A comparative survey of chemistry-driven in silico methods to identify hazardous substances under REACH

This paper presents an inventory of in silico screening tools to identify substance properties of concern under the European chemicals’ legislation REACH. The objective is to support the selection and implementation of appropriate tools as building blocks within integrated testing strategies (ITS). The relevant concerns addressed are persistence, bioaccumulation potential, acute and long-term aquatic toxicity, PBT/vPvB properties ((very) persistent, (very) bioaccumulative, toxic), CMR (carcinogenicity, mutagenicity, reproductive toxicity), endocrine disruption and skin sensitisation. The inventory offers a comparative evaluation of methods with respect to the underlying algorithms (how does the method work?) and the applicability domains (when does the method work?) as well as their limitations (when does the method not work?). The inventory explicitly addresses the reliability of predictions of different in silico models for diverse chemicals by applicability domain considerations. The confidence in predictions can be greatly improved by consensus modelling that allows for taking conflicting results into account. The inventory is complemented by a brief discussion of socio-economic tools for assessing the potential efficiency gains of using in silico methods compared to traditional in vivo testing of chemical hazards.     

Effects of trazodone on serotonin in the brain and platelets of the rat.

Trazodone. a novel antidepressant with a structure different from the tricyclic compounds. inhibits the release of brain 5-HT induced by fenfluramine and blocks the uptake of 5-HT by rat platelets. Two known metabolites of trazodone. oxatriazolepyridin propionic acid and trazodone-N-oxide. do not share the properties of trazodone. A suggested hut unproven metabolite of trazodone. m-chlorophenyl piperazine. is however more active than trazodone as an inhibitor of 5-HT uptake. Trazodone and its derivatives are devoid of activity as releasers of 5-HT from rat platelets.     

阿司匹林作为心血管事件的初级预防：随机对照试验的性别特异性荟萃分析

背景:阿司匹林治疗可以降低心血管疾病高危成人患者的发病风险。然而,女性是否与男性一样从该治疗中受益尚不清楚。目的:确定阿司匹林在心血管疾病初级预防中的利益和风险是否因性别不同而变化。数据源和研究选择:M EDLINE和Cochrane中心对照试验数据库(1966年至2005年3月)、检     

Stroke in two young siblings with congenital dysfibrinogenemia

Two young siblings (a male of 21 and his sister of 26 years) suffered from arterial thrombosis episodes of the carotid and abdominal aorta documented by angiographic studies. In the absence of any known predisposing factor in the family and personal history, the laboratory investigation of both patients revealed coagulation abnormalities compatible with a dysfibrinogenemia. The occurrence of a similar defect also in plasma of one of the propositi's asymptomatic relatives is suggestive of an inherited fibrinogen disorder This work was supported by the Italian National Research Council (Clinical Pharmacology and Rare Diseases) and by a grant of the Mario Negri Foundation, New York, N.Y., USA.     

Hyperglycemia during acute coronary syndrome: A nurse-managed insulin infusion protocol for stricter and safer control

Background

Diabetic patients with acute coronary syndromes (ACS) might benefit from tight glycemic control by means of insulin infusion. Nurse-implemented insulin infusion protocols (IIP) are available but none validated in patients with ACS admitted to a coronary care unit (CCU).

Aims

To assess feasibility, effectiveness and safety of a new nurse-managed IIP (Desio Diabetes Diagram, DDD) for intensive glucose control in patients with suspected ACS and known diabetes or blood glucose (BG) > 200 mg/dL.

Methods and results

To reach and maintain a target BG level of 100-139 mg/dL we adopted a nomogram based on the percent changes in the insulin infusion rate according to the current BG value and the percent change from previous BG level.Ninety-one consecutive patients (53 men, mean age 69.7 ± 11.2 years) were treated with DDD IIP. Baseline BG was 202.2 ± 86.8 mg/dL. The median time to achieve the target was 3 h (Q1-Q3 2-5 h). Afterwards target BG levels were maintained for 70.4 ± 15.9% of the time. During 5004 h of insulin infusion BG never fell below 40 mg/dL.

Conclusions

The nurse-managed DDD IIP was easily implemented in our CCU and permitted strict and safe glycemic control in hyperglycemic patients with ACS.     

Early coronary reperfusion blunts the procoagulant response of plasminogen activator inhibitor-1 and von Willebrand factor in acute myocardial infarction

The effects of early coronary recanalization on the plasma levels of two procoagulant acute phase proteins, the fastacting plasminogen activator inhibitor and von Willebrand factor, were investigated in 24 patients with myocardial infarction receiving intravenous recombinant tissue-type plasminogen activator (rt-PA) within 6 h of the onset of symptoms. Coronary angiography was performed before and 90 min after the start of rt-PA infusion. Continuous electrocardiographic recordings and 4 h plasma creatine kinase MB isoenzyme (CK MB) were performed over the first 24 h. Plasma plasminogen activator inhibitor activity, von Willebrand factor and C-reactive protein were measured before rt-PA infusion, daily for the first 3 days and after 90 days. In the entire group, plasminogen activator inhibitor activity peaked at 24 h (day 1), representing a significant increase over values at all other times (p = 0.03). von Willebrand factor was higher in the first 2 days of infarction compared with after 90 days (p = 0.001). C-reactive protein peaked on day 2, with an eightfold increase over values on admission (p = 0.001). In the 16 patients with a patent infarct-related artery at 90 min, infarct size estimated by integrated 24 h CK MB, time for ST segment elevation to decrease to half-maximum and peak C-reactive protein were reduced significantly by more than twofold compared with values in the 8 patients with an occluded artery at 90 min. The patients with early recanalization also had lower plasminogen activator inhibitor activity on day 2 (p = 0.05) and day 3 (p = 0.02) and lower 0 to 72 h averaged von Willebrand factor (p = 0.01). Thus, early coronary recanalization curtails the response of plasminogen activator inhibitor activity and von Willebrand factor to myocardial infarction, most likely by reducing the extent of ischemia and necrosis and the consequent acute phase reaction. By blunting the early postinfarction procoagulant state, prompt recanalization may reduce the risk of thromboembolic complications in the first days after myocardial infarction.