Epidemiology

R01 OH009471/OH/NIOSH CDC HHS/United States2018-05-01T00:00:00Z28151743PMC5378634vault:2220

The microbiome activates CD4 T-cell-mediated immunity to compensate for increased intestinal permeability

Background & Aims: Despite a prominent association, chronic intestinal barrier loss is insufficient to induce disease in human subjects or experimental animals. We hypothesized that compensatory mucosal immune activation might protect individuals with increased intestinal permeability from disease. We used a model in which intestinal barrier loss is triggered by intestinal epithelial-specific expression of constitutively active myosin light chain kinase (CA-MLCK). Here we asked whether constitutive tight junction barrier loss impacts susceptibility to enteric pathogens. Methods: Acute or chronic Toxoplasma gondii or Salmonella typhimurium infection was assessed in CA-MLCK transgenic or wild-type mice. Germ-free mice or those lacking specific immune cell populations were used to investigate the effect of microbial-activated immunity on pathogen translocation in the context of increased intestinal permeability. Results: Acute T gondii and S typhimurium translocation across the epithelial barrier was reduced in CA-MLCK mice. This protection was due to enhanced mucosal immune activation that required CD4^+ T cells and interleukin 17A but not immunoglobulin A. The protective mucosal immune activation in CA-MLCK mice depended on segmented filamentous bacteria (SFB), because protection against early S typhimurium invasion was lost in germ-free CA-MLCK mice but could be restored by conventionalization with SFB-containing, not SFB-deficient, microbiota. In contrast, chronic S typhimurium infection was more severe in CA-MLCK mice, suggesting that despite activation of protective mucosal immunity, barrier defects ultimately result in enhanced disease progression. Conclusions: Increased epithelial tight junction permeability synergizes with commensal bacteria to promote intestinal CD4^+ T-cell expansion and interleukin 17A production that limits enteric pathogen invasion

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

A national cross-sectional analysis of dermatology away rotations using the Visiting Student Application Service database

The highly competitive nature of the dermatology match requires applicants to undertake a variety of measures in the hopes of securing a residency position. Among the opportunities available to applicants is the chance to participate in away or “audition” rotations during their final year of undergraduate medical education. Away rotations are now performed by a majority of medical students applying into dermatology, but littleresearch has been done to describe the nature of this opportunity for interested applicants. An analysis of all dermatology electives offered in the Visiting Student Application Service (VSAS) database wasperformed. Results indicate that students have the option to pursue electives in a variety of subjects offered by 100 sponsoring institutions spread across a wide geographic distribution. Although manyopportunities exist, this analysis sheds light on several areas for improving the quality of this experience for interested applicants, including providing more electives in advanced subject matter, permitting more flexibility in scheduling, and promoting wider participation in VSAS

A national cross-sectional analysis of dermatology away rotations using the Visiting Student Application Service database

The highly competitive nature of the dermatology match requires applicants to undertake a variety of measures in the hopes of securing a residency position. Among the opportunities available to applicants is the chance to participate in away or “audition” rotations during their final year of undergraduate medical education. Away rotations are now performed by a majority of medical students applying into dermatology, but littleresearch has been done to describe the nature of this opportunity for interested applicants. An analysis of all dermatology electives offered in the Visiting Student Application Service (VSAS) database wasperformed. Results indicate that students have the option to pursue electives in a variety of subjects offered by 100 sponsoring institutions spread across a wide geographic distribution. Although manyopportunities exist, this analysis sheds light on several areas for improving the quality of this experience for interested applicants, including providing more electives in advanced subject matter, permitting more flexibility in scheduling, and promoting wider participation in VSAS

A 65-Year-Old Male with Primary Central Nervous System Diffuse Large B-Cell Lymphoma on Nivolumab with Oral Mucositis and Targetoid Plaques

Background/Aims: The development of programmed cell death-1 (PD-1) inhibitors has greatly improved patient outcomes in the treatment of a variety of advanced malignancies. These novel immunotherapies are not without adverse effects, the most common of which are dermatologic. Methods: We report our experience with an atypical erythema multiforme-like eruption in a patient with primary central nervous system diffuse large B-cell lymphoma treated with nivolumab. Results: The patient presented with oral mucositis and scattered erythematous papules which progressed to targetoid purpuric plaques with hyperkeratotic centers. Histopathology demonstrated interface dermatitis with dyskeratotic keratinocytes and pigment incontinence. The patient experienced improvement of the eruption with discontinuation of nivolumab and on systemic and topical glucocorticoids. Conclusion: As PD-1 inhibitors become more widely used in the treatment of advanced malignancies, the early recognition and treatment of rare dermatologic toxicities remain of great importance

A 65-Year-Old Male with Primary Central Nervous System Diffuse Large B-Cell Lymphoma on Nivolumab with Oral Mucositis and Targetoid Plaques

Background/Aims The development of programmed cell death-1 (PD-1) inhibitors has greatly improved patient outcomes in the treatment of a variety of advanced malignancies. These novel immunotherapies are not without adverse effects, the most common of which are dermatologic. Methods: We report our experience with an atypical erythema multiforme-like eruption in a patient with primary central nervous system diffuse large B-cell lymphoma treated with nivolumab. Results: The patient presented with oral mucositis and scattered erythematous papules which progressed to targetoid purpuric plaques with hyperkeratotic centers. Histopathology demonstrated interface dermatitis with dyskeratotic keratinocytes and pigment incontinence. The patient experienced improvement of the eruption with discontinuation of nivolumab and on systemic and topical glucocorticoids. Conclusion: As PD-1 inhibitors become more widely used in the treatment of advanced malignancies, the early recognition and treatment of rare dermatologic toxicities remain of great importance

The Microbiome Activates CD4 T-cellâmediated Immunity to Compensate for Increased Intestinal PermeabilitySummary

Background & Aims: Despite a prominent association, chronic intestinal barrier loss is insufficient to induce disease in human subjects or experimental animals. We hypothesized that compensatory mucosal immune activation might protect individuals with increased intestinal permeability from disease. We used a model in which intestinal barrier loss is triggered by intestinal epithelial-specific expression of constitutively active myosin light chain kinase (CA-MLCK). Here we asked whether constitutive tight junction barrier loss impacts susceptibility to enteric pathogens. Methods: Acute or chronic Toxoplasma gondii or Salmonella typhimurium infection was assessed in CA-MLCK transgenic or wild-type mice. Germ-free mice or those lacking specific immune cell populations were used to investigate the effect of microbial-activated immunity on pathogen translocation in the context of increased intestinal permeability. Results: Acute T gondii and S typhimurium translocation across the epithelial barrier was reduced in CA-MLCK mice. This protection was due to enhanced mucosal immune activation that required CD4+ T cells and interleukin 17A but not immunoglobulin A. The protective mucosal immune activation in CA-MLCK mice depended on segmented filamentous bacteria (SFB), because protection against early S typhimurium invasion was lost in germ-free CA-MLCK mice but could be restored by conventionalization with SFB-containing, not SFB-deficient, microbiota. In contrast, chronic S typhimurium infection was more severe in CA-MLCK mice, suggesting that despite activation of protective mucosal immunity, barrier defects ultimately result in enhanced disease progression. Conclusions: Increased epithelial tight junction permeability synergizes with commensal bacteria to promote intestinal CD4+ T-cell expansion and interleukin 17A production that limits enteric pathogen invasion. Keywords: Barrier Function, Tight Junction, Microbiota, CD4 T Cell, Mucosal Immunity, Salmonell