation phase, gains in the two sensory stimulation groups. These results suggest that background sensory stimulation can selectively modify off-line, procedural memory consolidation processes, despite well-preserved on-line learning. Classical studies have shown that neural plasticity in sensory systems is modulated by motor input. The current results extend this notion and suggest that some types of task-irrelevant sensory stimulation, concurrent with motor training, may constitute a 'gating' factor - modulating the triggering of long-term procedural memory consolidation processes. Thus, vibratory stimulation may be considered as a behavioral counterpart of pharmacological interventions that do not interfere with short term neural plasticity but block long-term plasticity.

  1. Selective alpha adrenergic antagonist reduces severity of transient hypertension during sexual stimulation after spinal cord injury.

    PubMed

    Phillips, Aaron A; Elliott, Stacy L; Zheng, Mei M Z; Krassioukov, Andrei V

    2015-03-15

    On a daily basis, the majority of those with high-level spinal cord injury have autonomic dysreflexia, which describes a life-threatening episode of transient extreme hypertension (i.e., as high as 300 mm Hg) as many as 90% of people living with this condition. Unfortunately, ejaculation is a major initiating factor for autonomic dysreflexia, which discourages sexual activity. In order to obtain a sperm specimen, or for initial assessment of fertility, penile vibrostimulation is clinically performed. Nifedipine, a selective calcium channel blocker, is the most commonly prescribed pharmaceutical for a priori management of autonomic dysreflexia secondary to ejaculation or other causes; however, it is limited because of its potential exacerbation of low resting pressure, which also affects this population. The present study examined the effect of a short-acting selective α1 antagonist (prazosin) on autonomic dysreflexia severity using a randomized placebo trial during medically supervised penile vibrostimulation in six males with cervical spinal cord injury. Beat-by-beat blood pressure and heart rate were recorded throughout penile vibrostimulation during placebo and prazosin-treated days. The increase in systolic blood pressure was mitigated during vibrostimulation in subjects administered prazosin as compared with those administered placebo (+140±19 mm Hg vs. +96±14 mmHg; p<0.05). On average, the peak in systolic blood pressure was 46 mm Hg lower during penile vibrostimulation when patients were administered prazosin (p<0.05), whereas resting blood pressure was not affected. Prazosin appears to be effective at reducing the severity of autonomic dysreflexia during sexual stimulation in patients with spinal cord injury, without exacerbating resting hypotension in high-level spinal cord injury.

  2. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD.

    PubMed

    Umanath, Kausik; Jalal, Diana I; Greco, Barbara A; Umeukeje, Ebele M; Reisin, Efrain; Manley, John; Zeig, Steven; Negoi, Dana G; Hiremath, Anand N; Blumenthal, Samuel S; Sika, Mohammed; Niecestro, Robert; Koury, Mark J; Ma, Khe-Ni; Greene, Tom; Lewis, Julia B; Dwyer, Jamie P

    2015-10-01

    Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders. Copyright © 2015 by the American Society of Nephrology.

  3. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD

    PubMed Central

    Jalal, Diana I.; Greco, Barbara A.; Umeukeje, Ebele M.; Reisin, Efrain; Manley, John; Zeig, Steven; Negoi, Dana G.; Hiremath, Anand N.; Blumenthal, Samuel S.; Sika, Mohammed; Niecestro, Robert; Koury, Mark J.; Ma, Khe-Ni; Greene, Tom; Lewis, Julia B.; Dwyer, Jamie P.

    2015-01-01

    Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0–28.9] versus 26.8 [13.4–47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023–9695] versus 6954 [2664–12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders. PMID:25736045

  4. Assisted movement with proprioceptive stimulation reduces impairment and restores function in incomplete spinal cord injury.

    PubMed

    Backus, Deborah; Cordo, Paul; Gillott, Amanda; Kandilakis, Casey; Mori, Motomi; Raslan, Ahmed M

    2014-08-01

    To test whether treatment with assisted movement with enhanced sensation (AMES) using vibration to the antagonist muscle would reduce impairments and restore upper limb function in people with incomplete tetraplegia. Prospective, pre-post study. Laboratory and rehabilitation hospital. We recruited 15 arms from 10 individuals (8 men; mean age, 40.5 y; mean years postspinal cord injury [SCI], 3) with chronic, incomplete tetraplegia. Two or three 20-minute sessions per week over 9 to 13 weeks (25 sessions total) on the AMES device, which combines repeated movement with targeted vibration to the antagonist muscle. Strength and active motion tests on the AMES device; International Standards for the Neurological Classification of SCI (ISNCSCI) motor and sensory examinations; Modified Ashworth Scale (MAS); grasp and release test (GRT); Van Lieshout Test (VLT); and Capabilities of Upper Extremity questionnaire (CUE). The AMES strength test scores improved significantly in metacarpophalangeal flexion (P=.024) and extension (P=.007) and wrist flexion (P=.001) and extension (P<.000). The AMES active motion scores improved in the hand (P=.001) and wrist (P=.001). The MAS and ISNCSCI scores remained unchanged, whereas the GRT scores increased (P=.025). Post hoc analysis showed a trend from pre- to posttreatment (P=.068) and a significant change from pretreatment to 3-month follow-up (P=.046). There was no significant change in the VLT (P=.951) or the CUE (P=.164). Five of the 10 participants reported a return of sensation to the digits after the first, second, or third treatment session. People with chronic, incomplete tetraplegia may experience improvements in impairments and function after treatment on a device combining assisted movement and proprioceptive stimulation. Further investigation is warranted. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  5. Delayed Treatment with Lidocaine Reduces Mouse Microglial Cell Injury and Cytokine Production After Stimulation with Lipopolysaccharide and Interferon γ

    PubMed Central

    Jeong, Hae-Jeong; Lin, Daowei; Li, Liaoliao; Zuo, Zhiyi

    2012-01-01

    Background Neuroinflammation is an important pathological process for almost all acquired neurological diseases. Microglial cells play a critical role in neuroinflammation. We determined whether lidocaine, a local anesthetic with antiinflammatory property, protected microglial cells and attenuated cytokine production from activated microglial cells. Methods Mouse microglial cultures were incubated with or without 1 µg/ml lipopolysaccharide and 10 U/ml interferon γ (IFNγ) for 24 h in the presence or absence of lidocaine for 1 h started at 2, 3 or 4 h after the onset of lipopolysaccharide and IFNγ stimulation. Lactate dehydrogenase release and cytokine production were determined after the cells were stimulated by lipopolysaccharide and IFNγ for 24 h. Results Lidocaine dose-dependently reduced lipopolysaccharide and IFNγ-induced microglial cell injury as measured by lactate dehydrogenase release. This effect was apparent with lidocaine at 2 µg/ml (30.3 ± 5.8 and 23.1 ± 9.7%, respectively, for stimulation alone and the stimulation in the presence of lidocaine, n = 18, P = 0.025). Lidocaine applied at 2, 3 or 4 h after the onset of lipopolysaccharide and IFNγ stimulation reduced the cell injury. This lidocaine effect was not affected by the mitochondrial KATP channel inhibitor 5-hydroxydecanoate. Similar to lidocaine, QX314, a permanently charged lidocaine analog that usually does not permeate through the plasma membrane, reduced lipopolysaccharide and IFNγ-induced microglial cell injury. QX314 also attenuated the stimulation-induced interleukin-1β production. Conclusions Delayed treatment with lidocaine protects microglial cells and reduces cytokine production from these cells. These effects may involve action site(s) on the cell surface. PMID:22253275

  6. Insulin-like growth factor I stimulates lipid oxidation, reduces protein oxidation, and enhances insulin sensitivity in humans.

    PubMed Central

    Hussain, M A; Schmitz, O; Mengel, A; Keller, A; Christiansen, J S; Zapf, J; Froesch, E R

    1993-01-01

    To elucidate the effects of insulin-like growth factor I (IGF-I) on fuel oxidation and insulin sensitivity, eight healthy subjects were treated with saline and recombinant human (IGF-I (10 micrograms/kg.h) during 5 d in a crossover, randomized fashion, while receiving an isocaloric diet (30 kcal/kg.d) throughout the study period. On the third and fourth treatment days, respectively, an L-arginine stimulation test and an intravenous glucose tolerance test were performed. A euglycemic, hyperinsulinemic clamp combined with indirect calorimetry and a glucose tracer infusion were performed on the fifth treatment day. IGF-I treatment led to reduced fasting and stimulated (glucose and/or L-arginine) insulin and growth hormone secretion. Basal and stimulated glucagon secretion remained unchanged. Intravenous glucose tolerance was unaltered despite reduced insulin secretion. Resting energy expenditure and lipid oxidation were both elevated, while protein oxidation was reduced, and glucose turnover rates were unaltered on the fifth treatment day with IGF-I as compared to the control period. Enhanced lipolysis was reflected by elevated circulating free fatty acids. Moreover, insulin-stimulated oxidative and nonoxidative glucose disposal (i.e., insulin sensitivity) were enhanced during IGF-I treatment. Thus, IGF-I treatment leads to marked changes in lipid and protein oxidation, whereas, at the dose used, carbohydrate metabolism remains unaltered in the face of reduced insulin levels and enhanced insulin sensitivity. Images PMID:8227340

  7. Partial Sleep Deprivation Reduces the Efficacy of Orexin-A to Stimulate Physical Activity and Energy Expenditure.

    PubMed

    DePorter, Danielle P; Coborn, Jamie E; Teske, Jennifer A

    2017-10-01

    Sufficient sleep is required for weight maintenance. Sleep deprivation due to noise exposure stimulates weight gain by increasing hyperphagia and reducing energy expenditure (EE). Yet the mechanistic basis underlying the weight gain response is unclear. Orexin-A promotes arousal and negative energy balance, and orexin terminals project to the ventrolateral preoptic area (VLPO), which is involved in sleep-to-wake transitions. To determine whether sleep deprivation reduces orexin function in VLPO and to test the hypothesis that sleep deprivation would attenuate the orexin-A-stimulated increase in arousal, physical activity (PA), and EE. Electroencephalogram, electromyogram, distance traveled, and EE were determined in male Sprague-Dawley rats following orexin-A injections into VLPO both before and after acute (12-h) and chronic (8 h/d, 9 d) sleep deprivation by noise exposure. Orexin-A in the VLPO significantly increased arousal, PA, total EE, and PA-related EE and reduced sleep and respiratory quotient before sleep deprivation. In contrast to after acute sleep deprivation in which orexin-A failed to stimulate EE during PA only, orexin-A failed to significantly increase arousal, PA, fat oxidation, total EE, and PA-related EE after chronic sleep deprivation. Sleep deprivation may reduce sensitivity to endogenous stimuli that enhance EE due to PA and thus stimulate weight gain. © 2017 The Obesity Society.

  8. Preparation of a small intestinal submucosa modified polypropylene hybrid mesh via a mussel-inspired polydopamine coating for pelvic reconstruction.

    PubMed

    Ge, Liangpeng; Liu, Lubin; Wei, Haoche; Du, Lei; Chen, Shixuan; Huang, Yong; Huang, Renshu

    2016-04-01

    Pelvic organ prolapse (POP) is a serious health issue that affects many adult women. Surgical treatments for POP patients comprise a common strategy in which scaffold materials are used to reconstruct the prolapsed pelvic. However, the existing materials for pelvic reconstruction cannot meet clinical requirements in terms of biocompatibility, mechanics and immunological rejection. To address these concerns, polypropylene (PP) mesh was selected because of its strong mechanical properties. Small intestinal submucosa (SIS) was used to modify the PP mesh via a mussel-inspired polydopamine coating to enhance its biocompatibility. The scanning electron microscopy (SEM) and atomic force microscopy (AFM) results demonstrated that SIS was successfully conjugated on the surface of the PP mesh. Moreover, the cytotoxicity results indicated that the PP mesh and SIS-modified PP mesh were safe to use. Furthermore, in vivo tests demonstrated that the fibroplasia around the implanted site in the SIS-modified PP mesh group was significantly less than the fibroplasia around the PP mesh group. In addition, the immunohistochemistry staining results indicated that the expression of pro-inflammatory macrophages (M1) was substantially lower and that the expression of pro-healing macrophages (M2) was higher in the SIS-modified PP mesh group. Furthermore, ELISA detection indicated that the expression of IL-1β and IL-6 in the SIS-modified PP mesh group was reduced compared with the PP mesh group. These findings suggest that a SIS-modified polypropylene hybrid mesh via a mussel-inspired polydopamine coating is a promising approach in pelvic reconstruction. © The Author(s) 2016.

  9. Evaluation of decellularization protocols for production of tubular small intestine submucosa scaffolds for use in oesophageal tissue engineering.

    PubMed

    Syed, Omaer; Walters, Nick J; Day, Richard M; Kim, Hae-Won; Knowles, Jonathan C

    2014-12-01

    Small intestine submucosa (SIS) has emerged as one of a number of naturally derived extracellular matrix (ECM) biomaterials currently in clinical use. In addition to clinical applications, ECM materials form the basis for a variety of approaches within tissue engineering research. In our preliminary work it was found that SIS can be consistently and reliably made into tubular scaffolds which confer certain potential advantages. Given that decellularization protocols for SIS are applied to sheet-form SIS, it was hypothesized that a tubular-form SIS would behave differently to pre-existing protocols. In this work, tubular SIS was produced and decellularized by the conventional peracetic acid-agitation method, peracetic acid under perfusion along with two commonly used detergent-perfusion protocols. The aim of this was to produce a tubular SIS that was both adequately decellularized and possessing the mechanical properties which would make it a suitable scaffold for oesophageal tissue engineering, which was one of the goals of this work. Analysis was carried out via mechanical tensile testing, DNA quantification, scanning electron and light microscopy, and a metabolic assay, which was used to give an indication of the biocompatibility of each decellularization method. Both peracetic acid protocols were shown to be unsuitable methods with the agitation-protocol-produced SIS, which was poorly decellularized, and the perfusion protocol resulted in poor mechanical properties. Both detergent-based protocols produced well-decellularized SIS, with no adverse mechanical effects; however, one protocol emerged, SDS/Triton X-100, which proved superior in both respects. However, this SIS showed reduced metabolic activity, and this cytotoxic effect was attributed to residual reagents. Consequently, the use of SIS produced using the detergent SD as the decellularization agent was deemed to be the most suitable, although the elimination of the DNase enzyme would give further

  10. Human mucosa/submucosa interactions during intestinal inflammation: involvement of the enteric nervous system in interleukin-8 secretion.

    PubMed

    Tixier, Emmanuelle; Lalanne, Florent; Just, Ingo; Galmiche, Jean-Paul; Neunlist, Michel

    2005-12-01

    Interleukin-8 (IL-8) is a key chemokine upregulated in various forms of intestinal inflammation, especially those induced by bacteria such as Clostridium difficile (C. difficile). Although interactions between different mucosal and submucosal cellular components have been reported, whether such interactions are involved in the regulation of IL-8 secretion during C. difficile infection is unknown. Moreover, whether the enteric nervous system, a major component of the submucosa, is involved in IL-8 secretion during an inflammatory challenge remains to be determined. In order to investigate mucosa/submucosa interactions that regulate IL-8 secretion, we co-cultured human intestinal mucosa and submucosa. In control condition, IL-8 secretion in co-culture was lower than the sum of the IL-8 secretion of both tissue layers cultured alone. Contrastingly, IL-8 secretion increased in co-culture after mucosal challenge with toxin B of C. difficile through an IL-1 beta-dependent pathway. Moreover, we observed that toxin B of C. difficile increased IL-8 immunoreactivity in submucosal enteric neurones in co-culture and in intact preparations of mucosa/submucosa, through an IL-1 beta-dependent pathway. IL-1 beta also increased IL-8 secretion and IL-8 mRNA expression in human neuronal cell lines (NT2-N and SH-SY5Y), through p38 and ERK1/2 MAP kinase-dependent pathways. Our results demonstrate that mucosa/submucosa interactions regulate IL-8 secretion during inflammatory processes in human through IL-1 beta-dependent pathways. Finally we observed that human submucosal neurones synthesize IL-8, whose production in neurones is induced by IL-1 beta via MAPK-dependent pathways.

  11. Transcranial direct current stimulation of the prefrontal cortex reduces cue-reactivity in alcohol-dependent patients.

    PubMed

    Wietschorke, Katharina; Lippold, Julian; Jacob, Christian; Polak, Thomas; Herrmann, Martin J

    2016-10-01

    Alcohol craving has been shown to be an important factor for relapses in alcohol-dependent patients. Furthermore, brain activity in reward-related areas in response to alcohol-related cues is positively related to the amount of post-relapse alcohol consumption. On the other hand, it has been shown that cue-exposure based extinction training (CET) leads to larger decrease of striatal and left dorsolateral prefrontal cortex (dLPFC) cue-induced activation compared to standard clinical day-care treatment, but the effect sizes are relatively small. The question of this study was, whether it is possible to change cue-reactivity and subjective craving by applying bilateral prefrontal transcranial direct current stimulation (tDCS). We stimulated 30 detoxified alcohol-dependent patients (50 % with a sham and 50 % with left cathodal/right anodal stimulation) and presented emotional as well as alcohol-related pictures. We measured the emotional startle modulation and found significantly increased startle amplitudes in the verum stimulation condition for alcohol-related cues, indicating a more negative processing of this cues in alcohol-dependent patients after verum tDCS stimulation. Additionally we found tendencies for stronger reduction in subjective craving in verum-stimulated patients. Therefore our study underscores the positive value of DCS in reducing craving and might help to improve the understanding and therapy of alcohol dependence.

  12. Single vagus nerve stimulation reduces early postprandial C-peptide levels but not other hormones or postprandial metabolism.

    PubMed

    Tang, M W; van Nierop, F S; Koopman, F A; Eggink, H M; Gerlag, D M; Chan, M W; Zitnik, R; Vaz, F M; Romijn, J A; Tak, P P; Soeters, M R

    2017-04-08

    A recent study in rheumatoid arthritis (RA) patients using electrical vagus nerve stimulation (VNS) to activate the inflammatory reflex has shown promising effects on disease activity. Innervation by the autonomic nerve system might be involved in the regulation of many endocrine and metabolic processes and could therefore theoretically lead to unwanted side effects. Possible effects of VNS on secretion of hormones are currently unknown. Therefore, we evaluated the effects of a single VNS on plasma levels of pituitary hormones and parameters of postprandial metabolism. Six female patients with RA were studied twice in balanced assignment (crossover design) to either VNS or no stimulation. The patients selected for this substudy had been on VNS therapy daily for at least 3 months and at maximum of 24 months. We compared 10-, 20-, and 30-min poststimulus levels to baseline levels, and a 4-h mixed meal test was performed 30 min after VNS. We also determined energy expenditure (EE) by indirect calorimetry before and after VNS. VNS did not affect pituitary hormones (growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, follicle-stimulating hormone, and luteinizing hormone), postprandial metabolism, or EE. Of note, VNS reduced early postprandial insulin secretion, but not AUC of postprandial plasma insulin levels. Cortisol and catecholamine levels in serum did not change significantly. Short stimulation of vagal activity by VNS reduces early postprandial insulin secretion, but not other hormone levels and postprandial response. This suggests VNS as a safe treatment for RA patients.

  13. Functional electrical stimulation improves quality of life by reducing intermittent claudication.

    PubMed

    Embrey, David G; Alon, Gad; Brandsma, Brenna A; Vladimir, Felix; Silva, Angela; Pflugeisen, Bethann M; Amoroso, Paul J

    2017-09-15

    To determine if Functional Electrical Stimulation (FES) would improve ischemic pain, walking distance, and quality of life of patients with intermittent claudication. Single blind, randomized block, two factorial design. Patients diagnosed with Peripheral Artery Disease (PAD) and intermittent claudication (IC). Ankle Brachial Index ranged 0.4-0.9 on at least one leg. Patients were randomly assigned to experimental (FES+Walk, N=13) or control (WALK, N=14) groups. Experimental group patients received FES to the dorsiflexor and plantarflexor muscles while walking for 1h/day, six days/week for eight weeks. Control group patients received similar intervention without FES. A Follow-up period of both groups lasted eight weeks. Outcome measures were taken at baseline (T0), after intervention (T1), and after follow-up (T2). Primary measures included Perceived Pain Intensity (PPI), Six minute walk (6MW), and Peripheral Arterial Disease Quality of Life (PADQOL). Secondary measures included Intermittent Claudication Questionnaire (ICQ) and Timed Up and Go (TUG). Group by time interactions in PPI were significant (P<0.001) with differences of 27.9 points at T1 and 36.9 points at T2 favoring the FES+Walk group. Groups difference in Symptoms and Limitations in Physical Function of the PADQOL reached significance (T1=8.9, and T2=8.3 improvements; P=0.007). ICQ was significant (T1=9.3 and T2=13.1 improvements; P=0.003). Improvement in 6MW and TUG tests were similar between groups. Walking with FES markedly reduced ischemic pain and enhanced QOL compared to just walking. FES while walking may offer an effective treatment option for the elderly with PAD and Intermittent Claudication. NIH-NIA 1R21AG048001 https://projectreporter.nih.gov/project_info_description.cfm?aid=8748641&icde=30695377&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC. https://clinicaltrials.gov/ct2/show/NCT02384980?term=David+Embrey&rank=1. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  14. Controlled pulse delivery of electrical stimulation differentially reduces epileptiform activity in Mg2+-free-treated hippocampal slices.

    PubMed

    Albensi, Benedict C; Toupin, Justin D; Oikawa, Kensuke; Oliver, Derek R

    2008-08-21

    Electrical stimulation for applications in epilepsy has been attempted in multiple brain regions [corrected] using high- or low-frequency stimulation protocols. Data suggest that specific frequencies may have more benefit at controlling seizure activity. To this end, investigators have tested low-frequency stimulation (LFS) protocols (0.1 to 25 Hz) in both animal models and in human epileptic patients and reported reduced epileptiform synchronization, afterdischarge thresholds, and seizure activity in general. Collectively, these studies imply that LFS may have benefit in reducing epileptiform activity, however, the effectiveness of various electrical parameters still needs to be determined in specific targets. This study aimed to systematically control the total number of stimulation pulses when using primarily LFS protocols (0.5, 0.75, 1, 2, 5, 10, and 25 Hz) delivered for the suppression of seizure-like activity in the hippocampal brain slice using a Mg2+-free model of epilepsy. Fifty Hz was also tested as a reference higher frequency protocol. Regulating the total number of pulses also controlled the amount of electrical work delivered. Of the LFS protocols tested, 0.5 Hz, and 1 Hz were optimal and significantly (p<0.05) reduced several measures of epileptiform activity. However, the higher frequency protocol, 50 Hz was similarly effective at significantly (p < 0.05) suppressing several aspects of epileptiform activity (but not for reduction of population-spike amplitude). The data show that these protocols, which had a controlled number of pulses differentially reduced epileptiform activity in our model where increasing the frequency of stimulation did not result in increased attenuation.

  15. Lateral Hypothalamic Stimulation Reduces Hyperalgesia Through Spinally Descending Orexin-A Neurons in Neuropathic Pain.

    PubMed

    Wardach, Jacob; Wagner, Monica; Jeong, Younhee; Holden, Janean E

    2016-03-01

    No evidence to date shows that lateral hypothalamic (LH) stimulation produces orexin-A-mediated antinociception in the spinal cord dorsal horn (SCDH) in a model of neuropathic pain. We conducted experiments to examine the effect of orexin-A-mediated LH stimulation in female rats with chronic constriction injury (CCI) on thermal hyperalgesia. Rats receiving carbachol into the LH demonstrated antinociception on both the left CCI and right nonligated paws (p < .05). Rats were given carbachol in the LH followed by intrathecal injection of the orexin-1 (OX1) receptor antagonist SB-334867, which blocked LH-induced antinociception compared with control groups (p < .05) in the left paw, but not in the right paw. These findings support the hypothesis that LH stimulation produces antinociception in rats with thermal hyperalgesia from neuropathic pain via an orexin-A connection between the LH and the SCDH. Identification of this pathway may lead to studies using orexins to manage clinical pain.

  16. Zapping the gap: Reducing the multisensory temporal binding window by means of transcranial direct current stimulation (tDCS).

    PubMed

    Zmigrod, Sharon; Zmigrod, Leor

    2015-09-01

    Synchrony among the senses lies at the heart of our possession of a unified conscious perception of the world. However, due to discrepancies in physical and neural information processing from different senses, the brain accommodates a limited range of temporal asynchronies between sensory inputs, i.e. the multisensory temporal binding window (TBW). Using non-invasive brain stimulation, we sought to modulate the audio-visual TBW and to identify cortical areas implicated in the conscious perception of multisensory synchrony. Participants performed a simultaneity judgment task while experiencing anodal (Experiment 1) or cathodal (Experiment 2) transcranial direct current stimulation (tDCS) over parietal and frontal regions. The results demonstrate that stimulating the right posterior parietal cortex significantly reduces the audio-visual TBW by approximately 30%, thereby causally linking this region to the plasticity of the TBW. This highlights a potential interventional technique for populations with a wider TBW, such as in autism and dyslexia.

  17. Subthalamic Stimulation Reduces Vowel Space at the Initiation of Sustained Production: Implications for Articulatory Motor Control in Parkinson's Disease.

    PubMed

    Sidtis, John J; Alken, Amy G; Tagliati, Michele; Alterman, Ron; Van Lancker Sidtis, Diana

    2016-03-19

    Stimulation of the subthalamic nuclei (STN) is an effective treatment for Parkinson's disease, but complaints of speech difficulties after surgery have been difficult to quantify. Speech measures do not convincingly account for such reports. This study examined STN stimulation effects on vowel production, in order to probe whether DBS affects articulatory posturing. The objective was to compare positioning during the initiation phase with the steady prolongation phase by measuring vowel spaces for three "corner" vowels at these two time frames. Vowel space was measured over the initial 0.25 sec of sustained productions of high front (/i/), high back (/u/) and low vowels (/a/), and again during a 2 sec segment at the midpoint. Eight right-handed male subjects with bilateral STN stimulation and seven age-matched male controls were studied based on their participation in a larger study that included functional imaging. Mean values: age = 57±4.6 yrs; PD duration = 12.3±2.7 yrs; duration of DBS = 25.6±21.2 mos, and UPDRS III speech score = 1.6±0.7. STN subjects were studied off medication at their therapeutic DBS settings and again with their stimulators off, counter-balanced order. Vowel space was larger in the initiation phase compared to the midpoint for both the control and the STN subjects off stimulation. With stimulation on, however, the initial vowel space was significantly reduced to the area measured at the mid-point. For the three vowels, the acoustics were differentially affected, in accordance with expected effects of front versus back position in the vocal tract. STN stimulation appears to constrain initial articulatory gestures for vowel production, raising the possibility that articulatory positions normally used in speech are similarly constrained.

  18. Combined sub-threshold dosages of phenobarbital and low-frequency stimulation effectively reduce seizures in amygdala-kindled rats.

    PubMed

    Asgari, Azam; Semnanian, Saeed; Atapour, Nafiseh; Shojaei, Amir; Moradi, Homeira; Mirnajafi-Zadeh, Javad

    2014-08-01

    Low-frequency stimulation (LFS) is a potential therapy utilized in patients who do not achieve satisfactory control of seizures with pharmacological treatments. Here, we investigated the interaction between anticonvulsant effects of LFS and phenobarbital (a commonly used medicine) on amygdala-kindled seizures in rats. Animals were kindled by electrical stimulation of basolateral amygdala in a rapid manner (12 stimulations/day). Fully kindled animals randomly received one of the three treatment choices: phenobarbital (1, 2, 3, 4 and 8 mg/kg; i.p.; 30 min before kindling stimulation), LFS (one or 4 packages contained 100 or 200 monophasic square wave pulses, 0.1-ms pulse duration at 1 Hz, immediately before kindling stimulation) or a combination of both (phenobarbital at 3 mg/kg and LFS). Phenobarbital alone at the doses of 1, 2 and 3 mg/kg had no significant effect on the main seizure parameters. LFS application always produced anticonvulsant effects unless applied with the pattern of one package of 100 pulses, which is considered as non-effective. All the seizure parameters were significantly reduced when phenobarbital (3 mg/kg) was administered prior to the application of the non-effective pattern of LFS. Phenobarbital (3 mg/kg) also increased the anticonvulsant actions of the effective LFS pattern. Our results provide an evidence of a positive cumulative anticonvulsant effect of LFS and phenobarbital, suggesting a potential combination therapy at sub-threshold dosages of phenobarbital and LFS to achieve a satisfactory clinical effect.

  19. Caloric Vestibular Stimulation Reduces Pain and Somatoparaphrenia in a Severe Chronic Central Post-Stroke Pain Patient: A Case Study

    PubMed Central

    2016-01-01

    Central post-stroke pain is a neuropathic syndrome characterized by intolerable contralesional pain and, in rare cases, somatic delusions. To date, there is limited evidence for the effective treatments of this disease. Here we used caloric vestibular stimulation to reduce pain and somatoparaphrenia in a 57-year-old woman suffering from central post-stroke pain. Resting-state functional magnetic resonance imaging was used to assess the neurological effects of this treatment. Following vestibular stimulation we observed impressive improvements in motor skills, pain, and somatic delusions. In the functional connectivity study before the vestibular stimulation, we observed differences in the patient’s left thalamus functional connectivity, with respect to the thalamus connectivity of a control group (N = 20), in the bilateral cingulate cortex and left insula. After the caloric stimulation, the left thalamus functional connectivity with these regions, which are known to be involved in the cortical response to pain, disappeared as in the control group. The beneficial use of vestibular stimulation in the reduction of pain and somatic delusion in a CPSP patient is now documented by behavioral and imaging data. This evidence can be applied to theoretical models of pain and body delusions. PMID:27028404

  20. Caloric Vestibular Stimulation Reduces Pain and Somatoparaphrenia in a Severe Chronic Central Post-Stroke Pain Patient: A Case Study.

    PubMed

    Spitoni, Grazia Fernanda; Pireddu, Giorgio; Galati, Gaspare; Sulpizio, Valentina; Paolucci, Stefano; Pizzamiglio, Luigi

    2016-01-01

    Central post-stroke pain is a neuropathic syndrome characterized by intolerable contralesional pain and, in rare cases, somatic delusions. To date, there is limited evidence for the effective treatments of this disease. Here we used caloric vestibular stimulation to reduce pain and somatoparaphrenia in a 57-year-old woman suffering from central post-stroke pain. Resting-state functional magnetic resonance imaging was used to assess the neurological effects of this treatment. Following vestibular stimulation we observed impressive improvements in motor skills, pain, and somatic delusions. In the functional connectivity study before the vestibular stimulation, we observed differences in the patient's left thalamus functional connectivity, with respect to the thalamus connectivity of a control group (N = 20), in the bilateral cingulate cortex and left insula. After the caloric stimulation, the left thalamus functional connectivity with these regions, which are known to be involved in the cortical response to pain, disappeared as in the control group. The beneficial use of vestibular stimulation in the reduction of pain and somatic delusion in a CPSP patient is now documented by behavioral and imaging data. This evidence can be applied to theoretical models of pain and body delusions.

  1. Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult.

    PubMed

    Kleim, Jeffrey A; Bruneau, Rochelle; VandenBerg, Penny; MacDonald, Erin; Mulrooney, Renee; Pocock, David

    2003-12-01

    Recovery of motor function following stroke is believed to be supported, at least in part, by functional compensation involving residual neural tissue. The present study used a rodent model of focal ischemia and intracortical microstimulation (ICMS) to examine the behavioral and physiological effects of cortical stimulation in combination with motor rehabilitation. Adult rats were trained to criterion on a single pellet reaching task before ICMS was used to derive maps of movement representations within forelimb motor cortex contralateral to the trained paw. All animals then received a focal ischemic infarct within the motor map. A cortical surface electrode was implanted over the motor cortex. Low levels of electrical stimulation were applied during rehabilitative training on the same reaching task for 10 days and ICMS used to derive a second motor map. Results showed that both monopolar and bipolar cortical stimulation significantly enhanced motor recovery and increased the area of cortex from which microstimulation movements could be evoked. The results demonstrate the behavioral and neurophysiological benefits of cortical stimulation in combination with rehabilitation for recovery from stroke.

  2. Basal and adenosine receptor-stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients

    SciTech Connect

    Diamond, I.; Wrubel, B.; Estrin, W.; Gordon, A.

    1987-03-01

    Alcoholism causes serious neurologic disease that may be due, in part, to the ability of ethanol to interact with neural cell membranes and change neuronal function. Adenosine receptors are membrane-bound proteins that appear to mediate some of the effects of ethanol in the brain. Human lymphocytes also have adenosine receptors, and their activation causes increases in cAMP levels. To test the hypothesis that basal and adenosine receptor-stimulated cAMP levels in lymphocytes might be abnormal in alcoholism, the authors studied lymphocytes from 10 alcoholic subjects, 10 age- and sex-matched normal individuals, and 10 patients with nonalcoholic liver disease. Basal and adenosine receptor-stimulated cAMP levels were reduced 75% in lymphocytes from alcoholic subjects. Also, there was a 76% reduction in ethanol stimulation of cAMP accumulation in lymphocytes from alcoholics. Similar results were demonstrable in isolated T cells. Unlike other laboratory tests examined, these measurements appeared to distinguish alcoholics from normal subjects and from patients with nonalcoholic liver disease. Reduced basal and adenosine receptor-stimulated levels of cAMP in lymphocytes from alcoholics may reflect a change in cell membranes due either to chronic alcohol abuse or to a genetic predisposition unique to alcoholic subjects.

  3. On the role of reduced auditory feedback and kinesic self-stimulation during Stroop Color-Word Performance.

    PubMed

    Grand, S; Breslow, R; Freedman, N

    1980-06-01

    Feedback from one's own voice provides important vocal-motor cues for effective cognitive processing. Reduction of such feedback is known to disturb such functioning. Work in our laboratory has shown that kinesic self-stimulation also plays an important role in cognition, and appears to regulate the focusing of attention under conditions of distraction. The present study investigated the effects of both auditory feedback and kinesic self-stimulation in the regulation of cognitive interference during performance of the Stroop Color-Word Task. Twelve subjects were tested on the Stroop task under conditions of normal and occluded hearing. Kinesic self-stimulation and response errors during color-word performance were recorded on video tape. The findings indicated that not only did self-stimulation increase when voice feedback was reduced, but that this increase was associated with a reduction in specific types of color-word performance errors. Individual differences revealed that high kinesic responders made significantly fewer errors in task performance than did low kinesic responders. Results were interpreted as revealing a kinesic feedback mechanism which has adaptive significance in regard to self-editing when auditory feedback is reduced.

  4. Long pacing pulses reduce phrenic nerve stimulation in left ventricular pacing.

    PubMed

    Hjortshøj, Søren; Heath, Finn; Haugland, Morten; Eschen, Ole; Thøgersen, Anna Margrethe; Riahi, Sam; Toft, Egon; Struijk, Johannes Jan

    2014-05-01

    Phrenic nerve stimulation is a major obstacle in cardiac resynchronization therapy (CRT). Activation characteristics of the heart and phrenic nerve are different with higher chronaxie for the heart. Therefore, longer pulse durations could be beneficial in preventing phrenic nerve stimulation during CRT due to a decreased threshold for the heart compared with the phrenic nerve. We investigated if long pulse durations decreased left ventricular (LV) thresholds relatively to phrenic nerve thresholds in humans. Eleven patients, with indication for CRT and phrenic nerve stimulation at the intended pacing site, underwent determination of thresholds for the heart and phrenic nerve at different pulse durations (0.3-2.9 milliseconds). The resulting strength duration curves were analyzed by determining chronaxie and rheobase. Comparisons for those parameters were made between the heart and phrenic nerve, and between the models of Weiss and Lapicque as well. In 9 of 11 cases, the thresholds decreased faster for the LV than for the phrenic nerve with increasing pulse duration. In 3 cases, the thresholds changed from unfavorable for LV stimulation to more than a factor 2 in favor of the LV. The greatest change occurred for pulse durations up to 1.5 milliseconds. The chronaxie of the heart was significantly higher than the chronaxie of the phrenic nerve (0.47 milliseconds vs. 0.22 milliseconds [P = 0.029, Lapicque] and 0.79 milliseconds vs. 0.27 milliseconds [P = 0.033, Weiss]). Long pulse durations lead to a decreased threshold of the heart relatively to the phrenic nerve and may prevent stimulation of the phrenic nerve in a clinical setting. © 2013 Wiley Periodicals, Inc.

  5. Quercetin Stimulates Insulin Secretion and Reduces the Viability of Rat INS-1 Beta-Cells.

    PubMed

    Kittl, Michael; Beyreis, Marlena; Tumurkhuu, Munkhtuya; Fürst, Johannes; Helm, Katharina; Pitschmann, Anna; Gaisberger, Martin; Glasl, Sabine; Ritter, Markus; Jakab, Martin

    2016-01-01

    Previously we described insulinotropic effects of Leonurus sibiricus L. plant extracts used for diabetes mellitus treatment in Traditional Mongolian Medicine. The flavonoid quercetin and its glycoside rutin, which exert anti-diabetic properties in vivo by interfering with insulin signaling in peripheral target tissues, are constituents of these extracts. This study was performed to better understand short- and long-term effects of quercetin and rutin on beta-cells. Cell viability, apoptosis, phospho-protein abundance and insulin release were determined using resazurin, annexin-V binding assays, Western blot and ELISA, respectively. Membrane potentials (Vmem), whole-cell Ca2+ (ICa)- and ATP-sensitive K+ (IKATP) currents were measured by patch clamp. Intracellular Ca2+ (Cai) levels were measured by time-lapse imaging using the ratiometric Ca2+ indicator Fura-2. Rutin, quercetin and the phosphoinositide-3-kinase (PI3K) inhibitor LY294002 caused a dose-dependent reduction in cell viability with IC50 values of ∼75 µM, ∼25 µM and ∼3.5 µM, respectively. Quercetin (50 µM) significantly increased the percentage of Annexin-V+ cells within 48 hrs. The mean cell volume (MCV) of quercetin-treated cells was significantly lower. Within 2 hrs, quercetin significantly decreased basal- and insulin-stimulated Akt(T308) phosphorylation and increased Erk1/2 phosphorylation, without affecting P-Akt(S473) abundance. Basal- and glucose-stimulated insulin release were significantly stimulated by quercetin. Quercetin significantly depolarized Vmem by ∼25 mV which was prevented by the KATP-channel opener diazoxide, but not by the L-type ICa inhibitor nifedipine. Quercetin significantly stimulated ICa and caused a 50% inhibition of IKATP. The effects on Vmem, ICa and IKATP rapidly reached peak values and then gradually diminished to control values within ∼1 minute. With a similar time-response quercetin induced an elevation in Cai which was completely abolished in the absence of

  6. Brain Rewarding Stimulation Reduces Extracellular Glutamate Through Glial Modulation in Medial Prefrontal Cortex of Rats.

    PubMed

    Murakami, Gen; Nakamura, Masato; Takita, Masatoshi; Ishida, Yasushi; Ueki, Takatoshi; Nakahara, Daiichiro

    2015-11-01

    Growing evidence implicates a critical involvement of prefrontal glial modulation of extracellular glutamate (GLU) in aversive behaviors. However, nothing is known about whether prefrontal glial cells modulate GLU levels in rewarding behaviors. To address this question, we measured GLU efflux in the medial prefrontal cortex (PFC) of rats associated with rewarding behaviors. We used intracranial self-stimulation (ICSS) of the medial forebrain bundle (MFB) as the rewarding behavior. GLU was indirectly measured using microdialysis combined with on-line fluorometric detection of NADH resulting from the reaction of GLU and NAD(+) catalyzed by GLU dehydrogenase with a time resolution of 1 min. ICSS caused a minute-by-minute change of extracellular GLU in the medial PFC, with a slight decrease during the stimulation, followed by an increase afterward. This bidirectional change was tetrodotoxin insensitive and abolished by the gliotoxin fluorocitrate. To confirm and extend the previous studies of aversion-induced increase of extracellular GLU in the medial PFC, we also measured prefrontal GLU efflux associated with an aversive stimulation, immobilization stress. The temporal change in extracellular GLU caused by this stress was markedly different from that observed during ICSS. A rapid increase in GLU was detected during the aversive stimulation, followed by a large increase afterward. This bimodal change was tetrodotoxin insensitive, similar to that detected for ICSS. These findings indicate a bidirectional regulation of extracellular GLU by prefrontal glial cells associated with rat ICSS behavior, and reveal that glial modulation of GLU neurochemistry in the medial PFC contributes to rewarding as well as aversive behaviors in rats.

  7. Repeated transcranial direct current stimulation reduces food craving in Wistar rats.

    PubMed

    Macedo, I C; de Oliveira, C; Vercelino, R; Souza, A; Laste, G; Medeiros, L F; Scarabelot, V L; Nunes, E A; Kuo, J; Fregni, F; Caumo, W; Torres, I L S

    2016-08-01

    It has been suggested that food craving-an intense desire to consume a specific food (particularly foods high in sugar and fat)-can lead to obesity. This behavior has also been associated with abuse of other substances, such as drugs. Both drugs and food cause dependence by acting on brain circuitry involved in reward, motivation, and decision-making processes. The dorsolateral prefrontal cortex (DLPFC) can be activated following evocation and is implicated in alterations in food behavior and craving. Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique capable of modulates brain activity significantly, has emerged as a promising treatment to inhibit craving. This technique is considered safe and inexpensive; however, there is scant research using animal models. Such studies could help elucidate the behavioral and molecular mechanisms of eating disorders, including food craving. The aim of our study was to evaluate palatable food consumption in rats receiving tDCS treatment (anode right/cathode left). Eighteen adult male Wistar rats were randomized by weight and divided into three groups (n = 6/group): control, with no stimulation; sham, receiving daily 30 s tDCS (500 μA) sessions for 8 consecutive days; and tDCS, receiving daily 20 min tDCS (500 μA) sessions for 8 consecutive days. All rats were evaluated for locomotor activity and anxiety-like behavior. A palatable food consumption test was performed at baseline and on treatment completion (24 h after the last tDCS session) under fasting and feeding conditions and showed that tDCS decreased food craving, thus corroborating human studies. This result confirms the important role of the prefrontal cortex in food behavior, which can be modulated by noninvasive brain stimulation.

  8. Antibody Formation: Reduced Responses After Administration of Excessive Amounts of Nonspecific Stimulators

    PubMed Central

    Braun, Werner; Ishizuka, Masaaki

    1971-01-01

    Enhancement of antibody formation in vitro and in vivo by poly(A·U), cyclic AMP, dibutyryl cyclic AMP, or any one of these agents in combination with theophylline or caffeine, is usually limited to certain dose ranges. High doses of these nonspecific stimulators can produce less or no enhancement, or may actually inhibit antibody formation. Such dose-response relationships may be pertinent to an understanding of phenomena of specific immunological nonresponsiveness and certain types of antigenic competition. PMID:4331082

  9. Bi-frontal transcranial alternating current stimulation in the ripple range reduced overnight forgetting.

    PubMed

    Ambrus, Géza Gergely; Pisoni, Alberto; Primaßin, Annika; Turi, Zsolt; Paulus, Walter; Antal, Andrea

    2015-01-01

    High frequency oscillations in the hippocampal structures recorded during sleep have been proved to be essential for long-term episodic memory consolidation in both animals and in humans. The aim of this study was to test if transcranial Alternating Current Stimulation (tACS) of the dorsolateral prefrontal cortex (DLPFC) in the hippocampal ripple range, applied bi-frontally during encoding, could modulate declarative memory performance, measured immediately after encoding, and after a night's sleep. An associative word-pair learning test was used. During an evening encoding phase, participants received 1 mA 140 Hz tACS or sham stimulation over both DLPFCs for 10 min while being presented twice with a list of word-pairs. Cued recall performance was investigated 10 min after training and the morning following the training session. Forgetting from evening to morning was observed in the sham condition, but not in the 140 Hz stimulation condition. 140 Hz tACS during encoding may have an effect on the consolidation of declarative material.

  10. Evaluation of Small Intestine Submucosa and Poly(caprolactone-co-lactide) Conduits for Peripheral Nerve Regeneration

    PubMed Central

    Shim, Sun Woo; Kwon, Doo Yeon; Lee, Bit Na; Kwon, Jin Seon; Park, Ji Hoon; Lee, Jun Hee; Kim, Jae Ho; Lee, Il Woo; Shin, Jung-Woog; Lee, Hai Bang; Kim, Wan-Doo

    2015-01-01

    The present study employed nerve guidance conduits (NGCs) only, which were made of small intestine submucosa (SIS) and poly(caprolactone-co-lactide) (PCLA) to promote nerve regeneration in a peripheral nerve injury (PNI) model with nerve defects of 15 mm. The SIS- and PCLA-NGCs were easily prepared by rolling of a SIS sheet and a bioplotter using PCLA, respectively. The prepared SIS- and PCLA-NGCs fulfilled the general requirement for use as artificial peripheral NGCs such as easy fabrication, reproducibility for mass production, suturability, sterilizability, wettability, and proper mechanical properties to resist collapsing when applied to in vivo implantation. The SIS- and PCLA-NGCs appeared to be well integrated into the host sciatic nerve without causing dislocations and serious inflammation. All NGCs stably maintained their NGC shape for 8 weeks without collapsing, which matched well with the nerve regeneration rate. Staining of the NGCs in the longitudinal direction showed that the regenerated nerves grew successfully from the SIS- and PCLA-NGCs through the sciatic nerve-injured gap and connected from the proximal to distal direction along the NGC axis. SIS-NGCs exhibited a higher nerve regeneration rate than PCLA-NGCs. Collectively, our results indicate that SIS- and PCLA-NGCs induced nerve regeneration in a PNI model, a finding that has significant implications in the future with regard to the feasibility of clinical nerve regeneration with SIS- and PCLA-NGCs prepared through an easy fabrication method using promising biomaterials. PMID:25435200

  11. [Experiment of oral mucosa epithelial cells cultured on small intestinal submucosa in vitro].

    PubMed

    Tan, Bo; Wei, Ren-Qian; Yang, Zhi-Ming; Li, Xiu-Qun; Han, Ping; Zhi, Wei; Xie, Hui-Qi; Ren, Yan; Tan, Zhong-Xia

    2010-02-01

    To explore an effective method to culture oral mucosa epithelial cells (OMECs) of canine in vitro, and to observe the biological characteristics of OMECs growing on small intestinal submucosa (SIS) in order to provide the experimental basis for epithelium tissue engineering. The primary OMECs were cultivated with DKSFM (defined keratinocyte serum free medium) containing 6% fetal bovine serum (FBS). The morphological characteristics and the growth curve of OMECs were observed. The expressions of OMECs marker (CK19) were examined by immunocytochemistry. The 2nd passage of OMECs were seeded on SIS, OMECs co-cultured with SIS were observed by hematoxylin-eosin staining, immunohistochemical staining, and scanning electron microscope (SEM). OMECs were grown well in DKSFM. Immunohistochemical staining of the 2nd passage cultured canine OMECs with broadly reacting anti-cytokeratin anyibodies (CK19) was positive. OMECs formed a single layer on the surface of SIS, and eight days later the cells were polygong and arranged like slabstone. Culture of canine OMECs in DKSFM containing 6% FBS is a simple and feasible method. SIS has good biocompatibility, it is a kind of good bioscafold in the tissue-engineered epithelium.

  12. Reducing Current Spread by Use of a Novel Pulse Shape for Electrical Stimulation of the Auditory Nerve

    PubMed Central

    Ballestero, Jimena; Recugnat, Matthieu; Laudanski, Jonathan; Smith, Katie E.; Jagger, Daniel J.; Gnansia, Daniel

    2015-01-01

    Improving the electrode-neuron interface to reduce current spread between individual electrodes has been identified as one of the main objectives in the search for future improvements in cochlear-implant performance. Here, we address this problem by presenting a novel stimulation strategy that takes account of the biophysical properties of the auditory neurons (spiral ganglion neurons, SGNs) stimulated in electrical hearing. This new strategy employs a ramped pulse shape, where the maximum amplitude is achieved through a linear slope in the injected current. We present the theoretical framework that supports this new strategy and that suggests it will improve the modulation of SGNs’ activity by exploiting their sensitivity to the rising slope of current pulses. The theoretical consequence of this sensitivity to the slope is a reduction in the spread of excitation within the cochlea and, consequently, an increase in the neural dynamic range. To explore the impact of the novel stimulation method on neural activity, we performed in vitro recordings of SGNs in culture. We show that the stimulus efficacy required to evoke action potentials in SGNs falls as the stimulus slope decreases. This work lays the foundation for a novel, and more biomimetic, stimulation strategy with considerable potential for implementation in cochlear-implant technology. PMID:26721928

  13. Stimulation of fatty acid oxidation by a 3-thia fatty acid reduces triacylglycerol secretion in cultured rat hepatocytes.

    PubMed

    Skrede, S; Bremer, J; Berge, R K; Rustan, A C

    1994-08-01

    The present work shows that when mitochondrial beta-oxidation is stimulated by the hypolipemic, non-beta-oxidizable fatty acid analogue tetradecylthioacetic acid, there is a decrease in the secretion of triacylglycerol in cultured rat hepatocytes. In order to study the effects of tetradecylthioacetic acid in cells with different fatty acid oxidation rates, cells were grown without or with L-carnitine supplement or with addition of the beta-oxidation inhibitor L-aminocarnitine. In cells grown without and with L-carnitine in the medium, the oxidation of [1-14C]oleic acid was stimulated by tetradecylthioacetic acid, whereas it was not significantly changed by palmitic acid. In cells grown with L-aminocarnitine, oxidation of [1-14C]oleic acid was almost abolished both in the absence and in presence of tetradecylthioacetic acid. The effect of tetradecylthioacetic acid and palmitic acid on incorporation of [1-14C]oleic acid into triacylglycerol was similar under all conditions. In the presence of L-carnitine, secretion of oleic acid-labeled triacylglycerol was reduced significantly more by tetradecylthioacetic acid than by palmitic acid. The effects of tetradecylthioacetic acid and palmitic acid on secretion of oleic acid-labeled triacylglycerol were reversed in cells grown with L-aminocarnitine, where palmitic acid was the stronger inhibitor. These results were substantiated by determination of mass of triacylglycerol secreted. It is concluded that tetradecylthioacetic acid reduces secretion of triacylglycerol from rat hepatocytes mainly by acutely stimulating fatty acid oxidation.

  14. α-Lipoic acid, a scavenging agent for H₂O₂, reduces ethanol-stimulated locomotion in mice.

    PubMed

    Ledesma, Juan Carlos; Aragon, Carlos M G

    2012-01-01

    The main system of central ethanol oxidation is mediated by the enzyme catalase. By reacting with H(2)O(2), brain catalase forms compound I (the catalase-H(2)O(2) system), which is able to oxidize ethanol to acetaldehyde in the brain. Previous studies have demonstrated that pharmacological manipulations of brain catalase activity modulate the stimulant effects of ethanol in mice. However, the role of H(2)O(2) in the behavioral effects of ethanol has not yet been clearly addressed. In the present study, we investigated the effects of alpha-lipoic acid (LA), a scavenging agent for H(2)O(2), on ethanol-induced locomotor stimulation. CD-1 mice were pretreated with LA [0-100 mg/kg, intraperitoneally (IP)] 0-60 min prior to administration of ethanol (0-3.75 g/kg, IP). In another experiment, animals were pretreated with LA (0, 25, or 50 mg/kg, IP) 30 min before cocaine (10 mg/kg, IP), amphetamine (2 mg/kg, IP), or caffeine (25 mg/kg, IP). After these treatments the animals were placed in an open-field chamber and their locomotor activity was measured for 20 min. LA 25, 50, and 100 mg/kg IP prevented ethanol-induced locomotor stimulation. LA did not affect the locomotor-stimulating effects of cocaine, amphetamine, and caffeine. Additionally, we demonstrated that LA prevents the inactivation of brain catalase by 3-amino-1,2,4-triazole, thus indicating that H(2)O(2) levels are reduced by LA. These data support the idea that a decrease in cerebral H(2)O(2) production by LA administration inhibits ethanol-stimulated locomotion. This study suggests that the brain catalase-H(2)O(2) system, and by implication centrally formed acetaldehyde, plays a key role in the psychopharmacological effects of ethanol.

  15. Sensory trigeminal ULF-TENS stimulation reduces HRV response to experimentally induced arithmetic stress: A randomized clinical trial.

    PubMed

    Monaco, Annalisa; Cattaneo, Ruggero; Ortu, Eleonora; Constantinescu, Marian Vladimir; Pietropaoli, Davide

    2017-05-01

    Ultra Low Frequency Transcutaneous Electric Nervous Stimulation (ULF-TENS) is extensively used for pain relief and for the diagnosis and treatment of temporomandibular disorders (TMD). In addition to its local effects, ULF-TENS acts on the autonomic nervous system (ANS), with particular reference to the periaqueductal gray (PAG), promoting the release of endogenous opioids and modulating descending pain systems. It has been suggested that the PAG participates in the coupling between the emotional stimulus and the appropriate behavioral autonomic response. This function is successfully investigated by HRV. Therefore, our goal is to investigate the effects of trigeminal ULF-TENS stimulation on autonomic behavior in terms of HRV and respiratory parameters during an experimentally-induced arithmetic stress test in healthy subjects. Thirty healthy women between 25 and 35years of age were enrolled and randomly assigned to either the control (TENS stimulation off) or test group (TENS stimulation on). Heart (HR, LF, HF, LF/HF ratio, DET, RMSSD, PNN50, RR) and respiratory (BR) rate were evaluated under basal, T1 (TENS off/on), and stress (mathematical task) conditions. Results showed that HRV parameters and BR significantly changed during the arithmetic stress paradigm (p<0.01). Independently of stress conditions, TENS and control group could be discriminated only by non-linear HRV data, namely RR and DET (p=0.038 and p=0.027, respectively). During the arithmetic task, LF/HF ratio was the most sensitive parameter to discriminate between groups (p=0.019). Our data suggest that trigeminal sensory ULF-TENS reduces the autonomic response in terms of HRV and BR during acute mental stress in healthy subjects. Future directions of our work aim at applying the HRV and BR analysis, with and without TENS stimulation, to individuals with dysfunctional ANS among those with TMD. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Modeling electrical stimulation of retinal ganglion cell with optimizing additive noises for reducing threshold and energy consumption.

    PubMed

    Wu, Jing; Jin, Menghua; Qiao, Qingli

    2017-03-27

    Epiretinal prosthesis is one device for the treatment of blindness, which target retinal ganglion cells (RGCs) by electrodes on retinal surface. The stimulating current of epiretinal prosthesis is an important factor that influences the safety threshold and visual perception. Stochastic resonance (SR) can be used to enhance the detection and transmission of subthreshold stimuli in neurons. Here, it was assumed that SR was a potential way to improve the performance of epiretinal prosthesis. The effect of noises on the response of RGCs to electrical stimulation and the energy of stimulating current was studied based on a RGC model. The RGC was modeled as a multi-compartment model consisting of dendrites and its branches, soma and axon. To evoke SR, a subthreshold signal, a series of bipolar rectangular pulse sequences, plus stochastic biphasic pulse sequences as noises, were used as a stimulus to the model. The SR-type behavior in the model was characterized by a "power norm" measure. To decrease energy consumption of the stimulation waveform, the stochastic biphasic pulse sequences were only added to the cathode and anode phase of the subthreshold pulse and the noise parameters were optimized by using a genetic algorithm (GA). When certain intensity of noise is added to the subthreshold signal, RGC model can fire. With the noise's RMS amplitudes increased, more spikes were elicited and the curve of power norm presents the inverted U-like graph. The larger pulse width of stochastic biphasic pulse sequences resulted in higher power norm. The energy consumption and charges of the single bipolar rectangular pulse without noise in threshold level are 468.18 pJ, 15.30 nC, and after adding optimized parameters's noise to the subthreshold signal, they became 314.8174 pJ, 11.9281 nC and were reduced by 32.8 and 22.0%, respectively. The SR exists in the RGC model and can enhance the representation of RGC model to the subthreshold signal. Adding the stochastic biphasic

  17. Galvanic zinc-copper microparticles produce electrical stimulation that reduces the inflammatory and immune responses in skin.

    PubMed

    Kaur, Simarna; Lyte, Peter; Garay, Michelle; Liebel, Frank; Sun, Ying; Liu, Jue-Chen; Southall, Michael D

    2011-10-01

    The human body has its own innate electrical system that regulates the body's functions via communications among organs through the well-known neural system. While the effect of low-level electrical stimulation on wound repair has been reported, few studies have examined the effect of electric potential on non-wounded, intact skin. A galvanic couple comprised of elemental zinc and copper was used to determine the effects of low-level electrical stimulation on intact skin physiology using a Dermacorder device. Zn-Cu induced the electrical potential recorded on intact skin, enhanced H(2)O(2) production and activated p38 MAPK and Hsp27 in primary keratinocytes. Treatment with Zn-Cu was also found to reduce pro-inflammatory cytokines, such as IL-1α, IL-2, NO and TNF-α in multiple cell types after stimulation with PHA or Propionibacterium acnes bacteria. The Zn-Cu complex led to a dose-dependent inhibition of TNF-α-induced NF-κB levels in keratinocytes as measured by a dual-luciferase promoter assay, and prevented p65 translocation to the nucleus observed via immunofluorescence. Suppression of NF-κB activity via crosstalk with p38 MAPK might be one of the potential pathways by which Zn-Cu exerted its inflammatory effects. Topical application of Zn-Cu successfully mitigated TPA-induced dermatitis and oxazolone-induced hypersensitivity in mice models of ear edema. Anti-inflammatory activity induced by the Zn-Cu galvanic couple appears to be mediated, at least in part, by production of low level of hydrogen peroxide since this activity is reversed by the addition of Catalase enzyme. Collectively, these results show that a galvanic couple containing Zn-Cu strongly reduces the inflammatory and immune responses in intact skin, providing evidence for the role of electric stimulation in non-wounded skin.

  18. Circulating macrophage colony-stimulating factor is not reduced in malignant osteopetrosis.

    PubMed

    Orchard, P J; Dahl, N; Aukerman, S L; Blazar, B R; Key, L L

    1992-01-01

    Malignant osteopetrosis is a disorder characterized by a deficiency in osteoclast number or function. In one animal model of osteopetrosis, the op/op mouse, macrophage colony-stimulating factor (M-CSF) is absent, and the administration of M-CSF corrects the defects. We evaluated the serum of 13 patients with malignant osteopetrosis by an M-CSF radioimmunoassay to determine if a quantitative M-CSF deficiency existed in these patients. All patients had M-CSF present in levels equal to or higher than control serum. In addition, serum from 6 osteopetrotic patients was tested in a bioassay to determine if the M-CSF present is biologically active, and in all cases there was demonstrable activity in these samples. We provide evidence that deficiency of circulating M-CSF is unlikely to be a major contributor to the etiologic basis for the majority of children with malignant osteopetrosis.

  19. Serum and CNTF stimulate oligodendroglia and reduce fiber outgrowth from striatal cultures.

    PubMed

    Dahl-Jørgensen, A; Ostergaard, K; Pedersen, E B; Zimmer, J

    1999-05-01

    Organotypic slice cultures of newborn rat striatal tissue displayed an exceptionally dense and fasciculated outgrowth of GABAergic fibers when grown in a chemically defined medium, compared to serum-containing medium. The enhanced fiber growth was not the result of an increased density of GABAergic neurons in the cultures, but coincided with a marked reduction of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)-immunoreactive cells within and around the cultures. An inverse, causal relationship between the number of CNPase-positive cells, presumably of oligodendroglial lineage, and GABAergic fiber outgrowth was further evidenced by the observation that addition of ciliary neurotrophic factor (CNTF) to the chemically defined medium resulted in both an increase in CNPase-positive cells and a decrease in GABAergic fiber outgrowth. The observations suggest that CNTF and serum indirectly inhibit axonal growth by stimulating oligodendroglial cells.

  20. Repetitive transcranial magnetic stimulation of human MT+ reduces apparent motion perception.

    PubMed

    Matsuyoshi, Daisuke; Hirose, Nobuyuki; Mima, Tatsuya; Fukuyama, Hidenao; Osaka, Naoyuki

    2007-12-18

    We investigated the effects of repetitive transcranial magnetic stimulation (rTMS) over the human cerebral cortex on apparent motion perception. Previous studies have shown that human extrastriate visual area MT+ (V5) processes not only real but also apparent motion. However, the functional relevance of MT+ on long-range apparent motion perception remains unclear. Here, we show direct evidence for the involvement of MT+ in apparent motion perception using rTMS, which is known to temporarily inhibit a localized region in the cerebral cortex. The results showed that apparent motion perception decreased after applying rTMS over MT+, but not after applying rTMS over the control region (inferior temporal gyrus). The decrease in performance caused by applying rTMS to MT+ suggests that MT+ is a causally responsible region for apparent motion perception, and thus, further supports the idea that MT+ plays a major role in the perception of motion.

  1. Hypothalamic deep brain stimulation reduces weight gain in an obesity-animal model.

    PubMed

    Melega, William P; Lacan, Goran; Gorgulho, Alessandra A; Behnke, Eric J; De Salles, Antonio A F

    2012-01-01

    Prior studies of appetite regulatory networks, primarily in rodents, have established that targeted electrical stimulation of ventromedial hypothalamus (VMH) can alter food intake patterns and metabolic homeostasis. Consideration of this method for weight modulation in humans with severe overeating disorders and morbid obesity can be further advanced by modeling procedures and assessing endpoints that can provide preclinical data on efficacy and safety. In this study we adapted human deep brain stimulation (DBS) stereotactic methods and instrumentation to demonstrate in a large animal model the modulation of weight gain with VMH-DBS. Female Göttingen minipigs were used because of their dietary habits, physiologic characteristics, and brain structures that resemble those of primates. Further, these animals become obese on extra-feeding regimens. DBS electrodes were first bilaterally implanted into the VMH of the animals (n = 8) which were then maintained on a restricted food regimen for 1 mo following the surgery. The daily amount of food was then doubled for the next 2 mo in all animals to produce obesity associated with extra calorie intake, with half of the animals (n = 4) concurrently receiving continuous low frequency (50 Hz) VMH-DBS. Adverse motoric or behavioral effects were not observed subsequent to the surgical procedure or during the DBS period. Throughout this 2 mo DBS period, all animals consumed the doubled amount of daily food. However, the animals that had received VMH-DBS showed a cumulative weight gain (6.1±0.4 kg; mean ± SEM) that was lower than the nonstimulated VMH-DBS animals (9.4±1.3 kg; p<0.05), suggestive of a DBS-associated increase in metabolic rate. These results in a porcine obesity model demonstrate the efficacy and behavioral safety of a low frequency VMH-DBS application as a potential clinical strategy for modulation of body weight.

  2. Hypothalamic Deep Brain Stimulation Reduces Weight Gain in an Obesity-Animal Model

    PubMed Central

    Melega, William P.; Lacan, Goran; Gorgulho, Alessandra A.; Behnke, Eric J.; De Salles, Antonio A. F.

    2012-01-01

    Prior studies of appetite regulatory networks, primarily in rodents, have established that targeted electrical stimulation of ventromedial hypothalamus (VMH) can alter food intake patterns and metabolic homeostasis. Consideration of this method for weight modulation in humans with severe overeating disorders and morbid obesity can be further advanced by modeling procedures and assessing endpoints that can provide preclinical data on efficacy and safety. In this study we adapted human deep brain stimulation (DBS) stereotactic methods and instrumentation to demonstrate in a large animal model the modulation of weight gain with VMH-DBS. Female Göttingen minipigs were used because of their dietary habits, physiologic characteristics, and brain structures that resemble those of primates. Further, these animals become obese on extra-feeding regimens. DBS electrodes were first bilaterally implanted into the VMH of the animals (n = 8) which were then maintained on a restricted food regimen for 1 mo following the surgery. The daily amount of food was then doubled for the next 2 mo in all animals to produce obesity associated with extra calorie intake, with half of the animals (n = 4) concurrently receiving continuous low frequency (50 Hz) VMH-DBS. Adverse motoric or behavioral effects were not observed subsequent to the surgical procedure or during the DBS period. Throughout this 2 mo DBS period, all animals consumed the doubled amount of daily food. However, the animals that had received VMH-DBS showed a cumulative weight gain (6.1±0.4 kg; mean ± SEM) that was lower than the nonstimulated VMH-DBS animals (9.4±1.3 kg; p<0.05), suggestive of a DBS-associated increase in metabolic rate. These results in a porcine obesity model demonstrate the efficacy and behavioral safety of a low frequency VMH-DBS application as a potential clinical strategy for modulation of body weight. PMID:22295102

  3. Nano-hydroxyapatite-thermally denatured small intestine sub-mucosa composites for entheses applications.

    PubMed

    Perla, Venu; Webster, Thomas J

    2006-01-01

    The objective of the present in vitro study was to estimate the adhesion strength of nanometer crystalline hydroxyapatite (HA)-small intestine sub-mucosa (SIS) composites on model implant surfaces. Techniques of thermal denaturation (60 degrees C, 20 min) of SIS were used to enhance the adhesion strength of entheses materials to underlying implants. Specifically, results indicated that the adhesion strength of thermally denatured SIS was 2-3 times higher than that for normal unheated SIS. In addition, aqua-sonicated, hydrothermally treated nano-HA dispersions enhanced the adhesion strength of SIS on implant surfaces. Importantly, results of the present study demonstrated that human skeletal muscle cell (hSkMC) numbers were not affected by thermally denaturing SIS in nano-HA composite coatings; however, they increased on aqua-sonicated nano-HA/SIS composites compared with SIS alone. Interestingly, thermally denatured SIS that contained aqua-sonicated, hydrothermally treated nano-HA decreased human osteoblasts (hOBs) numbers compared with respective unheated composites; all other composites when thermally denatured did not influence hOB numbers. Results also showed that the number of hOBs increased on nano-HA/SIS composites compared with SIS composites alone. Human mesenchymal stem cell (hMSC) numbers were not affected by the presence of nano-HA in SIS composites. For these reasons, the collective results of this in vitro study demonstrated a technique to increase the coating strength of entheses coatings on implant surfaces (using thermally denatured SIS and aqua-sonicated, hydrothermally prepared nano-HA) while, at the same time, supporting cell functions important for entheses regeneration.

  4. Percutaneous Vein Occlusion with Small Intestinal Submucosa: An Experimental Pilot Study in Swine and Sheep

    SciTech Connect

    Kim, Man Deuk; Hoppe, Hanno; Pavcnik, Dusan Kaufman, John A.; Uchida, Barry T.; Correa, Luiz O.; Timmermans, Hans A.; Park, Won Kyu; Corless, Christopher L.; Keller, Frederick S.; Roesch, Josef

    2007-07-15

    Purpose. The objective of this study was to investigate the feasibility, outcomes, and amount of small intestinal submucosa (SIS) material needed for embolization of jugular vein (JV) in a swine and sheep model. Our hypothesis was that SIS would cause vein occlusion. Materials and Methods. The external JVs (EJV) in swine (n = 6) and JVs in sheep (n = 6) were occluded with SIS fan-folded compressed strips. After percutaneous puncture of the peripheral portion of the EJV or JV, a TIPS set was used to exit their lumen centrally through the skin. The SIS strips were delivered into the isolated venous segment with a pull-through technique via a 10-Fr sheath. Follow-up venograms were done immediately after placement and at the time of sacrifice at 1 or 3 months. Gross examinations focused on the EJV or JV and their surrounding structures. Specimens were evaluated by histology. Results. SIS strip(s) placement was successful in all cases, with immediate vein occlusion seen in 23 of 24 veins (95.8%). All EJVs treated with two strips and all JVs treated with three or four strips remained closed on 1- and 3-month follow-up venograms. Two EJVs treated with one strip and one JV treated with two strips were partially patent on venograms at 1 and 3 months. There has been one skin inflammatory reaction. Necropsies revealed excluded EJV or JV segments with SIS incorporation into the vein wall. Histology demonstrated various stages of SIS remodeling with fibrocytes, fibroblasts, endothelial cells, capillaries, and inflammatory cells. Conclusion. We conclude that EJV and JV ablation with SIS strips using percutaneous exit catheterization is feasible and effective in animal models. Further exploration of SIS as vein ablation material is recommended.

  5. Small Intestinal Submucosa Grafting for Peyronie Disease: Outcomes and Patient Satisfaction.

    PubMed

    Valente, Pedro; Gomes, Carolina; Tomada, Nuno

    2017-02-01

    To evaluate surgical outcomes and complications and assess overall patient satisfaction after small intestinal submucosa (SIS) grafting for Peyronie disease. Twenty-eight patients were treated with tunical incision and grafting with SIS. Mean age of the patients was 58 (range: 43-71) years. A preoperative protocol was applied to all patients. Patients were also evaluated at follow-up clinic visits. The International Index of Erectile Function, a modified Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire, postoperative self-reports, and clinical characteristics were used to measure outcomes. Hypertension, hypercholesterolemia, and type 2 diabetes were reported in 53,6%, 46,4%, and 28,6% of patients, respectively. Previous penile trauma was reported by 10,7%. The mean operative time was 151 ± 23 minutes. Average follow-up was 18 months (range: 3-36). The only surgical complication was 1 case of infected hematoma treated with surgical drainage. Self-reported complete resolution of curvature was 82,1%. Subjective perception of penile shortening was reported by 71,4% of patients. However, only 4 patients objectively showed postoperative penile shortening. Erectile function was completely preserved in 64,2%. Four patients complained of erectile dysfunction despite medication, even though no objective vascular etiology was shown on postoperative penile Doppler ultrasound. Overall, 82,2% of patients reported high levels of satisfaction. Surgical treatment of Peyronie disease using SIS grafting is a safe option, with low rate of major complications. It has good surgical outcomes and high patient satisfaction rates. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Reconstruction of abdominal wall musculofascial defects with small intestinal submucosa scaffolds seeded with tenocytes in rats.

    PubMed

    Song, Zhicheng; Peng, Zhiyou; Liu, Zhengni; Yang, Jianjun; Tang, Rui; Gu, Yan

    2013-07-01

    The repair of abdominal wall defects following surgery remains a difficult challenge. Although multiple methods have been described to restore the integrity of the abdominal wall, there is no clear consensus on the ideal material for reconstruction. This study explored the feasibility of in vivo reconstruction of a rat model of an abdominal wall defect with a composite scaffold of tenocytes and porcine small intestinal submucosa (SIS). In the current study, we created a 2×1.5 cm abdominal wall defect in the anterolateral abdominal wall of Sprague-Dawley rats, which were assigned into three groups: the cell-SIS construct group, the cell-free SIS scaffold group, and the abdominal wall defect group. Tenocytes were obtained from the tendons of rat limbs. After isolation and expansion, cells (2×10(7)/mL) were seeded onto the three-layer SIS scaffolds and cultured in vitro for 5 days. Cell-SIS constructs or cell-free constructs were implanted to repair the abdominal wall defects. The results showed that the tenocytes could grow on the SIS scaffold and secreted corresponding matrices. In addition, both scaffolds could repair the abdominal wall defects with no hernia recurrence. In comparison to the cell-free SIS scaffold, the composite scaffold exhibited increased vascular regeneration and mechanical strength. Furthermore, following increased time in vivo, the mechanical strength of the composite scaffold became stronger. The results indicate that the composite scaffold can provide increased mechanical strength that may be suitable for repairing abdominal wall defects.

  7. Improved biocompatibility of small intestinal submucosa (SIS) following conditioning by human endothelial cells.

    PubMed

    Woods, A M; Rodenberg, E J; Hiles, M C; Pavalko, F M

    2004-02-01

    Small intestinal submucosa (SIS) is a naturally occurring tissue matrix composed of extracellular matrix proteins and various growth factors. SIS is derived from the porcine jejunum and functions as a remodeling scaffold for tissue repair. While SIS has proven to be a useful biomaterial for implants in vivo, problems associated with endothelialization and thrombogenicity of SIS implants may limit its vascular utility. The goal of this study was to determine if the biological properties of SIS could be improved by growing human umbilical vein endothelial cells (HUVEC) on SIS and allowing these cells to deposit human basement membrane proteins on the porcine substrate to create what we have called "conditioned" SIS (c-SIS). Using an approach in which HUVEC were grown for 2 weeks on SIS and then removed via a technique that leaves behind an intact basement membrane, we hypothesized that the surface properties of SIS might be improved. We found that when re-seeded on c-SIS, HUVEC exhibited enhanced organization of cell junctions and had increased metabolic activity compared to cells on native SIS (n-SIS). Furthermore, HUVEC grown on c-SIS released lower amounts of the pro-inflammatory prostaglandin PGI2 into the media compared to cells grown on n-SIS. Additionally, we found that adhesion of resting or activated human platelets to c-SIS was significantly decreased compared to n-SIS suggesting that, in addition to improved cell growth characteristics, conditioning SIS with human basement membrane proteins might decrease its thrombogenic potential. In summary, conditioning of porcine SIS by human endothelial cells improves key biological properties of the material that may improve its usefulness as remodeling scaffold for tissue repair. Identification of critical modifications of SIS by human endothelial cells should help guide future efforts to develop more biocompatible vascular grafts.

  8. Bond strength of fibrin glue between layers of porcine small intestine submucosa (SIS).

    PubMed

    Nicoson, Zach R; Buckley, Christine A

    2002-01-01

    This study investigated the strength of the bond between layers of small intestine submucosa (SIS, Cook Biotech, Inc., West Lafayette, IN) glued with commercially available fibrin glue (Haemacure Corporation). To determine the conditions leading to the highest bond strength, three parameters were varied: the concentration of the fibrin component, the concentration of the thrombin component, and the type of applicator used to apply the two components. Five glue concentrations and two applicator types, a Paasch Airbrush and one provided with the Haemacure glue kit, were studied. To make the test specimens, two pieces of SIS were each sprayed separately with 1 mL of one of the glue components. The two pieces were then adhered and allowed to cure for two minutes. After the panels were glued, frozen, and lyophilized, they were cut to size according to ASTM Standard D 1876: Peel Resistance of Adhesives (T-Peel Test). The panels were then rehydrated, and tests were performed in an MTS tensile testing machine set to pull at a constant rate of 1 mm/sec over a 100 mm span. The mean force over the duration of the test was computed as specified in the ASTM standard. The airbrush was found to produce a stronger bond than the applicator supplied by Haemacure. Judged qualitatively, the airbrush also produced a much more uniform spray and consistent flow rate than the glue manufacturer's applicator. The data suggest that a decrease in concentration of both glue components yields increased bond strength, although variability in the results also increased with decreased glue component concentration.

  9. Porcine Small Intestinal Submucosa Mesh for Treatment of Pelvic Organ Prolapsed

    PubMed Central

    Cao, Ting-Ting; Sun, Xiu-Li; Wang, Shi-Yan; Yang, Xin; Wang, Jian-Liu

    2016-01-01

    Background: Pelvic organ prolapse (POP) is a major health concern that affects women. Surgeons have increasingly used prosthetic meshes to correct POP. However, the most common used is synthetic mesh, and absorbable mesh is less reported. This research aimed to evaluate the clinical effectiveness of porcine small intestinal submucosa (SIS). Methods: Consecutive forty POP patients who met the inclusion criteria underwent pelvic reconstruction surgery with SIS between March 2012 and December 2013. The patients’ clinical characteristics were recorded preoperatively. Surgical outcomes, measured by objective and subjective success rates, were investigated. We evaluated the quality of life (QOL) using the Pelvic Floor Distress Inventory-20 (PFDI-20) and the Pelvic Floor Impact Questionnaire-7 (PFIQ-7). Sexual QOL was assessed by the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire-12 (PISQ-12). Results: At postoperative 12 months, the subjective recurrence rate (7.5%) was much lower than the objective recurrence rate (40.0%). Postoperatively, no erosion was identified. One underwent a graft release procedure because of urinary retention, and one had anus sphincter reconstruction surgery due to defecation urgency. Another experienced posterior vaginal wall infection where the mesh was implanted, accompanied by severe vaginal pain. Estrogen cream relieved the pain. One patient with recurrence underwent a secondary surgery with Bard Mesh because of stage 3 anterior vaginal wall prolapse. Scoring system of PFDI-20 was from 59.150 ± 13.143 preoperatively to 8.400 ± 4.749 postoperatively and PFIQ-7 was from 73.350 ± 32.281 to 7.150 ± 3.110, while PISQ-12 was from 15.825 ± 4.050 to 12.725 ± 3.471. Conclusions: QOL and the degree of subjective satisfaction were significantly improved postoperatively. Anterior repair deserves more attention because of the higher recurrence rate. The long-term follow-up of the patient is warranted to draw firm

  10. Penile enhancement using a porcine small intestinal submucosa graft in a rat model.

    PubMed

    Leungwattanakij, S; Pummangura, N; Ratana-Olarn, K

    2006-01-01

    Several biodegradable materials have been experimented for penile enhancement, but none show the potential for clinical use. This study was designed to use porcine small intestinal submucosa (SIS) augmenting the normal tunica albuginea to increase the functional girth of the rat penis. In all, 20 adult male Sprague-Dawley rats constituted the study population. The animals were divided into two groups: group 1 consisted of the control (n=10) and group 2 (n=10) consisted of rats that underwent penile enhancement by a longitudinal I-shaped incision of the tunica albuginea on both sides, and the dissection of the plane between tunica albuginea and cavernosal tissue was carried out (n=10). The incision was then patched with a 3 x 10 mm2 piece of SIS, using a 6/0 nylon suture material. The penile length and mid-circumference were then measured using a Vernier Caliper before and 2 months after surgery. All rat penises underwent histological examination using Masson's trichome and Verhoff's van Giesen's stain for collagen and elastic fibers. The penile length, mid-circumference and degree of fibrosis score were expressed as mean+/-s.e. (standard error) and analyzed using a Wilcoxon rank-sum test. A statistical significance was accepted at P-value < or =0.05. Our results showed similar preoperative penile length and circumference in both groups. However, 2 months after the surgery, the mean penile circumference of the SIS group has grown significantly larger than the control group, while the mean penile length remained unchanged. The histological study of the rat penises revealed minimal amounts of fibrosis under the graft, and the elastic fibers of the graft showed orientation in a circular manner. In conclusion, SIS appears promising for material use in a penile enhancement.

  11. Multilayer composite scaffolds with mechanical properties similar to small intestinal submucosa.

    PubMed

    Lawrence, Benjamin J; Maase, Eric L; Lin, Hsueh-Kung; Madihally, Sundararajan V

    2009-03-01

    Use of biodegradable scaffolds to engineer new tissues has become an attractive option in various transplantation protocols. In particular, small intestinal submucosa (SIS) has generated immense interest in various tissue engineering applications because of its diverse favorable properties. However, it is a natural matrix, which leads to problems in large-scale preparations and contains sample to sample heterogeneity. In this study, we explored the formation of synthetic matrix mimicking the characteristics of the SIS. Three-dimensional composite structures were developed by sandwiching 50:50 PLGA film between porous chitosan matrices. The outer chitosan layers provide biological activity while the inner PLGA layer provides mechanical strength. PLGA films were initially perforated at 1 cm distance, and the porous chitosan matrix was formed sequentially on each side by controlled rate freezing and lyophilization technique at -80 degrees C. Scanning electron microscopy analysis showed a layered microarchitecture with chitosan filling the perforations of PLGA membrane. Urea permeability studies confirmed that the perforations were filled (negligible urea transfer across composite over 8 h). Tensile strength analysis showed that the matrices formed using 160 kDa PLGA had sufficient break stress ( approximately 4.5 MPa). Degradation analysis over 8 weeks in the presence of 10 mg/L lysozyme showed a 50% decrease in total weight and an 80% decrease in PLGA molecular weight. When cellular adhesion and actin distribution of mouse embryonic fibroblasts were evaluated, for 7 days, cells showed their typical spindle shape and redistribution of actin fibers on composite matrices. Viability studies and MMP-2/MMP-9 activity showed that the cells were viable and functional, similar to tissue culture plastic. Further, canine bladder smooth muscle cells also showed similar cell adhesion and spreading on the composite matrix. In summary, composite structures mimicking SIS were

  12. Tissue engineered esophagus scaffold constructed with porcine small intestinal submucosa and synthetic polymers.

    PubMed

    Fan, Mei-Rong; Gong, Mei; Da, Lin-Cui; Bai, Lin; Li, Xiu-Qun; Chen, Ke-Fei; Li-Ling, Jesse; Yang, Zhi-Ming; Xie, Hui-Qi

    2014-02-01

    Acellular porcine small intestinal submucosa (SIS) has been successfully used for reconstructing esophagus with half circumferential defects. However, repairing full circumferential esophageal defects with SIS has been restricted due to the latter's poor mechanical properties. In the present study, synthetic polyesters biomaterial poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) and poly(lactide-co-glycolide) (PLGA) have been used to improve the mechanical properties of SIS. Feasibility of SIS/PHBHHx-PLGA composite material scaffold for esophageal tissue engineering has been assessed through a series of testing. The appropriate mixing ratio of PHBHHx and PLGA polymers has been determined as 5:5 by mechanical testing and in vitro degradation experiment. The morphology of constructed membranous and tubular scaffolds was also characterized. As confirmed by enzyme-linked immunosorbent assay, the contents of VEGF and TGF-β have respectively reached 657 ± 18 ng mL(-1) and 130 ± 4 pg mL(-1) within the SIS/PHBHHx-PLGA specimens. Biocompatibility of the SIS/PHBHHx-PLGA specimens with rat bone marrow mesenchymal stem cells (MSCs) was also evaluated by scanning electron microscopy and a live-dead cell viability assay. Actin filaments of MSCs on the composite materials were labeled. Biological safety of the extract from SIS/PHBHHx-PLGA specimens, measured as hemolysis rate, was all lower than 5%. Compared with SIS and SIS/PHBHHx-PLGA specimens, inflammatory reaction provoked by the PHBHHx-PLGA specimens in rats was however more severe. Our results have suggested that SIS/PHBHHx-PLGA composite material can offer a new approach for esophageal tissue engineering.

  13. Bladder augmentation with small intestinal submucosa leads to unsatisfactory long-term results.

    PubMed

    Schaefer, M; Kaiser, A; Stehr, M; Beyer, H J

    2013-12-01

    To evaluate the use of small intestinal submucosa (SIS) for bladder augmentation in a series of select patients. Six patients (age 6.5-15.4, mean 9.8 years) underwent bladder augmentation with SIS: one after a cloacal exstrophy repair, one after multiple surgery of the bladder because of vesicoureteral reflux, two with spina bifida, two after bladder exstrophy repair. All suffered from a microbladder with a mean volume of 61.5 ml (range 15-120, 7-36% of expected bladder capacity for age). Preoperative bladder compliance ranged from 1.0 to 3.3 (mean 1.3) ml/cmH2O. Follow-up time ranged from 4.6 to 33.5 (mean 24.4) months. An increase of bladder volume was achieved in four patients (53-370 ml, 16-95% of expected bladder capacity for age). Bladder compliance postoperatively ranged from 0.9 to 5.6 (mean 3.0) ml/cmH2O. Histological examinations showed a complete conversion of SIS, leaving irregular urothelial lining and bladder wall containing muscular, vascular and relatively thick connective tissue in four patients and regular urothelium in two patients. Major complications were bladder stones in two patients and a bladder rupture in one patient. Bladder augmentation with SIS in humans failed to fulfill the hopes raised by animal studies. Due to the insufficient increase in bladder compliance and therefore failure to accomplish sufficient protection of the upper urinary tract, bladder augmentation with SIS cannot be recommended as a substitute for enterocystoplasty. Copyright © 2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

  14. Hydrodynamic Assessment of Aortic Valves Prepared from Porcine Small Intestinal Submucosa.

    PubMed

    Ramaswamy, Sharan; Lordeus, Makensley; Mankame, Omkar V; Valdes-Cruz, Lilliam; Bibevski, Steven; Bell, Sarah M; Baez, Ivan; Scholl, Frank

    2017-03-01

    Infants and children born with severe cardiac valve lesions have no effective long term treatment options since currently available tissue or mechanical prosthetic valves have sizing limitations and no avenue to accommodate the growth of the pediatric patient. Tissue engineered heart valves (TEHVs) which could provide for growth, self-repair, infection resistance, and long-term replacement could be an ideal solution. Porcine small intestinal submucosa (PSIS) has recently emerged as a potentially attractive bioscaffold for TEHVs. PSIS may possess the ability to recruit endogenous cardiovascular cells, leading to phenotypically-matched replacement tissue when the scaffold has completely degraded. Our group has successfully implanted custom-made PSIS valves in 4 infants with critical valve defects in whom standard bioprosthetic or mechanical valves were not an option. Short term clinical follow-up has been promising. However, no hydrodynamic data has been reported to date on these valves. The purpose of this study was to assess the functional effectiveness of tri-leaflet PSIS bioscaffolds in the aortic position compared to standard tri-leaflet porcine bioprosthetic valves. Hydrodynamic evaluation of acute PSIS function was conducted using a left heart simulator in our laboratory. Our results demonstrated similar flow and pressure profiles (p > 0.05) between the PSIS valves and the control valves. However, forward flow energy losses were found to be significantly greater (p < 0.05) in the PSIS valves compared to the controls possibly as a result of stiffer material properties of PSIS relative to glutaraldehyde-fixed porcine valve tissue. Our findings suggest that optimization of valve dimensions and shape may be important in accelerating de novo valve tissue growth and avoidance of long-term complications associated with higher energy losses (e.g. left ventricular hypertrophy). Furthermore, long term animal and clinical studies will be needed in order to

  15. Functional electrical stimulation mediated by iterative learning control and 3D robotics reduces motor impairment in chronic stroke.

    PubMed

    Meadmore, Katie L; Hughes, Ann-Marie; Freeman, Chris T; Cai, Zhonglun; Tong, Daisy; Burridge, Jane H; Rogers, Eric

    2012-06-07

    Novel stroke rehabilitation techniques that employ electrical stimulation (ES) and robotic technologies are effective in reducing upper limb impairments. ES is most effective when it is applied to support the patients' voluntary effort; however, current systems fail to fully exploit this connection. This study builds on previous work using advanced ES controllers, and aims to investigate the feasibility of Stimulation Assistance through Iterative Learning (SAIL), a novel upper limb stroke rehabilitation system which utilises robotic support, ES, and voluntary effort. Five hemiparetic, chronic stroke participants with impaired upper limb function attended 18, 1 hour intervention sessions. Participants completed virtual reality tracking tasks whereby they moved their impaired arm to follow a slowly moving sphere along a specified trajectory. To do this, the participants' arm was supported by a robot. ES, mediated by advanced iterative learning control (ILC) algorithms, was applied to the triceps and anterior deltoid muscles. Each movement was repeated 6 times and ILC adjusted the amount of stimulation applied on each trial to improve accuracy and maximise voluntary effort. Participants completed clinical assessments (Fugl-Meyer, Action Research Arm Test) at baseline and post-intervention, as well as unassisted tracking tasks at the beginning and end of each intervention session. Data were analysed using t-tests and linear regression. From baseline to post-intervention, Fugl-Meyer scores improved, assisted and unassisted tracking performance improved, and the amount of ES required to assist tracking reduced. The concept of minimising support from ES using ILC algorithms was demonstrated. The positive results are promising with respect to reducing upper limb impairments following stroke, however, a larger study is required to confirm this.

  16. Synthesis and biological evaluation of amino-pyridines as androgen receptor antagonists for stimulating hair growth and reducing sebum production.

    PubMed

    Hu, Lain-Yen; Lei, Huangshu John; Du, Daniel; Johnson, Theodore R; Fedij, Victor; Kostlan, Catherine; Yue, Wen Song; Lovdahl, Mark; Li, Jie Jack; Carroll, Mathew; Dettling, Danielle; Asbill, Jeffrey; Fan, Conglin; Wade, Kimberly; Pocalyko, David; Lapham, Kimberly; Yalamanchili, Radhika; Samas, Brian; Vrieze, Derek; Ciotti, Susan; Krieger-Burke, Teresa; Sliskovic, Drago; Welgus, Howard

    2007-10-15

    A series of amino-pyridines were synthesized and evaluated for androgen antagonist activities. Among these compounds, (R)-(+)-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile was the most active example of this class. This compound displayed potent androgen receptor antagonist activity as well as favorable pharmacokinetic characteristics for a potential topical agent. It also demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.

  17. INCREASE IN OSMIOPHILIA OF AXONAL MEMBRANES OF CRAYFISH AS A RESULT OF ELECTRICAL STIMULATION, ASPHYXIA, OR TREATMENT WITH REDUCING AGENTS

    PubMed Central

    Peracchia, Camillo; Robertson, J. David

    1971-01-01

    Certain axonal membranes of crayfish abdominal nerve cord display ultrastructural changes if the axons are fixed, during electrical stimulation, by aldehydes followed by osmium. Such changes are characterized by an increase in electron opacity and thickness of the unit membranes' dense strata in the axon surface, endoplasmic reticulum, and outer mitochondrial membranes. The electron opacity completely disappears if the sections are treated with hydrogen peroxide solutions. This suggests that the changes represent an increase in the membranes' reactivity for osmium. An unmasking of SH groups could explain such increased osmiophilia, since SH groups are very reactive with osmium, while disulfide bonds are considerably less reactive. This hypothesis was tested by treating control, glutaraldehydefixed nerve cords with disulfide reducing agents. In these preparations an increase in electron opacity and thickness was observed to be localized in the same axonal membranes which reacted as a result of electrical stimulation. The phenomenon did not appear if the SH groups were blocked by maleimide or N-ethylmaleimide before treatment with osmium. These findings seem to suggest that certain axonal membranes of crayfish contain proteins rich in sulfur whose SH groups are unmasked as a result of electrical stimulation. In preliminary experiments an increase in osmiophilia localized in the same membranes with the same characteristics and distribution was observed also in axons from nerve cords asphyxiated either in vitro or in the living animal. PMID:5111876

  18. EPO reduces reactive gliosis and stimulates neurotrophin expression in Muller cells.

    PubMed

    Hu, Liu-Mei; Luo, Yan; Zhang, Jingfa; Lei, Xia; Shen, Jianfeng; Wu, Yalan; Qin, Mei; Unver, Yaprak Banu; Zhong, Yong; Xu, Guo-Tong; Li, Weiye

    2011-06-01

    To characterize Müller cell-mediated neuroprotective and neurotrophic functions of the erythropoietin (EPO)/EPO receptor (EpoR) system in diabetic rat retina. A single intravitreal injection of EPO (8 mU/eye) was administered in rats 4 or 24 weeks after diabetes onset. The results showed that intravitreal EPO ameliorated the up-regulation of GFAP and vimentin in the diabetic retina evaluated by immunofluorescence and Western blotting; but up-regulated BDNF and CNTF expressions, quantified by real-time PCR and ELISA, in the 24-week diabetic rat retinas. In vitro, BDNF and CNTF expressions were stimulated by EPO through both extracellular signal-regulated kinase1/2 (ERK1/2) and Akt pathways. The neuro-regenerative function of EPO, as indicated by promotion of neurite outgrowth, was corroborated in vitro. BDNF was involved in EPO-induced neurite outgrowth of primary rat retinal neurons. Exogenous EPO exerts neuroprotective and neurotrophic functions by attenuating reactive gliosis and promoting neurotrophic factors in Muller cells in diabetic retina. Signaling pathways that are responsible for these Muller cell-mediated EPO/EpoR functions may be therapeutic targets for diabetic retinopathy.

  19. Transcutaneous Electrical Nerve Stimulation Reduces Post-Thoractomy Ipsilateral Shoulder Pain. A Prospective Randomized Study.

    PubMed

    Esteban González, Pedro; Novoa, Nuria M; Varela, Gonzalo

    2015-12-01

    The patient's position during an axillary thoracotomy can cause postoperative pain and decrease mobility of the ipsilateral shoulder. In this study, we assessed whether the implementation of a standardized analgesia program using transcutaneous electrical nerve stimulation (TENS) decreases local pain and improves ipsilateral shoulder mobility. Randomized, single-blind, single-center clinical trial of 50 patients who had undergone anatomical lung resection via axillary muscle-sparing thoracotomy. Patients were treated with TENS devices for 30 minutes every 8 hours, beginning on postoperative day 1. Pain and mobility of the affected limb were recorded at the same time on postoperative days 1 through 3. A visual analogue scale was used for pain assessment and shoulder mobility was assessed with a goniometer. Results were compared using a non-parametric test. Twenty-five patients were randomized to each group. Mean age of the control group was 62.7±9.3 years and 63.4±10.2 years in the experimental group. Shoulder mobility parameters were similar in both groups on all postoperative days. However, pain during flexion significantly decreased on day 2 (P=.03) and day 3 (P=.04) in the experimental group. The use of TENS decreases pain from shoulder flexion in patients undergoing axillary thoracotomy for pulmonary resection. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.

  20. Reduced Verbal Fluency following Subthalamic Deep Brain Stimulation: A Frontal-Related Cognitive Deficit?

    PubMed Central

    Houvenaghel, Jean-François; Le Jeune, Florence; Dondaine, Thibaut; Esquevin, Aurore; Robert, Gabriel Hadrien; Péron, Julie; Haegelen, Claire; Drapier, Sophie; Jannin, Pierre; Lozachmeur, Clément; Argaud, Soizic; Duprez, Joan; Drapier, Dominique; Vérin, Marc; Sauleau, Paul

    2015-01-01

    Objective The decrease in verbal fluency in patients with Parkinson’s disease (PD) undergoing subthalamic nucleus deep brain stimulation (STN-DBS) is usually assumed to reflect a frontal lobe-related cognitive dysfunction, although evidence for this is lacking. Methods To explore its underlying mechanisms, we combined neuropsychological, psychiatric and motor assessments with an examination of brain metabolism using F-18 fluorodeoxyglucose positron emission tomography, in 26 patients with PD, 3 months before and after surgery. We divided these patients into two groups, depending on whether or not they exhibited a postoperative deterioration in either phonemic (10 patients) or semantic (8 patients) fluency. We then compared the STN-DBS groups with and without verbal deterioration on changes in clinical measures and brain metabolism. Results We did not find any neuropsychological change supporting the presence of an executive dysfunction in patients with a deficit in either phonemic or semantic fluency. Similarly, a comparison of patients with or without impaired fluency on brain metabolism failed to highlight any frontal areas involved in cognitive functions. However, greater changes in cognitive slowdown and apathy were observed in patients with a postoperative decrease in verbal fluency. Conclusions These results suggest that frontal lobe-related cognitive dysfunction could play only a minor role in the postoperative impairment of phonemic or semantic fluency, and that cognitive slowdown and apathy could have a more decisive influence. Furthermore, the phonemic and semantic impairments appeared to result from the disturbance of distinct mechanisms. PMID:26448131

  1. Reduced salmonella fecal shedding in swine administered porcine granulocyte-colony stimulating factor (G-CSF)

    USDA-ARS?s Scientific Manuscript database

    Salmonella colonization of food animals is a concern for animal health, food safety and public health. Key objectives of pre-harvest food safety programs are to detect asymptomatic Salmonella carriage in food animals, reduce colonization, and prevent transmission of Salmonella to other animals and ...

  2. Vagal nerve stimulation activates vagal afferent fibers that reduce cardiac efferent parasympathetic effects

    PubMed Central

    Yamakawa, Kentaro; Rajendran, Pradeep S.; Takamiya, Tatsuo; Yagishita, Daigo; So, Eileen L.; Mahajan, Aman; Shivkumar, Kalyanam

    2015-01-01

    Vagal nerve stimulation (VNS) has been shown to have antiarrhythmic effects, but many of these benefits were demonstrated in the setting of vagal nerve decentralization. The purpose of this study was to evaluate the role of afferent fiber activation during VNS on efferent control of cardiac hemodynamic and electrophysiological parameters. In 37 pigs a 56-electrode sock was placed over the ventricles to record local activation recovery intervals (ARIs), a surrogate of action potential duration. In 12 of 37 animals atropine was given systemically. Right and left VNS were performed under six conditions: both vagal trunks intact (n = 25), ipsilateral right (n = 11), ipsilateral left (n = 14), contralateral right (n = 7), contralateral left (n = 10), and bilateral (n = 25) vagal nerve transection (VNTx). Unilateral VNTx significantly affected heart rate, PR interval, Tau, and global ARIs. Right VNS after ipsilateral VNTx had augmented effects on hemodynamic parameters and increase in ARI, while subsequent bilateral VNTx did not significantly modify this effect (%change in ARI in intact condition 2.2 ± 0.9% vs. ipsilateral VNTx 5.3 ± 1.7% and bilateral VNTx 5.3 ± 0.8%, P < 0.05). Left VNS after left VNTx tended to increase its effects on hemodynamics and ARI response (P = 0.07), but only after bilateral VNTx did these changes reach significance (intact 1.1 ± 0.5% vs. ipsilateral VNTx 3.6 ± 0.7% and bilateral VNTx 6.6 ± 1.6%, P < 0.05 vs. intact). Contralateral VNTx did not modify VNS response. The effect of atropine on ventricular ARI was similar to bilateral VNTx. We found that VNS activates afferent fibers in the ipsilateral vagal nerve, which reflexively inhibit cardiac parasympathetic efferent electrophysiological and hemodynamic effects. PMID:26371172

  3. Reduced GABA Content in the Motor Thalamus during Effective Deep Brain Stimulation of the Subthalamic Nucleus

    PubMed Central

    Stefani, Alessandro; Fedele, Ernesto; Pierantozzi, Mariangela; Galati, Salvatore; Marzetti, Francesco; Peppe, Antonella; Pastore, Francesco Saverio; Bernardi, Giorgio; Stanzione, Paolo

    2011-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN), in Parkinson's disease (PD) patients, is a well established therapeutic option, but its mechanisms of action are only partially known. In our previous study, the clinical transitions from OFF- to ON-state were not correlated with significant changes of GABA content inside GPi or substantia nigra reticulata. Here, biochemical effects of STN-DBS have been assessed in putamen (PUT), internal pallidus (GPi), and inside the antero-ventral thalamus (VA), the key station receiving pallidothalamic fibers. In 10 advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP, an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in VA (−30%). Simultaneously, cGMP extracellular concentrations were enhanced in PUT (+200%) and GPi (+481%). These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy. PMID:21519387

  4. Transcranial direct current stimulation reduces negative affect but not cigarette craving in overnight abstinent smokers.

    PubMed

    Xu, Jiansong; Fregni, Felipe; Brody, Arthur L; Rahman, Ardeshir S

    2013-01-01

    Transcranial direct current stimulation (tDCS) can enhance cognitive control functions including attention and top-down regulation over negative affect and substance craving in both healthy and clinical populations, including early abstinent (∼1.5 h) smokers. The aim of this study was to assess whether tDCS modulates negative affect, cigarette craving, and attention of overnight abstinent tobacco dependent smokers. In this study, 24 smokers received a real and a sham session of tDCS after overnight abstinence from smoking on two different days. We applied anode to the left dorsolateral prefrontal cortex and cathode to the right supra-orbital area for 20 min with a current of 2.0 mA. We used self-report questionnaires Profile of Mood States (POMS) to assess negative affect and Urge to Smoke (UTS) Scale to assess craving for cigarette smoking, and a computerized visual target identification task to assess attention immediately before and after each tDCS. Smokers reported significantly greater reductions in POMS scores of total mood disturbance and scores of tension-anxiety, depression-dejection, and confusion-bewilderment subscales after real relative to sham tDCS. Furthermore, this reduction in negative affect positively correlated with the level of nicotine dependence as assessed by Fagerström scale. However, reductions in cigarette craving after real vs. sham tDCS did not differ, nor were there differences in reaction time or hit rate change on the visual task. Smokers did not report significant side effects of tDCS. This study demonstrates the safety of tDCS and its promising effect in ameliorating negative affect in overnight abstinent smokers. Its efficacy in treating tobacco dependence deserves further investigation.

  5. Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.

    PubMed

    Steele, J W; Ju, S; Lachenmayer, M L; Liken, J; Stock, A; Kim, S H; Delgado, L M; Alfaro, I E; Bernales, S; Verdile, G; Bharadwaj, P; Gupta, V; Barr, R; Friss, A; Dolios, G; Wang, R; Ringe, D; Protter, A A; Martins, R N; Ehrlich, M E; Yue, Z; Petsko, G A; Gandy, S

    2013-08-01

    Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.

  6. Acute exercise induces cortical inhibition and reduces arousal in response to visual stimulation in young children.

    PubMed

    Mierau, Andreas; Hülsdünker, Thorben; Mierau, Julia; Hense, Andreas; Hense, Johannes; Strüder, Heiko K

    2014-05-01

    Physical exercise is known to induce a range of transient or sustained psychophysiological effects including stress reduction and improvements in cognitive performance. Previous studies in the area have focused on adults and there has been little research on the relationship between physical exercise and brain function in young children. This study examined the relationship between cortical oscillations, arousal and cognitive performance following physical exercise in 5/6-year preschoolers. Participants completed two counterbalanced sessions of 45 min exercise or a control condition. Electroencephalography (EEG) was measured at rest with the eyes closed and the eyes open, as well as during cognitive performance in a task requiring attention and reaction speed. This was done before (PRE) and after (POST) each session once the participants' heart rate returned to within 10% of pre-exercise values. The percentage change in spectral power from PRE to POST (Δ) differed significantly between conditions. Specifically, Δ alpha-1 power differed significantly between exercise (+5%) and the control condition (-5.9%) with the eyes-open, but not with the eyes-closed. This effect did not significantly differ between cortical regions (i.e., it was global). Further, Δ beta-1 and Δ beta-2 power differed significantly between exercise (beta-1: -10.8%, beta-2: -23.8%) and the control condition (beta-1: -4.3%, beta-2: -5.3%) at frontal sites independent of visual input. Despite significant changes in resting state EEG, cognitive performance and task-related EEG remained unaffected by exercise. The results were interpreted to indicate cortical inhibition and attenuation of arousal in response to visual stimulation following exercise in young children.

  7. Laser stimulated grain growth in 304 stainless steel anodes for reduced hydrogen outgassing

    NASA Astrophysics Data System (ADS)

    Gortat, D.; Sparkes, M.; Fairchild, S. B.; Murray, P. T.; Cahay, M. M.; Back, T. C.; Gruen, G. J.; Lockwood, N. P.; O'Neill, W.

    2017-02-01

    Metal anodes in high power microwave (HPM) devices erode during operation due to hydrogen outgassing and plasma formation; both of which are thermally driven phenomena generated by the electron beam impacting the anode's surface. This limits the lowest achievable pressure in an HPM device, which reduces its efficiency. Laser surface melting the 304 stainless steel anodes by a continuous wave fiber laser showed a reduction in hydrogen outgassing by a factor of 4 under 50 keV electron bombardment, compared to that from untreated stainless steel. This is attributed to an increase in the grain size (from 40 - 3516 μm2), which effectively reduces the number of characterized grain boundaries that serve as hydrogen trapping sites, making such laser treated metals excellent candidates for use in HPM applications.

  8. Alcohol Reduces Arterial Remodeling by Inhibiting Sonic Hedgehog-Stimulated Sca1(+) Progenitor Stem Cell Expansion.

    PubMed

    Fitzpatrick, Emma; Han, Xu; Liu, Weimin; Corcoran, Eoin; Burtenshaw, Denise; Alshamrani, Maryam; Morrow, David; Helt, Jay-Christian; Cahill, Paul A; Redmond, Eileen M

    2017-09-18

    Cell and molecular mechanisms mediating the cardiovascular effects of alcohol are not fully understood. Our aim was to determine the effect of moderate Ethanol (EtOH) on Sonic Hedgehog (SHh) signaling in regulating possible Sca1(+) progenitor stem cell involvement during pathologic arterial remodeling. Partial ligation or sham-operation of the left carotid artery was performed in transgenic Sca1-eGFP mice gavaged with or without 'daily moderate' EtOH. The EtOH group had reduced adventitial thickening and less neo-intimal formation, compared to ligated controls. There was expansion of eGFP expressing (i.e., Sca1(+) ) cells in remodeled vessels post-ligation (14d), especially in the neo-intima. Ethanol treatment reduced the number of Sca1(+) cells in ligated vessel cross-sections concomitant with diminished remodeling, compared to control ligated vessels. Moreover, EtOH attenuated SHh signaling in injured carotids as determined by immunohistochemical analysis of the target genes patched 1 (Ptch1) and Gli2, and RT-PCR of whole vessel Gli2 mRNA levels. Intraperitoneal injection of ligated Sca1 - eGFP mice with the SHh signaling inhibitor cyclopamine diminished hedgehog target gene expression, reduced the number of Sca1(+) cells, and ameliorated carotid remodeling. EtOH treatment of purified Sca1(+) adventitial progenitor stem cells in vitro inhibited SHh signaling, and their rSHh-induced differentiation to vascular smooth muscle cells. EtOH reduces SHh - responsive Sca1(+) progenitor cell myogenic differentiation/expansion in vitro and during arterial remodeling in response to ligation injury in vivo. Regulation of vascular Sca1(+) progenitor cells in this way may be an important novel mechanism contributing to alcohol's cardiovascular protective effects. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  9. Buffer-stimulated citrate efflux in Penicillium simplicissimum: an alternative charge balancing ion flow in case of reduced proton backflow?

    PubMed

    Burgstaller, W; Zanella, A; Schinner, F

    1994-01-01

    Organic acids excreted by filamentous fungi may be used to win metals from industrial secondary raw materials. For a future commercial use a high production rate of organic acids is necessary. The conditions under which the commercially used fungus Aspergillus niger excretes high amounts of citric acid can not be maintained in metal leaching processes. However, Penicillium simplicissimum showed an enhanced citric acid efflux in the presence of an industrial filter dust containing 50% zinc oxide. Because Good buffers of high molarity were able to mimic the effect of zinc oxide, the high buffering capacity of zinc oxide and not an effect of the zinc ions was held responsible for the enhanced citric acid efflux. The presence of ammonium and trace elements reduced this buffer-stimulated citric acid efflux, whereas the plant hormone auxine canceled this reduction. This citric acid efflux was influenced by a depolarization of the membrane: the freely permeable compound tetraphenylphosphoniumbromide decreased the citric acid efflux, without decreasing intracellular citric acid or consumption of glucose and oxygen. Vanadate, an inhibitor of the plasma membrane H(+)-ATPase also reduced the buffer-stimulated citric acid efllux. The role of the efflux of citrate anions as an alternative charge balancing ion flow in case of impaired backflow of extruded protons because of a high extracellular buffering capacity is discussed.

  10. Tibolone Reduces Oxidative Damage and Inflammation in Microglia Stimulated with Palmitic Acid through Mechanisms Involving Estrogen Receptor Beta.

    PubMed

    Hidalgo-Lanussa, Oscar; Ávila-Rodriguez, Marco; Baez-Jurado, Eliana; Zamudio, Jairo; Echeverria, Valentina; Garcia-Segura, Luis Miguel; Barreto, George E

    2017-09-25

    High concentrations of palmitic acid in plasma increase both the inflammation associated with obesity and the susceptibility to develop a neurodegenerative event. In the brain, the inflammatory response is mediated by activated microglial cells, which undergo morphological and biochemical changes and can directly affect cell viability. Recent evidence shows that the use of estrogenic compounds can control microglia-induced inflammation with promising results. In this study, we explored the actions of the synthetic steroid tibolone on BV-2 microglia cells stimulated with palmitic acid. Our results demonstrated that tibolone increased cell viability and reduced nuclear fragmentation and the production of reactive oxygen species, as well as preserved mitochondrial membrane potential. These effects were accompanied by reduced nuclear translocation of NF-κB p65, upregulation of neuroglobin, and improved antioxidant defense. Furthermore, estrogen receptor beta (ERβ) inhibition partially dampened tibolone's protective actions in BV-2 cells stimulated with palmitic acid. In conclusion, tibolone protects BV-2 cells by a mechanism involving ERβ and upregulation of neuroglobin.

  11. Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury

    PubMed Central

    Henes, Janek; Schmit, Marthe A.; Morote-Garcia, Julio C.; Mirakaj, Valbona; Köhler, David; Glover, Louise; Eldh, Therese; Walter, Ulrich; Karhausen, Jörn; Colgan, Sean P.; Rosenberger, Peter

    2009-01-01

    Acute lung injury (ALI) is an inflammatory disorder associated with reduced alveolar-capillary barrier function, increased pulmonary vascular permeability, and infiltration of leukocytes into the alveolar space. Pulmonary function might be compromised, its most severe form being the acute respiratory distress syndrome. A protein central to physiological barrier properties is vasodilator-stimulated phosphoprotein (VASP). Given the fact that VASP expression is reduced during periods of cellular hypoxia, we investigated the role of VASP during ALI. Initial studies revealed reduced VASP expressional levels through cytokines in vitro. Studies in the putative human VASP promoter identified NF-κB as a key regulator of VASP transcription. This VASP repression results in increased paracellular permeability and migration of neutrophils in vitro. In a model of LPS-induced ALI, VASP−/− mice demonstrated increased pulmonary damage compared with wild-type animals. These findings were confirmed in a second model of ventilator-induced lung injury. Studies employing bone marrow chimeric animals identified tissue-specific repression of VASP as the underlying cause of decreased barrier properties of the alveolar-capillary barrier during ALI. Taken together these studies identify tissue-specific VASP as a central protein in the control of the alveolar-capillary barrier properties during ALI.—Henes, J., Schmit, M. A., Morote-Garcia, J. C., Mirakaj, V., Köhler, D., Glover, L., Eldh, T., Walter, U., Karhausen, J., Colgan, S. P., Rosenberger, P. Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury. PMID:19690214

  12. Human face-only immersion in cold water reduces maximal apnoeic times and stimulates ventilation.

    PubMed

    Jay, Ollie; Christensen, Julia P H; White, Matthew D

    2007-01-01

    In two studies, the cold shock and diving responses were investigated after human face immersion without prior hyperventilation to explore the mechanism(s) accounting for reductions in maximal apnoeic times (ATmax) at low water temperatures. In study 1, ATmax, heart rate (HR) and cutaneous blood cell velocity were measured in 13 non-apnoea-trained males during apnoeic face immersion in 0, 10, 20 and 33 degrees C water and room air (AIR). In study 2, six males were measured during non-apnoeic face immersion in 0, 10 and 33 degrees C water for ventilation (VE), respiratory exchange ratio (RER), HR and oxygen consumption (VO2), as well for end-tidal partial pressures of oxygen (PET,O2) and carbon dioxide (PET,CO2). Results indicated that the ATmax of 30.7 s (S.D. 7.1 s) at 0 degrees C (P < 0.001) and 48.2 s (S.D. 16.0 s) at 10 degrees C (P < 0.05) were significantly shorter than that of 58 s in AIR or 33 degrees C. During apnoea at 0, 10, 20 and 33 degrees C, both the deceleration of HR (P < 0.05) and peripheral vasoconstriction (P < 0.05), as well as the peak HR at 0 degrees C (P = 0.002) were significantly greater than in AIR. At 0 degrees C in comparison with 33 degrees C, non-apnoeic face immersions gave peaks in (P = 0.039), RER (P = 0.025), (P = 0.032) and HR (P = 0.011), as well as lower minimum values for (P = 0.033) and HR (P = 0.002). With as the covariate, ANCOVA showed that remained significantly greater (P = 0.003) at lower water temperatures. In conclusion, during face immersion at 10 degrees C and below, there is a non-metabolic, neurally mediated cold shock-like response that shortens apnoea, stimulates ventilation and predominates over the oxygen conserving effects of the dive response.

  13. Indigenous microfungi and plants reduce soil nonylphenol contamination and stimulate resident microfungal communities.

    PubMed

    Girlanda, Mariangela; Favero-Longo, Sergio Enrico; Lazzari, Alexandra; Segreto, Rossana; Perotto, Silvia; Siniscalco, Consolata

    2009-02-01

    Nonylphenol, the most abundant environmental pollutant with endocrine disrupting activity, is also toxic to plants and microorganisms, but its actual impact in the field is unknown. In this study, diversity of culturable soil microfungal and plant communities was assessed in a disused industrial estate, at three sites featuring different nonylphenol pollution. Although soil microfungal assemblages varied widely among the sites, no significant correlation was found with point pollutant concentrations, thus suggesting indirect effects of soil contamination on microfungal assemblages. The potential of indigenous fungi and plants to remove nonylphenol was assessed in mesocosm experiments. Poplar plants and a fungal consortium consisting of the most abundant strains in the nonylphenol-polluted soil samples were tested alone or in combination for their ability to reduce, under greenhouse conditions, nonylphenol levels either in a sterile, artificially contaminated sand substrate, or in two non-sterile soils from the original industrial area. Introduction of indigenous fungi consistently reduced nonylphenol levels in all substrates, up to ca. 70% depletion, whereas introduction of the plant proved to be effective only with high initial pollutant levels. In native non-sterile soil, nonylphenol depletion following fungal inoculation correlated with biostimulation of indigenous fungi, suggesting positive interactions between introduced and resident fungi.

  14. Stimulated Osteogenic Differentiation of Human Mesenchymal Stem Cells by Reduced Graphene Oxide.

    PubMed

    Jin, Linhua; Lee, Jong Ho; Jin, Oh Seong; Shin, Yong Cheol; Kim, Min Jeong; Hong, Suck Won; Lee, Mi Hee; Park, Jong-Chul; Han, Dong-Wook

    2015-10-01

    Osteoprogenitor cells play a significant role in the growth or repair of bones, and have great potential as cell sources for regenerative medicine and bone tissue engineering, but control of their specific differentiation into bone cells remains a challenge. Graphene-based nanomaterials are attractive candidates for biomedical applications as substrates for stem cell (SC) differentiation, scaffolds in tissue engineering, and components of implant devices owing to their biocompatible, transferable and implantable properties. This study examined the enhanced osteogenic differentiation of human mesenchymal stem cells (hMSCs) by reduced graphene oxide (rGO) nanoparticles (NPs), and rGO NPs was prepared by reducing graphene oxide (GO) with a hydrazine treatment followed by annealing in argon and hydrogen. The cytotoxicity profile of each particle was examined using a water-soluble tetrazolium-8 (WST-8) assay. At different time-points, a WST-8 assay, alkaline phosphatase (ALP) activity assay and alizarin red S (ARS) staining were used to determine the effects of rGO NPs on proliferation, differentiation and mineralization, respectively. The results suggest that graphene-based materials have potential as a platform for stem cells culture and biomedical applications.

  15. ω-3 Fatty Acids Reduce Chemotherapy-Induced Hematological Toxicity by Bone Marrow Stimulation in Mice.

    PubMed

    Murakami, Kohei; Miyata, Hiroshi; Miyazaki, Yasuhiro; Makino, Tomoki; Takahashi, Tsuyoshi; Kurokawa, Yukinori; Yamasaki, Makoto; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro

    2017-07-01

    ω-3 Fatty acids exert several benefits during chemotherapy, such as preventing intestinal mucosal damage and improving response to chemotherapy. However, little is known about the effect of ω-3 fatty acids on chemotherapy-induced hematological toxicities. Mice that had consumed either an ω-3-rich or an ω-3-poor diet for 2 weeks were intraperitoneally administered cisplatin. The resultant changes in blood cell count, bone marrow cell count, and cytokine levels in bone marrow supernatant were analyzed. The effect of ω-3 fatty acids on human peripheral blood mononuclear cells (PBMCs) exposed to cisplatin was also examined. Although peripheral blood cell counts decreased after cisplatin treatment in both groups of mice, the decrease in white blood cell count was significantly lower in mice that consumed the ω-3-rich diet. The decrease in bone marrow cells after cisplatin treatment was also reduced in mice that consumed the ω-3-rich diet. Levels of stem cell factor (SCF) and fibroblast growth factor 1 (FGF-1) were significantly higher in bone marrow supernatants from mice that consumed the ω-3-rich diet. The rate of apoptosis in PBMCs (after exposure to cisplatin) cultured in medium containing ω-3 fatty acids was significantly lower than in PBMCs cultured in control medium. ω-3-Rich diets reduced chemotherapy-induced leukopenia in mice. This may be the result of increased numbers of bone marrow cells due to higher levels of SCF and FGF-1 in the bone marrow.

  16. Detection of Enterobius vermicularis eggs in the submucosa of the transverse colon of a man presenting with colon carcinoma.

    PubMed

    Lee, Sai-Cheong; Hwang, Kao-Pin; Tsai, Wen-Sy; Lin, Chin-Yew; Lee, Ning

    2002-11-01

    We report a case of a chronic infiltrate of the intestinal wall of the transverse colon by the eggs of Enterobius vermicularis in a man who had immigrated to Taiwan from mainland China 50 years ago. During surgery for suspected transverse colon carcinoma, histologic examination of the tumor mass revealed eggs of E. vermicularis embedded in granulation tissue in the submucosa of the transverse colon. Results of a stool examination were negative for eggs but strongly positive for occult blood. The mass in the transverse colon was completely removed during surgery. At the present time, the patient remains asymptomatic.

  17. Reducing conditions can alter the source of respired carbon and stimulate decomposition in mineral soils

    NASA Astrophysics Data System (ADS)

    Huang, W.; Hall, S. J.

    2016-12-01

    Soil organic matter decomposition is widely thought to be constrained by reducing conditions in flooded wetland ecosystems. However, the potential impact of periodic reducing conditions on carbon (C) mineralization in terrestrial mineral soils that experience transient moisture saturation has received less attention. Here we incubated three Mollisols amended with C4 leaf litter at three different soil moisture levels (field capacity for the control, intermediate, and saturation) over three months in the laboratory. Soil CO2 and CH4 production and isotope ratios of CO2 (δ13CO2) were measured daily using a tunable diode laser for the first two weeks and weekly thereafter. Soil Eh dropped from 516 mV to -184 mV in the intermediate and saturated soils during the first seventeen days; iron (Fe) reduction occurred in both intermediate and saturated soils after the seventh day. Total CO2 production rate in the intermediate and saturated soils was initially lower than the control, but exceeded the control after the eleventh day. After three months, mean cumulative CO2 production was significantly higher in the intermediate soil moisture treatment (152 μmol CO2 g-1 soil, P < 0.01) and equivalent between the saturated and control soils (128 and 141 μmol CO2 g-1 soil, P = 0.11). The intermediate and saturated soils also induced substantial CH4 production. Differences in mean δ13CO2 (-14.0‰ for the control and -22.7‰ for the saturated soils) over the first two weeks (before CH4 production began) showed that CO2 production from the saturated soils was derived from different C source(s) compared to the control. These findings challenge traditional paradigms by showing that reducing conditions can enhance C mineralization, perhaps by facilitating microbial access to alternative or occluded C sources. We suggest that Fe reduction could be an important mechanism of C loss in mineral soils due to the release of adsorbed or co-precipitated organic matter during Fe

  18. Low frequency stimulation of ventral hippocampal commissures reduces seizures in a rat model of chronic temporal lobe epilepsy.

    PubMed

    Rashid, Saifur; Pho, Gerald; Czigler, Michael; Werz, Mary A; Durand, Dominique M

    2012-01-01

    To investigate the effects of low frequency stimulation (LFS) of a fiber tract for the suppression of spontaneous seizures in a rat model of human temporal lobe epilepsy. Stimulation electrodes were implanted into the ventral hippocampal commissure (VHC) in a rat post-status epilepticus (SE) model of human temporal lobe epilepsy (n = 7). Two recording electrodes were placed in the CA3 regions bilaterally and neural data were recorded for a minimum of 6 weeks. LFS (60 min train of 1 Hz biphasic square wave pulses, each 0.1 ms in duration and 200 μA in amplitude, followed by 15 min of rest) was applied to the VHC for 2 weeks, 24 h a day. The baseline mean seizure frequency of the study animals was 3.7 seizures per day. The seizures were significantly reduced by the application of LFS in every animal (n = 7). By the end of the 2-week period of stimulation, there was a significant, 90% (<1 seizure/day) reduction of seizure frequencies (p < 0.05) and a 57% reduction during the period following LFS (p < 0.05) when compared to baseline. LFS also resulted in a significant reduction of hippocampal interictal spike frequency (71%, p < 0.05), during 2 weeks of LFS session. The hippocampal histologic analysis showed no significant difference between rats that received LFS and SE induction and those that had received only SE-induction. None of the animals showed any symptomatic hemorrhage, infection, or complication. Low frequency stimulation applied at a frequency of 1 Hz significantly reduced both the excitability of the neural tissue as well as the seizure frequency in a rat model of human temporal lobe epilepsy. The results support the hypothesis that LFS of fiber tracts can be an effective method for the suppression of spontaneous seizures in a temporal lobe model of epilepsy in rats and could lead to the development of a new therapeutic modality for human patients with temporal lobe epilepsy. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

  19. Zolpidem reduces the blood oxygen level-dependent signal during visual system stimulation

    PubMed Central

    Licata, Stephanie C.; Lowen, Steven B.; Trksak, George H.; MacLean, Robert R.; Lukas, Scott E.

    2011-01-01

    Zolpidem is a short-acting imidazopyridine hypnotic that binds at the benzodiazepine binding site on specific GABAA receptors to enhance fast inhibitory neurotransmission. The behavioral and receptor pharmacology of zolpidem has been studied extensively, but little is known about its neuronal substrates in vivo. In the present within-subject, double-blind, and placebo-controlled study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) at 3 Tesla was used to assess the effects of zolpidem within the brain. Healthy participants (n=12) were scanned 60 minutes after acute oral administration of zolpidem (0, 5, 10, or 20 mg), and changes in BOLD signal were measured in the visual cortex during presentation of a flashing checkerboard. Heart rate and oxygen saturation were monitored continuously throughout the session. Zolpidem (10 and 20 mg) reduced the robust visual system activation produced by presentation of this stimulus, but had no effects on physiological activity during the fMRI scan. Zolpidem’s modulation of the BOLD signal within the visual cortex is consistent with the abundant distribution of GABAA receptors localized in this region, as well as previous studies showing a relationship between increased GABA-mediated neuronal inhibition and a reduction in BOLD activation. PMID:21640782

  20. Decreased adrenoceptor stimulation in heart failure rats reduces NGF expression by cardiac parasympathetic neurons.

    PubMed

    Hasan, Wohaib; Smith, Peter G

    2014-04-01

    Postganglionic cardiac parasympathetic and sympathetic nerves are physically proximate in atrial cardiac tissue allowing reciprocal inhibition of neurotransmitter release, depending on demands from central cardiovascular centers or reflex pathways. Parasympathetic cardiac ganglion (CG) neurons synthesize and release the sympathetic neurotrophin nerve growth factor (NGF), which may serve to maintain these close connections. In this study we investigated whether NGF synthesis by CG neurons is altered in heart failure, and whether norepinephrine from sympathetic neurons promotes NGF synthesis. NGF and proNGF immunoreactivity in CG neurons in heart failure rats following chronic coronary artery ligation was investigated. NGF immunoreactivity was decreased significantly in heart failure rats compared to sham-operated animals, whereas proNGF expression was unchanged. Changes in neurochemistry of CG neurons included attenuated expression of the cholinergic marker vesicular acetylcholine transporter, and increased expression of the neuropeptide vasoactive intestinal polypeptide. To further investigate norepinephrine's role in promoting NGF synthesis, we cultured CG neurons treated with adrenergic receptor (AR) agonists. An 82% increase in NGF mRNA levels was detected after 1h of isoproterenol (β-AR agonist) treatment, which increased an additional 22% at 24h. Antagonist treatment blocked isoproterenol-induced increases in NGF transcripts. In contrast, the α-AR agonist phenylephrine did not alter NGF mRNA expression. These results are consistent with β-AR mediated maintenance of NGF synthesis in CG neurons. In heart failure, a decrease in NGF synthesis by CG neurons may potentially contribute to reduced connections with adjacent sympathetic nerves.

  1. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

    PubMed

    Wilkins, Heather M; Harris, Janna L; Carl, Steven M; E, Lezi; Lu, Jianghua; Eva Selfridge, J; Roy, Nairita; Hutfles, Lewis; Koppel, Scott; Morris, Jill; Burns, Jeffrey M; Michaelis, Mary L; Michaelis, Elias K; Brooks, William M; Swerdlow, Russell H

    2014-12-15

    Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis.

  2. Sulfate-reducing bacteria stimulate gut immune responses and contribute to inflammation in experimental colitis.

    PubMed

    Figliuolo, Vanessa Ribeiro; Dos Santos, Liliane Martins; Abalo, Alessandra; Nanini, Hayandra; Santos, Angela; Brittes, Nilda M; Bernardazzi, Claudio; de Souza, Heitor Siffert Pereira; Vieira, Leda Quercia; Coutinho-Silva, Robson; Coutinho, Claudia Mara Lara Melo

    2017-11-15

    The intestinal microbiota is critical for mammalian immune system development and homeostasis. Sulfate-reducing bacteria (SRB) are part of the normal gut microbiota, but their increased levels may contribute to colitis development, likely in association with hydrogen sulfide (H2S) production. Here, we investigated the effects of SRB in the gut immune response in germ-free mice, and in experimental colitis. After 7days of colonization with Desulfovibrio indonesiensis or with a human SRB consortium (from patients with colitis), germ-free mice exhibited alterations in the colonic architecture, with increased cell infiltration in the lamina propria. SRB colonization upregulated the Th17 and Treg profiles of cytokine production/cell activation, in T cells from mesenteric lymph nodes. These alterations were more pronounced in mice colonized with the human SRB consortium, although D. indonesiensis colonization produced higher levels of H2S. Importantly, the colon of C57BL/6 mice with colitis induced by TNBS or oxazolone had increased SRB colonization, and the administration of D. indonesiensis to mice with TNBS-induced colitis clearly exacerbated the alterations in colonic architecture observed in the established disease, and also increased mouse weight loss. We conclude that SRB contribute to immune response activation in the gut and play an important role in colitis development. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Transcranial direct current stimulation (tDCS) reduces the cost of performing a cognitive task on gait and postural control

    PubMed Central

    Zhou, Junhong; Hao, Ying; Wang, Ye; Jor’dan, Azizah; Pascual-Leone, Alvaro; Zhang, Jue; Fang, Jing; Manor, Brad

    2014-01-01

    This proof-of-concept, double-blind study is designed to determine the effects of transcranial direct current stimulation (tDCS) on the “cost” of performing a secondary cognitive task on gait and postural control in healthy young adults. Twenty adults aged 22±2yrs completed two separate double-blind visits in which gait and postural control were assessed immediately before and after a 20-minute session of either real or sham tDCS (1.5 mA) targeting the left dorsolateral prefrontal cortex. Gait speed and stride duration variability, along with standing postural sway speed and area, were recorded under normal conditions and while simultaneously performing a serial-subtraction cognitive task. Dual task cost was calculated as the percent change in each outcome from normal to dual task conditions. tDCS was well-tolerated by all subjects. Stimulation did not alter gait or postural control under normal conditions. As compared to sham stimulation, real tDCS led to increased gait speed (p=0.006), as well as decreased standing postural sway speed (p=0.01) and area (p=0.01), when performing serial-subtraction task. Real tDCS also diminished (p<0.01) the dual task cost on each of these outcomes. No effects of tDCS were observed for stride duration variability. A single session of tDCS targeting the left dorsolateral prefrontal cortex improved the ability to adapt one’s gait and postural control to a concurrent cognitive task and reduced the cost normally associated with such dual tasking. These results highlight the involvement of cortical brain networks in gait and posture control, and implicate the modulation of prefrontal cortical excitability as a potential therapeutic intervention. PMID:24443958

  4. Transcranial direct current stimulation reduces food-craving and measures of hyperphagia behavior in participants with Prader-Willi syndrome.

    PubMed

    Bravo, Gabriela L; Poje, Albert B; Perissinotti, Iago; Marcondes, Bianca F; Villamar, Mauricio F; Manzardo, Ann M; Luque, Laura; LePage, Jean F; Stafford, Diane; Fregni, Felipe; Butler, Merlin G

    2016-03-01

    Prader-Willi syndrome (PWS) is a neurodevelopmental genetic disorder characterized by intellectual disabilities and insatiable appetite with compulsive eating leading to severe obesity with detrimental health consequences. Transcranial direct current stimulation (tDCS) has been shown to modulate decision-making and cue-induced food craving in healthy adults. We conducted a pilot double blind, sham-controlled, multicenter study of tDCS modulation of food drive and craving in 10 adult PWS participants, 11 adult obese (OB) and 11 adult healthy-weight control (HWC) subjects. PWS and OB subjects received five consecutive daily sessions of active or sham tDCS over the right dorsolateral prefrontal cortex (DLPFC), while HWC received a single sham and active tDCS in a crossover design. Standardized psychometric instruments assessed food craving, drive and hyperphagia by self-report and caregiver assessment over 30 days. Robust baseline differences were observed in severity scores for the Three-Factor Eating Questionnaire (TFEQ) and Dykens Hyperphagia Questionnaire (DHQ) for PWS compared to HWC while obese participants were more similar to HWC. Active tDCS stimulation in PWS was associated with a significant change from baseline in TFEQ Disinhibition (Factor II) (Ƶ = 1.9, P < 0.05, 30 days) and Total Scores (Ƶ = 2.3, P < 0.02, 30 days), and participant ratings of the DHQ Severity (Ƶ = 1.8, P < 0.06, 5 days) and Total Scores (Ƶ = 1.9, P < 0.05, 15 days). These findings support sustained neuromodulatory effects and efficacy of tDCS to reduce food drive and behaviors impacting hyperphagia in PWS. Transcranial direct current stimulation may represent a straight-forward, low risk and low cost method to improve care, management and quality of life in PWS.

  5. Role of reduced insulin-stimulated bone blood flow in the pathogenesis of metabolic insulin resistance and diabetic bone fragility.

    PubMed

    Hinton, Pamela S

    2016-08-01

    Worldwide, 387 million adults live with type 2 diabetes (T2D) and an additional 205 million cases are projected by 2035. Because T2D has numerous complications, there is significant morbidity and mortality associated with the disease. Identification of early events in the pathogenesis of insulin resistance and T2D might lead to more effective treatments that would mitigate health and monetary costs. Here, we present our hypothesis that impaired bone blood flow is an early event in the pathogenesis of whole-body metabolic insulin resistance that ultimately leads to T2D. Two recent developments in different fields form the basis for this hypothesis. First, reduced vascular function has been identified as an early event in the development of T2D. In particular, before the onset of tissue or whole body metabolic insulin resistance, insulin-stimulated, endothelium-mediated skeletal muscle blood flow is impaired. Insulin resistance of the vascular endothelium reduces delivery of insulin and glucose to skeletal muscle, which leads to tissue and whole-body metabolic insulin resistance. Second is the paradigm-shifting discovery that the skeleton has an endocrine function that is essential for maintenance of whole-body glucose homeostasis. Specifically, in response to insulin signaling, osteoblasts secret osteocalcin, which stimulates pancreatic insulin production and enhances insulin sensitivity in skeletal muscle, adipose, and liver. Furthermore, the skeleton is not metabolically inert, but contributes to whole-body glucose utilization, consuming 20% that of skeletal muscle and 50% that of white adipose tissue. Without insulin signaling or without osteocalcin activity, experimental animals become hyperglycemic and insulin resistant. Currently, it is not known if insulin-stimulated, endothelium-mediated blood flow to bone plays a role in the development of whole body metabolic insulin resistance. We hypothesize that it is a key, early event. Microvascular dysfunction is a

  6. Elevated CO2 and phosphate limitation favor Micromonas pusilla through stimulated growth and reduced viral impact.

    PubMed

    Maat, Douwe S; Crawfurd, Katherine J; Timmermans, Klaas R; Brussaard, Corina P D

    2014-05-01

    Growth and viral infection of the marine picoeukaryote Micromonas pusilla was studied under a future-ocean scenario of elevated partial CO2 (pCO2; 750 μatm versus the present-day 370 μatm) and simultaneous limitation of phosphorus (P). Independent of the pCO2 level, the ratios of M. pusilla cellular carbon (C) to nitrogen (N), C:P and N:P, increased with increasing P stress. Furthermore, in the P-limited chemostats at growth rates of 0.32 and 0.97 of the maximum growth rate (μmax), the supply of elevated pCO2 led to an additional rise in cellular C:N and C:P ratios, as well as a 1.4-fold increase in M. pusilla abundance. Viral lysis was not affected by pCO2, but P limitation led to a 150% prolongation of the latent period (6 to 12 h) and an 80% reduction in viral burst sizes (63 viruses per cell) compared to P-replete conditions (4 to 8 h latent period and burst size of 320). Growth at 0.32 μmax further prolonged the latent period by another 150% (12 to 18 h). Thus, enhanced P stress due to climate change-induced strengthened vertical stratification can be expected to lead to reduced and delayed virus production in picoeukaryotes. This effect is tempered, but likely not counteracted, by the increase in cell abundance under elevated pCO2. Although the influence of potential P-limitation-relieving factors, such as the uptake of organic P and P utilization during infection, is unclear, our current results suggest that when P limitation prevails in future oceans, picoeukaryotes and grazing will be favored over larger-sized phytoplankton and viral lysis, with increased matter and nutrient flow to higher trophic levels.

  7. Electrospun silk fibroin scaffolds coated with reduced graphene promote neurite outgrowth of PC-12 cells under electrical stimulation.

    PubMed

    Aznar-Cervantes, Salvador; Pagán, Ana; Martínez, Jose G; Bernabeu-Esclapez, Antonia; Otero, Toribio F; Meseguer-Olmo, Luis; Paredes, Juan I; Cenis, Jose L

    2017-10-01

    Novel approaches to neural research require biocompatible materials capable to act as electrode structures or scaffolds for tissue engineering in order to stimulate or restore the functionality of damaged tissues. This work offers promising results that indicate the potential use of electrospun silk fibroin (SF) scaffolds coated with reduced graphene oxide (rGO) in this sense. The coated material becomes conductor and electroactive. A complete characterisation of SF/rGO scaffolds is provided in terms of electrochemistry, mechanical behaviour and chemical conformation of fibroin. The excellent biocompatibility of this novel material is proved with cultures of PC-12 cells. The coating with rGO improved the adhesion of cells in comparison with cells growing onto the surface of pure SF scaffolds. Also, the use of SF/rGO scaffolds combined with electrical stimulation promoted the differentiation into neural phenotypes reaching comparable or even superior levels to those obtained by means of the traditional treatment with neural growth factor (NGF). Copyright © 2017 Elsevier B.V. All rights reserved.

  8. The perceived position of moving objects: transcranial magnetic stimulation of area MT+ reduces the flash-lag effect.

    PubMed

    Maus, Gerrit W; Ward, Jamie; Nijhawan, Romi; Whitney, David

    2013-01-01

    How does the visual system assign the perceived position of a moving object? This question is surprisingly complex, since sluggish responses of photoreceptors and transmission delays along the visual pathway mean that visual cortex does not have immediate information about a moving object's position. In the flash-lag effect (FLE), a moving object is perceived ahead of an aligned flash. Psychophysical work on this illusion has inspired models for visual localization of moving objects. However, little is known about the underlying neural mechanisms. Here, we investigated the role of neural activity in areas MT+ and V1/V2 in localizing moving objects. Using short trains of repetitive Transcranial Magnetic Stimulation (TMS) or single pulses at different time points, we measured the influence of TMS on the perceived location of a moving object. We found that TMS delivered to MT+ significantly reduced the FLE; single pulse timings revealed a broad temporal tuning with maximum effect for TMS pulses, 200 ms after the flash. Stimulation of V1/V2 did not significantly influence perceived position. Our results demonstrate that area MT+ contributes to the perceptual localization of moving objects and is involved in the integration of position information over a long time window.

  9. The Perceived Position of Moving Objects: Transcranial Magnetic Stimulation of Area MT+ Reduces the Flash-Lag Effect

    PubMed Central

    Ward, Jamie; Nijhawan, Romi; Whitney, David

    2013-01-01

    How does the visual system assign the perceived position of a moving object? This question is surprisingly complex, since sluggish responses of photoreceptors and transmission delays along the visual pathway mean that visual cortex does not have immediate information about a moving object's position. In the flash-lag effect (FLE), a moving object is perceived ahead of an aligned flash. Psychophysical work on this illusion has inspired models for visual localization of moving objects. However, little is known about the underlying neural mechanisms. Here, we investigated the role of neural activity in areas MT+ and V1/V2 in localizing moving objects. Using short trains of repetitive Transcranial Magnetic Stimulation (TMS) or single pulses at different time points, we measured the influence of TMS on the perceived location of a moving object. We found that TMS delivered to MT+ significantly reduced the FLE; single pulse timings revealed a broad temporal tuning with maximum effect for TMS pulses, 200 ms after the flash. Stimulation of V1/V2 did not significantly influence perceived position. Our results demonstrate that area MT+ contributes to the perceptual localization of moving objects and is involved in the integration of position information over a long time window. PMID:22302116

  10. Berberine reduces leukocyte adhesion to LPS-stimulated endothelial cells and VCAM-1 expression both in vivo and in vitro.

    PubMed

    Wu, Y-H; Chuang, S-Y; Hong, W-C; Lai, Y-J; Chang, G-J; Pang, J-H S

    2012-01-01

    Leukocyte adhesion to endothelium plays a critical initiating role in inflammation. Berberine, an anti-inflammatory natural compound, is known to attenuate lipopolysaccharide (LPS)-induced lung injury and improve survival of endotoxemic animals with mechanism not fully clarified. This study investigated the effects of berberine on the LPS-induced leukocyte-endothelial cell adhesion both in vivo and in vitro. We first established an animal model to observe the in vivo LPS-induced adhesion of leukocytes to the endothelium of venules in the lung tissue dose-dependently. Pretreatment of LPS-stimulated rats with berberine for 1 h reduced the leukocyte-endothelium adhesion and vascular cell adhesion molecule-1 (VCAM-1) expression in lung. Pretreatment of LPS-stimulated vascular endothelial cells with berberine also dose-dependently decreased the number of adhered THP-1 cells and VCAM-1 expression at both RNA and protein levels. Berberine was further confirmed to inhibit the nuclear translocation and DNA binding activity of LPS-activated nuclear factor-kappa B (NF-kappa B). These data demonstrated an additional molecular mechanism for the profound anti-inflammatory effect of berberine.

  11. Interpersonal Multisensory Stimulation reduces the overwhelming distracting power of self-gaze: psychophysical evidence for ‘engazement'

    PubMed Central

    Porciello, Giuseppina; Holmes, Brittany Serra; Liuzza, Marco Tullio; Crostella, Filippo; Aglioti, Salvatore Maria; Bufalari, Ilaria

    2014-01-01

    One's own face and gaze are never seen directly but only in a mirror. Yet, these stimuli capture attention more powerfully than others' face and gaze, suggesting the self is special for brain and behavior. Synchronous touches felt on one's own and seen on the face of others induce the sensation of including others in one's own face (enfacement). We demonstrate that enfacement may also reduce the overwhelming distracting power of self-gaze. This effect, hereafter called ‘engazement', depends on the perceived physical attractiveness and inner beauty of the pair partner. Thus, we highlight for the first time the close link between enfacement and engazement by showing that changes of the self-face representation induced by facial visuo-tactile stimulation extend to gaze following, a separate process likely underpinned by different neural substrates. Moreover, although gaze following is a largely automatic, engazement is penetrable to the influence of social variables, such as positive interpersonal perception. PMID:25327255

  12. Staphylococcus aureus screening and decolonization reduces the risk of surgical site infections in patients undergoing deep brain stimulation surgery.

    PubMed

    Lefebvre, J; Buffet-Bataillon, S; Henaux, P L; Riffaud, L; Morandi, X; Haegelen, C

    2017-02-01

    In a controlled before-and-after study in a single centre, it was aimed to determine whether identification of Staphylococcus aureus nasal carriers followed by nasal mupirocin ointment and chlorhexidine soap reduced surgical site infections (SSIs) among 182 patients undergoing deep brain stimulation. In all, 119 patients were included in the control group and 63 in the screening group. There was a significant SSI decrease from 10.9% to 1.6% between the two groups (P<0.04; relative risk: 0.13; 95% confidence interval: 0.003-0.922). There were eight SSIs involving S. aureus in the control group, none in the screening group. No specific risk factors for SSI were identified. Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

  13. A new scaffold containing small intestinal submucosa and mesenchymal stem cells improves pancreatic islet function and survival in vitro and in vivo

    PubMed Central

    Wang, Dan; Ding, Xiaoming; Xue, Wujun; Zheng, Jin; Tian, Xiaohui; Li, Yang; Wang, Xiaohong; Song, Huanjin; Liu, Hua; Luo, Xiaohui

    2017-01-01

    It is unknown whether a scaffold containing both small intestinal submucosa (SIS) and mesenchymal stem cells (MSCs) for transplantation may improve pancreatic islet function and survival. In this study, we examined the effects of a SIS-MSC scaffold on islet function and survival in vitro and in vivo. MSCs and pancreatic islets were isolated from Sprague-Dawley rats, and SIS was isolated from Bamei pigs. The islets were apportioned among 3 experimental groups as follows: SIS-islets, SIS-MSC-islets and control-islets. In vitro, islet function was measured by a glucose-stimulated insulin secretion test; cytokines in cultured supernatants were assessed by enzyme-linked immunosorbent assay; and gene expression was analyzed by reverse transcription-quantitative PCR. In vivo, islet transplantation was performed in rats, and graft function and survival were monitored by measuring the blood glucose levels. In vitro, the SIS-MSC scaffold was associated with improved islet viability and enhanced insulin secretion compared with the controls, as well as with the increased the expression of insulin 1 (Ins1), pancreatic and duodenal homeobox 1 (Pdx1), platelet endothelial cell adhesion molecule 1 [Pecam1; also known as cluster of differentiation 31 (CD31)] and vascular endothelial growth factor A (Vegfa) in the islets, increased growth factor secretion, and decreased tumor necrosis factor (TNF) secretion. In vivo, the SIS-MSC scaffold was associated with improved islet function and graft survival compared with the SIS and control groups. On the whole, our findings demonstrate that the SIS-MSC scaffold significantly improved pancreatic islet function and survival in vitro and in vivo. This improvement may be associated with the upregulation of insulin expression, the improvement of islet microcirculation and the secretion of cytokines. PMID:27909715

  14. Angiographic Evaluation of Carotid Artery Grafting with Prefabricated Small-Diameter, Small-Intestinal Submucosa Grafts in Sheep

    SciTech Connect

    Pavcnik, Dusan; Obermiller, Josef; Uchida, Barry T.; Van Alstine, William; Edwards, James M.; Landry, Gregory J.; Kaufman, John A.; Keller, Frederick S.; Roesch, Josef

    2009-01-15

    The purpose of this study was to report the longitudinal angiographic evaluation of prefabricated lyophilized small-intestinal submucosa (SIS) grafts placed in ovine carotid arteries and to demonstrate a variety of complications that developed. A total of 24 grafts, 10 cm long and 6 mm in diameter, were placed surgically as interposition grafts. Graft patency at 1 week was evaluated by Doppler ultrasound, and angiography was used for follow-up at 1 month and at 3 to 4 months. A 90% patency rate was found at 1 week, 65% at 1 month, and 30% at 3 to 4 months. On the patent grafts, angiography demonstrated a variety of changes, such as anastomotic stenoses, graft diffuse dilations and dissections, and aneurysm formation. These findings have not been previously demonstrated angiographically by other investigators reporting results with small-diameter vessel grafts made from fresh small-intestinal submucosa (SIS). The complications found were partially related to the graft construction from four SIS layers. Detailed longitudinal angiographic study should become an essential part of any future evaluation of small-vessel SIS grafting.

  15. Transcutaneous Electrical Nerve Stimulation (TENS) reduces pain, fatigue, and hyperalgesia while restoring central inhibition in primary fibromyalgia

    PubMed Central

    Dailey, Dana L; Rakel, Barbara A; Vance, Carol GT; Liebano, Richard E; Anand, Amrit S; Bush, Heather M; Lee, Kyoung S; Lee, Jennifer E; Sluka, Kathleen A

    2014-01-01

    Because TENS works by reducing central excitability and activating central inhibition pathways, we tested the hypothesis that TENS would reduce pain and fatigue and improve function and hyperalgesia in people with fibromyalgia who have enhanced central excitability and reduced inhibition. The current study used a double-blinded randomized, placebo controlled cross-over design to test effects of a single treatment of TENS in people with fibromyalgia. Three treatments were assessed in random order: active TENS, placebo TENS, no TENS. The following measures were assessed before and after each TENS treatment: pain and fatigue at rest and movement, pressure pain thresholds (PPTs), 6 minute walk test (6MWT), range of motion (ROM), five time sit to stand test (FTSTS), and single leg stance (SLS). Conditioned pain modulation (CPM) was completed at end of testing. There was a significant decrease in pain and fatigue with movement for active TENS compared to placebo and no TENS. PPTs increased at site of TENS (spine) and outside site of TENS (leg) when compared to placebo TENS or no TENS. During Active TENS CPM was significantly stronger compared to placebo TENS and no TENS. No changes in functional tasks were observed with TENS. Thus, the current study suggests TENS has short-term efficacy in relieving symptoms of fibromyalgia while the stimulator is active. Future clinical trials should examine the effects of repeated daily delivery of TENS, similar to how TENS is used clinically, on pain, fatigue, function and quality of life in individuals with fibromyalgia. PMID:23900134

  16. Efficacy of pulsed low-intensity electric neuromuscular stimulation in reducing pain and disability in patients with myofascial syndrome.

    PubMed

    Iodice, P; Lessiani, G; Franzone, G; Pezzulo, G

    2016-01-01

    Myofascial pain syndrome (MPS) is characterized by chronic pain in multiple myofascial trigger points and fascial constrictions. In recent years, the scientific literature has recognized the need to include the patient with MPS in a multidimensional rehabilitation project. At the moment, the most widely recognized therapeutic methods for the treatment of myofascial syndrome include the stretch and spray pressure massage. Microcurrent electric neuromuscular stimulation was proposed in pain management for its effects on normalizing bioelectricity of cells and for its sub-sensory application. In this study, we tested the efficacy of low-intensity pulsed electric neuromuscular stimulus (PENS) on pain in patients with MPS of cervical spine muscles. We carried out a prospective-analytic longitudinal study at an outpatient clinic during two weeks. Forty subjects (mean age 42±13 years) were divided into two groups: treatment (TrGr, n=20) and control group (CtrlGr, n=20). Visual-analog scale (VAS) values, concerning the spontaneous and movement-related pain in the cervical-dorsal region at baseline (T0) and at the end of the study (T1), showed a reduction from 7 to 3.81 (p < 0.001) in TrGr. In the CtrlGr, VAS was reduced from 8.2 to 7.2 (n.s.). Moreover, the pressure pain threshold at T0 was 2.1 vs 4.2 at T1 (p < 0.001) in TrG. In the CtrlGR we observed no significant changes. Modulated low-intensity PENS is an innovative therapy permitting to act on the transmission of pain and on the restoration of tissue homeostasis. It seems to affect the transmission of pain through the stimulation of A-beta fibers. The above results show that low-intensity PENS can be considered as an effective treatment to reduce pain and disability in patients with MPS.

  17. EPINEPHRINE OR GV-26 ELECTRICAL STIMULATION REDUCES INHALANT ANESTHESTIC RECOVERY TIME IN COMMON SNAPPING TURTLES (CHELYDRA SERPENTINA).

    PubMed

    Goe, Alexandra; Shmalberg, Justin; Gatson, Bonnie; Bartolini, Pia; Curtiss, Jeff; Wellehan, James F X

    2016-06-01

    Prolonged anesthetic recovery times are a common clinical problem in reptiles following inhalant anesthesia. Diving reptiles have numerous adaptations that allow them to submerge and remain apneic for extended periods. An ability to shunt blood away from pulmonary circulation, possibly due to changes in adrenergic tone, may contribute to their unpredictable inhalant anesthetic recovery times. Therefore, the use of epinephrine could antagonize this response and reduce recovery time. GV-26, an acupuncture point with reported β-adrenergic and respiratory effects, has reduced anesthetic recovery times in other species. In this prospective randomized crossover study, six common snapping turtles (Chelydra serpentina) were anesthetized with inhalant isoflurane for 90 min. Turtles were assigned one of three treatments, given immediately following discontinuation of isoflurane: a control treatment (0.9% saline, at 0.1 ml/kg i.m.), epinephrine (0.1 mg/kg i.m.), or acupuncture with electrical stimulation at GV-26. Each turtle received all treatments, and treatments were separated by 48 hr. Return of spontaneous ventilation was 55% faster in turtles given epinephrine and 58% faster in the GV-26 group versus saline (P < 0.001). The times to movement and to complete recovery were also significantly faster for both treatments than for saline (P < 0.02). Treated turtles displayed increases in temperature not documented in the control (P < 0.001). Turtles administered epinephrine showed significantly increased heart rates and end-tidal CO(2) (P < 0.001). No adverse effects were noted in the study animals. The mechanisms of action were not elucidated in the present investigation. Nevertheless, the use of parenteral epinephrine or GV-26 stimulation in the immediate postanesthetic period produces clinically relevant reductions in anesthetic recovery time in common snapping turtle. Further research is necessary to evaluate the effects of concurrent GV-26 and epinephrine administration

  18. Reduced use of erythropoiesis-stimulating agents and intravenous iron with ferric citrate: a managed care cost-offset model

    PubMed Central

    Mutell, Richard; Rubin, Jaime L; Bond, T Christopher; Mayne, Tracy

    2013-01-01

    Background Ferric citrate (FC) is a phosphate binder in development for the treatment of hyperphosphatemia in patients with end-stage renal disease (ESRD). In clinical trials, FC improved patient serum phosphorus levels and increased serum ferritin and percent transferrin saturation. Because nephrologists respond to increases in these iron measures by reducing intravenous (IV) iron and erythropoiesis-stimulating agent (ESA) doses, the decreased use of iron and ESA associated with FC may reduce costs. Objectives To develop a cost-offset model from a managed care perspective estimating the cost savings associated with FC use. Methods We created a cost-offset model from the managed care payer perspective that compared the treatment costs of ESRD for patients given FC. The model considered the number of dialysis sessions per month; number of ESRD patients enrolled in the health plan; cost of ESAs, iron, and dialysis sessions; and the proportion of patients on phosphate binder therapy. The model assumed equivalent efficacy and cost neutrality between FC and other phosphate binders. Monte Carlo simulations were conducted by varying model inputs. Results When FC was compared to other phosphate binders, the monthly cost of ESA and IV iron per 500 patients with ESRD (85% treated with phosphate binders) was reduced by 8.15% and 33.2%, respectively. When incorporated into the total cost of dialysis for patients with ESRD (dialysis, ESA, and IV iron), the decrease in the monthly cost of dialysis care was US$80,214 per 500 ESRD patients. Monte Carlo simulations suggest that a plan serving 500 dialysis patients could save between US$626,000 and US$1,106,000 annually with the use of FC. Conclusion The use of FC in ESRD patients with hyperphosphatemia may help reduce treatment costs. PMID:23662073

  19. Cannabinoid type 2 receptor stimulation attenuates brain edema by reducing cerebral leukocyte infiltration following subarachnoid hemorrhage in rats.

    PubMed

    Fujii, Mutsumi; Sherchan, Prativa; Krafft, Paul R; Rolland, William B; Soejima, Yoshiteru; Zhang, John H

    2014-07-15

    Early brain injury (EBI), following subarachnoid hemorrhage (SAH), comprises blood-brain barrier (BBB) disruption and consequent edema formation. Peripheral leukocytes can infiltrate the injured brain, thereby aggravating BBB leakage and neuroinflammation. Thus, anti-inflammatory pharmacotherapies may ameliorate EBI and provide neuroprotection after SAH. Cannabinoid type 2 receptor (CB2R) agonism has been shown to reduce neuroinflammation; however, the precise protective mechanisms remain to be elucidated. This study aimed to evaluate whether the selective CB2R agonist, JWH133 can ameliorate EBI by reducing brain-infiltrated leukocytes after SAH. Adult male Sprague-Dawley rats were randomly assigned to the following groups: sham-operated, SAH with vehicle, SAH with JWH133 (1.0mg/kg), or SAH with a co-administration of JWH133 and selective CB2R antagonist SR144528 (3.0mg/kg). SAH was induced by endovascular perforation, and JWH133 was administered 1h after surgery. Neurological deficits, brain water content, Evans blue dye extravasation, and Western blot assays were evaluated at 24h after surgery. JWH133 improved neurological scores and reduced brain water content; however, SR144528 reversed these treatment effects. JWH133 reduced Evans blue dye extravasation after SAH. Furthermore, JWH133 treatment significantly increased TGF-β1 expression and prevented an SAH-induced increase in E-selectin and myeloperoxidase. Lastly, SAH resulted in a decreased expression of the tight junction protein zonula occludens-1 (ZO-1); however, JWH133 treatment increased the ZO-1 expression. We suggest that CB2R stimulation attenuates neurological outcome and brain edema, by suppressing leukocyte infiltration into the brain through TGF-β1 up-regulation and E-selectin reduction, resulting in protection of the BBB after SAH.

  20. Reduced use of erythropoiesis-stimulating agents and intravenous iron with ferric citrate: a managed care cost-offset model.

    PubMed

    Mutell, Richard; Rubin, Jaime L; Bond, T Christopher; Mayne, Tracy

    2013-01-01

    Ferric citrate (FC) is a phosphate binder in development for the treatment of hyperphosphatemia in patients with end-stage renal disease (ESRD). In clinical trials, FC improved patient serum phosphorus levels and increased serum ferritin and percent transferrin saturation. Because nephrologists respond to increases in these iron measures by reducing intravenous (IV) iron and erythropoiesis-stimulating agent (ESA) doses, the decreased use of iron and ESA associated with FC may reduce costs. To develop a cost-offset model from a managed care perspective estimating the cost savings associated with FC use. We created a cost-offset model from the managed care payer perspective that compared the treatment costs of ESRD for patients given FC. The model considered the number of dialysis sessions per month; number of ESRD patients enrolled in the health plan; cost of ESAs, iron, and dialysis sessions; and the proportion of patients on phosphate binder therapy. The model assumed equivalent efficacy and cost neutrality between FC and other phosphate binders. Monte Carlo simulations were conducted by varying model inputs. When FC was compared to other phosphate binders, the monthly cost of ESA and IV iron per 500 patients with ESRD (85% treated with phosphate binders) was reduced by 8.15% and 33.2%, respectively. When incorporated into the total cost of dialysis for patients with ESRD (dialysis, ESA, and IV iron), the decrease in the monthly cost of dialysis care was US$80,214 per 500 ESRD patients. Monte Carlo simulations suggest that a plan serving 500 dialysis patients could save between US$626,000 and US$1,106,000 annually with the use of FC. The use of FC in ESRD patients with hyperphosphatemia may help reduce treatment costs.

  1. Cost-effectiveness of using adjunctive porcine small intestine submucosa tri-layer matrix compared with standard care in managing diabetic foot ulcers in the US.

    PubMed

    Guest, J F; Weidlich, D; Singh, H; La Fontaine, J; Garrett, A; Abularrage, C J; Waycaster, C R

    2017-01-02

    To estimate the cost-effectiveness of using tri-layer porcine small intestine submucosa (SIS; Oasis Ultra) as an adjunct to standard care compared with standard care alone in managing diabetic foot ulcers (DFUs) in the US, from the perspective of Medicare. A Markov model was constructed to simulate the management of diabetic neuropathic lower extremity ulcers over a period of one year in the US. The model was used to estimate the cost-effectiveness of initially using adjunctive SIS compared with standard care alone to treat a DFU in the US at 2016 prices. At 12 months after the start of treatment, the use of adjunctive SIS instead of standard care alone is expected to lead to a 42 % increase in the number of ulcer-free months, 32 % increase in the probability of healing, a 3 % decrease in the probability of developing complicated ulcers and a 1 % decrease in the probability of undergoing an amputation. Health-care resource use is expected to be reduced by 11-14 % among patients who are initially managed with adjunctive SIS compared with those initially managed with standard care alone, with the exception of debridement, which is expected to be reduced by 35 %. Hence, the total health-care cost of starting treatment with adjunctive SIS instead of standard care alone was estimated to reduce payer costs by 1% (i.e. $105 per patient) over 12 months following the start of treatment. Within the study's limitations, the use of adjunctive SIS instead of standard care alone improves outcome for less cost and thereby affords a cost-effective use of Medicare-funded resources in the management of neuropathic foot ulcers among adult patients with type 1 or 2 diabetes mellitus in the US.

  2. Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism.

    PubMed

    Anderson, Collin J; Sheppard, Daylan T; Huynh, Rachel; Anderson, Daria Nesterovich; Polar, Christian A; Dorval, Alan D

    2015-01-01

    The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS) partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson's disease (PD) are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons and that therapeutic DBS of the subthalamic nucleus (STN) treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian (hPD) onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms.

  3. Ferric pyrophosphate citrate administered via dialysate reduces erythropoiesis-stimulating agent use and maintains hemoglobin in hemodialysis patients.

    PubMed

    Gupta, Ajay; Lin, Vivian; Guss, Carrie; Pratt, Raymond; Ikizler, T Alp; Besarab, Anatole

    2015-11-01

    Ferric pyrophosphate citrate (FPC) is a water-soluble iron salt administered via dialysate to supply iron directly to transferrin. The PRIME study tested whether treatment with FPC could reduce prescribed erythropoiesis-stimulating agent (ESA) use and maintain hemoglobin in hemodialysis patients. This 9-month, randomized, placebo-controlled, double-blind, multicenter clinical study included 103 patients undergoing hemodialysis 3-4 times weekly. The FPC group received dialysate containing 2 μmol/l of iron. The placebo group received standard dialysate. A blinded central anemia management group facilitated ESA dose adjustments. Intravenous iron was administered according to the approved indication when ferritin levels fell below 200 μg/l. The primary end point was the percentage change from baseline in prescribed ESA dose at end of treatment. Secondary end points included intravenous iron use and safety. At the end of treatment, there was a significant 35% reduction in prescribed ESA dose in FPC-treated patients compared with placebo. The FPC patients used 51% less intravenous iron than placebo. Adverse and serious adverse events were similar in both groups. Thus, FPC delivered via dialysate significantly reduces the prescribed ESA dose and the amount of intravenous iron needed to maintain hemoglobin in chronic hemodialysis patients.

  4. Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism

    PubMed Central

    Anderson, Collin J.; Sheppard, Daylan T.; Huynh, Rachel; Anderson, Daria Nesterovich; Polar, Christian A.; Dorval, Alan D.

    2015-01-01

    The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS) partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson’s disease (PD) are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons and that therapeutic DBS of the subthalamic nucleus (STN) treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian (hPD) onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms. PMID:26217192

  5. Ferric pyrophosphate citrate administered via dialysate reduces erythropoiesis-stimulating agent use and maintains hemoglobin in hemodialysis patients

    PubMed Central

    Gupta, Ajay; Lin, Vivian; Guss, Carrie; Pratt, Raymond; Ikizler, T Alp; Besarab, Anatole

    2015-01-01

    Ferric pyrophosphate citrate (FPC) is a water-soluble iron salt administered via dialysate to supply iron directly to transferrin. The PRIME study tested whether treatment with FPC could reduce prescribed erythropoiesis-stimulating agent (ESA) use and maintain hemoglobin in hemodialysis patients. This 9-month, randomized, placebo-controlled, double-blind, multicenter clinical study included 103 patients undergoing hemodialysis 3–4 times weekly. The FPC group received dialysate containing 2 μmol/l of iron. The placebo group received standard dialysate. A blinded central anemia management group facilitated ESA dose adjustments. Intravenous iron was administered according to the approved indication when ferritin levels fell below 200 μg/l. The primary end point was the percentage change from baseline in prescribed ESA dose at end of treatment. Secondary end points included intravenous iron use and safety. At the end of treatment, there was a significant 35% reduction in prescribed ESA dose in FPC-treated patients compared with placebo. The FPC patients used 51% less intravenous iron than placebo. Adverse and serious adverse events were similar in both groups. Thus, FPC delivered via dialysate significantly reduces the prescribed ESA dose and the amount of intravenous iron needed to maintain hemoglobin in chronic hemodialysis patients. PMID:26154926

  6. Rice protein hydrolysates stimulate GLP-1 secretion, reduce GLP-1 degradation, and lower the glycemic response in rats.

    PubMed

    Ishikawa, Yuki; Hira, Tohru; Inoue, Daisuke; Harada, Yukikazu; Hashimoto, Hiroyuki; Fujii, Mikio; Kadowaki, Motoni; Hara, Hiroshi

    2015-08-01

    Rice has historically been consumed in Asia as a major source of carbohydrates, however, little is known regarding the functional roles of rice proteins as dietary factors. In the present study, we investigated whether peptides derived from rice proteins could stimulate GLP-1 secretion, which results in reducing glycemia via the incretin effect in normal rats. Hydrolysates were prepared from the protein fraction of rice endosperm or rice bran, and the effects of these hydrolysates on GLP-1 secretion were examined in a murine enteroendocrine cell line GLUTag. Plasma was collected after oral administration of the rice protein hydrolysates, under anesthesia, or during glucose tolerance tests in rats. In anesthetized rats, plasma dipeptidyl peptidase-IV (DPP-IV) activity was measured after ileal administration of the rice protein hydrolysates. GLP-1 secretion from GLUTag cells was potently stimulated by the rice protein hydrolysates, especially by the peptic digest of rice endosperm protein (REPH) and that of rice bran protein (RBPH). Oral administration of REPH or RBPH elevated plasma GLP-1 concentrations, which resulted in the reduction of glycemia under the intraperitoneal glucose tolerance test. In addition, the plasma DPP-IV activity was attenuated after ileal administration of REPH or RBPH, which resulted in a higher ratio of intact (active) GLP-1 to total GLP-1 in the plasma. These results demonstrate that rice proteins exert potent stimulatory effects on GLP-1 secretion, which could contribute to the reduction of postprandial glycemia. The inhibitory effect of these peptides on the plasma DPP-IV activity may potentiate the incretin effect of GLP-1.

  7. Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain

    PubMed Central

    Chen, Wanqiu; Guo, Yi; Walker, Espen J.; Shen, Fanxia; Jun, Kristine; Oh, S. Paul; Degos, Vincent; Lawton, Michael T.; Tihan, Tarik; Davalos, Dimitrios; Akassoglou, Katerina; Nelson, Jeffrey; Pile-Spellman, John; Su, Hua; Young, William L.

    2013-01-01

    Objective Vessels in brain arteriovenous malformations (bAVM) are prone to rupture. The underlying pathogenesis is not clear. Hereditary hemorrhagic telangiectasia type 2 (HHT2) patients with activin receptor-like kinase 1 (Alk1) mutation have a higher incidence of bAVM than the general population. We tested the hypothesis that vascular endothelial growth factor (VEGF) impairs vascular integrity in the Alk1-deficient brain through reduction of mural cell-coverage. Methods and Results Adult Alk11f/2f mice (loxP sites flanking exons 4-6) and wild-type (WT) mice were injected with 2×107 PFU Ad-Cre and 2×109 genome copies of AAV-VEGF to induce focal homozygous Alk1 deletion (in Alk11f/2f mice) and angiogenesis. Brain vessels were analyzed eight weeks later. Compared to WT mice, the Alk1-deficient brain had more fibrin (99±30×103 pixels/mm2 vs. 40±13×103, P=0.001), iron deposition (508±506 pixels/mm2 vs. 6 ±49, P=0.04), and Iba1+ microglia/macrophage infiltration (888±420 Iba1+ cells/mm2 vs. 240±104 Iba1+, P=0.001) after VEGF stimulation. In the angiogenic foci, the Alk1-deficient brain had more α-SMA- vessels (52±9% vs. 12±7%, P<0.001), fewer vascular associated pericytes (503±179/mm2 vs. 931±115, P<0.001), and reduced PDGFR-β expression (26±9%, P<0.001). Conclusion Reduction of mural cell coverage in response to VEGF stimulation is a potential mechanism for the impairment of vessel wall integrity in HHT2-associated bAVM. PMID:23241407

  8. A single trial of transcutaneous electrical nerve stimulation reduces chronic neuropathic pain following median nerve injury in rats.

    PubMed

    Cho, Hwi-Young; Suh, Hye Rim; Han, Hee Chul

    2014-01-01

    Neuropathic pain is a devastating chronic condition and is often induced in the upper limb following nerve injury or damage. Various drugs or surgical methods have been used to manage neuropathic pain; however, these are frequently accompanied by undesirable side effects. Transcutaneous electrical nerve stimulation (TENS) is a safe and non-invasive intervention that has been used to alleviate different types of pain in the clinic, but it is unclear whether TENS can improve chronic neuropathic pain in the upper limb. Thus, the aim of this study was to investigate the effects of a single trial of TENS on chronic neuropathic pain following median nerve injury. Male rats weighing 200-250 g received median nerve-ligation of the right forearm, while the control group received only skin-incision without nerve-ligation. Neuropathic pain-behaviors, including mechanical, cold, and thermal allodynia, were measured for 4 weeks. After the development of chronic neuropathic pain, TENS (100 Hz, 200 µs, sub-motor threshold) or placebo-TENS (sham stimulation) was applied for 20 min to the ipsilateral or contralateral side. Neuropathic pain behavior was assessed before and after intervention. Median nerve-ligation significantly induced and maintained neuropathic pain in the ipsilateral side. TENS application to the ipsilateral side effectively attenuated the three forms of chronic neuropathic pain in the ipsilateral side compared to sham-treated rats (peripheral and central effects), while TENS application to contralateral side only reduced mechanical allodynia in the ipsilateral side (central effect). Our findings demonstrate that TENS can alleviate chronic neuropathic pain following median nerve injury.

  9. Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.

    PubMed

    Matsuo, Hideaki; Uchida, Kenzo; Nakajima, Hideaki; Guerrero, Alexander Rodriguez; Watanabe, Shuji; Takeura, Naoto; Sugita, Daisuke; Shimada, Seiichiro; Nakatsuka, Terumasa; Baba, Hisatoshi

    2014-09-01

    Although transcutaneous electrical nerve stimulation (TENS) is widely used for the treatment of neuropathic pain, its effectiveness and mechanism of action in reducing neuropathic pain remain uncertain. We investigated the effects of early TENS (starting from the day after surgery) in mice with neuropathic pain, on hyperalgesia, glial cell activation, pain transmission neuron sensitization, expression of proinflammatory cytokines, and opioid receptors in the spinal dorsal horn. Following nerve injury, TENS and behavioral tests were performed every day. Immunohistochemical, immunoblot, and flow cytometric analysis of the lumbar spinal cord were performed after 8 days. Early TENS reduced mechanical and thermal hyperalgesia and decreased the activation of microglia and astrocytes (P<0.05). In contrast, the application of TENS at 1 week (TENS-1w) or 2 weeks (TENS-2w) after injury was ineffective in reducing hyperalgesia (mechanical and thermal) or activation of microglia and astrocytes. Early TENS decreased p-p38 within microglia (P<0.05), the expression levels of protein kinase C (PKC-γ), and phosphorylated anti-phospho-cyclic AMP response element-binding protein (p-CREB) in the superficial spinal dorsal horn neurons (P<0.05), mitogen-activated protein (MAP) kinases, and proinflammatory cytokines, and increased the expression levels of opioid receptors (P<0.05). The results suggested that the application of early TENS relieved hyperalgesia in our mouse model of neuropathic pain by inhibiting glial activation, MAP kinase activation, PKC-γ, and p-CREB expression, and proinflammatory cytokines expression, as well as maintenance of spinal opioid receptors. The findings indicate that TENS treatment is more effective when applied as early after nerve injury as possible.

  10. Effects of toluene exposure on signal transduction: toluene reduced the signaling via stimulation of human muscarinic acetylcholine receptor m2 subtypes in CHO cells.

    PubMed

    Tsuga, Hirofumi; Haga, Tatsuya; Honma, Takeshi

    2002-07-01

    The organic solvent toluene is used widely in industry and is toxic to the central nervous system (CNS). To clarify the mechanisms of CNS toxicity following toluene exposure, especially with respect to the G protein-coupling of receptors, we determined the effects of toluene on the activation of Gi by stimulating human muscarinic acetylcholine receptor m2 subtypes (hm2 receptors) expressed in Chinese hamster ovary (CHO) cells. We first examined whether toluene affects the inhibition of adenylyl cyclase by Gi. The attenuation of forskolin-stimulated cAMP formation by the stimulation of hm2 receptors was reduced in a medium containing toluene. Next, we determined the effects of toluene on carbamylcholine-stimulated [35S]GTPgammaS binding using membrane fractions of CHO cell expressing hm2 receptors. Carbamylcholine-stimulated [35S]GTPgammaS binding activity was markedly reduced when assayed using reaction buffers containing toluene. However, carbamylcholine-stimulated [35S]GTPgammaS binding activity was essentially unchanged following pretreatment of the cells with a toluene-saturated medium prior to membrane isolation. Toluene pretreatment and the toluene itself did not alter the characteristics of the binding of carbamylcholine and [3H]N-methylscopolamine to hm2 receptors. On the contrary of the effect of toluene for [35S]GTPgammaS binding, the effect of toluene for attenuation of forskolin-stimulated cAMP formation by the stimulation of hm2 receptors was irreversible. These observations indicate that toluene acts as an inhibitor of the signal transduction via hm2 receptor stimulation in CHO cells, and at least two mechanisms exist in the inhibition mechanisms by toluene.

  11. Assisting people with attention deficit hyperactivity disorder by actively reducing limb hyperactive behavior with a gyration air mouse through a controlled environmental stimulation.

    PubMed

    Shih, Ching-Hsiang

    2011-01-01

    The latest researches have adopted software technology turning the gyration air mouse into a high performance limb movement detector, and have assessed whether two persons with multiple disabilities would be able to control an environmental stimulation using limb movement. This study extends gyration air mouse functionality by actively reducing limb hyperactive behavior to assess whether two persons with attention deficit hyperactivity disorder (ADHD) would be able to actively reduce their limb hyperactive behavior by controlling their favorite stimulation on/off using a gyration air mouse with a newly developed actively limb hyperactive behavior reducing program (ALHBRP). The study was performed according to an ABAB design, in which A represented the baseline and B represented intervention phases. Data showed that both participants significantly increased their time duration of maintaining a static limb posture (TDMSLP) to activate the control system in order to produce environmental stimulation during the intervention phases. Practical and developmental implications of the findings are discussed.

  12. Isolation, characterization, and in vitro evaluation of bovine rumen submucosa films of collagen or chitosan-treated collagen.

    PubMed

    Gopal Shankar, K; Udhaya Kumar, S; Sowndarya, S; Suresh Babu, P; Rose, C

    2016-01-01

    Bovine rumen is hitherto considered as an inedible waste of meat industry. The rumen tissues can be used as an alternative source of collagen to produce biocompatible materials for clinical application. In an effort to develop a functional biomaterial from the inedible mammalian tissues, this study aims to isolate and characterize bovine rumen submucosa. Initially, the rumen tissue was sequentially processed using chemical and enzymatic treatment to decellularize, neutralize, stabilize, and to produce a native collagen matrix which is referred as collagen film (COL-F). Thus, prepared matrix was treated with 1% (w/v) chitosan solution to produce a hybrid film which is referred as collagen-chitosan film (COL/CS-F). The comparative study includes the evaluation of physical, chemical, and biological properties of the biofilms prepared. The surface topology of COL-F exhibited a continuous collagenous network with fibrous nature, while the chitosan treatment provided smooth plain surface to the parent film. Incorporation of chitosan in COL-F increased the tensile properties, as well as the thermal stability and durability of the films. The Fourier Transform Infrared spectroscopy results revealed the presence of respective amide peaks, which corresponds to protein (collagen), and the evidence of collagen-chitosan interlinking. The submucosa layer was electrophoretically found to have type I collagen. The X-ray diffraction data showed the presence of amorphous and crystalline peak which attributes to the triple helical structure of collagen in the films. Cytotoxicity studies on the films were performed in vitro using human keratinocytes. The results of cell viability and proliferation demonstrated that COL-F and COL/CS-F exhibit good biocompatibility and therefore can augment cell infiltration and proliferation. However, enhanced cellular activity was observed on the chitosan treated COL-F. These observations demonstrate that the biofilms prepared in this study can be

  13. Heavy Water Reduces GFP Expression in Prokaryotic Cell-Free Assays at the Translation Level While Stimulating Its Transcription

    PubMed Central

    Hohlefelder, Luisa S.; Opitz, Madeleine; Bayerl, Thomas M.; Rädler, Joachim O.

    2013-01-01

    The in vitro proliferation of prokaryotic and eukaryotic cells is remarkably hampered in the presence of heavy water (D2O). Impairment of gene expression at the transcription or translation level can be the base for this effect. However, insights into the underlying mechanisms are lacking. Here, we employ a cell-free expression system for the quantitative analysis of the effect of increasing percentages of D2O on the kinetics of in-vitro GFP expression. Experiments are designed to discriminate the rates of transcription, translation, and protein folding using pDNA and mRNA vectors, respectively. We find that D2O significantly stimulates GFP expression at the transcription level but acts as a suppressor at translation and maturation (folding) in a linear dose-dependent manner. At a D2O concentration of 60%, the GFP expression rate was reduced to 40% of an undisturbed sample. We observed a similar inhibition of GFP expression by D2O in a recombinant Escherichia coli strain, although the inhibitory effect is less pronounced. These results demonstrate the suitability of cell-free systems for quantifying the impact of heavy water on gene expression and establish a platform to further assess the potential therapeutic use of heavy water as antiproliferative agent. PMID:24455706

  14. Heavy water reduces GFP expression in prokaryotic cell-free assays at the translation level while stimulating its transcription.

    PubMed

    Hohlefelder, Luisa S; Stögbauer, Tobias; Opitz, Madeleine; Bayerl, Thomas M; Rädler, Joachim O

    2013-01-01

    The in vitro proliferation of prokaryotic and eukaryotic cells is remarkably hampered in the presence of heavy water (D2O). Impairment of gene expression at the transcription or translation level can be the base for this effect. However, insights into the underlying mechanisms are lacking. Here, we employ a cell-free expression system for the quantitative analysis of the effect of increasing percentages of D2O on the kinetics of in-vitro GFP expression. Experiments are designed to discriminate the rates of transcription, translation, and protein folding using pDNA and mRNA vectors, respectively. We find that D2O significantly stimulates GFP expression at the transcription level but acts as a suppressor at translation and maturation (folding) in a linear dose-dependent manner. At a D2O concentration of 60%, the GFP expression rate was reduced to 40% of an undisturbed sample. We observed a similar inhibition of GFP expression by D2O in a recombinant Escherichia coli strain, although the inhibitory effect is less pronounced. These results demonstrate the suitability of cell-free systems for quantifying the impact of heavy water on gene expression and establish a platform to further assess the potential therapeutic use of heavy water as antiproliferative agent.

  15. Repeated moderate stress stimulates the production of dehydroepiandrosterone sulfate (DHEAS) and reduces corticosteroid imbalance in old Macaca Mulatta.

    PubMed

    Goncharova, N D; Vengerin, A A; Chigarova, O A

    2012-09-01

    Young (6-8 years) and old (21-30 years) Macaca mulatta females were subjected to gentle immobilization (2 h daily at 15.00) for 10 days. Blood specimens were collected before the exposure and 15, 30, 60, 120, 240 min and 24 h after the beginning of exposure on days 1, 3, and 10. The adrenocortical reaction to stress was maximum on day 1 in all animals. The increase of cortisol (F) and dehydroepiandrosterone sulfate (DHEAS) concentrations in young monkeys decreased on days 3 and 10, DHEAS drop being less pronounced in comparison with F, as a result of which F/DHEAS molar concentration ratio changed negligibly. In old monkeys the basal DHEAS levels were lower, while the F/DHEAS ratio was higher than in young animals. Repeated immobilizations inhibited F elevation on day 3, caused no changes in DHEAS reaction, led to increase of basal DHEAS levels and to a reduction of F/DHEAS ratio on days 2, 3, 4, 10, 11. Hence, chronic moderate stress stimulated the production of DHEAS and reduced the corticosteroid imbalance in old monkeys.

  16. Personality and Augmenting/Reducing (A/R) in auditory event-related potentials (ERPs) during emotional visual stimulation

    PubMed Central

    De Pascalis, Vilfredo; Fracasso, Francesca; Corr, Philip J.

    2017-01-01

    An auditory augmenting/reducing ERP paradigm recorded for 5 intensity tones with emotional visual stimulation was used, for the first time, to test predictions derived from the revised Reinforcement Sensitivity Theory (rRST) of personality with respect to two major factors: behavioral inhibition system (BIS), fight/flight/freeze system (FFFS). Higher BIS and FFFS scores were negatively correlated with N1/P2 slopes at central sites (C3, Cz, C4). Conditional process analysis revealed that the BIS was a mediator of the association between the N1/P2 slope and the FFFS scores. An analysis of covariance showed that lower BIS scorers exhibited larger N1/P2 amplitudes across all tone intensities while watching negative, positive and neutral pictures. Additionally, lower FFFS scorers compared to higher FFFS scorers disclosed larger N1/P2 amplitudes to the highest tone intensities and these differences were even more pronounced while watching positive emotional pictures. Findings were explained assuming the operation of two different, but related processes: transmarginal inhibition for the BIS; the attention/emotional gating mechanism regulating cortical sensory input for the FFFS trait. These findings appear consistent with predictions derived from the rRST, which traced fear and anxiety to separate but interacting neurobehavioural systems. PMID:28164996

  17. Taurolidine reduces the tumor stimulating cytokine interleukin-1beta in patients with resectable gastrointestinal cancer: a multicentre prospective randomized trial

    PubMed Central

    Braumann, Chris; Gutt, Carsten N; Scheele, Johannes; Menenakos, Charalambos; Willems, Wilhelm; Mueller, Joachim M; Jacobi, Christoph A

    2009-01-01

    Background The effect of additional treatment strategies with antineoplastic agents on intraperitoneal tumor stimulating interleukin levels are unclear. Taurolidine and Povidone-iodine have been mainly used for abdominal lavage in Germany and Europe. Methods In the settings of a multicentre (three University Hospitals) prospective randomized controlled trial 120 patients were randomly allocated to receive either 0.5% taurolidine/2,500 IU heparin (TRD) or 0.25% povidone-iodine (control) intraperitoneally for resectable colorectal, gastric or pancreatic cancers. Due to the fact that IL-1beta (produced by macrophages) is preoperatively indifferent in various gastrointestinal cancer types our major outcome criterion was the perioperative (overall) level of IL-1beta in peritoneal fluid. Results Cytokine values were significantly lower after TRD lavage for IL-1beta, IL-6, and IL-10. Perioperative complications did not differ. The median follow-up was 50.0 months. The overall mortality rate (28 vs. 25, p = 0.36), the cancer-related death rate (17 vs. 19, p = .2), the local recurrence rate (7 vs. 12, p = .16), the distant metastasis rate (13 vs. 18, p = 0.2) as well as the time to relapse were not statistically significant different. Conclusion Reduced cytokine levels might explain a short term antitumorigenic intraperitoneal effect of TRD. But, this study analyzed different types of cancer. Therefore, we set up a multicentre randomized trial in patients undergoing curative colorectal cancer resection. Trial registration ISRCTN66478538 PMID:19309495

  18. Angiogenesis Is Induced and Wound Size Is Reduced by Electrical Stimulation in an Acute Wound Healing Model in Human Skin

    PubMed Central

    Ud-Din, Sara; Sebastian, Anil; Giddings, Pamela; Colthurst, James; Whiteside, Sigrid; Morris, Julie; Nuccitelli, Richard; Pullar, Christine; Baguneid, Mo; Bayat, Ardeshir

    2015-01-01

    Angiogenesis is critical for wound healing. Insufficient angiogenesis can result in impaired wound healing and chronic wound formation. Electrical stimulation (ES) has been shown to enhance angiogenesis. We previously showed that ES enhanced angiogenesis in acute wounds at one time point (day 14). The aim of this study was to further evaluate the role of ES in affecting angiogenesis during the acute phase of cutaneous wound healing over multiple time points. We compared the angiogenic response to wounding in 40 healthy volunteers (divided into two groups and randomised), treated with ES (post-ES) and compared them to secondary intention wound healing (control). Biopsy time points monitored were days 0, 3, 7, 10, 14. Objective non-invasive measures and H&E analysis were performed in addition to immunohistochemistry (IHC) and Western blotting (WB). Wound volume was significantly reduced on D7, 10 and 14 post-ES (p = 0.003, p = 0.002, p<0.001 respectively), surface area was reduced on days 10 (p = 0.001) and 14 (p<0.001) and wound diameter reduced on days 10 (p = 0.009) and 14 (p = 0.002). Blood flow increased significantly post-ES on D10 (p = 0.002) and 14 (p = 0.001). Angiogenic markers were up-regulated following ES application; protein analysis by IHC showed an increase (p<0.05) in VEGF-A expression by ES treatment on days 7, 10 and 14 (39%, 27% and 35% respectively) and PLGF expression on days 3 and 7 (40% on both days), compared to normal healing. Similarly, WB demonstrated an increase (p<0.05) in PLGF on days 7 and 14 (51% and 35% respectively). WB studies showed a significant increase of 30% (p>0.05) on day 14 in VEGF-A expression post-ES compared to controls. Furthermore, organisation of granulation tissue was improved on day 14 post-ES. This randomised controlled trial has shown that ES enhanced wound healing by reduced wound dimensions and increased VEGF-A and PLGF expression in acute cutaneous wounds, which further substantiates the role of ES in up

  19. Deep brain stimulation may reduce the relative risk of clinically important worsening in early stage Parkinson's disease.

    PubMed

    Hacker, Mallory L; Tonascia, James; Turchan, Maxim; Currie, Amanda; Heusinkveld, Lauren; Konrad, Peter E; Davis, Thomas L; Neimat, Joseph S; Phibbs, Fenna T; Hedera, Peter; Wang, Lily; Shi, Yaping; Shade, David M; Sternberg, Alice L; Drye, Lea T; Charles, David

    2015-10-01

    The Vanderbilt pilot trial of deep brain stimulation (DBS) in early Parkinson's disease (PD) enrolled patients on medications six months to four years without motor fluctuations or dyskinesias. We conducted a patient-centered analysis based on clinically important worsening of motor symptoms and complications of medical therapy for all subjects and a subset of subjects with a more focused medication duration. Continuous outcomes were also analyzed for this focused cohort. A post hoc analysis was conducted on all subjects from the pilot and a subset of subjects taking PD medications 1-4 years at enrollment. Clinically important worsening is defined as both a ≥ 3 point increase in UPDRS Part III and a ≥ 1 point increase in Part IV. DBS plus optimal drug therapy (DBS + ODT) subjects experienced a 50-80% reduction in the relative risk of worsening after two years. The DBS + ODT group was improved compared to optimal drug therapy (ODT) at each time point on Total UPDRS and Part III (p = 0.04, p = 0.02, respectively, at 24 months). Total UPDRS, Part IV, and PDQ-39 scores significantly worsened in the ODT group after two years (p < 0.003), with no significant change in the DBS + ODT group. DBS + ODT in early PD may reduce the risk of clinically important worsening. These findings further confirm the need to determine if DBS + ODT is superior to medical therapy for managing symptoms, reducing the complications of medications, and improving quality of life. The FDA has approved the conduct of a large-scale, pivotal clinical trial of DBS in early stage PD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Exercise reduced pentraxin 3 levels produced by endotoxin-stimulated human peripheral blood mononuclear cells in obese individuals.

    PubMed

    Slusher, Aaron L; Shibata, Yoshimi; Whitehurst, Michael; Maharaj, Arun; Quiles, Justin M; Huang, Chun-Jung

    2017-01-01

    The purpose of this study was to determine whether obesity would reduce the capacity of peripheral blood mononuclear cells (PBMCs) to produce the anti-inflammatory protein pentraxin 3 (PTX3) in response to ex vivo stimulation with lipopolysaccharide (LPS), and if acute aerobic exercise would enhance this PTX3 production capacity. In addition, the inter-relationships of LPS-induced PTX3 with the inflammatory cytokines (interleukin 6 [IL-6], IL-10, and tumor necrosis factor alpha) were examined. Twenty-one healthy subjects (10 obese and 11 normal-weight) performed an acute bout of aerobic exercise at 75% VO2max. The capacity of PBMCs to produce PTX3 ex vivo following LPS stimulation was the same in obese and normal-weight subjects at rest, and decreased equally in both subject groups following acute aerobic exercise. This is in contrast to plasma PTX3, which is lower in obese subjects at rest and increased equally in both obese and normal-weight subjects following exercise. In addition, ex vivo PTX3 production was positively associated with IL-6 and IL-10 in response to acute aerobic exercise ( r = 0.686, P = 0.020; r = 0.744, P = 0.009, respectively) in normal-weight, but not in obese individuals ( r = 0.429, P = 0.249; r = 0.453, P = 0.189, respectively). These findings indicate that concentrations of PTX3 observed in plasma are relatively independent of those produced by PBMCs ex vivo and the mechanisms associated with PTX3-mediated anti-inflammatory signaling may differ during obesity. Impact statement Our laboratory has previously demonstrated that obese individuals present with lower plasma concentrations of the anti-inflammatory protein pentraxin 3 (PTX3), whereas acute aerobic exercise increases plasma PTX3 levels similarly compared to normal-weight individuals. As a follow-up, the present study demonstrates that PBMCs isolated from obese and normal-weight individuals produce comparable amounts of PTX3 ex vivo in response to

  1. High- and low-frequency transcutaneous electrical nerve stimulation does not reduce experimental pain in elderly individuals

    PubMed Central

    Bergeron-Vézina, Kayla; Corriveau, Hélène; Martel, Marylie; Harvey, Marie-Philippe; Léonard, Guillaume

    2015-01-01

    Abstract Despite its widespread clinical use, the efficacy of transcutaneous electrical nerve stimulation (TENS) remains poorly documented in elderly individuals. In this randomized, double-blind crossover study, we compared the efficacy of high-frequency (HF), low-frequency (LF), and placebo (P) TENS in a group of 15 elderly adults (mean age: 67 ± 5 years). The effect of HF-, LF-, and P-TENS was also evaluated in a group of 15 young individuals (26 ± 5 years; same study design) to validate the effectiveness of the TENS protocols that were used in the elderly group. Each participant came to the laboratory on 3 separate occasions to receive, in random order, HF-, LF-, and P-TENS. Pain intensity and pain perception thresholds were assessed before, during, and after TENS, using an experimental heat pain paradigm. For the young group, there was a significant decrease in pain intensity during and after HF- and LF-TENS when compared with baseline, with both HF- and LF-TENS being superior to P-TENS. In the older group, HF- and LF-TENS did not reduce pain when compared with baseline and no difference was observed between the 2 active TENS sessions and P-TENS. High-frequency, LF-, and P-TENS all increased pain thresholds in young individuals, whereas in older individuals, only LF-TENS increased pain thresholds. Taken together, these results suggest that TENS is effective in young, but not in older, individuals. Future studies should be conducted to confirm these results in pain populations and to identify strategies that could enhance the effect of TENS in the elderly. PMID:26101836

  2. Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis.

    PubMed

    Garcia, Samuel; Hartkamp, Linda M; Malvar-Fernandez, B; van Es, Inge E; Lin, Haishan; Wong, Justin; Long, Li; Zanghi, James A; Rankin, Andrew L; Masteller, Emma L; Wong, Brian R; Radstake, Timothy R D J; Tak, Paul P; Reedquist, Kris A

    2016-03-31

    CSF-1 or IL-34 stimulation of CSF1R promotes macrophage differentiation, activation and osteoclastogenesis, and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis. The objective of this study was to determine the relative contributions of CSF-1 and IL-34 signaling to CSF1R in RA. CSF-1 and IL-34 were detected by immunohistochemical and digital image analysis in synovial tissue from 15 biological-naïve rheumatoid arthritis (RA) , 15 psoriatic arthritis (PsA) and 7 osteoarthritis (OA) patients . Gene expression in CSF-1- and IL-34-differentiated human macrophages was assessed by FACS analysis and quantitative PCR. RA synovial explants were incubated with CSF-1, IL-34, control antibody (Ab), or neutralizing/blocking Abs targeting CSF-1, IL-34, or CSF1R. The effect of a CSF1R-blocking Ab was examined in murine collagen-induced arthritis (CIA). CSF-1 (also known as M-CSF) and IL-34 expression was similar in RA and PsA synovial tissue, but lower in controls (P < 0.05). CSF-1 expression was observed in the synovial sublining, and IL-34 in the sublining and the intimal lining layer. CSF-1 and IL-34 differentially regulated the expression of 17 of 336 inflammation-associated genes in macrophages, including chemokines, extra-cellular matrix components, and matrix metalloproteinases. Exogenous CSF-1 or IL-34, or their independent neutralization, had no effect on RA synovial explant IL-6 production. Anti-CSF1R Ab significantly reduced IL-6 and other inflammatory mediator production in RA synovial explants, and paw swelling and joint destruction in CIA. Simultaneous inhibition of CSF1R interactions with both CSF-1 and IL-34 suppresses inflammatory activation of RA synovial tissue and pathology in CIA, suggesting a novel therapeutic strategy for RA.

  3. High- and low-frequency transcutaneous electrical nerve stimulation does not reduce experimental pain in elderly individuals.

    PubMed

    Bergeron-Vézina, Kayla; Corriveau, Hélène; Martel, Marylie; Harvey, Marie-Philippe; Léonard, Guillaume

    2015-10-01

    Despite its widespread clinical use, the efficacy of transcutaneous electrical nerve stimulation (TENS) remains poorly documented in elderly individuals. In this randomized, double-blind crossover study, we compared the efficacy of high-frequency (HF), low-frequency (LF), and placebo (P) TENS in a group of 15 elderly adults (mean age: 67 ± 5 years). The effect of HF-, LF-, and P-TENS was also evaluated in a group of 15 young individuals (26 ± 5 years; same study design) to validate the effectiveness of the TENS protocols that were used in the elderly group. Each participant came to the laboratory on 3 separate occasions to receive, in random order, HF-, LF-, and P-TENS. Pain intensity and pain perception thresholds were assessed before, during, and after TENS, using an experimental heat pain paradigm. For the young group, there was a significant decrease in pain intensity during and after HF- and LF-TENS when compared with baseline, with both HF- and LF-TENS being superior to P-TENS. In the older group, HF- and LF-TENS did not reduce pain when compared with baseline and no difference was observed between the 2 active TENS sessions and P-TENS. High-frequency, LF-, and P-TENS all increased pain thresholds in young individuals, whereas in older individuals, only LF-TENS increased pain thresholds. Taken together, these results suggest that TENS is effective in young, but not in older, individuals. Future studies should be conducted to confirm these results in pain populations and to identify strategies that could enhance the effect of TENS in the elderly.

  4. GLP-1 Receptor Stimulation of the Lateral Parabrachial Nucleus Reduces Food Intake: Neuroanatomical, Electrophysiological, and Behavioral Evidence

    PubMed Central

    Richard, Jennifer E.; Farkas, Imre; Anesten, Fredrik; Anderberg, Rozita H.; Dickson, Suzanne L.; Gribble, Fiona M.; Reimann, Frank; Jansson, John-Olov; Liposits, Zsolt

    2014-01-01

    The parabrachial nucleus (PBN) is a key nucleus for the regulation of feeding behavior. Inhibitory inputs from the hypothalamus to the PBN play a crucial role in the normal maintenance of feeding behavior, because their loss leads to starvation. Viscerosensory stimuli result in neuronal activation of the PBN. However, the origin and neurochemical identity of the excitatory neuronal input to the PBN remain largely unexplored. Here, we hypothesize that hindbrain glucagon-like peptide 1 (GLP-1) neurons provide excitatory inputs to the PBN, activation of which may lead to a reduction in feeding behavior. Our data, obtained from mice expressing the yellow fluorescent protein in GLP-1-producing neurons, revealed that hindbrain GLP-1-producing neurons project to the lateral PBN (lPBN). Stimulation of lPBN GLP-1 receptors (GLP-1Rs) reduced the intake of chow and palatable food and decreased body weight in rats. It also activated lPBN neurons, reflected by an increase in the number of c-Fos-positive cells in this region. Further support for an excitatory role of GLP-1 in the PBN is provided by electrophysiological studies showing a remarkable increase in firing of lPBN neurons after Exendin-4 application. We show that within the PBN, GLP-1R activation increased gene expression of 2 energy balance regulating peptides, calcitonin gene-related peptide (CGRP) and IL-6. Moreover, nearly 70% of the lPBN GLP-1 fibers innervated lPBN CGRP neurons. Direct intra-lPBN CGRP application resulted in anorexia. Collectively, our molecular, anatomical, electrophysiological, pharmacological, and behavioral data provide evidence for a functional role of the GLP-1R for feeding control in the PBN. PMID:25116706

  5. Reducing renal uptake of 90Y- and 177Lu-labeled alpha-melanocyte stimulating hormone peptide analogues

    SciTech Connect

    Miao, Yubin; Fisher, Darrell R.; Quinn, Thomas P.

    2006-06-15

    The purpose of this study was to improve the tumor-to-kidney uptake ratios of 90Y- and 177Lu-[1,2,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Re-Cys,D-Phe,Arg]alpha-melanocyte stimulating hormone (DOTA-RE(Arg)CCMSH), through coupling a negatively charged glutamic acid (Glu) to the peptide sequence. A new peptide of DOTA-Re(Glu,Arg)CCMSH was designed, synthesized and labeled with 90Y and 177Lu. Pharmacokinetics of 90Y- and 177Lu-DOTA-RE(Glu,Arg)CCNSH were determined in B16/F1 murine melanoma-bearing C57 mice. Both exhibited significantly less renal uptake than 90Y- and 177Lu-DOTA-Re(Arg)CCMSH at 30 min and at 2, 3, and 24 h after dose administration. The renal uptake values of 90Y- and 177Lu-DOTA-Re(Glu,Arg)CCMSH were 28.16% and 28.81% of those of 90Y- and 177Lu-DOTA-RE(Arg)CCMSH, respectively, at 4 hr post-injection. We also showed higher tumor-to-kidney uptake ratios 2.28 and 1.69 times that of 90Y- and 177Lu-DOTA-Re(Arg)CCMSH, respectively, at 4 h post-injection. The90Y- and 177Lu-DOTA-Re(Glu,Arg)CCMSH activity accumulation was low in normal organs except for kidneys. Coupling a negatively charged amino acid (Glu) to the CCMSH peptide sequence dramatically reduced the renal uptake values and increased the tumor-to-kidney uptake ratios of 90Y- and 177Lu-DOTA-Re(Glu,Arg)CCMSH, facilitating their potential applications as radiopharmaceuticals for targeted radionuclide therapy of melanoma.

  6. Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction.

    PubMed

    Henri, Orianne; Pouehe, Chris; Houssari, Mahmoud; Galas, Ludovic; Nicol, Lionel; Edwards-Lévy, Florence; Henry, Jean-Paul; Dumesnil, Anais; Boukhalfa, Inès; Banquet, Sébastien; Schapman, Damien; Thuillez, Christian; Richard, Vincent; Mulder, Paul; Brakenhielm, Ebba

    2016-04-12

    The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI. We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, leading to reduced cardiac lymphatic transport capacity. Consequently, myocardial edema persisted for several months post-MI, extending from the infarct to noninfarcted myocardium. Intramyocardial-targeted delivery of the vascular endothelial growth factor receptor 3-selective designer protein VEGF-CC152S, using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited precollector remodeling post-MI. As a result, myocardial fluid balance was improved, and cardiac inflammation, fibrosis, and dysfunction were attenuated. We show that, despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to the development of chronic myocardial edema and inflammation-aggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases. © 2016 American Heart Association, Inc.

  7. (1R,2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile, a potent androgen receptor antagonist for stimulating hair growth and reducing sebum production.

    PubMed

    Hu, Lain-Yen; Du, Daniel; Hoffman, Jennifer; Smith, Yvonne; Fedij, Victor; Kostlan, Catherine; Johnson, Theodore R; Huang, Yun; Kesten, Steve; Harter, William; Yue, Wen Song; Li, Jie Jack; Barvian, Nicole; Mitchell, Lorna; Lei, Huangshu John; Lefker, Bruce; Carroll, Mathew; Dettling, Danielle; Krieger-Burke, Teresa; Samas, Brian; Yalamanchili, Radhika; Lapham, Kimberly; Pocalyko, David; Sliskovic, Drago; Ciotti, Susan; Stoller, Brenda; Hena, Mostofa A; Ding, Qizhu; Maiti, Samarendra N; Stier, Michael; Welgus, Howard

    2007-11-01

    Synthesis, pharmacology, and pharmacokinetic profiles of (1R, 2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile are reported. This compound demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.

  8. Reduced malonyl-CoA content in recovery from exercise correlates with improved insulin-stimulated glucose uptake in human skeletal muscle.

    PubMed

    Frøsig, Christian; Roepstorff, Carsten; Brandt, Nina; Maarbjerg, Stine J; Birk, Jesper B; Wojtaszewski, Jørgen F P; Richter, Erik A; Kiens, Bente

    2009-04-01

    This study evaluated whether improved insulin-stimulated glucose uptake in recovery from acute exercise coincides with reduced malonyl-CoA (MCoA) content in human muscle. Furthermore, we investigated whether a high-fat diet [65 energy-% (Fat)] would alter the content of MCoA and insulin action compared with a high-carbohydrate diet [65 energy-% (CHO)]. After 4 days of isocaloric diet on two occasions (Fat/CHO), 12 male subjects performed 1 h of one-legged knee extensor exercise (approximately 80% peak workload). Four hours after exercise, insulin-stimulated glucose uptake was determined in both legs during a euglycemic-hyperinsulinemic clamp. Muscle biopsies were obtained in both legs before and after the clamp. Four hours after exercise, insulin-stimulated glucose uptake was improved (approximately 70%, P<0.001) independent of diet composition and despite normal insulin-stimulated regulation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase, Akt, GSK-3, and glycogen synthase. Interestingly, exercise resulted in a sustained reduction (approximately 20%, P<0.05) in MCoA content 4 h after exercise that correlated (r=0.65, P<0.001) with improved insulin-stimulated glucose uptake. Four days of Fat diet resulted in an increased content of intramyocellular triacylglycerol (P<0.01) but did not influence muscle MCoA content or whole body insulin-stimulated glucose uptake. However, at the muscular level proximal insulin signaling and insulin-stimulated glucose uptake appeared to be compromised, although to a minor extent, by the Fat diet. Collectively, this study indicates that reduced muscle MCoA content in recovery from exercise may be part of the adaptive response leading to improved insulin action on glucose uptake after exercise in human muscle.

  9. Noninvasive low-frequency electromagnetic stimulation of the left stellate ganglion reduces myocardial infarction-induced ventricular arrhythmia

    PubMed Central

    Wang, Songyun; Zhou, Xiaoya; Huang, Bing; Wang, Zhuo; Zhou, Liping; Wang, Menglong; Yu, Lilei; Jiang, Hong

    2016-01-01

    Noninvasive magnetic stimulation has been widely used in autonomic disorders in the past few decades, but few studies has been done in cardiac diseases. Recently, studies showed that low-frequency electromagnetic field (LF-EMF) might suppress atrial fibrillation by mediating the cardiac autonomic nervous system. In the present study, the effect of LF-EMF stimulation of left stellate ganglion (LSG) on LSG neural activity and ventricular arrhythmia has been studied in an acute myocardium infarction canine model. It is shown that LF-EMF stimulation leads to a reduction both in the neural activity of LSG and in the incidence of ventricular arrhythmia. The obtained results suggested that inhibition of the LSG neural activity might be the causal of the reduction of ventricular arrhythmia since previous studies have shown that LSG hyperactivity may facilitate the incidence of ventricular arrhythmia. LF-EMF stimulation might be a novel noninvasive substitute for the existing implant device-based electrical stimulation or sympathectomy in the treatment of cardiac disorders. PMID:27470078

  10. Functional electrical stimulation of gluteus medius reduces the medial joint reaction force of the knee during level walking.

    PubMed

    Rane, Lance; Bull, Anthony Michael James

    2016-11-03

    By altering muscular activation patterns, internal forces acting on the human body during dynamic activity may be manipulated. The magnitude of one of these forces, the medial knee joint reaction force (JRF), is associated with disease progression in patients with early osteoarthritis (OA), suggesting utility in its targeted reduction. Increased activation of gluteus medius has been suggested as a means to achieve this. Motion capture equipment and force plate transducers were used to obtain kinematic and kinetic data for 15 healthy subjects during level walking, with and without the application of functional electrical stimulation (FES) to gluteus medius. Musculoskeletal modelling was employed to determine the medial knee JRF during stance phase for each trial. A further computer simulation of increased gluteus medius activation was performed using data from normal walking trials by a manipulation of modelling parameters. Relationships between changes in the medial knee JRF, kinematics and ground reaction force were evaluated. In simulations of increased gluteus medius activity, the total impulse of the medial knee JRF was reduced by 4.2 % (p = 0.003) compared to control. With real-world application of FES to the muscle, the magnitude of this reduction increased to 12.5 % (p < 0.001), with significant inter-subject variation. Across subjects, the magnitude of reduction correlated strongly with kinematic (p < 0.001) and kinetic (p < 0.001) correlates of gluteus medius activity. The results support a major role for gluteus medius in the protection of the knee for patients with OA, establishing the muscle's central importance to effective therapeutic regimes. FES may be used to achieve increased activation in order to mitigate distal internal loads, and much of the benefit of this increase can be attributed to resulting changes in kinematic parameters and the ground reaction force. The utility of interventions targeting gluteus medius can be assessed

  11. Fat-reducing effects of dehydroepiandrosterone involve upregulation of ATGL and HSL expression, and stimulation of lipolysis in adipose tissue.

    PubMed

    Karbowska, Joanna; Kochan, Zdzislaw

    2012-11-01

    Dehydroepiandrosterone (DHEA) reduces body fat in rodents and humans, and increases glycerol release from isolated rat epididymal adipocytes and human visceral adipose tissue explants. It suggests that DHEA stimulates triglyceride hydrolysis in adipose tissue; however, the mechanisms underlying this action are still unclear. We examined the effects of DHEA on the expression of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), the key enzymes of lipolysis, in rat epididymal white adipose tissue (eWAT). Male Wistar rats were fed a diet containing 0.6% DHEA for 2 weeks and eWAT was analyzed for mRNA and protein expression of ATGL and HSL, as well as mRNA expression of peroxisome proliferator-activated receptor γ 2 (PPARγ2) and its downstream target fatty acid translocase (FAT). Glycerol release from eWAT explants and serum free fatty acids (FFA) were also measured. Rats that received DHEA gained less weight, had 23% lower eWAT mass and 31% higher serum FFA levels than controls. Cultured explants of eWAT from DHEA-treated rats released 81% more glycerol than those from control rats. DHEA administration upregulated ATGL mRNA (1.62-fold, P<0.05) and protein (1.78-fold, P<0.05) expression as well as augmented HSL mRNA levels (1.36-fold, P<0.05) and Ser660 phosphorylation of HSL (2.49-fold, P<0.05). PPARγ2 and FAT mRNA levels were also increased in DHEA-treated rats (1.61-fold, P<0.05 and 2.16-fold, P<0.05; respectively). Moreover, ATGL, HSL, and FAT mRNA levels were positively correlated with PPARγ2 expression. This study demonstrates that DHEA promotes lipid mobilization in adipose tissue by increasing the expression and activity of ATGL and HSL. The effects of DHEA appear to be mediated, at least in part, via PPARγ2 activation, which in turn upregulates ATGL and HSL gene expression. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Acupuncture transcutaneous electrical nerve stimulation reduces discomfort associated with barostat-induced rectal distension: a randomized-controlled study.

    PubMed

    Leung, Wing-Wa; Jones, Alice Y M; Ng, Simon S M; Wong, Cherry Y N; Lee, Janet F Y

    2013-01-21

    To explore the effectiveness of acupuncture transcutaneous electrical nerve stimulation (Acu-TENS), a non-invasive modality in reduction of rectal discomfort during barostat-induced rectal distension. Forty healthy subjects were randomized to receive 45 min of either Acu-TENS or placebo-TENS (no electrical output) over acupuncture points Hegu (large-intestine 4), Neiguan (pericardium 6) and Zusanli (stomach 36). A balloon catheter attached to a dual-drive barostat machine was then inserted into the subjects' rectum. A step-wise (4 mmHg) increase in balloon pressure was induced until maximal tolerable or 48 mmHg. Visual analogue scale and a 5-point subjective discomfort scale (no perception, first perception of distension, urge to defecate, discomfort/pain and extreme pain) were used to assess rectal discomfort at each distension pressure. Blood beta-endorphin levels were measured before, immediately after intervention, at 24 mmHg and at maximal tolerable distension pressure. There was no difference in the demographic data and baseline plasma beta-endorphin levels between the two groups. Perception threshold levels were higher in the Acu-TENS group when compared to the placebo group, but the difference reached statistical significance only at the sensations "urge to defecate" and "pain". The distension pressures recorded at the "urge to defecate" sensation for the Acu-TENS and placebo-TENS groups were 28.0 ± 4.5 mmHg and 24.6 ± 5.7 mmHg, respectively (P = 0.043); and the pressures recorded for the "pain" sensation for these two groups were 36.0 ± 4.2 mmHg and 30.5 ± 4.3 mmHg respectively (P = 0.002). Compared to the placebo group, a higher number of participants in the Acu-TENS group tolerated higher distension pressures (> 40 mmHg) (65% in Acu-TENS vs 25% in placebo, P = 0.02). The plasma beta-endorphin levels of the Acu-TENS group were significantly higher than that of the placebo group at barostat inflation pressure of 24 mmHg (1.31 ± 0.40 ng/mL vs 1.04 ± 0

  13. Dynamic optimization of stimulation frequency to reduce isometric muscle fatigue using a modified Hill-Huxley model.

    PubMed

    Doll, Brian D; Kirsch, Nicholas A; Bao, Xuefeng; Dicianno, Brad E; Sharma, Nitin

    2017-08-18

    Optimal frequency modulation during functional electrical stimulation (FES) may minimize or delay the onset of FES-induced muscle fatigue. An offline dynamic optimization method, constrained to a modified Hill-Huxley model, was used to determine the minimum number of pulses that would maintain a constant desired isometric contraction force. Six able-bodied participants were recruited for the experiments, and their quadriceps muscles were stimulated while they sat on a leg extension machine. The force-time (F-T) integrals and peak forces after the pulse train was delivered were found to be statistically significantly greater than the force-time integrals and peak forces obtained after a constant frequency train was delivered. Experimental results indicated that the optimized pulse trains induced lower levels of muscle fatigue compared with constant frequency pulse trains. This could have a potential advantage over current FES methods that often choose a constant frequency stimulation train. Muscle Nerve, 2017. © 2017 Wiley Periodicals, Inc.

  14. MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1.

    PubMed

    Salvucci, Ombretta; Jiang, Kan; Gasperini, Paola; Maric, Dragan; Zhu, Jinfang; Sakakibara, Shuhei; Espigol-Frigole, Georgina; Wang, Shushang; Tosato, Giovanna

    2012-06-01

    Mobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs. We analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells. We show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor. Our results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells.

  15. Subthalamic Stimulation Reduces Vowel Space at the Initiation of Sustained Production: Implications for Articulatory Motor Control in Parkinson’s Disease

    PubMed Central

    Sidtis, John J.; Alken, Amy G.; Tagliati, Michele; Alterman, Ron; Van Lancker Sidtis, Diana

    2016-01-01

    Background: Stimulation of the subthalamic nuclei (STN) is an effective treatment for Parkinson’s disease, but complaints of speech difficulties after surgery have been difficult to quantify. Speech measures do not convincingly account for such reports. Objective: This study examined STN stimulation effects on vowel production, in order to probe whether DBS affects articulatory posturing. The objective was to compare positioning during the initiation phase with the steady prolongation phase by measuring vowel spaces for three “corner” vowels at these two time frames. Methods: Vowel space was measured over the initial 0.25 sec of sustained productions of high front (/i/), high back (/u/) and low vowels (/a/), and again during a 2 sec segment at the midpoint. Eight right-handed male subjects with bilateral STN stimulation and seven age-matched male controls were studied based on their participation in a larger study that included functional imaging. Mean values: age = 57±4.6 yrs; PD duration = 12.3±2.7 yrs; duration of DBS = 25.6±21.2 mos, and UPDRS III speech score = 1.6±0.7. STN subjects were studied off medication at their therapeutic DBS settings and again with their stimulators off, counter-balanced order. Results: Vowel space was larger in the initiation phase compared to the midpoint for both the control and the STN subjects off stimulation. With stimulation on, however, the initial vowel space was significantly reduced to the area measured at the mid-point. For the three vowels, the acoustics were differentially affected, in accordance with expected effects of front versus back position in the vocal tract. Conclusions: STN stimulation appears to constrain initial articulatory gestures for vowel production, raising the possibility that articulatory positions normally used in speech are similarly constrained. PMID:27003219

  16. Efficacy of transcranial direct current stimulation (tDCS) in reducing consumption in patients with alcohol use disorders: study protocol for a randomized controlled trial.

    PubMed

    Trojak, Benoit; Soudry-Faure, Agnès; Abello, Nicolas; Carpentier, Maud; Jonval, Lysiane; Allard, Coralie; Sabsevari, Foroogh; Blaise, Emilie; Ponavoy, Eddy; Bonin, Bernard; Meille, Vincent; Chauvet-Gelinier, Jean-Christophe

    2016-05-17

    effects of transcranial direct current stimulation on tobacco consumption. Several studies have reported a beneficial effect of transcranial direct current stimulation on substance use disorders by reducing craving, impulsivity, and risk-taking behavior, and suggest that transcranial direct current stimulation may be a promising treatment in addiction. However, to date, no studies have included sufficiently large samples and sufficient follow-up to confirm the hypothesis. Results from this large randomized controlled trial will give a better overview of the therapeutic potential of transcranial direct current stimulation in alcohol use disorders. Clinical Trials Gov, NCT02505126 (registration date: July 15 2015).

  17. Nicotine-stimulated release of [3H]norepinephrine is reduced in the hippocampus of an animal model of attention-deficit/hyperactivity disorder, the spontaneously hypertensive rat.

    PubMed

    Sterley, Toni-Lee; Howells, Fleur M; Russell, Vivienne A

    2014-07-14

    Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous, developmental disorder, and is one of the most common child-psychiatric disorders. It is also a risk factor for early smoking and adult nicotine dependence. Nicotine has been shown to improve symptoms associated with ADHD, including problems with attention, working memory and response inhibition. Norepinephrine, a neurotransmitter involved in attention, is highly implicated in ADHD, and often targeted in the treatment thereof. In the present study we investigated nicotine׳s effect on release of norepinephrine in the hippocampus of a validated rat model of ADHD, the spontaneously hypertensive rat (SHR), as well as in two control strains: Wistar-Kyoto rats (WKY) and Sprague-Dawley rats (SD). Hippocampal slices obtained from male SHR, WKY and SD (postnatal day 31-33) were pre-incubated with radioactively labelled norepinephrine ([3H]NE) and perfused with buffer. The slices were stimulated by exposure to different concentrations of nicotine (1, 10, 100 or 1000 µM) for 1 min at 2 intervals (S1 and S2, separated by 20 min). Following a 10 min wash, slices were stimulated with 25 mM potassium. Since glutamate and GABA receptor function differ in SHR and WKY, we investigated the possible involvement of AMPA and GABA(A) receptors in nicotine (100 µM)-stimulated release of hippocampal [3H]NE in each of the strains by blocking these receptors with CNQX (AMPA receptor antagonist, 10 µM) or bicuculline (GABAA receptor antagonist, 30 µM) respectively. Nicotine-stimulated release (S1) of [3H]NE from SHR hippocampal slices was less than that of WKY and SD, at 100 µM and 1000 µM nicotine, suggesting reduced density and/or function of nicotinic receptors in SHR hippocampus. Nicotine-stimulated release of [3H]NE in response to S2 was reduced compared to S1 in all strains, indicating desensitization of receptors involved in stimulation of [3H]NE by nicotine. Potassium-stimulated release of [3H]NE following the

  18. A Flexible Stent with Small Intestinal Submucosa Covering for Direct Intrahepatic Portocaval Shunt: Experimental Pilot Study in Swine

    SciTech Connect

    Niyyati, Mahtab; Petersen, Bryan D.; Pavcnik, Dusan Uchida, Barry T.; Timmermans, Hans A.; Hiraki, Takao; Wu Renghong; Brountzos, Elias; Keller, Frederick S.; Roesch, Josef

    2005-04-15

    The suitability of the flexible sandwich Zilver stent-graft (SZSG) with a biologically active tissue layer (small intestinal submucosa) for creation of the intravascular ultrasound (IVUS)-guided direct intrahepatic portocaval shunt (DIPS) was explored in six young swine in a search for a flexible system to replace the rigid polytetrafluoroethylene (PTFE) stent originally used by this group with limited success. The portal vein was punctured from the inferior vena cava through the caudate lobe of the liver using IVUS guidance. After balloon dilation of the puncture tract, DIPS was successfully created in all animals with use of an SZSG 9 mm in diameter and 6 cm or 8 cm long. Only one DIPS remained well patent at 14 days when the animal had to be killed because of encephalopathy. DIPS in the other five animals were found to be either severely stenosed (3 animals) or occluded (2 animals) at 4 weeks due to accelerated formation of neointimal hyperplasia (NIH) in the liver parenchymal portion of the shunt and superimposed thrombosis. The lack of high pressure in the portal system contributed to early endograft closure. The flexible stent and the covering fail badly. The reason for this could be due to either component. More work is required to find a reliable flexible system with long-term patency. Exploration of the IVUS-guided direct extrahepatic portocaval shunt is suggested.

  19. Carbon nanotubes as VEGF carriers to improve the early vascularization of porcine small intestinal submucosa in abdominal wall defect repair

    PubMed Central

    Liu, Zhengni; Feng, Xueyi; Wang, Huichun; Ma, Jun; Liu, Wei; Cui, Daxiang; Gu, Yan; Tang, Rui

    2014-01-01

    Insufficient early vascularization in biological meshes, resulting in limited host tissue incorporation, is thought to be the primary cause for the failure of abdominal wall defect repair after implantation. The sustained release of exogenous angiogenic factors from a biocompatible nanomaterial might be a way to overcome this limitation. In the study reported here, multiwalled carbon nanotubes (MWNT) were functionalized by plasma polymerization to deliver vascular endothelial growth factor165 (VEGF165). The novel VEGF165-controlled released system was incorporated into porcine small intestinal submucosa (PSIS) to construct a composite scaffold. Scaffolds incorporating varying amounts of VEGF165-loaded functionalized MWNT were characterized in vitro. At 5 weight percent MWNT, the scaffolds exhibited optimal properties and were implanted in rats to repair abdominal wall defects. PSIS scaffolds incorporating VEGF165-loaded MWNT (VEGF–MWNT–PSIS) contributed to early vascularization from 2–12 weeks postimplantation and obtained more effective collagen deposition and exhibited improved tensile strength at 24 weeks postimplantation compared to PSIS or PSIS scaffolds, incorporating MWNT without VEGF165 loading (MWNT–PSIS). PMID:24648727

  20. Comparison of Porcine Small Intestinal Submucosa versus Polypropylene in Open Inguinal Hernia Repair: A Systematic Review and Meta-Analysis

    PubMed Central

    Nie, Xin; Xiao, Dongdong; Wang, Wenyue; Song, Zhicheng; Yang, Zhi; Chen, Yuanwen; Gu, Yan

    2015-01-01

    Background A systematic review and meta-analysis was performed in randomized controlled trials (RCTs) to compare porcine small intestinal submucosa (SIS) with polypropylene in open inguinal hernia repair. Method Electronic databases MEDLINE, Embase, and the Cochrane Library were used to compare patient outcomes for the two groups via meta-analysis. Result A total of 3 randomized controlled trials encompassing 200 patients were included in the meta-analysis. There was no significant difference in recurrence (P = 0.16), hematomas (P = 0.06), postoperative pain within 30 days (P = 0.45), or postoperative pain after 1 year (P = 0.12) between the 2 groups. The incidence of discomfort was significantly lower (P = 0.0006) in the SIS group. However, the SIS group experienced a significantly higher incidence of seroma (P = 0.03). Conclusions Compared to polypropylene, using SIS in open inguinal hernia repair is associated with a lower incidence of discomfort and a higher incidence of seroma. However, well-designed larger RCT studies with a longer follow-up period are needed to confirm these findings. PMID:26252895

  1. Electrospun micro/nanofibrous conduits composed of poly(epsilon-caprolactone) and small intestine submucosa powder for nerve tissue regeneration.

    PubMed

    Hong, Soongee; Kim, Geunhyung

    2010-08-01

    Three-dimensional biocompatible and biodegradable scaffolds play important roles in tissue engineering. In this study, fibrous mats composed of electrospun poly(epsilon-caprolactone) (PCL)/small intestine submucosa (SIS) tubes were fabricated with a high degree of longitudinal alignment as a conduit for peripheral nerves. Fourier transform infrared analyses of electrospun PCL/SIS mats with various amounts of SIS showed that the SIS was well embedded within the PCL matrix. The diameter of the PCL/SIS fibers with the 3 wt % of SIS in the PCL solution decreased 40% relative to that of pure PCL fibers due to increased electrical conductivity and decreased surface tension. PCL/SIS (3 wt %) electrospun mats exhibited various synergistic effects, including stronger mechanical properties (Young's modulus = more than 80%) and enhanced hydrophilicity (water contact angle at 30 min = 54 degrees ) relative to pure PCL (water contact angle at 30 min = 142 degrees ). Cell attachment and proliferation experiments demonstrated that the interactions between nerve cells (PC-12) and the PCL/SIS conduits were more favorable than those between PC-12 cells and a pure PCL conduit. This study contributes to the understanding of the effects of including SIS in electrospun composite mats. The ability to fabricate highly aligned tubes of PCL/SIS with appropriate mechanical properties and cellular interactions shows great potential for the design of nerve regeneration conduits.

  2. The Management of Diabetic Foot Ulcers with Porcine Small Intestine Submucosa Tri-Layer Matrix: A Randomized Controlled Trial

    PubMed Central

    Cazzell, Shawn M.; Lange, Darrell L.; Dickerson, Jaime E.; Slade, Herbert B.

    2015-01-01

    Objective: This study demonstrates that superior outcomes are possible when diabetic foot ulcers (DFU) are managed with tri-layer porcine small intestine submucosa (SIS). Approach: Patients with DFU from 11 centers participated in this prospective randomized controlled trial. Qualified subjects were randomized (1:1) to either SIS or standard care (SC) selected at the discretion of the Investigator and followed for 12 weeks or complete ulcer closure. Results: Eighty-two subjects (41 in each group) were evaluable in the intent-to-treat analysis. Ulcers managed with SIS had a significantly greater proportion closed by 12 weeks than for the Control group (54% vs. 32%, p=0.021) and this proportion was numerically higher at all visits. Time to closure for ulcers achieving closure was 2 weeks earlier for the SIS group than for SC. Median reduction in ulcer area was significantly greater for SIS at each weekly visit (all p values<0.05). Review of reported adverse events found no safety concerns. Innovation: These data support the use of tri-layer SIS for the effective management of DFU. Conclusion: In this randomized controlled trial, SIS was found to be associated with more rapid improvement, and a higher likelihood of achieving complete ulcer closure than those ulcers treated with SC. PMID:26634183

  3. Gastric submucosa is inferior to the liver as transplant site for autologous islet transplantation in pancreatectomized diabetic Beagles.

    PubMed

    Yin, Zhu-Zeng; Wang, Shu-Sen; Li, Qiang; Huang, Ying; Chen, Li; Chen, Gang; Liu, Rong; Wang, Xi-Mo

    2016-08-01

    Intraportal transplantation of islets is no longer considered to be an ideal procedure and finding the extrahepatic alternative site is becoming a subject of high priority. Herein, in this study, we would introduce our initial outcomes of using gastric submucosa (GS) and liver as sites of islet autotransplantation in pancreatectomized diabetic Beagles. Total pancreatectomy was performed in Beagles and then their own islets extracted from the excised pancreas were transplanted into GS (GS group, n=8) or intrahepatic via portal vein (PV group, n=5). Forty-eight hours post transplantation, graft containing tissue harvested from the recipients revealed the presence of insulin-positive cells. All recipients in GS group achieved euglycemia within 1 day, but returned to a diabetic state at 6 to 8 days post-transplantation (mean survival time, 7.16±0.69 days). However, all of the animals kept normoglycemic until 85 to 155 days post-transplantation in PV group (mean survival time, 120±28.58 days; P<0.01 vs. GS group). The results of intravenous glucose tolerance test (IVGTT) confirmed that the marked improvement in glycometabolism was obtained in intrahepatic islet autotransplantation. Thus, our findings indicate that the liver is still superior to the GS as the site of islet transplantation, at least in our islet autotransplant model in pancreatectomized diabetic Beagles.

  4. Effects of fabrication on the mechanics, microstructure and micromechanical environment of small intestinal submucosa scaffolds for vascular tissue engineering.

    PubMed

    Sánchez-Palencia, Diana M; D'Amore, Antonio; González-Mancera, Andrés; Wagner, William R; Briceño, Juan C

    2014-08-22

    In small intestinal submucosa scaffolds for functional tissue engineering, the impact of scaffold fabrication parameters on success rate may be related to the mechanotransductory properties of the final microstructural organization of collagen fibers. We hypothesized that two fabrication parameters, 1) preservation (P) or removal (R) of a dense collagen layer present in SIS and 2) SIS in a final dehydrated (D) or hydrated (H) state, have an effect on scaffold void area, microstructural anisotropy (fiber alignment) and mechanical anisotropy (global mechanical compliance). We further integrated our experimental measurements in a constitutive model to explore final effects on the micromechanical environment inside the scaffold volume. Our results indicated that PH scaffolds might exhibit recurrent and large force fluctuations between layers (up to 195 pN), while fluctuations in RH scaffolds might be larger (up to 256 pN) but not as recurrent. In contrast, both PD and RD groups were estimated to produce scarcer and smaller fluctuations (not larger than 50 pN). We concluded that the hydration parameter strongly affects the micromechanics of SIS and that an adequate choice of fabrication parameters, assisted by the herein developed method, might leverage the use of SIS for functional tissue engineering applications, where forces at the cellular level are of concern in the guidance of new tissue formation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Anodal Direct Current Stimulation of the Cerebellum Reduces Cerebellar Brain Inhibition but Does Not Influence Afferent Input from the Hand or Face in Healthy Adults.

    PubMed

    Doeltgen, Sebastian H; Young, Jessica; Bradnam, Lynley V

    2016-08-01

    The cerebellum controls descending motor commands by outputs to primary motor cortex (M1) and the brainstem in response to sensory feedback. The cerebellum may also modulate afferent input en route to M1 and the brainstem. The objective of this study is to determine if anodal transcranial direct current stimulation (tDCS) to the cerebellum influences cerebellar brain inhibition (CBI), short afferent inhibition (SAI) and trigeminal reflexes (TRs) in healthy adults. Data from two studies evaluating effects of cerebellar anodal and sham tDCS are presented. The first study used a twin coil transcranial magnetic stimulation (TMS) protocol to investigate CBI and combined TMS and cutaneous stimulation of the digit to assess SAI. The second study evaluated effects on trigemino-cervical and trigemino-masseter reflexes using peripheral nerve stimulation of the face. Fourteen right-handed healthy adults participated in experiment 1. CBI was observed at baseline and was reduced by anodal cerebellar DCS only (P < 0.01). There was SAI at interstimulus intervals of 25 and 30 ms at baseline (both P < 0.0001), but cerebellar tDCS had no effect. Thirteen right-handed healthy adults participated in experiment 2. Inhibitory reflexes were evoked in the ipsilateral masseter and sternocleidomastoid muscles. There was no effect of cerebellar DCS on either reflex. Anodal DCS reduced CBI but did not change SAI or TRs in healthy adults. These results require confirmation in individuals with neurological impairment.

  6. The Effect of External Thermomechanical Stimulation and Distraction on Reducing Pain Experienced by Children During Blood Drawing.

    PubMed

    Inal, Sevil; Kelleci, Meral

    2017-09-05

    This study aimed to investigate the sole and combined effects of external thermomechanical stimulation and distraction in pain relief of children during blood drawing.This is a randomized clinical trial. The sample consisted of 218 children aged 6 to 12 years who were randomly assigned to 4 groups: group 1 received no intervention, group 2 received external thermomechanical stimulation using Buzzy, group 3 received distraction via DistrACTION Cards, and group 4 received a combination of both external thermomechanical stimulation and distraction. Preprocedural anxiety was assessed through parents' and observers' observations using the Children's Anxiety and Pain Scale. Children's pain levels were assessed by themselves, observers, and parents, as reported using the Faces Pain Scale-Revised. Preprocedural anxiety did not differ significantly (P > 0.05). When the 3 study groups were compared with the control group, all 3 groups had significantly lower pain levels than the control group (P < 0.001). The lowest pain level was measured in the combined condition (Buzzy and DistrACTION Cards). The mean score of the device group was lower than the distraction group.

  7. INS-1 cell glucose-stimulated insulin secretion is reduced by the downregulation of the 67 kDa laminin receptor.

    PubMed

    Sabra, Georges; Dubiel, Evan A; Kuehn, Carina; Khalfaoui, Taoufik; Beaulieu, Jean-François; Vermette, Patrick

    2015-12-01

    Understanding β cell-extracellular matrix (ECM) interactions can advance our knowledge of the mechanisms that control glucose homeostasis and improve culture methods used in islet transplantation for the treatment of diabetes. Laminin is the main constituent of the basement membrane and is involved in pancreatic β cell survival and function, even enhancing glucose-stimulated insulin secretion. Most of the studies on cell responses towards laminin have focused on integrin-mediated interactions, while much less attention has been paid on non-integrin receptors, such as the 67 kDa laminin receptor (67LR). The specificity of the receptor-ligand interaction through the adhesion of INS-1 cells (a rat insulinoma cell line) to CDPGYIGSR-, GRGDSPC- or CDPGYIGSR + GRGDSPC-covered surfaces was evaluated. Also, the effects of the 67LR knocking down over glucose-stimulated insulin secretion were investigated. Culture of the INS-1 cells on the bioactive surfaces was improved compared to the low-fouling carboxymethyl dextran (CMD) surfaces, while downregulation of the 67LR resulted in reduced cell adhesion to surfaces bearing the CDPGYIGSR peptide. Glucose-stimulated insulin secretion was hindered by downregulation of the 67LR, regardless of the biological motif available on the biomimetic surfaces on which the cells were cultured. This finding illustrates the importance of the 67LR in glucose-stimulated insulin secretion and points to a possible role of the 67LR in the mechanisms of insulin secretion. Copyright © 2013 John Wiley & Sons, Ltd.

  8. Reduced Response of Human Meniscal Cells to Osteogenic Protein 1 during Osteoarthritis and Pro-inflammatory Stimulation

    PubMed Central

    Vanderman, Kadie S.; Loeser, Richard F.; Chubinskaya, Susan; Anderson, Andrea; Ferguson, Cristin M.

    2016-01-01

    Objective Many cell types lose responsiveness to anabolic factors during inflammation and disease. Osteogenic Protein 1 (OP1/BMP7) was evaluated for the ability to enhance extracellular matrix synthesis in healthy and OA meniscus cells. Mechanisms of cell response to OP1 were explored. Design Meniscus and cartilage tissues from healthy tissue donors and osteoarthritis patients undergoing total knee arthroplasties were acquired. Primary cell cultures were stimulated with OP1 and/or inflammatory factors (IL1α, IL1β, or fibronectin fragments (FnF)) and cellular responses were analyzed by RT-qPCR and immunoblots. Frozen section immunohistochemistry was conducted to assess OP1 and receptor proteins in normal and OA meniscus. Results OP1 treatment of normal meniscus cells resulted in significant, dose-dependent increases in ACAN (aggrecan) and COL2A1, and decreased MMP13 gene transcription, while only ACAN was upregulated (p<0.01) at the highest dose of OP1 in OA meniscus cells. OP1 induced significantly more ACAN gene transcription in normal meniscus than normal articular cartilage (p=0.05), and no differences between normal and OA cartilage were detected. Receptor expression and kinetics of canonical signaling activation were similar between normal and OA specimens. Normal meniscus cells treated with inflammatory factors were refractory to OP1 stimulation. Smad1 phosphorylation at an inhibitory site was induced (p=0.01 for both normal and OA meniscus) by inflammatory cytokine treatment. Conclusions The meniscus demonstrates resistance to OP1 stimulation in OA and in the presence of inflammatory mediators. MAPK-mediated Smad1 linker phosphorylation is a possible mediator of the loss of anabolic extracellular matrix production in the inflammatory cytokine affected meniscus. PMID:26778533

  9. No midterm advantages in the middle term using small intestinal submucosa and human amniotic membrane in Achilles tendon transverse tenotomy.

    PubMed

    Liu, Yushu; Peng, Yinbo; Fang, Yong; Yao, Min; Redmond, Robert W; Ni, Tao

    2016-11-24

    The study was aimed to compare the effects of small intestinal submucosa (SIS) and human amniotic membrane (HAM) on Achilles tendon healing. A total of 48 New Zealand white rabbits were divided into two groups. A full-thickness transverse tenotomy was made at the right leg of the rabbits. Then, the laceration site was wrapped with HAM (P/A group) or SIS (P/S group). The ultimate stress (US) and Young's modulus (E) of the tendons were detected for biomechanical analysis. Histological evaluation was performed using hematoxylin and eosin, immunohistochemical, and immunofluorescent stain. Expression of collagen I was detected by western blot analysis, and levels of inflammatory cytokines IL-1β, IL-6, and TNF-α were measured. Finally, adhesion formation was evaluated. There were no significant differences in filamentous adhesion, cross-sectional areas of the laceration sites, levels of inflammatory response, and collagen type I expression between the P/A and P/S groups (p > 0.05). Compared with the P/A group, the US and E values were significantly higher in the P/S group at day 7 (p < 0.05) and at day 14 (p < 0.05). In addition, vascularity was significantly higher in the P/S group than that in the P/A group at day 3 (p < 0.05), day 7 (p < 0.01), and day 9 (p < 0.05). SIS showed superior biomechanical properties and neovascularization over HAM in treatment of Achilles tendon injury in the early stage of healing.

  10. Endoluminal Treatment of Ruptured Abdominal Aortic Aneurysm with Small Intestinal Submucosa Sandwich Endografts: A Pilot Study in Sheep

    SciTech Connect

    Yamada, Katsuyuki; Pavcnik, Dusan; Uchida, Barry T.; Timmermans, Hans A.; Corless, Christopher L.; Yin, Qiang; Yamakado, Koichiro; Wha Park, Joong; Roesch, Josef; Keller, Frederick S.; Sato, Morio; Yamada, Ryusaku

    2001-03-15

    Purpose: To evaluate efficacy of small intestinal submucosa (SIS) Sandwich endografts for the treatment of acute rupture of abdominal aortic aneurysms (AAA) and to explore the short-term reaction of the aorta to this material.Methods: In eight adult sheep, an infrarenal AAA was created transluminally by dilation of a short Palmaz stent. In six sheep, the aneurysm was then ruptured by overdilation of the stent with a large angioplasty balloon. Two sheep with AAAs that were not ruptured served as controls. A SIS Sandwich endograft, consisting of a Z stent frame with 5 bodies and covered inside and out with SIS, was used to exclude the ruptured and non-ruptured AAAs. Follow-up aortography was done immediately after the procedure and before sacrifice at 4, 8, or 12 weeks. Autopsy and histologic studies followed.Results: Endograft placement was successful in all eight sheep. Both ruptured and non-ruptured AAAs were successfully excluded. Three animals with AAA rupture developed hind leg paralysis due to compromise of the arterial supply to the lower spinal cord and were sacrificed 1 day after the procedure. In five animals, three with rupture and two controls, follow-up aortograms revealed no aortic stenoses and no perigraft leaks. Gross and histologic studies revealed incorporation of the endografts into the aortic wall with replacement of SIS by dense neointima that was completely endothelialized in areas where the endograft was in direct contact with the aortic wall. In central portions of the endograft, in contact with the thrombosed aneurysm, endothelialization was incomplete even at 12 weeks.Conclusion: The SIS Sandwich endografts effectively excluded simple AAAs and ruptured AAAs. They were rapidly incorporated into the aortic wall. A detailed long-term study is warranted.

  11. Identification and quantification of granulocytes in caecal mucosa and submucosa of chickens experimentally infected with Eimeria tenella and Salmonella enteritidis.

    PubMed

    Petrone, V M; Constantino, C F; Pradal-Roa, P

    2002-12-01

    1. Poultry granulocytes are not clearly distinguished from each other with haematoxylin-eosin (HE) stain; thus, histochemical techniques must be used. Three experiments were carried out using 4-week-old Leghorn chickens. 2. Three, 80-chicken groups were orally infected with (1) 10(8) colony forming units (CFUs) Salmonella enteritidis, or (2) 10(4) Eimeria tenella oocysts, or (3) 10(8) CFUs S. enteritidis + 10(4) E. tenella oocysts. Ten chickens from each group were euthanased and caecum samples obtained. Caecum samples were fixed in 10% formalin (buffered, pH 7.4) at 4, 8, 12 h, 1, 3, 5, 7, and 14 d post-inoculation (PI). 3. Samples were stained using three different staining techniques: HE for the identification of heterophils and eosinophils, Ziehl-Neelsen for mast cells, and p-phenilenediamine dihydrochloride plus pyrocatechol (PPD + PC) for eosinophils. 4. Birds from Experiment 1 showed no changes in the numbers of granulocytes. Birds from Experiments 2 and 3 showed higher numbers of heterophils in caecal mucosa and submucosa separately, on d 5 and 7. In Experiment 3, a decrease was observed in submucosal mast cells on d 3. Chickens from Experiments 2 and 3 showed increased numbers of mucosal mast cells between d 7 and 14. 5. PPD + PC positively stained eosinophils, but not heterophils. 6. Numbers of heterophils and mast cells were increased during the acute inflammatory process caused by E. tenella. Therefore, mast cells could play a role as primary inflammatory cells. Eosinophils seem not to be part of the inflammatory process caused by E. tenella.

  12. Electrical Stimulation Using Conductive Polymer Polypyrrole Counters Reduced Neurite Outgrowth of Primary Prefrontal Cortical Neurons from NRG1-KO and DISC1-LI Mice.

    PubMed

    Zhang, Qingsheng; Esrafilzadeh, Dorna; Crook, Jeremy M; Kapsa, Robert; Stewart, Elise M; Tomaskovic-Crook, Eva; Wallace, Gordon G; Huang, Xu-Feng

    2017-02-15

    Deficits in neurite outgrowth, possibly involving dysregulation of risk genes neuregulin-1 (NRG1) and disrupted in schizophrenia 1 (DISC1) have been implicated in psychiatric disorders including schizophrenia. Electrical stimulation using conductive polymers has been shown to stimulate neurite outgrowth of differentiating human neural stem cells. This study investigated the use of the electroactive conductive polymer polypyrrole (Ppy) to counter impaired neurite outgrowth of primary pre-frontal cortical (PFC) neurons from NRG1-knock out (NRG1-KO) and DISC1-locus impairment (DISC1-LI) mice. Whereas NRG1-KO and DISC1-LI exhibited reduced neurite length and number of neurite branches compared to wild-type controls, this was not apparent for cultures on electroactive Ppy. Additionally, the use of the Ppy substrate normalised the synaptophysin and PSD95 protein and mRNA expression whereas both are usually reduced by NRG1-KO or DISC1-LI. Our findings support the utility of Ppy mediated electrical stimulation to prevent the reduction of neurite outgrowth and related synaptic protein expression in the primary PFC neurons from NRG1-KO and DISC1-LI mice, providing proof-of-concept for treating neurodevelopmental diseases including schizophrenia.

  13. Electrical Stimulation Using Conductive Polymer Polypyrrole Counters Reduced Neurite Outgrowth of Primary Prefrontal Cortical Neurons from NRG1-KO and DISC1-LI Mice

    PubMed Central

    Zhang, Qingsheng; Esrafilzadeh, Dorna; Crook, Jeremy M.; Kapsa, Robert; Stewart, Elise M.; Tomaskovic-Crook, Eva; Wallace, Gordon G.; Huang, Xu-Feng

    2017-01-01

    Deficits in neurite outgrowth, possibly involving dysregulation of risk genes neuregulin-1 (NRG1) and disrupted in schizophrenia 1 (DISC1) have been implicated in psychiatric disorders including schizophrenia. Electrical stimulation using conductive polymers has been shown to stimulate neurite outgrowth of differentiating human neural stem cells. This study investigated the use of the electroactive conductive polymer polypyrrole (Ppy) to counter impaired neurite outgrowth of primary pre-frontal cortical (PFC) neurons from NRG1-knock out (NRG1-KO) and DISC1-locus impairment (DISC1-LI) mice. Whereas NRG1-KO and DISC1-LI exhibited reduced neurite length and number of neurite branches compared to wild-type controls, this was not apparent for cultures on electroactive Ppy. Additionally, the use of the Ppy substrate normalised the synaptophysin and PSD95 protein and mRNA expression whereas both are usually reduced by NRG1-KO or DISC1-LI. Our findings support the utility of Ppy mediated electrical stimulation to prevent the reduction of neurite outgrowth and related synaptic protein expression in the primary PFC neurons from NRG1-KO and DISC1-LI mice, providing proof-of-concept for treating neurodevelopmental diseases including schizophrenia. PMID:28198409

  14. Reducing the dose of gonadotrophin-releasing hormone agonist on starting ovarian stimulation: effect on ovarian response and in-vitro fertilization outcome.

    PubMed

    Elgendy, M; Afnan, M; Holder, R; Lashen, H; Afifi, Y; Lenton, W; Sharif, K

    1998-09-01

    The aim of this study was to examine if lowering the dose of gonadotrophin-releasing hormone agonist (GnRHa) on starting ovarian stimulation could be beneficial in in-vitro fertilization (IVF) programmes. A total of 64 normally ovulating patients entering an IVF programme were randomized to receive GnRHa (nafarelin acetate/Synarel) as an intranasal spray commencing in the midluteal phase, either at a dosage of 200 microg three times daily until the day of human chorionic gonadotrophin (HCG) administration, or to be reduced to 200 microg twice daily as ovarian stimulation was initiated. Patients in both groups were below 35 years with a body mass index below 30. All patients received three ampoules of Metrodin HP per day. Blood samples were taken on the day of HCG administration to measure luteinizing hormone (LH), oestradiol, and progesterone. LH and oestradiol were found to be significantly higher in the lower Synarel dose group. Our results show that reducing the GnRHa dose during ovarian stimulation in IVF might be beneficial in terms of significantly more oocytes recovered, and significantly greater number of embryos available for transfer and freezing, with no incidence of premature luteinization.

  15. Electroacupuncture Reduces the Effects of Acute Noxious Stimulation on the Electrical Activity of Pain-Related Neurons in the Hippocampus of Control and Neuropathic Pain Rats

    PubMed Central

    Wang, Jun-Ying; Chen, Renbo; Feng, Xiu-Mei; Yan, Yaxia; Lippe, Irmgard Th.

    2016-01-01

    To study the effects of acupuncture analgesia on the hippocampus, we observed the effects of electroacupuncture (EA) and mitogen-activated protein kinase (MEK) inhibitor on pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal area CA1 of sham or chronic constrictive injury (CCI) rats. The animals were randomly divided into a control, a CCI, and a U0126 (MEK1/2 inhibitor) group. In all experiments, we briefly (10-second duration) stimulated the sciatic nerve electrically and recorded the firing rates of PENs and PINs. The results showed that in both sham and CCI rats brief sciatic nerve stimulation significantly increased the electrical activity of PENs and markedly decreased the electrical activity of PINs. These effects were significantly greater in CCI rats compared to sham rats. EA treatment reduced the effects of the noxious stimulus on PENs and PINs in both sham and CCI rats. The effects of EA treatment could be inhibited by U0126 in sham-operated rats. The results suggest that EA reduces effects of acute sciatic nerve stimulation on PENs and PINs in the CA1 region of the hippocampus of both sham and CCI rats and that the ERK (extracellular regulated kinase) signaling pathway is involved in the modulation of EA analgesia. PMID:27833763

  16. A nutritional supplement containing lactoferrin stimulates the immune system, extends lifespan, and reduces amyloid β peptide toxicity in Caenorhabditis elegans.

    PubMed

    Martorell, Patricia; Llopis, Silvia; Gonzalez, Nuria; Ramón, Daniel; Serrano, Gabriel; Torrens, Ana; Serrano, Juan M; Navarro, Maria; Genovés, Salvador

    2017-03-01

    Lactoferrin is a highly multifunctional glycoprotein involved in many physiological functions, including regulation of iron absorption and immune responses. Moreover, there is increasing evidence for neuroprotective effects of lactoferrin. We used Caenorhabditis elegans as a model to test the protective effects, both on phenotype and transcriptome, of a nutraceutical product based on lactoferrin liposomes. In a dose-dependent manner, the lactoferrin-based product protected against acute oxidative stress and extended lifespan of C. elegans N2. Furthermore, Paralysis of the transgenic C. elegans strain CL4176, caused by Aβ1-42 aggregates, was clearly ameliorated by treatment. Transcriptome analysis in treated nematodes indicated immune system stimulation, together with enhancement of processes involved in the oxidative stress response. The lactoferrin-based product also improved the protein homeostasis processes, cellular adhesion processes, and neurogenesis in the nematode. In summary, the tested product exerts protection against aging and neurodegeneration, modulating processes involved in oxidative stress response, protein homeostasis, synaptic function, and xenobiotic metabolism. This lactoferrin-based product is also able to stimulate the immune system, as well as improving reproductive status and energy metabolism. These findings suggest that oral supplementation with this lactoferrin-based product could improve the immune system and antioxidant capacity. Further studies to understand the molecular mechanisms related with neuronal function would be of interest.

  17. Inhibitory responses mediated by vagal nerve stimulation are diminished in stomachs of mice with reduced intramuscular interstitial cells of Cajal

    PubMed Central

    Beckett, Elizabeth A. H.; Sanders, Kenton M.; Ward, Sean M.

    2017-01-01

    Intramuscular interstitial cells of Cajal (ICC-IM) are closely associated with enteric motor nerve terminals and electrically coupled to smooth muscle cells within the gastric musculature. Previous studies investigating the role of ICC-IM in motor neurotransmission have used indiscriminate electric field stimulation of neural elements within the gastric wall. To determine the role of ICC-IM in transduction of vagally-mediated motor input to gastric muscles electrical and mechanical responses to selective electrical vagal stimulation (EVS) were recorded from gastric fundus and antral regions of wild type and W/WV mice, which lack most ICC-IM. EVS evoked inhibitory junction potentials (IJPs) in wild type muscles that were attenuated or abolished by L-NNA. IJPs were rarely evoked in W/WV muscles by EVS, and not affected by L-NNA. EVS evoked relaxation of wild type stomachs, but the predominant response of W/WV stomachs was contraction. EVS applied after pre-contraction with bethanechol caused relaxation of wild type gastric tissues and these were inhibited by the nitric oxide synthase inhibitor L-NNA. Relaxation responses were of smaller amplitude in W/WV muscles and L-NNA did not attenuate relaxation responses in W/WV fundus muscles. These data suggest an important role for ICC-IM in vagally-mediated nitrergic relaxation in the proximal and distal stomach. PMID:28317837

  18. Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production

    SciTech Connect

    Yoon, Jeongyeon; Ryoo, Sungwoo

    2013-06-07

    Highlights: •Arginase inhibition suppressed proliferation of IL-1β-stimulated VSMCs in dose-dependent manner. •NO production from IL-1β-induced iNOS expression was augmented by arginase inhibition, reducing VSMC proliferation. •Incubation with cGMP analogues abolished IL-1β-dependent proliferation of VSMCs. -- Abstract: We investigated whether arginase inhibition suppressed interleukin (IL)-1β-stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1β stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21Waf1/Cip1. IL-1β incubation induced inducible nitric oxide synthase (iNOS) mRNA expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1β stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific iNOS inhibitor 1400W abolished IL-1β-mediated NO production and further accentuated IL-1β-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1β abolished VSMCs proliferation and increased p21Waf1/Cip1 protein content. Furthermore, incubation with the cGMP analogue 8-Br-cGMP prevented IL-1β-induced VSMCs proliferation. In conclusion, arginase inhibition augmented iNOS-dependent NO production that resulted in suppression of IL-1β-induced VSMCs proliferation in a cGMP-dependent manner.

  19. Acoustic tone or medial geniculate stimulation cue training in the rat is associated with neocortical neuroplasticity and reduced akinesia under haloperidol challenge.

    PubMed

    Brown, Andrew R; Hu, Bin; Kolb, Bryan; Teskey, G Campbell

    2010-12-06

    Sensory cues can improve movement deficits in Parkinson's disease, but little is known about the mechanisms involved. To investigate neuroplastic changes following sensorimotor cue training, rats were shaped to respond to acoustic tone or medial geniculate stimulation cues by retrieving a food reward. Neuroplasticity associated with training was assessed by changes in auditory neocortical evoked field potentials and dendritic morphology. Stimulation cue training was associated with changes in dendritic arbour length and complexity in auditory and motor neocortices, but was without effect on evoked electrophysiological responses. Tone cue training was associated with a significant increase in peak height of the evoked auditory response and then under haloperidol challenge, demonstrated reduced akinesia. Results indicate that cue-training induces neuroplastic changes that may be related to improved sensorimotor function under dopaminergic antagonism.

  20. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.

    PubMed

    Schaap, Frank G; Rensen, Patrick C N; Voshol, Peter J; Vrins, Carlos; van der Vliet, Hendrik N; Chamuleau, Robert A F M; Havekes, Louis M; Groen, Albert K; van Dijk, Ko Willems

    2004-07-02

    ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 x 10(8) plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29-37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68-88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.

  1. Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression.

    PubMed

    Kim, I; Moon, S O; Park, S K; Chae, S W; Koh, G Y

    2001-09-14

    Vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) are potent vasculogenic and angiogenic factors that hold promise as a means to produce therapeutic vascularization and angiogenesis. However, VEGF also acts as a proinflammatory cytokine by inducing adhesion molecules that bind leukocytes to endothelial cells, an initial and essential step toward inflammation. In the present study, we used human umbilical vascular endothelial cells (HUVECs) to examine the effect of Ang1 on VEGF-induced expression of three adhesion molecules: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Interestingly, Ang1 suppressed VEGF-induced expression of these adhesion molecules. Furthermore, Ang1 reduced VEGF-induced leukocyte adhesion to HUVECs. These results demonstrate that Ang1 counteracts VEGF-induced inflammation by reducing VEGF-induced endothelial adhesiveness.

  2. Inhibition of xanthine oxidase reduces oxidative stress and improves skeletal muscle function in response to electrically stimulated isometric contractions in aged mice

    PubMed Central

    Ryan, Michael J.; Jackson, Janna R.; Hao, Yanlei; Leonard, Stephen S.; Alway, Stephen E.

    2012-01-01

    Oxidative stress is a putative factor responsible for reducing function and increasing apoptotic signaling in skeletal muscle with aging. This study examined the contribution and functional significance of the xanthine oxidase enzyme as a potential source of oxidant production in aged skeletal muscle during repetitive in situ electrically stimulated isometric contractions. Xanthine oxidase activity was inhibited in young adult and aged mice via a subcutaneously placed time release (2.5 mg/day) allopurinol pellet, 7 days prior to the start of in situ electrically stimulated isometric contractions. Gastrocnemius muscles were electrically activated with 20 maximal contractions for three consecutive days. Xanthine oxidase activity was 65% greater in the gastrocnemius muscle of aged mice compared to young mice. Xanthine oxidase activity also increased after in situ electrically stimulated isometric contractions in muscles from both young (33%) and aged (28%) mice, relative to contralateral non-contracted muscles. Allopurinol attenuated the exercise-induced increase in oxidative stress, but it did not affect the elevated basal levels of oxidative stress that was associated with aging. In addition, inhibition of xanthine oxidase activity decreased caspase 3 activity, but it had no effect on other markers of mitochondrial associated apoptosis. Our results show that compared to control conditions, suppression of xanthine oxidase activity by allopurinol reduced xanthine oxidase activity, H2O2 levels, lipid peroxidation and caspase-3 activity, prevented the in situ electrically stimulated isometric contraction-induced loss of glutathione, prevented the increase of catalase and copper-zinc superoxide dismutase activities, and increased maximal isometric force in the plantar flexor muscles of aged mice after repetitive electrically evoked contractions. PMID:21530649

  3. Feeling worse to feel better: pain-offset relief simultaneously stimulates positive affect and reduces negative affect.

    PubMed

    Franklin, Joseph C; Lee, Kent M; Hanna, Eleanor K; Prinstein, Mitchell J

    2013-04-01

    Although pain itself induces negative affect, the removal (or offset) of pain induces a powerful state of relief. Despite being implicated in a wide range of psychological and behavioral phenomena, relief remains a poorly understood emotion. In particular, some theorists associate relief with increased positive affect, whereas others associate relief with diminished negative affect. In the present study, we examined the affective nature of relief in a pain-offset paradigm with psychophysiological measures that were specific to negative valence (startle eyeblink reactivity) and positive valence (startle postauricular reactivity). Results revealed that pain offset simultaneously stimulates positive affect and diminishes negative affect for at least several seconds. Results also indicated that pain intensity differentially affects the positive and negative valence aspects of relief. These findings clarify the affective nature of relief and provide insight into why people engage in both normal and abnormal behaviors associated with relief.

  4. Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency.

    PubMed

    Fauser, B C J M; Mannaerts, B M J L; Devroey, P; Leader, A; Boime, I; Baird, D T

    2009-01-01

    Recombinant DNA technologies have been used to develop longer-acting therapeutic proteins. One approach is to introduce sequences containing additional glycosylation sites. Using this technique, a new chimeric gene has been developed containing the coding sequences of the FSH beta-subunit and the C-terminal peptide of the hCG beta-subunit, which bears four O-linked oligosaccharide binding sites. Co-expression of the alpha-subunit and the chimeric FSH beta-subunit produces a new recombinant molecule, named corifollitropin alfa, with a prolonged elimination half-life and enhanced in vivo bioactivity compared with wild-type FSH. Medline searches by subject and additional searching by hand. Initial studies in pituitary suppressed female volunteers confirmed the extended half-life of the compound. Phase II studies have shown that corifollitropin alfa is able to induce and sustain multi-follicular growth for an entire week in women undergoing ovarian stimulation using GnRH antagonist co-treatment for IVF. Corifollitropin alfa regimens have been developed with dosages of 100 and 150 microg, for patients with body weight 60 kg, respectively. Corifollitropin alfa is the first long-acting hybrid molecule with sustained follicle-stimulating activity developed for the induction of multi-follicular growth along with GnRH antagonist co-treatment for IVF. This new treatment option may be simpler and more convenient for patients compared with conventional long protocols of daily FSH injections in combination with GnRH agonist co-treatment. The safety and efficacy of such regimens is currently being evaluated in large comparative phase III clinical trials. The development of corifollitropin alfa is the first step towards a new generation of recombinant gonadotrophins.

  5. Early childhood stunting is associated with poor psychological functioning in late adolescence and effects are reduced by psychosocial stimulation.

    PubMed

    Walker, Susan P; Chang, Susan M; Powell, Christine A; Simonoff, Emily; Grantham-McGregor, Sally M

    2007-11-01

    Stunting is associated with deficits in cognition and school achievement from early childhood to late adolescence; however, there has been little investigation of emotional and behavioral outcomes. The objective of this study was to determine whether linear growth retardation (stunting) in early childhood is associated with poorer psychological functioning in late adolescence. The study was a prospective cohort study of stunted and nonstunted children. Participants were identified at age 9-24 mo by a survey of poor neighborhoods in Kingston, Jamaica, and a 2-y intervention trial of supplementation and stimulation was conducted in the stunted children. Psychological functioning was assessed at age 17 y in 103 of 129 stunted children enrolled and 64 of 84 nonstunted participants. Anxiety, depressive symptoms, self-esteem, and antisocial behavior were reported by participants using interviewer-administered questionnaires and attention deficit, hyperactivity, and oppositional behavior were reported by parent interviews. The stunted participants reported significantly more anxiety (regression coefficient = 3.03; 95% CI = 0.99, 5.08) and depressive symptoms (0.37; 95% CI = 0.01, 0.72) and lower self-esteem (-1.67; 95% CI = -0.38, -2.97) than nonstunted participants and were reported by their parents to be more hyperactive (1.29; 95% CI = 0.12, 2.46). Effect sizes were 0.4-0.5 SD. Participants who received stimulation in early childhood differed from the nonstunted group in hyperactivity only. Children stunted before age 2 y thus have poorer emotional and behavioral outcomes in late adolescence. The findings expand the range of disadvantages associated with early stunting, which affects 151 million children <5 y old in developing countries.

  6. P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse

    PubMed Central

    Zheng, Wei; Talley Watts, Lora; Holstein, Deborah M; Wewer, Jimmy; Lechleiter, James D

    2013-01-01

    Glia-based neuroprotection strategies are emerging as promising new avenues to treat brain damage. We previously reported that activation of the glial-specific purinergic receptor, P2Y1R, reduces both astrocyte swelling and brain infarcts in a photothrombotic mouse model of stroke. These restorative effects were dependent on astrocyte mitochondrial metabolism. Here, we extend these findings and report that P2Y1R stimulation with the purinergic ligand 2-methylthioladenosine 5′ diphosphate (2MeSADP) reduces and partially reverses neuronal damage induced by photothrombosis. In vivo neuronal morphology was confocally imaged in transgenic mice expressing yellow fluorescent protein under the control of the Thy1 promoter. Astrocyte mitochondrial membrane potentials, monitored with the potential sensitive dye tetra-methyl rhodamine methyl ester, were depolarized after photothrombosis and subsequently repolarized when P2Y1Rs were stimulated. Mice deficient in the astrocyte-specific type 2 inositol 1,4,5 trisphosphate (IP3) receptor exhibited aggravated ischemic dendritic damage after photothrombosis. Treatment of these mice with 2MeSADP did not invoke an intracellular Ca2+ response, did not repolarize astrocyte mitochondria, and did not reduce or partially reverse neuronal lesions induced by photothrombotic stroke. These results demonstrate that IP3-Ca2+ signaling in astrocytes is not only critical for P2Y1R-enhanced protection, but suggest that IP3-Ca2+ signaling is also a key component of endogenous neuroprotection. PMID:23321785

  7. Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice.

    PubMed

    Mårtensson, Ulrika E A; Salehi, S Albert; Windahl, Sara; Gomez, Maria F; Swärd, Karl; Daszkiewicz-Nilsson, Joanna; Wendt, Anna; Andersson, Niklas; Hellstrand, Per; Grände, Per-Olof; Owman, Christer; Rosen, Clifford J; Adamo, Martin L; Lundquist, Ingmar; Rorsman, Patrik; Nilsson, Bengt-Olof; Ohlsson, Claes; Olde, Björn; Leeb-Lundberg, L M Fredrik

    2009-02-01

    In vitro studies suggest that the G protein-coupled receptor (GPR) 30 is a functional estrogen receptor. However, the physiological role of GPR30 in vivo is unknown, and it remains to be determined whether GPR30 is an estrogen receptor also in vivo. To this end, we studied the effects of disrupting the GPR30 gene in female and male mice. Female GPR30((-/-)) mice had hyperglycemia and impaired glucose tolerance, reduced body growth, increased blood pressure, and reduced serum IGF-I levels. The reduced growth correlated with a proportional decrease in skeletal development. The elevated blood pressure was associated with an increased vascular resistance manifested as an increased media to lumen ratio of the resistance arteries. The hyperglycemia and impaired glucose tolerance in vivo were associated with decreased insulin expression and release in vivo and in vitro in isolated pancreatic islets. GPR30 is expressed in islets, and GPR30 deletion abolished estradiol-stimulated insulin release both in vivo in ovariectomized adult mice and in vitro in isolated islets. Our findings show that GPR30 is important for several metabolic functions in female mice, including estradiol-stimulated insulin release.

  8. alpha1-Adrenoceptors stimulate a Galphas protein and reduce the transient outward K+ current via a cAMP/PKA-mediated pathway in the rat heart.

    PubMed

    Gallego, Mónica; Setién, Raúl; Puebla, Lilian; Boyano-Adánez, María Del Carmen; Arilla, Eduardo; Casis, Oscar

    2005-03-01

    alpha(1)-Adrenoceptor stimulation prolongs the duration of the cardiac action potentials and leads to positive inotropic effects by inhibiting the transient outward K(+) current (I(to)). In the present study, we have examined the role of several protein kinases and the G protein involved in I(to) inhibition in response to alpha(1)-adrenoceptor stimulation in isolated adult rat ventricular myocytes. Our findings exclude the classic alpha(1)-adrenergic pathway: activation of the G protein G(alphaq), phospholipase C (PLC), and protein kinase C (PKC), because neither PLC, nor PKC, nor G(alphaq) blockade prevents the alpha(1)-induced I(to) reduction. To the contrary, the alpha(1)-adrenoceptor does not inhibit I(to) in the presence of protein kinase A (PKA), adenylyl cyclase, or G(alphas) inhibitors. In addition, PKA and adenylyl cyclase activation inhibit I(to) to the same extent as phenylephrine. Finally, we have shown a functional coupling between the alpha(1)-adrenoceptor and G(alphas) in a physiological system. Moreover, this coupling seems to be compartmentalized, because the alpha(1)-adrenoceptor increases cAMP levels only in intact cells, but not in isolated membranes, and the effect on I(to) disappears when the cytoskeleton is disrupted. We conclude that alpha(1)-adrenoceptor stimulation reduces the amplitude of the I(to) by activating a G(alphas) protein and the cAMP/PKA signaling cascade, which in turn leads to I(to) channel phosphorylation.

  9. Reduced Seminal Concentration of CD45pos Cells after Follicle-Stimulating Hormone Treatment in Selected Patients with Idiopathic Oligoasthenoteratozoospermia

    PubMed Central

    Condorelli, Rosita A.; Calogero, Aldo E.; Vicari, Enzo; Mongioi', Laura; Cannarella, Rossella; Giacone, Filippo; Iacoviello, Linda; Favilla, Vincenzo; La Vignera, Sandro

    2014-01-01

    The present study evaluated the conventional sperm parameters and the seminal concentration of CD45pos cells (pan-leukocyte marker) of infertile patients with idiopathic oligoasthenoteratozoospermia (OAT). The patients were arbitrarily divided into three groups treated with recombinant follicle-stimulating hormone FSH: α (Group A = 20 patients), recombinant FSH-β (Group B = 20 patients), and highly purified human FSH (Group C = 14 patients). All treated groups achieved a similar improvement of the main sperm parameters (density, progressive motility, and morphology), but only the increase in the percentage of spermatozoa with normal morphology was significant compared to the baseline in all three examined groups. Moreover, all groups had a significant reduction of the seminal concentration of CD45pos cells and of the percentage of immature germ cells. Before and after the treatment, the concentration of CD45pos cells showed a positive linear correlation with the percentage of immature germ cells and a negative correlation with the percentage of spermatozoa with regular morphology. These results demonstrate that treatment with FSH is effective in patients with idiopathic OAT and that there are no significant differences between the different preparations. The novelty of this study is in the significant reduction of the concentration of CD45pos cells observed after the treatment. PMID:24550984

  10. Reduced Seminal Concentration of CD45pos Cells after Follicle-Stimulating Hormone Treatment in Selected Patients with Idiopathic Oligoasthenoteratozoospermia.

    PubMed

    Condorelli, Rosita A; Calogero, Aldo E; Vicari, Enzo; Mongioi', Laura; Burgio, Giovanni; Cannarella, Rossella; Giacone, Filippo; Iacoviello, Linda; Morgia, Giuseppe; Favilla, Vincenzo; Cimino, Sebastiano; La Vignera, Sandro

    2014-01-01

    The present study evaluated the conventional sperm parameters and the seminal concentration of CD45pos cells (pan-leukocyte marker) of infertile patients with idiopathic oligoasthenoteratozoospermia (OAT). The patients were arbitrarily divided into three groups treated with recombinant follicle-stimulating hormone FSH: α (Group A = 20 patients), recombinant FSH- β (Group B = 20 patients), and highly purified human FSH (Group C = 14 patients). All treated groups achieved a similar improvement of the main sperm parameters (density, progressive motility, and morphology), but only the increase in the percentage of spermatozoa with normal morphology was significant compared to the baseline in all three examined groups. Moreover, all groups had a significant reduction of the seminal concentration of CD45pos cells and of the percentage of immature germ cells. Before and after the treatment, the concentration of CD45pos cells showed a positive linear correlation with the percentage of immature germ cells and a negative correlation with the percentage of spermatozoa with regular morphology. These results demonstrate that treatment with FSH is effective in patients with idiopathic OAT and that there are no significant differences between the different preparations. The novelty of this study is in the significant reduction of the concentration of CD45pos cells observed after the treatment.

  11. Transcranial ultrasound stimulation promotes brain-derived neurotrophic factor and reduces apoptosis in a mouse model of traumatic brain injury.

    PubMed

    Su, Wei-Shen; Wu, Chun-Hu; Chen, Szu-Fu; Yang, Feng-Yi

    2017-09-07

    The protein expressions of brain-derived neurotrophic factor (BDNF) can be elevated by transcranial ultrasound stimulation in the rat brain. The purpose of this study was to investigate the effects and underlying mechanisms of BDNF enhancement by low-intensity pulsed ultrasound (LIPUS) on traumatic brain injury (TBI). Mice subjected to controlled cortical impact injury were treated with LIPUS in the injured region daily for a period of 4 days. Western blot analysis and immunohistochemistry were performed to assess the effects of LIPUS. The results showed that the LIPUS treatment significantly promoted the neurotrophic factors BDNF and vascular endothelial growth factor (VEGF) at day 4 after TBI. Meanwhile, LIPUS also enhanced the phosphorylation of Tropomyosin-related kinase B (TrkB), Akt, and cAMP-response element binding protein (CREB). Furthermore, treatment with LIPUS significantly decreased the level of cleaved caspase-3. The reduction of apoptotic process was inhibited by the anti-BDNF antibody. In short, post-injury LIPUS treatment increased BDNF protein levels and inhibited the progression of apoptosis following TBI. The neuroprotective effects of LIPUS may be associated with enhancements of the protein levels of neurotrophic factors, at least partially via the TrkB/Akt-CREB signaling pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Stimulation of Strontium Accumulation in Linoleate-Enriched Saccharomyces cerevisiae Is a Result of Reduced Sr2+ Efflux

    PubMed Central

    Avery, Simon V.; Smith, Shareeka L.; Ghazi, A. Mohamad; Hoptroff, Michael J.

    1999-01-01

    The influence of modified plasma membrane fatty acid composition on cellular strontium accumulation in Saccharomyces cerevisiae was investigated. Growth of S. cerevisiae in the presence of 1 mM linoleate (18:2) (which results in 18:2 incorporation to ∼70% of total cellular and plasma membrane fatty acids, with no effect on growth rate) yielded cells that accumulated Sr2+ intracellularly at approximately twice the rate of S. cerevisiae grown without a fatty acid supplement. This effect was evident over a wide range of external Sr2+ concentrations (25 μM to 5 mM) and increased with the extent of cellular 18:2 incorporation. Stimulation of Sr2+ accumulation was not evident following enrichment of S. cerevisiae with either palmitoleate (16:1), linolenate (18:3) (n-3 and n-6 isomers), or eicosadienoate (20:2) (n-6 and n-9 isomers). Competition experiments revealed that Ca2+- and Mg2+-induced inhibition of Sr2+ accumulation did not differ between unsupplemented and 18:2-supplemented cells. Treatment with trifluoperazine (TFP) (which can act as a calmodulin antagonist and Ca2+-ATPase inhibitor), at a low concentration that precluded nonspecific K+ efflux, increased intracellular Sr2+ accumulation by approximately 3.6- and 1.4-fold in unsupplemented and 18:2-supplemented cells, respectively. Thus, TFP abolished the enhanced Sr2+ accumulation ability of 18:2-supplemented cells. Moreover, the rate of Sr2+ release from Sr2+-loaded fatty acid-unsupplemented cells was found to be at least twice as great as that from Sr2+-loaded 18:2-enriched cells. The influence of enrichment with other fatty acids on Sr2+ efflux was variable. The results reveal an enhanced Sr2+ accumulation ability of S. cerevisiae following 18:2-enrichment, which is attributed to diminished Sr2+ efflux activity in these cells. PMID:10049882

  13. Stimulation of strontium accumulation in linoleate-enriched Saacharomyces cerevisiae is a result of reduced Sr{sup 2+} efflux

    SciTech Connect

    Avery, S.V.; Smith, S.L.; Ghazi, A.M.; Hoptroff, M.J.

    1999-03-01

    The influence of modified plasma membrane fatty acid composition on cellular strontium accumulation in Saccharomyces cerevisiae was investigated. Growth of S. cerevisiae in the presence of 1 mM linoleate (18:2) yielded cells that accumulated Sr{sup 2+} intracellularly at approximately twice the rate of S. cerevisiae grown without a fatty acid supplement. This effect was evident over a wide range of external Sr{sup 2+} concentrations and increased with the extent of cellular 18:2 incorporation. Stimulation of Sr{sup 2+} accumulation was not evident following enrichment of S. cerevisiae with either palmitoleate (16:1), linolenate (18:3) (n-3 and n-6 isomers), or eicosadienoate (20:2) (n-6 and n-9 isomers). Competition experiments revealed that Ca{sup 2+}- and Mg{sup 2+}-induced inhibition of Sr{sup 2+} accumulation did not differ between unsupplemented and 18:2-supplemented cells. Treatment with trifluoperazine (TFP) (which can act as a calmodulin antagonist and Ca{sup 2+}-ATPase inhibitor), at a low concentration that precluded nonspecific K{sup +} efflux, increased intracellular Sr{sup 2+} accumulation by approximately 3.6- and 1.4-fold in unsupplemented and 18:2-supplemented cells, respectively. Thus, TFP abolished the enhanced Sr{sup 2+} accumulation ability of 18:2 supplemented cells. Moreover, the rate of Sr{sup 2+} release from Sr{sup 2+}-loaded fatty acid-unsupplemented cells was found to be at least twice as great as that from Sr{sup 2+}-loaded 18:2-enriched cells. The influence of enrichment with other fatty acids on Sr{sup 2+} efflux was variable. The results reveal an enhanced Sr{sup 2+} accumulation ability of S. cerevisiae following 18:2-enrichment, which is attributed to diminished Sr{sup 2+} efflux activity in these cells.

  14. Transcutaneous electrical nerve stimulation (TENS) reduces pain and postpones the need for pharmacological analgesia during labour: a randomised trial.

    PubMed

    Santana, Licia Santos; Gallo, Rubneide Barreto Silva; Ferreira, Cristine Homsi Jorge; Duarte, Geraldo; Quintana, Silvana Maria; Marcolin, Alessandra Cristina

    2016-01-01

    In the active phase of the first stage of labour, does transcutaneous electrical nerve stimulation (TENS) relieve pain or change its location? Does TENS delay the request for neuraxial analgesia during labour? Does TENS produce any harmful effects in the mother or the foetus? Are women in labour satisfied with the care provided? Randomised trial with concealed allocation, assessor blinding for some outcomes, and intention-to-treat analysis. Forty-six low-risk, primigravida parturients with a gestational age > 37 weeks, cervical dilation of 4cm, and without the use of any medications from hospital admission until randomisation. The principal investigator applied TENS to the experimental group for 30minutes starting at the beginning of the active phase of labour. A second investigator assessed the outcomes in both the control and experimental groups. Both groups received routine perinatal care. The primary outcome was pain severity after the intervention period, which was assessed using the 100-mm visual analogue scale. Secondary outcomes included: pain location, duration of the active phase of labour, time to pharmacological labour analgesia, mode of birth, neonatal outcomes, and the participant's satisfaction with the care provided. After the intervention, a significant mean difference in change in pain of 15mm was observed favouring the experimental group (95% CI 2 to 27). The application of TENS did not alter the location or distribution of the pain. The mean time to pharmacological analgesia after the intervention was 5.0hours (95% CI 4.1 to 5.9) longer in the experimental group. The intervention did not significantly impact the other maternal and neonatal outcomes. Participants in both groups were satisfied with the care provided during labour. TENS produces a significant decrease in pain during labour and postpones the need for pharmacological analgesia for pain relief. NCT01600495. Copyright © 2015. Published by Elsevier B.V.

  15. Chronic leucine exposure results in reduced but reversible glucose-stimulated insulin secretion in INS-1 cells.

    PubMed

    Zhang, Xiujuan; Han, Wenxia; Jiang, Xiuyun; Li, Min; Gao, Ling; Zhao, Jia Jun

    2014-06-01

    Previous studies have demonstrated that sustained high leucine exposure decreases glucose-stimulated insulin secretion (GSIS). However, whether this effect is recoverable following the removal of leucine is unclear. Pancreatic/duodenal homeobox-1 (PDX-1) and its downstream target, glucose transporter 2 (GLUT2), are reported to be positively associated with insulin secretion. However, it also remains unclear whether the effect of leucine on GSIS is accompanied by alterations in PDX-1 and GLUT2. In the present study, insulin secretion, insulin content, PDX-1 and GLUT2 protein expression in INS-1 (rat insulinoma cell line) cells were assessed following a 24-h incubation in 40 mmol/l leucine. Half of the cells were incubated in leucine-free media for a further 24 h to observe the abovementioned effects. In contrast to the control, 40 mmol/l leucine for 24 or 48 h diminished GSIS at high glucose concentrations by 11% (P=0.026) or 22% (P=0.003), insulin content by 14% (P=0.008) or 20% (P=0.002), as well as decreasing PDX-1 and GLUT2 expression. When leucine was removed from the media for a further 24-h incubation, in comparison with those cells that were maintained in leucine treatment for 24 and 48 h, the high GSIS increased by 13% (P=0.032) and 27% (P=0.002), insulin content was augmented by 10% (P=0.014) and 20% (P=0.003), and the protein expression of PDX-1 and GLUT2 also increased. The present study demonstrates that sustained high concentrations of leucine induce a reversible impairment of GSIS and alter insulin content, which is mediated by PDX-1 and GLUT2, in INS-1 cells.

  16. Probiotic Lactobacillus gasseri SBT2055 improves glucose tolerance and reduces body weight gain in rats by stimulating energy expenditure.

    PubMed

    Shirouchi, Bungo; Nagao, Koji; Umegatani, Minami; Shiraishi, Aya; Morita, Yukiko; Kai, Shunichi; Yanagita, Teruyoshi; Ogawa, Akihiro; Kadooka, Yukio; Sato, Masao

    2016-08-01

    Probiotic Lactobacillus gasseri SBT2055 (LG2055) reduces postprandial TAG absorption and exerts anti-obesity effects in rats and humans; however, the underlying mechanisms are not fully understood. In the present study, we addressed the mechanistic insights of the anti-obesity activity of LG2055 by feeding Sprague-Dawley rats diets containing skimmed milk fermented or not by LG2055 for 4 weeks and by analysing energy expenditure, glucose tolerance, the levels of SCFA in the caecum and serum inflammatory markers. Rats fed the LG2055-containing diet demonstrated significantly higher carbohydrate oxidation in the dark cycle (active phase for rats) compared with the control group, which resulted in a significant increase in energy expenditure. LG2055 significantly reduced cumulative blood glucose levels (AUC) compared with the control diet after 3 weeks and increased the molar ratio of butyrate:total SCFA in the caecum after 4 weeks. Furthermore, the LG2055-supplemented diet significantly reduced the levels of serum amyloid P component - an indicator of the inflammatory process. In conclusion, our results demonstrate that, in addition to the inhibition of dietary TAG absorption reported previously, the intake of probiotic LG2055 enhanced energy expenditure via carbohydrate oxidation, improved glucose tolerance and attenuated inflammation, suggesting multiple additive and/or synergistic actions underlying the anti-obesity effects exerted by LG2055.

  17. Maternal immune stimulation reduces both placental morphologic damage and down-regulated placental growth-factor and cell cycle gene expression caused by urethane: are these events related to reduced teratogenesis?

    PubMed

    Sharova, L V; Sharov, A A; Sura, P; Gogal, R M; Smith, B J; Holladay, S D

    2003-07-01

    Activation of the maternal immune system in mice decreased cleft palate caused by the chemical teratogen, urethane. Direct and indirect mechanisms for this phenomenon have been suggested, including maternal macrophages that cross the placenta to find and eliminate pre-teratogenic cells, or maternal immune proteins (cytokines) that cross placenta to alleviate or partially alleviate toxicant-mediated effects in the developing fetus. A third mechanism to explain improved fetal developmental outcome in teratogen-challenged pregnant mice might involve beneficial effects of immune stimulation on the placenta. In the present experiments, urethane treatment altered placental morphology and impaired placental function, the latter indicated by down-regulated activity of cell cycle genes and of genes encoding cytokines and growth factors. Maternal immune stimulation with either Freund's complete adjuvant (FCA) or interferon-gamma (IFNgamma) reduced morphologic damage to the placenta caused by urethane and normalized expression of several genes that were down-regulated by urethane. Urethane treatment also shifted placental cytokine gene expression toward a T cell helper 1 (Th1) profile, while immunostimulation tended to restore a Th2 profile that may be more beneficial to pregnancy and fetal development. These data suggest that the beneficial effects of maternal immune stimulation on fetal development in teratogen-exposed mice may, in part, result from improved placental structure and function.

  18. A 1,4-dihydropyridine derivative reduces DNA damage and stimulates DNA repair in human cells in vitro.

    PubMed

    Ryabokon, Nadezhda I; Goncharova, Rose I; Duburs, Gunars; Rzeszowska-Wolny, Joanna

    2005-11-10

    Compounds of the 1,4-dihydropyridine (1,4-DHP) series have been shown to reduce spontaneous, alkylation- and radiation-induced mutation rates in animal test systems. Here we report studies using AV-153, the 1,4-DHP derivative that showed the highest antimutagenic activity in those tests, to examine if it modulates DNA repair in human peripheral blood lymphocytes and in two human lymphoblastoid cell lines, Raji and HL-60. AV-153 caused a 50% inhibition of growth (IC50) of Raji and HL-60 cells at 14.9+/-1.2 and 10.3+/-0.8mM, respectively, but did not show a cytotoxic effect at concentrations <100 microM. Alkaline single-cell gel electrophoresis (comet) assays showed that AV-153 reduced the number of DNA strand breaks in untreated cells and also in cells exposed to 2 Gy of gamma-radiation, 100 microM ethylmethane sulfonate (EMS), or 100 microM H2O2. DNA damage was reduced by up to 87% at AV-153 concentrations between 1 and 10nM, and a positive dose-effect relationship was seen between 0.01 and 1 nM. Comparison of the kinetics of DNA strand-break rejoining in the presence and absence of AV-153 revealed a considerable influence on the rate of repair. In view of the resemblance of this compound's structure to that of dihydronicotinamide, a substrate for poly(ADP-rybose)polymerase, the modulation of DNA repair by AV-153 could involve an influence on poly(ADP)ribosylation.

  19. The reduced state of the plastoquinone pool is required for chloroplast-mediated stomatal closure in response to calcium stimulation.

    PubMed

    Wang, Wen-Hua; He, En-Ming; Chen, Juan; Guo, Ying; Chen, Juan; Liu, Xiang; Zheng, Hai-Lei

    2016-04-01

    Besides their participation in photosynthesis, leaf chloroplasts function in plant responses to stimuli, yet how they direct stimulus-induced stomatal movement remains elusive. Here, we showed that over-reduction of the plastoquinone (PQ) pool by dibromothymoquinone (DBMIB) was closely associated with stomatal closure in plants which required chloroplastic H2O2 generation in the mesophyll. External application of H2 O2 reduced the PQ pool, whereas the cell-permeable reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) reversed the DBMIB-induced over-reduction of the PQ pool and stomatal closure. Mesophyll chloroplasts are key players of extracellular Ca(2+) (Ca(2+)o)-induced stomatal closure, but when treated with either 3-(3',4'-dichlorophenyl)-1,1-dimethylurea (DCMU) or NAC they failed to facilitate Ca(2+)o-induced stomatal closure due to the inhibition of chloroplastic H2 O2 synthesis in mesophyll. Similarly, the Arabidopsis electron transfer chain-related mutants npq4-1, stn7 and cas-1 exhibited diverse responses to Ca(2+)o or DBMIB. Transcriptome analysis also demonstrated that the PQ pool signaling pathway shared common responsive genes with the H2 O2 signaling pathway. These results implicated a mechanism for chloroplast-mediated stomatal closure involving the generation of mesophyll chloroplastic H2O2 based on the reduced state of the PQ pool, which is calcium-sensing receptor (CAS) and LHCII phosphorylation dependent.

  20. A Single Hot Event Stimulates Adult Performance but Reduces Egg Survival in the Oriental Fruit Moth, Grapholitha molesta

    PubMed Central

    Ma, Gang; Hoffmann, Ary A.; Ma, Chun-Sen

    2014-01-01

    Climate warming is expected to increase the exposure of insects to hot events (involving a few hours at extreme high temperatures). These events are unlikely to cause widespread mortality but may modify population dynamics via impacting life history traits such as adult fecundity and egg hatching. These effects and their potential impact on population predictions are still largely unknown. In this study, we simulated a single hot event (maximum of 38°C lasting for 4 h) of a magnitude increasingly found under field conditions and examined its effect in the oriental fruit moth, Grapholitha molesta. This hot event had no impact on the survival of G. molesta adults, copulation periods or male longevity. However, the event increased female lifespan and the length of the oviposition period, leading to a potential increase in lifetime fecundity and suggesting hormesis. In contrast, exposure of males to this event markedly reduced the net reproductive value. Male heat treatment delayed the onset of oviposition in the females they mated with, as well as causing a decrease in the duration of oviposition period and lifetime fecundity. Both male and female stress also reduced egg hatch. Our findings of hormetic effects on female performance but concurrent detrimental effects on egg hatch suggest that hot events have unpredictable consequences on the population dynamics of this pest species with implications for likely effects associated with climate warming. PMID:25551751

  1. The role of nitric oxide synthase in reduced vasocontractile responsiveness induced by prolonged α1-adrenergic receptor stimulation in rat thoracic aorta

    PubMed Central

    Gürdal, Hakan; Can, Alp; Uğur, Mehmet

    2005-01-01

    Prolonged exposure (6–12 h) of rat aorta to alpha1-adrenergic receptor (α1AR) agonist phenylephrine (Phe) leads to a decrease in α1AR-mediated vasoconstriction. This reduced responsiveness to α1AR stimulation was strongly dependent on the intactness of the endothelium. We examined the effect of Phe on nitric oxide synthase (NOS) activity by measuring the conversion of [3H]L-arginine to [3H]L-citrulline in rat aorta or in endothelial cells isolated from rat aorta. Phe stimulation increased NOS activity in control aortas. This response was antagonized by prazosin. However, Phe increased neither the activity of NOS nor intracellular Ca2+ in the isolated endothelial cells from the control aortas, whereas acetylcholine (Ach) was able to stimulate both responses in these cells. This result suggests that Phe stimulates α1AR on vascular smooth muscle cells and has an indirect influence on endothelial cells to increase NOS activity. In Phe-exposed aortic rings, basal NOS activity was found to have increased compared to vehicle-exposed control rings. Stimulation with Phe or Ach caused a small increase over basal NOS activity in these preparations. Prolonged exposure to Phe also caused an enhancement of Ach-mediated vasorelaxation in rat aorta. Immunoblot and reverse transcription–polymerase chain reaction experiments showed that prolonged exposure of rat aorta to Phe resulted in an increased expression of eNOS, but not iNOS. This increase was antagonized by nonselective antagonist prazosin. Immunohistochemical staining experiments also showed that expression of eNOS increased in endothelial cells after Phe exposure of the aortas. These results, all together, showed that prolonged exposure of rat aorta to α1AR agonist Phe enhanced the expression of eNOS and basal NOS activity, which probably causes a decreased vasocontractile response to Phe or to other agonists such as 5HT (5-hydroxytryptamine) in rat aorta. This phenomenon can be considered more as a functional

  2. Evaluation of loading parameters for murine axial tibial loading: Stimulating cortical bone formation while reducing loading duration.

    PubMed

    Sun, David; Brodt, Michael D; Zannit, Heather M; Holguin, Nilsson; Silva, Matthew J

    2017-09-09

    Classic studies in bone mechanobiology have established the importance of loading parameters on the anabolic response. Most of these early studies were done using loading methods not currently in favor, and using non-murine species. Our objective was to re-examine the effects of several loading parameters on the response of cortical bone using the contemporary murine axial tibial compression model. We subjected tibias of 5-month old, female C57Bl/6 mice to cyclic (4 Hz) mechanical loading and examined bone formation responses using dynamic and static histomorphometry. First, using a reference protocol of 1200 cycles/day, 5 days/week for 2 weeks, we confirmed the significant influence of peak strain magnitude on periosteal mineralizing surface (Ps.MS/BS) and bone formation rate (Ps.BFR/BS) (p < 0.05, ANOVA). There was a significant induction of periosteal lamellar bone at a lower threshold of approx. -1000 μϵ and a transition from lamellar-woven bone near -2000 μϵ. In contrast, on the endocortical surface, bone formation indices did not exhibit a load magnitude-dependent response and no incidence of woven bone. Next, we found that reducing daily cycle number from 1200 to 300 to 60 did not diminish the bone formation response (p > 0.05). On the other hand, reducing the daily frequency of loading from 5 consecutive days/week to 3 alternate days/week significantly diminished the periosteal response, from a loading-induced increase in Ps.MS/BS of 38% (loaded vs. control) for 5 days/week to only 15% for 3 days/week (p < 0.05). Finally, we determined that reducing the study duration from 2 to 1 weeks of loading did not affect bone formation outcomes. In conclusion, cyclic loading to -1800 μϵ peak strain, at 4 Hz and 60 cycles/day for 5 consecutive days (1 week) induces an increase in periosteal lamellar bone formation with minimal incidence of woven bone in 5-month old C57Bl/6 female mice. Our results provide a basis for reduction of loading

  3. Warming reduces tall fescue abundance but stimulates toxic alkaloid concentrations in transition zone pastures of the U.S.

    PubMed Central

    McCulley, Rebecca L.; Bush, Lowell P.; Carlisle, Anna E.; Ji, Huihua; Nelson, Jim A.

    2014-01-01

    Tall fescue pastures cover extensive acreage in the eastern half of the United States and contribute to important ecosystem services, including the provisioning of forage for grazing livestock. Yet little is known concerning how these pastures will respond to climate change. Tall fescue's ability to persist and provide forage under a warmer and wetter environment, as is predicted for much of this region as a result of climate change, will likely depend on a symbiotic relationship the plant can form with the fungal endophyte, Epichloë coenophiala. While this symbiosis can confer environmental stress tolerance to the plant, the endophyte also produces alkaloids toxic to insects (e.g., lolines) and mammals (ergots; which can cause “fescue toxicosis” in grazing animals). The negative animal health and economic consequences of fescue toxicosis make understanding the response of the tall fescue symbiosis to climate change critical for the region. We experimentally increased temperature (+3°C) and growing season precipitation (+30% of the long-term mean) from 2009–2013 in a mixed species pasture, that included a tall fescue population that was 40% endophyte-infected. Warming reduced the relative abundance of tall fescue within the plant community, and additional precipitation did not ameliorate this effect. Warming did not alter the incidence of endophyte infection within the tall fescue population; however, warming significantly increased concentrations of ergot alkaloids (by 30–40%) in fall-harvested endophyte-infected individuals. Warming alone did not affect loline alkaloid concentrations, but when combined with additional precipitation, levels increased in fall-harvested material. Although future warming may reduce the dominance of tall fescue in eastern U.S. pastures and have limited effect on the incidence of endophyte infection, persisting endophyte-infected tall fescue will have higher concentrations of toxic alkaloids which may exacerbate fescue

  4. Warming reduces tall fescue abundance but stimulates toxic alkaloid concentrations in transition zone pastures of the U.S.

    NASA Astrophysics Data System (ADS)

    Mcculley, Rebecca; Bush, Lowell; Carlisle, Anna; Ji, Huihua; Nelson, Jim

    2014-10-01

    Tall fescue pastures cover extensive acreage in the eastern half of the United States and contribute to important ecosystem services, including the provisioning of forage for grazing livestock. Yet little is known concerning how these pastures will respond to climate change. Tall fescue’s ability to persist and provide forage under a warmer and wetter environment, as is predicted for much of this region as a result of climate change, will likely depend on a symbiotic relationship the plant can form with the fungal endophyte, Epichloë coenophiala. While this symbiosis can confer environmental stress tolerance to the plant, the endophyte also produces alkaloids toxic to insects (e.g., lolines) and mammals (ergots; which can cause ‘fescue toxicosis’ in grazing animals). The negative animal health and economic consequences of fescue toxicosis make understanding the response of the tall fescue symbiosis to climate change critical for the region. We experimentally increased temperature (+3oC) and growing season precipitation (+30% of the long-term mean) from 2009 - 2013 in a mixed species pasture, that included a tall fescue population that was 40% endophyte-infected. Warming reduced the relative abundance of tall fescue within the plant community, and additional precipitation did not ameliorate this effect. Warming did not alter the incidence of endophyte infection within the tall fescue population; however, warming significantly increased concentrations of ergot alkaloids (by 30-40%) in fall-harvested endophyte-infected individuals. Warming alone did not affect loline alkaloid concentrations, but when combined with additional precipitation, levels increased in fall-harvested material. Although future warming may reduce the dominance of tall fescue in eastern U.S. pastures and have limited effect on the incidence of endophyte infection, persisting endophyte-infected tall fescue will have higher concentrations of toxic alkaloids which may exacerbate fescue

  5. Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome

    PubMed Central

    Rizza, Stefano; Muniyappa, Ranganath; Iantorno, Micaela; Kim, Jeong-a; Chen, Hui; Pullikotil, Philomena; Senese, Nicoletta; Tesauro, Manfredi; Lauro, Davide; Cardillo, Carmine

    2011-01-01

    Context: Hesperidin, a citrus flavonoid, and its metabolite hesperetin may have vascular actions relevant to their health benefits. Molecular and physiological mechanisms of hesperetin actions are unknown. Objective: We tested whether hesperetin stimulates production of nitric oxide (NO) from vascular endothelium and evaluated endothelial function in subjects with metabolic syndrome on oral hesperidin therapy. Design, Setting, and Interventions: Cellular mechanisms of action of hesperetin were evaluated in bovine aortic endothelial cells (BAEC) in primary culture. A randomized, placebo-controlled, double-blind, crossover trial examined whether oral hesperidin administration (500 mg once daily for 3 wk) improves endothelial function in individuals with metabolic syndrome (n = 24). Main Outcome Measure: We measured the difference in brachial artery flow-mediated dilation between placebo and hesperidin treatment periods. Results: Treatment of BAEC with hesperetin acutely stimulated phosphorylation of Src, Akt, AMP kinase, and endothelial NO synthase to produce NO; this required generation of H2O2. Increased adhesion of monocytes to BAEC and expression of vascular cell adhesion molecule-1 in response to TNF-α treatment was reduced by pretreatment with hesperetin. In the clinical study, when compared with placebo, hesperidin treatment increased flow-mediated dilation (10.26 ± 1.19 vs. 7.78 ± 0.76%; P = 0.02) and reduced concentrations of circulating inflammatory biomarkers (high-sensitivity C-reactive protein, serum amyloid A protein, soluble E-selectin). Conclusions: Novel mechanisms for hesperetin action in endothelial cells inform effects of oral hesperidin treatment to improve endothelial dysfunction and reduce circulating markers of inflammation in our exploratory clinical trial. Hesperetin has vasculoprotective actions that may explain beneficial cardiovascular effects of citrus consumption. PMID:21346065

  6. Aspirin-Triggered Lipoxin A4 Stimulates Alternative Activation of Microglia and Reduces Alzheimer Disease–Like Pathology in Mice

    PubMed Central

    Medeiros, Rodrigo; Kitazawa, Masashi; Passos, Giselle F.; Baglietto-Vargas, David; Cheng, David; Cribbs, David H.; LaFerla, Frank M.

    2014-01-01

    Microglia play an essential role in innate immunity, homeostasis, and neurotropic support in the central nervous system. In Alzheimer disease (AD), these cells may affect disease progression by modulating the buildup of β-amyloid (Aβ) or releasing proinflammatory cytokines and neurotoxic substances. Discovering agents capable of increasing Aβ uptake by phagocytic cells is of potential therapeutic interest for AD. Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory properties directly involved in inflammatory resolution, an active process essential for appropriate host responses, tissue protection, and the return to homeostasis. Herein, we demonstrate that aspirin-triggered LXA4 (15 μg/kg) s.c., twice a day, reduced NF-κB activation and levels of proinflammatory cytokines and chemokines, as well as increased levels of anti-inflammatory IL-10 and transforming growth factor-β. Such changes in the cerebral milieu resulted in recruitment of microglia in an alternative phenotype, as characterized by the up-regulation of YM1 and arginase-1 and the down-regulation of inducible nitric oxide synthase expression. Microglia in an alternative phenotype–positive cells demonstrated improved phagocytic function, promoting clearance of Aβ deposits and ultimately leading to reduction in synaptotoxicity and improvement in cognition. Our data indicate that activating LXA4 signaling may represent a novel therapeutic approach for AD. PMID:23506847

  7. Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice.

    PubMed

    Medeiros, Rodrigo; Kitazawa, Masashi; Passos, Giselle F; Baglietto-Vargas, David; Cheng, David; Cribbs, David H; LaFerla, Frank M

    2013-05-01

    Microglia play an essential role in innate immunity, homeostasis, and neurotropic support in the central nervous system. In Alzheimer disease (AD), these cells may affect disease progression by modulating the buildup of β-amyloid (Aβ) or releasing proinflammatory cytokines and neurotoxic substances. Discovering agents capable of increasing Aβ uptake by phagocytic cells is of potential therapeutic interest for AD. Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory properties directly involved in inflammatory resolution, an active process essential for appropriate host responses, tissue protection, and the return to homeostasis. Herein, we demonstrate that aspirin-triggered LXA4 (15 μg/kg) s.c., twice a day, reduced NF-κB activation and levels of proinflammatory cytokines and chemokines, as well as increased levels of anti-inflammatory IL-10 and transforming growth factor-β. Such changes in the cerebral milieu resulted in recruitment of microglia in an alternative phenotype, as characterized by the up-regulation of YM1 and arginase-1 and the down-regulation of inducible nitric oxide synthase expression. Microglia in an alternative phenotype-positive cells demonstrated improved phagocytic function, promoting clearance of Aβ deposits and ultimately leading to reduction in synaptotoxicity and improvement in cognition. Our data indicate that activating LXA4 signaling may represent a novel therapeutic approach for AD. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. beta-Adrenoceptor stimulation up-regulates phosphodiesterase 4 activity and reduces prostaglandin E2-inhibitory effects in human neutrophils.

    PubMed

    Ortiz, J L; Dasí, F J; Cortijo, J; Morcillo, E J

    2000-04-01

    Human neutrophils were treated for 4 h with a combination of salbutamol (1 microM), a beta2-adrenoceptor agonist, and rolipram (30 microM), a selective phosphodiesterase 4 inhibitor, to investigate whether this treatment produces up-regulation of phosphodiesterase activity with functional consequences. Anion-exchange chromatography coupled with the use of selective activators and inhibitors demonstrated that a phosphodiesterase activity with characteristics of the isoenzyme type 4 was increased in drug-treated cells. Kinetic analysis showed a approximately 1.5-fold increase in Vmax without alteration of Km values. The augmented phosphodiesterase activity in drug-treated cells was abolished by actinomycin D. Cyclic AMP content in drug-treated cells was higher than resting values (27.28+/-2.79 pmol/10(6) cells vs. 0.34+/-0.03 pmol/10(6) cells). Reverse transcriptase-polymerase chain reaction showed increased expression of mRNA transcripts for PDE4B and PDE4A in drug-treated cells. Functionally, up-regulation of phosphodiesterase 4 reduced the inhibition by prostaglandin E2 of zymosan-induced superoxide generation.

  9. Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation.

    PubMed

    Su, Wei-Shen; Tsai, Min-Lan; Huang, Sin-Luo; Liu, Shing-Hwa; Yang, Feng-Yi

    2015-12-08

    It has been shown that the blood-brain barrier (BBB) can be locally disrupted by focused ultrasound (FUS) in the presence of microbubbles (MB) while sustaining little damage to the brain tissue. Thus, the safety issue associated with FUS-induced BBB disruption (BBBD) needs to be investigated for future clinical applications. This study demonstrated the neuroprotective effects induced by low-intensity pulsed ultrasound (LIPUS) against brain injury in the sonicated brain. Rats subjected to a BBB disruption injury received LIPUS exposure for 5 min after FUS/MB application. Measurements of BBB permeability, brain water content, and histological analysis were then carried out to evaluate the effects of LIPUS. The permeability and time window of FUS-induced BBBD can be effectively modulated with LIPUS. LIPUS also significantly reduced brain edema, neuronal death, and apoptosis in the sonicated brain. Our results show that brain injury in the FUS-induced BBBD model could be ameliorated by LIPUS and that LIPUS may be proposed as a novel treatment modality for controllable release of drugs into the brain.

  10. The regulatory effect of choice in Situation Selection reduces experiential, exocrine and respiratory arousal for negative emotional stimulations.

    PubMed

    Thuillard, Simon; Dan-Glauser, Elise S

    2017-10-03

    Situation selection is a seldom studied emotion regulation strategy that entails choosing an upcoming emotional situation. Two mechanisms may drive its regulatory effect on emotional responses. One relates to the evaluation of the chosen option, people generally selecting the most positive. The other one implies that having the choice regarding the upcoming emotional situation is already regulatory, independently of what we choose. This research aimed at investigating this latter hypothesis. In a within-subject design, we compared emotional responses of 65 participants when they viewed negative and positive images they could select (use of Situation selection) vs. when they were imposed the exact same images (Situation selection not used). Results show that having the choice in negative contexts decreased negative experience, skin conductance, and respiration reactivity, while enhancing expressivity and cardiovascular reactivity. In positive contexts, choosing generally reinforced the image calming effect. Thus, contrary to other strategies that are efficient for negative but usually impair positive reactions (e.g., distraction), Situation selection may be used widely to reduce negative experience, while avoiding depletion of positive responses. This is particularly notable in emotion experience. Remarkably, these effects are not driven by the content of the situations, but by the act of choosing itself.

  11. Peripheral blood mononuclear cell supernatants from asymptomatic dogs immunized and experimentally challenged with Leishmania chagasi can stimulate canine macrophages to reduce infection in vitro.

    PubMed

    Rodrigues, Cleusa Alves Theodoro; Batista, Luís Fábio da Silva; Teixeira, Márcia Cristina Aquino; Pereira, Andréa Mendes; Santos, Patrícia Oliveira Meira; de Sá Oliveira, Geraldo Gileno; de Freitas, Luiz Antônio Rodrigues; Veras, Patrícia Sampaio Tavares

    2007-02-28

    Leishmania chagasi is the causative agent of visceral leishmaniasis in both humans and dogs in the New World. The dog is the main domestic reservoir and its infection displays different clinical presentations, from asymptomatic to severe disease. Macrophages play an important role in the control of Leishmania infection. Although it is not an area of intense study, some data suggest a role for canine macrophages in parasite killing by a NO-dependent mechanism. It has been proposed that control of human disease could be possible with the development of an effective vaccine against canine visceral leishmaniasis. Development of a rapid in vitro test to predict animal responses to Leishmania infection or vaccination should be helpful. In this study, an in vitro model was established to test whether peripheral blood mononuclear cell (PBMC) supernatants from dogs immunized with promastigote lysates and infected with L. chagasi promastigotes could stimulate macrophages from healthy dogs in order to control parasite infection. PBMC from a majority of the immunized and experimentally infected dogs expressed IFN-gamma mRNA and secreted IFN-gamma when stimulated with soluble L. chagasi antigen (SLA) in vitro. Additionally, the supernatants from stimulated PBMC were able to reduce the percentage of infected donor macrophages. The results also indicate that parasite killing in this system is dependent on NO, since aminoguanidine (AMG) reversed this effect. This in vitro test appears to be useful for screening animal responses to parasite inoculation as well as studying the lymphocyte effector mechanisms involved in pathogen killing by canine macrophages.

  12. Selective Loss of Dentate Hilar Interneurons Contributes to Reduced Synaptic Inhibition of Granule Cells in an Electrical Stimulation-Based Animal Model of Temporal Lobe Epilepsy

    PubMed Central

    SUN, CHENGSAN; MTCHEDLISHVILI, ZAKARIA; BERTRAM, EDWARD H.; ERISIR, ALEV; KAPUR, JAIDEEP

    2010-01-01

    Neuropeptide-containing hippocampal interneurons and dentate granule cell inhibition were investigated at different periods following electrical stimulation-induced, self-sustaining status epilepticus (SE) in rats. Immunohistochemistry for somatostatin (SOM), neuropeptide Y (NPY), parvalbumin (PV), cholecystokinin (CCK), and Fluoro-Jade B was performed on sections from hippocampus contralateral to the stimulated side and studied by confocal laser scanning microscopy. Compared to paired age-matched control animals, there were fewer SOM and NPY-immunoreactive (IR) interneurons in the hilus of the dentate gyrus in animals with epilepsy (40 – 60 days after SE), and 1, 3, and 7 days following SE. In the hilus of animals that had recently undergone SE, some SOM-IR and NPY-IR interneurons also stained for Fluoro-Jade B. Furthermore, there was electron microscopic evidence of the degeneration of SOM-IR interneurons following SE. In contrast, the number of CCK and PV-IR basket cells in epileptic animals was similar to that in controls, although it was transiently diminished following SE; there was no evidence of degeneration of CCK or PV-IR interneurons. Patch-clamp recordings revealed a diminished frequency of inhibitory postsynaptic currents in dentate granule cells (DGCs) recorded from epileptic animals and animals that had recently undergone SE compared with controls. These results confirm the selective vulnerability of a particular subset of dentate hilar interneurons after prolonged SE. This loss may contribute to the reduced GABAergic synaptic inhibition of granule cells in epileptic animals. PMID:17177260

  13. Chronic in vitro shear stress stimulates endothelial cell retention on prosthetic vascular grafts and reduces subsequent in vivo neointimal thickness.

    PubMed

    Dardik, A; Liu, A; Ballermann, B J

    1999-01-01

    . Confluent intimal endothelial cell monolayers also were present 1 week and 3 months after implantation. However, 1 week after implantation, macrophage infiltration was observed beneath the luminal cell monolayer. Three months after the implantation in vivo, subendothelial neointimal cells that contained alpha-smooth muscle actin were present. The thickness of this neointima averaged 41 +/- 12 micrometer and 60 +/- 23 micrometer in endothelial cell-seeded grafts that were pretreated with 25 dyne/cm2 shear stress and 1 dyne/cm2 shear stress, respectively, and 158 +/- 46 micrometer in grafts that were not seeded with endothelial cells. The effect of chronic shear stress on the enhancement of endothelial cell retention in vitro can be exploited to fully endothelialize synthetic vascular grafts, which reduces immediate in vivo graft thrombosis and subsequent neointimal thickness.

  14. Assisting children with Attention Deficit Hyperactivity Disorder actively reduces limb hyperactive behavior with a Nintendo Wii Remote Controller through controlling environmental stimulation.

    PubMed

    Shih, Ching-Hsiang; Yeh, Jui-Chi; Shih, Ching-Tien; Chang, Man-Ling

    2011-01-01

    The latest studies have adopted software technology which turns the Wii Remote Controller into a high-performance limb action detector, we assessed whether two persons with multiple disabilities would be able to control an environmental stimulus through limb action. This study extends the functionality of the Wii Remote Controller to the correction of limb hyperactive behavior to assess whether two children with Attention Deficit Hyperactivity Disorder (ADHD) would be able to actively reduce their limb hyperactive behavior through controlling their favorite stimuli by turning them on/off using a Wii Remote Controller. An ABAB design, in which A represented the baseline and B represented intervention phases, was adopted in this study. Result showed that both participants significantly increased their time duration of maintaining a static limb posture (TDMSLP) to activate the control system in order to produce environmental stimulation in the intervention phases. Practical and developmental implications of the findings are discussed.

  15. Granulocyte-Colony Stimulating Factor Increases Cerebral Blood Flow via a NO Surge Mediated by Akt/eNOS Pathway to Reduce Ischemic Injury

    PubMed Central

    Liew, Hock-Kean; Kuo, Jon-Son; Wang, Jia-Yi; Pang, Cheng-Yoong

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) protects brain from ischemic/reperfusion (I/R) injury, and inhibition of nitric oxide (NO) synthases partially reduces G-CSF protection. We thus further investigated the effects of G-CSF on ischemia-induced NO production and its consequence on regional cerebral blood flow (rCBF) and neurological deficit. Endothelin-1 (ET-1) microinfused above middle cerebral artery caused a rapid reduction of rCBF (ischemia) which lasted for 30 minutes and was followed by a gradual recovery of blood flow (reperfusion) within the striatal region. Regional NO concentration increased rapidly (NO surge) during ischemia and recovered soon to the baseline. G-CSF increased rCBF resulting in shorter ischemic duration and an earlier onset of reperfusion. The enhancement of the ischemia-induced NO by G-CSF accompanied by elevation of phospho-Akt and phospho-eNOS was noted, suggesting an activation of Akt/eNOS. I/R-induced infarct volume and neurological deficits were also reduced by G-CSF treatment. Inhibition of NO synthesis by L-NG-Nitroarginine Methyl Ester (L-NAME) significantly reduced the effects of G-CSF on rCBF, NO surge, infarct volume, and neurological deficits. We conclude that G-CSF increases rCBF through a NO surge mediated by Akt/eNOS, which partially contributes to the beneficial effect of G-CSF on brain I/R injury. PMID:26146654

  16. Granulocyte-Colony Stimulating Factor Increases Cerebral Blood Flow via a NO Surge Mediated by Akt/eNOS Pathway to Reduce Ischemic Injury.

    PubMed

    Liew, Hock-Kean; Kuo, Jon-Son; Wang, Jia-Yi; Pang, Cheng-Yoong

    2015-01-01

    Granulocyte-colony stimulating factor (G-CSF) protects brain from ischemic/reperfusion (I/R) injury, and inhibition of nitric oxide (NO) synthases partially reduces G-CSF protection. We thus further investigated the effects of G-CSF on ischemia-induced NO production and its consequence on regional cerebral blood flow (rCBF) and neurological deficit. Endothelin-1 (ET-1) microinfused above middle cerebral artery caused a rapid reduction of rCBF (ischemia) which lasted for 30 minutes and was followed by a gradual recovery of blood flow (reperfusion) within the striatal region. Regional NO concentration increased rapidly (NO surge) during ischemia and recovered soon to the baseline. G-CSF increased rCBF resulting in shorter ischemic duration and an earlier onset of reperfusion. The enhancement of the ischemia-induced NO by G-CSF accompanied by elevation of phospho-Akt and phospho-eNOS was noted, suggesting an activation of Akt/eNOS. I/R-induced infarct volume and neurological deficits were also reduced by G-CSF treatment. Inhibition of NO synthesis by L-N(G)-Nitroarginine Methyl Ester (L-NAME) significantly reduced the effects of G-CSF on rCBF, NO surge, infarct volume, and neurological deficits. We conclude that G-CSF increases rCBF through a NO surge mediated by Akt/eNOS, which partially contributes to the beneficial effect of G-CSF on brain I/R injury.

  17. Add-on high frequency deep transcranial magnetic stimulation (dTMS) to bilateral prefrontal cortex reduces cocaine craving in patients with cocaine use disorder.

    PubMed

    Rapinesi, Chiara; Del Casale, Antonio; Di Pietro, Simone; Ferri, Vittoria Rachele; Piacentino, Daria; Sani, Gabriele; Raccah, Ruggero Nessim; Zangen, Abraham; Ferracuti, Stefano; Vento, Alessandro Emiliano; Angeletti, Gloria; Brugnoli, Roberto; D Kotzalidis, Georgios; Girardi, Paolo

    2016-08-26

    Cocaine dependence is a substantial public health problem. The aim of this study is to evaluate the effect of high frequency deep transcranial magnetic stimulation (dTMS) on craving in patients with cocaine use disorder (CUD). Seven men (mean age, 48.71 years; standard deviation [SD], 9.45; range 32-60 years) with CUD and no concurrent axis 1 or 2 disorder save nicotine abuse, underwent three sessions of alternate day 20Hz dTMS in 20 trains delivered to the dorsolateral prefrontal cortex (DLPFC) preferentially to the left hemisphere, for 12 sessions spread over one month, added to unchanged prior drug treatment. We used a visual analogue scale (VAS) to measure cocaine craving the week before, each week during, and one month after dTMS treatment. DLPFC stimulation significantly reduced craving over time: within-subjects main effect of time of treatment (ANOVA, F[3,18]=46.154; p<0.001; η(2)=0.88). The reduction of craving from baseline was significant at two weeks (p<0.001), and four weeks (p<0.001) of treatment, and at the week eight, four weeks after treatment interruption (p=0.003), although the increase of craving was significant from week four and eight (p=0.014). dTMS over left DLPFC reduced craving in CUD patients in a small sample that is to be considered preliminary. However, maintenance sessions would be needed to maintain the achieved results. Our findings highlight the potential of noninvasive neuromodulation as a therapeutic tool for cocaine addiction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Inhibition of small HA fragment activity and stimulation of A2A adenosine receptor pathway limit apoptosis and reduce cartilage damage in experimental arthritis.

    PubMed

    Campo, Giuseppe M; Micali, Antonio; Avenoso, Angela; D'Ascola, Angela; Scuruchi, Michele; Pisani, Antonina; Bruschetta, Antongiulio; Calatroni, Alberto; Puzzolo, Domenico; Campo, Salvatore

    2015-05-01

    Recent studies have found that the inactivation of small hyaluronan (HA) fragments originating from native HA during inflammation reduced the inflammatory response in models of experimental arthritis. The stimulation of adenosine receptors A2A reduced inflammation by inhibiting NF-kB activation. The combination of both treatments was significantly more effective than either of the individual treatments. The aim of this study was to further investigate the effects of a combined treatment using the HA inhibitor Pep-1 and a selective A2AR agonist (CV-1808) on the structure and ultrastructure of the articular cartilage and on apoptosis in a model of collagen-induced arthritis (CIA) in mice. Arthritic mice were treated with Pep-1 and/or CV-1808 intraperitoneally daily for 20 days. At day 35, the hind limbs were processed for light microscopy (hematoxylin/eosin and Safranin-O-Fast Green) and for transmission and scanning electron microscopy. CIA increased IL-6, caspase-3 and caspase-7 mRNA expression and the related protein levels in arthritic articular cartilage, and significantly increased concentrations of Bcl-2-associated X protein (Bax), while B cell-lymphoma-2 protein (Bcl-2) was markedly reduced. The combined Pep-1/CV-1808 treatment significantly reduced CIA injury, particularly at the highest doses, demonstrated by the presence of Safranin-O-positive cartilage, with a smooth surface and normal chondrocytes in the superficial, intermediate and deep zones. Morphological data and histological scoring were strongly supported by the reduction in inflammation and apoptotic markers. The results further support the role of HA degradation and A2A receptors in arthritis.

  19. Striatal 5-HT1A receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat

    PubMed Central

    Dupre, Kristin B.; Eskow, Karen L.; Barnum, Christopher J.; Bishop, Christopher

    2008-01-01

    Summary Convergent evidence suggests that serotonin 5-HT1A receptor (5-HT1AR) agonists reduce L-DOPA-induced dyskinesia by auto-regulating aberrant release of L-DOPA-derived dopamine (DA) from raphestriatal neurons. However, recent findings indicate that 5-HT1AR stimulation also modifies D1 receptor (D1R)-mediated dyskinesia and rotations implicating a previously unexplored extra-raphe mechanism. In order to characterize the contribution of the striatum to these effects, rats with medial forebrain bundle DA lesions were tested for abnormal involuntary movements (AIMs) and rotations following striatal microinfusions of the 5-HT1AR agonist ±8-OH-DPAT and systemic D1R agonist treatment with SKF81297. Additional rats with multi-site striatal DA lesions were tested for motor disability following systemic or intrastriatal ±8-OH-DPAT with or without systemic SKF81297. In rats with medial forebrain bundle lesions, striatal infusions of ±8-OH-DPAT dose-dependently reduced AIMs while conversely increasing rotations. In rats with striatal lesions, ±8-OH-DPAT alone, both systemic and intrastriatal administration, optimally reversed motor disability. Collectively, these results support an important functional interaction between 5-HT1AR and D1R in the striatum with implications for the improved treatment of Parkinson’s disease. PMID:18824001

  20. TNF-α reduces g0s2 expression and stimulates lipolysis through PPAR-γ inhibition in 3T3-L1 adipocytes.

    PubMed

    Jin, Dan; Sun, Jun; Huang, Jing; He, Yiduo; Yu, An; Yu, Xiaoling; Yang, Zaiqing

    2014-10-01

    Tumor necrosis factor-α (TNF-α) is a multifunctional cytokine that acts as a mediator of obesity-linked insulin resistance (IR). It is commonly accepted that macrophage-derived TNF-α acts in a paracrine manner on adjacent adipocytes, induces lipolysis, which contributes to obesity-linked hyperglycemia. Several studies suggested that G0/G1 switch gene 2 (g0s2) was up-regulated during adipogenesis, and its protein could be degraded in response to TNF-α stimulation. The aim of the present work was to investigate the transcriptional regulation of g0s2 by TNF-α stimulation. In this study, 3T3-L1 pre-adipocytes were differentiated, and treated with TNF-α for 24h. The effects of TNF-α on lipolysis and lipase expression were then examined. Our results revealed that TNF-α exerted dose- and time-dependent lipolytic effects, which could be partially reversed by overexpression of g0s2 and peroxisome proliferator-activated receptor-γ (ppar-γ). In addition, TNF-α treatment significantly reduced the expression of adiponectin, ppar-γ, hormone-sensitive Lipase (hsl), adipose triglyceride lipase (atgl) as well as ATGL co-factors. Interestingly, TNF-α significantly decreased adiponectin and PPAR-γ protein levels, while treatment with the proteasomal inhibitor MG-132 maintained PPAR-γ levels. Degradation of PPAR-γ almost completely abolished the binding of PPAR-γ to the g0s2 promoter in adipocytes treated with TNF-α. We propose that proteasomal degradation of PPAR-γ and the reduction of g0s2 content are permissive for prolonged TNF-α induced lipolysis. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Improving the antibacterial property of porcine small intestinal submucosa by nano-silver supplementation: a promising biological material to address the need for contaminated defect repair.

    PubMed

    Zhou, Hai Yang; Zhang, Jian; Yan, Rong Lin; Wang, Qiang; Fan, Lie Ying; Zhang, Qi; Wang, Wei Jun; Hu, Zhi Qian

    2011-05-01

    We hypothesize that introduction of nano-silver particles to porcine-derived small intestinal submucosa (NS-PSIS) would lead to significant enhancement in antibacterial property in repairing contaminated abdominal defect. Porcine-derived small intestinal submucosa (PSIS) is an acellular and xenogenic biological material intensively used in repairing and regenerating wounded and dysfunctional tissues. Surgical site infection (SSI) remains so far a serious problem and major challenge, particularly in contaminated tissue-deficient repairing. Self-assembly was used to fabricate NS-PSIS. The antibacterial property was evaluated in vitro and in vivo by means of repairing full-thickness contaminated abdominal defect in rats. The native PSIS and polypropylene-oxidized regenerated cellulose were served as controls. In addition, changes in biomechanical resistance, morphology and immunohistochemistry for inflammatory reaction and neovasculation in the repaired abdominal wall were analyzed. Biosafety was investigated by pyrogen test, skin irritation test and silver measurement in vivo. NS-PSIS exhibited strong antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa on agar diffusion, with mean diameters of inhibition zone ranging from 11.9 to 23.5 mm. There were significantly lower SSI incidence and a tendency of better abdominal wall resistance in the NS-PSIS group as compared with the PSIS or polypropylene-oxidized regenerated cellulose group after repairing contaminated abdominal defect in rats. Nano-silver modified PSIS did not change the native PSIS property in the tissue recolonization, remodeling and neovascularization. NS-PSIS was not pyrogenic or skin irritated, without silver residual in vivo after repairing contaminated abdominal defect. Nano-silver particles to PSIS lead to significant enhancements in antibacterial property in vitro and in vivo without decreasing its biomechanical resistance

  2. Intermittent Left Cervical Vagal Nerve Stimulation Damages the Stellate Ganglia and Reduces Ventricular Rate During Sustained Atrial Fibrillation in Ambulatory Dogs

    PubMed Central

    Chinda, Kroekkiat; Tsai, Wei-Chung; Chan, Yi-Hsin; Lin, Andrew Y.-T.; Patel, Jheel; Zhao, Ye; Tan, Alex Y; Shen, Mark J; Lin, Hongbo; Shen, Changyu; Chattipakorn, Nipon; Rubart-von der Lohe, Michael; Chen, Lan S.; Fishbein, Michael C.; Lin, Shien-Fong; Chen, Zhenhui; Chen, Peng-Sheng

    2015-01-01

    Background The effects of intermittent open loop vagal nerve stimulation (VNS) on ventricular rate (VR) during atrial fibrillation (AF) remain unclear. Objective To test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF. Methods We performed left cervical VNS in ambulatory dogs while simultaneously recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in SG. Results We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 s) and long OFF-time (66 s). The integrated SGNA (iSGNA) and VR during AF were 4.84 mV-s [95% confidence interval, CI, 3.08 to 6.60] and 142 bpm [CI, 116 to 168], respectively. VNS reduced iSGNA and VR, respectively, during AF to 3.74 mV-s [CI, 2.27 to 5.20; p=0.021] and 115 bpm [CI, 96 to 134; p=0.016] during 66-s OFF-time, and to 4.07 mV-s [CI, 2.42 to 5.72; p=0.037] and 114 bpm [CI, 83 to 146; p=0.039] during 3-min OFF-time. VNS increased the frequencies of prolonged (>3 s) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG. Conclusions VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF. PMID:26607063

  3. Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury

    PubMed Central

    Acosta, Sandra A.; Tajiri, Naoki; Shinozuka, Kazutaka; Ishikawa, Hiroto; Sanberg, Paul R.; Sanchez-Ramos, Juan; Song, Shijie; Kaneko, Yuji; Borlongan, Cesar V.

    2014-01-01

    Traumatic brain injury (TBI) is associated with neuro-inflammation, debilitating sensory-motor deficits, and learning and memory impairments. Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI. Here, we tested the potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model. Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function

  4. Electrical Stimulation at the ST36 Acupoint Protects against Sepsis Lethality and Reduces Serum TNF Levels through Vagus Nerve- and Catecholamine-Dependent Mechanisms

    PubMed Central

    Villegas-Bastida, Albino; Torres-Rosas, Rafael; Arriaga-Pizano, Lourdes Andrea; Flores-Estrada, Javier; Gustavo-Acosta, Altamirano; Moreno-Eutimio, Mario Adan

    2014-01-01

    Electrical vagus nerve (VN) stimulation during sepsis attenuates tumor necrosis factor (TNF) production through the cholinergic anti-inflammatory pathway, which depends on the integrity of the VN and catecholamine production. To characterize the effect of electroacupuncture at ST36 (EA-ST36) on serum TNF, IL-6, nitrite, and HMGB1 levels and survival rates, based on VN integrity and catecholamine production, a sepsis model was induced in rats using cecal ligation and puncture (CLP). The septic rats were subsequently treated with EA-ST36 (CLP+ST36), and serum samples were collected and analyzed for cytokines levels. The serum TNF, IL-6, nitrite, and HMGB1 levels in the CLP+ST36 group were significantly lower compared with the group without treatment, the survival rates were significantly higher (P < 0.05), and the acute organ injury induced by CLP was mitigated by EA-ST36; however, when subdiaphragmatic vagotomy was performed, the serum levels of TNF in the CLP+ST36 group did not show a significant difference compared with the group without electrostimulation, and, similarly, no significant difference in serum TNF levels was found under the pharmacological blockade of catecholamines. These results suggest that in rats with CLP sepsis models EA-ST36 reduces serum TNF levels through VN- and atecholamine-dependent mechanisms. PMID:25057275

  5. Ultratrace Naked-Eye Colorimetric Detection of Hg(2+) in Wastewater and Serum Utilizing Mercury-Stimulated Peroxidase Mimetic Activity of Reduced Graphene Oxide-PEI-Pd Nanohybrids.

    PubMed

    Zhang, Shouting; Zhang, Dongxu; Zhang, Xuehong; Shang, Denghui; Xue, Zhonghua; Shan, Duoliang; Lu, Xiaoquan

    2017-03-21

    Herein, we developed a general strategy for rapid, highly selective, and ultratrace naked-eye colorimetric detection of Hg(2+) in aqueous solutions. Two dimensional rGO/PEI/Pd nanohybrids, where rGO, PEI, and Pd were referred to as reduced graphene oxide, polyethylenimine, and Pd nanoparticles, respectively, were synthesized and used as mimetic peroxidase for selective and ultrasensitive detection of Hg(2+) in water and human serum samples. In the presence of mercury ions, the peroxidase mimetic activity of rGO/PEI/Pd nanohybrids was found to be stimulated and enhanced significantly, which promoted the effective oxidation and color change of 3,3',5,5'-tetramethylbenzidine (TMB) in solution to dark blue that was detected by the naked-eye and the absorption spectroscopic method. The proposed sensing strategy coupled with spectroscopic detection method showed an ultralow detection limit of 0.39 nM for Hg(2+) in ddH2O and ∼1 nM in wastewater as well as serum samples, respectively. On the basis of the colorimetric assay, a minimum concentration of ∼10 nM for Hg(2+) in wastewater and human serum can be detected with the naked-eye. The naked-eye-based colorimetric assay for sensitive and selective detection of mercury is expected to hold huge potentials in applications such as environmental monitoring, clinical diagnosis, and pharmaceutical analysis.

  6. The clinical utility of repetitive transcranial magnetic stimulation in reducing the risks of transitioning from acute to chronic pain in traumatically injured patients.

    PubMed

    Jodoin, Marianne; Rouleau, Dominique; Larson-Dupuis, Camille; Gosselin, Nadia; De Beaumont, Louis

    2017-07-08

    Pain is a multifaceted condition and a major ongoing challenge for healthcare professionals having to treat patients in whom pain put them at risk of developing other conditions. Significant efforts have been invested in both clinical and research settings in an attempt to demystify the mechanisms at stake and develop optimal treatments as well as to reduce individual and societal costs. It is now universally accepted that neuroinflammation and central sensitization are two key underlying factors causing pain chronification as they result from maladaptive central nervous system plasticity. Recent research has shown that the mechanisms of action of repetitive transcranial magnetic stimulation (rTMS) make it a particularly promising avenue in treating various pain conditions. This review will first discuss the contribution of neuroinflammation and central sensitization in the transition from acute to chronic pain in traumatically injured patients. A detailed discussion on how rTMS may allow the restoration from maladaptive plasticity in addition to breaking down the chain of events leading to pain chronification will follow. Lastly, this review will provide a theoretical framework of what might constitute optimal rTMS modalities in dealing with pain symptoms in traumatically injured patients based on an integrated perspective of the physiopathological mechanisms underlying pain. Copyright © 2017. Published by Elsevier Inc.

  7. Brief training of psychoneuroendocrinoimmunology-based meditation (PNEIMED) reduces stress symptom ratings and improves control on salivary cortisol secretion under basal and stimulated conditions.

    PubMed

    Bottaccioli, Francesco; Carosella, Antonia; Cardone, Raffaella; Mambelli, Monica; Cemin, Marisa; D'Errico, Marcello M; Ponzio, Elisa; Bottaccioli, Anna Giulia; Minelli, Andrea

    2014-01-01

    Meditation is proposed as an anti-stress practice lowering allostatic load and promoting well-being, with brief formats providing some of the benefits of longer interventions. PsychoNeuroEndocrinoImmunology-based meditation (PNEIMED) combines the teaching of philosophy and practice of Buddhist meditation with a grounding in human physiology from a systemic and integrative perspective. We evaluated the effects of four-day PNEIMED training (30 h) on subjective and objective indices of stress in healthy adults. A non-randomized, controlled, before-and-after study was conducted. Participants (n = 125, mostly health practitioners) answered a questionnaire rating stress symptom before (T0) and after (Tf) a PNEIMED course. In an additional sample (n = 40; smokers, overweight persons, women taking contraceptives, and subjects with oral pathologies were excluded), divided into PNEIMED-attending (intervention, n = 21) and non-meditating (control, n = 19) groups, salivary cortisol was measured upon awakening and during a challenging mental task. Self-rated distress scores were highly reduced after the PNEIMED course. In the intervention group, improvement of psychological well-being was accompanied by decrease in cortisol levels at awakening. No T0-vs-Tf changes in distress scores and morning cortisol were found in controls. Based on baseline-to-peak increment of cortisol response at T0, 26 subjects (n = 13 for each group) were classified as task-responders. The amplitude and duration of the cortisol response decreased after PNEIMED, whereas no effects were found in controls. Brief PNEIMED training yields immediate benefits, reducing distress symptoms and adrenocortical activity under basal and stimulated conditions. PNEIMED may represent an effective practice to manage stress and anxiety, particularly among subjects facing a multitude of job-related stressors, such as healthcare workers. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Anterior thalamic nuclei deep brain stimulation reduces disruption of the blood-brain barrier, albumin extravasation, inflammation and apoptosis in kainic acid-induced epileptic rats.

    PubMed

    Chen, Ying-Chuan; Zhu, Guan-Yu; Wang, Xiu; Shi, Lin; Du, Ting-Ting; Liu, De-Feng; Liu, Yu-Ye; Jiang, Yin; Zhang, Xin; Zhang, Jian-Guo

    2017-09-18

    Objective The therapeutic efficacy of anterior thalamic nuclei deep brain stimulation (ATN-DBS) against seizures has been largely accepted; however, the effects of ATN-DBS on disruption of the blood-brain barrier (BBB), albumin extravasation, inflammation and apoptosis still remain unclear. Methods Rats were distributed into four treatment groups: physiological saline (PS, N = 12), kainic acid (KA, N = 12), KA-sham-DBS (N = 12) and KA-DBS (N = 12). Seizures were monitored using video-electroencephalogram (EEG). One day after surgery, all rats were sacrificed. Then, samples were prepared for quantitative real-time PCR (qPCR), western blot, immunofluorescence (IF) staining, and transmission electron microscopy to evaluate the disruption of the BBB, albumin extravasation, inflammation, and apoptosis. Result Because of the KA injection, the disruption of the BBB, albumin extravasation, inflammation and apoptosis were more severe in the KA and the KA-sham-DBS groups compared to the PS group (all Ps < 0.05 or < 0.01). The ideal outcomes were observed in the KA-DBS group. ATN-DBS produced a 46.3% reduction in seizure frequency and alleviated the disruption of the BBB, albumin extravasation, inflammatory reaction and apoptosis in comparison to the KA-sham-DBS group (all Ps < 0.05 or < 0.01). Conclusion (1) Seizures can be reduced using ATN-DBS in the epileptogenic stage. (2) ATN-DBS can reduce the disruption of the BBB and albumin extravasation. (3) ATN-DBS has an anti-inflammatory effect in epileptic models.

  9. Ginsenosides Have a Suppressive Effect on c-Fos Expression in Brain and Reduce Cardiovascular Responses Increased by Noxious Stimulation to the Rat Tooth

    PubMed Central

    Jung, Ji-Yeon; Seong, Kyung-Joo; Moon, In-Ohk; Cho, Jin-Hyoung; Kim, Sun-Hun

    2013-01-01

    The purpose of this study is to investigate the antinociceptive effects of ginsenosides on toothache. c-Fos immunoreactive (IR) neurons were examined after noxious intrapulpal stimulation (NS) by intrapulpal injection of 2 M KCl into upper and lower incisor pulps exposed by bone cutter in Sprague Dawley rats. The number of Fos-IR neurons was increased in the trigeminal subnucleus caudalis (Vc) and the transitional region between Vc and subnucleus interpolaris (Vi) by NS to tooth. The intradental NS raised arterial blood pressure (BP) and heart rate (HR). The number of Fos-IR neurons was also enhanced in thalamic ventral posteromedial nucleus (VPMN) and centrolateral nucleus (CLN) by NS to tooth. The intradental NS increased the number of Fos-IR neurons in the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM), hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN), central cardiovascular regulation centers. Ginsenosides reduced the number of c-Fos-IR increased by NS to tooth in the trigeminal Vc and thalamic VPMN and CLN. Naloxone, an opioid antagonist, did not block the effect of ginsenoside on the number of Fos-IR neurons enhanced by NS to tooth in the trigeminal Vc and thalamic VPMN and CLN. Ginsenosides ameliorated arterial BP and HR raised by NS to tooth and reduced the number of Fos-IR neurons increased by NS to tooth in the NTS, RVLM, hypothalamic SON, and PVN. These results suggest that ginsenosides have an antinociceptive effect on toothache through non-opioid system and attenuates BP and HR increased by NS to tooth. PMID:23626473

  10. Prostacyclin inhibits IFN-γ-stimulated cytokine expression by reduced recruitment of p300/CBP to STAT1 in a SOCS-1 independent manner

    PubMed Central

    Strassheim, Derek; Riddle, Suzzette R.; Burke, Danielle L.; Geraci, Mark W; Stenmark, Kurt R.

    2009-01-01

    Increasing evidence indicates that Pulmonary Arterial Hypertension (PAH) is a vascular inflammatory disease. Prostacyclin (PGI2) is widely used to treat PAH and is believed to benefit patients largely through vasodilatory effects. PGI2 is also increasingly believed to have anti-inflammatory effects; including decreasing leukocyte cytokine production, yet few mechanistic details exist to explain how these effects are mediated at the transcriptional level. Since activated monocytes are critical sources of MCP-1 and other cytokines in cardiovascular inflammation, we examined the effects of iloprost on IFN-γ and IL-6 stimulated cytokine production in human monocytes. We found iloprost inhibited IFN-γ and IL-6-induced MCP-1, IL-8, RANTES, and TNF-α production in monocytes indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN-γ-induced MCP-1 production and demonstrated that iloprost inhibited STAT1 activation by several actions: 1) iloprost inhibited the phosphorylation of STAT1-S727 in the transactivation domain (TAD), thereby reducing recruitment of the histone acetylase and co-activator CBP/p300 to STAT1; 2) iloprost selectively inhibited activation of janus kinase 2 (JAK2), but not JAK1, both responsible for activation STAT1 via phosphorylation of STAT1-Y701, resulting in reduced nuclear recruitment and activation of STAT1; 3) SOCS-1, which normally terminates IFN-γ-signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN-γ-signaling. We conclude that PGI2 exerts anti-inflammatory action by inhibiting STAT1 induced cytokine production, in part by targeting the transactivation domain induced recruitment of the histone acetylase CBP/p300. PMID:19915063

  11. Reduced ethanol consumption by alcohol-preferring (P) rats following pharmacological silencing and deep brain stimulation of the nucleus accumbens shell.

    PubMed

    Wilden, Jessica A; Qing, Kurt Y; Hauser, Sheketha R; McBride, William J; Irazoqui, Pedro P; Rodd, Zachary A

    2014-04-01

    There is increasing interest in deep brain stimulation (DBS) for the treatment of addiction. Initial testing must be conducted in animals, and the alcohol-preferring (P) rat meets the criteria for an animal model of alcoholism. This study is composed of 2 experiments designed to examine the effects of 1) pharmacological inactivation and 2) DBS of the nucleus accumbens shell (AcbSh) on the consumption of alcohol by P rats. In the first experiment, the effects of reversible inactivation of the AcbSh were investigated by administering intracranial injections of γ-aminobutyric acid (GABA) agonists. Bilateral microinjections of drug were administered to the AcbSh in P rats (8-10 rats/group), after which the animals were placed in operant chambers containing 2 levers--one used to administer water and the other to administer 15% EtOH--to examine the acquisition and maintenance of oral EtOH self-administration. In the second experiment, a DBS electrode was placed in each P rat's left AcbSh. The animals then received 100 or 200 μA (3-4 rats/group) of DBS to examine the effect on daily consumption of oral EtOH in a free-access paradigm. In the first experiment, pharmacological silencing of the AcbSh with GABA agonists did not decrease the acquisition of EtOH drinking behavior but did reduce EtOH consumption by 55% in chronically drinking rats. Similarly, in the second experiment, 200 μA of DBS consistently reduced EtOH intake by 47% in chronically drinking rats. The amount of EtOH consumption returned to baseline levels following termination of therapy in both experiments. Pharmacological silencing and DBS of the AcbSh reduced EtOH intake after chronic EtOH use had been established in rodents. The AcbSh is a neuroanatomical substrate for the reinforcing effects of alcohol and may be a target for surgical intervention in cases of alcoholism.

  12. Intermittent left cervical vagal nerve stimulation damages the stellate ganglia and reduces the ventricular rate during sustained atrial fibrillation in ambulatory dogs.

    PubMed

    Chinda, Kroekkiat; Tsai, Wei-Chung; Chan, Yi-Hsin; Lin, Andrew Y-T; Patel, Jheel; Zhao, Ye; Tan, Alex Y; Shen, Mark J; Lin, Hongbo; Shen, Changyu; Chattipakorn, Nipon; Rubart-von der Lohe, Michael; Chen, Lan S; Fishbein, Michael C; Lin, Shien-Fong; Chen, Zhenhui; Chen, Peng-Sheng

    2016-03-01

    The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear. The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF. We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in the SG. We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 seconds) and long OFF-time (66 seconds). The integrated SGNA and VR during AF were 4.84 mV·s (95% confidence interval [CI] 3.08-6.60 mV·s) and 142 beats/min (95% CI 116-168 beats/min), respectively. During AF, VNS reduced the integrated SGNA and VR, respectively, to 3.74 mV·s (95% CI 2.27-5.20 mV·s; P = .021) and 115 beats/min (95% CI 96-134 beats/min; P = .016) during 66-second OFF-time and to 4.07 mV·s (95% CI 2.42-5.72 mV·s; P = .037) and 114 beats/min (95% CI 83-146 beats/min; P = .039) during 3-minute OFF-time. VNS increased the frequencies of prolonged (>3 seconds) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells, and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG. VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  13. Efficacy of polyethylene glycol-conjugated bovine granulocyte colony-stimulating factor for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cows and heifers.

    PubMed

    Hassfurther, Renee L; TerHune, Terry N; Canning, Peter C

    2015-03-01

    To evaluate effects of various doses of polyethylene glycol (PEG)-conjugated bovine granulocyte colony-stimulating factor (bG-CSF) on the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. 211 periparturient Holstein cows and heifers. Approximately 7 days before the anticipated date of parturition (day of parturition = day 0), healthy cattle received SC injections of sterile saline (0.9% NaCl) solution (control treatment) or PEG-bG-CSF at 5, 10, or 20 μg/kg. Cattle were commingled and housed in a pen with dirt flooring, which was kept wet to maximize the incidence of naturally occurring clinical mastitis. Within 24 hours after parturition, each animal again received the assigned treatment. Mammary glands and milk were visually scored for abnormalities twice daily for 28 days after parturition. Milk samples were aseptically collected from mammary glands with an abnormal appearance or abnormal milk and submitted for microbial culture. Daily milk production was recorded, and milk composition was assessed on days 3, 5, 7, and 10. Cattle treated with PEG-bG-CSF at 10 and 20 μg/kg had significantly fewer cases of clinical mastitis (9/54 and 5/53, respectively), compared with control cattle (18/53). Administration of PEG -bG-CSF did not significantly affect daily milk production or milk composition. Results suggested that PEG-bG-CSF was effective for reducing the incidence of naturally occurring clinical mastitis in periparturient dairy cattle. Further investigations of the use of PEG-bG-CSF as a potential preventative intervention should be conducted.

  14. Surface-Displayed IL-10 by Recombinant Lactobacillus plantarum Reduces Th1 Responses of RAW264.7 Cells Stimulated with Poly(I:C) or LPS.

    PubMed

    Cai, Ruopeng; Jiang, Yanlong; Yang, Wei; Yang, Wentao; Shi, Shaohua; Shi, Chunwei; Hu, Jingtao; Gu, Wei; Ye, Liping; Zhou, Fangyu; Gong, Qinglong; Han, Wenyu; Yang, Guilian; Wang, Chunfeng

    2016-02-01

    Recently, poly-γ-glutamic acid synthetase A (pgsA) has been applied to display exogenous proteins on the surface of Lactobacillus casei or Lactococcus lactis, which results in a surfacedisplayed component of bacteria. However, the ability of carrying genes encoded by plasmids and the expression efficiency of recombinant bacteria can be somewhat affected by the longer gene length of pgsA (1,143 bp); therefore, a truncated gene, pgsA, was generated based on the characteristics of pgsA by computational analysis. Using murine IL-10 as an exogenous gene, recombinant Lactobacillus plantarum was constructed and the capacity of the surface-displayed protein and functional differences between exogenous proteins expressed by these strains were evaluated. Surface expression of IL-10 on both recombinant bacteria with anchorins and the higher expression levels in L. plantarum-pgsA'-IL-10 were confirmed by western blot assay. Most importantly, up-regulation of IL-1β, IL-6, TNF-α, IFN-γ, and the nuclear transcription factor NF-κB p65 in RAW264.7 cells after stimulation with Poly(I:C) or LPS was exacerbated after co-culture with L. plantarum-pgsA. By contrast, IL-10 expressed by these recombinant strains could reduce these factors, and the expression of these factors was associated with recombinant strains that expressed anchorin (especially in L. plantarum-pgsA'-IL-10) and was significantly lower compared with the anchorin-free strains. These findings indicated that exogenous proteins could be successfully displayed on the surface of L. plantarum by pgsA or pgsA', and the expression of recombinant bacteria with pgsA' was superior compared with bacteria with pgsA.

  15. Chronic vagus nerve stimulation attenuates vascular endothelial impairments and reduces the inflammatory profile via inhibition of the NF-κB signaling pathway in ovariectomized rats.

    PubMed

    Li, Ping; Liu, Huaipu; Sun, Peng; Wang, Xiaoyu; Wang, Chen; Wang, Ling; Wang, Tinghuai

    2016-02-01

    Vagus nerve stimulation (VNS), a method for activating cholinergic anti-inflammatory pathways, could suppress endothelial activation and minimize tissue injury during inflammation. The aim of this study was to investigate the effects of chronic VNS on endothelial impairments and the inflammatory profile in ovariectomized (OVX) rats. Sprague-Dawley rats (7-8 months old) were randomly assigned to the following four groups: sham-OVX, OVX, OVX+sham-VNS, and OVX+VNS. Throughout the experimental period, the OVX+VNS group received VNS for 3h (20.0 Hz, 1.0 mA, and 10.00 ms pulse width) at the same time every other day. After 12 weeks of VNS, blood samples and thoracic aortas were collected for further analyses. Light microscopy and electron microscopy analyses showed that chronic VNS prevented endothelial swelling, desquamation and even necrosis in the OVX rats. In addition, it obviously improved endothelial function in the OVX rats by restoring the endothelial nitric oxide synthase (e-NOS) and serum endothelin-1 level. Increased expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin) in the thoracic aortas and increases in the levels of circulating cytokines (TNF-α, IL-6, MCP-1, and CINC/KC) were also observed in the OVX rats. Chronic VNS significantly restored these detrimental changes partly by increasing the ACh concentrations in vascular walls and blocking NF-κB pathway activity. The results of this in vivo study have shown that the administration of chronic VNS during, in the early stage of estrogen deficiency, protects OVX rats from endothelial impairments and the inflammatory profile. These findings indicate that activation of the vagus nerve could be a promising supplemental therapy for reducing the risks of suffering from further CVDs in postmenopausal women.

  16. Methoxypolyethylene glycol-block-polycaprolactone diblock copolymers reduce P-glycoprotein efflux in the absence of a membrane fluidization effect while stimulating P-glycoprotein ATPase activity.

    PubMed

    Zastre, Jason; Jackson, John K; Wong, Wesley; Burt, Helen M

    2007-04-01

    We have previously shown that amphiphilic diblock copolymers composed of methoxypolyethylene glycol-b-polycaprolactone (MePEG-b-PCL) increased the cellular accumulation and reduced the basolateral to apical flux of the P-glycoprotein substrate, rhodamine 123 (R-123) in caco-2 cells. The purpose of this study was to investigate membrane perturbation effects of MePEG-b-PCL diblock copolymers with erythrocyte membranes and caco-2 cells and the effect on P-gp ATPase activity. The diblock copolymer MePEG(17)-b-PCL(5) induced increasing erythrocyte hemolysis at concentrations which correlated with increasing accumulation of R-123 into caco-2 cells. However, no increase in cellular accumulation of R-123 by non-P-gp expressing cells was observed, suggesting that diblock did not enhance the transmembrane passive diffusion of R-123, but that the accumulation enhancement effect of the diblock in caco-2 cells was likely mediated primarily via P-gp inhibition. Fluorescence anisotropy measurements of membrane fluidity and P-gp ATPase activity demonstrated that MePEG(17)-b-PCL(5) decreased caco-2 membrane fluidity while stimulating ATPase activity approximately threefold at concentrations that maximally enhanced R-123 caco-2 accumulation. These results suggest that inhibition of P-gp efflux by MePEG(17)-b-PCL(5) does not appear to be related to increases in membrane fluidity or through inhibition in P-gp ATPase activities, which are two commonly reported cellular effects for P-gp inhibition mediated by surfactants.

  17. Neuromuscular electrical stimulation via the peroneal nerve is superior to graduated compression socks in reducing perceived muscle soreness following intense intermittent endurance exercise.

    PubMed

    Ferguson, Richard A; Dodd, Matthew J; Paley, Victoria R

    2014-10-01

    A novel technique of neuromuscular electrical stimulation (NMES) via the peroneal nerve has been shown to augment limb blood flow which could enhance recovery following exercise. The present study examined the effects of NMES, compared to graduated compression socks on muscle soreness, strength, and markers of muscle damage and inflammation following intense intermittent exercise. Twenty-one (age 21 ± 1 years, height 179 ± 7 cm, body mass 76 ± 9 kg,) healthy males performed a 90-min intermittent shuttle running test on three occasions. Following exercise, the following interventions were applied: passive recovery (CON), graduated compression socks (GCS) or NMES. Perceived muscle soreness (PMS) and muscle strength (isometric maximal voluntary contraction of knee extensors and flexors) were measured and a venous blood sample taken pre-exercise and 0, 1, 24, 48 and 72 h following exercise for measurement of creatine kinase (CK) and Lactate dehydrogenase (LDH) activity and IL-6 and CRP concentrations. PMS increased in all conditions immediately, 1 and 24 h post-exercise. At 24 h PMS was lower in NMES compared to GCS and CON (2.0 ± 1.6, 3.2 ± 2.1, 4.6 ± 2.0, respectively). At 48 h PMS was lower in NMES compared to CON (1.3 ± 1.5 and 3.1 ± 1.8, respectively). There were no differences between treatments for muscle strength, CK and LDH activity, IL-6 and CRP concentrations. The novel NMES technique is superior to GCS in reducing PMS following intense intermittent endurance exercise.

  18. Reduced input from foot sole skin through cooling differentially modulates the short latency and medium latency vestibular reflex responses to galvanic vestibular stimulation.

    PubMed

    Muise, Stephanie B; Lam, Chris K; Bent, Leah R

    2012-04-01

    Sensory afferent information from the skin of the foot sole and information from the vestibular system converge within the central nervous system; however, their mode of interaction remains unknown. The purpose of this study was to investigate the effect of reduced cutaneous foot sole information on the ability of the vestibular system to evoke short latency (SL) and medium latency (ML) lower limb muscle reflex responses. Galvanic vestibular stimulation (GVS; bipolar; binaural; 25 ms; 2 mA square-wave pulse) was applied to standing human subjects (four women, eight men, average age 21.1 ± 3.0 years) both before and after cooling the foot soles in 1°C ice water (15 min initially, followed by 5 min between blocks of 200 GVS pulses). Changes in soleus reflex amplitude were examined. Following ice water immersion, there was a 35.16% increase in the size of the ML response in the soleus muscle when expressed as a percentage of pre-stimulus electromyographic (EMG) activity (control 26.48 ± 4.91%; ice 36.16 ± 6.52%) with no change in size of the SL response (control 7.42 ± 1.12%; ice 8.72 ± 1.10%). These results support the previously proposed dissociation of the SL and ML responses with respect to their circuitry and functions. The results also suggest a greater role for cutaneous-vestibular interaction in the modulation of the ML than the SL response and at a location prior to the motoneuron pool.

  19. Anaesthetic agents inhibit gastrin-stimulated but not basal histamine release from rat stomach ECL cells.

    PubMed

    Norlén, P; Kitano, M; Lindström, E; Håkanson, R

    2000-06-01

    By mobilizing histamine in response to gastrin, the ECL cells in the oxyntic mucosa play a key role in the control of the parietal cells and hence of gastric acid secretion. General anaesthesia suppresses basal and gastrin- and histamine-stimulated acid secretion. The present study examines if the effect of anaesthesia on basal and gastrin-stimulated acid secretion is associated with suppressed ECL-cell histamine secretion. A microdialysis probe was implanted in the submucosa of the ventral aspect of the acid-producing part of the stomach (32 rats). Three days later, ECL-cell histamine mobilization was monitored 2 h before and 4 h after the start of intravenous infusion of gastrin (5 nmol kg(-1) h(-1)). The rats were either conscious or anaesthetized. Four commonly used anaesthetic agents were given 1 h before the start of the experiments by intraperitoneal injection: chloral hydrate (300 mg kg(-1)), pentobarbitone (40 mg kg(-1)), urethane (1.5 g kg(-1)) and a mixture of fluanisone/fentanyl/midazolam (15/0.5/7.5 mg kg(-1)). In a parallel series of experiments, basal- and gastrin-induced acid secretion was monitored in six conscious and 25 anaesthetized (see above) chronic gastric fistula rats. All anaesthetic agents lowered gastrin-stimulated acid secretion; also the basal acid output was reduced (fluanisone/fentanyl/midazolam was an exception). Anaesthesia reduced gastrin-stimulated but not basal histamine release by 55 - 80%. The reduction in gastrin-induced acid response (70 - 95%) was strongly correlated to the reduction in gastrin-induced histamine mobilization. The correlation is in line with the view that the reduced acid response to gastrin reflects impaired histamine mobilization. Rat stomach ECL cells were purified by counter-flow elutriation. Gastrin-evoked histamine mobilization from the isolated ECL cells was determined in the absence or presence of anaesthetic agents in the medium. With the exception of urethane, they inhibited gastrin

  20. Granulocyte colony stimulating factor reduces brain injury in a cardiopulmonary bypass-circulatory arrest model of ischemia in a newborn piglet

    PubMed Central

    Pastuszko, Peter; Schears, Gregory J.; Greeley, William J.; Kubin, Joanna; Wilson, David F.; Pastuszko, Anna

    2014-01-01

    Background Ischemic brain injury continues to be of major concern in patients undergoing cardiopulmonary bypass (CPB) surgery for congenital heart disease. Striatum and hippocampus are particularly vulnerable to injury during these processes. Our hypothesis is that the neuronal injury resulting from CPB and the associated circulatory arrest can be at least partly ameliorated by pre-treatment with granulocyte colony stimulating factor (G-CSF). Material and Methods Fourteen male newborn piglets were assigned to three groups: deep hypothermic circulatory arrest (DHCA), DHCA with G-CSF, and sham-operated. The first two groups were placed on CPB, cooled to 18°C, subjected to 60 min of DHCA, re-warmed and recovered for 8-9 hrs. At the end of experiment, the brains were perfused, fixed and cut into 10 μm transverse sections. Apoptotic cells were visualized by in-situ DNA fragmentation assay (TUNEL), with the density of injured cells expressed as a mean number ± SD per mm2. Results The number of injured cells in the striatum and CA1 and CA3 regions of the hippocampus increased significantly following DHCA. In the striatum, the increase was from 0.46±0.37 to 3.67±1.57 (p=0.002); in the CA1, from 0.11±0.19 to 5.16±1.57 (p=0.001), and in the CA3, from 0.28±0.25 to 2.98±1.82 (p=0.040). Injection of G-CSF prior to bypass significantly reduced the number of injured cells in the striatum and CA1 region, by 51% and 37%, respectively. In the CA3 region, injured cell density did not differ between the G-CSF and control group. Conclusion In a model of hypoxic brain insult associated with CPB, G-CSF significantly reduces neuronal injury in brain regions important for cognitive functions, suggesting it can significantly improve neurological outcomes from procedures requiring DHCA. PMID:25082120

  1. Warmer temperatures stimulate respiration and reduce net ecosystem productivity in a northern Great Plains grassland: Analysis of CO2 exchange in automatic chambers

    NASA Astrophysics Data System (ADS)

    Flanagan, L. B.

    2013-12-01

    The interacting effects of altered temperature and precipitation are expected to have significant consequences for ecosystem net carbon storage. Here I report the results of an experiment that evaluated the effects of elevated temperature and altered precipitation on ecosystem CO2 exchange in a northern Great Plains grassland, near Lethbridge, Alberta Canada. Open-top chambers were used to establish an experiment in 2012 with three treatments (control, warmed, warmed plus 50% of normal precipitation input). A smaller experiment with only the two temperature treatments (control and warmed) was conducted in 2013. Continuous half-hourly net CO2 exchange measurements were made using nine automatic chambers during May-October in both years. My objectives were to determine the sensitivity of the ecosystem carbon budget to temperature and moisture manipulations, and to test for direct and indirect effects of the environmental changes on ecosystem CO2 exchange. The experimental manipulations resulted primarily in a significant increase in air temperature in the warmed treatment plots. A cumulative net loss of carbon or negative net ecosystem productivity (NEP) occurred during May through September in the warmed treatment (NEP = -659 g C m-2), while in the control treatment there was a cumulative net gain of carbon (NEP = +50 g C m-2). An eddy covariance system that operated at the site, over a footprint region that was not influenced by the experimental treatments, also showed a net gain of carbon by the ecosystem. The reduced NEP was due to higher plant and soil respiration rates in the warmed treatment that appeared to be caused by a combination of: (i) higher carbon substrate availability indirectly stimulating soil respiration in the warmed relative to the control treatment, and (ii) a strong increase in leaf respiration likely caused by a shift in electron partitioning to the alternative pathway respiration in the warmed treatment, particularly when exposed to high

  2. Healing rate and autoimmune safety of full-thickness wounds treated with fish skin acellular dermal matrix versus porcine small-intestine submucosa: a noninferiority study.

    PubMed

    Baldursson, Baldur Tumi; Kjartansson, Hilmar; Konrádsdóttir, Fífa; Gudnason, Palmar; Sigurjonsson, Gudmundur F; Lund, Sigrún Helga

    2015-03-01

    A novel product, the fish skin acellular dermal matrix (ADM) has recently been introduced into the family of biological materials for the treatment of wounds. Hitherto, these products have been produced from the organs of livestock. A noninferiority test was used to compare the effect of fish skin ADM against porcine small-intestine submucosa extracellular matrix in the healing of 162 full-thickness 4-mm wounds on the forearm of 81 volunteers. The fish skin product was noninferior at the primary end point, healing at 28 days. Furthermore, the wounds treated with fish skin acellular matrix healed significantly faster. These results might give the fish skin ADM an advantage because of its environmental neutrality when compared with livestock-derived products. The study results on these acute full-thickness wounds might apply for diabetic foot ulcers and other chronic full-thickness wounds, and the shorter healing time for the fish skin-treated group could influence treatment decisions. To test the autoimmune reactivity of the fish skin, the participants were tested with the following ELISA (enzyme-linked immunosorbent assay) tests: RF, ANA, ENA, anti ds-DNA, ANCA, anti-CCP, and anticollagen I and II. These showed no reactivity. The results demonstrate the claims of safety and efficacy of fish skin ADM for wound care.

  3. Comparison of Small Intestinal Submucosa-Covered and Noncovered Nitinol Stents with PTFE Endografts in Injured Ovine Femoral Arteries: A Pilot Study

    SciTech Connect

    Nakata, Manabu; Pavcnik, Dusan Uchida, Barry T.; Van Alstine, William; Timmermans, Hans A.; Toyota, Naoyuki; Terada, Masaki; Brountzos, Elias; Kaufman, John A.; Keller, Frederick S.; Rosch, Josef

    2003-09-15

    The purpose of this study was to compare performance of small intestinal submucosa (SIS)-covered endografts (SCEs) to polytetra-fluoroethylene (PTFE)-covered endografts (PCEs) and to bare nitinol stents (BSs) in injured sheep femoral artery (FA). Bare Zilver 6 mm x 40 mm nitinol stents (n = 6), Zilver stents covered with SIS (n = 6), and Palmaz stents 6 mm x 37 mm covered with PTFE (n = 6) were implanted in the balloon-injured FAs of nine female sheep. Follow-up arteriograms were obtained before animal sacrifice at 1, 3 and 6 months, with three animals at each time point. The FAs with the implanted device were explanted for histologic studies and morphologic measurements. Stent implantation was technically successful in all sheep. All BS and SCEs were patent at each time point. Five BSs and five SCEs exhibited formation of progressive eccentric intimal hyperplasia (IH) that was more advanced in SCE at 6 months. Cross-sectional area narrowing averaged 60% for BSs and 67% for SCEs. One BS, one SCE and two patent PCEs exhibited mild-to-moderate formation of concentric IH. Four PCS occluded one at 1 month, two at 3 months and one at 6 months. Performance of the devices placed into sheep FAs depended on their relation to the curving peri-articular portion of the FA during extremity flexion. BSs and SCEs placed in this portion exhibited progressive growth of eccentric IH while PCEs placed in this portion occluded.

  4. Effects of small intestinal submucosa content on the adhesion and proliferation of retinal pigment epithelial cells on SIS-PLGA films.

    PubMed

    Lee, Ga Young; Kang, Su Ji; Lee, So Jin; Song, Jeong Eun; Joo, Choun-Ki; Lee, Dongwon; Khang, Gilson

    2017-01-01

    The retinal pigment epithelium (RPE) plays a critical role in the maintenance of the normal functions of the retina, particularly the photoreceptors. RPE dysfunction, vision loss and degeneration have been implicated as the cause of many retinal diseases, including retinitis pigmentosa and age-related macular degeneration (AMD). To overcome such disorders, tissue engineering could offer useful strategies, using biodegradable polymeric films to replace diseased or lost RPE. Synthetic/natural hybrid films have been studied as a temporary substrate for growing RPEs in biological implantations. In this study, we prepared small intestinal submucosa (SIS)-poly(lactic-co-glycolic) (PLGA) hybrid films and seeded human RPE cells (ARPE-19 cells) onto the film surface. We investigated the film suitability for RPE cell proliferation by MTT assay. The morphology of cellular adhesion on the film was confirmed by scanning electron microscopy (SEM). Reverse transcription-polymerase chain reaction (RT-PCR) and 3-amino-9-ethylcarbazole (AEC) staining were performed to examine mRNA expression and to compare cell proliferation on the films, using cytokeratin as a marker of RPE. Conclusively, we confirmed the higher cell survival rate and much stronger phenotype expression of RPEs on SIS-PLGA films compared to pure PLGA films. These results demonstrated the potential application of SIS-PLGA films in tissue-engineering strategies. Copyright © 2014 John Wiley & Sons, Ltd. Copyright © 2014 John Wiley & Sons, Ltd.

  5. Meniscus reconstruction through coculturing meniscus cells with synovium-derived stem cells on small intestine submucosa--a pilot study to engineer meniscus tissue constructs.

    PubMed

    Tan, Yunbing; Zhang, Yuanyuan; Pei, Ming

    2010-01-01

    The purpose of this study was to investigate the feasibility of coculturing meniscus cells (MCs) and synovium-derived stem cells (SDSCs) on small intestine submucosa (SIS) to establish an innovative method to engineer in vitro meniscus constructs. About 0.9 million cells (MCs, prelabeled SDSCs [with Vybrant DiI], and a coculture of MCs and prelabeled SDSCs [50:50]) were mixed with fibrin gel and seeded onto freeze-dried SIS discs (5 mm diameter x 1-2 mm thickness) individually. The tissue constructs were incubated in a serum-free defined medium supplemented with 10 ng/mL transforming growth factor beta-1 and 500 ng/mL insulin-like growth factor I for 1 month. One day after cell seeding, samples for scanning electron microscopy were prepared to evaluate cell attachment on the SIS surface. During incubation, fluorescent microscopy was used to trace cell migration (with 4',6-diamidino-2-phenylindole as a counterstain) on SIS scaffold. The tissue constructs were assessed using histology, immunostaining, biochemical analysis, real-time polymerase chain reaction, and compressive modulus. All three groups of cells attached well on SIS. The coculture with SDSCs yielded MC-based tissue constructs with greater cell survival and differentiation into chondrogenic phenotypes, which exhibited higher glycosaminoglycan, collagen II, and Sox 9 but relatively low collagen I, resulting in the concomitant increase in equilibrium modulus. This pilot study demonstrates the advantages of coculturing MCs with SDSCs on SIS for meniscus tissue engineering and regeneration.

  6. Comparison of small intestinal submucosa-covered and noncovered nitinol stents with PTFE endografts in injured ovine femoral arteries: a pilot study.

    PubMed

    Nakata, Manabu; Pavcnik, Dusan; Uchida, Barry T; VanAlstine, William; Timmermans, Hans A; Toyota, Naoyuki; Terada, Masaki; Brountzos, Elias; Kaufman, John A; Keller, Frederick S; Rosch, Josef

    2003-01-01

    The purpose of this study was to compare performance of small intestinal submucosa (SIS)-covered endografts (SCEs) to polytetra-fluoroethylene (PTFE)-covered endografts (PCEs) and to bare nitinol stents (BSs) in injured sheep femoral artery (FA). Bare Zilver 6 mm X 40 mm nitinol stents (n = 6), Zilver stents covered with SIS (n = 6), and Palmaz stents 6 mm x 37 mm covered with PTFE (n = 6) were implanted in the balloon-injured FAs of nine female sheep. Follow-up arteriograms were obtained before animal sacrifice at 1, 3 and 6 months, with three animals at each time point. The FAs with the implanted device were explanted for histologic studies and morphologic measurements. Stent implantation was technically successful in all sheep. All BS and SCEs were patent at each time point. Five BSs and five SCEs exhibited formation of progressive eccentric intimal hyperplasia (IH) that was more advanced in SCE at 6 months. Cross-sectional area narrowing averaged 60% for BSs and 67% for SCEs. One BS, one SCE and two patent PCEs exhibited mild-to-moderate formation of concentric IH. Four PCS occluded one at 1 month, two at 3 months and one at 6 months. Performance of the devices placed into sheep FAs depended on their relation to the curving peri-articular portion of the FA during extremity flexion. BSs and SCEs placed in this portion exhibited progressive growth of eccentric IH while PCEs placed in this portion occluded.

  7. T cell clone exposed to high levels of interleukin-2 (IL-2) synthesizes reduced amounts of lymphokine mRNA in response to antigenic stimulation

    SciTech Connect

    Otten, G.; Herold, K.C.; Fitch, F.W.

    1986-03-01

    The Mls-reactive, murine helper T cell clone, designated L2, both proliferates and secretes lymphokines including IL-2 and interleukin-3 (IL-3) when stimulated with alloantigen or with a combination of phorbol myristate acetate (PMA) and the divalent cation ionophore A23187. L2 cells were exposed to a low concentration (1 Unit(U)/ml) or to a high concentration (50-100 U/ml) of recombinant human IL-2 and cultured for 48-72 hours prior to restimulation with antigen or with PMA + A23187. Compared to L2 cells exposed to a low concentration of rIL-2, cells exposed to a high concentration of rIL-2 were profoundly less responsive to antigen as indicated a 6-16 fold reduction in antigen-stimulated lymphokine secretion. Consistent with the reduction in antigen-stimulated lymphokine secretion, levels of antigen-stimulated mRNA for both IL-2 and IL-3 were diminished 8-16 fold in L2 cells previously exposed to a high concentration of rIL-2. In contrast, L2 cells exposed to a high or low concentration of rIL-2 produced similar amounts of IL-2 and IL-3 when stimulated with PMA + A23187. These data suggest that exposure of L2 cells to a high concentration of IL-2 may inhibit the intracellular pathway which links antigen recognition to the production of lymphokine mRNA.

  8. Selenium reduces the proapoptotic signaling associated to NF-kappaB pathway and stimulates glutathione peroxidase activity during excitotoxic damage produced by quinolinate in rat corpus striatum.

    PubMed

    Santamaría, Abel; Vázquez-Román, Beatriz; La Cruz, Verónica Pérez-De; González-Cortés, Carolina; Trejo-Solís, Ma Cristina; Galván-Arzate, Sonia; Jara-Prado, Aurelio; Guevara-Fonseca, Jorge; Ali, Syed F

    2005-12-15

    Quinolinate (QUIN) neurotoxicity has been attributed to degenerative events in nerve tissue produced by sustained activation of N-methyl-D-aspartate receptor (NMDAr) and oxidative stress. We have recently described the protective effects that selenium (Se), an antioxidant, produces on different markers of QUIN-induced neurotoxicity (Santamaría et al., 2003, J Neurochem 86:479-488.). However, the mechanisms by which Se exerts its protective actions remain unclear. Since some of these events are thought to be related with inhibition of deadly molecular cascades through the activation of antioxidant selenoproteins, in this study we investigated the effects of Se on QUIN-induced cell damage elicited by the nuclear factor kappaB (NF-kappaB) pathway, as well as the time-course response of striatal glutathione peroxidase (GPx) activity. Se (sodium selenite, 0.625 mg/kg/day, i.p.) was administered to rats for 5 days, and 120 min after the last administration, animals received a single striatal injection of QUIN (240 nmol/mul). Twenty-four hours later, their striata were tested for the expression of IkappaB-alpha (the NF-kappaB cytosolic binding protein), the immunohistochemical expression of NF-kappaB (evidenced as nuclear expression of P65), caspase-3-like activation, and DNA fragmentation. Additional groups were killed at 2, 6, and 24 h for measurement of GPx activity. Se reduced the QUIN-induced decrease in IkappaB-alpha expression, evidencing a reduction in its cytosolic degradation. Se also prevented the QUIN-induced increase in P65-immunoreactive cells, suggesting a reduction of NF-kappaB nuclear translocation. Caspase-3-like activation and DNA fragmentation produced by QUIN were also inhibited by Se. Striatal GPx activity was stimulated by Se at 2 and 6 h, but not at 24 h postlesion. Altogether, these data suggest that the protective effects exerted by Se on QUIN-induced neurotoxicity are partially mediated by the inhibition of proapoptotic events underlying Ikappa

  9. Antithrombin III, but not C1 esterase inhibitor reduces inflammatory response in lipopolysaccharide-stimulated human monocytes in an ex-vivo whole blood setting.

    PubMed

    Kellner, Patrick; Nestler, Frank; Leimert, Anja; Bucher, Michael; Czeslick, Elke; Sablotzki, Armin; Raspè, Christoph

    2014-12-01

    In order to examine the immunomodulatory effects of antithrombin III (AT-III) and C1 esterase inhibitor (C1-INH) in human monocytes, we investigated the intracellular expression of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in an ex-vivo laboratory study in a whole blood setting. Heparinized whole blood samples from 23 healthy male and female volunteers (mean age: 27±7years) were pre-incubated with clinically relevant concentrations of AT-III (n=11) and C1-INH (n=12), then stimulated with 0.2 ng/mL lipopolysaccharide (LPS) for 3h. After phenotyping CD14⁺ monocytes, intracellular expression of IL-6, IL-8, and TNF-α was assessed using flow cytometry. In addition, 12 whole blood samples (AT-III and C1-INH, n=6 each) were examined using hirudin for anticoagulation; all samples were processed in the same way. To exclude cytotoxicity effects, 7-amino-actinomycin D and Nonidet P40 staining were used to investigate probes. This study is the first to demonstrate the influence of C1-INH and AT-III on the monocytic inflammatory response in a whole blood setting, which mimics the optimal physiological setting. Cells treated with AT-III exhibited significant downregulation of the proportion of gated CD14⁺ monocytes for IL-6 and IL-8, in a dose-dependent manner; downregulation for TNF-α did not reach statistical significance. There were no significant effects on mean fluorescence intensity (MFI). In contrast, C1-INH did not significantly reduce the proportion of gated CD14⁺ monocytes or the MFI regarding IL-6, TNF-α, and IL-8. When using hirudin for anticoagulation, no difference in the anti-inflammatory properties of AT-III and C1-INH in monocytes occurs. Taken together, in contrast to TNF-α, IL-6 and IL-8 were significantly downregulated in monocytes in an ex-vivo setting of human whole blood when treated with AT-III. This finding implicates monocytes as an important point of action regarding the anti-inflammatory properties of AT-III in sepsis. C1

  10. Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: Role of tumor necrosis factor alpha and apoptosis

    PubMed Central

    Woller, Sarah A.; Huie, J. Russell; Hartman, John J.; Hook, Michelle A.; Miranda, Rajesh C.; Huang, Yung-Jen; Ferguson, Adam R.; Grau, James W.

    2014-01-01

    We previously showed that peripheral noxious input after spinal cord injury (SCI) inhibits beneficial spinal plasticity and impairs recovery of locomotor and bladder functions. These observations suggest that noxious input may similarly affect the development and maintenance of chronic neuropathic pain, an important consequence of SCI. In adult rats with a moderate contusion SCI, we investigated the effect of noxious tail stimulation, administered one day after SCI, on mechanical withdrawal responses to von Frey stimuli from 1 to 28 days, post-treatment. In addition, because the pro-inflammatory cytokine tumor necrosis factor α (TNFα) is implicated in numerous injury-induced processes including pain hypersensitivity, we assessed the temporal and spatial expression of TNFα, TNF receptors, and several downstream signaling targets after stimulation. Our results showed that unlike sham surgery or SCI only, nociceptive stimulation following SCI induced mechanical sensitivity by 24 hours. These behavioral changes were accompanied by increased expression of TNFα. Cellular assessments of downstream targets of TNFα revealed that nociceptive stimulation increased the expression of caspase 8 and the active subunit (12 kDa) of caspase 3 at a time point consistent with the onset of mechanical allodynia, indicative of active apoptosis. In addition, immunohistochemical analysis revealed distinct morphological signs of apoptosis in neurons and microglia at 24 hours post-stimulation. Interestingly, expression of the inflammatory mediator NFκB was unaltered by nociceptive stimulation. These results suggest that noxious input caudal to the level of SCI can increase the onset and expression of behavioral responses indicative of pain, potentially involving TNFα signaling. PMID:25180012

  11. Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis.

    PubMed

    Garraway, Sandra M; Woller, Sarah A; Huie, J Russell; Hartman, John J; Hook, Michelle A; Miranda, Rajesh C; Huang, Yung-Jen; Ferguson, Adam R; Grau, James W

    2014-11-01

    We previously showed that peripheral noxious input after spinal cord injury (SCI) inhibits beneficial spinal plasticity and impairs recovery of locomotor and bladder functions. These observations suggest that noxious input may similarly affect the development and maintenance of chronic neuropathic pain, an important consequence of SCI. In adult rats with a moderate contusion SCI, we investigated the effect of noxious tail stimulation, administered 1 day after SCI on mechanical withdrawal responses to von Frey stimuli from 1 to 28 days after treatment. In addition, because the proinflammatory cytokine tumor necrosis factor alpha (TNFα) is implicated in numerous injury-induced processes including pain hypersensitivity, we assessed the temporal and spatial expression of TNFα, TNF receptors, and several downstream signaling targets after stimulation. Our results showed that unlike sham surgery or SCI only, nociceptive stimulation after SCI induced mechanical sensitivity by 24h. These behavioral changes were accompanied by increased expression of TNFα. Cellular assessments of downstream targets of TNFα revealed that nociceptive stimulation increased the expression of caspase 8 and the active subunit (12 kDa) of caspase 3, indicative of active apoptosis at a time point consistent with the onset of mechanical allodynia. In addition, immunohistochemical analysis revealed distinct morphological signs of apoptosis in neurons and microglia at 24h after stimulation. Interestingly, expression of the inflammatory mediator NFκB was unaltered by nociceptive stimulation. These results suggest that noxious input caudal to the level of SCI can increase the onset and expression of behavioral responses indicative of pain, potentially involving TNFα signaling. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  12. Perinatal hypoxia-ischemia reduces α 7 nicotinic receptor expression and selective α 7 nicotinic receptor stimulation suppresses inflammation and promotes microglial Mox phenotype.

    PubMed

    Hua, Sansan; Ek, C Joakim; Mallard, Carina; Johansson, Maria E

    2014-01-01

    Inflammation plays a central role in neonatal brain injury. During brain inflammation the resident macrophages of the brain, the microglia cells, are rapidly activated. In the periphery, α 7 nicotinic acetylcholine receptors ( α 7R) present on macrophages can regulate inflammation by suppressing cytokine release. In the current study we investigated α 7R expression in neonatal mice after hypoxia-ischemia (HI). We further examined possible anti-inflammatory role of α 7R stimulation in vitro and microglia polarization after α 7R agonist treatment. Real-time PCR analysis showed a 33% reduction in α 7R expression 72 h after HI. Stimulation of primary microglial cells with LPS in combination with increasing doses of the selective α 7R agonist AR-R 17779 significantly attenuated TNF α release and increased α 7R transcript in microglial cells. Gene expression of M1 markers CD86 and iNOS, as well as M2 marker CD206 was not influenced by LPS and/or α 7R agonist treatment. Further, Mox markers heme oxygenase (Hmox1) and sulforedoxin-1 (Srx1) were significantly increased, suggesting a polarization towards the Mox phenotype after α 7R stimulation. Thus, our data suggest a role for the α 7R also in the neonatal brain and support the anti-inflammatory role of α 7R in microglia, suggesting that α 7R stimulation could enhance the polarization towards a reparative Mox phenotype.

  13. Stimulant Treatment Reduces Lapses in Attention among Children with ADHD: The Effects of Methylphenidate on Intra-Individual Response Time Distributions

    ERIC Educational Resources Information Center

    Spencer, Sarah V.; Hawk, Larry W., Jr.; Richards, Jerry B.; Shiels, Keri; Pelham, William E., Jr.; Waxmonsky, James G.

    2009-01-01

    Recent research has suggested that intra-individual variability in reaction time (RT) distributions of children with ADHD is characterized by a particularly large rightward skew that may reflect lapses in attention. The purpose of the study was to provide the first randomized, placebo-controlled test of the effects of the stimulant methylphenidate…

  14. Assisting People with Attention Deficit Hyperactivity Disorder by Actively Reducing Limb Hyperactive Behavior with a Gyration Air Mouse through a Controlled Environmental Stimulation

    ERIC Educational Resources Information Center

    Shih, Ching-Hsiang

    2011-01-01

    The latest researches have adopted software technology turning the gyration air mouse into a high performance limb movement detector, and have assessed whether two persons with multiple disabilities would be able to control an environmental stimulation using limb movement. This study extends gyration air mouse functionality by actively reducing…

  15. Assisting People with Attention Deficit Hyperactivity Disorder by Actively Reducing Limb Hyperactive Behavior with a Gyration Air Mouse through a Controlled Environmental Stimulation

    ERIC Educational Resources Information Center

    Shih, Ching-Hsiang

    2011-01-01

    The latest researches have adopted software technology turning the gyration air mouse into a high performance limb movement detector, and have assessed whether two persons with multiple disabilities would be able to control an environmental stimulation using limb movement. This study extends gyration air mouse functionality by actively reducing…

  16. Stimulant Treatment Reduces Lapses in Attention among Children with ADHD: The Effects of Methylphenidate on Intra-Individual Response Time Distributions

    ERIC Educational Resources Information Center

    Spencer, Sarah V.; Hawk, Larry W., Jr.; Richards, Jerry B.; Shiels, Keri; Pelham, William E., Jr.; Waxmonsky, James G.

    2009-01-01

    Recent research has suggested that intra-individual variability in reaction time (RT) distributions of children with ADHD is characterized by a particularly large rightward skew that may reflect lapses in attention. The purpose of the study was to provide the first randomized, placebo-controlled test of the effects of the stimulant methylphenidate…

  17. Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction: The SOCRATES-REDUCED Randomized Trial.

    PubMed

    Gheorghiade, Mihai; Greene, Stephen J; Butler, Javed; Filippatos, Gerasimos; Lam, Carolyn S P; Maggioni, Aldo P; Ponikowski, Piotr; Shah, Sanjiv J; Solomon, Scott D; Kraigher-Krainer, Elisabeth; Samano, Eliana T; Müller, Katharina; Roessig, Lothar; Pieske, Burkert

    2015-12-01

    Worsening chronic heart failure (HF) is a major public health problem. To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks. The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point. Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a

  18. Pamidronate treatment stimulates the onset of recovery phase reducing fracture rate and skeletal deformities in patients with idiopathic juvenile osteoporosis: comparison with untreated patients.

    PubMed

    Baroncelli, Giampiero I; Vierucci, Francesco; Bertelloni, Silvano; Erba, Paola; Zampollo, Elisa; Giuca, Maria Rita

    2013-09-01

    Although spontaneous remission occurs in patients with idiopathic juvenile osteoporosis (IJO), permanent bone deformities may occur. The effects of long-term pamidronate treatment on clinical findings, bone mineral status, and fracture rate were evaluated. Nine patients (age 9.8 ± 1.1 years, 7 males) with IJO were randomized to intravenous pamidronate (0.8 ± 0.1 mg/kg per day for 3 days; cycles per year 2.0 ± 0.1; duration 7.3 ± 1.1 years; n = 5) or no treatment (n = 4). Fracture rate, phalangeal quantitative ultrasound, and lumbar bone mineral density (BMD) by dual energy X-ray absorptiometry at entry and during follow-up (range 6.3-9.4 years) were assessed. Bone pain improved in treated patients. Difficulty walking continued for 3-5 years in untreated patients, and vertebral collapses occurred in three of them. During follow-up, phalangeal amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), and lumbar BMDarea and BMDvolume progressively increased in treated patients (P < 0.05-P < 0.0001). In untreated patients AD-SoS and BTT decreased during the first 2-4 years of follow-up (P < 0.05-P < 0.01); lumbar BMDarea increased after 6 years (P < 0.001) whereas BTT and lumbar BMDvolume increased after 7 years of follow-up (P < 0.05 and P < 0.001, respectively). At the end of follow-up, AD-SoS, BTT, lumbar BMDarea, and BMDvolume Z-scores were lower in untreated patients than in treated patients (-2.2 ± 0.3 and -0.5 ± 0.2; -1.9 ± 0.2 and -0.6 ± 0.2; -2.3 ± 0.3 and -0.7 ± 0.3; -2.4 ± 0.2 and -0.7 ± 0.3, P < 0.0001, respectively). Fracture rate was higher in untreated patients than in treated patients during the first 3 years of follow-up (P < 0.02). Our study showed that spontaneous recovery of bone mineral status is unsatisfactory in patients with IJO. Pamidronate treatment stimulated the onset of recovery phase reducing fracture rate and permanent disabilities without evidence of

  19. Study Protocol Evaluating the Use of Bowel Stimulation Before Loop Ileostomy Closure to Reduce Postoperative Ileus: A Multicenter Randomized Controlled Trial.

    PubMed

    Garfinkle, Richard; Trabulsi, Nora; Morin, Nancy; Phang, Terry; Liberman, Sender; Feldman, Liane; Fried, Gerald; Boutros, Marylise

    2017-05-12

    Postoperative ileus is the most commonly observed morbidity following ileostomy closure. Studies have demonstrated that the defunctionalized bowel of a loop ileostomy undergoes a series of functional and structural changes, such as atrophy of the intestinal villi and muscular layers, which may contribute to ileus. A single-center study in Spain demonstrated that preoperative bowel stimulation via the distal limb of the loop ileostomy decreased postoperative ileus, length of stay, and time to gastrointestinal function. A multicenter randomized controlled trial involving patients from Canadian institutions was designed to evaluate the effect of preoperative bowel stimulation before ileostomy closure on postoperative ileus. Stimulation will include canalizing the distal limb of the ileostomy loop with an 18Fr Foley catheter and infusing it with a solution of 500mL of normal saline mixed with 30g of a thickening-agent (Nestle© Thicken-Up©). This will be performed 10 times over the three weeks prior to ileostomy closure on an outpatient clinic setting by a trained Enterostomal Therapy nurse. Surgeons and the treating surgical team will be blinded to their patient's group allocation. Data regarding patient demographics, operative, and postoperative variables will be collected prospectively. Primary outcome will be postoperative ileus, defined as an intolerance to oral food in the absence of clinical or radiological signs of obstruction, that either a) requires nasogastric tube insertion; or b) is associated with 2 of the following: nausea/vomiting, abdominal distension, and the absence of flatus, on or after post-operative day 3. Secondary outcomes will include length of stay, time to tolerating a regular diet, time to first passage of flatus or stool, and overall morbidity. A cost-analysis will be performed to compare the costs of conventional care to conventional care plus preoperative stimulation. This manuscript discusses the potential benefits of preoperative

  20. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation.

    PubMed

    Ubaldi, Filippo Maria; Capalbo, Antonio; Vaiarelli, Alberto; Cimadomo, Danilo; Colamaria, Silvia; Alviggi, Carlo; Trabucco, Elisabetta; Venturella, Roberta; Vajta, Gábor; Rienzi, Laura

    2016-06-01

    To compare the euploid blastocyst formation rates obtained after follicular phase (FP) versus luteal phase (LP) stimulation performed in the same menstrual cycle in a preimplantation genetic diagnosis for aneuploidy testing (PGD-A) program in patients with reduced ovarian reserve. Prospective paired noninferiority observational study. Private infertility program. Forty-three reduced ovarian reserve patients undergoing a PGD-A. Both FP and LP stimulations using follicle-stimulating hormone and luteinizing hormone in combination with gonadotropin-releasing hormone (GnRH) antagonist starting on day 2 of the cycle and 5 days after the first oocyte retrieval, respectively, where GnRH agonist was used for both FP and LP ovulation triggering; a trophectoderm biopsy quantitative polymerase chain reaction-based PGD-A strategy; and single euploid blastocyst transfers during a subsequent natural cycle. euploid blastocyst rate per injected metaphase 2 (MII) oocyte; secondary outcome measures: number of cumulus-oocyte complexes (COCs), MII oocytes, and blastocysts. Patients with an antimüllerian hormone level of <1.5 ng/mL, antral follicle count of <6 follicles, and/or <5 oocytes retrieved in a previous cycle were included. No statistically significant differences were found in the number of retrieved COCs (5.1 ± 3.4 vs. 5.7 ± 3.3), MII oocytes (3.4 ± 1.9 vs. 4.1 ± 2.5), or biopsied blastocysts per stimulated cycle (1.2 ± 1.2 vs. 1.4 ± 1.7) from FP versus LP stimulation, respectively. No differences were observed in the euploid blastocyst rate calculated either per biopsied blastocyst (46.9% vs. 44.8%) or injected MII oocyte (16.2% vs. 15.0%). Stimulation with an identical protocol in the FP and LP of the same menstrual cycle resulted in a similar number of blastocysts in patients with reduced ovarian response. The LP stimulation statistically significantly contributed to the final transferable blastocyst yield, thus increasing the number of patients undergoing

  1. The use of bi-layer silk fibroin scaffolds and small intestinal submucosa matrices to support bladder tissue regeneration in a rat model of spinal cord injury

    PubMed Central

    Chung, Yeun Goo; Algarrahi, Khalid; Franck, Debra; Tu, Duong D.; Adam, Rosalyn M.; Kaplan, David L.; Estrada, Carlos R.; Mauney, Joshua R.

    2014-01-01

    Adverse side-effects associated with enterocystoplasty for neurogenic bladder reconstruction have spawned the need for the development of alternative graft substitutes. Bi-layer silk fibroin (SF) scaffolds and small intestinal submucosa (SIS) matrices were investigated for their ability to support bladder tissue regeneration and function in a rat model of spinal cord injury (SCI). Bladder augmentation was performed with each scaffold configuration in SCI animals for 10 wk of implantation and compared to non-augmented control groups (normal and SCI alone). Animals subjected to SCI alone exhibited a 72% survival rate (13/18) while SCI rats receiving SIS and bi-layer SF scaffolds displayed respective survival rates of 83% (10/12) and 75% (9/12) over the course of the study period. Histological (Masson’s trichrome analysis) and immunohistochemical (IHC) evaluations demonstrated both implant groups supported de novo formation of smooth muscle layers with contractile protein expression [α-smooth muscle actin (α-SMA) and SM22α] as well as maturation of multi-layer urothelia expressing cytokeratin (CK) and uroplakin 3A proteins. Histomorphometric analysis revealed bi-layer SF and SIS scaffolds respectively reconstituted 64% and 56% of the level of α-SMA+ smooth muscle bundles present in SCI-alone controls, while similar degrees of CK+ urothelium across all experimental groups were detected. Parallel evaluations showed similar degrees of vascular area and synaptophysin+ boutons in all regenerated tissues compared to SCI-alone controls. In addition, improvements in certain urodynamic parameters in SCI animals, such as decreased peak intravesical pressure, following implantation with both matrix configurations were also observed. The data presented in this study detail the ability of acellular SIS and bi-layer SF scaffolds to support formation of innervated, vascularized smooth muscle and urothelial tissues in a neurogenic bladder model. PMID:24917031

  2. Small intestinal submucosa versus salt-extracted polyglycolic acid-poly-L-lactic acid: a comparison of neocartilage formed in two scaffold materials.

    PubMed

    Beatty, Mark W; Ojha, Ajay K; Cook, James L; Alberts, L Russell; Mahanna, Gordon K; Iwasaki, Laura R; Nickel, Jeffrey C

    2002-12-01

    This study sought to compare differences in neocartilage produced over time from two types of resorbable scaffold materials. One material was entirely synthetic and contained a polyglycolic acid-poly-L-lactic acid matrix (PGA-PLLA). The second scaffold material was bioactive and consisted of a four-layered construct of porcine small intestinal submucosa (SIS). Disk-shaped scaffolds were seeded with canine chondrocytes and implanted into athymic mice for periods of 5, 8, 12, and 24 weeks. Constructs were examined microscopically, assayed for hydroxyproline (HP) and glycosaminoglycan (GAG) content, and collagen typed (I or II) at each time period. Creep indentation tests determined aggregate and shear modulus, permeability, and thickness. Results indicated that SIS maintained its thickness through the first 12 weeks, and then doubled by week 24. The 24-week tissue appeared chondroid-like and possessed high GAG content. Tissues derived from PGA-PLLA scaffolds were lower in HP content than SIS-derived tissues, but type II collagen was demonstrated only in PGA-PLLA-derived tissues at 24 weeks. Mechanical properties were not significantly different for any tissue over time (p > 0.05), but aggregate and shear modulus mean values were consistently higher for PGA-PLLA-derived tissues at nearly every time interval. This, coupled with the presence of collagen types I and II, suggested a more congruent solid phase may be forming within the extracellular matrix of tissues derived from PGA-PLLA scaffolds. Future study is necessary to compare these materials under simulated loading conditions.

  3. Kinetic study of the replacement of porcine small intestinal submucosa grafts and the regeneration of meniscal-like tissue in large avascular meniscal defects in dogs.

    PubMed

    Cook, J L; Tomlinson, J L; Arnoczky, S P; Fox, D B; Reeves Cook, C; Kreeger, J M

    2001-06-01

    Porcine small intestinal submucosa (SIS) was used to replace large, avascular defects in the medial menisci of dogs. Twelve dogs received SIS grafts and 3 dogs were left untreated as controls. Dogs were evaluated at 4, 8, and 12 weeks by means of lameness scoring and ultrasonography. Dogs were sacrificed at 1, 6, or 12 weeks after implantation, and the tissue at the site of meniscal resection was evaluated for gross and histologic appearance, cross-sectional and surface area, and collagen types I and II. The femoral and tibial condyles were assessed for articular cartilage damage. Control dogs were significantly more lame than grafted dogs 8 and 12 weeks after instrumentation. Grafted dogs' replacement tissue appeared meniscal-like when evaluated grossly and ultrasonographically 12 weeks after instrumentation. The amount of replacement tissue was significantly greater in both cross-sectional and surface area for grafted dogs than for controls at all time points. Histologically, the SIS biomaterial could be identified in all grafted dogs at 1 week post-implantation, but in none at 6 weeks post-implantation. Subjectively, grafted dogs' replacement tissue was histologically superior to that of controls with respect to tissue type, organization, and architecture. Collagen types I and II immunoreactivity in grafted menisci were similar to that of normal menisci. Control dogs had significantly more articular cartilage damage than grafted dogs. SIS appears to induce regeneration of meniscal-like tissue in large, avascular meniscal defects in dogs, resulting in superior clinical function and articular cartilage protection compared to ungrafted controls.

  4. 5-AED Enhances Survival of Irradiated Mice in a G-CSF-Dependent Manner, Stimulates Innate Immune Cell Function, Reduces Radiation-induced DNA Damage and Induces Genes that Modulate Cell Cycle Progression and Apoptosis

    DTIC Science & Technology

    2012-01-01

    pre-irradiation) radio- protectants and (post-irradiation) therapeutics, as recognized by civilian and military government agencies [2– 4 ]. 5-AED is...2012 4 . TITLE AND SUBTITLE 5-AED Enhances Survival of Irradiated Mice in a G-CSF-Dependent Manner, Stimulates Innate Immune Cell Function, Reduces...control after 4 days, but not 8 days. The time course of plasma 5-AED after buccal de- livery (60 mg/kg) was similar, but levels were significantly lower

  5. Cooling reduces cAMP-stimulated exocytosis and adiponectin secretion at a Ca2+-dependent step in 3T3-L1 adipocytes.

    PubMed

    El Hachmane, Mickaël F; Komai, Ali M; Olofsson, Charlotta S

    2015-01-01

    We investigated the effects of temperature on white adipocyte exocytosis (measured as increase in membrane capacitance) and short-term adiponectin secretion with the aim to elucidate mechanisms important in regulation of white adipocyte stimulus-secretion coupling. Exocytosis stimulated by cAMP (included in the pipette solution together with 3 mM ATP) in the absence of Ca2+ (10 mM intracellular EGTA) was equal at all investigated temperatures (23°C, 27°C, 32°C and 37°C). However, the augmentation of exocytosis induced by an elevation of the free cytosolic [Ca2+] to ~1.5 μM (9 mM Ca2+ + 10 mM EGTA) was potent at 32°C or 37°C but less distinct at 27°C and abolished at 23°C. Adiponectin secretion stimulated by 30 min incubations with the membrane permeable cAMP analogue 8-Br-cAMP (1 mM) or a combination of 10 μM forskolin and 200 μM IBMX was unaffected by a reduction of temperature from 32°C to 23°C. At 32°C, cAMP-stimulated secretion was 2-fold amplified by inclusion of the Ca2+ ionophore ionomycin (1μM), an effect that was not observed at 23°C. We suggest that cooling affects adipocyte exocytosis/adiponectin secretion at a Ca2+-dependent step, likely involving ATP-dependent processes, important for augmentation of cAMP-stimulated adiponectin release.

  6. Reducing the rate of misdiagnosis in patients with chronic disorders of consciousness: Is there a place for audiovisual stimulation?

    PubMed

    Naro, Antonino; Leo, Antonino; Bruno, Rocco; Cannavò, Antonino; Buda, Antonio; Manuli, Alfredo; Bramanti, Alessia; Bramanti, Placido; Calabrò, Rocco Salvatore

    2017-08-11

    The patients with chronic Disorders of Consciousness (DoC) mostly present with extremely challenging differential diagnosis. The advanced analysis of electroencephalographic (EEG) signals induced by brain stimulation paradigms may provide an appropriate approach to differentiate patients with DoC, besides the clinical assessment. This study was performed with an objective of identifying residual brain network perturbations following an innovative, non-invasive audiovisual stimulation protocol, which could be related to behavioral responsiveness in patients with DoC. The study comprised of ten healthy controls (HC), seven patients with Minimally Conscious State (MCS), and nine patients with Unresponsive Wakefulness Syndrome (UWS). Both synchronous as well as asynchronous transorbital and transauricolar alternating current were employed as stimuli and their effects were measured in terms of functional and effective connectivity. A more noticeable deterioration of long range connectivity patterns were found in patients with UWS than in those with MCS, with an exception of two patients with UWS, who showed connectivity values similar to those of patients with MCS. The audiovisual stimulation paradigm used in the present study may be employed as a supportive bedside tool for improving the differential diagnosis in patients with DoC.

  7. G-quadruplex and G-rich sequence stimulate Pif1p-catalyzed downstream duplex DNA unwinding through reducing waiting time at ss/dsDNA junction.

    PubMed

    Zhang, Bo; Wu, Wen-Qiang; Liu, Na-Nv; Duan, Xiao-Lei; Li, Ming; Dou, Shuo-Xing; Hou, Xi-Miao; Xi, Xu-Guang

    2016-09-30

    Alternative DNA structures that deviate from B-form double-stranded DNA such as G-quadruplex (G4) DNA can be formed by G-rich sequences that are widely distributed throughout the human genome. We have previously shown that Pif1p not only unfolds G4, but also unwinds the downstream duplex DNA in a G4-stimulated manner. In the present study, we further characterized the G4-stimulated duplex DNA unwinding phenomenon by means of single-molecule fluorescence resonance energy transfer. It was found that Pif1p did not unwind the partial duplex DNA immediately after unfolding the upstream G4 structure, but rather, it would dwell at the ss/dsDNA junction with a 'waiting time'. Further studies revealed that the waiting time was in fact related to a protein dimerization process that was sensitive to ssDNA sequence and would become rapid if the sequence is G-rich. Furthermore, we identified that the G-rich sequence, as the G4 structure, equally stimulates duplex DNA unwinding. The present work sheds new light on the molecular mechanism by which G4-unwinding helicase Pif1p resolves physiological G4/duplex DNA structures in cells.

  8. G-quadruplex and G-rich sequence stimulate Pif1p-catalyzed downstream duplex DNA unwinding through reducing waiting time at ss/dsDNA junction

    PubMed Central

    Zhang, Bo; Wu, Wen-Qiang; Liu, Na-Nv; Duan, Xiao-Lei; Li, Ming; Dou, Shuo-Xing; Hou, Xi-Miao; Xi, Xu-Guang

    2016-01-01

    Alternative DNA structures that deviate from B-form double-stranded DNA such as G-quadruplex (G4) DNA can be formed by G-rich sequences that are widely distributed throughout the human genome. We have previously shown that Pif1p not only unfolds G4, but also unwinds the downstream duplex DNA in a G4-stimulated manner. In the present study, we further characterized the G4-stimulated duplex DNA unwinding phenomenon by means of single-molecule fluorescence resonance energy transfer. It was found that Pif1p did not unwind the partial duplex DNA immediately after unfolding the upstream G4 structure, but rather, it would dwell at the ss/dsDNA junction with a ‘waiting time’. Further studies revealed that the waiting time was in fact related to a protein dimerization process that was sensitive to ssDNA sequence and would become rapid if the sequence is G-rich. Furthermore, we identified that the G-rich sequence, as the G4 structure, equally stimulates duplex DNA unwinding. The present work sheds new light on the molecular mechanism by which G4-unwinding helicase Pif1p resolves physiological G4/duplex DNA structures in cells. PMID:27471032

  9. Effectiveness of local delivery of alendronate in reducing alveolar bone loss following periodontal surgery in rats.

    PubMed

    Binderman, I; Adut, M; Yaffe, A

    2000-08-01

    Mucoperiosteal flaps are used to access bone and root surfaces for debridement, pocket elimination, management of periodontal defects, and in regenerative procedures, as well as in implant surgery. Many reports show that periodontal surgery stimulates osteoclast activity with varying amounts of alveolar bone loss. Alendronate given intravenously significantly reduced alveolar bone loss in mucoperiosteal flap procedures. In the present study, we explored the effectiveness of different concentrations of alendronate, delivered at the surgical site at the time of surgery, in distant delivery in reducing alveolar bone loss. Following elevation of a mucoperiosteal flap next to molars of the rat mandible, a gelatin sponge soaked with different concentrations of alendronate (0, 1, 5, 20, or 40 mg/ml; experiment A) was applied to exposed bone on the experimental side. In the second group (experiment B), alendronate (0, 50, 200, or 400 microg) was topically delivered in the cheek submucosa on the left side (distant to the surgical site) in a small cut into which the gelatin sponge soaked with the drug was placed. Topical application of 200 microg and 400 microg doses of alendronate at the time of surgery was significantly effective (P <0.001) in reducing bone loss. Generally, the percentage of sections with mild bone loss (V1, V2) increased with an increase in the dose of alendronate, while the percentage of sections with severe bone loss (H1, H2) decreased with an increase in alendronate dose. Topical application of 400 microg of alendronate had a systemic effect. This study implies that topical delivery of alendronate at the time of surgery reduces bone loss in periodontal procedures involving mucoperiosteal flap surgery. The most effective dose is 200 microg for topical delivery at the surgical site and 400 microg for distant sites.

  10. MD2 expression is reduced in large airways of smokers and COPD smokers.

    PubMed

    Pace, Elisabetta; Ferraro, Maria; Chiappara, Giuseppina; Vitulo, Patrizio; Pipitone, Loredana; Di Vincenzo, Serena; Gjomarkaj, Mark

    2015-09-01

    Toll-like receptor 4 (TLR4) signaling requires a number of accessory proteins to initiate a signal. MD-2 is one of the accessory proteins with a relevant role in lipopolysaccharide responses. Although cigarette smoke increases TLR4 expression, TLR4 signaling is altered in smokers and in smokers COPD patients. The main aims of this study were to explore whether MD2 is altered in large and small airways of COPD and of smokers without COPD. The expression of MD2 ex vivo was assessed by immunohistochemistry in surgical specimens from current smokers COPD (s-COPD; n = 14), smokers without COPD (S; n = 7), and from non-smoker non-COPD subjects (C; n = 11. The in vitro effects of cigarette smoke extracts on the MD2 expression in a human bronchial epithelial cell line (16-HBE) were also assessed by flow cytometry. MD2 is reduced in the epithelium and in the submucosa in large airways but not in the epithelium and in the submucosa in small airways of smokers and of s-COPD. The expression of MD2 in the submucosa of the large airways is significantly higher in comparison to the submucosa of the small airways in all the studied groups. In vitro, cigarette smoke is able to increase TLR4 but it reduces MD2 in a dose-dependent manner in bronchial epithelial cells. Cigarette smoke may alter innate immune responses reducing the expression of the MD2, a molecule with an important role in TLR4 signaling.

  11. The Δ133p53 Isoform Reduces Wtp53-induced Stimulation of DNA Pol γ Activity in the Presence and Absence of D4T

    PubMed Central

    Liu, Kai; Zang, Yunjin; Guo, Xianghua; Wei, Feili; Yin, Jiming; Pang, Lijun; Chen, Dexi

    2017-01-01

    The mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTIs) is due to the inhibition of mitochondrial DNA (mtDNA) polymerase γ (pol γ). Previous studies have shown that wild type p53 (wtp53) can interact with pol γ and mtDNA to enhance mitochondrial DNA base excision repair (mtBER) activity and increase the accuracy of DNA synthesis. The N-terminal transactivation domain and central specific DNA-binding domain of p53 play critical roles in the stimulation of BER. In this study, we identified the possible roles of wtp53, Δ40p53 and Δ133p53 in regulating mtDNA pol γ activity in cells with d4T treatment. The results show that Δ40p53 and Δ133p53 can exist in mitochondrial fragments and form polymers with themselves or wtp53. Unlike wtP53, Δ133p53 alone cannot increase DNA pol γ activity. More importantly, we found that Δ133p53 played a negative role in p53 stimulation of DNA pol γ activity when studied in d4T-treated and d4T-untreated mitochondrial extracts. Gel shift data also indicate that Δ40p53 and Δ133p53 cannot interact with APE. Wtp53 and Δ40p53 can act antagonize the effect of d4T inhibition of DNA pol γ activity. However, when wtp53 interacted with Δ133p53, DNA pol γ activity was significantly decreased. Conclusion: Δ133p53 negatively regulates p53’s stimulation of pol γ in the presence and absence of d4T. PMID:28400988

  12. Lesion of the Ventral Periaqueductal Gray Reduces Conditioned Fear but Does Not Change Freezing Induced by Stimulation of the Dorsal Periaqueductal Gray

    PubMed Central

    Vianna, Daniel M.L.; Graeff, Frederico G.; Landeira-Fernandez, Jesus; Brandão, Marcus L.

    2001-01-01

    Previously-reported evidence showed that freezing to a context previously associated with footshock is impaired by lesion of the ventral periaqueductal gray (vPAG). It has also been shown that stepwise increase in the intensity of the electrical stimulation of the dorsal periaqueductal gray (dPAG) produces alertness, then freezing, and finally escape. These aversive responses are mimicked by microinjections of GABA receptor antagonists, such as bicuculline, or blockers of the glutamic acid decarboxylase (GAD), such as semicarbazide, into the dPAG. In this work, we examined whether the expression of these defensive responses could be the result of activation of ventral portion of the periaqueductal gray. Sham- or vPAG electrolytic–lesioned rats were implanted with an electrode in the dPAG for the determination of the thresholds of freezing and escape responses. The vPAG electrolytic lesions were behaviorally verified through a context-conditioned fear paradigm. Results indicated that lesion of the vPAG disrupted conditioned freezing response to contextual cues associated with footshocks but did not change the dPAG electrical stimulation for freezing and escape responses. In a second experiment, lesion of the vPAG also did not change the amount of freezing and escape behavior produced by microinjections of semicarbazide into the dPAG. These findings indicate that freezing and escape defensive responses induced by dPAG stimulation do not depend on the integrity of the vPAG. A discussion on different neural circuitries that might underlie different inhibitory and active defensive behavioral patterns that animals display during threatening situations is presented. PMID:11390636

  13. Reduced HIV-stimulated T-helper cell reactivity in cord blood with short-course antiretroviral treatment for prevention of maternal–infant transmission

    PubMed Central

    Kuhn, L; Meddows-Taylor, S; Gray, G; Trabattoni, D; Clerici, M; Shearer, G M; Tiemessen, C

    2001-01-01

    T-helper cell responses to HIV have been associated with protection against maternal-infant HIV transmission in the absence of antiretroviral treatment, but the effects of antiretroviral treatment, now widely used for prevention, on development of these cell-mediated responses is unknown. We tested whether development of T-helper cell responses to HIV and other antigens would be affected by exposure to short-course regimens of zidovudine-lamivudine (ZDV-3TC) given to prevent maternal-infant HIV transmission. Cord blood samples were collected from 41 infants of HIV-infected mothers enrolled in a clinical trial in which they were treated with regimens of ZDV-3TC and from 29 infants whose HIV-infected mothers were not treated with any antiretroviral drugs. T-helper cell reactivity to HIV envelope peptides and other antigens was measured in vitro using a sensitive culture supernatant titration assay based on IL-2-dependent proliferation. Infants in the clinical trial were followed to 18 months to determine their HIV infection status, and venous blood samples were re-tested at 4·5 and 9 months for T-cell reactivity to HIV. HIV-stimulated T-helper cell reactivity in cord blood was detected 10-fold less frequently among those exposed to antiretroviral prophylaxis (2·4%) than among those unexposed (24·1%) (P = 0·007). Reductions in HIV-stimulated responses in cord blood occurred despite detectable HIV RNA (mean 3·38 standard deviation 0·76 log10 copies per ml) at delivery among treated women and occurred independent of treatment duration. Our results suggest that short-course antiretroviral treatment given to prevent maternal-infant HIV transmission may attenuate HIV-stimulated T-cell memory responses in the neonate. PMID:11298132

  14. Cathodic Voltage-controlled Electrical Stimulation Plus Prolonged Vancomycin Reduce Bacterial Burden of a Titanium Implant-associated Infection in a Rodent Model.

    PubMed

    Nodzo, Scott R; Tobias, Menachem; Ahn, Richard; Hansen, Lisa; Luke-Marshall, Nicole R; Howard, Craig; Wild, Linda; Campagnari, Anthony A; Ehrensberger, Mark T

    2016-07-01

    Cathodic voltage-controlled electrical stimulation (CVCES) of titanium implants, either alone or combined with a short course of vancomycin, has previously been shown to reduce the bone and implant bacterial burden in a rodent model of methicillin-resistant Staphylococcus aureus (MRSA) implant-associated infection (IAI). Clinically, the goal is to achieve complete eradication of the IAI; therefore, the rationale for the present study was to evaluate the antimicrobial effects of combining CVCES with prolonged antibiotic therapy with the goal of decreasing the colony-forming units (CFUs) to undetectable levels. (1) In an animal MRSA IAI model, does combining CVCES with prolonged vancomycin therapy decrease bacteria burden on the implant and surrounding bone to undetectable levels? (2) When used with prolonged vancomycin therapy, are two CVCES treatments more effective than one? (3) What are the longer term histologic effects (inflammation and granulation tissue) of CVCES on the surrounding tissue? Twenty adult male Long-Evans rats with surgically placed shoulder titanium implants were infected with a clinical strain of MRSA (NRS70). One week after infection, the rats were randomly divided into four groups of five: (1) VANCO: only vancomycin treatment (150 mg/kg, subcutaneous, twice daily for 5 weeks); (2) VANCO + 1STIM: vancomycin treatment (same as the VANCO group) coupled with one CVCES treatment (-1.8 V for 1 hour on postoperative day [POD] 7); (3) VANCO + 2STIM: vancomycin treatment (same as the VANCO group) coupled with two CVCES treatments (-1.8 V for 1 hour on POD 7 and POD 21); or (4) CONT: no treatment. On POD 42, the implant, bone, and peripheral blood were collected for CFU enumeration and histological analysis, where we compared CFU/mL on the implants and bone among the groups. A pathologist, blinded to the experimental conditions, performed a semiquantitative analysis of inflammation and granulation tissue present in serial sections of the humeral head

  15. Reduced response of splenocytes after mitogen-stimulation in the prion protein (PrP) gene-deficient mouse: PrPLP/Doppel production and cerebral degeneration

    SciTech Connect

    Kim, Chi-Kyeong; Hirose, Yuko; Sakudo, Akikazu; Takeyama, Natsumi; Kang, Chung-Boo; Taniuchi, Yojiro; Matsumoto, Yoshitsugu; Itohara, Shigeyoshi; Sakaguchi, Suehiro; Onodera, Takashi . E-mail: aonoder@mail.ecc.u-tokyo.ac.jp

    2007-06-29

    Splenocytes of wild-type (Prnp {sup +/+}) and prion protein gene-deficient (Prnp {sup -/-}) mice were treated with various activation stimuli such as T cell mitogen concanavalin A (ConA), phorbol 12-myristate 13-acetate (PMA) + ionomycin (Io), or B cell mitogen lipopolysaccharide (LPS). Cellular prion protein (PrP{sup C}) expression was enhanced following ConA stimulation, but not PMA + Io or LPS in Prnp {sup +/+} splenocytes. Rikn Prnp {sup -/-} splenocytes elicited lower cell proliferations than Prnp {sup +/+} or Zrch I Prnp {sup -/-} splenocytes after LPS stimulation and showed sporadic nerve cells in the cerebral cortex and deeper structure. Around the degenerated nerve cells, mild vacuolation in the neuropil was observed. This neural alteration correlated well to the suppressed response of B cells in the spleen. The finding that discrete lesions within the central nervous systems induced marked modulation of immune function probably indicates the existence of a delicately balanced neural-endocrine network by PrP{sup C} and PrPLP/Doppel.

  16. Transcutaneous electrical nerve stimulation on Yongquan acupoint reduces CFA-induced thermal hyperalgesia of rats via down-regulation of ERK2 phosphorylation and c-Fos expression.

    PubMed

    Yang, Lin; Yang, Lianxue; Gao, Xiulai

    2010-07-01

    Activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and its involvement in regulating gene expression in spinal dorsal horn, cortical and subcortical neurons by peripheral noxious stimulation contribute to pain hypersensitivity. Transcutaneous electrical nerve stimulation (TENS) is a treatment used in physiotherapy practice to promote analgesia in acute and chronic inflammatory conditions. In this study, a total number of 114 rats were used for three experiments. Effects of complete Freund's adjuvant (CFA)-induced inflammatory pain hypersensitivity and TENS analgesia on ERK1/2 phosphorylation and c-Fos protein expression were examined by using behavioral test, Western blot, and immunostaining methods. We found that CFA injection caused an area of localized swelling, erythema, hypersensitivity to thermal stimuli, the decreased response time of hind paw licking (HPL), as well as upregulation of c-Fos protein expression and ERK2 phosphorylation in the ipsilateral spinal dorsal horn and the contralateral primary somatosensory area of cortex and the amygdala of rats. TENS on Yongquan acupoint for 20 min produced obvious analgesic effects as demonstrated with increased HPL to thermal stimuli of CFA-treated rats. In addition, TENS application suppressed the CFA-induced ERK2 activation and c-Fos protein expression. These results suggest that down-regulation of ERK2 phosphorylation and c-Fos expression were involved in TENS inhibition on CFA-induced thermal hyperalgesia of rats.

  17. High-frequency transcranial magnetic stimulation of the supplementary motor area reduces bimanual coupling during anti-phase but not in-phase movements.

    PubMed

    Steyvers, Maarten; Etoh, Seiji; Sauner, Dieter; Levin, Oron; Siebner, Hartwig R; Swinnen, Stephan P; Rothwell, John C

    2003-08-01

    Previous electrophysiological and neuroimaging studies have provided evidence that the supplementary motor area (SMA) has an important role in the control of bimanual coordination. The present experiment investigated the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the SMA region on kinematic variables during cyclical bimanual coordination, with a particular focus on the quality of coordination. Subjects performed metronome-paced trials of in-phase and anti-phase bimanual index-finger movements at near-maximal cycling frequency. During movement execution, rTMS (20 Hz, 0.5 s, 120% hand motor threshold) was applied over one of three positions in the sagittal midline 2.0, 4.0 and 6.0 cm anterior to the primary motor leg area. Sham rTMS was included as a control condition. After rTMS, the mean relative phase error between hands increased, but only in the anti-phase trials. The maximum increase in phase error occurred immediately after rather than during the rTMS train. The effect was largest after stimulation 4 or 6 cm anterior to the leg area of the primary motor cortex. We did not observe any changes in the variability of relative phase or in cycle duration or movement amplitude. Findings are discussed in light of recent functional models on the role of the SMA in bimanual movement control.

  18. Paediatric Crohn disease patients with stricturing behaviour exhibit ileal granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody production and reduced neutrophil bacterial killing and GM-CSF bioactivity.

    PubMed

    Jurickova, I; Collins, M H; Chalk, C; Seese, A; Bezold, R; Lake, K; von Allmen, D; Frischer, J S; Falcone, R A; Trapnell, B C; Denson, L A

    2013-06-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies are associated with stricturing behaviour in Crohn disease (CD). We hypothesized that CD ileal lamina propria mononuclear cells (LPMC) would produce GM-CSF autoantibodies and peripheral blood (PB) samples would contain GM-CSF neutralizing capacity (NC). Paediatric CD and control PBMC and ileal biopsies or LPMC were isolated and cultured and GM-CSF, immunoglobulin (Ig)G and GM-CSF autoantibodies production were measured by enzyme-linked immunosorbent assay (ELISA). Basal and GM-CSF-primed neutrophil bacterial killing and signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation (pSTAT5) were measured by flow cytometry. GM-CSF autoantibodies were enriched within total IgG for LPMC isolated from CD ileal strictures and proximal margins compared to control ileum. Neutrophil bacterial killing was reduced in CD patients compared to controls. Within CD, neutrophil GM-CSF-dependent STAT5 activation and bacterial killing were reduced as GM-CSF autoantibodies increased. GM-CSF stimulation of pSTAT5 did not vary between controls and CD patients in washed PB granulocytes in which serum was removed. However, GM-CSF stimulation of pSTAT5 was reduced in whole PB samples from CD patients. These data were used to calculate the GM-CSF NC. CD patients with GM-CSF NC greater than 25% exhibited a fourfold higher rate of stricturing behaviour and surgery. The likelihood ratio (95% confidence interval) for stricturing behaviour for patients with elevation in both GM-CSF autoantibodies and GM-CSF NC was equal to 5 (2, 11). GM-CSF autoantibodies are produced by LPMC isolated from CD ileal resection specimens and are associated with reduced neutrophil bacterial killing. CD peripheral blood contains GM-CSF NC, which is associated with increased rates of stricturing behaviour. © 2013 British Society for Immunology.

  19. Paediatric Crohn disease patients with stricturing behaviour exhibit ileal granulocyte–macrophage colony-stimulating factor (GM-CSF) autoantibody production and reduced neutrophil bacterial killing and GM-CSF bioactivity

    PubMed Central

    Jurickova, I; Collins, M H; Chalk, C; Seese, A; Bezold, R; Lake, K; Allmen, D; Frischer, J S; Falcone, R A; Trapnell, B C; Denson, L A

    2013-01-01

    Granulocyte–macrophage colony-stimulating factor (GM-CSF) autoantibodies are associated with stricturing behaviour in Crohn disease (CD). We hypothesized that CD ileal lamina propria mononuclear cells (LPMC) would produce GM-CSF autoantibodies and peripheral blood (PB) samples would contain GM-CSF neutralizing capacity (NC). Paediatric CD and control PBMC and ileal biopsies or LPMC were isolated and cultured and GM-CSF, immunoglobulin (Ig)G and GM-CSF autoantibodies production were measured by enzyme-linked immunosorbent assay (ELISA). Basal and GM-CSF-primed neutrophil bacterial killing and signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation (pSTAT5) were measured by flow cytometry. GM-CSF autoantibodies were enriched within total IgG for LPMC isolated from CD ileal strictures and proximal margins compared to control ileum. Neutrophil bacterial killing was reduced in CD patients compared to controls. Within CD, neutrophil GM-CSF-dependent STAT5 activation and bacterial killing were reduced as GM-CSF autoantibodies increased. GM-CSF stimulation of pSTAT5 did not vary between controls and CD patients in washed PB granulocytes in which serum was removed. However, GM-CSF stimulation of pSTAT5 was reduced in whole PB samples from CD patients. These data were used to calculate the GM-CSF NC. CD patients with GM-CSF NC greater than 25% exhibited a fourfold higher rate of stricturing behaviour and surgery. The likelihood ratio (95% confidence interval) for stricturing behaviour for patients with elevation in both GM-CSF autoantibodies and GM-CSF NC was equal to 5 (2, 11). GM-CSF autoantibodies are produced by LPMC isolated from CD ileal resection specimens and are associated with reduced neutrophil bacterial killing. CD peripheral blood contains GM-CSF NC, which is associated with increased rates of stricturing behaviour. PMID:23600834

  20. Bone marrow stromal cells from aged male rats have delayed mineralization and reduced response to mechanical stimulation through nitric oxide and ERK1/2 signaling during osteogenic differentiation.

    PubMed

    Joiner, Danese M; Tayim, Riyad J; Kadado, Allen; Goldstein, Steven A

    2012-10-01

    Bone marrow stromal cells (MSCs) are a source of osteoblast precursors that can be recruited during bone remodeling or injury, both important processes in aging populations. With advancing age, alterations in bone structure and mineralization are often associated with an increase in osteoporosis and fracture risk. Changes in the number of osteoprogenitor cells and their osteogenic potential may occur with advancing age; however few studies have considered the influence of mechanical conditions. Here, we investigated the ability of bone MSCs from mature and aged rats to differentiate into osteoblasts and to respond to short and long periods of mechanical stimulation through signaling by ERK1/2, nitric oxide (NO), and prostaglandin E(2) (PGE(2)) during differentiation. Mineralization was delayed and reduced, but extracellular matrix production appeared less affected by increased age. Differentiating MSCs from aged animals had a decreased response to short and long periods of mechanical stimulation through ERK1/2 signaling, and to long periods of mechanical loading through NO signaling early and late during differentiation. Increases in relative PGE(2) signaling were higher in MSCs from aged animals, which could compensate for reduced ERK1/2 and NO signaling. The decreased mineralization may decrease the ability of cells from aged animals to respond to mechanical stimulation through ERK1/2 and NO signaling, with increased impairment over differentiation time. Decreasing the delay in mineralization of MSCs from aging animals might improve their ability to respond to mechanical stimulation during bone remodeling and injury, suggesting therapies for bone fragility diseases and tissue engineering treatments in elderly populations.

  1. [HUMAN ADIPOSE-DERIVED STEM CELLS COMBINED WITH SMALL INTESNITAL SUBMUCOSA POWDER/CHITOSAN CHLORIDE-β-GLYCEROL PHOSPHATE DISODIUM-HYDROXYETHYL CELLULOSE HYBRID FOR ADIPOSE TISSUE ENGINEERING].

    PubMed

    Zhang, Shu; Luo, Jingcong; Lü, Qing; Deng, Xueqin; Xiong, Bingjun

    2015-08-01

    To study the feasibility of human adipose-derived stem cells (hADSCs) combined with small intestinal submucosa powder (SISP)/chitosan chloride (CSCl)-β-glycerol phosphate disodium (GP)-hydroxyethyl cellulose (HEC) for adipose tissue engineering. hADSCs were isolated from human breast fat with collagenase type I digestion, and the third passage hADSCs were mixed with SISP/CSCl-GP-HEC at a density of 1 x 10(6) cells/mL. Twenty-four healthy female nude mice of 5 weeks old were randomly divided into experimental group (n = 12) and control group (n=12), and the mice were subcutaneously injected with 1 mL hADSCs+SISP/CSCl-GP-HEC or SISP/CSCl-GP-HEC respectively at the neck. The degradation rate was evaluated by implant volume measurement at 0, 1, 2, 4, and 8 weeks. Three mice were euthanized at 1, 2, 4, and 8 weeks respectively for general, histological, and immunohistochemical observations. The ability of adipogenesis (Oil O staining), angiopoiesis (CD31), and localized the hADSCs (immunostaining for human Vimentin) were identified. The volume of implants of both groups decreased with time, but it was greater in experimental group than the control group, showing significant difference at 8 weeks (t = 3.348, P = 0.029). The general observation showed that the border of implants was clear with no adhesion at each time point; fat-liked new tissues were observed with capillaries on the surface at 8 weeks in 2 groups. The histological examinations showed that the structure of implants got compact gradually after injection, and SISP gradually degraded with slower degradation speed in experimental group; adipose tissue began to form, and some mature adipose tissue was observed at 8 weeks in the experimental group. The Oil O staining positive area of experimental group was greater than that of the control group at each time point, showing significant difference at 8 weeks (t = 3.41 1, P = 0.027). Immunohistochemical staining for Vemintin showed that hADSCs could survive at

  2. Qualitative Neuromuscular Monitoring: How to Optimize the Use of a Peripheral Nerve Stimulator to Reduce the Risk of Residual Neuromuscular Blockade.

    PubMed

    Thilen, Stephan R; Bhananker, Sanjay M

    This review provides recommendations for anesthesia providers who may not yet have quantitative monitoring and sugammadex available and thus are providing care within the limitations of a conventional peripheral nerve stimulator (PNS) and neostigmine. In order to achieve best results, the provider needs to understand the limitations of the PNS. The PNS should be applied properly and early. All overdosing of neuromuscular blocking drugs should be avoided and the intraoperative neuromuscular blockade should be maintained only as deep as necessary. The adductor pollicis is the gold standard site and must be used for the pre-reversal assessment, also when the ulnar nerve and thumb were not accessible intraoperatively. Spontaneous recovery should be maximized and neostigmine should be administered after a TOF count of 4 has been confirmed at the adductor pollicis. Extubation should not occur within 10 min after administration of an appropriate dose of neostigmine.

  3. Reduced interferon-alpha production by Epstein-Barr virus transformed B-lymphoblastoid cell lines and lectin-stimulated lymphocytes in congenital dyserythropoietic anaemia type I.

    PubMed

    Wickramasinghe, S N; Hasan, R; Smythe, J

    1997-08-01

    The concentrations of interferon-alpha (IFN-alpha) in supernatants from cultures of Epstein-Barr virus (EBV) transformed B-lymphoblastoid cell lines derived from seven patients with congenital dyserythropoietic anaemia (CDA) type I were below the 95% confidence limits for those derived from six healthy subjects. In contrast, the concentrations of IFN-alpha in supernatants from cultures of EBV-transformed lymphoblastoid cell lines derived from four patients with other types of CDA and four patients with hereditary sideroblastic anaemia were normal. Supernatants from cultures of peripheral blood lymphocytes stimulated with phytohaemagglutinin or pokeweed mitogen contained less IFN-alpha when the cells were derived from patients with CDA type I than when derived from healthy subjects. Since patients with CDA type I show a substantial haematological response to treatment with IFN-alpha, the data suggest that impaired IFN-alpha production may be an important pathogenetic mechanism in CDA type I.

  4. Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor-expressing endothelial cells exhibit reduced migration and stimulated chemotaxis by chemokine inverse agonists.

    PubMed

    Couty, Jean-Pierre; Lupu-Meiri, Monica; Oron, Yoram; Gershengorn, Marvin C

    2009-06-01

    A constitutively active G protein-coupled receptor (GPCR) encoded by Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) (KSHV) is expressed in endothelial (spindle) cells of Kaposi's sarcoma lesions. In this study, we report novel effects of basal signaling by this receptor and of inverse agonist chemokines on migration of KSHV-GPCR-expressing mouse lung endothelial cells. We show that basal signaling by KSHV-GPCR inhibits migration of endothelial cells in two systems, movement through porous filters and in vitro wound closure. Naturally occurring chemokines, interferon gamma-inducible protein-10 and stromal-derived factor-1, which act as inverse agonists at KSHV-GPCR, abrogate the inhibition of migration and stimulate directed migration (or chemotaxis) of these cells. Thus, the expression of KSHV-GPCR may allow infected endothelial cells in situ to remain in a localized environment or to directionally migrate along a gradient of specific chemokines that are inverse agonists at KSHV-GPCR.

  5. An apolipoprotein A-I mimetic peptide designed with a reductionist approach stimulates reverse cholesterol transport and reduces atherosclerosis in mice.

    PubMed

    Ditiatkovski, Michael; D'Souza, Wilissa; Kesani, Rajitha; Chin-Dusting, Jaye; de Haan, Judy B; Remaley, Alan; Sviridov, Dmitri

    2013-01-01

    Apolipoprotein A-I (apoA-I) mimetic peptides are considered a promising novel therapeutic approach to prevent and/or treat atherosclerosis. An apoA-I mimetic peptide ELK-2A2K2E was designed with a reductionist approach and has shown exceptional activity in supporting cholesterol efflux but modest anti-inflammatory and anti-oxidant properties in vitro. In this study we compared these in vitro properties with the capacity of this peptide to modify rates of reverse cholesterol transport and development of atherosclerosis in mouse models. The peptide enhanced the rate of reverse cholesterol transport in C57BL/6 mice and reduced atherosclerosis in Apoe(-/-) mice receiving a high fat diet. The peptide modestly reduced the size of the plaques in aortic arch, but was highly active in reducing vascular inflammation and oxidation. Administration of the peptide to Apoe(-/-) mice on a high fat diet reduced the levels of total, high density lipoprotein and non-high density lipoprotein cholesterol and triglycerides. It increased the proportion of smaller HDL particles in plasma at the expense of larger HDL particles, and increased the capacity of the plasma to support cholesterol efflux. Thus, ELK-2A2K2E peptide reduced atherosclerosis in Apoe(-/-) mice, however, the functional activity profile after chronic in vivo administration was different from that found in acute in vitro studies.

  6. The group II metabotropic glutamate receptor agonist LY379268 reduces toluene-induced enhancement of brain-stimulation reward and behavioral disturbances

    PubMed Central

    Chan, Ming-Huan; Tsai, Yi-Ling; Lee, Mei-Yi; Stoker, Astrid K.; Markou, Athina; Chen, Hwei-Hsien

    2015-01-01

    Toluene, a widely abused solvent with demonstrated addictive potential in humans, has been reported to negatively modulate N-methyl-D-aspartate receptors (NMDARs) and alter glutamatergic neurotransmission. The group II metabotropic glutamate receptor (mGluR) agonist LY379268 has been shown to regulate glutamate release transmission and NMDAR function and block toluene-induced locomotor hyperactivity. However, remaining unknown is whether group II mGluRs are involved in the toluene-induced reward-facilitating effect and other behavioral manifestations. The present study evaluated the effects of LY379268 on toluene-induced reward enhancement, motor incoordination, recognition memory impairment, and social interaction deficits. Our data demonstrated that LY379268 significantly reversed the toluene-induced lowering of intracranial self-stimulation (ICSS) thresholds and impairments in novel object recognition, rotarod performance, and social interaction with different potencies. These results indicate a negative modulatory role of group II mGluRs in acute toluene-induced reward-facilitating and behavioral effects and suggest that group II mGluR agonists may have therapeutic potential for toluene addiction and the prevention of toluene intoxication caused by occupational or intentional exposure. PMID:26044619

  7. The group II metabotropic glutamate receptor agonist LY379268 reduces toluene-induced enhancement of brain-stimulation reward and behavioral disturbances.

    PubMed

    Chan, Ming-Huan; Tsai, Yi-Ling; Lee, Mei-Yi; Stoker, Astrid K; Markou, Athina; Chen, Hwei-Hsien

    2015-09-01

    Toluene, a widely abused solvent with demonstrated addictive potential in humans, hasbeen reported to negatively modulate N-methyl-D-aspartate receptors (NMDARs) and alter glutamatergicneurotransmission. The group II metabotropic glutamate receptor (mGluR) agonist LY379268 has beenshown to regulate glutamate release transmission and NMDAR function and block toluene-induced locomotorhyperactivity. However, remaining unknown is whether group II mGluRs are involved in the toluene-induced reward-facilitating effect and other behavioral manifestations. The present study evaluated the effects of LY379268 on toluene-induced reward enhancement, motor incoordination, recognition memory impairment, and social interaction deficits. Our data demonstrated that LY379268 significantly reversed the toluene-induced lowering of intracranial self-stimulation (ICSS) thresholds and impairments in novel object recognition, rotarod performance, and social interaction with different potencies. These results indicate a negative modulatory role of group II mGluRs in acute toluene-induced reward-facilitating and behavioral effects and suggest that group II mGluR agonists may have therapeutic potential for toluene addiction and the prevention of toluene intoxication caused by occupational or intentional exposure.

  8. Identification of the first biased NPS receptor agonist that retains anxiolytic and memory promoting effects with reduced levels of locomotor stimulation.

    PubMed

    Clark, Stewart D; Kenakin, Terrence P; Gertz, Steven; Hassler, Carla; Gay, Elaine A; Langston, Tiffany L; Reinscheid, Rainer K; Runyon, Scott P

    2017-03-03

    The neuropeptide S system has been implicated in a number of centrally mediated behaviors including memory consolidation, anxiolysis, and increased locomotor activity. Characterization of these behaviors has been primarily accomplished using the endogenous 20AA peptide (NPS) that demonstrates relatively equal potency for the calcium mobilization and cAMP second messenger pathways at human and rodent NPS receptors. This study is the first to demonstrate that truncations of the NPS peptide provides small fragments that retain significant potency only at one of two single polymorphism variants known to alter NPSR function (NPSR-107I), yet demonstrate a strong level of bias for the calcium mobilization pathway over the cAMP pathway. We have also determined that the length of the truncated peptide correlates with the degree of bias for the calcium mobilization pathway. A modified tetrapeptide analog (4) has greatly attenuated hyperlocomotor stimulation in vivo but retains activity in assays that correlate with memory consolidation and anxiolytic activity. Analog 4 also has a bias for the calcium mobilization pathway, at the human and mouse receptor. This suggests that future agonist ligands for the NPS receptor having a bias for calcium mobilization over cAMP production will function as non-stimulatory anxiolytics that augment memory formation.

  9. Stimulation of adenosine A2A receptors reduces intracellular cholesterol accumulation and rescues mitochondrial abnormalities in human neural cell models of Niemann-Pick C1.

    PubMed

    Ferrante, A; De Nuccio, C; Pepponi, R; Visentin, S; Martire, A; Bernardo, A; Minghetti, L; Popoli, P

    2016-04-01

    Niemann Pick C 1 (NPC1) disease is an incurable, devastating lysosomal-lipid storage disorder characterized by hepatosplenomegaly, progressive neurological impairment and early death. Current treatments are very limited and the research of new therapeutic targets is thus mandatory. We recently showed that the stimulation of adenosine A2A receptors (A2ARs) rescues the abnormal phenotype of fibroblasts from NPC1 patients suggesting that A2AR agonists could represent a therapeutic option for this disease. However, since all NPC1 patients develop severe neurological symptoms which can be ascribed to the complex pathology occurring in both neurons and oligodendrocytes, in the present paper we tested the effects of the A2AR agonist CGS21680 in human neuronal and oligodendroglial NPC1 cell lines (i.e. neuroblastoma SH-SY5Y and oligodendroglial MO3.13 transiently transfected with NPC1 small interfering RNA). The down-regulation of the NPC1 protein effectively resulted in intracellular cholesterol accumulation and altered mitochondrial membrane potential. Both effects were significantly attenuated by CGS21680 (500 nM). The protective effects of CGS were prevented by the selective A2AR antagonist ZM241385 (500 nM). The involvement of calcium modulation was demonstrated by the ability of Bapta-AM (5-7 μM) in reverting the effect of CGS. The A2A-dependent activity was prevented by the PKA-inhibitor KT5720, thus showing the involvement of the cAMP/PKA signaling. These findings provide a clear in vitro proof of concept that A2AR agonists are promising potential drugs for NPC disease.

  10. Reduced Mirror Neuron Activity in Schizophrenia and Its Association With Theory of Mind Deficits: Evidence From a Transcranial Magnetic Stimulation Study

    PubMed Central

    Mehta, Urvakhsh Meherwan; Thirthalli, Jagadisha; Basavaraju, Rakshathi; Gangadhar, Bangalore N.; Pascual-Leone, Alvaro

    2014-01-01

    Background: The “mirror-neuron system” has been proposed to be a neurophysiological substrate for social cognition (SC) ability. We used transcranial magnetic stimulation (TMS) paradigms to compare putative mirror neuron activity (MNA) in 3 groups: antipsychotic-naive, medicated schizophrenia patients, and healthy comparison subjects. We also explored the association between MNA and SC ability in patients. Methods: Fifty-four consenting right-handed schizophrenia patients (33 antipsychotic naive) and 45 matched healthy comparison subjects completed a TMS experiment to assess putative premotor MNA. We used 4 TMS paradigms of eliciting motor-evoked potentials (MEP) in the right first dorsal interosseous (FDI) muscle. These were applied while the subjects observed a goal-directed action involving the FDI (actual action and its video) and a static image. The difference in the amplitude of the MEP while they observed the static image and the action provided a measure of MNA. Subjects also underwent SC assessments (theory of mind [ToM], emotion processing, and social perception). Results: Two-way repeated measures ANOVA revealed significant group × occasion interaction effect in 3 TMS paradigms, indicating deficient motor facilitation during action observation relative to rest state in antipsychotic-naive schizophrenia patients as compared with the other two groups. Among patients, there were significant direct correlations between measures of MNA and ToM performance. Conclusions: Antipsychotic-naive schizophrenia patients have poorer MNA than medicated patients and healthy controls. Measures of putative MNA had significant and consistent associations with ToM abilities. These findings suggest a possibility of deficient mirror neuron system underlying SC deficits in schizophrenia. PMID:24214933

  11. Short-term transcutaneous electrical nerve stimulation reduces pain and improves the masticatory muscle activity in temporomandibular disorder patients: a randomized controlled trial.

    PubMed

    Ferreira, Ana Paula de Lima; Costa, Dayse Regina Alves da; Oliveira, Ana Izabela Sobral de; Carvalho, Elyson Adam Nunes; Conti, Paulo César Rodrigues; Costa, Yuri Martins; Bonjardim, Leonardo Rigoldi

    2017-01-01

    To investigate the short-term effect of transcutaneous electrical nerve stimulation (TENS) by examining pain intensity, pressure pain threshold (PPT) and electromyography (EMG) activity in patients with temporomandibular disorder (TMD). Forty patients with myofascial TMD were enrolled in this randomized placebo-controlled trial and were divided into two groups: active (n=20) and placebo (n=20) TENS. Outcome variables assessed at baseline (T0), immediately after (T2) and 48 hours after treatment (T1) were: pain intensity with the aid of a visual analogue scale (VAS); PPT of masticatory and cervical structures; EMG activity during mandibular rest position (MR), maximal voluntary contraction (MVC) and habitual chewing (HC). Two-way ANOVA for repeated measures was applied to the data and the significance level was set at 5%. There was a decrease in the VAS values at T1 and T2 when compared with T0 values in the active TENS group (p<0.050). The PPT between-group differences were significant at T1 assessment of the anterior temporalis and sternocleidomastoid (SCM) and T2 for the masseter and the SCM (p<0.050). A significant EMG activity reduction of the masseter and anterior temporalis was presented in the active TENS during MR at T1 assessment when compared with T0 (p<0.050). The EMG activity of the anterior temporalis was significantly higher in the active TENS during MVC at T1 and T2 when compared with placebo (p<0.050). The EMG activity of the masseter and anterior temporalis muscle was significantly higher in the active TENS during HC at T1 when compared with placebo (p<0.050). The short-term therapeutic effects of TENS are superior to those of the placebo, because of reported facial pain, deep pain sensitivity and masticatory muscle EMG activity improvement.

  12. Reduced mirror neuron activity in schizophrenia and its association with theory of mind deficits: evidence from a transcranial magnetic stimulation study.

    PubMed

    Mehta, Urvakhsh Meherwan; Thirthalli, Jagadisha; Basavaraju, Rakshathi; Gangadhar, Bangalore N; Pascual-Leone, Alvaro

    2014-09-01

    The "mirror-neuron system" has been proposed to be a neurophysiological substrate for social cognition (SC) ability. We used transcranial magnetic stimulation (TMS) paradigms to compare putative mirror neuron activity (MNA) in 3 groups: antipsychotic-naive, medicated schizophrenia patients, and healthy comparison subjects. We also explored the association between MNA and SC ability in patients. Fifty-four consenting right-handed schizophrenia patients (33 antipsychotic naive) and 45 matched healthy comparison subjects completed a TMS experiment to assess putative premotor MNA. We used 4 TMS paradigms of eliciting motor-evoked potentials (MEP) in the right first dorsal interosseous (FDI) muscle. These were applied while the subjects observed a goal-directed action involving the FDI (actual action and its video) and a static image. The difference in the amplitude of the MEP while they observed the static image and the action provided a measure of MNA. Subjects also underwent SC assessments (theory of mind [ToM], emotion processing, and social perception). Two-way repeated measures ANOVA revealed significant group × occasion interaction effect in 3 TMS paradigms, indicating deficient motor facilitation during action observation relative to rest state in antipsychotic-naive schizophrenia patients as compared with the other two groups. Among patients, there were significant direct correlations between measures of MNA and ToM performance. Antipsychotic-naive schizophrenia patients have poorer MNA than medicated patients and healthy controls. Measures of putative MNA had significant and consistent associations with ToM abilities. These findings suggest a possibility of deficient mirror neuron system underlying SC deficits in schizophrenia. © The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  13. Transcranial brain stimulation: closing the loop between brain and stimulation

    PubMed Central

    Karabanov, Anke; Thielscher, Axel; Siebner, Hartwig Roman

    2016-01-01

    Purpose of review To discuss recent strategies for boosting the efficacy of noninvasive transcranial brain stimulation to improve human brain function. Recent findings Recent research exposed substantial intra- and inter-individual variability in response to plasticity-inducing transcranial brain stimulation. Trait-related and state-related determinants contribute to this variability, challenging the standard approach to apply stimulation in a rigid, one-size-fits-all fashion. Several strategies have been identified to reduce variability and maximize the plasticity-inducing effects of noninvasive transcranial brain stimulation. Priming interventions or paired associative stimulation can be used to ‘standardize’ the brain-state and hereby, homogenize the group response to stimulation. Neuroanatomical and neurochemical profiling based on magnetic resonance imaging and spectroscopy can capture trait-related and state-related variability. Fluctuations in brain-states can be traced online with functional brain imaging and inform the timing or other settings of transcranial brain stimulation. State-informed open-loop stimulation is aligned to the expression of a predefined brain state, according to prespecified rules. In contrast, adaptive closed-loop stimulation dynamically adjusts stimulation settings based on the occurrence of stimulation-induced state changes. Summary Approaches that take into account trait-related and state-related determinants of stimulation-induced plasticity bear considerable potential to establish noninvasive transcranial brain stimulation as interventional therapeutic tool. PMID:27224087

  14. Vitamin D deficiency impairs glucose-stimulated insulin secretion and increases insulin resistance by reducing PPAR-γ expression in nonobese Type 2 diabetic rats.

    PubMed

    Park, Sunmin; Kim, Da Sol; Kang, Suna

    2016-01-01

    Human studies have provided relatively strong associations of poor vitamin D status with Type 2 diabetes but do not explain the nature of the association. Here, we explored the physiological pathways that may explain how vitamin D status modulates energy, lipid and glucose metabolisms in nonobese Type 2 diabetic rats. Goto-Kakizaki (GK) rats were fed high-fat diets containing 25 (VD-low), 1000 (VD-normal) or 10,000 (VD-high) cholecalciferol-IU/kg diet for 8 weeks. Energy expenditure, insulin resistance, insulin secretory capacity and lipid metabolism were measured. Serum 25-OH-D levels, an index of vitamin D status, increased dose dependently with dietary vitamin D. VD-low resulted in less fat oxidation without a significant difference in energy expenditure and less lean body mass in the abdomen and legs comparison to the VD-normal group. In comparison to VD-low, VD-normal had lower serum triglycerides and intracellular fat accumulation in the liver and skeletal muscles which was associated with down-regulation of the mRNA expressions of sterol regulatory element binding protein-1c and fatty acid synthase and up-regulation of gene expressions of peroxisome proliferator-activated receptors (PPAR)-α and carnitine palmitoyltransferase-1. In euglycemic hyperinsulinemic clamp, whole-body and hepatic insulin resistance was exacerbated in the VD-low group but not in the VD-normal group, possibly through decreasing hepatic insulin signaling and PPAR-γ expression in the adipocytes. In 3T3-L1 adipocytes 1,25-(OH)2-D (10 nM) increased triglyceride accumulation by elevating PPAR-γ expression and treatment with a PPAR-γ antagonist blocked the triglyceride deposition induced by 1,25-(OH)2-D treatment. VD-low impaired glucose-stimulated insulin secretion in hyperglycemic clamp and decreased β-cell mass by decreasing β-cell proliferation. In conclusion, vitamin D deficiency resulted in the dysregulation of glucose metabolism in GK rats by simultaneously increasing insulin

  15. Responders to Wide-Pulse, High-Frequency Neuromuscular Electrical Stimulation Show Reduced Metabolic Demand: A 31P-MRS Study in Humans

    PubMed Central

    Wegrzyk, Jennifer; Fouré, Alexandre; Le Fur, Yann; Maffiuletti, Nicola A.; Vilmen, Christophe; Guye, Maxime; Mattei, Jean-Pierre; Place, Nicolas; Bendahan, David; Gondin, Julien

    2015-01-01

    Conventional (CONV) neuromuscular electrical stimulation (NMES) (i.e., short pulse duration, low frequencies) induces a higher energetic response as compared to voluntary contractions (VOL). In contrast, wide-pulse, high-frequency (WPHF) NMES might elicit–at least in some subjects (i.e., responders)–a different motor unit recruitment compared to CONV that resembles the physiological muscle activation pattern of VOL. We therefore hypothesized that for these responder subjects, the metabolic demand of WPHF would be lower than CONV and comparable to VOL. 18 healthy subjects performed isometric plantar flexions at 10% of their maximal voluntary contraction force for CONV (25 Hz, 0.05 ms), WPHF (100 Hz, 1 ms) and VOL protocols. For each protocol, force time integral (FTI) was quantified and subjects were classified as responders and non-responders to WPHF based on k-means clustering analysis. Furthermore, a fatigue index based on FTI loss at the end of each protocol compared with the beginning of the protocol was calculated. Phosphocreatine depletion (ΔPCr) was assessed using 31P magnetic resonance spectroscopy. Responders developed four times higher FTI’s during WPHF (99 ± 37 ×103 N.s) than non-responders (26 ± 12 ×103 N.s). For both responders and non-responders, CONV was metabolically more demanding than VOL when ΔPCr was expressed relative to the FTI. Only for the responder group, the ∆PCr/FTI ratio of WPHF (0.74 ± 0.19 M/N.s) was significantly lower compared to CONV (1.48 ± 0.46 M/N.s) but similar to VOL (0.65 ± 0.21 M/N.s). Moreover, the fatigue index was not different between WPHF (-16%) and CONV (-25%) for the responders. WPHF could therefore be considered as the less demanding NMES modality–at least in this subgroup of subjects–by possibly exhibiting a muscle activation pattern similar to VOL contractions. PMID:26619330

  16. Short-term transcutaneous electrical nerve stimulation reduces pain and improves the masticatory muscle activity in temporomandibular disorder patients: a randomized controlled trial

    PubMed Central

    FERREIRA, Ana Paula de Lima; da COSTA, Dayse Regina Alves; de OLIVEIRA, Ana Izabela Sobral; CARVALHO, Elyson Adam Nunes; CONTI, Paulo César Rodrigues; COSTA, Yuri Martins; BONJARDIM, Leonardo Rigoldi

    2017-01-01

    Abstract Studies to assess the effects of therapies on pain and masticatory muscle function are scarce. Objective To investigate the short-term effect of transcutaneous electrical nerve stimulation (TENS) by examining pain intensity, pressure pain threshold (PPT) and electromyography (EMG) activity in patients with temporomandibular disorder (TMD). Material and Methods Forty patients with myofascial TMD were enrolled in this randomized placebo-controlled trial and were divided into two groups: active (n=20) and placebo (n=20) TENS. Outcome variables assessed at baseline (T0), immediately after (T2) and 48 hours after treatment (T1) were: pain intensity with the aid of a visual analogue scale (VAS); PPT of masticatory and cervical structures; EMG activity during mandibular rest position (MR), maximal voluntary contraction (MVC) and habitual chewing (HC). Two-way ANOVA for repeated measures was applied to the data and the significance level was set at 5%. Results There was a decrease in the VAS values at T1 and T2 when compared with T0 values in the active TENS group (p<0.050). The PPT between-group differences were significant at T1 assessment of the anterior temporalis and sternocleidomastoid (SCM) and T2 for the masseter and the SCM (p<0.050). A significant EMG activity reduction of the masseter and anterior temporalis was presented in the active TENS during MR at T1 assessment when compared with T0 (p<0.050). The EMG activity of the anterior temporalis was significantly higher in the active TENS during MVC at T1 and T2 when compared with placebo (p<0.050). The EMG activity of the masseter and anterior temporalis muscle was significantly higher in the active TENS during HC at T1 when compared with placebo (p<0.050). Conclusions The short-term therapeutic effects of TENS are superior to those of the placebo, because of reported facial pain, deep pain sensitivity and masticatory muscle EMG activity improvement. PMID:28403351

  17. Stimulation of sulfate-reducing bacteria in lake water from a former open-pit mine through addition of organic wastes

    SciTech Connect

    Castro, J.M.; Wielinga, B.W.; Gannon, J.E.; Moore, J.N.

    1999-03-01

    A method to improve water quality in a lake occupying a former open-pit mine was evaluated in a laboratory-scale study. Untreated pit lake water contained high levels of sulfate, iron, and arsenic and was mildly acidic ({approximately} pH 6). Varying amounts of two locally available organic waste products were added to pit water and maintained in microcosms under anoxic conditions. In selected microcosms, populations of sulfate-reducing bacteria increased with time; sulfide was generated by sulfate reduction; sulfate, iron, and arsenic concentrations approached zero; and pH approached neutrality. Best results were obtained with intermediate amounts of waste potato skin.

  18. Neonatal stimulation of 5-HT(2) receptors reduces androgen receptor expression in the rat anteroventral periventricular nucleus and sexually dimorphic preoptic area.

    PubMed

    Dakin, C L; Wilson, C A; Kalló, I; Coen, C W; Davies, D C

    2008-05-01

    Masculinization of the brain is dependent upon a perinatal surge in testosterone. It also requires a transient decrease in hypothalamic 5-HT concentration and turnover and an increase in androgen receptor (AR) expression during the second postnatal week. We have previously shown that increasing 5-HT activity over this period in male or androgenized female rats feminizes their adult behaviour and also feminizes the size of their anteroventral periventricular nucleus (AVPV) and sexually dimorphic nucleus of the preoptic area (SDN-POA). To investigate the role of 5-HT in sexual differentiation of the brain, 5-HT activity was raised over postnatal days 8-16 in male, female and androgenized female rats by daily administration of the 5-HT(2) receptor agonist (-)[2,5 dimethoxy-4-iodophenyl]-2-amino propane hydrochloride [(-)DOI]. By postnatal day 18, the size of the AVPV and SDN-POA was sexually dimorphic; their sizes were feminized by (-)DOI treatment. In the absence of (-)DOI treatment, there were significantly more AR-immunoreactive cells in the AVPV of males, and in the SDN-POA of males and androgenized females, than in those of females on postnatal day 18. (-)DOI treatment reduced the number of AR-immunoreactive cells in the AVPV and SDN-POA of males and androgenized females, but not of females, by postnatal day 18. These results suggest that 5-HT(2) receptor activation can influence sexual differentiation of the brain by controlling AR expression.

  19. 5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis

    PubMed Central

    Grace, Marcy B.; Singh, Vijay K.; Rhee, Juong G.; Jackson, William E.; Kao, Tzu-Cheg; Whitnall, Mark H.

    2012-01-01

    The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis. PMID:22843381

  20. 5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis.

    PubMed

    Grace, Marcy B; Singh, Vijay K; Rhee, Juong G; Jackson, William E; Kao, Tzu-Cheg; Whitnall, Mark H

    2012-11-01

    The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis.

  1. μ-Opioid receptor stimulation in the medial subnucleus of the tractus solitarius inhibits gastric tone and motility by reducing local GABA activity

    PubMed Central

    Herman, Melissa A.; Alayan, Alisa; Sahibzada, Niaz; Bayer, Barbara; Verbalis, Joseph; Dretchen, Kenneth L.

    2010-01-01

    We examined the effects of altering μ-opioid receptor (MOR) activity in the medial subnucleus of the tractus solitarius (mNTS) on several gastric end points including intragastric pressure (IGP), fundus tone, and the receptive relaxation reflex (RRR). Microinjection of the MOR agonist [d-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO; 1–10 fmol) into the mNTS produced dose-dependent decreases in IGP. Microinjection of the endogenous MOR agonists endomorphin-1 and endomorphin-2 (20 fmol) into the mNTS mimicked the effects of 10 fmol DAMGO. Microinjection of 1 and 100 pmol DAMGO into the mNTS produced a triphasic response consisting of an initial decrease, a transient increase, and a persistent decrease in IGP. The increase in IGP appeared to be due to diffusion to the dorsal motor nucleus of the vagus. The effects of 10 fmol DAMGO in the mNTS were blocked by vagotomy and by blockade of MORs, GABAA receptors, and ionotropic glutamate receptors in the mNTS. The RRR response was abolished by bilateral microinjection of the opioid receptor antagonist naltrexone into the mNTS and reduced by intravenous administration of naltrexone. Our data demonstrate that 1) activation of MORs in the mNTS with femtomole doses of agonist inhibits gastric motility, 2) the mechanism of MOR effects in the mNTS is through suppression of local GABA activity, and 3) blockade of MORs in the mNTS prevents the RRR response. These data suggest that opioids play an important role in mediating a vagovagal reflex through release of an endogenous opioid in the mNTS, which, in turn, inhibits ongoing local GABA activity and allows vagal sensory input to excite second-order mNTS neurons. PMID:20489046

  2. Fixed dose of long-acting erythropoietic stimulating agents at higher frequency improves appetite, reduces inflammation and corrects anaemia in patients on haemodialysis.

    PubMed

    Liu, Wen-Sheng; Chu, Da-Chen; Chan, Hsiang-Lin; Li, Szu-Yuan; Liu, Chih-Kuang; Yang, Chih-Yu; Chen, Yu-Wei; Lee, Pui-Ching; Lai, Yen-Ting; Lin, Chih-Ching

    2016-10-01

    Anaemia is an important issue in patients undergoing haemodialysis. We aimed to identify a better dosing schedule of a fixed monthly dose of continuous erythropoietin receptor activator (CERA) in patients with chronic kidney disease (CKD) on haemodialysis. The CERA dosing schedule included 100 μg once monthly for 2 months, 50 μg twice monthly for 2 months and then 100 μg once monthly for two months. The effectiveness was determined by comparing haematocrit, nutritional status (serum protein and albumin) and inflammatory markers (tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 and Hepcidin) at the beginning of the study with those at the end of the study. Forty-seven out of 67 patients completed the trial. At the end, haematocrit was significantly higher (34.51 vs 33.22%, P=.004), levels of inflammatory markers were significantly lower (TNF-α (30.71 vs 35.67 ng/mL, P=.007), IL-6 (5.12 vs 7.95 ng/mL, P=.033), hepcidin (60.39 vs 74.39 ng/mL, P=.002)), blood glucose levels were significantly lower (112.40 vs 139.02 mg/dL, P=.003) and albumin was significantly higher (4.11 vs 3.98, P=.001). Patients with a better than average response had a lower initial number of red blood cells (3.3 vs 3.6 × 10(6) /mm(3) , P=.025) and a lower IL-1 (3.8 vs 12.9 ng/mL, P=.01). They also had significantly lower blood glucose levels at the end. (91.3 vs 124.0 mg/dL, P=.03). We demonstrate that a fixed monthly dose of CERA at a twice monthly dosing schedule improves nutrition, reduces the inflammation and corrects anaemia in patients on haemodialysis. This finding may provide a new strategy for treating CKD-related anaemia. © 2016 John Wiley & Sons Australia, Ltd.

  3. Enhanced cognition and emotional recognition, and reduced obsessive compulsive symptoms in two adults with high-functioning autism as a result of deep Transcranial Magnetic Stimulation (dTMS): a case report.

    PubMed

    Avirame, Keren; Stehberg, Jimmy; Todder, Doron

    2017-08-08

    We report reduced repetitive behaviors similar to obsessive compulsive disorder and improved emotional recognition and cognitive abilities in two young patients diagnosed with high-functioning Autism as a result of deep transcranial magnetic stimulation (dTMS). The patients received daily high-frequency (5 Hz) dTMS with HAUT-coil over the medial prefrontal cortex for a period of 5-6 weeks. A computerized cognitive battery, tasks for testing emotional recognition, and clinical questionnaires were used to measure the effects of treatment. TMS might have modulated networks related to metalizing abilities and self-referential processes since both patients reported improved sociability and communication skills.

  4. Stimulating Curiosity.

    ERIC Educational Resources Information Center

    Necka, Edward

    1989-01-01

    Curiosity can be developed and nurtured through application of such educational principles as the rewarding of questioning, the use of open questions, delaying answers, accepting incompleteness in existing knowledge, etc. Teaching techniques for stimulating curiosity include brain questioning, role playing, hypothesizing, and pursuing curiosity.…

  5. Reduced miR-200b and miR-200c expression contributes to abnormal hepatic lipid accumulation by stimulating JUN expression and activating the transcription of srebp1

    PubMed Central

    Sun, Libo; Lu, Yonggang; Dou, Lin; Huang, Xiuqing; Sun, Mingxiao; Pang, Cheng; Qu, Jing; Liu, Guanghui; Li, Jian

    2016-01-01

    Previous studies indicated that miR-200s participated in IL-6-induced hepatic insulin resistance. However, the role of miR-200s in hepatic lipid accumulation has not been elucidated. Here we found that miR-200b and miR-200c were reduced in the steatotic livers of mice fed a high-fat diet (HFD) and patients with nonalcoholic fatty liver disease. This down-regulation was accompanied by an increase in the expression of lipogenic proteins such as sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS). The suppression of miR-200b and miR-200c in Hep1-6 and NCTC1469 hepatocytes enhanced intracellular triglyceride levels, which were associated with increased SREBP-1 and FAS protein levels. In contrast, the over-expression of miR-200b and miR-200c suppressed lipid accumulation and reduced the expression of SREBP1 and FAS in Hep1-6 and NCTC1469 cells transfected with miR-200b or miR-200c mimics. Importantly, the up-regulation of miR-200b and miR-200c could reverse oleic acid/palmitic acid-induced lipid accumulation in hepatocytes. A luciferase reporter assay identified that miR-200b and miR-200c could directly bind the 3′UTR of jun. JUN activated the transcription of srebp1 to increase lipid accumulation. The data also demonstrated that increased miR-200b and miR-200c expression might be associated with sitagliptin-reduced hepatic lipid accumulation in mice fed a HFD. These findings suggest, for the first time, that reduced miR-200b and miR-200c expression contributes to abnormal hepatic lipid accumulation by stimulating JUN expression and activating the transcription of srebp1. PMID:27166182

  6. Brain Stimulation Therapies

    MedlinePlus

    ... Magnetic Seizure Therapy Deep Brain Stimulation Additional Resources Brain Stimulation Therapies Overview Brain stimulation therapies can play ... for a shorter recovery time than ECT Deep Brain Stimulation Deep brain stimulation (DBS) was first developed ...

  7. Repetitive Transcranial Magnetic Stimulation (rTMS) improves symptoms and reduces clinical illness in patients suffering from OCD--Results from a single-blind, randomized clinical trial with sham cross-over condition.

    PubMed

    Haghighi, Mohammad; Shayganfard, Mehran; Jahangard, Leila; Ahmadpanah, Mohammad; Bajoghli, Hafez; Pirdehghan, Azar; Holsboer-Trachsler, Edith; Brand, Serge

    2015-09-01

    Both psychotherapeutic and psychopharmacological methods are used in the treatment of patients suffering from obsessive-compulsive disorders (OCD), and both with encouraging but also mixed results. Here, we tested the hypothesis that repetitive Transcranial Magnetic Stimulation (rTMS) improves symptoms and reduces illness severity in patients suffering from treatment-resistant OCD. A total of 21 patients (57% females; mean age: M = 35.8 years) suffering from treatment-resistant OCD were randomly assigned either to an rTMS-first-sham-second, or a sham-first-rTMS-second condition. Treatment sessions lasted for 4 weeks with five sessions per week, each of about 50 min duration. Symptoms were assessed via both self- and expert-ratings. Both self- and expert-reported symptom severity reduced in the rTMS condition as compared to the sham condition. Full- and partial responses were observed in the rTMS-condition, but not in the sham-condition. The pattern of results from this single-blind, sham- and cross-over design suggests that rTMS is a successful intervention for patients suffering from treatment-resistant OCD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Reduced Naive CD4 T Cell Numbers and Impaired Induction of CD27 in Response to T Cell Receptor Stimulation Reflect a State of Immune Activation in Chronic Hepatitis C Virus Infection

    PubMed Central

    Yonkers, Nicole L.; Sieg, Scott; Rodriguez, Benigno

    2011-01-01

    Background. Chronic hepatitis C virus (HCV) infection is characterized by reduced numbers of functional HCV-specific T cells. In addition, chronically HCV-infected individuals have reduced response to vaccine. Alterations in naive CD4 T cell phenotype or function may contribute to these immune impairments. Methods. Using flow cytometric analysis and enzyme-linked immunospot assay, we examined peripheral naive CD4 T cell phenotype and function in chronically HCV-infected patients and control subjects. Results. We observed significantly lower absolute cell numbers of naive CD4 T cells in HCV-infected patients, localized to the CD127+CD25low/- and CD31+ (RTE) subsets. Moreover, we found greater percentages of naive cells expressing CD25 and KI67 in HCV-infected patients, consistent with immune activation, further supported by higher plasma sCD27 levels. Functional analysis revealed an intact interferon-γ response to allogeneic B cell stimulus. However, after direct TCR stimulation, naive CD4 T cells from HCV-infected patients had altered up-regulation of KI67 and CD25 and less CD27 expression. The latter was associated with elevated baseline activation state. In addition, naive CD4 T cells from HCV-infected patients were more susceptible to cell death. Conclusions. These numerical and functional defects may contribute to inadequate formation of virus and neoantigen-specific T cell responses during chronic HCV infection. PMID:21220773

  9. Telmisartan, a possible PPAR-δ agonist, reduces TNF-α-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells

    SciTech Connect

    Kimura, Hideki; Mikami, Daisuke; Kamiyama, Kazuko; Sugimoto, Hidehiro; Kasuno, Kenji; Takahashi, Naoki; Yoshida, Haruyoshi; Iwano, Masayuki

    2014-11-14

    Highlights: • TNF-α increased VEGF-C expression by enhancing phosphorylation of p38MAPK and HSP27. • Telmisartan decreased TNF-α-stimulated expression of VEGF-C. • Telmisartan suppressed TNF-α-induced phosphorylation of p38MAPK and HSP27. • Telmisartan activated endogenous PPAR-δ protein. • Telmisartan suppressed p38MAPK phosphorylation in a PPAR-δ-dependent manner. - Abstract: Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation-associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-α dose-dependently induced the production of VEGF-C in HPTECs. The TNF-α-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator-activated receptor (PPAR), served as a PPAR-δ activator and reduced the TNF-α-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-δ-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-α induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-δ dependent manner. These results provide a novel insight into inflammation-associated lymphangiogenesis.

  10. Quantification of in vitro and in vivo angiogenesis stimulated by ovine forestomach matrix biomaterial.

    PubMed

    Irvine, Sharleen M; Cayzer, Juliet; Todd, Elise M; Lun, Stan; Floden, Evan W; Negron, Leonardo; Fisher, James N; Dempsey, Sandi G; Alexander, Alan; Hill, Michael C; O'Rouke, Annalee; Gunningham, Sarah P; Knight, Cameron; Davis, Paul F; Ward, Brian R; May, Barnaby C H

    2011-09-01

    Ovine forestomach matrix (OFM) biomaterial acts as a biomimetic of native extracellular matrix (ECM) by providing structural and functional cues to orchestrate cell activity during tissue regeneration. The ordered collagen matrix of the biomaterial is supplemented with secondary ECM-associated macromolecules that function in cell adhesion, migration and communication. As angiogenesis and vasculogenesis are critical processes during tissue regeneration we sought to quantify the angiogenic properties of the OFM biomaterial. In vitro studies demonstrated that soluble OFM components stimulated human umbilical vein endothelial cell (HUVEC) migration and increased vascular sprouting from an aorta. Blood vessel density and branch points increased in response to OFM in an ex ovo chicken chorioallantoic membrane (CAM) assay. The OFM biomaterial was shown to undergo remodeling in a porcine full-thickness excisional model and gave rise to significantly more blood vessels than wounds treated with small intestinal submucosa decellularized ECM or untreated wounds. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Electrical stimulation to restore respiration.

    PubMed

    Creasey, G; Elefteriades, J; DiMarco, A; Talonen, P; Bijak, M; Girsch, W; Kantor, C

    1996-04-01

    Electrical stimulation has been used for over 25 years to restore breathing to patients with high quadriplegia causing respiratory paralysis and patients with central alveolar hypoventilation. Three groups have developed electrical pacing systems for long-term support of respiration in humans. These systems consist of electrodes implanted on the phrenic nerves, connected by leads to a stimulator implanted under the skin, and powered and controlled from a battery-powered transmitter outside the body. The systems differ principally in the electrode design and stimulation waveform. Approximately 1,000 people worldwide have received one of the three phrenic pacing devices, most with strongly positive results: reduced risk of tracheal problems and chronic infection, the ability to speak and smell more normally, reduced risk of accidental interruption of respiration, greater independence, and reduced costs and time for ventilatory care. For patients with partial lesions of the phrenic nerves, intercostal muscle stimulation may supplement respiration.

  12. Telmisartan, a possible PPAR-δ agonist, reduces TNF-α-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells.

    PubMed

    Kimura, Hideki; Mikami, Daisuke; Kamiyama, Kazuko; Sugimoto, Hidehiro; Kasuno, Kenji; Takahashi, Naoki; Yoshida, Haruyoshi; Iwano, Masayuki

    2014-11-14

    Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation-associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-α dose-dependently induced the production of VEGF-C in HPTECs. The TNF-α-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator-activated receptor (PPAR), served as a PPAR-δ activator and reduced the TNF-α-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-δ-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-α induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-δ dependent manner. These results provide a novel insight into inflammation-associated lymphangiogenesis.

  13. Assisting children with attention deficit hyperactivity disorder to reduce the hyperactive behavior of arbitrary standing in class with a Nintendo Wii remote controller through an active reminder and preferred reward stimulation.

    PubMed

    Shih, Ching-Hsiang; Wang, Shu-Hui; Wang, Yun-Ting

    2014-09-01

    Recent studies in the field of special education have shown that in combination with software technology, high-tech commercial products can be applied as useful assistive technology devices to help people with disabilities. This study extended this concept to turn a Nintendo Wii Remote Controller into a high-performance limb action detector, in order to evaluate whether two students with Attention Deficit Hyperactivity Disorder (ADHD) could reduce their hyperactive behavior through an active reminder and stimulation in the form of the participants' preferred rewards. This study focused on one particular hyperactive behavior common to both students: standing up arbitrarily during class. The active reminder was in the form of vibration feedback provided via the built-in function of the Wii Remote Controller, which was controlled and triggered by a control system to remind participants when they were engaging in standing behavior. This study was performed according to a multiple baseline design across participants. The results showed that both participants significantly improved their control over their hyperactive behavior during the intervention phase, and retained this effective performance in the maintenance phase. The practical and developmental implications of the findings are discussed.

  14. Treatment with granulocyte-macrophage colony-stimulating factor is associated with reduced indoleamine 2,3-dioxygenase activity and kynurenine pathway catabolites in patients with severe sepsis and septic shock.

    PubMed

    Schefold, Joerg C; Zeden, Jan-Philip; Pschowski, Rene; Hammoud, Ben; Fotopoulou, Christina; Hasper, Dietrich; Fusch, Gerhard; Von Haehling, Stephan; Volk, Hans-Dieter; Meisel, Christian; Schütt, Christine; Reinke, Petra

    2010-03-01

    The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) controls tryptophan metabolism and is induced by pro-inflammatory stimuli. We investigated whether immunostimulatory treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) influences IDO activity and tryptophan metabolism in sepsis. Thirty-six patients with severe sepsis/septic shock and sepsis-associated immunosuppression (assessed using monocytic human leukocyte antigen-DR (mHLA-DR) expression) were assessed in a controlled trial of GM-CSF or placebo treatment for 8 days. Using tandem mass spectrometry, levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid, 5-hydroxytryptophan, serotonin, and estimated IDO activity were determined in a blinded fashion over a 9-day interval. At baseline, tryptophan and metabolite levels did not differ between the study groups. Although tryptophan levels were unchanged in both groups over the treatment interval (all p>0.8), IDO activity was markedly reduced after GM-CSF treatment (35.4 +/- 21.0 vs 21.6 +/-9.9 (baseline vs day 9), p = 0.02). IDO activity differed significantly between the 2 groups after therapy (p = 0.03). Metabolites downstream of IDO (kynurenine, quinolinic acid, kynurenic acid) were all induced in sepsis and declined in the GM-CSF group, but not in controls. Serotonin pathway metabolites remained unchanged in both groups (all p>0.15). Moreover, IDO activity correlated with procalcitonin (p< 0.0001, r = 0.56) and mHLA-DR levels (p = 0.005, r = -0.28) in the overall samples group. Thus, GM-CSF therapy is associated with decreased IDO activity and reduced kynurenine pathway catabolites in sepsis. This may be due to an improved antibacterial defence.

  15. Peroxisome proliferator-activated receptor-γ activation enhances insulin-stimulated glucose disposal by reducing ped/pea-15 gene expression in skeletal muscle cells: evidence for involvement of activator protein-1.

    PubMed

    Ungaro, Paola; Mirra, Paola; Oriente, Francesco; Nigro, Cecilia; Ciccarelli, Marco; Vastolo, Viviana; Longo, Michele; Perruolo, Giuseppe; Spinelli, Rosa; Formisano, Pietro; Miele, Claudia; Beguinot, Francesco

    2012-12-14

    The gene network responsible for inflammation-induced insulin resistance remains enigmatic. In this study, we show that, in L6 cells, rosiglitazone- as well as pioglitazone-dependent activation of peroxisome proliferator-activated receptor-γ (PPARγ) represses transcription of the ped/pea-15 gene, whose increased activity impairs glucose tolerance in mice and humans. Rosiglitazone enhanced insulin-induced glucose uptake in L6 cells expressing the endogenous ped/pea-15 gene but not in cells expressing ped/pea-15 under the control of an exogenous promoter. The ability of PPARγ to affect ped/pea-15 expression was also lost in cells and in C57BL/6J transgenic mice expressing ped/pea-15 under the control of an exogenous promoter, suggesting that ped/pea-15 repression may contribute to rosiglitazone action on glucose disposal. Indeed, high fat diet mice showed insulin resistance and increased ped/pea-15 levels, although these effects were reduced by rosiglitazone treatment. Both supershift and ChIP assays revealed the presence of the AP-1 component c-JUN at the PED/PEA-15 promoter upon 12-O-tetradecanoylphorbol-13-acetate stimulation of the cells. In these experiments, rosiglitazone treatment reduced c-JUN presence at the PED/PEA-15 promoter. This effect was not associated with a decrease in c-JUN expression. In addition, c-jun silencing in L6 cells lowered ped/pea-15 expression and caused nonresponsiveness to rosiglitazone, although c-jun overexpression enhanced the binding to the ped/pea-15 promoter and blocked the rosiglitazone effect. These results indicate that PPARγ regulates ped/pea-15 transcription by inhibiting c-JUN binding at the ped/pea-15 promoter. Thus, ped/pea-15 is downstream of a major PPARγ-regulated inflammatory network. Repression of ped/pea-15 transcription might contribute to the PPARγ regulation of muscle sensitivity to insulin.

  16. AICAR reduces the collagen-stimulated secretion of PDGF-AB and release of soluble CD40 ligand from human platelets: Suppression of HSP27 phosphorylation via p44/p42 MAP kinase.

    PubMed

    Tsujimoto, Masanori; Tokuda, Haruhiko; Kuroyanagi, Gen; Yamamoto, Naohiro; Kainuma, Shingo; Matsushima-Nishiwaki, Rie; Onuma, Takashi; Iida, Yuko; Kojima, Akiko; Sawada, Shigenobu; Doi, Tomoaki; Enomoto, Yukiko; Tanabe, Kumiko; Akamatsu, Shigeru; Iida, Hiroki; Ogura, Shinji; Otsuka, Takanobu; Kozawa, Osamu; Iwama, Toru

    2016-08-01

    We have previously reported that collagen-induced phosphorylation of heat shock protein (HSP) 27 via p44/p42 mitogen-activated protein (MAP) kinase in human platelets is sufficient to induce the secretion of platelet-derived growth factor (PDGF)-AB and the release of soluble cluster of differentiation 40 ligand (sCD40L). Adenosine monophosphate-activated protein kinase (AMPK), which is known to regulate energy homeostasis, has a crucial role as an energy sensor in various eukaryotic cells. The present study investigated the effects of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranosyl 5'-monophosphate (AICAR), which is an activator of AMPK, on the collagen-induced activation of human platelets. It was demonstrated that AICAR dose-dependently reduced collagen-stimulated platelet aggregation up to 1.0 µM. Analysis of the size of platelet aggregates demonstrated that AICAR decreased the ratio of large aggregates (50-70 µm), whereas the ratio of small aggregates (9-25 µm) was increased by AICAR administration. AICAR markedly attenuated the phosphorylation levels of p44/p42 MAP kinase and HSP27, which are induced by collagen. Furthermore, AICAR significantly decreased the secretion of PDGF-AB and the collagen-induced release of sCD40L. These results indicated that AICAR-activated AMPK may reduce the secretion of PDGF-AB and the collagen-induced release of sCD40L by inhibiting HSP27 phosphorylation via p44/p42 MAP kinase in human platelets.

  17. Replacement of the Lys linker with an Arg linker resulting in improved melanoma uptake and reduced renal uptake of Tc-99m-labeled Arg-Gly-Asp-conjugated alpha-melanocyte stimulating hormone hybrid peptide.

    PubMed

    Yang, Jianquan; Guo, Haixun; Padilla, R Steve; Berwick, Marianne; Miao, Yubin

    2010-09-15

    The purpose of this study was to reduce the non-specific renal uptake of Arg-Gly-Asp (RGD)-conjugated alpha-melanocyte stimulating hormone (alpha-MSH) hybrid peptide through structural modification or L-lysine co-injection. The RGD motif {cyclic(Arg-Gly-Asp-DTyr-Asp)} was coupled to [Cys(3,4,10), D-Phe7, Arg11] alpha-MSH3-13 {(Arg11)CCMSH} through the Arg linker (substituting the Lys linker) to generate a novel RGD-Arg-(Arg11)CCMSH hybrid peptide. The melanoma targeting and pharmacokinetic properties of 99mTc-RGD-Arg-(Arg11)CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The effect of L-lysine co-injection on the renal uptake was determined through the co-injection of L-lysine with 99mTc-RGD-Arg-(Arg11)CCMSH or 99mTc-RGD-Lys-(Arg11)CCMSH. Replacement of the Lys linker with an Arg linker exhibited a profound effect in reducing the non-specific renal uptake of 99mTc-RGD-Arg-(Arg11)CCMSH, as well as increasing the tumor uptake of 99mTc-RGD-Arg-(Arg11)CCMSH compared to 99mTc-RGD-Lys-(Arg11)CCMSH. 99mTc-RGD-Arg-(Arg11)CCMSH exhibited high tumor uptake (21.41+/-3.74% ID/g at 2 h post-injection) and prolonged tumor retention (6.81+/-3.71% ID/g at 24 h post-injection) in B16/F1 melanoma-bearing mice. The renal uptake values of 99mTc-RGD-Arg-(Arg11)CCMSH were 40.14-64.08% of those of 99mTc-RGD-Lys-(Arg11)CCMSH (p<0.05) at 0.5, 2, 4 and 24 h post-injection. Co-injection of L-lysine was effective in decreasing the renal uptakes of 99mTc-RGD-Arg-(Arg11)CCMSH by 27.7% and 99mTc-RGD-Lys-(Arg11)CCMSH by 52.1% at 2 h post-injection. Substitution of the Lys linker with an Arg linker dramatically improved the melanoma uptake and reduced the renal uptake of 99mTc-RGD-Arg-(Arg11)CCMSH, warranting the further evaluation of 188Re-labeled RGD-Arg-(Arg11)CCMSH as a novel MC1 receptor-targeting therapeutic peptide for melanoma treatment in the future.

  18. Movement disorders induced by deep brain stimulation.

    PubMed

    Baizabal-Carvallo, José Fidel; Jankovic, Joseph

    2016-04-01

    Deep brain stimulation represents a major advance in the treatment of several types of movement disorders. However, during stimulation new movement disorders may emerge, thus limiting the positive effects of this therapy. These movement disorders may be induced by: 1) stimulation of the targeted nucleus, 2) stimulation of surrounding tracts and nuclei, and 3) as a result of dose adjustment of accompanying medications, such as reduction of dopaminergic drugs in patients with Parkinson's disease. Various dyskinesias, blepharospasm, and apraxia of eyelid opening have been described mainly with subthalamic nucleus stimulation, whereas hypokinesia and freezing of gait have been observed with stimulation of the globus pallidus internus. Other deep brain stimulation-related movement disorders include dyskinesias associated with stimulation of the globus pallidus externus and ataxic gait as a side effect of chronic bilateral stimulation of the ventral intermediate nucleus of thalamus. These movement disorders are generally reversible and usually resolved once the stimulation is reduced or turned off. This, however, typically leads to loss of benefit of the underlying movement disorder which can be re-gained by using different contacts, changing targets or stimulation parameters, and adjusting pharmacological therapy. New and innovative emerging technologies and stimulation techniques may help to prevent or overcome the various deep brain stimulation-induced movement disorders. In this review we aim to describe the clinical features, frequency, pathophysiology, and strategies for treatment of these iatrogenic movement disorders.

  19. Erythropoiesis-stimulating agent use among non-dialysis-dependent CKD patients before and after the trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) using a large US health plan database.

    PubMed

    Thamer, Mae; Zhang, Yi; Kshirsagar, Onkar; Cotter, Dennis J; Kaufman, James S

    2014-11-01

    In a landmark study, TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) examined the use of erythropoiesis-stimulating agent (ESA) therapy to treat anemia among patients with chronic kidney disease (CKD) and found no benefit compared to placebo. A retrospective observational design was used to determine the impact of TREAT on clinical practice. A large US health plan database with more than 1.2 million claims for patients with non-dialysis-dependent CKD stages 3 and 4. ESA prescribing 2 years before and after publication of TREAT. Rate of ESA prescribing for ESA-naive and -prevalent cohorts. (1) Monthly ESA prescribing in the 2 years before and after publication of TREAT (ordinary least squares regression), (2) adjusted likelihood of prescribing ESA after TREAT (clustered logistic regression), and (3) probability of receiving ESA therapy based on anemia status (χ(2) test). For patients with CKD stage 3, the proportion prescribed ESA therapy declined from 17% pre-TREAT to 11% post-TREAT (a 38% decline), and for those with CKD stage 4, from 34% to 27% (a 22% decline). Prescribing of ESA therapy was declining even before TREAT, but the decline accelerated in the post-TREAT period (stage 3: change of slope, -0.08 [P<0.001]; stage 4: change of slope, -0.16 [P<0.001]). ESA prescribing declined after TREAT regardless of anemia status; among patients with hemoglobin levels <10g/dL, only 25% of patients with CKD stage 3 and 33% of patients with stage 4 were prescribed ESAs 2 years after TREAT, a notable 50% decline. After adjusting for all covariates, the probability of prescribing ESAs was 35% lower during the 2-year period after versus before publication of TREAT (OR, 0.65; 95% CI, 0.63-0.67). The cumulative effect of adverse safety concerns in the period before TREAT also influenced physician prescribing of ESA therapy and could not be separated from the influence of TREAT. TREAT appears to be a watershed study that was followed by a marked

  20. The "Paradoxical Effect" of Stimulants' Upon Hyperactive Children

    ERIC Educational Resources Information Center

    Brodemus, John; Swanson, Jon C.

    1977-01-01

    Amphetamines and other stimulant drugs are not causing so-called "paradoxical effects" in hyperactive children but are actually effective because they provide needed stimulation. According to the Swanson-Brodemus Model, amphetamines, et al., provide internal sources of stimulation, thus reducing the need for external stimulation. (Author)

  1. Vagus Nerve Stimulation

    MedlinePlus

    Vagus nerve stimulation Overview By Mayo Clinic Staff Vagus nerve stimulation is a procedure that involves implantation of a device that stimulates the vagus nerve with electrical impulses. There's one vagus nerve on ...

  2. A randomized clinical trial to compare the effectiveness of rotator cuff repair with or without augmentation using porcine small intestine submucosa for patients with moderate to large rotator cuff tears: a pilot study.

    PubMed

    Bryant, Dianne; Holtby, Richard; Willits, Kevin; Litchfield, Robert; Drosdowech, Darren; Spouge, Alison; White, David; Guyatt, Gordon

    2016-10-01

    The rate of rotator cuff repair failure is between 13% and 67%. Porcine small intestine submucosa (SIS) may be suitable to augment the repair. There were 62 patients with moderate and large cuff tears randomized to repair alone (control) or augmentation with SIS (Restore Orthobiologic Implant; DePuy, Warsaw, IN, USA). Primary outcome was repair failure using magnetic resonance arthrography. Randomization occurred on completion of the repair. Patients and assessors were blind to group. Assessments occurred preoperatively and postoperatively at 2 and 6 weeks and 3, 6, 12, and 24 months. There were 62 patients randomized (34 SIS, 28 control). Patient demographics, rotator cuff tear characteristics, and repair details were similar between groups. At 1 year, risk of failure was 52.9% (18/34) in the SIS group and 65.4% (17/26) in the control group for a risk difference of 12% (80% confidence interval, -7% to 32%) or relative risk of 0.81 (95% confidence interval, 0.53-1.24, P = .33) in favor of SIS. At 1 and 2 years, the mean difference between groups for patient-reported outcomes was small and consistent with chance but did not exclude the possibility of a clinically important difference. There was no statistically significant difference (P = .50) between the SIS group (59.6 ± 38.9; range, 3-112) and the control group (52.7 ± 38.6; range, 5-112) in number of days to being narcotic and pain free (<20 mm on a 100-mm visual analog scale). We found no evidence that SIS-augmented rotator cuff repair provides superior outcomes in patients with moderate rotator cuff tears. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

  3. Activation of the adenosine A3 receptor in RAW 264.7 cells inhibits lipopolysaccharide-stimulated tumor necrosis factor-alpha release by reducing calcium-dependent activation of nuclear factor-kappaB and extracellular signal-regulated kinase 1/2.

    PubMed

    Martin, Lynn; Pingle, Sandeep C; Hallam, Daniel M; Rybak, Leonard P; Ramkumar, Vickram

    2006-01-01

    Bacterial lipopolysaccharide (LPS) activates the immune system and promotes inflammation via Toll-like receptor (TLR) 4, which regulates the synthesis and release of tumor necrosis factor (TNF)-alpha and other inflammatory cytokines. Previous studies have shown that the nucleoside adenosine suppresses LPS-stimulated TNF-alpha release in human UB939 macrophages by activating an adenosine A(3) receptor (A(3)AR) subtype on these cells. In this study, we examined the mechanism(s) underlying A(3)AR-dependent inhibition of TNF-alpha release in a mouse (RAW 264.7) cell line. Treatment of RAW 264.7 cells with LPS (3 mug/ml) increased TNF-alpha release, which was reduced in a dose-dependent manner by adenosine analogs N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and R-phenylisopropyladenosine and reversed by selective A(3)AR blockade. The increase in TNF-alpha release was preceded by an increase in intracellular Ca(2+) levels. Inhibition of intracellular Ca(2+) release by IB-MECA, a selective agonist of the A(3)AR, or with BAPTA-AM, an intracellular Ca(2+) chelator, reduced LPS-stimulated TNF-alpha release. Activation of the A(3)AR or inhibition of intracellular Ca(2+) release also reduced LPS-stimulated nuclear factor-kappaB (NF-kappaB) activation and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Similar inhibition by A(3)AR was observed for LPS-stimulated inducible nitric-oxide synthase. These data support the contention that inhibition of LPS-stimulated release of inflammatory molecules, such as TNF-alpha and NO via the A(3)AR, involves suppression of intracellular Ca(2+)signaling, leading to suppression of NF-kappaB and ERK1/2 pathways.

  4. Transcranial Electrical Stimulation Accelerates Human Sleep Homeostasis

    PubMed Central

    Reato, Davide; Gasca, Fernando; Datta, Abhishek; Bikson, Marom; Marshall, Lisa; Parra, Lucas C.

    2013-01-01

    The sleeping brain exhibits characteristic slow-wave activity which decays over the course of the night. This decay is thought to result from homeostatic synaptic downscaling. Transcranial electrical stimulation can entrain slow-wave oscillations (SWO) in the human electro-encephalogram (EEG). A computational model of the underlying mechanism predicts that firing rates are predominantly increased during stimulation. Assuming that synaptic homeostasis is driven by average firing rates, we expected an acceleration of synaptic downscaling during stimulation, which is compensated by a reduced drive after stimulation. We show that 25 minutes of transcranial electrical stimulation, as predicted, reduced the decay of SWO in the remainder of the night. Anatomically accurate simulations of the field intensities on human cortex precisely matched the effect size in different EEG electrodes. Together these results suggest a mechanistic link between electrical stimulation and accelerated synaptic homeostasis in human sleep. PMID:23459152

  5. Transcranial electrical stimulation accelerates human sleep homeostasis.

    PubMed

    Reato, Davide; Gasca, Fernando; Datta, Abhishek; Bikson, Marom; Marshall, Lisa; Parra, Lucas C

    2013-01-01

    The sleeping brain exhibits characteristic slow-wave activity which decays over the course of the night. This decay is thought to result from homeostatic synaptic downscaling. Transcranial electrical stimulation can entrain slow-wave oscillations (SWO) in the human electro-encephalogram (EEG). A computational model of the underlying mechanism predicts that firing rates are predominantly increased during stimulation. Assuming that synaptic homeostasis is driven by average firing rates, we expected an acceleration of synaptic downscaling during stimulation, which is compensated by a reduced drive after stimulation. We show that 25 minutes of transcranial electrical stimulation, as predicted, reduced the decay of SWO in the remainder of the night. Anatomically accurate simulations of the field intensities on human cortex precisely matched the effect size in different EEG electrodes. Together these results suggest a mechanistic link between electrical stimulation and accelerated synaptic homeostasis in human sleep.

  6. Electrical brain stimulation for epilepsy.

    PubMed

    Fisher, Robert S; Velasco, Ana Luisa

    2014-05-01

    Neurostimulation enables adjustable and reversible modulation of disease symptoms, including those of epilepsy. Two types of brain neuromodulation, comprising anterior thalamic deep brain stimulation and responsive neurostimulation at seizure foci, are supported by Class I evidence of effectiveness, and many other sites in the brain have been targeted in small trials of neurostimulation therapy for seizures. Animal studies have mainly assisted in the identification of potential neurostimulation sites and parameters, but much of the clinical work is only loosely based on fundamental principles derived from the laboratory, and the mechanisms by which brain neurostimulation reduces seizures remain poorly understood. The benefits of stimulation tend to increase over time, with maximal effect seen typically 1-2 years after implantation. Typical reductions of seizure frequency are approximately 40% acutely, and 50-69% after several years. Seizure intensity might also be reduced. Complications from brain neurostimulation are mainly associated with the implantation procedure and hardware, including stimulation-related paraesthesias, stimulation-site infections, electrode mistargeting and, in some patients, triggered seizures or even status epilepticus. Further preclinical and clinical experience with brain stimulation surgery should lead to improved outcomes by increasing our understanding of the optimal surgical candidates, sites and parameters.

  7. Telocytes are reduced during fibrotic remodelling of the colonic wall in ulcerative colitis

    PubMed Central

    Manetti, Mirko; Rosa, Irene; Messerini, Luca; Ibba-Manneschi, Lidia

    2015-01-01

    Ulcerative colitis (UC) is characterized by chronic relapsing intestinal inflammation finally leading to extensive tissue fibrosis and resulting in a stiff colon unable to carry out peristalsis or to resorb fluids. Telocytes, a peculiar type of stromal cells, have been recently identified in the human gastrointestinal tract. Several roles have been proposed for telocytes, including mechanical support, intercellular signalling and modulation of intestinal motility. The aim of the present work was to investigate the presence and distribution of telocytes in colonic specimens from UC patients compared with controls. Archival paraffin-embedded samples of the left colon from UC patients who underwent elective bowel resection and controls were collected. Tissue sections were stained with Masson's trichrome to detect fibrosis. Telocytes were identified by CD34 immunohistochemistry. In early fibrotic UC cases, fibrosis affected the muscularis mucosae and submucosa, while the muscularis propria was spared. In advanced fibrotic UC cases, fibrosis extended to affect the muscle layers and the myenteric plexus. Few telocytes were found in the muscularis mucosae and submucosa of both early and advanced fibrotic UC colonic wall. In the muscle layers and myenteric plexus of early fibrotic UC, telocytes were preserved in their distribution. In the muscularis propria of advanced fibrotic UC, the network of telocytes was reduced or even completely absent around smooth muscle bundles and myenteric plexus ganglia, paralleling the loss of the network of interstitial cells of Cajal. In UC, a loss of telocytes accompanies the fibrotic remodelling of the colonic wall and might contribute to colonic dysmotility. PMID:25283476

  8. Dorsal column stimulator applications

    PubMed Central

    Yampolsky, Claudio; Hem, Santiago; Bendersky, Damián

    2012-01-01

    Background: Spinal cord stimulation (SCS) has been used to treat neuropathic pain since 1967. Following that, technological progress, among other advances, helped SCS become an effective tool to reduce pain. Methods: This article is a non-systematic review of the mechanism of action, indications, results, programming parameters, complications, and cost-effectiveness of SCS. Results: In spite of the existence of several studies that try to prove the mechanism of action of SCS, it still remains unknown. The mechanism of action of SCS would be based on the antidromic activation of the dorsal column fibers, which activate the inhibitory interneurons within the dorsal horn. At present, the indications of SCS are being revised constantly, while new applications are being proposed and researched worldwide. Failed back surgery syndrome (FBSS) is the most common indication for SCS, whereas, the complex regional pain syndrome (CRPS) is the second one. Also, this technique is useful in patients with refractory angina and critical limb ischemia, in whom surgical or endovascular treatment cannot be performed. Further indications may be phantom limb pain, chronic intractable pain located in the head, face, neck, or upper extremities, spinal lumbar stenosis in patients who are not surgical candidates, and others. Conclusion: Spinal cord stimulation is a useful tool for neuromodulation, if an accurate patient selection is carried out prior, which should include a trial period. Undoubtedly, this proper selection and a better knowledge of its underlying mechanisms of action, will allow this cutting edge technique to be more acceptable among pain physicians. PMID:23230533

  9. Vagus nerve stimulation inhibits cortical spreading depression.

    PubMed

    Chen, Shih-Pin; Ay, Ilknur; de Morais, Andreia Lopes; Qin, Tao; Zheng, Yi; Sadeghian, Homa; Oka, Fumiaki; Simon, Bruce; Eikermann-Haerter, Katharina; Ayata, Cenk

    2016-04-01

    Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ∼40%, and propagation speed of spreading depression was reduced by ∼15%. This effect developed within 30 minutes after vagus nerve stimulation and persisted for more than 3 hours. Noninvasive transcutaneous vagus nerve stimulation was as efficacious as direct invasive vagus nerve stimulation, and the efficacy did not differ between the ipsilateral and contralateral hemispheres. Our findings provide a potential mechanism by which vagus nerve stimulation may be efficacious in migraine and suggest that susceptibility to spreading depression is a suitable platform to optimize its efficacy.

  10. Electrical stimulation and motor recovery.

    PubMed

    Young, Wise

    2015-01-01

    In recent years, several investigators have successfully regenerated axons in animal spinal cords without locomotor recovery. One explanation is that the animals were not trained to use the regenerated connections. Intensive locomotor training improves walking recovery after spinal cord injury (SCI) in people, and >90% of people with incomplete SCI recover walking with training. Although the optimal timing, duration, intensity, and type of locomotor training are still controversial, many investigators have reported beneficial effects of training on locomotor function. The mechanisms by which training improves recovery are not clear, but an attractive theory is available. In 1949, Donald Hebb proposed a famous rule that has been paraphrased as "neurons that fire together, wire together." This rule provided a theoretical basis for a widely accepted theory that homosynaptic and heterosynaptic activity facilitate synaptic formation and consolidation. In addition, the lumbar spinal cord has a locomotor center, called the central pattern generator (CPG), which can be activated nonspecifically with electrical stimulation or neurotransmitters to produce walking. The CPG is an obvious target to reconnect after SCI. Stimulating motor cortex, spinal cord, or peripheral nerves can modulate lumbar spinal cord excitability. Motor cortex stimulation causes long-term changes in spinal reflexes and synapses, increases sprouting of the corticospinal tract, and restores skilled forelimb function in rats. Long used to treat chronic pain, motor cortex stimuli modify lumbar spinal network excitability and improve lower extremity motor scores in humans. Similarly, epidural spinal cord stimulation has long been used to treat pain and spasticity. Subthreshold epidural stimulation reduces the threshold for locomotor activity. In 2011, Harkema et al. reported lumbosacral epidural stimulation restores motor control in chronic motor complete patients. Peripheral nerve or functional electrical

  11. Optogenetic stimulation of the auditory pathway

    PubMed Central

    Hernandez, Victor H.; Gehrt, Anna; Reuter, Kirsten; Jing, Zhizi; Jeschke, Marcus; Mendoza Schulz, Alejandro; Hoch, Gerhard; Bartels, Matthias; Vogt, Gerhard; Garnham, Carolyn W.; Yawo, Hiromu; Fukazawa, Yugo; Augustine, George J.; Bamberg, Ernst; Kügler, Sebastian; Salditt, Tim; de Hoz, Livia; Strenzke, Nicola; Moser, Tobias

    2014-01-01

    Auditory prostheses can partially restore speech comprehension when hearing fails. Sound coding with current prostheses is based on electrical stimulation of auditory neurons and has limited frequency resolution due to broad current spread within the cochlea. In contrast, optical stimulation can be spatially confined, which may improve frequency resolution. Here, we used animal models to characterize optogenetic stimulation, which is the optical stimulation of neurons genetically engineered to express the light-gated ion channel channelrhodopsin-2 (ChR2). Optogenetic stimulation of spiral ganglion neurons (SGNs) activated the auditory pathway, as demonstrated by recordings of single neuron and neuronal population responses. Furthermore, optogenetic stimulation of SGNs restored auditory activity in deaf mice. Approximation of the spatial spread of cochlear excitation by recording local field potentials (LFPs) in the inferior colliculus in response to suprathreshold optical, acoustic, and electrical stimuli indicated that optogenetic stimulation achieves better frequency resolution than monopolar electrical stimulation. Virus-mediated expression of a ChR2 variant with greater light sensitivity in SGNs reduced the amount of light required for responses and allowed neuronal spiking following stimulation up to 60 Hz. Our study demonstrates a strategy for optogenetic stimulation of the auditory pathway in rodents and lays the groundwork for future applications of cochlear optogenetics in auditory research and prosthetics. PMID:24509078

  12. Vagus nerve stimulation regulates hemostasis in swine.

    PubMed

    Czura, Christopher J; Schultz, Arthur; Kaipel, Martin; Khadem, Anna; Huston, Jared M; Pavlov, Valentin A; Redl, Heinz; Tracey, Kevin J

    2010-06-01

    The central nervous system regulates peripheral immune responses via the vagus nerve, the primary neural component of the cholinergic anti-inflammatory pathway. Electrical stimulation of the vagus nerve suppresses proinflammatory cytokine release in response to endotoxin, I/R injury, and hypovolemic shock and protects against lethal hypotension. To determine the effect of vagus nerve stimulation on coagulation pathways, anesthetized pigs were subjected to partial ear resection before and after electrical vagus nerve stimulation. We observed that electrical vagus nerve stimulation significantly decreased bleeding time (pre-electrical vagus nerve stimulation = 1033 +/- 210 s versus post-electrical vagus nerve stimulation = 585 +/- 111 s; P < 0.05) and total blood loss (pre-electrical vagus nerve stimulation = 48.4 +/- 6.8 mL versus post-electrical vagus nerve stimulation = 26.3 +/- 6.7 mL; P < 0.05). Reduced bleeding time after vagus nerve stimulation was independent of changes in heart rate or blood pressure and correlated with increased thrombin/antithrombin III complex generation in shed blood. These data indicate that electrical stimulation of the vagus nerve attenuates peripheral hemorrhage in a porcine model of soft tissue injury and that this protective effect is associated with increased coagulation factor activity.

  13. Alcohol drinking increases the dopamine-stimulating effects of ethanol and reduces D2 auto-receptor and group II metabotropic glutamate receptor function within the posterior ventral tegmental area of alcohol preferring (P) rats.

    PubMed

    Ding, Zheng-Ming; Ingraham, Cynthia M; Rodd, Zachary A; McBride, William J

    2016-10-01

    Repeated local administration of ethanol (EtOH) sensitized the posterior ventral tegmental area (pVTA) to the local dopamine (DA)-stimulating effects of EtOH. Chronic alcohol drinking increased nucleus accumbens (NAC) DA transmission and pVTA glutamate transmission in alcohol-preferring (P) rats. The objectives of the present study were to determine the effects of chronic alcohol drinking by P rats on the (a) sensitivity and response of the pVTA DA neurons to the DA-stimulating actions of EtOH, and (b) negative feedback control of DA (via D2 auto-receptors) and glutamate (via group II mGlu auto-receptors) release in the pVTA. EtOH (50 or 150 mg%) or the D2/3 receptor antagonist sulpiride (100 or 200 μM) was microinjected into the pVTA while DA was sampled with microdialysis in the NAC shell (NACsh). The mGluR2/3 antagonist LY341495 (1 or 10 μM) was perfused through the pVTA via reverse microdialysis and local extracellular glutamate and DA levels were measured. EtOH produced a more robust increase of NACsh DA in the 'EtOH' than 'Water' groups (e.g., 150 mg% EtOH: to ∼ 210 vs 150% of baseline). In contrast, sulpiride increased DA release in the NACsh more in the 'Water' than 'EtOH' groups (e.g., 200 μM sulpiride: to ∼ 190-240 vs 150-160% of baseline). LY341495 (at 10 μM) increased extracellular glutamate and DA levels in the 'Water' (to ∼ 150-180% and 180-230% of baseline, respectively) but not the 'EtOH' groups. These results indicate that alcohol drinking enhanced the DA-stimulating effects of EtOH, and attenuated the functional activities of D2 auto-receptors and group II mGluRs within the pVTA.

  14. Single well electric oil stimulation

    SciTech Connect

    Perkins, Th. K.

    1985-06-11

    A single well method and apparatus for electrically applying heat and stimulating is comprised of a relatively lower surface area formation electrode and relatively high surface area overburden electrode extending downward into the borehole past low resistivity water zones. This long overburden electrode may be formed of nonmagnetic metal to reduce hysteresis losses in the electrode. This improved single well system causes most of power to be dissipated in the oil pay zone and thereby renders single well production economical.

  15. Brain Stimulation in Addiction.

    PubMed

    Salling, Michael C; Martinez, Diana

    2016-11-01

    Localized stimulation of the human brain to treat neuropsychiatric disorders has been in place for over 20 years. Although these methods have been used to a greater extent for mood and movement disorders, recent work has explored brain stimulation methods as potential treatments for addiction. The rationale behind stimulation therapy in addiction involves reestablishing normal brain function in target regions in an effort to dampen addictive behaviors. In this review, we present the rationale and studies investigating brain stimulation in addiction, including transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Overall, these studies indicate that brain stimulation has an acute effect on craving for drugs and alcohol, but few studies have investigated the effect of brain stimulation on actual drug and alcohol use or relapse. Stimulation therapies may achieve their effect through direct or indirect modulation of brain regions involved in addiction, either acutely or through plastic changes in neuronal transmission. Although these mechanisms are not well understood, further identification of the underlying neurobiology of addiction and rigorous evaluation of brain stimulation methods has the potential for unlocking an effective, long-term treatment of addiction.

  16. Strong Manual Acupuncture Stimulation of “Huantiao” (GB 30) Reduces Pain-Induced Anxiety and p-ERK in the Anterior Cingulate Cortex in a Rat Model of Neuropathic Pain

    PubMed Central

    Shao, Xiao-mei; Shen, Zui; Sun, Jing; Fang, Fang; Fang, Jun-fan; Wu, Yuan-yuan; Fang, Jian-qiao

    2015-01-01

    Persistent neuropathic pain is associated with anxiety. The phosphorylation of extracellular signal-regulated kinase (p-ERK) in the anterior cingulate cortex (ACC) plays an important role in pain-induced anxiety. Acupuncture is widely used for pain and anxiety. However, little is known about which acupuncture technique is optimal on pain-induced anxiety and the relationship between acupuncture effect and p-ERK. The rat model was induced by L5 spinal nerve ligation (SNL). Male adult SD rats were randomly divided into control, SNL, strong manual acupuncture (sMA), mild manual acupuncture (mMA), and electroacupuncture (EA) group. Bilateral “Huantiao” (GB 30) were stimulated by sMA, mMA, and EA, respectively. The pain withdrawal thresholds (PWTs) and anxiety behavior were measured, and p-ERK protein expression and immunoreactivity cells in ACC were detected. PWTs increased significantly in both sMA and EA groups. Meanwhile, anxiety-like behavior was improved significantly in the sMA and mMA groups. Furthermore, the overexpression of p-ERK induced by SNL was downregulated by strong and mild manual acupuncture. Therefore, strong manual acupuncture on bilateral “Huantiao” (GB 30) could be a proper therapy relieving both pain and pain-induced anxiety. The effect of different acupuncture techniques on pain-induced anxiety may arise from the regulation of p-ERK in ACC. PMID:26770252

  17. Silencing of ANGPTL 3 (angiopoietin-like protein 3) in human hepatocytes results in decreased expression of gluconeogenic genes and reduced triacylglycerol-rich VLDL secretion upon insulin stimulation

    PubMed Central

    Tikka, Anna; Soronen, Jarkko; Laurila, Pirkka-Pekka; Metso, Jari; Ehnholm, Christian; Jauhiainen, Matti

    2014-01-01

    Homozygosity of loss-of-function mutations in ANGPTL3 (angiopoietin-like protein 3)-gene results in FHBL2 (familial combined hypolipidaemia, OMIM #605019) characterized by the reduction of all major plasma lipoprotein classes, which includes VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), HDL (high-density lipoprotein) and low circulating NEFAs (non-esterified fatty acids), glucose and insulin levels. Thus complete lack of ANGPTL3 in humans not only affects lipid metabolism, but also affects whole-body insulin and glucose balance. We used wild-type and ANGPTL3-silenced IHHs (human immortalized hepatocytes) to investigate the effect of ANGPTL3 silencing on hepatocyte-specific VLDL secretion and glucose uptake. We demonstrate that both insulin and PPARγ (peroxisome-proliferator-activated receptor γ) agonist rosiglitazone down-regulate the secretion of ANGPTL3 and TAG (triacylglycerol)-enriched VLDL1-type particles in a dose-dependent manner. Silencing of ANGPTL3 improved glucose uptake in hepatocytes by 20–50% and influenced down-regulation of gluconeogenic genes, suggesting that silencing of ANGPTL3 improves insulin sensitivity. We further show that ANGPTL3-silenced cells display a more pronounced shift from the secretion of TAG-enriched VLDL1-type particles to secretion of lipid poor VLDL2-type particles during insulin stimulation. These data suggest liver-specific mechanisms involved in the reported insulin-sensitive phenotype of ANGPTL3-deficient humans, featuring lower plasma insulin and glucose levels. PMID:25495645

  18. Prophylactic administration of vector-encoded porcine granulocyte-colony stimulating factor reduces Salmonella shedding,tonsil colonization,& microbiota alterations of the gastrointestinal tract in Salmonella-challenged swine

    USDA-ARS?s Scientific Manuscript database

    Salmonella colonization of food animals is a concern for animal health and public health as a food safety risk. Various obstacles impede the effort to reduce asymptomatic Salmonella carriage in food animals, including the existence of numerous serovars and the ubiquitous nature of Salmonella. To d...

  19. Microscopic magnetic stimulation of neural tissue.

    PubMed

    Bonmassar, Giorgio; Lee, Seung Woo; Freeman, Daniel K; Polasek, Miloslav; Fried, Shelley I; Gale, John T

    2012-06-26

    Electrical stimulation is currently used to treat a wide range of cardiovascular, sensory and neurological diseases. Despite its success, there are significant limitations to its application, including incompatibility with magnetic resonance imaging, limited control of electric fields and decreased performance associated with tissue inflammation. Magnetic stimulation overcomes these limitations but existing devices (that is, transcranial magnetic stimulation) are large, reducing their translation to chronic applications. In addition, existing devices are not effective for deeper, sub-cortical targets. Here we demonstrate that sub-millimeter coils can activate neuronal tissue. Interestingly, the results of both modelling and physiological experiments suggest that different spatial orientations of the coils relative to the neuronal tissue can be used to generate specific neural responses. These results raise the possibility that micro-magnetic stimulation coils, small enough to be implanted within the brain parenchyma, may prove to be an effective alternative to existing stimulation devices.

  20. Microscopic magnetic stimulation of neural tissue

    PubMed Central

    Bonmassar, Giorgio; Lee, Seung Woo; Freeman, Daniel K.; Polasek, Miloslav; Fried, Shelley I.; Gale, John T.

    2012-01-01

    Electrical stimulation is currently used to treat a wide range of cardiovascular, sensory and neurological diseases. Despite its success, there are significant limitations to its application, including incompatibility with magnetic resonance imaging, limited control of electric fields and decreased performance associated with tissue inflammation. Magnetic stimulation overcomes these limitations but existing devices (that is, transcranial magnetic stimulation) are large, reducing their translation to chronic applications. In addition, existing devices are not effective for deeper, sub-cortical targets. Here we demonstrate that sub-millimeter coils can activate neuronal tissue. Interestingly, the results of both modelling and physiological experiments suggest that different spatial orientations of the coils relative to the neuronal tissue can be used to generate specific neural responses. These results raise the possibility that micro-magnetic stimulation coils, small enough to be implanted within the brain parenchyma, may prove to be an effective alternative to existing stimulation devices. PMID:22735449

  1. Ca2+-activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

    PubMed Central

    González-Corrochano, R; La Fuente, JM; Cuevas, P; Fernández, A; Chen, MX; Sáenz de Tejada, I; Angulo, J

    2013-01-01

    Background and Purpose We have evaluated the influence of calcium-activated potassium channels (KCa) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats. Experimental Approach Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non-diabetic rats. Key Results Concentration-dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS-8 (10 μM) significantly potentiated sildenafil-induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 μM). In HCC, sildenafil-induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large-conductance KCa (BK) and intermediate-conductance KCa (IK) contribute to NS-8-induced effects and were immunodetected in human and rat penile arteries. NS-8 potentiated sildenafil-induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes-induced ED in rats only when combined with KCa activation. Conclusions and Implications Activation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non-diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED. PMID:23441682

  2. Late reperfusion of a totally occluded infarct-related artery increases granulocyte-colony stimulation factor and reduces stroma-derived factor-1alpha blood levels in patients with ongoing ischemia after acute myocardial infarction.

    PubMed

    Kuo, Li-Tang; Chen, Shih-Jen; Cherng, Wen-Jin; Yang, Ning-I; Lee, Chen-Chin; Cheng, Chi-Wen; Verma, Subodh; Wang, Chao-Hung

    2009-07-01

    After acute myocardial infarction (AMI), reopening of a totally occluded infarct-related artery (IRA) at a subacute stage is still controversial in symptom-free patients. However, in patients with persistent ischemic symptoms and inadequate collaterals to the infarct area, recanalization is thought to provide beneficial effects. In addition to augmenting myocardial perfusion, we hypothesized that the benefit of recanalization involves the manipulation of circulating stem cell-mobilizing cytokines. This study included 30 patients with a totally occluded IRA and ongoing ischemic symptoms (the study group) and 30 patients with a partially occluded IRA (the control group). All patients underwent successful angioplasty and/or stenting. Before and immediately after the coronary intervention, blood granulocyte-colony-stimulating factor (G-CSF), stem-cell factor (SCF), vascular endothelial growth factor (VEGF), and stroma-derived factor-1 (SDF-1alpha) were measured. After recanalization, G-CSF levels significantly increased in the study group compared to the control group (P=0.03). SDF-1alpha levels in the study group decreased relative to the controls (P=0.02). However, no significant changes in VEGF or SCF levels between the two groups were found. In the multivariate analysis, reopening of a totally occluded IRA was independently and significantly associated with changes in G-CSF and SDF-1alpha levels after recanalization. In conclusion, our data suggest that the benefits of late reperfusion of a totally occluded IRA in patients with ongoing myocardial ischemia may involve mechanisms associated with stem cell-mobilizing and plaque-stabilizing cytokines. This study provides the rationale to investigate serial changes in cytokines and the numbers of circulating progenitors after reperfusion in the future.

  3. Ca2+ -activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction.

    PubMed

    González-Corrochano, R; La Fuente, Jm; Cuevas, P; Fernández, A; Chen, Mx; Sáenz de Tejada, I; Angulo, J

    2013-05-01

    We have evaluated the influence of calcium-activated potassium channels (KCa ) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats. Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non-diabetic rats. Concentration-dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS-8 (10 μM) significantly potentiated sildenafil-induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 μM). In HCC, sildenafil-induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large-conductance KCa (BK) and intermediate-conductance KCa (IK) contribute to NS-8-induced effects and were immunodetected in human and rat penile arteries. NS-8 potentiated sildenafil-induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes-induced ED in rats only when combined with KCa activation. Activation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non-diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

  4. Peripheral nerve stimulation: definition.

    PubMed

    Abejón, David; Pérez-Cajaraville, Juan

    2011-01-01

    Recently, there has been a tremendous evolution in the field of neurostimulation, both from the technological point of view and from development of the new and different indications. In some areas, such as peripheral nerve stimulation, there has been a boom in recent years due to the variations in the surgical technique and the improved results documented by in multiple published papers. All this makes imperative the need to classify and define the different types of stimulation that are used today. The confusion arises when attempting to describe peripheral nerve stimulation and subcutaneous stimulation. Peripheral nerve stimulation, in its pure definition, involves implanting a lead on a nerve, with the aim to produce paresthesia along the entire trajectory of the stimulated nerve. Copyright © 2011 S. Karger AG, Basel.

  5. Factors stimulating bone formation.

    PubMed

    Lind, M; Bünger, C

    2001-10-01

    The aim of this review is to describe major approaches for stimulating bone healing and to review other factors affecting bone healing. Spinal bone fusion after surgery is a demanding process requiring optimal conditions for clinical success. Bone formation and healing can be enhanced through various methods. Experimental studies have revealed an array of stimulative measures. These include biochemical stimulation by use of hormones and growth factors, physical stimulation through mechanical and electromagnetic measures, and bone grafting by use of bone tissue or bone substitutes. Newer biological techniques such as stem cell transplantation and gene therapy can also be used to stimulate bone healing. Apart from bone transplantation, clinical experience with the many stimulation modalities is limited. Possible areas for clinical use of these novel methods are discussed.

  6. Brain stimulation in posttraumatic stress disorder.

    PubMed

    Novakovic, Vladan; Sher, Leo; Lapidus, Kyle A B; Mindes, Janet; A Golier, Julia; Yehuda, Rachel

    2011-01-01

    Posttraumatic stress disorder (PTSD) is a complex, heterogeneous disorder that develops following trauma and often includes perceptual, cognitive, affective, physiological, and psychological features. PTSD is characterized by hyperarousal, intrusive thoughts, exaggerated startle response, flashbacks, nightmares, sleep disturbances, emotional numbness, and persistent avoidance of trauma-associated stimuli. The efficacy of available treatments for PTSD may result in part from relief of associated depressive and anxiety-related symptoms in addition to treatment of core symptoms that derive from reexperiencing, numbing, and hyperarousal. Diverse, heterogeneous mechanisms of action and the ability to act broadly or very locally may enable brain stimulation devices to address PTSD core symptoms in more targeted ways. To achieve this goal, specific theoretical bases derived from novel, well-designed research protocols will be necessary. Brain stimulation devices include both long-used and new electrical and magnetic devices. Electroconvulsive therapy (ECT) and Cranial electrotherapy stimulation (CES) have both been in use for decades; transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), deep brain stimulation (DBS), transcranial Direct Current Stimulation (tDCS), and vagus nerve stimulation (VNS) have been developed recently, over approximately the past twenty years. The efficacy of brain stimulation has been demonstrated as a treatment for psychiatric and neurological disorders such as anxiety (CES), depression (ECT, CES, rTMS, VNS, DBS), obsessive-compulsive disorder (OCD) (DBS), essential tremor, dystonia (DBS), epilepsy (DBS, VNS), Parkinson Disease (DBS), pain (CES), and insomnia (CES). To date, limited