Regulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene Dysbindin-1

AbstractBackgroundGenetic variations in dystrobrevin binding protein 1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in Dtnbp1 in mice disrupted both glutamatergic and gamma-aminobutyric acidergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs. However, the mechanism by which reduced dysbindin-1 activity causes inhibitory synaptic deficits remains unknown.MethodsWe investigated the role of dysbindin-1 in the exocytosis of brain-derived neurotrophic factor (BDNF) from cortical excitatory neurons, organotypic brain slices, and acute slices from dysbindin-1 mutant mice and determined how this change in BDNF exocytosis transsynaptically affected the number of inhibitory synapses formed on excitatory neurons via whole-cell recordings, immunohistochemistry, and live-cell imaging using total internal reflection fluorescence microscopy.ResultsA decrease in dysbindin-1 reduces the exocytosis of BDNF from cortical excitatory neurons, and this reduction in BDNF exocytosis transsynaptically resulted in reduced inhibitory synapse numbers formed on excitatory neurons. Furthermore, application of exogenous BDNF rescued the inhibitory synaptic deficits caused by the reduced dysbindin-1 level in both cultured cortical neurons and slice cultures.ConclusionsTaken together, our results demonstrate that these two genes linked to risk for schizophrenia (BDNF and dysbindin-1) function together to regulate interneuron development and cortical network activity. This evidence supports the investigation of the association between dysbindin-1 and BDNF in humans with schizophrenia

Sorption and Photodegradation Processes Govern Distribution and Fate of Sulfamethazine in Freshwater−Sediment Microcosms

The antibiotic sulfamethazine can be transported from manured fields to surface water bodies. We investigated the degradation and fate of sulfamethazine in pond water using 14C-phenyl-sulfamethazine in small pond water microcosms containing intact sediment and pond water. We found a 2.7-day half-life in pond water and 4.2-day half-life when sulfamethazine was added to the water (5 mg L–1 initial concentration) with swine manure diluted to simulate runoff. Sulfamethazine dissipated exponentially from the water column, with the majority of loss occurring via movement into the sediment phase. Extractable sulfamethazine in sediment accounted for 1.9–6.1% of the applied antibiotic within 14 days and then declined thereafter. Sulfamethazine was transformed mainly into nonextractable sediment-bound residue (40–60% of applied radioactivity) and smaller amounts of photoproducts. Biodegradation, as indicated by metabolite formation and 14CO2 evolution, was less significant than photodegradation. Two photoproducts accounted for 15–30% of radioactivity in the water column at the end of the 63-day study; the photoproducts were the major degradates in the aqueous and sediment phases. Other unidentified metabolites individually accounted for \u3c7% of radioactivity in the water or sediment. Less than 3% of applied radioactivity was mineralized to 14CO2. Manure input significantly increased sorption and binding of sulfamethazine residues to the sediment. These results show concurrent processes of photodegradation and sorption to sediment control aqueous concentrations and establish that sediment is a sink for sulfamethazine and sulfamethazine-related residues. Accumulation of the photoproducts and sulfamethazine in sediment may have important implications for benthic organisms

Intrinsic bias in breast cancer gene expression data sets

<p>Abstract</p> <p>Background</p> <p>While global breast cancer gene expression data sets have considerable commonality in terms of their data content, the populations that they represent and the data collection methods utilized can be quite disparate. We sought to assess the extent and consequence of these systematic differences with respect to identifying clinically significant prognostic groups.</p> <p>Methods</p> <p>We ascertained how effectively unsupervised clustering employing randomly generated sets of genes could segregate tumors into prognostic groups using four well-characterized breast cancer data sets.</p> <p>Results</p> <p>Using a common set of 5,000 randomly generated lists (70 genes/list), the percentages of clusters with significant differences in metastasis latencies (HR p-value < 0.01) was 62%, 15%, 21% and 0% in the NKI2 (Netherlands Cancer Institute), Wang, TRANSBIG and KJX64/KJ125 data sets, respectively. Among ER positive tumors, the percentages were 38%, 11%, 4% and 0%, respectively. Few random lists were predictive among ER negative tumors in any data set. Clustering was associated with ER status and, after globally adjusting for the effects of ER-α gene expression, the percentages were 25%, 33%, 1% and 0%, respectively. The impact of adjusting for ER status depended on the extent of confounding between ER-α gene expression and markers of proliferation.</p> <p>Conclusion</p> <p>It is highly probable to identify a statistically significant association between a given gene list and prognosis in the NKI2 dataset due to its large sample size and the interrelationship between ER-α expression and markers of proliferation. In most respects, the TRANSBIG data set generated similar outcomes as the NKI2 data set, although its smaller sample size led to fewer statistically significant results.</p

Preliminary Assessment of Celecoxib and Microdiode Pulse Laser Treatment of Diabetic Macular Edema

Purpose: Inflammation may play an important role in the pathogenesis of diabetic macular edema, a major cause of vision loss in persons with diabetes. The purpose of this study was to evaluate combined antiinflammatory therapy and laser approaches for treating patients with diabetic macular edema. Methods: In this prospective, factorial, randomized, multicenter trial, we compared cyclo-oxygenase-2 inhibitor (celecoxib) with placebo and diode grid laser with standard Early Treatment Diabetic Retinopathy Study focal laser treatment in 86 participants with diabetic macular edema. The primary outcome is change in visual acuity of ≥15 letters from baseline, and the secondary outcomes include a 50% reduction in the retinal thickening of diabetic macular edema measured by optical coherence tomography and a 50% reduction in leakage severity on fluorescein angiography. Results: Visual acuity and retinal thickening data from >2 years of follow-up did not show evidence of differences between the medical and laser treatments. However, participants assigned to the celecoxib group were more likely to have a reduction in fluorescein leakage when compared with the placebo group (odds ratio = 3.6; P < 0.01). Conclusion: This short-term study did not find large visual function benefits of treatment with celecoxib or diode laser compared with those of standard laser treatment. A suggestive effect of celecoxib in reducing fluorescein leakage was observed

Targeting vascular endothelial growth factor receptor 2 and protein kinase d1 related pathways by a multiple kinase inhibitor in angiogenesis and inflammation related processes in vitro.

Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-alpha -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways

Multidisciplinary Service Utilization Pattern by Advanced Head and Neck Cancer Patients: A Single Institution Study

Purpose. To analyze the patterns and associations of adjunctive service visits by head and neck cancer patients receiving primary, concurrent chemoradiation therapy. Methods. Retrospective chart review of patients receiving adjunctive support during a uniform chemoradiation regimen for stages III-IV head and neck squamous cell carcinoma. Univariate and multivariate models for each outcome were obtained from simple and multivariate linear regression analyses. Results. Fifty-two consecutive patients were assessed. Female gender, single marital status, and nonprivate insurance were factors associated with an increased number of social work visits. In a multivariate analysis, female gender and marital status were related to increased social work services. Female gender and stage IV disease were significant for increased nursing visits. In a multivariate analysis for nursing visits, living greater than 20 miles between home and hospital was a negative predictive factor. Conclusion. Treatment of advanced stage head and neck cancer with concurrent chemoradiation warrants a multidisciplinary approach. Female gender, single marital status, and stage IV disease were correlated with increased utilization of social work and nursing services. Distance over 20 miles from the center was a negative factor. This information may help guide the treatment team to allocate resources for the comprehensive care of patients

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

BACKGROUND: Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. DISCUSSION: A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. SUMMARY: A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons

FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m2, P = 1.9 × 10−105), and all participants (0.30 [0.30, 0.35] kg/m2, P = 3.6 × 10−107). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10−16), and relative weak associations with lower total energy intake (−6.4 [−10.1, −2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (−0.07 [−0.11, −0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10−9) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposit

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms