Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound

Fingolimod affords protection from MS by sequestering lymphocytes in secondary lymphoid organs via down regulation of their sphingosine 1 phosphate receptor (S1P1). Unexpectedly, accumulating evidence indicates that patients who discontinue fingolimod treatment may be at risk of rehearsal of magnetic resonance (MR) and clinical disease activity, sometimes featuring dramatic rebound.We therefore developed in vivo and in vitro models of post-fingolimod MS rebound to unravel its cellular and molecular mechanisms. The impact of fingolimod withdrawal on T regulatory lymphocytes was also investigated by means of cytofluorimetric analysis and antigen-specific lymphocyte proliferation assays. We show that mice with relapsing-remitting experimental autoimmune encephalomyelitis (EAE) undergo extremely severe, chronic disease rebound upon discontinuation of fingolimod. Remarkably, rebound is preceded by a burst of S1P1 overexpression in lymph node-entrapped lymphocytes that correlates with subsequent massive lymphocyte egress and widespread CNS immune infiltration. Also, consistent with the ability of S1P1 to counteract polarization and function of T regulatory lymphocytes their number and suppression of effector T cells is reduced by fingolimod suspension. Data disclose the first pathogenic mechanisms of post-fingolimod rebound that may be targeted for therapeutic intervention.     

吗啡依赖和戒断对大鼠杏仁核神经甾体和氨基酸递质水平的影响

目的研究吗啡依赖和戒断时大鼠杏仁核中神经甾体和氨基酸递质水平的变化。方法连续7天给予大鼠盐酸吗啡建立吗啡依赖模型。使用纳洛酮(2mg/kg)催促戒断,观察戒断症状并进行评分。将大鼠断头处死后,剥离大脑并分离出杏仁核,用液-液萃取和固相萃取法提取游离型和结合型神经甾体。神经甾体(包括脱氢表雄酮、孕烯醇酮、别孕烯醇酮、脱氢表雄酮硫酸酯和孕烯醇酮硫酸酯)的含量使用高效液相色谱-质谱法测定。甘氨酸、谷氨酸和γ-氨基丁酸的含量采用柱前OPA衍生-电化学检测-高效液相色谱法测定。结果与盐水对照组相比,吗啡依赖大鼠杏仁核中的脱氢表雄酮水平降低33 %(P<0·01)。与戒断对照组比较,吗啡戒断大鼠杏仁核中的孕烯醇酮和别孕烯醇酮水平分别升高45 %和42 %(P<0·05) ,γ-氨基丁酸水平降低18 %(P<0·01)。与吗啡依赖组比较,吗啡戒断组大鼠杏仁核中的孕烯醇酮和孕烯醇酮硫酸酯水平分别升高60 %和40 %(P<0·05) ,甘氨酸水平降低14 %(P<0·05)。结论吗啡依赖大鼠杏仁核中的脱氢表雄酮可能参与吗啡依赖的形成而与吗啡戒断症状的表达无关。其他神经甾体(包括孕烯醇酮、别孕烯醇酮和孕烯醇酮硫酸酯)则可能参与吗啡的戒断而与依赖的形成无关。纳洛酮催促戒断时,大鼠杏仁核中抑制性氨基酸递质的合成和释放受到抑制。表明大鼠杏仁核中的各种神经甾体和氨基酸递质在吗啡依赖和戒断时发生了不同的变化。     

Gamma-hydroxybutyric Acid Tolerance and Withdrawal in a Rat Model

Long-term daily use of gamma-hydroxybutyrate (GHB) and related compounds has recently been associated with a withdrawal syndrome. To the best of the authors' knowledge, there are currently no animal models of GHB withdrawal. OBJECTIVES: The authors studied and described the effect of chronic dosing of GHB (3-6 days) on tolerance and withdrawal in a rat model. METHODS: Rats were administered GHB every three hours via intraperitoneal catheter. Groups of rats (2 per group) were dosed with GHB for either 3 (24 doses), 4 (32 doses), 5 (40 doses), or 6 (48 doses) days. The GHB dose was 0.25 g/kg for doses 1-8, 0.75 g/kg for doses 9-12, 1 g/kg for doses 13-16, 1.25 g/kg for doses 17-24, 1.5 g/kg for doses 25-32, 1.75 g/kg for doses 33-40, and 2 g/kg for doses 41-48. Following the last dose of GHB, the rats were scored using a 16-point ethanol intoxication-withdrawal scale rating spontaneous behaviors, response to handling, grooming, and neurological signs. Lower scores indicate intoxication, while higher scores indicate withdrawal. Scores were recorded at hours 0, 1, 2, 3, 4, 5, 6, 9, 12, and 24. RESULTS: Tolerance: Rats dosed with GHB for more days were less intoxicated one hour after their last GHB dose despite receiving higher doses. WITHDRAWAL: The scores for all rats dosed with GHB increased at hours 4 (p = 0.028), 5 (p = 0.037), 6 (p = 0.007), and 9 (p = 0.024) after the last dose, indicating withdrawal. The scores demonstrated a linear increase dependent upon the number of days of GHB dosing at hours 3 (p < 0.000), 4 (p = 0.004), 5 (p = 0.002), and 12 (p = 0.039) as well as prior to the last dose at hour 0 (p = 0.000). No rats developed seizures. CONCLUSIONS: Tolerance and mild withdrawal in rats can be induced by administering intraperitoneal GHB every three hours for 3-6 days. More prolonged dosing and higher doses of GHB may be necessary to induce severe withdrawal.     

Effects of d-amphetamine injected into the nucleus accumbens on ethanol reinforced behavior

Rats, initiated to self-administer 10% (v/v) ethanol in an operant situation using the sucrose-fading procedure, received bilateral n. accumbens microinjections of d-amphetamine prior to operant sessions. Doses of 4 micrograms, 10 micrograms and 20 micrograms/brain were administered and some animals also received a 4 microgram/brain dose of LY171555. Three different effects were observed: increased, decreased and no change in total session responding. There was no clear relation between injection area in the n. accumbens and type of effect observed. For either an increase or decrease in total session responding, momentary response rates were decreased. Both d-amphetamine and LY171555 produced similar results. The data support the hypothesis that dopamine in the n. accumbens is involved with ethanol reinforced operant responding but in a complex manner.     

Ethical aspects of withdrawing/withholding renal replacement therapies on patients in acute renal failure in an intensive care unit

The majority of patients being treated for acute renal failure in intensive care units have multiple medical problems. Accordingly, the withdrawal of renal replacement therapies should be considered as part of a general decision about whether to initiate or continue with treatment per se. Several guidelines on withdrawing and withholding therapy have been produced and some common themes emerge: concerns to avoid euthanasia, potential for benefit, patient consent (shared decision‐making), team consensus/decision‐making, and the provision of appropriate palliative care and resource implications. Each of these is considered in turn, although the word limit for this paper does not permit detailed exposition.     

山芋干酒精废糟粗滤液全回流新工艺的研究

本文介绍了对山芋干酒精废糟进行粗滤,所得滤液全部回用于酒精生产的实验室研究结果。其方案之一是将粗滤液先培养丝状茵,再将二次过滤液回用;方案二是将粗滤液直接回流。经过十三到十五次的全回流表明,粗滤液全回流是可行的。另外,每100ml酒糟粗滤时可得到含干物质15%左右的湿滤渣约33g,其粗蛋白含量为17.5%(干基)。将粗滤液摇瓶培养根霉26号茵株10小时可得粗干茵体1.5—2.0g/100ml,其粗蛋白含量25%左右。     

精神病人与正常人戒烟前后焦虑抑郁症状的对照研究

目的　了解精神病人和正常人戒烟前后精神状况的变化及差异性 ,探讨戒烟措施。方法　对 71例精神病人和 5 0例正常人戒烟前及戒烟后 1周分别应用汉密顿焦虑量表 (HAMA)、汉密顿抑郁量表 (HAMD)、焦虑自评量表 (SAS)、抑郁自评量表 (SDS)、简明精神病量表 (BPRS )进行测评。结果　精神病人强制性戒烟前HAMA、HAMD、SAS、SDS、BPRS分值分别为 (8.2 1± 6 .4 1)、(7.6 4± 5 .71)、(36 .81± 7.14 )、(33.71± 7.1)、(2 9.4 5± 8.4 7) ;戒烟后HAMA、HAMD、SAS、SDS、BPRS分值分别为 (16 .4 5± 6 .34)、(19.73± 8.71)、(5 8.1± 12 .12 )、(5 6 .31± 11.4 )、(37.32± 7.95 ) ;戒烟前后 5种量表分值变化与正常人戒烟前后分值变化比较有极显著性差异(P <0 .0 1)。结论　对精神病人强制性戒烟可引起明显的情绪反应 ,应适宜控制病人吸烟 ,建立一个合理的管理制度     

胃饲乙醇预处理诱导肝脏缺血耐受性的可行性探讨

目的探讨胃饲乙醇预处理对肝脏缺血再灌流损伤的影响,并初步评价其预处理的可行性。方法40%乙醇胃饲Wistar大鼠。分组:①大鼠36只,随机分6组:A组8g/kg、B组7g/kg、C组6g/kg、D组5g/kg、E组4g/kg、正常组0g/kg;以中毒症状及肝组织病理为指标,判定大鼠乙醇急性中毒剂量。②大鼠78只,随机分为4组:正常对照组(N)、单纯乙醇组(E)、单纯缺血组(ISCH)、胃饲乙醇预处理组(EPC);采用尾叶转流下的肝缺血模型,于再灌流3、6、12、24h留取标本。结果急性胃饲乙醇≤5g/kg预处理后,动物中毒症状轻,无死亡;乙醇预处理可以在一定程度上减轻肝脏90min的缺血再灌流损伤。结论适当剂量的乙醇胃饲预处理是一种安全的预处理措施,有望成为增强肝脏对缺血再灌流损伤耐受性的一种较好的预处理方式。