Binge Alcohol Drinking Exacerbates Ulcerative Colitis Flare

Inflammatory Bowel Disease (IBD) remains a prominent medical concern affecting over 1.4 million people in the U.S. One of the most common forms of the disease is ulcerative colitis (UC), and UC patients will often head doctor\u27s advice to refrain from drinking alcohol. However, whether this phenomenon of alcohol exacerbating UC symptoms occurs is still unknown, which necessitated the generation of a mouse model of UC and binge alcohol. Therefore, we examined a range of DSS concentrations (2-4%) and 2 alcohol paradigms in C57BL/6 mice. Mice receiving 2% DSS ad libitum for five days with a three-day alcohol binge had increased weight loss, colonic shortening, histopathology and clinical scores, and intestinal inflammation.During UC remission, IL-22 levels are upregulated. Following cessation of DSS, Vehicle treated mice were allowed to recover for 3 days. This resulted in increased levels of large intestine IL-22 in DSS Vehicle mice. Isolation of large intestine lamina propria cells revealed that DSS Vehicle treated mice had increased IL-22+ γδ T cells. However, these increased IL-22 levels and IL-22+ γδ T cells were abolished in DSS Ethanol mice.Alcohol\u27s role in diminishing the IL-22 response needed for entrance into UC remission could potentially explain the UC symptom exacerbation we observed. Hence, we sought to induce IL-22 with either rIL-22 or treatment with the probiotic, Lactobacillus delbrueckii. Administration of rIL-22 attenuated alcohol induced exacerbation of UC symptoms. Furthermore, IL-22-mediated protection required STAT3 signaling, as STAT3-/- mice did not benefit from IL-22 treatment following DSS-induced colitis and alcohol. Lacto treatment also mediated protection against exacerbated UC symptoms by increasing pSTAT3.UC patients experience higher rates of intestinal infections. To model this, we utilized the enteropathogen, C. rodentium, and found DSS Ethanol + C. rod mice had decreased survival, increased weight loss, colon shortening, more severe histopathology scores, decreased colonic mucosal layer, reduced goblet cell number, decreased tight junction protein expression, increased inflammation, and increased colonization by C. rod.Our laboratory established a new model of binge alcohol exacerbating an UC flare while highlighting the protective role of IL-22, which could present a potential new therapeutic option for UC patients

Role of Heat Shock Proteins in Maintenance of the Gut Barrier Following Burn Injury

Introduction: Burn injury remains a prominent clinical problem. Patients suffering from burns often succumb to secondary infectious complications leading to sepsis and widespread tissue injury ending in Multiple Organ Dysfunction. However, the mechanism behind the onset of these extraneous symptoms following burn injury is not fully understood. The integrity of the gut barrier is of critical importance as it harbors the largest bacterial reservoir in the body. Following burn injury, we observed a breakdown of the gut barrier resulting in increased gut leakiness and bacterial translocation. Under homeostatic conditions, heat shock proteins (HSPs) stabilize tight junction proteins. Particularly, HSP72 is shown to play a role in stabilizing tight junctional complexes of the blood brain barrier. Since tight junction proteins are responsible for maintaining gut barrier integrity, we examined the effect of burn injury on the heat shock response via HSPs and the claudin and occludin family of tight junction proteins. Hypothesis: Burn injury suppresses heat shock protein expression, which leads to alterations in tight junction proteins contributing to increased intestinal permeability and bacterial translocation after injury. Methods: Male C57BL/6 (10-12 week old) mice were anesthetized and administered an ~20% total body surface area dorsal scald burn using 85⁰C water for ~7-9 seconds and resuscitated with 1mL normal saline. The small and large intestines were harvested 4 hours, one, and three days following burn injury and processed for isolation of intestinal epithelial cells (IEC). IEC HSP25, 72, and 90 mRNA expression was examined by q-RTPCR along with claudin-4, claudin-8, and occludin. Protein levels of HSP25 and 72 and then claudin-4 and claudin-8 were examined by ELISA and immunofluorescence staining respectively. Results: We found significant decreases in HSP25, 72, and 90 expression (25%, 85%, and 51% respectively) in IECs harvested from the small intestine one day post burn injury compared to sham controls. This accompanied a significant decrease in claudin-4 and -8 expression (54% and 49%) in small intestine IECs of burn animals one day after burn compared to sham controls. At the protein level, burn injury resulted in a decrease of 85% in HSP25 four hours after burn injury and significant decreases in HSP72 four (51%) and three days (46%) in small intestine IECs compared to sham controls. Upon assessment of immunofluorescence staining of TJ proteins one day after burn injury, we observed significant decreases in claudin-4 levels, but claudin-8 immunofluorescence staining is still in progress. To discourage biases, we are currently expanding our immunofluorescence staining of tight junction proteins to include more tissue sections. Analysis of expression HSP25, 72, and 90 in large intestine IECS one day after burn injury resulted in a significant decrease in all three HSPs 4 hours of 44%, 79%, and 33% respectively after injury compared to sham. This significant decrease in HSP72 expression (81%) persisted to one day post burn injury. No significant changes in the expression of the tight junction proteins claudin-4, -8 or occludin were observed large intestine IECs. Protein levels of HSP25 mimicked mRNA expression with significant decreases in HSP25 (71%) in large intestine IECs four hours after burn injury. Yet, HSP72 levels post burn injury were significantly down in large intestine IECs on both one (63%) and three days (46%) compared to sham controls. Immunofluorescence staining of large intestine tissue sections for claudin-4 and claudin-8 is being done at the present time. We attempted to induce HSPs in our murine model of burn injury with the hypothesis that if HSPs stabilize TJ proteins, up-regulating HSPs after burn injury could potentially restore the decrease in TJ proteins we observe and bring back normal barrier function. We examined whether treatment of mice with mesalamine (5-ASA), an agent used in vitro to up-regulate HSPs, influences the expression of HSPs after burn injury. We found that mice treated with 100mg/kg 5-ASA at time of resuscitation, did not up-regulate HSPs in either small or large intestine IECs, but it did significantly restore claudin-4 and trends toward restoration of occludin expression in small intestine IECs one day after burn injury. Furthermore, 5-ASA significantly reduced the small intestine IEC pro-inflammatory cytokines IL-18 (62% increase one day after burn and back to sham levels with 5-ASA) and IL-6 (34% increase back to sham levels one day post burn) in IECs after burn injury. There was a trend towards a reduction in IL-6 and the pro-inflammatory cytokine KC in large intestine IECs with 5-ASA treatment one day following burn injury. Interestingly, there was a significant decrease (63%) in the pro-inflammatory chemokine MCP-1 following 5-ASA treatment one day after burn injury in large intestine IECs. Additionally, we found that 5-ASA reduces intestinal permeability back to that of sham controls one day after burn injury. Treatment with 5-ASA also allows for more efficient intestinal transit one day after burn injury. Conclusion: Our data suggest that burn results in significant decreases in HSPs in both small and large intestinal epithelial cells, which correlates with a significant decreases in levels of the tight junction proteins, claudin 4,8 and occludin. Although 5-ASA did not up-regulate HSP expression after burn injury, it did normalize claudin 4 and 8 expression and reduced IL-18 and IL-6 levels after burn injury in the small intestine. Levels of IL-6 and KC after burn injury in large intestine IECs are trending towards that of sham with 5-ASA treatment, but levels of MCP-1 did normalize as a result of treatment. 5-ASA also allowed for a complete reduction in the increased intestinal permeability we observe after burn injury and a partial restoration of intestinal peristalsis one day after injury. Together, these findings suggest that 5-ASA-mediated protective effects on the gut barrier integrity appears to be independent of HSPs

Conquering APA Style: Advice From APA Style Experts

Learning and teaching APA style is often a challenge because of the detailed rules for the writing style. Resources that provide accurate information about APA style that are easy for learners to consume can be useful tools for students and instructors. The goal of this article is to provide information to help writers become more competent and comfortable with APA style. The first section of this article contains lists of common APA style mistakes that are made when papers are submitted for publication. Editors look for very specific APA formatting and style, and this section will cover these issues. Moreover, the second section includes a list of APA style rules frequently encountered by an APA style tutor. The third section has information to help students navigate writing assignments in a research methods class. The fourth section addresses additional APA style rules that many writers do not know about. Finally, this information can serve as a guide for writers to use when writing APA style papers

Knowledge and Awareness of Congenital Cytomegalovirus Among Women

Background. Congenital cytomegalovirus (CMV) infection is a leading cause of disabilities in children, yet the general public appears to have little awareness of CMV. Methods. Women were surveyed about newborn infections at 7 different geographic locations. Results. Of the 643 women surveyed, 142 (22%) had heard of congenital CMV. Awareness increased with increasing levels of education (P < .0001). Women who had worked as a healthcare professional had a higher prevalence of awareness of CMV than had other women (56% versus 16%, P < .0001). Women who were aware of CMV were most likely to have heard about it from a healthcare provider (54%), but most could not correctly identify modes of CMV transmission or prevention. Among common causes of birth defects and childhood illnesses, women's awareness of CMV ranked last. Conclusion. Despite its large public health burden, few women had heard of congenital CMV, and even fewer were aware of prevention strategies

Cardiovascular and renal outcomes with canagliflozin according to baseline diuretic use:a post hoc analysis from the CANVAS Program

Aims The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes.Methods and results The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed-effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age +/- standard deviation, 64.3 +/- 8.0 vs. 62.5 +/- 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all P-difference &lt; 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54-0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93-1.36), P-heterogeneity &lt; 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin-to-creatinine ratio, were similar between groups (all P-difference &gt; 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (-0.52% vs. -0.64%, P-heterogeneity = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all P-heterogeneity &gt; 0.07).Conclusions Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes.</p

NineML: the network interchange for neuroscience modeling language

The growing number of large-scale neuronal network models has created a need for standards and guidelines to ease model sharing and facilitate the replication of results across different simulators. To foster community efforts towards such standards, the International Neuroinformatics Coordinating Facility (INCF) has formed its Multiscale Modeling program, and has assembled a task force of simulator developers to propose a declarative computer language for descriptions of large-scale neuronal networks. The name of the proposed language is "Network Interchange for Neuroscience Modeling Language" (NineML) and its initial focus is restricted to point neuron models. The INCF Multiscale Modeling task force has identified the key concepts of network modeling to be 1) spiking neurons 2) synapses 3) populations of neurons and 4) connectivity patterns across populations of neurons. Accordingly, the definition of NineML includes a set of mathematical abstractions to represent these concepts. NineML aims to provide tool support for explicit declarative definition of spiking neuronal network models both conceptually and mathematically in a simulator independent manner. In addition, NineML is designed to be self-consistent and highly flexible, allowing addition of new models and mathematical descriptions without modification of the previous structure and organization of the language. To achieve these goals, the language is being iteratively designed using several representative models with various levels of complexity as test cases. The design of NineML is divided in two semantic layers: the Abstraction Layer, which consists of core mathematical concepts necessary to express neuronal and synaptic dynamics and network connectivity patterns, and the User Layer, which provides constructs to specify the instantiation of a network model in terms that are familiar to computational neuroscience modelers. As part of the Abstraction Layer, NineML includes a flexible block diagram notation for describing spiking dynamics. The notation represents continuous and discrete variables, their evolution according to a set of rules such as a system of ordinary differential equations, and the conditions that induce a regime change, such as the transition from subthreshold mode to spiking and refractory modes. The User Layer provides syntax for specifying the structure of the elements of a spiking neuronal network. This includes parameters for each of the individual elements (cells, synapses, inputs) and the grouping of these entities into networks. In addition, the user layer defines the syntax for supplying parameter values to abstract connectivity patterns. The NineML specification is defined as an implementation-neutral object model representing all the concepts in the User and Abstraction Layers. Libraries for creating, manipulating, querying and serializing the NineML object model to a standard XML representation will be delivered for a variety of languages. The first priority of the task force is to deliver a publicly available Python implementation to support the wide range of simulators which provide a Python user interface (NEURON, NEST, Brian, MOOSE, GENESIS-3, PCSIM, PyNN, etc.). These libraries will allow simulator developers to quickly add support for NineML, and will thus catalyze the emergence of a broad software ecosystem supporting model definition interoperability around NineML

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Creative Destruction: The Role of Animal Disturbance in Structuring Tropical Seagrass Beds

Disturbance plays a significant role in structuring a variety of habitats, but in seagrass beds disturbance by animals may be more ecologically important than disturbance by abiotic factors. However, not all animal disturbances have identical impacts on seagrass beds and humans have increased the frequency of some animal impacts and decreased the frequency of others. This research investigated the impacts of disturbance by sea turtles (leaf-eating megaherbivores), manatees (leaf-and-root-eating megaherbivores), stingrays (bioturbators), and fish and urchins (macroherbivores) on seagrass beds in Bocas del Toro, Panamá. Repeated simulated sea turtle grazing was found to reduce percent cover and productivity of the late successional seagrass Thalassia testudinum, suggesting that seagrass beds in Bocas del Toro can no longer tolerate pre-Colombian levels of turtle grazing, likely due to increased sedimentation as a result of terrestrial deforestation. Artificially grazed plots were also vulnerable to subsequent bioturbation by stingrays. One-time simulated manatee grazing was not as attractive to stingrays although still did facilitate stingray bioturbation in comparison to undisturbed seagrass. T. testudinum in this study recovered quickly and with no colonization of experimentally created bare patches by species other than T. testudinum. High nutrient availability in Bocas del Toro may allow T. testudinum to colonize sediment gaps without prior facilitation by other organisms. Other organisms’ failure to colonize bare patches created due to simulated turtle or manatee grazing suggests they are not primarily limited by competition with T. testudinum. A third experiment was conducted to investigate whether the early successional seagrass, Syringodium filiforme, is excluded from monospecific beds of T. testudinum by runoff regimes or macroherbivores. Results indicated that S. filiforme only thrives in Bocas del Toro where the impact of runoff is limited and urchins in the genus Echinometra are not abundant. Echinometra is not usually thought to be a seagrass-associated species and may be colonizing this habitat as a result of overfishing of its predators. Human impacts in Bocas del Toro have reduced the ecological impacts of disturbances by megaherbivores, increased the impacts of one genus of macroherbivore, and made seagrass less resilient to repeated disturbance. Human impacts on disturbance by bioturbators are less clear and require further study

Alcohol and inflammatory responses: Highlights of the 2015 Alcohol and Immunology Research Interest Group (AIRIG) meeting

On September 27, 2015 the 20th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite symposium at the annual meeting of the Society for Leukocyte Biology in Raleigh, NC. The 2015 meeting focused broadly on adverse effects of alcohol and alcohol-use disorders in multiple organ systems. Divided into two plenary sessions, AIRIG opened with the topic of pulmonary inflammation as a result of alcohol consumption, which was followed by alcohol\u27s effect on multiple organs, including the brain and liver. With presentations showing the diverse range of underlying pathology and mechanisms associated with multiple organs as a result of alcohol consumption, AIRIG emphasized the importance of continued alcohol research, as its detrimental consequences are not limited to one or even two organs, but rather extend to the entire host as a whole