Evidence for Cytokine Dysregulation in Multiple Sclerosis: Peripheral Blood Mononuclear Cell Production of Pro-inflammatory and Anti-inflammatory Cytokines During Relapse and Remission

We investigated circulating anti-inflammatory and pro-inflammatory cytokines, and their ex vivo PBMC production in the absence or presence of the neuroantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) and T cell mitogen (PHA) in MS patients in relapse and remission, patients with other neurological disorders (OND) and normal healthy controls. MS patients in relapse exhibited significantly increased PBMC production of TNF-α spontaneously compared with MS remission and healthy controls and with MBP compared with MS remission. Patients in relapse had significantly increased spontaneous, PHA- and MBP-induced PBMC IL-1β production compared with remission MS, and was increased compared (PHA only) with OND and healthy controls. In relapse there was also significantly increased PBMC IFN-γ production (PHA only) compared with remission and a significantly lower production of biologically active TGF-β1 (PHA only) compared with remission MS and OND. In contrast, MS patients in remission produced significantly less spontaneous and MBP-induced TNF-α, spontaneous, PHA- and MBP-induced IL-1β and PHA-induced IFN-γ together with increased production of biologically active TGF-β1. MOG non-specifically increased PBMC TNF-α and IL-1β production in all groups. Pro-inflammatory cytokines in corresponding plasma samples were undetectable whilst the concentration of biologically active TGF-β1 was the reverse of ex vivo PBMC findings. The increase in biologically active TGF-β1 production ex vivo in OND patients, despite active disease, compared with the low level in the MS relapse may indicate a regulatory defect in MS. We conclude that the balance between biologically active TGF-β1 and the pro-inflammatory TNF-α, IL-1β and IFN-γ is dysregulated during MS relapse-remission and that normal counter-regulatory mechanisms during the relapse phase are defective.     

Predictors of relapse in patients with major depressive disorder in a 52-week,fixed dose,double blind,randomized trial of selegiline transdermal system (STS)

Objective

We investigated patient and disease characteristics predictive of relapse of MDD during a 52-week placebo controlled trial of selegiline transdermal system (STS) to identify patient characteristics relevant for STS treatment.

Method

After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24 h) or placebo (PLB). Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of ≥14 and a CGI-S score of ≥3 with at least 2-point increase from the beginning of the double blind phase on 2 consecutive visits. Cox's proportional hazards regression was used to examine the effect of potential predictors (age, sex, age at onset of first MDD, early response pattern, number of previous antidepressant trials, severity of index episode, number of previous episodes, melancholic features, atypical features and anxious feature) on outcome. Exploratory analyses examined additional clinical variables (medical history, other psychiatric history, and individual items of HAM-D 28) on relapse.

Results

For all predictor variables analyzed, treatment Hazard Ratio (HR=0.48~0.54) was significantly in favor of STS (i.e., lower relapse risk than PLB). Age of onset was significantly predictive of relapse. Type, duration, and severity of depressive episodes, previous antidepressant trials, or demographic variables did not predict relapse. In additional exploratory analysis, eating disorder history and suicidal ideation were significant predictors of relapse after controlling for the effect of treatment in individual predictor analysis.

Conclusions

While age of onset, eating disorder history and suicidal ideation were significant predictors, the majority of clinical and demographic variables were not predictive of relapse. Given the post-hoc nature of analysis, the findings need confirmation from a prospective study. It appears that selegiline transdermal system was broadly effective in preventing relapse across different subtypes and symptoms clusters of MDD.     

海洛因戒断与复吸对大鼠结肠5-羟色胺和 P物质表达的影响

目的 探讨海洛因戒断、脱毒和复吸期间5-羟色胺(5-HT)、P物质(SP)在大鼠结肠表达的变化.方法 将正常雄性SD大鼠35只,随机分为实验组15只、盐水对照组15只和正常对照组5只,实验组大鼠又分戒断组(HWG)、脱毒治疗组(MDG)和复吸组(HRG).取正常对照组、盐水对照组及实验组大鼠的结肠组织,采用免疫组织化学SABC法及图像分析方法进行研究.结果 戒断组和复吸组大鼠结肠内的5-HT-、SP-免疫反应(IR)细胞的平均灰度值低于正常及盐水对照组,免疫反应细胞计数增多,差异有统计学意义(P<0.05).脱毒治疗组与正常及盐水对照组比较,大鼠结肠内的5-HT-、SP-IR细胞的平均灰度值及细胞计数差异均无统计学意义(P>0.05).结论 在海洛因戒断、复吸期间,结肠分泌5-HT、SP增多;美沙酮脱毒治疗后,5-HT、SP的表达与正常组差异无显著性,提示结肠分泌的5-HT、SP参与了海洛因戒断、脱毒和复吸期间机体的调节.     

亚急性硬膜下血肿两种手术方法疗效比较

目的采用钻孔引流术治疗亚急性硬膜下血肿,并与开颅术的疗效相比较。方法从2005年1月至2010年7月,收治亚急性硬膜下血肿患者65例,回顾性分析65例患者的临床及神经影像学特征、手术方法和治疗效果,对比钻孔引流术与开颅血肿清除术的疗效差异。结果 65例患者均采用手术治疗;钻孔引流组38例,其中36例治愈,2例复发,无死亡;开颅组27例,其中治愈26例,1例死于术后并发肺部感染,无复发;两组在治愈率、复发率、及死亡率上均无显著性差异。结论钻孔引流术与开颅术均是治疗亚急性硬膜下血肿的有效方法,前者具有操作简便、微创、及避免行开颅手术等优势,可作为治疗的首选。     

Application of a quality of life measure, the life situation survey (LSS), to alcohol-dependent subjects in relapse and remission

BACKGROUND: Recent studies have shown that quality of life (QOL) is improved significantly when subjects do not relapse to heavy drinking, and QOL deteriorates significantly on prolonged relapse. This article further investigates these relationships using a QOL index, the Life Situation Survey (LSS). METHODS: Eighty-two DSM-IV alcohol-dependent subjects admitted for alcohol detoxification were studied at baseline and 12 week follow-up. Sociodemographic data were collected, and severity of alcohol dependence (SADQ) and General Health Questionnaire (GHQ-12) were baseline indices only. The main outcome measure, the LSS, was administered at both time points. RESULTS: Two subjects were lost to follow-up and one died during the study period. Thus, the relapse/ nonrelapse analysis related to 79 subjects. Fifty subjects (63%) had relapsed to heavy drinking at 3 months follow-up. There was a significant correlation between LSS and GHQ-12 scores. Significant changes occurred in total LSS scores as a result of relapse and nonrelapse. The improvement in LSS scores associated with nonrelapse was larger than the deterioration that accompanied relapse. In those subjects who did not relapse to heavy drinking, the mean follow-up score remained in the poor/borderline LSS range. Remission from heavy drinking was accompanied by significant improvements in appetite, sleep, and self-esteem. Relapse to heavy drinking coincided with a significant deterioration in mood/affect, public support, and work/life role scores. CONCLUSION: QOL as assessed by the LSS in recently detoxified alcoholics is impaired significantly. In the nonrelapse group, there was a significant improvement in LSS scores after 3 months. Relapse was accompanied by a smaller deterioration in LSS scores. The LSS can play an important role in monitoring the clinical care and progress of alcohol-dependent subjects.     

Use of a high-risk alcohol relapse scale in evaluating liver transplant candidates

BACKGROUND: Methods to improve assessment, selection, and monitoring of patients with alcoholic cirrhosis who pursue liver transplantation are sought continuously. We chose to investigate the use of the High-Risk Alcohol Relapse (HRAR) scale in our transplant population in the hope that it would improve our ability to identify and follow patients at highest risk for alcohol relapse. METHODS: Detailed alcohol histories of 207 patients evaluated for liver transplantation were collected and graded for severity by using the HRAR. The HRAR provides information on the duration of alcohol use (a measure of chronicity), daily quantity of alcohol use, and rehabilitation experiences (treatment responsiveness). Posttransplant alcohol use was monitored through clinical follow-up in the transplant clinic. RESULTS: Although men and women had similar years of heavy drinking pretransplant, women's daily alcohol consumption was significantly less than men's. HRAR scores did not distinguish those listed for transplant from those not listed or those who drank posttransplant from those who did not. Transplant patients were predominantly in the low-risk group (83% had an HRAR score <4). CONCLUSIONS: The HRAR did not have predictive ability in our transplant population. Few of our patients were rated as high risk, and few drank posttransplant. Nevertheless, identifying patients at high risk may improve clinical care and decrease the rate of posttransplant alcohol consumption.     

幽门螺杆菌感染与十二指肠球部溃疡相关性的临床研究

目的研究根除幽门螺杆菌（Hp）治疗对Hp阳性的十二指肠球部溃疡愈合率、愈合质量及复发的影响。方法将78例Hp阳性的十二指肠球部溃疡患者随机分为除菌组和非除菌组，除菌组给予泮托拉唑40mg＋克拉霉素0．5g＋呋喃唑酮0．1g口眼，2次／d，1周后泮托拉唑改为40mg，1次，d，共治疗6周。非除菌组单独给予泮托拉唑，剂赶方法同上。分别于6周及1年后复查胃镜。结果除菌组和非除菌组比较，6周后溃疡愈合率差异无统计学意义（分别为97．6％和91．7％，P〉0．05）。6周后溃疡愈合质量比较差异有统计学意义。1年后两组溃疡复发率比较，除菌组低于非除菌组，差异有统计学意义（分别为6．7％和59．3％，P〈0．01），Hp根除率除菌组高于非除菌组，差异有统计学意义（分别为86．7％和3．7％，P〈0．01）。结论Hp感染与十二指肠球部溃疡存在相关性，根除Hp治疗不仅可以提高溃疡的愈合质量，而且还可以减少溃疡的复发。     

Significance of Serum Neuron-specific Enolase as a Predictor of Relapse of Small Cell Lung Cancer

We conducted a prospective study to evaluate the significanceof serum neuron-specific enolase (NSE) as a predictor of relapseof small cell lung cancer (SCLC). Patients entered into thestudy were drawn from those who had shown a complete or partialresponse to first-line chemotherapy with a concurrent declinein the NSE level to less than 10 ng/ml. When the serum NSE levelincreased to more than 15 ng/ml, the patient was restaged onthe basis of clinical, radiological, and bronchoscopic examinations.During the period from August 1988 to December 1990, 57 patientswith SCLC were enrolled and followed up until May 1992; Of thesepatients, 45 had clinical relapses, and 14 (31%) of them showeda clear elevation of the serum NSE level prior to the clinicalrecognition of relapse. Although one false-positive case wasnoted, this involved only a transient elevation of the NSE level.In patients who showed increased NSE levels, the relapses occurredin more difficult to detect silent sites such as the adrenalgland, liver, and deep lymph nodes. In addition, the percentageof patients demonstrating high NSE levels who were able to benefitfrom salvage chemotherapy was higher than for those who didnot (P<0.05). Our results indicate that serial NSE measurementsare useful for the early prediction of SCLC relapse and shouldhelp to facilitate early administration of salvage chemotherapyfor affected patients.(P<0.05)     

Reactivation of morphine conditioned place preference by drug priming: role of environmental cues and sensitization

RATIONALE: Relapse is a major characteristic of drug addiction and remains the primary problem in treating drug abuse. Despite a great deal of research, the exact factors that determine renewed drug-seeking and persistent craving for them remain unclear. OBJECTIVE: The present study was designed to evaluate the role of environmental cues and behavioral sensitization in reactivation of place preference following long-term extinction of morphine conditioned place preference (CPP) in rats. METHODS: After being injected with morphine and saline alternately for 6 days to induce morphine CPP, the rats were subjected to extinction of conditioning for 21 days. The rats were then administered various doses of morphine, heroin, or cocaine and confined in the previous drug- or saline-paired compartment. CPP was determined. Some rats were treated with scopolamine or naloxone prior to administration of these three drugs. RESULTS: Morphine CPP disappeared following a 21-day extinction. A single injection of morphine, heroin, or cocaine evoked place preference for the previous drug-paired side. However, place preference for the previous vehicle-paired side was induced after the animals received a single injection of morphine, heroin or cocaine and confined to the previous vehicle-paired compartment. Administration of naloxone prior to drug treatment significantly attenuated the place preference induced by morphine or heroin, but had no significant effect on the place preference elicited by cocaine. Administration of the cholinergic antagonist scopolamine before morphine, heroin and cocaine inhibited the expression of place preference. CONCLUSIONS: Environment-related cues and behavioral sensitization play critical roles in the incentive motivation underlying drug-seeking behaviors.     

Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats

RATIONALE: D(1) dopamine receptor antagonists and agonists attenuate cocaine reinstatement of cocaine-seeking behavior (i.e., responding in the absence of cocaine reinforcement). OBJECTIVES: The present study investigated the effects of a D(1) antagonist (SCH-23390), partial agonist (SKF-38393), and full agonist (SKF-81297) on reinstatement of cocaine-seeking behavior elicited by presentation of cocaine-paired cues. METHODS: Rats that had been trained to self-administer cocaine with a light/tone stimulus complex paired with each infusion underwent extinction across days. After responding diminished, rats were given response-contingent access to the cocaine-paired stimulus complex. The effects of SCH-23390 (0-10.0 microg/kg), SKF-38393 (0-3.0 mg/kg), and SKF-81297 (0-3.0 mg/kg) on cue reinstatement of cocaine-seeking behavior were examined. The ability of the two D(1) agonists to independently reinstate cocaine-seeking behavior and the effects of SKF-81297 on cocaine reinstatement were also examined. To investigate the possibility of behavioral interference, the effects of SKF-38393 and SKF-81297 on grooming and stereotypy were assessed. RESULTS: SCH-23390 and SKF-81297, but not SKF-38393, attenuated cue reinstatement. However, while SKF-81297 dose-dependently increased response latency, SCH-23390 did not. SKF-81297 also independently reinstated responding at the two lowest doses tested while SKF-38393 had no effect. Furthermore, SKF-81297 decreased cocaine reinstatement and increased response latency only at the highest dose. Finally, stereotypy was observed at all doses of SKF-81297 that also decreased responding, although the patterns of changes in these behaviors did not completely correspond. CONCLUSIONS: While the antagonist and full agonist produced similar effects on cocaine-seeking behavior, only the agonist increased response latency, suggesting that different processes mediate the effects of these drugs.