N-methyl-D-aspartate (NMDA) receptor antagonists relieve neuropathic pain in animal models, but side effects of dissociative anesthetic channel blockers, such as ketamine, have discouraged clinical application. Based on the hypothesis that low-affinity NMDA channel blockers might have a better therapeutic ratio, we carried out two randomized, double-blind, crossover trials comparing six weeks of oral dextromethorphan to placebo in two groups, made up of 14 patients with painful distal symmetrical diabetic neuropathy and 18 with postherpetic neuralgia. Thirteen patients with each diagnosis completed the comparison. Dosage was titrated in each patient to the highest level reached without disrupting normal activities; mean doses were 381 mg/day in diabetics and 439 mg/day in postherpetic neuralgia patients. In diabetic neuropathy, dextromethorphan decreased pain by a mean of 24% (95% CI: 6% to 42%, p = 0.01), relative to placebo. In postherpetic neuralgia, dextromethorphan did not reduce pain (95% CI: 10% decrease in pain to 14% increase in pain, p = 0.72). Five of 31 patients who took dextromethorphan dropped out due to sedation or ataxia during dose escalation, but the remaining patients all reached a reasonably well-tolerated maintenance dose. We conclude that dextromethorphan or other low-affinity NMDA channel blockers may have promise in the treatment of painful diabetic neuropathy.

Previous studies have identified stress system dysregulation in fibromyalgia (FM) patients; such dysregulation may be involved in the generation and/or maintenance of pain and other symptoms. Corticotropin-releasing factor (CRF) is the principal known central nervous system mediator of the stress response; however, to date no studies have examined cerebrospinal fluid (CSF) CRF levels in patients with FM. The relationship between CSF CRF level, heart rate variability (HRV), and pain, fatigue, and depressive symptoms was examined in patients with FM. Among participants (n ¼ 26), CSF CRF levels were associated with sensory pain symptoms (r ¼ 0.574, p ¼ 0.003) and affective pain symptoms (r ¼ 0.497, p ¼ 0.011), but not fatigue symptoms. Increased HRV was also strongly associated with increased CSF CRF and FM pain. In multivariate analyses adjusting for age, sex, and depressive symptoms, the association between CSF CRF and sensory pain symptoms (t ¼ 2.54, p ¼ 0.027) persisted. Women with FM who reported a history of physical or sexual abuse had lower CSF CRF levels than women who did not report such a history. CSF CRF levels are associated with both pain symptoms and variation in autonomic function in FM. Differences in CSF CRF levels among women with and without a self-reported history of physical or sexual abuse suggest that subgroups of FM patients may exist with different neurobiological characteristics. Further studies are needed to better understand the nature of the association between CSF CRF and pain symptoms in FM.

Objective To report outcomes and risk factors for mortality in dogs that underwent surgical management of lung lobe torsion. Study design Retrospective case series from 5 veterinary teaching hospitals (2005–2017). Animals Fifty dogs with 52 instances of lung lobe torsion. Methods Data collected from medical records included signalment, clinical findings, results of clinicopathologic testing and diagnostic imaging, surgical treatment, lung lobe affected, intraoperative and postoperative complications, histopathologic and microbiologic findings, and outcome. Follow‐up was obtained from medical records and telephone contact with primary care veterinarians. Results Fifty‐two instances of lung lobe torsion were identified in 50 dogs, with a median follow‐up of 453 days (range, 0–3075). Forty‐six (92%) dogs survived to discharge. Dogs with concurrent torsion of the right cranial and middle lung lobes were less likely to survive (2/4) than those with torsion of the left cranial lung lobe (22/22). No other risk factors for mortality prior to hospital discharge were identified. Overall median survival time after hospital discharge was 1369 days. Four dogs had >1 episode of lung lobe torsion. Conclusion The percentage of dogs surviving to discharge after surgical treatment of lung lobe torsion was higher than previously reported. The short‐ and long‐term prognosis was excellent with surgical treatment of lung lobe torsion. Clinical significance Surgery should be recommended when lung lobe torsion is suspected because of the high survival to discharge rate and excellent long‐term prognosis.

PurposeThe pace of Mendelian gene discovery is slowed by the “n-of-1 problem” – the difficulty of establishing causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier but is often impeded by lack of a convenient or widely-available way to share data on candidate variants / genes among families, clinicians and researchers.MethodsSocial networking among families, clinicians and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.ResultsDe novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.ConclusionSocial networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with non-specific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP). Design and development of a web-based tool, MyGene2, that enables families, clinicians and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP is underway.

Purpose-The pace of Mendelian gene discovery is slowed by the "n-of-1 problem" -the difficulty of establishing causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Web resources Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript variant in the same gene can overcome this barrier but is often impeded by lack of a convenient or widely-available way to share data on candidate variants / genes among families, clinicians and researchers.Methods-Social networking among families, clinicians and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.Results-De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.Conclusion-Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with non-specific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP).Design and development of a web-based tool, MyGene2, that enables families, clinicians and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP is underway.

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OBJECTIVE: To evaluate the appropriateness of proton-pump inhibitor (PPI) prescribing and reduce the number of outpatients on long-term PPI therapy, defined as greater than or equal to one year.<br/> DESIGN: Phase I was retrospective and evaluated the appropriateness of PPI prescribing. Phase II was prospective and involved implementation of a pharmacist-driven PPI step-down protocol.<br/> SETTING: This study was conducted in an outpatient setting at Veterans Affairs Hudson Valley Health Care System.<br/> PATIENTS, PARTICIPANTS: Patients were limited to a single primary care provider and were required to fill an outpatient PPI prescription between August 15, 2015, and August 15, 2016.<br/> INTERVENTIONS: After patients were identified in Phase I as having an inappropriate indication for long-term PPI therapy, they were contacted by a pharmacist to complete the step-down protocol. The patients then received a call two weeks after completing each step.<br/> MAIN OUTCOME MEASURE(S): To determine the number of patients without an indication for long-term PPI therapy that could successfully complete the PPI step-down protocol.<br/> RESULTS: Phase I identified that long-term PPI therapy was not indicated in 68.4% of patients. Phase II implementation demonstrated that 71.4% of patients were able to successfully step-down from PPI therapy in an average of 13 weeks with the use of alternative acid-suppression therapy.<br/> CONCLUSION: This study concluded that a majority of PPI prescriptions were not indicated for a duration of greater than or equal to 1 year. With the implementation of a pharmacist-driven PPI step-down protocol, a majority of patients were able to tolerate the PPI step-down with the use of alternative acidsuppression therapy.

Adult stem cell function relies on the prior specification and organization of appropriate numbers of stem cells and supportive niche cells during development. Insights into those developmental processes could facilitate the synthesis of organoid mimics. Drosophila Follicle Stem Cells (FSCs) present an amenable paradigm with many similarities to mammalian gut stem cells. In an adult germarium a central domain of about 16 FSCs produces a posterior stream of transit-amplifying Follicle Cells (FCs), which encapsulate mature germline cysts to support egg development and, from their anterior face, quiescent Escort Cells (EC), which support the maturation of germline cysts. The behavior of FSCs is guided in part by niche signals produced by ECs and by a specialized polar cell FC derivative. Thus, ECs and FCs are both adult stem cell products and niche cells. Here we show by lineage analyses that adult ECs, FSCs and FCs derive from common precursors during pupal development. We infer that disparities in initial anterior-posterior (AP) precursor location followed by limited dispersal of progeny leads to a gradual acquisition of distinct fates determined by final AP location, with progeny of a single precursor commonly straddling EC and FSC, FSC and FC, or all three territories through most of pupal development. Direct visualization of pupal ovaries, including live imaging revealed a transient population of FC precursors posterior to the developing germarium awaiting emergence of the most mature germline cyst. The consequent budding process was quite different from the budding of egg chambers in adults. An anterior to posterior gradient of Wnt signaling develops shortly after pupariation. Loss of pathway activity cell autonomously resulted in more posterior adult progeny fates, while increased pathway activity elicited the opposite response, suggesting that stronger Wnt signaling favors anterior migration. Clearly detectable JAK-STAT pathway activity emerges only halfway through pupation after polar cells form, and spreads from posterior to anterior.Loss of JAK-STAT activity had similar consequences to increased Wnt pathway activity, drastically reducing FSC and FC production cell autonomously, while increased JAK-STAT activity promoted excessive precursor proliferation. We conclude that FSCs develop in co-ordination with their niche and product cells, that specification of stem cell identity is gradual, subject to stochastic influences and guided by graded extracellular signals, presaging similar regulation of adult stem cell behavior by the same pathways. cytokinesis to yield a progression of 2-, 4-, 8-and 16-cell germline cysts. Their maturation is accompanied by posterior movement and depends on interactions with neighboring quiescent, somatic