【特刊综述】雄激素对骨骼肌的作用：对乏力的发展和治疗的意义

雄激素对骨骼肌合成有明显影响,随着年龄增大,雄激素的下降常伴随肌量和肌力的下降。这种肌量和肌功能的下降,被称为少肌症或肌体老化,是老年人体质弱化（男性化减退）进展的关键事项。也是导致快速机能衰退及其不良后果的关键。雄激素水平下降对老年男性体质弱化（男性化减退）的潜在影响和对躯体功能的促进治疗作用无疑已经引起了相当的关注。本综述概述了近期关于肌肉老化、少肌症、老年体质弱化的概念、定义,并评估了关于雄激素和老年体质弱化的研究进展。近期源于观测性和介入性研究的证据强烈支持雄激素对老年男性肌量的作用,但雄激素对肌力和特有的躯体功能的效用并不明确。研究显示,雄激素治疗在老年男性中通常有良好的耐受性,而近期的研究则关注于雄激素的高剂量治疗和对于心血管风险较高人群的治疗。雄激素受体调节剂（SARMs）的初期试验研究显示传统雄激素治疗对于老年患者在肌量和肌功能方面有相同的效用。将来的重要研究方向包括利用这类雄激素治疗并结合适用于不同老年患者群体促进躯体功能的运动训练,同时将更多地关注近期关于激素水平、身体成分及躯体功能间关系的观测性（回顾性）研究。     

Acute appendicitis in the developing world is a morbid disease

IntroductionAcute appendicitis in the developing world has a markedly different disease profile to that in the developed world.MethodsA retrospective study was undertaken over a four-year period at a university hospital in South Africa to review the disease spectrum and the clinical outcome of acute appendicitis.ResultsA total of 1,004 patients (54% male, median age: 18 years) with intraoperatively confirmed appendicitis were reviewed. Over half (56%) were from the urban district within the city of Pietermaritzburg and the remaining 44% were from the rural health district. The median duration of illness from onset to definitive care was 4 days. Sixty per cent of appendices were perforated and associated with intra-abdominal contamination. Forty per cent of patients required reoperation to control intra-abdominal sepsis. Ten per cent required admission to the intensive care unit. The median overall length of hospital stay was 5 days. The mortality rate was 1%.Rural patients had a longer median duration of illness (3 vs 5 days, p<0.001) as well as a more advanced disease profile associated with perforation and severe intra-abdominal sepsis (19% vs 71%, p<0.001). Female patients had a longer median duration of illness (3 vs 4 days, p<0.001), were more likely to present with severe intra-abdominal sepsis (31% vs 54%, p<0.001) and were more likely to require a laparotomy (50% vs 73%, p<0.001). The total cost of managing the entire cohort of 1,004 patients over the 4-year period was £2,060,972.ConclusionsAcute appendicitis in South Africa is a serious disease associated with significant morbidity. Late presentation is common. Female and rural patients have the worst clinical outcomes, with significant cost to the health system.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

自体骨粉移植修复下颌骨部分缺损的组织学检测

目的:通过动物实验进行组织学光镜及扫描电镜检测,观察自体骨粉移植修复下颌骨缺损的愈合过程。方法:实验于2005-05/11在南方医科大学动物实验中心完成,选用12只健康雄性大耳白兔。实验分为两组:一侧为自体骨粉移植组,另一侧为空白对照组,均采用自体左右对照。①缺损模型建立:于双侧下颌骨体部下缘用磨削机器各造成1.0×1.0cm的全层骨缺损。②自体骨粉移植:将所有自体骨粉回填一侧缺损处作为自体骨粉移植组,另一侧缺损旷置作为空白对照组。③分别于术后2,4及8周各处死4只动物,获取整块下颌骨标本作组织学光镜及扫描电镜检测,光镜切片应用苏木精-伊红染色,扫描电镜只观察自体骨粉移植组标本。结果:12只大耳白兔均进入结果分析,无脱失。①两组标本组织学观察结果:自体骨粉移植组术后2周时形成薄层骨痂;4周时为新生的骨小梁,但排列紊乱;8周时骨小梁形成的编织骨已逐渐向板层骨过渡。空白对照组术后8周时骨小梁分布仍稀疏。②自体骨粉移植组标本超微结构观察结果:术后4周骨基质钙化程度提高,大量成骨细胞位于骨陷窝内。缺损间隙逐渐变窄形成多孔较疏松的新骨组织,新生骨小梁形成,新骨超微结构呈“蜂窝状”。8周时骨小梁钙化程度继续升高,形成的板状骨排列出现一定方向性,新生骨组织由多孔疏松的结构向致密性结构转化,新原骨组织基本上融为一体产生骨性结合,髓腔相通。结论:自体骨粉移植修复下颌骨成骨可靠,愈合加快,愈合方式以骨传导爬行替代为主,且应用方法简便。     

ENALAPRIL IN RAYNAUD''S PHENOMENON

The effect of enalapril in the treatment of Raynaud's phenomenon was assessed in a prospective double-blind cross-over trial in 17 patients (nine primary Raynaud's, eight Raynaud's associated with scleroderma). Each patient received 20 mg enalapril daily and placebo for 3 weeks with a 2-week washout period in between. The severity and frequency of Raynaud's attacks were measured subjectively by a diary count and objectively by measurement of finger systolic pressure changes in response to cooling (cold challenge test). Enalapril was associated with a reduction in the frequency of Raynaud's attacks, especially in patients with primary Raynaud's, compared with placebo, but there was no effect on the cold challenge test. We conclude that enalapril, like other vasodilator drugs, helps the symptoms of Raynaud's phenomenon, especially in patients with idiopathic or primary disease.     

骨关节炎大鼠关节软骨修复与橄榄叶提取物的干预效应

目的:观察橄榄叶提取物对白陶土及鹿角菜胶诱导的大鼠骨关节炎组织炎症的预防作用及对关节软骨的修复作用。方法:试验于2005-11/12在大连医科大学中日合作医药科学研究所进行。实验动物:选择健康雄性SD大鼠80只。实验材料:受试物橄榄叶提取物[由日本国Eisai食品与化学有限公司(日本国东京市)提供]。实验分组及给药:按体质量将大鼠随机分为5组,每组16只。模型对照组,灌胃给予蒸馏水,消炎痛组,灌胃给予消炎痛2mg/kg体质量,其余3组为橄榄叶提取物组,分别给予橄榄叶提取物(活性成分为以羟基酪醇为主的多酚)25,50,100mg/kg体质量灌胃,连续5d。第1天给药后1h,采用白陶土与鹿角菜胶诱发大鼠单发亚急性关节炎。实验评估:①诱发关节炎后1,3,5d,用容积测量法测定每组8只大鼠的左右后肢足跖体积,计算肿胀度,并同时用游标卡尺测定其胫跗骨关节最大径。②诱发关节炎后第5天,测定大鼠足跖伊文思蓝含量。每组的另8只大鼠,在诱发关节炎第5天麻醉后处死,剪下右足跖做组织病理学检查,观察橄榄叶提取物对大鼠骨关节炎中组织炎症的预防作用及对关节软骨的修复作用。结果:80只大鼠全部进入结果分析。①足跖肿胀度及胫跗骨关节径:诱发关节炎后1,3,5d,橄榄叶提取物50mg/kg组和100mg/kg组大鼠的右后足跖肿胀度均明显小于模型对照组大鼠[1d:(46.7±4.2)%,(44.8±6.8)%,(52.5±4.0)%;3d:(40.4±4.8)%,(37.4±5.7)%,(45.0±2.9)%;5d:(34.5±4.8),(31.7±5.3)%,(40.4±4.0)%,P<0.05],橄榄叶提取物25mg/kg体质量组,50mg/kg体质量组,100mg/kg体质量组大鼠的右后胫跗骨关节径与模型对照组大鼠比较差异无显著性(P>0.05)。②足跖伊文思蓝含量:诱发关节炎后第5天,橄榄叶提取物50mg/kg,100mg/kg组大鼠的右后足跖伊文思蓝含量均明显小于模型对照组大鼠(P<0.05)。③组织病理学检查及评分:组织病理学检查可见,与模型对照组比较,橄榄叶提取物50mg/kg组,100mg/kg组大鼠骨关节炎中组织炎症浸润明显减少,软骨组织无破坏,且组织病理学评分也明显小于模型对照组(P<0.05)。结论:橄榄叶提取物在50mg/kg体质量及以上剂量能有效地预防白陶土与鹿角菜胶诱发的大鼠骨关节炎中组织炎症,且对软骨有修复作用。     

家兔失神经支配腓肠肌肌纤维退行性变与修复性再生的超微结构观察

目的:观察家兔腓肠肌失神经支配后肌纤维在退行性变与修复性再生过程中超微结构的变化,探讨失神经支配骨骼肌修复性再生障碍的机制。方法:实验于2005-04/2006-04在南方医科大学中心实验室完成。选择成年新西兰大白兔20只,切断一侧胫神经腓肠肌肌支,术后1,4,8,12,16周分别采用耳缘静脉注射空气处死4只。取实验侧和对照侧腓肠肌内侧头肌组织少许,用于制备超薄切片标本,透射电镜观察各时间点兔失神经腓肠肌肌纤维形态。结果:纳入动物20只,均进入结果分析。①正常家兔腓肠肌肌原纤维排列整齐,肌小节和Z线清晰,线粒体均匀分布在肌原纤维之间,排列规则,细胞核位于质膜周边,未见溶酶体。②失神经支配1周,肌原纤维排列基本整齐,线粒体增多,无明显肿胀。③失神经支配4周,线粒体明显增多肿胀,部分线粒体空泡样变,溶酶体增多,Z线模糊,肌原纤维间隙增大。④失神经支配8周,肌纤维明显萎缩退行性变,大部分肌原纤维消失,残留的肌原纤维变得模糊,间隙增大,肌小结丧失正常的结构,胞浆内含有大量空泡变性的细胞器,可发现畸形核,染色质浓缩、边集,肌细胞膜极度皱缩。镜下发现较多的位于基膜下活化的肌卫星细胞,细胞内含有发达的粗面内质网和丰富的胞浆。一些肌卫星细胞直接与肌纤维融合。同时在间质中可发现一些形态上很象成纤维细胞的细胞,不过这些细胞含有大量的粗面内质网,胞浆内有颗粒和微丝,少量的圆形的线粒体。在退行性变的肌纤维基膜下也可发现肌管样结构的再生肌细胞,在这些肌管内一些肌丝在一起聚集成束,没有组装成肌原纤维,没有正常的肌小结结构。在它们周围有细小的空肌管样结构,可能是以往再生的肌细胞退行性变后的残余体。在间质中可发现一些细小的肌纤维。⑤失神经支配12周,大部分肌纤维萎缩退行性变,但是仍可发现没有萎缩的肌纤维,这些肌纤维细胞核位于周边,有良好的收缩系统,纤维排列规则,Z线清晰,有完整的肌膜。⑥失神经支配16周,肌卫星细胞的数量明显减少,并可发现大量细小的肌纤维,多分布在较大的肌纤维附近,肌膜完整平滑,无皱褶。可发现核位于中央的肌纤维,胞浆内肌原纤维结构清楚,但是肌原纤维的排列远不如核位于周边的肌纤维整齐,说明其收缩系统发育不良。结论:失神经支配后肌细胞退行性变和修复性再生同时存在,再生的肌细胞不能,化发育为成熟的肌纤维,进而发生退行性变。长时间失神经支配,肌卫星细胞的耗竭是失神经支配骨骼肌晚期的主要超微结构变化。     

彩色多普勒超声对移植肾急性排斥反应的评价

目的:肾移植的成功与否关键在于及时发现和正确处理排斥反应。探讨无创伤性形态学和血流动力学检查手段彩色多普勒超声在移植肾急性排斥反应中的作用,为临床评估肾移植效果及移植肾功能提供客观的辅助性数据。方法:选择2004-01/2005-12在南京医科大学附属第一医院、江苏省人民医院行同种异体移植肾患者57例,其中经穿刺活检证实或最后临床诊断为急性移植肾排斥反应者22例,未发生排斥反应等并发症的移植肾功能正常者35例,患者均知情同意。采用Philips EnVisor彩色多普勒超声血流显像仪,对急性排斥反应肾移植患者进行二维超声和彩色多普勒血流显像检测,观察排斥反应患者甲基强的松龙冲击治疗前后移植肾脏的大小、形态结构、肾内血管树分布、血流灌注以及各级动脉血流参数(阻力指数,搏动指数)等指标的变化,并与移植肾功能正常患者进行比较。结果:急性排斥反应组2例患者发生严重并发症死亡,进入结果分析急性排斥反应组20例,移植肾功能正常组35例。①发生急性排斥反应时肾移植患者移植肾体积明显大于肾功能正常组(P<0.01);肾实质增厚,皮髓质界限模糊。给予甲基强的松龙冲击治疗后急性排斥反应组患者肾脏厚径显著小于治疗前(P<0.05);肾实质回声减低,皮髓质交界变清。②发生急性排斥反应时肾移植患者移植肾血流阻力指数、搏动指数均显著高于移植肾功能正常组(P<0.01)。治疗后急性排斥反应组患者肾血流阻力指数、搏动指数均显著低于治疗前(P<0.01),与移植肾功能正常组差异无显著性意义(P>0.05)。结论:彩色多普勒超声作为一种简便、经济的无创性技术,对移植肾血流阻力指数、搏动指数的追踪观察可为临床上评估肾移植效果提供较可靠的客观依据,对移植肾急性排斥反应的早期诊断有较高的评估价值。     

颈椎椎后肌肉组织中肌膜Na^＋-K^＋-ATP酶活性与颈椎病

目的:探讨颈椎椎后肌肉组织Na -K -ATP酶活性变化与颈椎病的关系。资料来源:应用计算机检索PubMed1988-01/2004-12相关骨骼肌损伤与肌组织Na -K -ATP酶关系的文献,检索词“Na -K pump,Na -K -ATPase,muscle”,限定文献语言种类为English。同时计算机检索CNKI1990-01/2005-12相关Na -K -ATP酶与骨骼肌损伤的关系及颈椎病发病病因的文献,检索词“Na -K -ATP酶,骨骼肌,颈椎病病因”,限定文献语言种类为中文。资料选择:对资料进行初审,选取包括Na -K -ATP酶与肌组织损伤关系的文献,开始查找全文。纳入标准:Na -K -ATP酶活性变化与骨骼肌损伤密切相关的文献研究。排除标准:重复研究,Meta分析类文章。资料提炼:共检索到939篇关于Na -K -ATP酶与骨骼肌损伤相关方面的文献,最终纳入20篇符合标准的文献。资料综合:众多研究表明,Na 、K 与骨骼肌的兴奋、收缩、疲劳有密切关系,而Na -K -ATP酶又是调节细胞内外Na 、K 浓度必不可少的高分子蛋白,也就是说,骨骼肌一系列活动均离不开Na -K -ATP酶,Na -K -ATP酶活性变化与骨骼肌损伤是相互影响的。而强迫屈颈体位作为颈椎病发病的危险因素之一,可使颈椎椎后肌肉Na -K -ATP酶活性降低,酶活性降低致使肌细胞损伤,并最终导致骨骼肌损伤而发病。结论:以颈椎椎后肌肉酶活性的变化来阐释中医药对颈椎病确切疗效的相关研究未见,这有待于进一步研究,以充分展示中医药在颈椎病等相关疾病中的治疗优势。