CRISPR-Cas9-Mediated ELANE Mutation Correction in Hematopoietic Stem and Progenitor Cells to Treat Severe Congenital Neutropenia

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Identification of a possible role for atrial natriuretic peptide in MDMA-induced hyperthermia

MDMA (3,4-methylenedioxymethamphetamine) induces thermogenesis in a mitochondrial uncoupling protein 3-dependent manner. There is evidence that this hyperthermia is mediated in part by the lipolytic release of free fatty acids, that subsequently activate uncoupling protein 3 in skeletal muscle mitochondria. We hypothesize that atrial natriuretic peptide (ANP), a strong lipolytic mediator, may contribute to the induction and maintenance of MDMA-induced thermogenesis. The specific aims of this study were to (1) determine if ANP is released following MDMA administration, and (2) use the ANP receptor antagonist, Anantin, to ascertain the role of ANP in MDMA-induced hyperthermia. ANP levels were measured in plasma at baseline, 10, 20, 30 and 60 min following MDMA (40 mg/kg, sc) administration in 16 male Sprague-Dawley rats. A robust increase in ANP was seen within 10 min of MDMA administration. ANP levels returned to baseline at 20 min and then gradually rose over the 60 min monitoring period. The administration of Anantin (40 mg, ip), 15 min before and after MDMA, significantly attenuated the MDMA-induced hyperthermia. We conclude that ANP signaling contributes to the hyperthermia induced by MDMA.     

乌司他丁对体外循环肺静脉血中CD11b、ICAM-1、NE、ET-1的影响

目的探讨乌司他丁对体外循环患者肺静脉血中CD11b、ICAM-1、NE、ET-1的影响。方法选择40例主动脉阻断时间30min以上的心内直视手术患者,随机分成乌司他丁实验组(U组)和对照组(C组),每组20例。U组于麻醉诱导后静注乌司他丁1.2×104 U/kg,C组不用乌司他丁,用等量生理盐水代替。分别在麻醉诱导后(T1)、主动脉开放10min(T2)、停机后10min(T3)和1h(T4)测定肺静脉血粘附分子CD11b、ICAM-1、NE、ET-1浓度,流式细胞仪测定中性粒细胞CD11b的活性表达,ELISA法测定肺静脉血ICAM-1、NE、ET-1浓度。结果1.麻醉诱导后两组患者肺静脉血CD11b、ICAM-1、NE、ET-1水平差异无显著性(P0.05)。2.CPB开始后各时点CD11b、NE、ET-1的水平明显上升(P0.05)。U明显低于C组(P0.05)。3.停机后1 h(T4)对照组(C组)肺静脉ICAM-1值逐渐上升并超过基础值,实验组逐渐下降至基础值,差异明显(P0.05),两组比较U明显低于C组(P0.05)。结论1.体外循环可引起静脉中CD11b、ICAM-1、NE、ET-1水平升高,导致肺损伤。2.乌司他丁可通过抑制CD11b、ICAM-1、NE、ET-1表达,减轻肺部炎症反应,对体外循环所致肺损伤提供保护作用。     

柴胡对肝郁证中枢神经递质作用的实验研究

目的探索柴胡对肝郁证大鼠中枢神经递质的作用。方法利用中医证候模型,研究柴胡对单胺类神经递质的作用。结果肝郁证模型组大鼠脑内NE与DA水平与对照组比较下降明显(P<0.05);肝郁证模型加逍遥散组大鼠脑内NE与DA水平与对照组比较无显著性差异(P>0.05);肝郁证模型加柴胡组大鼠脑内NE与DA水平与对照组比较也无显著性差异(P>0.05)。结论肝郁证大鼠脑内NE与DA水平明显降低,柴胡舒肝解郁,有增加肝郁证大鼠脑内NE、DA神经递质的作用。     

Contribution of neutrophil elastase to the lysis of obliterative thrombi in the context of their platelet and fibrin content

Leukocytes invade newly formed thrombi through interactions with platelets and fibrin and later contribute to the removal of fibrin deposits mainly through the action of neutrophil elastase. The present study attempts to express in quantitative terms the impact of neutrophils on the lytic processes in obliterative thrombi based on the local presence of elastase-specific fibrin degradation products (NE-FDP) in relation to the leukocyte, platelet and fibrin content of thrombi. Immunofluorescent detection of fibrin, NE-FDP and platelet antigens was performed in sections of thrombi from 28 patients subjected to thrombectomy in combination with DNA-staining for identification of nucleated cells. The digitalized fluorescent microscopic images were decomposed according to the color channel of each thrombus constituent. The integrated intensity values for all thrombus constituents were statistically evaluated with correlation, hierarchical agglomerative clustering , Hotelling's T² and F-statistics. Association between NE-FDP and leukocyte content of thrombi is evidenced by a significant Pearson correlation coefficient of 0.71 (p = 0.00002). Cluster analysis reveals two classes of thrombi according to NE-FDP, leukocyte and platelet content and also two according to NE-FDP, leukocyte and fibrin content. When NE-FDP, fibrin and platelet content is normalized to the leukocyte count in the same thrombus, clusters with platelet-related thrombolytic resistance (inversely related NE-FDP and platelet content) and advanced cell-dependent thrombolysis (inversely related NE-FDP and fibrin content) are identified. These distinct patterns of thrombus constituents are snapshots of characteristic stages in the cell-dependent thrombolysis, which indicate a clot-stabilizing role for platelets in this process similar to their impact on the plasmin-dependent lysis.     

Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review

The objective of the International Society for the Study of Women's Sexual Health expert consensus panel was to develop a concise, clinically relevant, evidence-based review of the epidemiology, physiology, pathogenesis, diagnosis, and treatment of hypoactive sexual desire disorder (HSDD), a sexual dysfunction affecting approximately 10% of adult women. Etiologic factors include conditions or drugs that decrease brain dopamine, melanocortin, oxytocin, and norepinephrine levels and augment brain serotonin, endocannabinoid, prolactin, and opioid levels. Symptoms include lack or loss of motivation to participate in sexual activity due to absent or decreased spontaneous desire, sexual desire in response to erotic cues or stimulation, or ability to maintain desire or interest through sexual activity for at least 6 months, with accompanying distress. Treatment follows a biopsychosocial model and is guided by history and assessment of symptoms. Sex therapy has been the standard treatment, although there is a paucity of studies assessing efficacy, except for mindfulness-based cognitive behavior therapy. Bupropion and buspirone may be considered off-label treatments for HSDD, despite limited safety and efficacy data. Menopausal women with HSDD may benefit from off-label testosterone treatment, as evidenced by multiple clinical trials reporting some efficacy and short-term safety. Currently, flibanserin is the only Food and Drug Administration–approved medication to treat premenopausal women with generalized acquired HSDD. Based on existing data, we hypothesize that all these therapies alter central inhibitory and excitatory pathways. In conclusion, HSDD significantly affects quality of life in women and can effectively be managed by health care providers with appropriate assessments and individualized treatments.     

Short- and long-lasting consequences of novelty,deviance and surprise on brain and cognition

When one encounters a novel stimulus this sets off a cascade of brain responses, activating several neuromodulatory systems. As a consequence novelty has a wide range of effects on cognition; improving perception and action, increasing motivation, eliciting exploratory behavior, and promoting learning. Here, we review these benefits and how they may arise in the brain. We propose a framework that organizes novelty's effects on brain and cognition into three groups. First, novelty can transiently enhance perception. This effect is proposed to be mediated by novel stimuli activating the amygdala and enhancing early sensory processing. Second, novel stimuli can increase arousal, leading to short-lived effects on action in the first hundreds of milliseconds after presentation. We argue that these effects are related to deviance, rather than to novelty per se, and link them to activation of the locus-coeruleus norepinephrine system. Third, spatial novelty may trigger the dopaminergic mesolimbic system, promoting dopamine release in the hippocampus, having longer-lasting effects, up to tens of minutes, on motivation, reward processing, and learning and memory.