Oklahoma City VA Health Care System

Descriptive epidemiological information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population-based studies. Data obtained following adoption of the World Health Organization classification of haematopoietic neoplasms and JAK2 V617F mutation testing are sparse. Using population-based data, we comprehensively assessed subtype-specific MPN and MDS/MPN incidence rates (IRs), IR ratios (IRRs) and relative survival (RS) in the United States (2001-12). IRs were highest for polycythaemia vera (PV) (IR = 10·9) and essential thrombocythaemia (ET) (IR = 9·6). Except for ET and mastocytosis, overall IRs were significantly higher among males (IRRs = 1·4-2·3). All evaluable MPNs were associated with lower IRs among Hispanic whites than non-Hispanic whites (NHWs), with the exception of BCR-ABL1-positive chronic myeloid leukaemia (CML), chronic eosinophilic leukaemia (CEL) and juvenile myelomonocytic leukaemia. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN-unclassifiable and CEL IRs were 18%, 19% and 60% higher, respectively, among blacks than NHWs. Five-year RS was more favourable for younger (<60 years) than older individuals and for women compared with men, except for PV at older ages. RS was highest (>90%) for younger PV and ET patients and lowest (<20%) for older chronic myelomonocytic leukaemia and atypical BCR-ABL1-negative CML patients. Varying MPN and MDS/MPN incidence patterns by subtype support distinct aetiologies and/or susceptible populations. Decreased survival rates as compared to that expected in the general population were associated with every MPN subtype, highlighting the need for new treatments, particularly among older individuals.

When administering unfractionated heparin (UFH), therapeutic levels of anticoagulation must be achieved rapidly and maintained consistently in the therapeutic range. The basic assays for monitoring UFH therapy are the activated partial thromboplastin time (APTT) and/or the chromogenic antifactor Xa or antithrombin assays. For many laboratories, the APTT is the preferred standard of practice; however, the APTT is a surrogate marker that only estimates the heparin concentration. Many factors, including patient variation, reagents of the APTT, UFH composition, and concentration can influence the APTT result. This article reviews various methods to determine the heparin therapeutic range and presents recommendations for the laboratory to establish an APTT heparin therapeutic range for all sizes of hospitals.

Importance: Traditional approaches to practice guidelines frequently result in dissociation between strength of recommendation and quality of evidence. Objective: To construct a clinical guideline for pyogenic osteomyelitis management, with a new standard of evidence to resolve the gap between strength of recommendation and quality of evidence, through the use of a novel open access approach utilizing social media tools. Evidence Review: This consensus statement and systematic review study used a novel approach from the WikiGuidelines Group, an open access collaborative research project, to construct clinical guidelines for pyogenic osteomyelitis. In June 2021 and February 2022, authors recruited via social media conducted multiple PubMed literature searches, including all years and languages, regarding osteomyelitis management; criteria for article quality and inclusion were specified in the group's charter. The GRADE system for evaluating evidence was not used based on previously published concerns regarding the potential dissociation between strength of recommendation and quality of evidence. Instead, the charter required that clear recommendations be made only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were drafted to discuss pros and cons of care choices. Both clear recommendations and clinical reviews were planned with the intention to be regularly updated as new data become available. Findings: Sixty-three participants with diverse expertise from 8 countries developed the group's charter and its first guideline on pyogenic osteomyelitis. These participants included both nonacademic and academic physicians and pharmacists specializing in general internal medicine or hospital medicine, infectious diseases, orthopedic surgery, pharmacology, and medical microbiology. Of the 7 questions addressed in the guideline, 2 clear recommendations were offered for the use of oral antibiotic therapy and the duration of therapy. In addition, 5 clinical reviews were authored addressing diagnosis, approaches to osteomyelitis underlying a pressure ulcer, timing for the administration of empirical therapy, specific antimicrobial options (including empirical regimens, use of antimicrobials targeting resistant pathogens, the role of bone penetration, and the use of rifampin as adjunctive therapy), and the role of biomarkers and imaging to assess responses to therapy. Conclusions and Relevance: The WikiGuidelines approach offers a novel methodology for clinical guideline development that precludes recommendations based on low-quality data or opinion. The primary limitation is the need for more rigorous clinical investigations, enabling additional clear recommendations for clinical questions currently unresolved by high-quality data.

Vascular mechanisms of Alzheimer's disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits. Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice. Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.

Symptoms of functional gastrointestinal disorders (FGIDs), including fullness, bloating, abdominal pain, and altered gastrointestinal (GI) motility, present a significant clinical problem, with a reported prevalence of 25%-40% within the general population. More than 60% of those affected seek and require healthcare, and affected individuals report a significantly decreased quality of life. FGIDs are highly correlated with episodes of acute and chronic stress and are increased in prevalence and reported severity in women compared with men. Although there is evidence that sex and stress interact to exacerbate FGID symptoms, the physiological mechanisms that mediate these sex-dependent disparities are incompletely understood, although hormonal-related differences in GI motility and visceral sensitivity have been purported to play a significant role in the etiology. In this mini review, we will discuss brain-gut axis control of GI motility and sensitivity, the influence of estrogen on GI motility and sensitivity, and stress modulation of the brain-gut axis.

Schistosomiasis is of public health importance to an estimated one billion people in 79 countries. A vaccine is urgently needed. Here, we report the results of four independent, double-blind studies of an Sm-p80-based vaccine in baboons. The vaccine exhibited potent prophylactic efficacy against transmission of Schistosoma mansoni infection and was associated with significantly less egg-induced pathology, compared with unvaccinated control animals. Specifically, the vaccine resulted in a 93.45% reduction of pathology-producing female worms and significantly resolved the major clinical manifestations of hepatic/intestinal schistosomiasis by reducing the tissue egg-load by 89.95%. A 35-fold decrease in fecal egg excretion in vaccinated animals, combined with an 81.51% reduction in hatching of eggs into the snail-infective stage (miracidia), demonstrates the parasite transmission-blocking potential of the vaccine. Substantially higher Sm-p80 expression in female worms and Sm-p80-specific antibodies in vaccinated baboons appear to play an important role in vaccine-mediated protection. Preliminary analyses of RNA sequencing revealed distinct molecular signatures of vaccine-induced effects in baboon immune effector cells. This study provides comprehensive evidence for the effectiveness of an Sm-p80-based vaccine for schistosomiasis.

A solitary pulmonary nodule (SPN) is a well-defined radiographic opacity up to 3 cm in diameter that is surrounded by unaltered aerated lung. Frequently, it is an incidental finding on chest radiographs and chest CT scans. Determining the probability of malignancy is the first step in the evaluation of SPN. This can be done by looking at specific risk factors and the rate of radiographic progression. Subsequent management is guided by the type of the nodule. Patients with solid nodules and low pretest probability can be followed radiographically; those with high probability, who are good surgical candidates, can be referred for surgical resection. When the pretest probability is in the intermediate range additional testing such as biopsy should be done. Various modalities are now available to obtain tissue diagnosis. These modalities differ in their yield and complication rate. Patients with SPN should be well informed of each approach's risks and benefits and should be able to make an informed decision regarding the different diagnostic and therapeutic modalities.

The proteasome has key roles in neuronal proteostasis, including the removal of misfolded and oxidized proteins, presynaptic protein turnover, and synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD). We show that prevention of proteasome dysfunction by genetic manipulation delays mortality, cell death, and cognitive deficits in fly and cell culture AD models. We developed a transgenic mouse with neuronal-specific proteasome overexpression that, when crossed with an AD mouse model, showed reduced mortality and cognitive deficits. To establish translational relevance, we developed a set of TAT-based proteasome-activating peptidomimetics that stably penetrated the blood-brain barrier and enhanced 20 S /26 S proteasome activity. These agonists protected against cell death, cognitive decline, and mortality in cell culture, fly, and mouse AD models. The protective effects of proteasome overexpression appear to be driven, at least in part, by the proteasome’s increased turnover of the amyloid precursor protein along with the prevention of overall proteostatic dysfunction.

// Xingmin Wang 1, 2 , Yonghong Yang 3, 4 and Mark M. Huycke 2, 5 1 Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA 2 The Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, Oklahoma City, OK 73104, USA 3 Gansu Province Children&rsquo;s Hospital, Lanzhou, Gansu 730030, China 4 Key Laboratory of Gastrointestinal Cancer, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China 5 Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA Correspondence to: Xingmin Wang, email: xingmin-wang@ouhsc.edu Mark M. Huycke, email: mark-huycke@ouhsc.edu Keywords: macrophage; bystander effect; Wnt/&beta;-catenin; dedifferentiation; cancer stem cell Received: May 03, 2017&emsp;&emsp;&emsp;&emsp; Accepted: September 29, 2017&emsp;&emsp;&emsp;&emsp; Published: November 01, 2017 ABSTRACT The colonic microbiome contributes to the initiation of colorectal cancer through poorly characterized mechanisms. We have shown that commensal-polarized macrophages induce gene mutation, chromosomal instability, and endogenous transformation through microbiome-induced bystander effects (MIBE). In this study we show that MIBE activates Wnt/&beta;-catenin signaling and pluripotent transcription factors associated with dedifferentiation, reprogramming, and the development of colorectal cancer stem cells (CSCs). Exposure of murine primary colon epithelial cells (YAMC) to Enterococcus faecalis -infected macrophages increased Wnt3&alpha; expression while suppressing Wnt inhibitor factor 1 (Wif1). Wnt/&beta;-catenin activation was confirmed by increased active &beta;-catenin and Tcf4. in vivo , active &beta;-catenin was evident in colon biopsies from E. faecalis -colonized Il10 knockout mice compared to sham-colonized mice. This effect was mediated, in part, by 4-hydroxy-2-nonenal and tumor necrosis factor &alpha;. MIBE also activated pluripotent transcription factors c-Myc, Klf4, Oct4, and Sox2 in YAMC cells and colons from E. faecalis -colonized Il10 knockout mice. These transcription factors are associated with cellular reprogramming, dedifferentiation, and induction of colorectal CSC progenitors. In support of this was an increase in the expression of Dclk1 and CD44, two colorectal CSC markers, in YAMC cells that were exposed to MIBE. Finally, compared to normal colon biopsies and hyperplastic polyps, DCLK1 expression increased in human tubular adenomas and invasive colorectal cancers. Blocking &beta;-catenin/TCF4 signaling using FH535 and CTNNB1 -specific small interfering RNA decreased DCLK1 expression in HCT116 human colon cancer cells. These findings provide mechanism for microbiome-induced colorectal cancer and identify new potential targets for colorectal cancer prevention.

BACKGROUND: In contrast to the well-described epidemiology and behavior of small cell lung carcinoma (SCLC), little is known about extrapulmonary small cell carcinoma (EPSCC). METHODS: Using data from the Surveillance, Epidemiology and End Results (SEER) Program (1992-2010), we calculated age-adjusted incidence rates (IRs), IR ratios (IRRs), annual percent change (APC), relative survival (RS), RS ratios (RSRs), and the respective 95% confidence intervals (95% CI) of SCLC and EPSCC according to primary site. We used the SEER historic stage variable that includes localized (confined to the organ of origin), regional (direct extension to adjacent organ/tissue or regional lymph nodes), and distant (discontinuous metastases) stages and combined localized and regional stages into "limited" stage. RESULTS: The incidence of SCLC (IR = 76.3/million person-years; n = 51,959) was 22-times that of EPSCC (IR = 3.5; n = 2,438). Of the EPSCC sites, urinary bladder, prostate, and uterine cervix had the highest incidence (IRs = 0.7-0.8); urinary bladder (IRR = 4.91) and stomach (IRR = 3.46) had the greatest male/female disparities. Distant-to-limited stage site-specific IRRs of EPSCC were significantly elevated for pancreas (IRR = 6.87; P < 0.05), stomach, colon/rectum, ovary, and prostate (IRRs = 1.62-2.42; P < 0.05) and significantly decreased for salivary glands, female breast, uterine cervix, and urinary bladder (IRRs = 0.32-0.46). During 1992-2010, significant changes in IRs were observed for EPSCC overall (APC = 1.58), small cell carcinoma of the urinary bladder (APC = 6.75), SCLC (APC = -2.74) and small cell carcinoma of unknown primary site (APC = -4.34). Three-year RS was significantly more favorable for patients with EPSCC than SCLC for both limited (RSR = 2.06; 95% CI 1.88, 2.26) and distant stages (RSR = 1.55; 95% CI 1.16, 2.07). Among limited stage small cell carcinoma, RS was most favorable for salivary glands, female breast, and uterine cervix (RS = 52-68%), whereas RS for nearly all sites with distant stage disease was <10%. CONCLUSION: EPSCC comprises a heterogeneous group of diseases that appears, at least in part, etiologically distinct from SCLC and is associated with more favorable stage-specific patient survival.

BACKGROUND: During March 2004, a large outbreak of legionnaires disease and Pontiac fever occurred among hotel guests in Oklahoma. An investigation was conducted to identify the source and evaluate the utility of the Legionella urine antigen assay and serologic testing for the identification of Pontiac fever. METHODS: A retrospective cohort investigation of hotel guests and employees and an environmental evaluation were performed. Participants were interviewed, and clinical specimens were collected from consenting individuals. RESULTS: Six cases of legionnaires disease and 101 cases of Pontiac fever were identified. Exposure to the indoor pool and hot tub area was associated with legionellosis (relative risk, 4.4; 95% confidence interval, 2.8-6.9). Specimens from the pool and hot tub tested positive for Legionella pneumophila serogroup 1 by polymerase chain reaction. For Pontiac fever, the sensitivity and positive predictive value were 35.7% and 100%, respectively, for the urine antigen assay, and 46.4% and 90%, respectively, for serologic testing. The specificity and negative predictive value were 100% and 47.8%, respectively, for the urine antigen assay, and 89.3% and 45.5%, respectively, for serologic testing. CONCLUSIONS: Urine antigen testing, with or without serologic testing, can be used to confirm outbreak-associated cases of Pontiac fever caused by L. pneumophila serogroup 1.

Sepsis is a clinical syndrome encompassing physiologic and biological abnormalities caused by a dysregulated host response to infection. Sepsis progression into septic shock is associated with a dramatic increase in mortality, hence the importance of early identification and treatment. Over the last two decades, the definition of sepsis has evolved to improve early sepsis recognition and screening, standardize the terms used to describe sepsis and highlight its association with organ dysfunction and higher mortality. The early 2000s witnessed the birth of early goal-directed therapy (EGDT), which showed a dramatic reduction in mortality leading to its wide adoption, and the surviving sepsis campaign (SSC), which has been instrumental in developing and updating sepsis guidelines over the last 20 years. Outside of early fluid resuscitation and antibiotic therapy, sepsis management has transitioned to a less aggressive approach over the last few years, shying away from routine mixed venous oxygen saturation and central venous pressure monitoring and excessive fluids resuscitation, inotropes use, and red blood cell transfusions. Peripheral vasopressor use was deemed safe and is rising, and resuscitation with balanced crystalloids and a restrictive fluid strategy was explored. This review will address some of sepsis management's most important yet controversial components and summarize the available evidence from the last two decades.

BACKGROUND: Primary care clinics present challenges to implementing evidence-based psychotherapies (EBPs) for depression and anxiety, and frontline providers infrequently adopt these treatments. The current study explored providers' perspectives on fidelity to a manualized brief cognitive behavioral therapy (CBT) as delivered in primary care clinics as part of a pragmatic randomized trial. Data from the primary study demonstrated the clinical effectiveness of the treatment and indicated that providers delivered brief CBT with high fidelity, as evaluated by experts using a standardized rating form. Data presented here explore challenges providers faced during implementation and how they adapted nonessential intervention components to make the protocol "fit" into their clinical practice. METHODS: A multiprofessional group of providers (n = 18) completed a one-time semi-structured interview documenting their experiences using brief CBT in the primary care setting. Data were analyzed via directed content analysis, followed by inductive sorting of interview excerpts to identify key themes agreed upon by consensus. The Dynamic Adaptation Process model provided an overarching framework to allow better understanding and contextualization of emergent themes. RESULTS: Providers described a variety of adaptations to the brief CBT to better enable its implementation. Adaptations were driven by provider skills and abilities (i.e., using flexible content and delivery options to promote treatment engagement), patient-emergent issues (i.e., addressing patients' broader life and clinical concerns), and system-level resources (i.e., maximizing the time available to provide treatment). CONCLUSIONS: The therapeutic relationship, individual patient factors, and system-level factors were critical drivers guiding how providers adapted EBP delivery to improve the "fit" into their clinical practice. Adaptations were generally informed by tensions between the EBP protocol and patient and system needs and were largely not addressed in the EBP protocol itself. Adaptations were generally viewed as acceptable by study fidelity experts and helped to more clearly define delivery procedures to improve future implementation efforts. It is recommended that future EBP implementation efforts examine the concept of fidelity on a continuum rather than dichotomized as adherent/not adherent with focused efforts to understand the context of EBP delivery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01149772.

Chronic obstructive pulmonary disease (COPD) represents an important global public health concern. Malnutrition is common in patients with COPD and often leads to worse outcomes for these patients. Recognition of overall nutrition status for patients with COPD is an important aspect of their care and treatment. Several methods have been studied that move beyond the standard/frequent use of body mass index alone. The purpose of this review is to summarize the current evidence for other tools to evaluate nutrition status in patients with COPD and highlight patients who may benefit from nutrition interventions.

For years the human microbiota has been implicated in the etiology of colorectal cancer (CRC). However, identifying the molecular mechanisms for how aneuploidy and chromosomal instability (CIN) arise in sporadic and colitis-associated CRC has been difficult. In this Addendum we review recent work from our laboratory that explore mechanisms by which intestinal commensals polarize colon macrophages to an M1 phenotype to generate a bystander effect (BSE) that leads to mutations, spindle malfunction, cell cycle arrest, tetraploidy, and aneuploidy in epithelial cells. BSE represents the application of a phenomenon initially described in the radiation biology field. The result of commensal-driven BSE on colon epithelial cells is aneuploidy, chromosomal instability (CIN), expression of stem cell and tumor stem cell markers and, ultimately, malignant transformation. Our findings provide a conceptual framework for integrating the microbiota with aging, cyclooxygenase (COX)-2, and inflammation as risk factors for CRC.

The classification of chronic visceral pain is complex, resulting from persistent inflammation, vascular (ischemic) mechanisms, cancer, obstruction or distension, traction or compression, and combined mechanisms, as well as unexplained functional mechanisms. Despite the prevalence, treatment options for chronic visceral pain are limited. Given this unmet clinical need, the development of novel analgesic agents, with defined targets derived from preclinical studies, is urgently needed. While various animal models have played an important role in our understanding of visceral pain, our knowledge is far from complete. Due to the complexity of visceral pain, this document will focus on chronic abdominal pain, which is the major complaint in patients with disorders of the gut-brain interaction, also referred to as functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Models for IBS are faced with challenges including a complex clinical phenotype, which is comorbid with other conditions including anxiety, depression, painful bladder syndrome, and chronic pelvic pain. Based upon the multifactorial nature of IBS with complicated interactions between biological, psychological, and sociological variables, no single experimental model recapitulates all the symptoms of IBS. This position paper will contextualize chronic visceral pain using the example of IBS and focus on its pathophysiology while providing a critical review of current animal models that are most relevant, robust, and reliable in which to screen promising therapeutics to alleviate visceral pain and delineate the gaps and challenges with these models. We will also highlight, prioritize, and come to a consensus on the models with the highest face/construct validity.

Background & AimsPsychological stress is a trigger for the development of irritable bowel syndrome and associated symptoms including abdominal pain. Although irritable bowel syndrome patients show increased activation in the limbic brain, including the amygdala, the underlying molecular and cellular mechanisms regulating visceral nociception in the central nervous system are incompletely understood. In a rodent model of chronic stress, we explored the role of microglia in the central nucleus of the amygdala (CeA) in controlling visceral sensitivity. Microglia are activated by environmental challenges such as stress, and are able to modify neuronal activity via synaptic remodeling and inflammatory cytokine release. Inflammatory gene expression and microglial activity are regulated negatively by nuclear glucocorticoid receptors (GR), which are suppressed by the stress-activated pain mediator p38 mitogen-activated protein kinases (MAPK).MethodsFisher-344 male rats were exposed to water avoidance stress (WAS) for 1 hour per day for 7 days. Microglia morphology and the expression of phospho-p38 MAPK and GR were analyzed via immunofluorescence. Microglia-mediated synaptic remodeling was investigated by quantifying the number of postsynaptic density protein 95–positive puncta. Cytokine expression levels in the CeA were assessed via quantitative polymerase chain reaction and a Luminex assay (Bio-Rad, Hercules, CA). Stereotaxic infusion into the CeA of minocycline to inhibit, or fractalkine to activate, microglia was followed by colonic sensitivity measurement via a visceromotor behavioral response to isobaric graded pressures of tonic colorectal distension.ResultsWAS induced microglial deramification in the CeA. Moreover, WAS induced a 3-fold increase in the expression of phospho-p38 and decreased the ratio of nuclear GR in the microglia. The number of microglia-engulfed postsynaptic density protein 95–positive puncta in the CeA was increased 3-fold by WAS, while cytokine levels were unchanged. WAS-induced changes in microglial morphology, microglia-mediated synaptic engulfment in the CeA, and visceral hypersensitivity were reversed by minocycline whereas in stress-naïve rats, fractalkine induced microglial deramification and visceral hypersensitivity.ConclusionsOur data show that chronic stress induces visceral hypersensitivity in male rats and is associated with microglial p38 MAPK activation, GR dysfunction, and neuronal remodeling in the CeA. Psychological stress is a trigger for the development of irritable bowel syndrome and associated symptoms including abdominal pain. Although irritable bowel syndrome patients show increased activation in the limbic brain, including the amygdala, the underlying molecular and cellular mechanisms regulating visceral nociception in the central nervous system are incompletely understood. In a rodent model of chronic stress, we explored the role of microglia in the central nucleus of the amygdala (CeA) in controlling visceral sensitivity. Microglia are activated by environmental challenges such as stress, and are able to modify neuronal activity via synaptic remodeling and inflammatory cytokine release. Inflammatory gene expression and microglial activity are regulated negatively by nuclear glucocorticoid receptors (GR), which are suppressed by the stress-activated pain mediator p38 mitogen-activated protein kinases (MAPK). Fisher-344 male rats were exposed to water avoidance stress (WAS) for 1 hour per day for 7 days. Microglia morphology and the expression of phospho-p38 MAPK and GR were analyzed via immunofluorescence. Microglia-mediated synaptic remodeling was investigated by quantifying the number of postsynaptic density protein 95–positive puncta. Cytokine expression levels in the CeA were assessed via quantitative polymerase chain reaction and a Luminex assay (Bio-Rad, Hercules, CA). Stereotaxic infusion into the CeA of minocycline to inhibit, or fractalkine to activate, microglia was followed by colonic sensitivity measurement via a visceromotor behavioral response to isobaric graded pressures of tonic colorectal distension. WAS induced microglial deramification in the CeA. Moreover, WAS induced a 3-fold increase in the expression of phospho-p38 and decreased the ratio of nuclear GR in the microglia. The number of microglia-engulfed postsynaptic density protein 95–positive puncta in the CeA was increased 3-fold by WAS, while cytokine levels were unchanged. WAS-induced changes in microglial morphology, microglia-mediated synaptic engulfment in the CeA, and visceral hypersensitivity were reversed by minocycline whereas in stress-naïve rats, fractalkine induced microglial deramification and visceral hypersensitivity. Our data show that chronic stress induces visceral hypersensitivity in male rats and is associated with microglial p38 MAPK activation, GR dysfunction, and neuronal remodeling in the CeA.

Acute Respiratory Distress Syndrome remains a major source of morbidity and mortality in the modern intensive care unit (ICU). Major advances in the understanding and management of this condition were made in the last two decades. The use of low tidal ventilation is a well-established therapy. Conservative fluid management is now another cornerstone of management. However, much remains to be understood in this arena. Assessing volume status in these patients may be challenging and the tools available to do so are far from perfect. Several dynamic measures including pulse pressures variation are used. Ultrasound of the lungs and the vascular system may also have a role. In addition, the type of fluid to administer when needed is still open to debate. Finally, supportive measures in these patients, early during their ICU stay and later after discharge continue to be crucial for survival and adequate recovery.

PURPOSE: Previous studies have reported that survivors of non-Hodgkin lymphoma (NHL) have an increased risk of developing cutaneous melanoma; however, risks associated with specific treatments and immune-related risk factors have not been quantified. PATIENTS AND METHODS: We evaluated second melanoma risk among 44,870 1-year survivors of first primary NHL diagnosed at age 66 to 83 years from 1992 to 2009 and included in the Surveillance, Epidemiology, and End Results-Medicare database. Information on NHL treatments, autoimmune diseases, and infections was derived from Medicare claims. RESULTS: A total of 202 second melanoma cases occurred among survivors of NHL, including 91 after chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 111 after other NHL subtypes (cumulative incidence by age 85 years: CLL/SLL, 1.37%; other NHL subtypes, 0.78%). Melanoma risk after CLL/SLL was significantly increased among patients who received infused fludarabine-containing chemotherapy with or without rituximab (n=18: hazard ratio [HR], 1.92; 95% CI, 1.09 to 3.40; n=10: HR, 2.92; 95% CI, 1.42 to 6.01, respectively). Significantly elevated risks also were associated with T-cell activating autoimmune diseases diagnosed before CLL/SLL (n=36: HR, 2.27; 95% CI, 1.34 to 3.84) or after CLL/SLL (n=49: HR, 2.92; 95% CI, 1.66 to 5.12). In contrast, among patients with other NHL subtypes, melanoma risk was not associated with specific treatments or with T-cell/B-cell immune conditions. Generally, infections were not associated with melanoma risk, except for urinary tract infections (CLL/SLL), localized scleroderma, pneumonia, and gastrohepatic infections (other NHLs). CONCLUSION: Our findings suggest immune perturbation may contribute to the development of melanoma after CLL/SLL. Increased vigilance is warranted among survivors of NHL to maximize opportunities for early detection of melanoma.

Patients with irritable bowel syndrome (IBS) show altered amygdala activity. We showed previously that stress induces visceral hypersensitivity partially through microglia-modulated synaptic plasticity in the central nucleus of the amygdala (CeA). Our current data suggest that the C1q/C3-CR3 cascade initiates microglia-mediated synaptic remodeling in the CeA. Blocking C3-CR3 interaction attenuates stress-induced visceral hypersensitivity. These findings uncover a role of microglia-synapse signaling in the brain-gut regulation and support a future therapeutic target to treat visceral pain.