Targeting sirtuin activity with nicotinamide riboside reduces neuroinflammation in a GWI mouse model

Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War (GW), who suffer from symptoms that reflect ongoing mitochondria dysfunction. Brain mitochondria bioenergetics dysfunction in GWI animal models corresponds with astroglia activation and neuroinflammation. In a pilot study of GW veterans (n = 43), we observed that blood nicotinamide adenine dinucleotide (NAD) and sirtuin 1 (Sirt1) protein levels were decreased in the blood of veterans with GWI compared to healthy GW veterans. Since nicotinamide riboside (NR)-mediated targeting of Sirt1 is shown to improve mitochondria function, we tested whether NR can restore brain bioenergetics and reduce neuroinflammation in a GWI mouse model. We administered a mouse diet supplemented with NR at 100μg/kg daily for 2-months to GWI and control mice (n = 27). During treatment, mice were assessed for fatigue-type behavior using the Forced Swim Test (FST), followed by euthanasia for biochemistry and immunohistochemistry analyses. Fatigue-type behavior was elevated in GWI mice compared to control mice and lower in GWI mice treated with NR compared to untreated GWI mice. Levels of plasma NAD and brain Sirt1 were low in untreated GWI mice, while GWI mice treated with NR had higher levels, similar to those of control mice. Deacetylation of the nuclear-factor κB (NFκB) p65 subunit and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) was an increase in the brains of NR-treated GWI mice. This corresponded with a decrease in pro-inflammatory cytokines and lipid peroxidation and an increase in markers of mitochondrial bioenergetics in the brains of GWI mice. These findings suggest that targeting NR mediated Sirt1 activation restores brain bioenergetics and reduces inflammation in GWI mice. Further evaluation of NR in GWI is warranted to determine its potential efficacy in treating GWI.     

Anosognosia in patients with Alzheimer's disease: current perspectives

Alzheimer?s disease (AD) is a neurodegenerative disease characterised by neurocognitive impairments, especially memory impairment, as core symptoms linked to reductions in activities of daily life. As marginal symptoms, neuropsychiatric symptoms (NPSs) appear during the progressive course of the disease. A lack of self‐awareness (anosognosia) of cognitive and functional impairments is often seen in patients with AD, and associations between anosognosia and other NPSs have been previously reported. To account for anosognosia pathogenesis neurocognitively, the cognitive awareness model (CAM) has been helpful for explaining the stream of events from sensory input to behavioural/affective and metacognitive outputs. According to CAM, there are three types of anosognosia: (i) primary anosognosia, (ii) executive anosognosia, and (iii) mnemonic anosognosia. These types of anosognosia are generated from different neurocognitive modulations leading to metacognitive outputs or behavioural/affective regulations. Primary anosognosia is considered to be caused by deficits in the metacognitive awareness system (MAS). While preserved MAS function is associated with milder depression and anxiety in AD, a severer depressive mood in patients with mild AD can inversely cause self‐underestimation. The modulation of executive anosognosia is thought to be associated with dangerous/disinhibition behaviours and apathy among NPS sub‐symptoms, via impairments of comparator mechanism (Cm) within the central executive system. Other neurobehavioral reactions linked to self‐awareness include ‘denying’ and ‘confabulation’, and each of these reactions is thought to be affected by the MAS and a Cm. Denial of one?s own memory impairments appears as a defensive reaction to protect against dysphoric feelings, and the confabulatory comment is instantly reaction constructed by fabrications according to misinterpretations of memory information about oneself. Similarly, the innovative development of a theoretical model (CAM) has contributed to explaining the mechanism of anosognosia and some neurobehavioral outputs from a neurocognitive perspective.     

Target specific effects of direct current stimulation in schizo-obsessive disorder: A case report

Transcranial direct current stimulation (tDCS) is a type of non-invasive brain stimulation technique that is explored as an add-on treatment for the alleviation of symptoms across the diverse symptom domains in neuropsychiatric disorders. In psychiatry, data is emerging on the effects of tDCS as an add-on treatment in schizophrenia as well as obsessive-compulsive disorder (OCD). But despite high prevalence, the effectiveness of tDCS in co-morbid schizophrenia and OCD is lacking. This case report for the first time examines the clinical utility with target-specific effects of the add-on tDCS in a patient diagnosed with schizo-obsessive disorder.     

术前白蛋白碱性磷酸酶比值对根治性膀胱切除术后总体生存期的影响

目的探讨术前白蛋白碱性磷酸酶比值(AAPR)与根治性膀胱切除术后患者总体生存期(OS)的关系。方法回顾性分析2007年1月至2015年12月青岛大学附属医院收治的166例膀胱癌患者的临床病理资料。男148例,女18例。年龄(65.1±9.4)岁。伴高血压病31例、糖尿病14例。体质指数(BMI)(24.00±3.32)kg/m^2。肿瘤单发92例,多发74例。肿瘤直径<3 cm者43例,≥3 cm者123例。合并肾积水33例,无肾积水133例。术前AAPR(0.62±0.23)。根据AAPR的三分位点将患者分为低AAPR组55例,AAPR(0.42±0.09);中AAPR组55例,AAPR(0.58±0.05);高AAPR组56例,AAPR(0.86±0.21)。美国麻醉医师协会(ASA)分级1级4例,2级65例,3级86例,4级11例。根治术前患者均行经尿道膀胱肿瘤切除术,病理诊断均为膀胱癌,高级别144例,低级别22例。166例均行根治性膀胱切除术,其中腹腔镜手术140例,开放手术26例。术中行输尿管皮肤造口55例,回肠代膀胱96例,回肠原位新膀胱15例。将AAPR连续性变量和AAPR分组作为原始模型,调整年龄、肿瘤大小、pT分期、pN分期、肾积水、ASA分级、辅助化疗的数据作为校准模型1,在校准模型1基础上增加BMI、肿瘤数目、病理等级的数据作为校准模型2。采用趋势性检验检测不同AAPR组间危险比(HR)变化趋势。分析不同因素分层的AAPR与OS的关系。采用Kaplan-Meier法绘制生存曲线。采用基于广义相加模型的曲线拟合表示AAPR与OS的关系。结果本组166例中位随访63个月,生存95例,死亡71例。3年生存率为61%,5年生存率为50%。术后病理分期:T1期27例,T2期82例,T3期48例,T4期9例;N0期145例,N1期14例,N2期6例,N3期1例。术后52例行辅助化疗。单因素Cox回归分析结果显示,AAPR(HR=0.09,95%CI 0.022~0.391,P=0.001)、高AAPR组(HR=0.40,95%CI 0.216~0.742,P=0.003)、年龄(HR=2.42,95%CI 1.294~4.531,P=0.006)、肿瘤大小(HR=2.11,95%CI 1.112~4.014,P=0.023)、肿瘤数目(HR=0.62,95%CI 0.378~1.022,P=0.061)、pT3期(HR=8.93,95%CI 3.173~25.114,P<0.001)、pT4期(HR=10.39,95%CI 3.110~34.707,P<0.001)、N1期(HR=2.80,95%CI 1.422~5.531,P=0.003)、N3期(HR=17.06,95%CI 2.192~132.863,P=0.007)、病理分级(HR=0.30,95%CI 0.113~0.817,P=0.019)、肾积水(HR=2.36,95%CI 1.406~3.939,P=0.001)、术后辅助化疗(HR=2.66,95%CI 1.674~4.247,P<0.001)均与术后OS相关。调整年龄、肿瘤大小、pT分期、pN分期、肾积水、ASA分级、辅助化疗、BMI、肿瘤数目、病理分级后,Cox回归分析结果显示,与低AAPR组相比,高AAPR组的死亡风险降低约59%(HR=0.406,95%CI 0.200~0.822,P=0.012),AAPR每升高1个单位,死亡风险下降约80%(HR=0.199,95%CI 0.051~0.779,P=0.020)。趋势性检验结果显示,原始模型和校准模型中,AAPR不同分组间OS的HR下降趋势均有统计学意义(P=0.016),提示两者呈线性关系。调整年龄、肿瘤大小、pT分期、pN分期、肾积水、ASA分级、辅助化疗、BMI、肿瘤数目、病理分级后,曲线拟合图显示,AAPR与OS呈线性相关,随AAPR升高,术后死亡风险下降,OS延长。结论AAPR与膀胱肿瘤患者根治性膀胱切除术后的OS成线性相关,随AAPR升高,患者术后死亡风险下降,OS延长。     

Over 55 years of critical power: Fact or artifact?

This report aims to generate an evidence-based debate of the Critical Power (CP), or its analogous Critical Speed (CS), concept. Race times of top Spanish runners were utilized to calculate CS based on three (1500-m to 5000-m; CS_1.5-5km) and four (1500-m to 10000-m; CS_1.5-10km) distance performances. Male running world records from 1000 to 5000-m (CS_1-5km), 1000 to 10,000-m (CS_1-10km), 1000-m to half marathon (CS_{1km-half marathon}), and 1000-m to marathon (CS_1km-marathon) distance races were also utilized for CS calculations. CS_1.5-5km (19.62 km h^?1) and CS_1.5-10km (18.68 km h^?1) were different (p < 0.01), but both approached the average race speed of the longest distance chosen in the model, and were remarkably homogeneous among subjects (97% ±1% and 98% ±1%, respectively). Similar results were obtained using the world records. CS values progressively declined, until reaching a CS_1km-marathon value of 20.77 km h^?1 (10% lower than CS_1-5km). Each CS value approached the average speed of the longest distance chosen in the model (96.4%–99.8%). A power function better fitted the speed-time relationship compared with the standardized hyperbolic function. However, the horizontal asymptote of a power function is zero. This better approaches the classical definition of CP: the power output that can be maintained almost indefinitely without exhaustion. Beyond any sophisticated mathematical calculation, CS corresponds to 95%–99% of the average speed of the longest distance chosen as an exercise trial. CP could be considered a mathematical artifact rather than an important endurance performance marker. In such a case, the consideration of CP as a physiological “gold-standard” should be reevaluated.     

Permanent brain arrest as the sole criterion of death in systemic circulatory arrest

Historically, there has been a tendency to think that there are two types of death: circulatory and neurological. Holding onto this tendency is making it harder to navigate emerging resuscitative technologies, such as extracorporeal membrane oxygenation and the recent well-publicised experiment that demonstrated the possibility of restoring cellular function to some brain neurons 4 h after normothermic circulatory arrest (decapitation) in pigs. Attempts have been made to respond to these difficulties by proposing a unified brain-based criterion for human death, which we call ‘permanent brain arrest’. The clinical characteristics of permanent brain arrest are the permanent loss of capacity for consciousness and permanent loss of all brainstem functions, including the capacity to breathe. These losses could arise from a primary brain injury or as a result of systemic circulatory arrest. We argue that permanent brain arrest is the true and sole criterion for the death of human beings and show that this is already implicit in the circulatory-respiratory criterion itself. We argue that accepting the concept of permanent cessation of brain function in patients with systemic permanent circulatory arrest will help us better navigate the medical advances and new technologies of the future whilst continuing to provide sound medical criteria for the determination of death.     

低频电刺激联合膀胱功能训练治疗脊髓损伤诱发的神经源性膀胱的效果评价

目的 评价低频电刺激联合膀胱功能训练治疗脊髓损伤(SCI)诱发的神经源性膀胱(NB)的效果。方法 选取2017年5月～2019年2月我院骨科门诊就诊的SCI诱发NB患者90例,随机分为观察组与单纯组,每组各45例。观察组予以低频电刺激联合膀胱功能训练治疗,单纯组予以单纯的膀胱功能训练,两组均治疗6周。评估两组治疗前后排尿情况及尿动力学指标的变化,并比较其临床疗效。结果 治疗6周后,两组日均单次排尿量和日单次最大排尿量较治疗前明显增加,日均排尿次数较治疗前明显下降(P0.05或P0.01),且观察组变化幅度较单纯组更显著(P0.05);两组膀胱内压力和Qmax较治疗前明显上升,RU较治疗前明显下降(P0.05或P0.01),且观察组变化幅度较单纯组更显著(P0.05);同时观察组临床总有效率(95.56%)明显高于单纯组(82.22%)(χ2=4.053,P0.05)。结论 低频电刺激联合膀胱功能训练用于治疗SCI诱发NB患者的效果确切,能更明显改善患者的排尿情况及尿动力学状态。