bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroprotection of hypoxic postconditioning against global cerebral ischemia through influencing posttranslational regulations of heat shock protein 27 in adult rats
Authors: Zhan Lixuan , Liu Liu , Li Kongping , Wu Baoxing , Liu Dandan , Liang Donghai , Wen Haixia , Wang Yanmei , Sun Weiwen , Liao Weiping , Xu En 
Published: December 2016

AbstractWe previously reported that hypoxic postconditioning (HPC) ameliorated hippocampal neuronal death induced by transient global cerebral ischemia (tGCI) in adult rats. However, the mechanism of HPC‐induced neuroprotection is still elusive. Notably, heat shock protein 27 (Hsp27) has recently emerged as a potent neuroprotectant in cerebral ischemia. Although its robust protective effect on stroke has been recognized, the mechanism of Hsp27‐mediated neuroprotection is largely unknown. Here, we investigated the potential molecular mechanism by which HPC modulates the posttranslational regulations of Hsp27 after tGCI. We found that HPC increased expression of Hsp27 in CA1 subregion after tGCI. Inhibition of Hsp27 expression with lentivirus‐mediated short hairpin RNA (shRNA) abolished the neuroprotection induced by HPC in vivo. Furthermore, pretreatment with cycloheximide, a protein synthesis inhibitor, resulted in a significant decrease in the degradation rate of Hsp27 protein in postconditioned rats, suggesting that the increase in the expression of Hsp27 after HPC might result from its decreased degradation. Next, pretreatment with leupeptin, a lysosomal inhibitor, resulted in an accumulation of Hsp27 after tGCI, indicating that autophagic pathway may be responsible for the degradation of Hsp27. We further showed that the formation of LC3‐II and autophagosomes increased after tGCI. Meanwhile, the degradation of Hsp27 was suppressed and neuronal damage was reduced when blocking autophagy with 3‐Methyladenine, whereas activating autophagy with rapamycin showed an opposite tendency. Lastly, we confirmed that HPC increased the expression of phosphorylated MAPKAP kinase 2 (MK2) and Hsp27 after tGCI. Also, administration of SB203580, a p38 mitogen‐activated protein kinase inhibitor, decreased the expressions of phosphorylated MK2 and Hsp27. Our results suggested that inhibition of Hsp27 degradation mediated by down‐regulation of autophagy may induce ischemic tolerance after HPC. Additionally, phosphorylation of Hsp27 induced by MK2 might be associated with the neuroprotection of HPC.
Relaxin‐like peptides in male reproduction – a human perspective
Authors: Ivell Richard , Agoulnik Alexander I , Anand‐Ivell Ravinder 
Published: December 2016

AbstractThe relaxin family of peptide hormones and their cognate GPCRs are becoming physiologically well‐characterized in the cardiovascular system and particularly in female reproductive processes. Much less is known about the physiology and pharmacology of these peptides in male reproduction, particularly as regards humans. H2‐relaxin is involved in prostate function and growth, while insulin‐like peptide 3 (INSL3) is a major product of the testicular Leydig cells and, in the adult, appears to modulate steroidogenesis and germ cell survival. In the fetus, INSL3 is a key hormone expressed shortly after sex determination and is responsible for the first transabdominal phase of testicular descent. Importantly, INSL3 is becoming a very useful constitutive biomarker reflecting both fetal and post‐natal development. Nothing is known about roles for INSL4 in male reproduction and only very little about relaxin‐3, which is mostly considered as a brain peptide, or INSL5. The former is expressed at very low levels in the testes, but has no known physiology there, whereas the INSL5 knockout mouse does exhibit a testicular phenotype with mild effects on spermatogenesis, probably due to a disruption of glucose homeostasis. INSL6 is a major product of male germ cells, although it is relatively unexplored with regard to its physiology or pharmacology, except that in mice disruption of the INSL6 gene leads to a disruption of spermatogenesis. Clinically, relaxin analogues may be useful in the control of prostate cancer, and both relaxin and INSL3 have been considered as sperm adjuvants for in vitro fertilization.Linked ArticlesThis article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc
Morphostructure, tectono‐sedimentary evolution and seismic potential of the Horseshoe Fault, SW Iberian Margin
Authors: Martínez‐Loriente Sara , Gràcia Eulàlia , Bartolome Rafael , Perea Hector , Klaeschen Dirk , Dañobeitia Juan José , Zitellini Nevio , Wynn Russell B. , Masson Douglas G. 
Published: December 2016

AbstractHigh‐resolution acoustic and seismic data acquired 100 km offshore Cape São Vicente, image with unprecedented detail one of the largest active reverse faults of the SW Iberian Margin, the Horseshoe Fault (HF). The HF region is an area seismogenically active, source of the largest magnitude instrumental and historical earthquake (Mw > 6) occurred in the SW Iberian Margin. The HF corresponds to a N40 trending, 110 km long, and NW‐verging active thrust that affects the whole sedimentary sequence and reaches up to the seafloor, generating a relief of more than 1 km. The along‐strike structural variability as well as fault trend suggests that the HF is composed by three main sub‐segments: North (N25), Central (N50) and South (N45). Swath‐bathymetry, TOBI sidescan sonar backscatter and parametric echosounder TOPAS profiles reveal the surface morphology of the HF block, characterized by several, steep (20°) small scarps located on the hangingwall, and a succession of mass transport deposits (i.e. turbidites) on its footwall, located in the Horseshoe Abyssal Plain. A succession of pre‐stack depth‐migrated multichannel seismic reflection profiles across the HF and neighbouring areas allowed us to constrain their seismo‐stratigraphy, structural geometry, tectono‐sedimentary evolution from Upper Jurassic to present‐day, and to calculate their fault parameters. Finally, on the basis of segment length, surface fault area and seismogenic depth we evaluated the seismic potential of the HF, which in the worst‐case scenario may generate an earthquake of magnitude Mw 7.8 ± 0.1. Thus, considering the tectonic behaviour and near‐shore location, the HF should be recognized in seismic and tsunami hazard assessment models of Western Europe and North Africa.
T-bet over-expression regulates aryl hydrocarbon receptor-mediated T helper type 17 differentiation through an interferon (IFN)γ-independent pathway
Authors: Yokosawa M , Kondo Y , Tahara M , Iizuka-Koga M , Segawa S , Kaneko S , Tsuboi H , Yoh K , Takahashi S , Matsumoto I , Sumida T 
Published: December 2016

SummaryVarious transcription factors are also known to enhance or suppress T helper type 17 (Th17) differentiation. We have shown previously that the development of collagen-induced arthritis was suppressed in T-bet transgenic (T-bet Tg) mice, and T-bet seemed to suppress Th17 differentiation through an interferon (IFN)-γ-independent pathway, although the precise mechanism remains to be clarified. The present study was designed to investigate further the mechanisms involved in the regulation of Th17 differentiation by T-bet over-expression, and we found the new relationship between T-bet and aryl hydrocarbon receptor (AHR). Both T-bet Tg mice and IFN-γ–/–-over-expressing T-bet (T-bet Tg/IFN-γ–/–) mice showed inhibition of retinoic acid-related orphan receptor (ROR)γt expression and IL-17 production by CD4+ T cells cultured under conditions that promote Th-17 differentiation, and decreased IL-6 receptor (IL-6R) expression and signal transducer and activator of transcription-3 (STAT-3) phosphorylation in CD4+ T cells. The mRNA expression of ahr and rorc were suppressed in CD4+ T cells cultured under Th-17 conditions from T-bet Tg mice and T-bet Tg/IFN-γ–/– mice. CD4+ T cells of wild-type (WT) and IFN-γ–/– mice transduced with T-bet-expressing retrovirus also showed inhibition of IL-17 production, whereas T-bet transduction had no effect on IL-6R expression and STAT-3 phosphorylation. Interestingly, the mRNA expression of ahr and rorc were suppressed in CD4+ T cells with T-bet transduction cultured under Th17 conditions. The enhancement of interleukin (IL)−17 production from CD4+ T cells by the addition of AHR ligand with Th17 conditions was cancelled by T-bet over-expression. Our findings suggest that T-bet over-expression-induced suppression of Th17 differentiation is mediated through IFN-γ-independent AHR suppression.
Ro52/TRIM21-deficient expression and function in different subsets of peripheral blood mononuclear cells is associated with a proinflammatory cytokine response in patients with idiopathic inflammatory myopathies
Authors: Gómez-Martín D , Galindo-Feria A S , Barrera-Vargas A , Merayo-Chalico J , Juárez-Vega G , Torres-Ruiz J , Alcocer-Varela J 
Published: December 2016

Summary
The presence of anti-Ro52/tripartite motif 21 (Trim21) autoantibodies has been associated with a distinctive clinical profile and has gained value as a prognostic marker in idiopathic inflammatory myopathies (IIM). The aim of the present work was to analyse Ro52/Trim21 expression in different subsets of peripheral blood mononuclear cells (PBMCs) of patients with IIM, as well as the ubiquitination profile and its association with proinflammatory cytokine production. We included 18 patients with recent-onset IIM and 18 age- and gender-matched healthy donors. PBMCs were isolated and different subsets (CD4+, CD8+, CD14+) were purified by magnetic selection. The expression of Ro52/Trim21 in different PBMC subsets of patients with IIM and healthy donors was analysed by Western blot. We assessed the presence of myositis-specific and associated autoantibodies by enzyme-linked immunosorbent assay (ELISA). Cytokine levels were measured by cytometric bead array. Patients with IIM showed decreased protein expression of Ro52/Trim21 in comparison to healthy controls in PBMC (0·97 ± 0·60 versus 1·84 ± 0·92, P = 0·016), CD4+ lymphocytes (0·79 ± 0·54 versus 2·41 ± 0·78, P = 0·017), and monocytes (0·87 ± 0·35 versus 1·89 ± 0·20, P &lt; 0·001). There were no significant differences among IIM groups. Also, a lower K48-mediated ubiquitination profile was found, predominantly in CD4+ lymphocytes. Furthermore, after mitogenic stimulation, there was a higher synthesis of proinflammatory cytokines by T cells [interleukin (IL)-17A and tumour necrosis factor (TNF)-α] and monocytes [IL-6 and interferon (IFN)-α] from IIM patients compared with healthy controls. Our data suggest that patients with IIM, mainly DM, are characterized by a deficient expression of Ro52/TRIM21 in different PBMC subsets (CD4+ lymphocytes and monocytes), along with lower K48-mediated ubiquitination, which is associated with a proinflammatory cytokine response.
Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission
Authors: Qin Qi , Zhi Lian‐Teng , Li Xian‐Ting , Yue Zhen‐Yu , Li Guo‐Zhong , Zhang Hui 
Published: December 2016

SummaryIntroductionMutations in leucine‐rich repeat kinase 2 (LRRK2) are the most prevalent cause of familial and sporadic Parkinson's disease (PD). Because most pathogenic LRRK2 mutations result in enhanced kinase activity, it suggests that LRRK2 inhibitors may serve as a potential treatment for PD. To evaluate whether LRRK2 inhibitors are effective therapies for PD, it is crucial to know whether LRRK2 inhibitors will affect dopaminergic (DAergic) neurotransmission. However, to date, there is no study to investigate the impact of LRRK2 inhibitors on DAergic neurotransmission.AimsTo address this gap in knowledge, we examined the effects of three types of LRRK2 inhibitors (LRRK2‐IN‐1, GSK2578215A, and GNE‐7915) on dopamine (DA) release in the dorsal striatum using fast‐scan cyclic voltammetry and DA neuron firing in the substantia nigra pars compacta (SNpc) using patch clamp in mouse brain slices.ResultsWe found that LRRK2‐IN‐1 at a concentration higher than 1 μM causes off‐target effects and decreases DA release, whereas GSK2578215A and GNE‐7915 do not. All three inhibitors at 1 μM have no effect on DA release and DA neuron firing rate. We have further assessed the effects of the inhibitors in two preclinical LRRK2 mouse models (i.e., BAC transgenic hG2019S and hR1441G) and demonstrated that GNE‐7915 enhances DA release and synaptic vesicle mobilization/recycling.ConclusionGNE‐7915 can be validated for further therapeutic development for PD.
Abdominal rectopexy for the treatment of internal rectal prolapse: a systematic review and meta‐analysis
Authors: Emile S. H. , Elfeki H. A. , Youssef M. , Farid M. , Wexner S. D. 
Published: December 2016

AbstractAimInternal rectal prolapse (IRP) is a unique functional disorder that presents with a wide spectrum of clinical symptoms, including constipation and/or faecal incontinence (FI). The present review aims to analyse the results of trials evaluating the role of abdominal rectopexy in the treatment of IRP with regard to regarding functional and technical outcomes.MethodA systematic review of the literature for the role of abdominal rectopexy in patients with IRP was conducted. PubMed/Medline, Embase and the Cochrane Central Register of Controlled Trials were searched for published and unpublished studies from January 2000 to December 2015.ResultsWe reviewed 14 studies including 1301 patients (1180 women) of a median age of 59 years. The weighted mean rates of improvement of obstructed defaecation (OD) and FI across the studies were 73.9% and 60.2%, respectively. Twelve studies reported clinical recurrence in 84 (6.9%) patients. The weighted mean recurrence rate of IRP among the studies was 5.8% (95% CI: 4.2–7.5). Two hundred and thirty complications were reported with a weighted mean complication rate of 15%. Resection rectopexy had lower recurrence rates than did ventral rectopexy, whereas ventral rectopexy achieved better symptomatic improvement, a shorter operative time and a lower complication rate.ConclusionAbdominal rectopexy for IRP attained satisfactory results with improvement of OD and, to a lesser extent, FI, a low incidence of recurrence and an acceptable morbidity rate. Although ventral rectopexy was associated with higher recurrence rates, lower complication rates and better improvement of bowel symptoms than resection rectopexy, these findings cannot be confirmed owing to the limitations of this review.
Endoscopic monopolar coagulation of internal haemorrhoids: a surgeon's experience of the first 100 cases
Authors: Loh W.‐L. , Tan S. , Ngooi M. S. , Ong Z. K. , Ngoi S. S. 
Published: December 2016

AbstractAimThe purpose of this study was to evaluate one surgeon's initial experience with a novel technique of retroflexed endoscopic coagulation of internal haemorrhoids.MethodPatients who presented with symptoms and signs indicating Grade II–III haemorrhoids were counselled before the procedure. Those who were assessed to require an examination of their colon, based on their age and symptoms, underwent a full colonoscopy before treatment of the haemorrhoids. After the procedure, patients were routinely prescribed nonsteroidal anti‐inflammatory drugs, antibiotics and laxatives.ResultsThe first 100 patients of median age 52.0 (20.8–78.5) years included 65 (65%) women. Five (5%) patients suffered from postprocedural complications, of which three (3%) were postprocedural bleeding and two (2%) were postprocedural pain, all treated conservatively. The recurrence rate was 6% at a median follow‐up time of 36 (6–76) months. The median duration of follow‐up was 36.5 (8.5–57.0) months.ConclusionThis novel technique appears to be safe and effective for the treatment of Grade II–III internal haemorrhoids, and can be incorporated seamlessly into the end of a colonoscopy for the evaluation of haematochezia. Comparative trials should be performed.
Three‐dimensional endoanal ultrasound is accurate and reproducible in determining type and height of anal fistulas
Authors: Kołodziejczak M. , Santoro G. A. , Obcowska A. , Lorenc Z. , Mańczak M. , Sudoł‐Szopińska I. 
Published: December 2016

AbstractAimSurgical treatment of high anal fistulas is associated with the potential risk of faecal incontinence and recurrence. The primary aim of this study was to determine the accuracy of three‐dimensional endoanal ultrasound (3D‐EAUS) in the assessment of height and type of anal fistulas, compared to the intra‐operative findings (gold standard). The secondary aim was to evaluate the inter‐observer reproducibility of 3D‐EAUS.MethodThe study design was a prospective analysis of retrospective data. 299 patients (202 men), mean age 45.3 years, who underwent surgery for anal fistulas, were included. All patients were preoperatively assessed by 3D‐EAUS. Two readers independently reviewed the volumes to determine the type and height of fistulas. Sensitivity, specificity, positive and negative predictive values, proportion of agreements and Cohen's kappa coefficient (κ) were calculated for both examiners. Ultrasound findings were compared with intra‐operative data (reference standard), evaluated blindly by the surgeons.ResultsAt surgery, 201 (67%) were transsphincteric, 49 (16%) suprasphincteric, 47 (16%) intersphincteric and two (1%) extrasphincteric fistulas. Intra‐operatively, 177 (59%) were low and 122 (41%) high fistulas. The overall accuracy of 3D‐EAUS was 91% for fistula type (271/299 fistulas: 97% transsphincteric, 100% intersphincteric, 57% suprasphincteric, 0% extrasphincteric) and 92% for fistula height (275/299 fistulas: 80% high and 100% low). Both readers reported very good agreement with surgery in the assessment of fistula type (proportion of agreement 0.88, κ = 0.89) and height (proportion of agreement 0.90, κ = 0.91).Conclusions3D‐EAUS is an accurate and reproducible modality for the assessment of type and height of anal fistulas.
Relation between postoperative ileus and anastomotic leakage after colorectal resection: a post hoc analysis of a prospective randomized controlled trial
Authors: Peters E. G. , Dekkers M. , van Leeuwen‐Hilbers F. W. , Daams F. , Hulsewé K. W. E. , de Jonge W. J. , Buurman W. A. , Luyer M. D. P. 
Published: December 2016

AbstractAimAnastomotic leakage (AL) following abdominal surgery is a critical determinant of postoperative recovery, of which the aetiology is largely unknown. Interestingly, interventions aimed at reducing the inflammatory response and postoperative ileus (POI) have an unexpected effect on AL. The aim of this study was to investigate the relation of POI with inflammation and AL after colorectal resection.MethodA post hoc analysis of a prospective randomized controlled trial in which patients underwent a colorectal resection was performed. Patients undergoing a colorectal resection were stratified into having or not having POI. The incidence of AL and other clinical parameters was registered prospectively. Intestinal fatty acid binding protein (I‐FABP, a marker for tissue damage) and the inflammatory response in plasma and colon tissue were determined.ResultsAL was present in nine of 43 patients in the POI group, and in one of 65 in the group without POI (P < 0.001). There was a significant association between POI and AL (OR 12.57, 95% CI: 2.73–120.65; P = 0.0005). Patients with POI had significantly higher plasma levels of soluble tumour necrosis factor receptor 1 (TNFRSF1A) at 4 h postoperatively (0.89 ng/l, interquartile range 0.56) than patients without POI (0.80 ng/l, interquartile range 0.37; P = 0.04) and higher plasma levels of C‐reactive protein on the second day postoperatively (234 ± 77 vs 163 ± 86 mg/l; P = 0.001). Patients who developed AL had significantly higher plasma levels of I‐FABP compared with patients without AL at 24 h after onset of surgery.ConclusionPOI is associated with a higher prevalence of AL and an increased inflammatory response.
Tolerability and efficacy of perampanel in children with refractory epilepsy
Authors: Heyman Eli , Lahat Eli , Levin Noa , Epstein Orna , Lazinger Mirit , Berkovitch Matitiahu , Gandelman‐Marton Revital 
Published: December 2016

AimThere are few reports on the tolerability and efficacy of perampanel, a new antiepileptic drug with a novel mechanism of action, in children and adolescents. We aimed to describe our experience with perampanel add‐on and mono‐therapy in children with refractory epilepsy.MethodComputerized medical records of children treated with perampanel in the paediatric neurology clinic from December 2012 to October 2015 were reviewed.ResultsTwenty‐four children treated with perampanel (15 females, 9 males) aged 1 year 6 months to 17 years (mean 10y, standard deviation [SD] 4y 5mo) were identified. Adverse events were more common in children aged 12 years or older (89%) compared to younger children (53%), and were mainly behavioural. Ten (42%) children had 50 per cent or higher seizure reduction, two (8%) children had 33 per cent seizure reduction, and seizures were less severe in one (4%) child. Perampanel was discontinued in 13 (54%) children mostly due to adverse events. The mean duration of follow‐up in the remaining 11 children was 8.1 months (SD 5.2) (range 1.3–17mo).InterpretationPerampanel is associated with a relatively high rate of behavioural adverse events mostly in adolescents with refractory epilepsy.
Long‐term use of dipeptidyl peptidase‐4 inhibitors and risk of fracture: A retrospective population‐based cohort study
Authors: Driessen Johanna H. M. , van den Bergh Joop P. W. , van Onzenoort Hein A. W. , Henry Ronald M. A. , Leufkens Hubert G. M. , de Vries Frank 
Published: December 2016

AimsTo investigate the association between long‐term dipeptidyl peptidase‐4 (DPP‐4) inhibitor use and risk of fracture among people with type 2 diabetes mellitus (T2DM).MethodsA retrospective population‐based cohort study, using data from the Clinical Practice Research Datalink database (2007‐2015), was conducted. All those (N = 328 254) with at least one prescription for a non‐insulin antidiabetic drug (NIAD), aged ≥18 years at the time of data collection, were included. Cox proportional hazards models were used to estimate the hazard ratios of any fracture, osteoporotic fracture and hip fracture in DPP‐4 inhibitor users compared with those using other NIADs. Analyses were stratified by continuous duration of DPP‐4 inhibitor use. Time‐dependent adjustments were made for age, sex, lifestyle, comorbidity and concomitant drug use.ResultsCurrent use of DPP‐4 inhibitors was not associated with risk of any fracture (adjusted hazard ratio [HR] 0.99 [95% confidence interval {CI} 0.93‐1.06]) as compared with current other NIAD use. Current use of DPP‐4 inhibitors was also not associated with risk of osteoporotic or hip fracture. After stratification by continuous duration of DPP‐4 inhibitor use the highest category was not associated with any (>4.0‐8.5 years of use, adjusted HR 0.99 [95% CI 0.70‐1.41]), osteoporotic (>3.0‐8.5 years of use, adjusted HR 0.75 [95% CI 0.52‐1.09]) or hip (>2.0‐8.5 years of use; adjusted HR 1.24 [95% CI 0.85‐1.79]) fracture.ConclusionContinuous long‐term DPP‐4 inhibitor use (defined as >4.0‐8.5 years of DPP‐4 inhibitor use for any fracture, >3.0‐8.5 years for osteoporotic fracture and >2.0‐8.5 years for hip fracture was not associated with risk of any, osteoporotic or hip fracture. These findings may be of value for clinical decisions regarding treatment of patients with T2DM, especially those at high risk of fracture.