Glibenclamide for the Treatment of Ischemic and Hemorrhagic Stroke

Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1–transient receptor potential melastatin 4 (Sur1–Trpm4) channels and, in some cases, microglial K_ATP (Sur1–Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke.     

Predicting Acute Renal Failure after Cardiac Surgery: Validation and Re‐definition of a Risk‐Stratification Algorithm

Background:  Acute renal failure (ARF) after cardiac surgery is associated with significant morbidity and mortality, irrespective of the need for dialysis. Previous studies have attempted to identify predictors of ARF and develop risk stratification algorithms. This study aims to validate the algorithm in an independent cohort of patients that includes a significant proportion of female and black patients and compares two different definitions of renal outcome.
Methods:  A large single center cardiac surgery database was examined (n, 24,660; 1993–2000) which included 29.9% females and 3.7% black patients. Post‐operative ARF was defined as: a) ARF requiring dialysis, b) > 50% reduction in creatinine clearance relative to baseline or requiring dialysis. Clinical variables related to baseline renal function and cardiovascular disease were used in recursive partitioning analysis for both outcome definitions. Chi‐square goodness of fit analysis was performed to validate the algorithm.
Results:  The frequency of post‐operative ARF requiring dialysis ranged between 0.5 and 15.5% based on the risk categories with the area under the receiver operating characteristic (ROC) curve of 0.78. Using the more inclusive definition of ARF, the frequency was significantly higher ranging from 2.6 to 25%(P < 0.001) with an area under ROC curve of 0.65.
Conclusions:  The renal risk stratification algorithm is valid in predicting post‐operative ARF in an independent cohort of patients, well represented by differences in gender and race. Since the need for dialysis remains subjective, a more objective and inclusive definition of ARF may help in identifying a larger number of patients 'at‐risk'.     

新生牛肝活性肽的制备及其毒性检测

目的制备新生牛肝活性肽并评价其安全性。方法采用膜法分离制备新生牛肝活性肽。将3批制品于37～40℃,75%相对湿度条件下存放3个月,以多肽含量为指标观察其稳定性,并进行急性毒性试验、小鼠骨髓细胞微核试验、Ames试验、小鼠精子畸形试验和大鼠喂养试验。结果制备的3批新生牛肝活性肽存放3个月后,多肽含量无明显下降,质量稳定。小鼠和大鼠经口灌人大于20.0g/kg体重的新生牛肝活性肽,均无急性毒性。3种致突变试验均未显示出致突变性,大鼠喂养试验各项指标均未见明显毒性。结论新生牛肝活性肽未表现出明显毒性。     

Interleukin 6 and Aneurysmal Subarachnoid Hemorrhage. A Narrative Review

Interleukin 6 (IL-6) is a prominent proinflammatory cytokine. Neuroinflammation in general, and IL-6 signaling in particular, appear to play a major role in the pathobiology and pathophysiology of aneurysm formation and aneurysmal subarachnoid hemorrhage (SAH). Most importantly, elevated IL-6 CSF (rather than serum) levels appear to correlate with delayed cerebral ischemia (DCI, “vasospasm”) and secondary (“vasospastic”) infarctions. IL-6 CSF levels may also reflect other forms of injury to the brain following SAH, i.e., early brain damage and septic complications of SAH and aneurysm treatment. This would explain why many researchers have found an association between IL-6 levels and patient outcomes. These findings clearly suggest CSF IL-6 as a candidate biomarker in SAH patients. However, at this point, discrepant findings in variable study settings, as well as timing and other issues, e.g., defining proper clinical endpoints (i.e., secondary clinical deterioration vs. angiographic vasospasm vs. secondary vasospastic infarct) do not allow for its routine use. It is also tempting to speculate about potential therapeutic measures targeting elevated IL-6 CSF levels and neuroinflammation in SAH patients. Corticosteroids and anti-platelet drugs are indeed used in many SAH cases (not necessarily with the intention to interfere with detrimental inflammatory signaling), however, no convincing benefit has been demonstrated yet. The lack of a robust clinical perspective against the background of a relatively large body of data linking IL-6 and neuroinflammation with the pathophysiology of SAH is somewhat disappointing. One underlying reason might be that most relevant studies only report correlative data. The specific molecular pathways behind elevated IL-6 levels in SAH patients and their various interactions still remain to be delineated. We are optimistic that future research in this field will result in a better understanding of the role of neuroinflammation in the pathophysiology of SAH, which in turn, will translate into the identification of suitable biomarkers and even potential therapeutic targets.     

α_1-抗胰蛋白酶的制备及其防治急性肺损伤的疗效

目的　以FIV 1为原料 ,制备较高纯度α1 AT制剂 ,用该制剂干预急性肺损伤动物模型作疗效考核。方法　FIV 1抽提液经PEG沉淀 ,离子交换 ,病毒灭活、超滤、除菌、分装 ,冻干制备α1 AT制剂。用急性肺损伤动物模型 ,比较静脉注射与雾化吸入α1 AT的治疗效果。结果　 3批制剂纯度 >70 % ,无菌、热原、安全试验均符合生物制品规程要求。静脉注射或雾化吸入 ,可降低由内毒素诱发急性肺损伤程度。结论　α1 AT制备工艺适合大规模生产。在防治急性肺损伤时有一定效果     

Detection of urinary biomarkers for early diagnosis of acute renal allograft rejection by proteomic analysis

Acute allograft rejection has been recognized as a major impediment to improved success in renal transplantation. Timely detection and control of rejection are very important for the improvement in long-term renal allograft survival. Thus, biomarkers for early diagnosis of acute rejection are required urgently to clinical medication. This study seeks to search for such biomarker candidates by comparing patients' pre-treatment urinary protein profiling with their post-treatment urinary protein profiling. A total of 15 significantly and consistently down-regulated protein candidates were identified. Among them, alpha-1-antichymotrypsin precursor (AACT), tumor rejection antigen gp96 (GP96) and Zn-Alpha-2-Glycoprotein (ZAG) were selected for further analysis. The results indicated that Western Blot assay of AACT, GP96 and ZAG had advanced the diagnosis time of acute renal rejection by 3 days, compared with current standard clinical observation and laboratory examination. Furthermore, the double-blind detection revealed that the accuracy, sensitivity and specificity of the diagnosis of acute renal rejection of AACT, GP96 and ZAG were 66.67%/100%/60%, 83.33%/100%/80% and 66.67%/100%/60%, respectively, and 100%/100%/100% in combination. In conclusion, urinary protein AACT, GP96 and ZAG could be a set of potential biomarkers for early non-invasive diagnosis of the acute rejection after renal transplantation.     

白蚁提取液急性毒性及致突变性研究

本文采用大,小鼠急性经口毒性试验、Ａｍｅｓ试验、小鼠骨髓细胞微核试验及小鼠精子畸变试验对白蚁提取液的毒理学安全性进行了研究,结果表明,白蚁提取液大,小鼠急性经口ＬＤ５０均大于１０ｇ／ｋｇ体重,属“实际无毒”：体内（包括体细胞和生殖细胞）、体外致突变性试验系统均未检出其致突性。     

Evaluation of the tamper-resistant properties of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets

Context: Abuse potential of extended-release (ER) opioid tablets increases if tampering causes rapid opioid release.

Objective: To evaluate the susceptibility to tampering of biphasic immediate-release (IR)/ER oxycodone (OC)/acetaminophen (APAP) tablets compared with IR OC/APAP tablets.

Materials and methods: IR/ER OC/APAP and IR OC/APAP tablets were tested at room temperature and after heating, freezing and microwaving. Resistance to crushing was tested using manual and powered tools (e.g. spoons, mortar and pestle, blender, coffee grinder). Tampered tablets were tested for suitability for snorting, OC extraction in solvents and ease of drawing into a syringe. Dissolution of IR/ER OC/APAP in gastric fluid with and without ethanol was tested to determine the potential for facilitating precipitous release of opioid from the tablet.

Results: IR/ER OC/APAP tablets were more crush resistant than IR OC/APAP tablets. Heating, freezing and microwaving had no effect on crush resistance of IR/ER OC/APAP tablets. Although a mortar and pestle pulverized IR/ER OC/APAP tablets, upon contact with solvent, the powder formed a thick gel judged unsuitable for absorption through the nasal mucosa and could not be drawn into a syringe. In contrast, powder from crushed IR OC/APAP tablets dissolved readily, was judged suitable for snorting, and was easily drawn into a syringe. Dissolution of IR/ER OC/APAP tablets in gastric fluid was slowed by the addition of ethanol.

Discussion: IR/ER OC/APAP tablets are resistant to crushing and dissolution compared with IR OC/APAP tablets.

Conclusion: IR/ER OC/APAP tablets may have less potential for abuse involving tampering compared with IR OC/APAP tablets.     

A model of cerebral cortex formation during fetal development using reaction-diffusion-convection equations with Turing space parameters

The cerebral cortex is a gray lamina formed by bodies of neurons covering the cerebral hemispheres, varying in thickness from 1.25 mm in the occipital lobe to 4 mm in the anterior lobe. The brain's surface is about 30 times greater that of the skull because of its many folds; such folds form the gyri, sulci and fissures and mark out areas having specific functions, divided into five lobes. Convolution formation may vary between individuals and is an important feature of brain formation; such patterns can be mathematically represented as Turing patterns. This article describes how a phenomenological model was developed by describing the formation pattern for the gyri occurring in the cerebral cortex by reaction diffusion equations with Turing space parameters. Numerical examples for simplified geometries of a brain were solved to study pattern formation. The finite element method was used for the numerical solution, in conjunction with the Newton–Raphson method. The numerical examples showed that the model can represent cerebral cortex fold formation and reproduce pathologies related to gyri formation, such as polymicrogyria and lissencephaly.