Measuring Frailty in HIV-infected Individuals. Identification of Frail Patients is the First Step to Amelioration and Reversal of Frailty

A simple, validated protocol consisting of a battery of tests is available to identify elderly patients with frailty syndrome. This syndrome of decreased reserve and resistance to stressors increases in incidence with increasing age. In the elderly, frailty may pursue a step-wise loss of function from non-frail to pre-frail to frail. We studied frailty in HIV-infected patients and found that ~20% are frail using the Fried phenotype using stringent criteria developed for the elderly^1,2. In HIV infection the syndrome occurs at a younger age.HIV patients were checked for 1) unintentional weight loss; 2) slowness as determined by walking speed; 3) weakness as measured by a grip dynamometer; 4) exhaustion by responses to a depression scale; and 5) low physical activity was determined by assessing kilocalories expended in a week''s time. Pre-frailty was present with any two of five criteria and frailty was present if any three of the five criteria were abnormal.The tests take approximately 10-15 min to complete and they can be performed by medical assistants during routine clinic visits. Test results are scored by referring to standard tables. Understanding which of the five components contribute to frailty in an individual patient can allow the clinician to address relevant underlying problems, many of which are not evident in routine HIV clinic visits.     

The effect of vibrissa deprivation pattern on the form of plasticity induced in rat barrel cortex

Plasticity was induced in the barrel cortex of adolescent rats by depriving every second vibrissa on the contralateral vibrissa pad.This produced a chessboard pattern of barrels in the cortex where each barrel receiving its principal input from a spared vibrissa was surrounded by barrels for which the principal vibrissa had been deprived and conversely, each barrel receiving its principal input from a deprived vibrissa was surrounded by barrels for which the principal vibrissa had been spared. After 7 days' deprivation, responses to the regrown vibrissae were depressed in layers II/III (49% of control levels) and IV (60%). Depression was far greater than that seen with "all vibrissa" deprivation, suggesting that activity in the spared vibrissae accentuated the depression of the deprived vibrissae. Depression was not due to subcortical changes as thalamic Ventral Posterior Medial (VPM) responses to deprived vibrissa were unchanged. The short latency responses in layer IV (5-7 ms) were unaffected by deprivation, but the number of cells responding at intermediate latencies (8-13 ms) was markedly reduced (to 66% of control). Potentiation of the spared vibrissa response was substantial in the near side of the neighbouring barrel (2.2-fold increase in layers II/III, 2.9-fold in layer IV) but had not spread to the far side after 7 days' deprivation. Sparing multiple vibrissae may increase the rate of potentiation since 7 days is insufficient time for potentiation in single vibrissa spared animals. Potentiation was not due to subcortical changes as thalamic VPm responses to the spared vibrissa were normal. However, in the spared barrel the response latency decreased by 1-2 ms. Only the cells responding at short latency exhibited potentiated responses (39% increase) suggesting that some thalamocortical plasticity is still possible at P28-35. These results show that chessboard pattern deprivation is capable of inducing substantial plasticity over a wide area of barrel cortex. All the major forms of plasticity seen with other vibrissa deprivation patterns were present, although no other single deprivation pattern studied so far causes the complete repertoire seen with chessboard deprivation.     

435例产妇产后相关激素水平的调查研究及闭经风险和抑郁状况的关系研究

目的:研究435例产妇产后相关激素水平及可能发生闭经的风险,并探讨其与抑郁状况的关系,为临床诊疗提供依据。方法:选取2017年3月到2019年5月期间我院收治的435例产妇为研究对象,根据出血情况将产妇分为出血≥400 m L组(n=26)和出血400 m L组(n=409),根据生产产程将产妇分为产程≥36h组(n=34)和产程36h组(n=401),根据催产素应用情况将产妇分为催产素用量≥20U组(n=41)和催产素用量20U组(n=394),根据是否发生产后抑郁将产妇分为产后抑郁组(n=69)和无产后抑郁组(n=366),检测并对比所有产妇血清中卵泡刺激素(FSH)、促黄体生成激素(LH)、泌乳素(PRL)以及雌二醇(E_2)水平。结果:出血≥400 m L组FSH、LH水平显著高于出血400 m L组,出血≥400 m L组E_2水平显著低于出血400 m L组(P0.05);产程≥36h组FSH、LH水平显著高于产程36h组,产程≥36h组E_2水平显著低于产程36h组(P0.05);催产素用量≥20U组FSH、LH水平显著高于催产素用量20U组,催产素用量≥20U组E_2水平显著低于催产素用量20U组,(P0.05);产后抑郁组FSH、LH水平显著高于无产后抑郁组,产后抑郁组的E_2水平显著低于无产后抑郁组(P0.05);不同组分的PRL水平比较无统计学意义(P0.05)。结论:出血量≥400 m L、产程≥36h和催产素用量≥20U可能是闭经的风险因素,而产后抑郁可能降低产妇的卵巢功能。     

The clinical characterization of the adult patient with depression aimed at personalization of management

Depression is widely acknowledged to be a heterogeneous entity, and the need to further characterize the individual patient who has received this diagnosis in order to personalize the management plan has been repeatedly emphasized. However, the research evidence that should guide this personalization is at present fragmentary, and the selection of treatment is usually based on the clinician's and/or the patient's preference and on safety issues, in a trial‐and‐error fashion, paying little attention to the particular features of the specific case. This may be one of the reasons why the majority of patients with a diagnosis of depression do not achieve remission with the first treatment they receive. The predominant pessimism about the actual feasibility of the personalization of treatment of depression in routine clinical practice has recently been tempered by some secondary analyses of databases from clinical trials, using approaches such as individual patient data meta‐analysis and machine learning, which indicate that some variables may indeed contribute to the identification of patients who are likely to respond differently to various antidepressant drugs or to antidepressant medication vs. specific psychotherapies. The need to develop decision support tools guiding the personalization of treatment of depression has been recently reaffirmed, and the point made that these tools should be developed through large observational studies using a comprehensive battery of self‐report and clinical measures. The present paper aims to describe systematically the salient domains that should be considered in this effort to personalize depression treatment. For each domain, the available research evidence is summarized, and the relevant assessment instruments are reviewed, with special attention to their suitability for use in routine clinical practice, also in view of their possible inclusion in the above‐mentioned comprehensive battery of measures. The main unmet needs that research should address in this area are emphasized. Where the available evidence allows providing the clinician with specific advice that can already be used today to make the management of depression more personalized, this advice is highlighted. Indeed, some sections of the paper, such as those on neurocognition and on physical comorbidities, indicate that the modern management of depression is becoming increasingly complex, with several components other than simply the choice of an antidepressant and/or a psychotherapy, some of which can already be reliably personalized.     

树鼩模型:抑郁症的社会竞争失败与学习和记忆的被捕获条件反射

最近基因组研究表明树鼩属于灵长类或是与灵长类亲缘关系最密切的姐妹种.因此,树鼩可能是应用于建立人类疾病动物模型的最佳动物之一.该文报道一种抑郁症的社会竞争失败病因学树鼩(Tupaia belangerichinensis)模型.一对雄性树鼩被饲养在一个双笼中,用网格把双笼隔开,网格上有一小门.适应1周后,把小门打开,这一对树鼩产生短暂的争斗,每天一次,连续21天.其中争斗失败者被称为服从者.这个过程可导致每天1 h的直接社交冲突和23 h的间接相互影响(比如通过气味、视觉等).与正常对照相比,失败者在第三周也就是社交冲突的最后一周显示了体重、自主活动、躲避行为、尿液皮质醇水平等的变化,并且这种改变可持续至少2周以上.此外,还报道全新的记忆模型,一种被捕获条件反射树鼩模型.在一个封闭的小房间中放置捕获笼,其中挂有一片苹果,小房间中有一只自由活动的树鼩.训练的前4次树鼩进入捕获笼吃苹果并不触发捕获笼关闭,但在第5次时触发捕获笼关闭,并持续一小时才释放树鼩.第1-5次树鼩进入捕获笼的延迟时时间作为适心性指标,其中第5次才是作为被捕获的一次学习训练.24 h后,测试树鼩进入捕获笼的延迟时间作为被捕获记忆能力指标.树鼩经过第5次被捕获训练,能形成很好的被捕获记忆,因为24 h后的延迟时间极人地增加.在训练前腹腔注射已知能阻断记忆形成的NMDA受体拮抗剂MK-801(0.2 mg/kg,腹腔注射),对适应指标没有显著影响,但足极大地缩短了24 h后测试的延迟时间,即阻断了被捕获记忆.这些结果表明了一种抑郁症的慢性社会竞争失败与学习和记忆的一次被捕获条件反射树鼩模型.这两种树趵模型对抑郁症与学习和记忆的机理研究、抗抑郁症新药的临床前药效学评价具有潜在的重要意义.

Abstract：

Recent genome studies indicate that tree shrew is in the order or a closest sister of primates, and thus may be one of the best animals to model human diseases. In this paper, we report on a social defeat model of depression in tree shrew (Tupaia belangeri chinensis). Two male tree shrews were housed in a pair-cage consisting of two independent cages separated by a wire mesh partition with a door connecting the two cages. After one week adaptation, the connecting door was opened and a brief fighting occurs between the two male tree shrews and this social conflict session consisted of 1 h direct conflict (fighting) and 23 h indirect influence (e.g. smell, visual cues) per day for 21 days. The defeated tree shrew was considered the subordinate. Compared with naive animals, subordinate tree shrews at the final week of social conflict session showed alterations in body weight, locomotion, avoidance behavior and urinary cortisol levels.Remarkably, these alterations persisted for over two weeks. We also report on a novel captive conditioning model of learning and memory in tree shrew. An automatic trapping cage was placed in a small closed room with a freely-moving tree shrew. For the first four trials, the tree shrew was not trapped when it entered the cage and ate the bait apple, but it was trapped and kept in the cage for 1 h on the fifth trial. Latency was defined as the time between release of the tree shrew and when it entered the captive cage. Latencies during the five trials indicated adaptation. A test trial 24 h later was used to measure whether the one-trial trapping during the fifth trial could form captive memory. Tree shrews showed much longer trapping latencies in the test trial than the adaptation trials. The N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (0.2 mg/kg, i.p.), known to prevent the formation of memory, did not affect latencies in the adaptation trails, but did block captive memory as it led to much shorter trapping latencies compared to saline treatment in the test trial. These results demonstrate a chronic social defeat model of depression and a novel one-trial captive conditioning model for learning and memory in tree shrews, which are important for mechanism studies of depression, learning,memory, and preclinical evaluation for new antidepressants.     

大鼠眶额叶GABA及其B型受体在应激性抑郁行为发生中的作用及其影响机制

为了探讨眶额叶(orbital frontal cortex,OFC)GABA及其B型受体在应激性抑郁行为发生中的作用及其影响机制,实验采用强迫游泳方法建立急性应激抑郁模型。在OFC区微量注射γ-氨基丁酸(γ-aminobutyric acid,GABA)及其B型受体阻断剂,通过开场实验、强迫游泳方式检测动物行为学表现,用免疫组织化学染色和Western blotting方法检测OFC区Kalirin表达,用高尔基染色法观察锥体细胞树突和树突棘。结果显示:强迫游泳应激引起动物抑郁样行为表现,同时,OFC区Kalirin阳性颗粒数及表达量显著减少,且锥体细胞树突棘密度下降;OFC区微量注射GABA具有抗抑郁效应,使OFC区Kalirin表达显著升高,锥体细胞树突棘密度增加;GABA-B型受体阻断剂CGP35348可以抑制GABA的这种效应。由此可见,通过强迫游泳应激诱发的抑郁样的行为变化与OFC区Kalirin表达减少和神经元树突棘密度降低有关,GABA可能通过GABA-B型受体增加OFC区Kalirin表达,以防止神经元退行性变化而产生抗抑郁作用。     

Behavioral effects of chronic adolescent stress are sustained and sexually dimorphic

Evidence suggests that women are more susceptible to stress-related disorders than men. Animal studies demonstrate a similar female sensitivity to stress and have been used to examine the underlying neurobiology of sex-specific effects of stress. Although our understanding of the sex-specific effects of chronic adolescent stress has grown in recent years, few studies have reported the effects of adolescent stress on depressive-like behavior. The purpose of this study was to determine if a chronic mixed modality stressor (consisting of isolation, restraint, and social defeat) during adolescence (PND 37-49) resulted in differential and sustained changes in depressive-like behavior in male and female Wistar rats. Female rats exposed to chronic adolescent stress displayed decreased sucrose consumption, hyperactivity in the elevated plus maze, decreased activity in the forced swim test, and a blunted corticosterone response to an acute forced swim stress compared to controls during both adolescence (PND 48-57) and adulthood (PND 96-104). Male rats exposed to chronic adolescent stress did not manifest significant behavioral changes at either the end of adolescence or in adulthood. These data support the proposition that adolescence may be a stress sensitive period for females and exposure to stress during adolescence results in behavioral effects that persist in females. Studies investigating the sex-specific effects of chronic adolescent stress may lead to a better understanding of the sexually dimorphic incidence of depressive and anxiety disorders in humans and ultimately improve prevention and treatment strategies.     

Stress and the pregnant female: Impact on hippocampal cell proliferation, but not affective-like behaviors

Fifteen percent of women worldwide develop postpartum depression; however, many women also suffer from mood disorders during pregnancy. Our knowledge of how these stress-related disorders affect the neurobiology of the mother is very limited. In animal models, depressive-like behavior is often associated with repeated stress and alterations in adult neurogenesis in the hippocampus. However, research has yet to investigate the effect of stress on affective-like behavior and hippocampal neurogenesis in the pregnant female. The aim of the present study was to determine whether stress during gestation alters affective-like behaviors, corticosterone levels, and hippocampal cell proliferation and new cell survival in the pregnant female, and whether these effects differ from virgin females. Age-matched pregnant and virgin Sprague-Dawley rats were divided into two conditions: 1) stress and 2) control. Females in the stress condition were repeatedly restrained during gestation, and at matched time points in virgin females. Affective-like behaviors were assessed at the end of gestation, and at matched time points in virgin females. Results demonstrate that regardless of repeated restraint stress, pregnant females have increased anxiety-like behavior, decreased depressive-like behavior, and lower corticosterone levels, compared to non-stressed, and at times stressed, virgin females. In addition, stressed virgin females have lower levels of depressive-like behavior compared to control virgin females. Interestingly, hippocampal cell proliferation was increased in both virgin and pregnant females after stress. Understanding how stress affects the female during different reproductive states will aid in improving the health and well being of the mother and child.     

Fluoxetine and nortriptyline affect NTPDase and 5'-nucleotidase activities in rat blood serum

Depression is a serious condition associated with considerable morbidity and mortality. Selective serotonin reuptake inhibitors and tricyclic antidepressants, such as fluoxetine and nortriptyline, respectively, were commonly used in treatment for depression. Selective serotonin reuptake inhibitors have been associated with increased risk of bleeding complications, possibly as a result of inhibition of platelet aggregation. ATP, ADP and adenosine are signaling molecules in the vascular system and nucleotidases activities are considered an important thromboregulatory system which functions in the maintenance of blood fluidity. Therefore, here we investigate the effect of in vivo (acute and chronic) and in vitro treatments with the antidepressant drugs on nucleotidases activities in rat blood serum. In acute treatment, nortriptyline decreased ATP hydrolysis (41%), but not altered ADP and AMP hydrolysis. In contrast, fluoxetine did not alter NTPDase and ecto-5'-nucleotidase activities. A significant inhibition of ATP, ADP, and AMP hydrolysis were observed in chronic treatment with fluoxetine (60%, 32%, and 42% for ATP, ADP, and AMP hydrolysis, respectively). Similar effects were shown in chronic treatment with nortriptyline (37%, 41%, and 30% for ATP, ADP, and AMP hydrolysis, respectively). In addition, there were no significant changes in NTPDase and ecto-5'-nucleotidase activities when fluoxetine and nortriptyline (100, 250, and 500 microM) were tested in vitro. Our results have shown that fluoxetine and nortriptyline changed the nucleotide catabolism, suggesting that homeostasis of vascular system can be altered by antidepressant treatments.     

Venlafaxine Modulates Depression-Induced Oxidative Stress in Brain and Medulla of Rat

Venlafaxine is an approved antidepressant that is an inhibitor of both serotonin and norepinephrine transporters. Medical treatment with oral venlafaxine can be beneficial to depression due to reducing free radical production in the brain and medulla of depression- induced rats because oxidative stress may a play role in some depression. We investigated the effect of venlafaxine administration and experimental depression on lipid peroxidation and antioxidant levels in cortex brain, medulla and erythrocytes of rats. Thirty male wistar rats were used and were randomly divided into three groups. Venlafaxine (20 mg/kg) was orally supplemented to depression-induced rats constituting the first group for four week. Second group was depression-induced group although third group was used as control. Depressions in the first and second groups were induced on day zero of the study by chronic mild stress. Brain, medulla and erythrocytes samples were taken from all animals on day 28. Depression resulted in significant decrease in the glutathione peroxidase (GSH-Px) activity and vitamin C concentrations of cortex brain, glutathione (GSH) value of medulla although their levels were increased by venlafaxine administration to the animals of depression group. The lipid peroxidation levels in the three tissues and nitric oxide value in cortex brain elevated although their levels were decreased by venlafaxine administration. There were no significant changes in cortex brain vitamin A, erythrocytes vitamin C, GSH-Px and GSH, medulla vitamin A, GSH and GSH-Px values. In conclusion, cortex brain within the three tissues was most affected by oxidative stress although there was the beneficial effect of venlafaxine in the brain of depression-induced rats on investigated antioxidant defenses in the rat model. The treatment of depression by venlafaxine may also play a role in preventing oxidative stress. Abstract of the paper was submitted in 1st Ion Channels and Oxidative Stress Congress, 14–16 September 2006, Isparta, Turkey.