Santanaalbrektsen0400

Cenobamate is a novel antiepileptic drug under investigation for use in patients with focal (partial-onset) seizures. To understand its potential molecular mechanism of action, the effects of cenobamate on GABAA-mediated currents and GABAA receptors in rodent hippocampal neurons were examined. Cenobamate potentiated GABA-induced currents (IGABA) in acutely isolated CA3 pyramidal cells in a concentration-dependent manner (EC50, 164 μM), which was not affected by flumazenil, a benzodiazepine receptor antagonist. Cenobamate enhanced tonic GABAA currents (Itonic), which is defined as a holding current shift by the GABAA receptor antagonist bicuculline (EC50, 36.63 μM). At therapeutically relevant concentrations, cenobamate induced minimal changes in the frequency, amplitudes, and decay time of spontaneous inhibitory postsynaptic currents in the CA1 neurons. Flumazenil failed to affect cenobamate-potentiated Itonic and Iphasic in CA1 neurons. Cenobamate showed positive allosteric modulation of GABA-induced IGABA mediated by GABAA receptors. This effect was similar for all tested hGABAA receptors containing six different alpha subunits (α1β2γ2 or α2-6β3γ2), with EC50 values ranging from 42 to 194 μM. Cenobamate did not displace the binding of flunitrazepam, a benzodiazepine derivative, or flumazenil to GABAA receptors. The results showed that cenobamate, a novel antiepileptic drug, acts as a positive allosteric modulator of high-affinity GABAA receptors, activated by GABA at a site independent of the benzodiazepine binding site and efficiently enhances Itonic inhibition in hippocampal neurons, which could be an underlying molecular mechanism stabilizing neural circuits of the epileptic hippocampus. Endoplasmic reticulum (ER) stress as well as oxidative stress have been shown to play important roles in metabolic and cardiovascular disease, and drugs that counteract the effects of ER and oxidative stresses may be clinically useful. To identify novel compounds that ameliorate ER and oxidative stresses, we screened two drug libraries purchased from Evotec, San Francisco, CA; the NIH clinical collection 1 (446 compounds) and the NIH clinical collection 2 (281 compounds). Human coronary artery endothelial cells (HCAEC) were tested for ER and oxidative stress. ER stress was measured with an ER stress-sensitive secreted alkaline phosphatase (SAP) assay. The cells were transfected with the plasmid pSAP2.Control, expressing a heat-resistant form of SAP, and treated with the ER stress inducer tunicamycin in the presence or absence of each of the various compounds for 24-h, at which time SAP activity was measured. Compounds exhibiting significant increases in SAP activity (41 compounds out of a total of 727 tested; 5.6%) were then assayed for their ability to suppress superoxide (SO) anion generation in cells treated with 27.5 mM dextrose. SO generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride chemiluminescence. Of the 41 compounds identified as ER stress reducers, only 33 (80.5%) suppressed dextrose-induced SO anion generation. Interestingly, 51% of the compounds found to be dual-stress modifiers consisted of cardioprotective drugs, including statins, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors as well as β-blockers. Future studies to validate the clinical effectiveness of these agents remain to be performed in pre-clinical and clinical trials. PURPOSE This study aimed to examine (1) the independent effects of hypoxia on cognitive function and (2) the effects of exercise on cognition while under hypoxia. METHODS Design Systematic review with meta-analysis. DATA SOURCES PubMed, Scopus, Web of Science, PsychInfo, and SPORTDiscus were searched. Eligibility Criteria for Selecting Studies Randomized controlled trials and non-randomized controlled studies that investigated the effects of chronic or acute exercise on cognition under hypoxia were considered (Aim 2), as were studies investigating the effects of hypoxia on cognition (Aim 1). RESULTS In total, 18 studies met our inclusionary criteria for the systematic review and 12 studies were meta-analyzed. Exposure to hypoxia impaired attentional ability (standardized mean difference [SMD) = -0.4), executive function (SMD = -0.18), and memory function (SMD = -0.26) but not information processing (SMD = 0.27). Aggregated results indicated that performing exercise under hypoxia setting had a significant effect on cognitive improvement (SMD = 0.3, 95% confidence interval 0.14 - 0.45, I2 = 54%, p less then 0.001). Various characteristics (e.g., age, cognitive task type, exercise type, exercise intensity, training type, and hypoxia level) moderated the effects of hypoxia and exercise on cognitive function. CONCLUSIONS Exercise during exposure to hypoxia improves cognitive function. This association appears to be moderated by individual and exercise/hypoxia-related characteristics. V.BACKGROUND The molecular cause of severe congenital neutropenia (SCN) is unknown in 30-50% of patients. SEC61A1 encodes the α subunit of the SEC61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease. OBJECTIVE To expand the spectrum of SEC61A1- mediated disease to include autosomal dominant SCN. METHODS WES findings were validated and reported mutations compared by western blotting, Ca+2 flux assays, differentiation of transduced HL-60 cells, in vitro differentiation of primary CD34 cells, qPCR for unfolded protein response genes and single-cell RNA-sequencing on whole bone marrow. RESULTS We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN born to non-consanguineous Belgian parents. The mutation results in diminished protein expression, disturbed protein translocation and an increase in calcium leakage from the ER. In vitro differentiation of CD34+ cells recapitulated the patient's clinical arrest in granulopoiesis. The impact of Q92R-SEC61α1 on neutrophil maturation was validated using HL-60 cells, where transduction reduced differentiation into CD11b+CD16+ cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response, with single-cell analysis of primary bone-marrow revealing perturbed UPR in myeloid precursors, and in vitro differentiation of primary CD34+ cells revealing upregulation of CHOP and BiP UPR-response genes. CONCLUSION Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR. High-pressure chronic retention (HPCR) is a well-recognized common urological emergency which requires prompt treatment. It usually presents with nocturnal enuresis, a tense and palpable bladder, and symptoms of uraemia from renal failure George et al 1983.1 There have been isolated cases in the literature of HPCR presenting with symptoms of venous occlusion secondary to extrinsic bladder compression2,3 but it remains a rare presenting complaint. We discuss the case of a 56-year-old man who presented primarily with right lower limb swelling which was later revealed to be due to HPCR. We present an unusual case of isolated urethral tuberculosis. The patient had a history of urethral strictures and persistent discharge from two peno-scrotal fistulas which was confirmed on urethrogram. He was treated with anti-tubercular treatment and a two stage urethroplasty. GGTI 298 cell line A 43-year-old woman with paralysis and neurogenic bladder secondary to a gunshot wound presented with worsening urinary incontinence and urinary tract infections. On workup she was found to have two large bladder stones with diameters of around 11 cm. She was managed with antibiotics and surgical removal. This case highlights the importance of a multidisciplinary team in managing patients with spinal cord injuries. OBJECTIVES To characterize trends in the characteristics of urologic surgeons performing vasectomy over time. METHODS We performed a retrospective, cross-sectional study examining surgeon characteristics for case logs from the American Board of Urology (ABU) between 2004 and 2013. We used generalized estimating equations (GEE) with a log link and negative binomial distribution to examine demographic differences (gender, rural location, and surgeon volume) in the number of vasectomies surgeons performed over time. RESULTS Between 2004 and 2013, 5,316 urologists had case logs collected within the 7-month certification window. The majority of these surgeons self-identified as general urologists (82.8%), and a small proportion identified as andrology and infertility specialists (1.7%). Across all years, the median number of vasectomies performed per certifying surgeon during the study period was 14 (interquartile range [IQR] 6-26). The majority of vasectomies were performed by high-volume surgeons (≥ 26 vasectomies) ranging from 49.2%-66.9% annually, whereas the proportion performed by low-volume (≤ 5 vasectomies) surgeons ranged from 3.3%-6.6% annually. Male surgeons performed vasectomies 2.20 times more frequently than female surgeons (95% confidence interval [CI] 1.93-2.49; p less then .0001) across the study period with no evidence to suggest this gap changed over time (gender-year interaction 1.01 [95% CI 0.97-1.06; p=0.576]). CONCLUSIONS While the majority of urologists performing vasectomy identify as general urologists, there appears to be a focus on vasectomy practice among a small number of high-volume surgeons. Furthermore, while the number of female surgeons performing vasectomies increased, a gender gap persists in the proportion of vasectomies performed by females. The term putty kidney was first used in 1906 by Dr. F. Tilden Brown, a genitourinary surgeon, to describe a well-defined density seen in kidney region on standard radiograph which is caused by a putty-like substance that had formed a cast inside a tuberculous kidney. The putty kidney is a classic imaging sign, rarely seen nowadays which represents a nonfunctioning autonephrectomized kidney seen in end stage renal tuberculosis.1-5 Here, we describe a 45-year-old female with left flank pain who on imaging had a classic putty kidney which led to an evaluation and later confirmation of a diagnosis of renal tuberculosis. AIM The neuronal damage and accompanied functional deficits induced by cerebral ischemia are among the most common causes of disabilities in adults. Activation of subtypes of peroxisome proliferator-activated receptors (PPARs); PPAR-α and PPAR-γ have shown neuroprotective effects in different neurodegenerative diseases including stroke. Thus, this study aimed to compare the effects of two different agonists PPAR-α (fenofibrate) and PPAR-γ (pioglitazone) as well as the effect of their combination in ameliorating post-ischemia behavioral deficits. METHODS Male Wistar rats were either pretreated with vehicle, fenofibrate (100 mg/kg/day p.o), pioglitazone (10 mg/kg/day p.o) or their combination for 14 days prior to bilateral common carotid artery occlusion followed by reperfusion for 24 hoursh. The sensory motor functions of rats were assessed, then rats were sacrificed to determine infarct volume and histopathological changes as well as oxidative stress, inflammatory and apoptotic markers in the brain tissue. KEY FINDINGS Pre-treatment with fenofibrate and pioglitazone in addition to their combination improved neurobehavioral dysfunction, reduced cerebral infarct volume, attenuated inflammatory and apoptotic markers and ameliorated histopathological changes in I/R injured rats.