Citations

AbstractContext:A subpopulation of hypothalamic neurons colocalize three neuropeptides, namely kisspeptin, neurokinin B (NKB), and dynorphin, collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates, and dynorphin (an opioid) inhibits.Objective:To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of the coadministration of kisspeptin-54, NKB, and an opioid receptor antagonist, naltrexone, on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release.Design, Setting, and Participants:This was an ethically approved prospective, single-blinded, placebo-controlled study. Healthy male volunteers (n = 5/group) attended our research facility for eight study visits.Intervention and Main Outcome Measure:After 1 hour of baseline blood sampling, participants received a different intervention at each visit: oral 50 mg naltrexone, 8-hour iv infusions of vehicle, 2.56 nmol/kg · h NKB, 0.1 nmol/kg · h kissspeptin-54 (KP) alone and in combination. Frequent blood sampling to measure plasma gonadotropins and sex steroids was conducted and LH pulsatility was determined using blinded deconvolution analysis.Results:All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (P < .001 vs vehicle). NKB alone did not affect gonadotropins. NKB+KP had significantly lower increases in gonadotropins compared with kisspeptin alone (P < .01). Naltrexone+KP was the only group to significantly increase LH pulse amplitude (P < .001 vs vehicle).Conclusions:Our results suggest significant interactions between the KNDy neuropeptides on LH pulsatility and gonadotropin release in humans. This has important implications for improving our understanding of GnRH pulse generation in humans.

Abstract The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1β, impaired blood–brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10lowIL-23/IL-1β/IL-6high), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35–55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35–55–primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4+ T cells were due to an autocrine effect of IL-1β/IL-23–mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype–Th17 axis in an animal model of multiple sclerosis.

AbstractObjectiveThe goal of this systematic review was to assess the effects of contrast media volume on transcatheter aortic valve replacement‐related acute kidney injury.MethodsA literature search was performed using Medline, EMbase, the Cochrane Database of Systematic Reviews, and clinicaltrials.gov from the inception of these databases through December 2015. Studies that reported relative risk, odds ratio, or hazard ratio comparing the risks of acute kidney injury following transcatheter aortic valve replacement in patients who received high contrast media volume were included. Pooled risk ratio (RR) and 95% confidence intervals (95% CI) were calculated using a random‐effect, generic inverse variance method.ResultsFour cohort studies composed of 891 patients were included in the analyses to assess the risk of acute kidney injury after transcatheter aortic valve replacement in patients who received high contrast media volume. The pooled RR of acute kidney injury after transcatheter aortic valve replacement in patients who received a large volume of contrast media was 1.41 (95% CI, 0.87 to 2.28) compared with low contrast media volume. The meta‐analysis was limited to studies using standard acute kidney injury definitions, and the pooled RR of acute kidney injury in patients who received high contrast media volume is 1.12 (95% CI, 0.78 to 1.62).ConclusionOur meta‐analysis shows no significant association between contrast media volume and risk of acute kidney injury after transcatheter aortic valve replacement.

Objectives/HypothesisIdiopathic subglottic stenosis (iSGS) is an unexplained obstruction involving the lower laryngeal and upper tracheal airway. Persistent mucosal inflammation is a hallmark of the disease. Epithelial microbiota dysbiosis is found in other chronic inflammatory mucosal diseases; however, the relationship between tracheal microbiota composition and iSGS is unknown.Given the critical role for host defense at mucosal barriers, we analyzed tissue specimens from iSGS patients for the presence of microbial pathogens.MethodsUtilizing 30 human iSGS, 20 intubation‐related tracheal stenosis (iLTS), and 20 healthy control specimens, we applied molecular, immunohistochemical, electron microscopic, immunologic, and Sanger‐sequencing techniques.ResultsWith unbiased culture‐independent nucleic acid, protein, and immunologic approaches, we demonstrate that Mycobacterium species are uniquely associated with iSGS. Phylogenetic analysis of the mycobacterial virulence factor rpoB suggests that, rather than Mycobacterium tuberculosis, a variant member of the Mycobacterium tuberculosis complex or a closely related novel mycobacterium is present in iSGS specimens.ConclusionThese studies identify a novel pathogenic role for established large airway bacteria and provide new targets for future therapeutic intervention.Level of EvidenceNA Laryngoscope, 127:179–185, 2017

Objectives/HypothesisIdiopathic subglottic stenosis (iSGS) is a rare and devastating extrathoracic obstruction involving the lower laryngeal and upper tracheal airway. It arises without known antecedent injury or associated disease process. Persistent mucosal inflammation and a localized fibrotic response are hallmarks of the disease. Despite the initial clinical description of iSGS more than 40 year ago, there have been no substantive investigations into the pathogenesis of this enigmatic and progressive airway obstruction. In these studies, we present the initial characterization of the molecular pathogenesis underlying the fibrosing phenotype of iSGS.MethodsUtilizing 20 human iSGS and healthy control specimens, we applied histologic, immunohistochemical, molecular, and immunologic techniques.ResultsWe demonstrate significant activation of the canonical IL‐23/IL‐17A pathway in the tracheal mucosa of iSGS patients, as well as identify γδ T cells as the primary cellular source of IL‐17A.ConclusionOur results suggest that aberrant mucosal immune activation is a component in of the pathogenesis of iSGS. Most critically, our work offers new targets for future therapeutic intervention.Level of EvidenceNA Laryngoscope, 126:E356–E361, 2016

Abstract Retroperitoneal abscess is an uncommon infection that is associated with high morbidity. Early diagnosis is imperative; however, due to its insidious onset and subtle presentation, the diagnosis is often missed. We report a case of a retroperitoneal abscess caused by Streptococcus mitis which is usually not implicated as a serious pathogen, at least in immunocompetent patients.

Purpose Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies. Methods In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti–PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression. Results Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks. Conclusion Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.

PurposeOur objective was to determine the prevalence and quality of restored external rotation (ER) in adult brachial plexus injury (BPI) patients who underwent spinal accessory nerve (SAN) to suprascapular nerve (SSN) transfer, and to identify patient and injury factors that may influence results.MethodsFifty‐one adult traumatic BPI patients who underwent SAN to SSN transfer between 2000 and 2013, all treated less than 1 year after injury with >1 year follow‐up. The primary outcome measured was shoulder ER. The outcomes we utilized included “clinically useful ER” (motion ≥ −35° with ≥MRC 2 strength), modified British Medical Research Council (MRC) grading, and electromyographic (EMG) reinnervation.ResultsEMG evidence of re‐innervation was found in 85% of patients. Surgery resulted in improved ER in 41% (21/51) of shoulders at an average of 28 months follow‐up. Of these, only 31% (17/51) had clinically useful ER. The average ER active range of motion was 12° from full internal rotation (Range: −60° to 90°) and MRC grade 2.2 (2–4). The only predictor of ER improvement was an isolated upper trunk (C5‐C6) injury. Improved ER was clinically evident in 76%, 37% and 26% of upper trunk (UT), C5‐C6‐C7 and panplexus injuries, respectively (P < 0.03).ConclusionsAlthough 85% had EMG signs of recovery, the SAN to SSN transfer failed to provide useful recovery of ER through reinnervation of the infraspinatus muscle in injuries involving more levels than a C5‐C6 root/upper trunk pattern. In patients with greater than C5‐6 level injuries alternatives to SAN to SSN transfer should be considered to restore shoulder ER. © 2016 Wiley Periodicals, Inc. Microsurgery 37:365–370, 2017.