Kaempferol attenuates neuroinflammation and blood brain barrier dysfunction to improve neurological deficits in cerebral ischemia/reperfusion rats

Both research and clinical medicine requires similar attributes of efficiency, diligence and effective teamwork. Furthermore, residents must succeed at scholarship and patient care to be competitive for fellowship training. It is unknown whether research productivity among residents is related to broad measures of clinical achievement. Our goal was to examine associations between the quantity of internal medicine residents’ publications and validated measures of their knowledge, skills and multi-source evaluations of performance. This was a longitudinal study of 308 residents graduating from Mayo Clinic from 2006 to 2012. We identified peer-reviewed articles in Ovid MEDLINE between July of each resident’s match year and the end of their graduation. Outcomes included American Board of Internal Medicine (ABIM) certification examination scores, mini clinical examination (mini-CEX) scores, and validated assessments of clinical performance by resident-peers, faculty and non-physicians. Performance assessments were averaged to form an overall score ranging from 1 to 5. Associations between quantity of resident publications – and ABIM, mini-CEX and performance assessment scores – were determined using multivariate linear regression. The residents published 642 papers, of which 443 (69.0 %) were research papers, 198 (30.8 %) were case reports, and 380 (59.2 %) were first-authored. On adjusted analysis, multi-source clinical performance evaluations were significantly associated (beta; 99 % CI; p-value) with the numbers of research articles (0.012; 0.001–0.024; 0.007), and overall publications (0.012; 0.002–0.022; 0.002). To our knowledge, this is the first study to demonstrate that scholarly productivity based on journal publication is associated with clinical performance during residency training. Our findings suggest that residents who invest substantial efforts in research are not compromised in their abilities to learn medicine and care for patients.

/pdf/associations-between-resident-physicians-publications-and-2wgqsmvebc.pdf

Associations between resident physicians’ publications and clinical performance during residency training

Epidemiological studies have found a higher prevalence of allergic symptoms and positive prick tests in patients with Meniere’s disease (MD); however the effect of allergenic extracts in MD has not been established. Thus, this study aims to determine the effect of Aspergillus and Penicillium stimulation in cytokine release and gene expression profile in MD. Patients with MD showed higher basal levels of IL-1β, IL-1RA, IL-6 and TNF-α when compared to healthy controls. We observed that IL-1β levels had a bimodal distribution suggesting two different subgroups of patients, with low and high basal levels of cytokines. Gene expression profile in peripheral blood mononuclear cells (PBMC) showed significant differences in patients with high and low basal levels of IL-1β. We found that both mold extracts triggered a significant release of TNF-α in MD patients, which were not found in controls. Moreover, after mold stimulation, MD patients showed a different gene expression profile in PBMC, according to the basal levels of IL-1β. The results indicate that a subset of MD patients have higher basal levels of proinflammatory cytokines and the exposure to Aspergillus and Penicillium extracts may trigger additional TNF-α release and contribute to exacerbate inflammation.

/pdf/proinflammatory-cytokines-and-response-to-molds-in-18breb4sv3.pdf

Proinflammatory cytokines and response to molds in mononuclear cells of patients with Meniere disease

Vestibular Migraine (VM) and Meniere's Disease (MD) are episodic vestibular syndromes defined by a set of associated symptoms such as tinnitus, hearing loss or migraine features during the attacks. Both conditions may show symptom overlap and there is no biological marker to distinguish them. Two subgroups of MD patients have been reported, according to their IL-1β profile. Therefore, considering the clinical similarity between VM and MD, we aimed to investigate the cytokine profile of MD and VM as a means to distinguish these patients. We have also carried out gene expression microarrays and measured the levels of 14 cytokines and 11 chemokines in 129 MD patients, 82 VM patients, and 66 healthy controls. Gene expression profile in peripheral blood mononuclear cells (PBMC) showed significant differences in MD patients with high and low basal levels of IL- 1β and VM patients. MD patients with high basal levels of IL- 1β (MDH) had overall higher levels of cytokines/chemokines when compared to the other subsets. CCL4 levels were significantly different between MDH, MD with low basal levels of IL- 1β (MDL), VM and controls. Logistic regression identified IL- 1β, CCL3, CCL22, and CXCL1 levels as capable of differentiating VM patients from MD patients (area under the curve = 0.995), suggesting a high diagnostic value in patients with symptoms overlap.

/pdf/differential-proinflammatory-signature-in-vestibular-5c528c85kx.pdf

Differential Proinflammatory Signature in Vestibular Migraine and Meniere Disease.

ABHD12 metabolizes bioactive lysophospholipids, including lysophosphatidylserine (lyso-PS). Deleterious mutations in human ABHD12 cause the neurological disease PHARC, and ABHD12-/- mice display PHARC-like phenotypes, including hearing loss, along with elevated brain lyso-PS and features of stimulated innate immune cell function. Here, we develop a selective and in vivo-active inhibitor of ABHD12 termed DO264 and show that this compound elevates lyso-PS in mouse brain and primary human macrophages. Unlike ABHD12-/- mice, adult mice treated with DO264 exhibited minimal perturbations in auditory function. On the other hand, both DO264-treated and ABHD12-/- mice displayed heightened immunological responses to lymphocytic choriomeningitis virus (LCMV) clone 13 infection that manifested as severe lung pathology with elevated proinflammatory chemokines. These results reveal similarities and differences in the phenotypic impact of pharmacological versus genetic blockade of ABHD12 and point to a key role for this enzyme in regulating immunostimulatory lipid pathways in vivo.

Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo

Objectives
Autoinflammatory diseases are a family of immune-mediated, rare diseases, some of which, exhibit sensorineural hearing loss (SNHL), suggesting potentially similar mechanisms of molecular pathogenesis between autoinflammatory-mediated hearing loss and autoimmune inner ear disease (AIED) may exist. The purpose of this review is to compare the clinical features of autoimmune and autoinflammatory diseases that affect hearing, discuss the limitations of our knowledge, and highlight potential new disease mechanisms and therapeutics.

Data sources
Pubmed Literature Review; Google Scholar Literature review.

Review methods
A focused comparison of AIED with a number of autoinflammatory diseases that manifest with sensorineural hearing loss was performed. The pathogenesis of these diseases is reviewed in the context of the innate and adaptive immune system, cytokine expression and genetic polymorphisms.

Results
AIED, since first described by Cogan and Lehnhardt and first clinically characterized by McCabe, has remained an enigmatic disease, with limited advances in both new diagnostics and new therapeutics. Since the discovery of autoinflammatory diseases, a number of systemic autoimmune diseases have either been re-classed as autoinflammatory diseases or identified to have features of autoinflammatory disease.

Conclusion
AIED has clinical features of both autoimmune and autoinflammatory disease. It is critical that autoinflammatory diseases be correctly identified, as failure to do so may result in systemic amyloidosis and kidney damage.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/lio2.28

AAO: Autoimmune and Autoinflammatory (Disease) in Otology: What is New in Immune-Mediated Hearing Loss

ObjectiveTo determine whether the research rotation experience affects the career path of otolaryngology residents.Study Design/SettingTwo web-based surveys were disseminated by the AAO-HNS; one to current and former resident trainees and the other to current residency program directors.Subjects and MethodsA web-based survey was disseminated to all AAO-HNS members classified as otolaryngology residents or residency graduates within the last 6 years, regarding their research rotation and its potential influence on their career path. A second web-based survey was delivered simultaneously to program directors to evaluate their perception of the need for research in a training program and their role in the rotation. Chi-square tests for independence as well as multivariate analyses were conducted to determine whether aspects of the resident research rotation related to career path.ResultsThe resident survey was completed by 350 respondents (25% response rate), and 39 program directors completed the second sur...

Resident Research Experience and Career Path Association: A National Survey of Recent Otolaryngology Graduates.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a protein implicated in the control of inflammation in a number of autoimmune diseases. We hypothesized that the balance of TIMP-1 and matrix metalloproteinase-9 (MMP-9) may influence the control or perpetuation of inflammation in corticosteroid-responsive (RES) and corticosteroid-resistant (NR) autoimmune inner ear disease (AIED) patients. In the present study, we observed that plasma from AIED patients exhibited greater levels of TIMP-1 values compared with normal healthy controls. TIMP-1 abrogates lipopolysaccharide-mediated interleukin (IL)-1β release from peripheral blood mononuclear cells in a dose-dependent manner. RES AIED patients have higher basal TIMP-1 levels and produce more TIMP-1 in response to IL-1β. Conversely, consistent with our previous studies, we found that NR patients have higher basal MMP-9 levels and produce more MMP-9 levels in response to IL-1β.

/pdf/the-balance-of-tissue-inhibitor-of-metalloproteinase-1-and-3dl0965ypq.pdf

The Balance of Tissue Inhibitor of Metalloproteinase-1 and Matrix Metalloproteinase-9 in the Autoimmune Inner Ear Disease Patients.

HYPOTHESIS Autoimmune inner ear disease (AIED) patients will differentially express interleukin (IL)-6 based on corticosteroid responsiveness. BACKGROUND AIED is characterized by periods of acute sensorineural hearing loss (SNHL). In a majority of patients corticosteroid responsiveness is lost over time. The mechanisms that control corticosteroid responsiveness have not been fully elucidated. METHODS Thirty-five AIED patients and 13 age-matched control subjects were enrolled in this study. Steroid responsive (n = 15) and steroid nonresponsive AIED patients (n = 20) were characterized based on audiometry before and after treatment for acute SNHL. Plasma and peripheral blood mononuclear cells (PBMC) were obtained at the time of acute SNHL to quantify plasma IL-6, soluble IL-6 receptor (sIL-6R), and C-C Motif Chemokine Ligand 3 (CCL3). PBMCs were stimulated with dexamethasone and release of soluble IL-6, sIL-6R, and CCL3 protein into conditioned supernatants was measured. Plasma IL-6 was also correlated to serum c-reactive protein (CRP), cardiac CRP, erythrocyte sedimentation rate. RESULTS Statistically significant differences were observed in the plasma IL-6 between AIED patients and controls (2.37 versus 2.03 pg/ml, p < 0.01), plasma IL-6, and CCL3 between responders and nonresponders (0.136 versus 3.84 pg/ml, p < 0.005; 30.5 versus 32.4, p < 0.05) and released IL-6 from dexamethasone stimulated PBMC in AIED patients compared with controls (0.54 versus 1.12 pg/ml, p < 0.001). There was a correlation between plasma IL-6 levels of AIED patients to both serum CRP and cardiac CRP (R2 = 0.83, R2 = 0.88). CONCLUSIONS We observed AIED patients, specifically nonresponders expressed greater levels of IL-6. Elevated IL-6 levels in AIED patients correlated with CRP levels, providing a commonly available laboratory test that may aid in rapid clinical decision-making in these patients.

The Correlation of Clinical Corticosteroid Responsiveness With Expression of IL-6 in Peripheral Blood Immune Cells (PBMC) in Patients With Autoimmune Inner Ear Disease (AIED).

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AAO: Autoimmune and Autoinflammatory (Disease) in Otology: What is New in Immune-Mediated Hearing Loss

Resident Research Experience and Career Path Association: A National Survey of Recent Otolaryngology Graduates.

The Balance of Tissue Inhibitor of Metalloproteinase-1 and Matrix Metalloproteinase-9 in the Autoimmune Inner Ear Disease Patients.

The Correlation of Clinical Corticosteroid Responsiveness With Expression of IL-6 in Peripheral Blood Immune Cells (PBMC) in Patients With Autoimmune Inner Ear Disease (AIED).