Post-Exposure Sleep Deprivation Facilitates Correctly Timed Interactions Between Glucocorticoid and Adrenergic Systems,which Attenuate Traumatic Stress Responses

Reliable evidence supports the role of sleep in learning and memory processes. In rodents, sleep deprivation (SD) negatively affects consolidation of hippocampus-dependent memories. As memory is integral to post-traumatic stress symptoms, the effects of post-exposure SD on various aspect of the response to stress in a controlled, prospective animal model of post-traumatic stress disorder (PTSD) were evaluated. Rats were deprived of sleep for 6 h throughout the first resting phase after predator scent stress exposure. Behaviors in the elevated plus-maze and acoustic startle response tests were assessed 7 days later, and served for classification into behavioral response groups. Freezing response to a trauma reminder was assessed on day 8. Urine samples were collected daily for corticosterone levels, and heart rate (HR) was also measured. Finally, the impact of manipulating the hypothalamus–pituitary–adrenal axis and adrenergic activity before SD was assessed. Mifepristone (MIFE) and epinephrine (EPI) were administered systemically 10-min post-stress exposure and behavioral responses and response to trauma reminder were measured on days 7–8. Hippocampal expression of glucocorticoid receptors (GRs) and morphological assessment of arborization and dendritic spines were subsequently evaluated. Post-exposure SD effectively ameliorated long-term, stress-induced, PTSD-like behavioral disruptions, reduced trauma reminder freezing responses, and decreased hippocampal expression of GR compared with exposed-untreated controls. Although urine corticosterone levels were significantly elevated 1 h after SD and the HR was attenuated, antagonizing GRs with MIFE or stimulation of adrenergic activity with EPI effectively abolished the effect of SD. MIFE- and EPI-treated animals clearly demonstrated significantly lower total dendritic length, fewer branches and lower spine density along dentate gyrus dendrites with increased levels of GR expression 8 days after exposure, as compared with exposed-SD animals. Intentional prevention of sleep in the early aftermath of stress exposure may well be beneficial in attenuating traumatic stress-related sequelae. Post-exposure SD may disrupt the consolidation of aversive or fearful memories by facilitating correctly timed interactions between glucocorticoid and adrenergic systems.     

DHCR24转基因小鼠的性别特异性自主活动和应激反应

目的 测定α-MHC 24-脱氢胆固醇还原酶基因(DHCR24)转基因小鼠的行为学特征,研究该基因对小鼠活跃性和探究行为的影响.方法 构建α-MHC DHCR24转基因表达载体,显微注射法获得C57BL/6背景DHCR24转基因小鼠,PCR鉴定小鼠基因型,选择DHCR24转基因和同窝阴性鼠进行旷场、modified SHIRPA和Rota～Rod转轮实验.结果 DHCR24转基因雌鼠对新环境的恐惧感较小,但自主活动件低于对照鼠,而DHCR24转基因雄鼠的自主活动性和在胁迫环境下的应激性高于对照组,DHCR24转基因鼠的行为变化具有显著的性别差异.另外,本研究中雌鼠的活跃性、运动协调性和平衡能力均显著高于雄鼠,对胁迫环境的应激性也大于雄鼠.结论 心脏特异表达DHCR24基因转基因小鼠自主活动和应激性的变化具有性别差异.     

Sex Differences in Depressive and Socioemotional Responses to an Inflammatory Challenge: Implications for Sex Differences in Depression

Substantial evidence demonstrates that inflammatory processes may underlie depression for a subset of patients, including work showing that healthy subjects exposed to an inflammatory challenge show increases in depressed mood and feelings of social disconnection. However, despite the fact that depression is two times as likely to occur in females than males, the vast majority of this work has been carried out in males. Thus, the objective of this study was to determine whether females (vs males) would show greater increases in proinflammatory cytokines, depressed mood, and social disconnection in response to an inflammatory challenge. One hundred and fifteen healthy participants (69 female) completed this double-blind, placebo-controlled, randomized clinical trial in which participants were randomly assigned to receive either a single infusion of low-dose endotoxin (derived from Escherichia coli; 0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline). Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), depressed mood, and feelings of social disconnection were assessed hourly. Results showed that endotoxin (vs placebo) led to increases in proinflammatory cytokines (TNF-α, IL-6), depressed mood, and feelings of social disconnection. Females exposed to endotoxin showed greater increases in depressed mood and feelings of social disconnection. Furthermore, increases in TNF-α and IL-6 were correlated with increases in social disconnection for females but not for males. These sex differences in the relationships between inflammatory and socioemotional responses to an inflammatory challenge may be particularly important for understanding why females are two times as likely as males to develop depressive disorders.     

Differences in Serum Concentrations of and Responses to Generic Verapamil in the Elderly

Study Objective . To determine if there are greater differences in bioavailability of generic verapamil at steady state in elderly patients than in healthy young subjects. Design . Double-blind, randomized, three-way crossover study. Setting . Clinical research center at a general teaching hospital. Subjects . Eight young, healthy subjects between ages 18 and 45 years, and eight elderly, hypertensive patients over 65 years of age. Interventions . Each participant was randomly assigned to receive brand-name verapamil or one of two generic preparations. Young subjects received each of the three preparations 80 mg twice/day for 7 days separated by a 1-week washout. Elderly patients took the three preparations for 21 days. Serum drug levels and blood pressure were measured and electrocardiograms performed 13 times after the last dose of drug. Main Results . In young subjects, the pharmacokinetics and pharmacodynamics of the three preparations were nearly identical. There was, however, a great deal of variability in the bioavailability of the generic products. In the elderly patients, one generic product had a maximum serum concentration and area under the curve that were 77% and 43% greater, respectively, than the brand-name product (p<0.02). Assessments of bioequivalency (based on confidence intervals) demonstrated that this generic drug's bioavailability was from 4–118% and peak serum concentration from 10–139% greater than the brand-name drug. This was associated with greater prolongation of the PR intervals. Conclusions . A generic verapamil product that is bioequivalent in young subjects may not be bioequivalent in elderly subjects. Testing of drugs with complex pharmacokinetics in young subjects may not reliably predict the clinical outcomes in elderly hypertensive patients.     

Species Differences in Cannabinoid Receptor 2 and Receptor Responses to Cocaine Self-Administration in Mice and Rats

The discovery of functional cannabinoid receptors 2 (CB₂Rs) in brain suggests a potential new therapeutic target for neurological and psychiatric disorders. However, recent findings in experimental animals appear controversial. Here we report that there are significant species differences in CB₂R mRNA splicing and expression, protein sequences, and receptor responses to CB₂R ligands in mice and rats. Systemic administration of JWH133, a highly selective CB₂R agonist, significantly and dose-dependently inhibited intravenous cocaine self-administration under a fixed ratio (FR) schedule of reinforcement in mice, but not in rats. However, under a progressive ratio (PR) schedule of reinforcement, JWH133 significantly increased breakpoint for cocaine self-administration in rats, but decreased it in mice. To explore the possible reasons for these conflicting findings, we examined CB₂R gene expression and receptor structure in the brain. We found novel rat-specific CB_2C and CB_2D mRNA isoforms in addition to CB_2A and CB_2B mRNA isoforms. In situ hybridization RNAscope assays found higher levels of CB₂R mRNA in different brain regions and cell types in mice than in rats. By comparing CB₂R-encoding regions, we observed a premature stop codon in the mouse CB₂R gene that truncated 13 amino-acid residues including a functional autophosphorylation site in the intracellular C-terminus. These findings suggest that species differences in the splicing and expression of CB₂R genes and receptor structures may in part explain the different effects of CB₂R-selective ligands on cocaine self-administration in mice and rats.     

Integrated Biological and Chemical Monitoring: In situ Physiological Responses of Freshwater Crayfish to Fluctuations in Environmental Ammonia Concentrations

A portable, computer-aided physiological monitoring system (CAPMON) has been integrated with an automated, flow injection (FI) based chemical monitor to enable continuous, long-term recording of cardiac activity in selected aquatic organisms, and total ammonia concentration in the surrounding environment. Heart rate of the freshwater crayfish Pacifastacus leniusculus was recorded using non-invasive infrared emitter/detectors to transduce heart beat from 4 animals simultaneously. Data were collected continuously and stored on a laptop computer. The chemical monitor incorporated a gas diffusion unit and a solid state photometric detector. Remote control and data processing were accomplished using an in-house designed microcomputer. The instrumentation was fully evaluated in the laboratory and the field and was shown to be capable of operating unattended for periods of at least 1 week. An exposure-response experiment showed that 4 h exposures to concentrations of ammonia greater than 5 mg l^-1 had a significant stimulatory effect on heart rate (ANOVA F=7.6; df=5; P<0.0005). The feasibility of using the system in situ was demonstrated in a 2 week field trial in which the integrated monitors were successfully deployed at a landfill leachate lagoon.     

Childhood Trauma and Neural Responses to Personalized Stress,Favorite-Food and Neutral-Relaxing Cues in Adolescents

Previous studies have found childhood trauma to be associated with functional and structural abnormalities in corticostriatal-limbic brain regions, which may explain the associations between trauma and negative mental and physical health outcomes. However, functional neuroimaging of maltreatment-related trauma has been limited by largely using generic and predominantly aversive stimuli. Personalized stress, favorite-food, and neutral/relaxing cues during functional magnetic resonance imaging were used to probe the neural correlates of emotional/motivational states in adolescents with varying exposure to maltreatment-related trauma. Sixty-four adolescents were stratified into high- or low-trauma-exposed groups. Cue-related measures of subjective anxiety and craving were collected. Relative to the low-trauma-exposed group, high-trauma-exposed adolescents displayed an increased activation of insula, anterior cingulate, and prefrontal cortex in response to stress cues. Activation in subcortical structures, including the hippocampus, was inversely correlated with subjective anxiety in the high- but not the low-trauma-exposed group. The high-trauma-exposed group displayed hypoactivity of cerebellar regions in response to neutral/relaxing cues. No group differences were observed in response to favorite-food cues. The relationship between trauma exposure and altered cortico-limbic circuitry may in part explain the association between childhood trauma and heightened vulnerability to emotional disturbances and risky behaviour. This may be particularly pertinent during adolescence when such difficulties often emerge. Further work is needed to elucidate the mechanism linking trauma to obesity.     

Individual Differences in Cue-Induced Motivation and Striatal Systems in Rats Susceptible to Diet-Induced Obesity

Pavlovian cues associated with junk-foods (caloric, highly sweet, and/or fatty foods), like the smell of brownies, can elicit craving to eat and increase the amount of food consumed. People who are more susceptible to these motivational effects of food cues may have a higher risk for becoming obese. Further, overconsumption of junk-foods leading to the development of obesity may itself heighten attraction to food cues. Here, we used a model of individual susceptibility to junk-foods diet-induced obesity to determine whether there are pre-existing and/or diet-induced increases in attraction to and motivation for sucrose-paired cues (ie, incentive salience or ‘wanting’). We also assessed diet- vs obesity-associated alterations in mesolimbic function and receptor expression. We found that rats susceptible to diet-induced obesity displayed heightened conditioned approach prior to the development of obesity. In addition, after junk-food diet exposure, those rats that developed obesity also showed increased willingness to gain access to a sucrose cue. Heightened ‘wanting’ was not due to individual differences in the hedonic impact (‘liking’) of sucrose. Neurobiologically, Mu opioid receptor mRNA expression was lower in striatal ‘hot-spots’ that generate eating or hedonic impact only in those rats that became obese. In contrast, prolonged exposure to junk-food resulted in cross-sensitization to amphetamine-induced locomotion and downregulation of striatal D2R mRNA regardless of the development of obesity. Together these data shed light on individual differences in behavioral and neurobiological consequences of exposure to junk-food diets and the potential contribution of incentive sensitization in susceptible individuals to greater food cue-triggered motivation.     

Hemodynamic Responses to Indoramin at Rest and During Exercise in Congestive Heart Failure

Twenty patients with congestive heart failure underwent hemodynamic studies before and over 10 hours after the administration of 25, 50, and 75 mg of indoramin, an alpha₁-adrenergic antagonist. Hemodynamic studies were repeated during exercise after the administration of the optimal dose of indoramin. The drug reduced resting and exercise pulmonary capillary wedge pressure, right atrial pressure, systemic blood pressure and vascular resistance, and pulmonary artery pressure and vascular resistance. Resting and exercise stroke volume and cardiac output rose in response to the fall in vascular resistances. Heart rate was not altered at rest or during exercise. The first dose of the alpha₁ blocker indoramin elicits a significant reduction in ventricular preload and afterload and augmentation of ventricular performance in patients with congestive heart failure.     

Regional Differences in Brain-Derived Neurotrophic Factor Levels and Dendritic Spine Density Confer Resilience to Inescapable Stress

Background:

In the learned helplessness (LH) paradigm, approximately 35% of rats are resilient to inescapable stress.

Methods:

The roles of brain-derived neurotrophic factor (BDNF) and dendritic spine density in the brain regions of LH (susceptible) and non-LH rats (resilient) were examined. Western blot analysis and Golgi staining were performed.

Results:

BDNF levels in the medial prefrontal cortex, CA3, and dentate gyrus (DG) were significantly lower in the LH group than in the control and non-LH groups, whereas BDNF levels in the nucleus accumbens (NAc) in the LH group but not the non-LH group were significantly higher than those in the control group. Furthermore, spine density in the prelimbic cortex, CA3, and DG was significantly lower in the LH group than in the control and non-LH groups, although spine density in the NAc was significantly higher in the LH group than in the control and non-LH groups.

Conclusions:

The results suggest that regional differences in BDNF levels and spine density in rat brain may contribute to resilience to inescapable stress.     

Effects of Methyl Jasmonate on Acute Stress Responses in Mice Subjected to Forced Swim and Anoxic Tests

Methyl jasmonate (MJ) is an anti-stress hormone released by plants in response to external stressors and aids adaptation to stress. In this study, we evaluated the anti-stress activity of MJ using the forced swim endurance test (FSET) and anoxic tolerance test in mice. Male Swiss mice were given MJ (25–100 mg/kg, i.p) 30 min before the FSET and anoxic test were carried out. The first occurrence of immobility, duration of immobility, time spent in active swimming, and latency to exhaustion were assessed in the FSET. The onset to anoxic convulsion was measured in the anoxic tolerance test. MJ significantly (p < 0.05) delayed the first occurrence of immobility and shortened the period of immobility, which indicates anti-stress property. MJ also increased the time spent in active swimming and prolonged the latency to exhaustion, which further suggests anti-stress activity. In addition, it also exhibited anti-stress property as evidenced by prolonged latency to first appearance of anoxic convulsions. The results of this study suggest that MJ demonstrated anti-stress activity and may be useful as an energizer in times of body weakness or exhaustion. Although more studies are necessary before concluding on how MJ exerts its anti-stress activity, the present data suggest an action similar to adaptogens in boosting energy and resilience in the face of stress.     

不同起始时间使用咖啡因对极低出生体质量早产儿呼吸暂停防治作用的系统评价

目的:探讨不同起始时间使用咖啡因防治极低出生体质量早产儿呼吸暂停的疗效和安全性。方法:检索PubMed、the Cochrane Library、EMBase、中国期刊全文数据库(CNKI)、万方数据、生物医学文献数据库(CBM)及维普等数据库,收集各数据库从建库至2020年6月有关极低出生体质量早产儿早期应用咖啡因防治呼吸暂停的病例对照研究,并采用Cochrane系统评价手册5.1.0和Newcastle-Ottawa量表(NOS)对不同类型研究进行质量评价,采用RevMan 5.3进行系统评价。结果:10项文献中,包括5项随机临床对照研究(RCT)和5项回顾性队列研究,文献质量评价结果显示,5项RCT质量等级为B级,5项回顾性队列研究NOS评分为7～9分。共2 665例患儿,其中早期用药组1 515例,晚期用药1 150例。Meta分析结果显示,早期用药组呼吸暂停(AOP)发生率(RR=0.48,95%CI 0.38～0.60,P<0.01)、吸氧时间(SMD=-0.97,95%CI-1.13～-0.80,P<0.01)、机械通气时间(SMD=-0.82,95%CI-1...     

不同髋关节置换术治疗髋臼骨折继发创伤性关节炎的术后疗效及安全性比较

目的:比较不同髋关节置换术治疗髋臼骨折的术后疗效及安全性。方法:选取某院2007年12月~2014年12月髋臼骨折继发创伤性关节炎患者30例,抽签随机分为两组,全髋关节组患者17例,半髋关节组患者13例,比较两组围手术期指标,手术后Harris评分优良率及Postel疗效评分。结果:全髋关节组手术时间、术中术中出血量较半髋关节组显著较高(P0.05);全髋关节组术后Harris评分优良率较半髋关节组显著较高(P0.05);全髋关节组的Postel疼痛评分、行走能力、髋关节活动范围较半髋关节组显著较高(P0.05)。结论:全髋关节置换术患者术后髋关节恢复情况更好,若患者身体状态良好且有一定耐受能力,则全髋关节置换术是较理想的选择。     

Differences in micronucleus induction in peripheral blood reticulocytes of mice exposed to N-ethyl-N-nitrosourea at light and dark dosing times

Mammals, including human beings, have a circadian clock system to regulate behavioral and physiological processes. In this study, we investigated the effect of dosing time on micronucleus induction in the bone marrow by evaluating the frequencies of micronucleated peripheral reticulocytes (MNRETs) in mice exposed to N-ethyl-N-nitrosourea (ENU) to assess any difference in genotoxic sensitivity to chemicals between light and dark periods (inactive phase for rodents and active phase for rodents). Male C3H/He mice were treated intraperitoneally with ENU (12.5 or 25 mg/kg body weight) at zeitgeber time (ZT) 3 in the light period or ZT15 in the dark period, and then the time courses of the frequencies of the MNRETs were determined. The frequencies of the MNRETs induced by ENU increased time-dependently and peaked at 48 hr after treatment for ZT3 and ZT15, and were obviously higher in the ZT15 treatment group than the ZT3 treatment group. The MNRETs were measured at 48 hr after treatment with ENU (25 mg/kg body weight) at various dosing times (ZT0, 3, 6, 12, 15 and 18). The frequencies of the MNRETs in mice treated at ZT0, 15 and 18 were significantly higher than those in mice treated at ZT3, 6 and 12. These results suggest that genotoxic sensitivity to chemicals in mouse bone marrow is different between light and dark periods maybe due to different biological responses (detoxification, cell cycle, DNA repair, etc.) related to circadian rhythms.     

Responses of exposure to cigarette smoke at three dosage levels on soleus muscle fibers in Wistar-Kyoto and spontaneously hypertensive rats

Overproduction of nitric oxide (NO) from inducible nitric oxide synthase (iNOS) is importantly involved in the pathogenesis of endotoxemia and atherosclerosis. Calcium antagonists are commonly used as cardiovascular drugs and have a beneficial effect on prolonging survival in various models of endotoxin shock. The present study was to investigate the effect of a calcium antagonist amlodipine on nitrite, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) formation and iNOS induction both in lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma)-treated rat aortic smooth muscle cells (RASMC) and in a rat model of endotoxemia. Incubation with amlodipine (0.1 - 10 microM) for 24 h resulted in a significant and dose-dependent attenuation in medium nitrite, TNF-alpha and IL-1beta formation as well as iNOS protein expression in LPS/IFN-gamma-treated RASMC. In addition, amlodipine inhibited leucigenin-induced superoxide formation in RASMC. In the rat endotoxic model, the serum nitrite/nitrate, TNF-alpha and IL-1beta levels as well as iNOS protein expression of lungs were also suppressed by administration of amlodipine (50 microg/kg, i.v.). These results suggest that amlodipine may exert vascular beneficial effects by suppressing pro-inflammatory cytokines and free radical generation as well as iNOS induction in smooth muscle cells during activation of inflammatory mechanism.     

Qualitative Differences between the Inotropic Responses in Rat Papillary Muscles to α-Adrenoceptor and β-Adrenoceptor Stimulation by both Noradrenaline and Adrenaline

Abstract: Mammalian heart has obviously both α- and β-adrenergic inotropic mechanisms, and stimulation of these two mechanisms by appropriate agonists lead to qualitatively different inotropic responses. This difference can serve to recognize the two adrenergic inotropic effects. In order to explore if the endogenous catecholamines, noradrenaline and adrenaline, could activate both these mechanisms, and if so, to characterize them qualitatively and quantitatively, the mechanical responses in electrically driven rat left ventricular papillary muscles were examined in the absence or presence of appropriate receptor blockade. Isometric tension (T), rate of rise and decline of tension (first derivative = T) and rate of transition from tension rise to tension decline (negative part of second derivative=T) were recorded. α-Adrenergic and β-adrenergic inotropic effects were demonstrated both for noradrenaline and adrenaline. Maximal β-adrenoceptor stimulation (agonist in the presence of an α-adrenoceptor blocker) caused a small increase in T_max, intermediate increases in T'_max and T'_min, and a considerable increase in T_min (β-type effect). Maximal α-adrenoceptor stimulation (agonist in the presence of a β-adrenoceptor blocker) increased all parts of the contraction-relaxation cycle by about the same degree (T_minT_minT'_maxT_max α-type effect). While β-adrenoceptor stimulation gave a dose dependent and pronounced increase in the ratio T_min/T_max (relaxation-onset index), α-adrenoceptor stimulation decreased it to subcontrol values. The time course of the response to the α-adrenoceptor stimulation was characterized by a transient decrease in all qualities followed by an increase which reached maximum at 4–5 min. β-Adrenoceptor stimulation gave a monophasic inotropic response which developed in the course of 1–2 min. Both agents alone gave a monophasic response with the characteristics of a β-type effect (i.e. relative maximal increase of T_minT_minT_maxT_max), and a marked increase in the relaxation-onset index (T_min/T_max). Thus the β-adrenergic inotropic component was the dominating one when the amines were used alone. The two different response patterns probably reflect a dual mechanism of action of the endogenous catecholamines: the β-adrenergic component which is dependent upon an increase in cyclic AMP levels and the α-adrenergic component which is independent on cyclic AMP.     

Differences in Characteristics of Heroin Inhalers and Heroin Injectors at Admission to Treatment: A Preliminary Study Using a Large Database of Client Records

Aims.?To compare the characteristics of heroin injectors vs. inhalers at their first admission to publicly funded treatment in Texas. Methods.?The sample consisted of 9732 unique clients who entered publicly funded treatment programs in Texas between 1997 and 2001 and who had a primary problem with either injected or inhaled heroin, which they had used in the past 30 days. The records were analyzed using a generalized linear model of logistic regression with the outcomes modeled as binomial and multinomial distribution and a hierarchical linear model for continuous outcomes to compare heroin inhalers and injectors. Findings.?There were large statistically significant differences between injectors and inhalers. Inhalers were more likely to be older at first use of heroin, to have entered treatment sooner, to have minor children at home, to have higher annual incomes, to be first admissions to treatment, and to have a secondary drug problem with crack cocaine. They were also more likely to be Hispanic [odds ratio (OR) = 1.74] or African-American (OR = 12.32). Conclusions.?Even though the race/ethnic differences in the Texas population and the type of heroin available for use in Texas differs from that studied elsewhere, many of the characteristics of heroin users are similar. Inhalers have more strengths in many areas, and these findings raise the possibility that there are factors, particularly among African-American participants in Texas, that lessen the risk of injecting heroin. Efforts should be directed to providing therapeutic interventions to discourage the transition to injecting and to encourage inhalers to enter treatment earlier rather than progressing on to injecting. This analysis is the first part of a larger study of heroin users in public and private treatment.