Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity

AIM: To investigate the precise roles of CAR in CCI4-induced acute hepatotoxicity. METHODS: To prepare an acute liver injury model,CCI4 was intraperitonealiy injected in CAR+/+ and CAR-/- mice, RESULTS: Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR-/- mice compared to CAR+/+ mice without PB. Administration of a CAR inducer, PB, revealed that CCl4-induced liver toxicity was partially inhibited in CAR-/-mice compared with CAR+/+ mice. On the other hand, androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR+/+ but not in CAR-/- mice. Thus, CAR activation caused CCI4 hepatotoxicity while CAR inhibition resulted in partial protection against CCl4-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl4, between CAR+/+ and CAR-/- mice. However, the expression of other CCI4-metabolizing enzymes, such as CYP2B10 and 3A11, was induced by PB in CAR+/+ but not in CAR-/1 mice. Although the main pathway of CCI4-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3A11 in the presence of activator or inhibitor. CONCLUSION: The nuclear receptor CAR modulates CCl4-induced liver injury via induction of CCI4-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drug-drug interaction even though such drugs themselves are not hepatotoxic.     

122例单采血小板输注的临床观察

目的：对122例血小板减少症患者输注1单位单采血小板效果的实验室观察。方法：按血小板输血史将患者分为3组，A组（首次输血者，41例）；B组（重复输血者，69例）；C组（频繁输血者，12例）。血小板输注1h和24h后，比较患者校正血小板计数增加值（CCI）和血小板回收率（PPR）。结果：A组、B组、C组间CCI、PPR差异有统计学意义（P〈0．05）；血小板减少症组血小板输注无效率低于血液病组。结论：单采血小板输注是临床控制出血重要方法，尤其对首次输血者及一般重复输血者（2～10次）有效，可起到更好的预防及治疗效果；频繁输血者（≥11次）输注血小板后疗效较低，可能与患者输血前血小板基数较低及频繁输血导致血小板输注无效有关，未来的研究需要收集患者临床资料以更好地把握此类患者血小板输注效果。     

虎杖提取物对神经病理性疼痛模型大鼠的镇痛作用研究

目的：研究虎杖提取物对神经病理性疼痛模型大鼠的镇痛作用,并探讨其作用机制。方法雄性SD大鼠,随机分为对照组和坐骨神经缩狭模型（chronic construction injury, CCI）组。CCI术后14 d,应用Von Frey法测定机械刺激缩足反射阈值（mechanical withdrawal threshold, MWT）,观察口服不同剂量的虎杖提取物对CCI大鼠机械性痛觉超敏的影响。并考察不同剂量虎杖提取物对CCI大鼠脊髓p-ERK、p-P38水平及小胶质细胞活化的影响。结果虎杖提取物可明显升高CCI大鼠术侧的MWT值（P〈0.05）,而对正常大鼠的MWT值没有显著影响（P〉0.05）。同时虎杖提取物可显著抑制CCI模型大鼠脊髓ERK和p38的磷酸化,并显著抑制IBA-1表达增加。结论虎杖提取物对CCI诱导的机械性痛觉超敏具有显著性的抑制作用,且镇痛作用维持时间长于吗啡,其机制可能是通过抑制脊髓水平ERK和p38的磷酸化,及通过抑制小胶质细胞活化而实现。     

Activation of extracellular signal-regulated protein kinases 5 in the spinal cord contributes to the neuropathic pain behaviors induced by CCI in rats

Abstract

Objective: To investigate whether activation and translocation of extracellular signal-regulated kinase 5 (ERK5) is involved in the induction and maintenance of neuropathic pain and observe the effects of activation and translocation of ERK5 on the expression of phosphorylated cAMP response element binding (pCREB) in the chronic neuropathic pain.

Methods: Lumbar intrathecal catheters were chronically implanted in male Sprague–Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciatica's trifurcation at ～ 1.0 mm intervals with 4-0 silk sutures. The phosphorothioate-modified antisense oligonucleotides (AS-ODNs) were intrathecally administered every 12 hours, 1 day pre-chronic constriction injury (CCI) and 3 day post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal latency to a radiant heat and von Frey filaments. Expressions of phosphorylated ERK5 (pERK5), pCREB, were assessed by both Western blotting and immunohistochemical analysis.

Results: Intrathecal injection of ERK5 AS-ODN significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CCI significantly increased the expression of pERK5 neurons in the ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. The time courses of pERK5 expression showed that the levels of both cytosol and nuclear pERK5 were increased at all points after CCI and reached a peak level on post-operative day 5. CCI significantly increased the expression of pERK5 neurons in the laminae I and II of ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. Phospho-CREB-positive neurons were distributed in all laminae of the bilateral spinal cord. Intrathecal injection AS-ODN markedly suppressed the increase of CCI-induced pERK5, pCREB expression in the spinal cord.

Conclusion: The activation of ERK5 pathways contributes to neuropathic pain in CCI rats, and the function of pERK5 may partly be accomplished via the CREB protein-dependent gene expression.     

Ileus is a predictor of local infection in patients with acute necrotizing pancreatitis

Background & objectivesInfected pancreatic necrosis (IPN) is associated with increased morbidity and mortality. Gut barrier dysfunction has been shown to increase the risk of bacterial translocation from the gut into the pancreatic bed. The primary aim of the study is to evaluate if ileus, a clinical marker of gut barrier dysfunction, can predict the development of IPN.MethodsA retrospective cohort study of patients with necrotizing pancreatitis (NP) was conducted from 2000 to 2014. Ileus was defined as ≥2 of the following criteria: nausea/vomiting; inability to tolerate a diet, absence of flatus, abdominal distension and features of ileus on imaging. Extensive necrosis was defined as >30% nonenhancing pancreatic parenchyma on contrast-enhanced CT. Multivariable cox proportional hazard analysis was used to evaluate known and potential predictors of IPN.Results142 patients were identified with NP, 61 with IPN and 81 with sterile necrosis. In comparison to a diagnosis of ileus documented in the medical chart, the ileus criteria had a sensitivity, specificity and positive and negative predictive value of 100%, 93%, 78% and 100%, respectively. On multivariate cox proportional hazard analysis, ileus [HR:2.6; 95%CI:1.4–4.9] and extensive necrosis [HR:2.8; 95%CI:1.3–5.8] were independently associated with the development of IPN while there was no association with bacteremia [HR:1.09; 95%CI:0.6–2.1].ConclusionIleus in NP can be accurately defined using surgical criteria. Ileus is independently associated with the future development of IPN. Further studies will be needed to determine if ileus can serve as a clinical marker to direct therapeutic interventions aimed at reducing the incidence of IPN.     

初探放射式冲击波治疗大鼠神经病理性疼痛模型的效果

目的:初步探讨不同强度的放射式冲击波疗法(radial shock wave therapy,RSWT)对大鼠坐骨神经慢性压迫(chronic constructive injury,CCI)模型的镇痛效果。方法 :本实验分为两部分,第一部分:单次RSWT。SD大鼠36只,随机等分为6组:假手术组(SHAM组),只暴露坐骨神经而不结扎。其余5组建立CCI模型,其中神经病理性疼痛模型组(NP组)不予治疗,另4个不同强度的RSWT组(1.0 bar、1.5 bar、2.0 bar和2.5 bar RSWT组)结扎坐骨神经后14 d,分别给与1.0 bar、1.5 bar、2.0bar或2.5 bar强度治疗。第二部分:重复RSWT。36只大鼠分组情况同第一部分,4个RSWT组自结扎后14 d分别给予重复的4个不同强度RSWT,1周1次,共4次。测量所有大鼠治疗前后机械缩足反射阈值(MWT)及热缩足反射潜伏期(TWL)变化以评价镇痛效果;测定大鼠坐骨神经功能指数并观察副作用发生情况。结果:单次RSWT后前3 d不同强度RSWT组大鼠的MWT和TWL均迅速提高。在第3 d达到峰值,显著高于NP组(P<0.01),此后逐渐降至基线。重复RSWT组大鼠治疗后MWT和TWL逐渐上升,4次治疗后维持在较高水平至少4 w,与NP组有显著性差异(P<0.01)。各组重复RSWT前后坐骨神经功能指数无显著性改变。结论:单次RSWT用于CCI模型所致神经病理性疼痛起效迅速,但维持时间短暂(5 d)。而重复RSWT对神经病理性疼痛来说是更为有效的治疗方法。     

Interleukin-6 significantly improves predictive value of systemic inflammatory response syndrome for predicting severe acute pancreatitis

Background

Predicting severe acute pancreatitis (AP) is important for triage, prognosis, and designing therapeutic trials. Persistent systemic inflammatory response syndrome (SIRS) predicts severe AP but its diagnostic accuracy is suboptimal. Our objective was to study if cytokine levels could improve the predictive value of clinical variables for the development of severe AP.

Is positron emission tomography useful in locoregional staging of esophageal cancer? Results of a multidisciplinary initiative comparing CT, positron emission tomography, and EUS

BACKGROUND: Various modalities including CT, positron emission tomography (PET), and EUS are being used for esophageal cancer staging. OBJECTIVE: We compared results of locoregional staging by CT, PET, and EUS with histologic staging. DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS AND INTERVENTIONS: Patients with esophageal cancer proven by endoscopy and biopsy underwent a CT scan of the chest and abdomen and a PET scan. Patients with no evidence of distant metastatic disease on CT and PET were referred for EUS for locoregional staging. MAIN OUTCOME MEASUREMENT: The tumor size (T) and lymph node (N) stage as determined by EUS were compared with surgical pathology or EUS-guided FNA cytology. The results of N staging with CT, PET, and EUS were compared with surgical pathology or EUS-FNA cytology. RESULTS: Between May 2005 and April 2006, 29 patients (24 men, mean age 68 years) underwent EUS. EUS was successful in 25 of 29 patients (86%). There were no EUS-related complications. Eleven of 16 patients with available lymph node histologic study had confirmed metastasis. Nodal metastasis was correctly identified by CT in 6 of 11 patients, by PET in 4 of 11 patients, and by EUS in 10 of 11 patients. Overall accuracy for N staging was 69% for CT, 56% for PET, and 81% for EUS. Fifteen patients had confirmed T staging by surgical pathologic examination. The percentage of agreement for T staging between EUS and surgical pathology was 80% (12/15 patients). LIMITATIONS: Single center, retrospective chart review. CONCLUSION: EUS is safe and accurate for tumor and node staging in esophageal cancer. The combination of CT plus EUS appears to be accurate for locoregional staging in esophageal cancer.     

Correlation of platelet crossmatch results by Solid Phase Red Cell Adherence Assay (SPRCA) with post-transfusion platelet count increment in adult hemato-oncology patients of a tertiary care oncology centre in India

AimsTo assess platelet crossmatch result by SPRCA and find its correlation with post-transfusion platelet count increment among adult hemato-oncology patients.MethodsA prospective observational pilot study of 50 adult hematologic malignancy patients previously transfused, but not already known to be transfusion-refractory and without any nonimmune causes for inadequate response to platelet transfusion were included after obtaining informed consent. They were transfused one unit of ABO identical single donor platelet. Ten minutes to 1 -h post-transfusion CCI was calculated.CCI ≥ 7500 was considered as adequate response. Post-transfusion crossmatching by SPRCA was performed by using preserved platelet samples from donor units with the serum of the respective patient. Statistical analysis of the correlation between platelet crossmatch results and CCI was done.ResultsOut of 50 crossmatches, 78% (39/50) showed compatible and 22% (11/50) showed incompatible results. Among 39 compatible results, 87.2% (34/39) showed adequate CCI and 12.8% (5/39) showed inadequate CCI. Among 11 incompatible results, 18.2% had adequate CCI and 81.8% had inadequate CCI. The difference between the response in terms of CCI to compatible and incompatible crossmatches was found to be statistically significant (p < 0.05). Other variables like age, sex, number of previous transfusions and underlying clinical condition of the patient were not found to have any effect on the compatibility of crossmatch.ConclusionsTransfusion of crossmatched platelets to non-refractory, multiply transfused hematological malignancy patients without serious illness might provide a small benefit over transfusing randomly selected platelets, though these data must be confirmed with a larger sample size.