急性心肌梗死后的延迟冠状动脉内支架植入治疗

目的　评估急性心肌梗死后梗死相关冠状动脉内支架植入的临床疗效。方法　 15 4例急性心肌梗死患者 ,平均年龄 (6 1± 12 )岁于发病后平均 13天行冠状动脉内支架术 ,所有患者常规服用肠溶阿司匹林和噻氯匹定。观察住院期和随访期的临床事件。结果　 15 4例患者共植入 173个支架 (平均 1 1个 /例 )。支架植入的指征 :选择性初发病变 (denovo)占 2 4 3 % ,急性或濒危闭塞占13 9% ,有发生闭塞高危因素的病变占 6 1 8%。所用支架主要为Nir支架 (2 6 % )、Multi Link支架(19% )、XT支架 (13% )、Crossflex支架 (10 % ) ,等等。支架植入时最大球囊充盈压力为 (12± 2 )大气压。平均残余狭窄 (7± 8) %。住院期间无一例死亡、心肌梗死和需重复再通治疗 ,但术后“微坏死(micronecrosis)”率为 1 3%。术后 6个月病死率为 3 9% ,Q波型或非Q波型心肌梗死率为 1 9% ,支架内再狭窄而行再次冠状动脉腔内成形术率 6 1%。总的无心脏事件存活率为 89 6 %。结论　心肌梗死后行冠状动脉内支架术是安全的 ,并能改善患者的近期预后 ,但其远期疗效尚需进一步研究。     

欧洲移民抗菌耐药性的系统性综述和元分析

正全球范围内抗菌耐药性发生率正逐步上升。人们担心,欧洲移民人数的增加会加剧抗菌耐药性的形势。但是,目前尚无全面性的研究来评估移民对欧洲抗菌耐药性发生率带来的影响。2018年7月的《The Lancet. Infectious diseases》刊载了一项研究,研究者们开展了一项系统性的综述和元分析,识别并汇总了欧洲移民中抗菌耐药性的携带和感染数据,以探索不同移民群体间以及不同环境中抗菌耐药性的模式差异。为开展该系统性综述和元分析,研究者们搜索了MEDLINE、Embase、PubMed和Scopus数据库,不设语言限制,设定时间为2000年1月1日至     

Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease

Background and Purpose

Huntington''s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. We have previously demonstrated that the cell signalling of the metabotropic glutamate receptor 5 (mGluR5) is altered in a mouse model of HD. Although mGluR5-dependent protective pathways are more activated in HD neurons, intracellular Ca²⁺ release is also more pronounced, which could contribute to excitotoxicity. In the present study, we aim to investigate whether mGluR5 positive allosteric modulators (PAMs) could activate protective pathways without triggering high levels of Ca²⁺ release and be neuroprotective in HD.

Experimental Approach

We performed a neuronal cell death assay to determine which drugs are neuroprotective, Western blot and Ca²⁺ release experiments to investigate the molecular mechanisms involved in this neuroprotection, and object recognition task to determine whether the tested drugs could ameliorate HD memory deficit.

Key Results

We find that mGluR5 PAMs can protect striatal neurons from the excitotoxic neuronal cell death promoted by elevated concentrations of glutamate and NMDA. mGluR5 PAMs are capable of activating Akt without triggering increased intracellular Ca²⁺ concentration ([Ca²⁺]_i); and Akt blockage leads to loss of PAM-mediated neuroprotection. Importantly, PAMs'' potential as drugs that may be used to treat neurodegenerative diseases is highlighted by the neuroprotection exerted by mGluR5 PAMs on striatal neurons from a mouse model of HD, BACHD. Moreover, mGluR5 PAMs can activate neuroprotective pathways more robustly in BACHD mice and ameliorate HD memory deficit.

Conclusions and Implications

mGluR5 PAMs are potential drugs that may be used to treat neurodegenerative diseases, especially HD.     

The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy

Potassium channels in the plasma membrane of the pancreatic beta cells are critical in maintaining glucose homeostasis by responding to ATP and coupling metabolic changes to insulin secretion. These channels consist of subunits denoted the sulfonylurea receptor SUR1 and the inwardly rectifying ion channel KIR6.2, which are encoded by the genes ABCC8 and KCNJ11 , respectively. Activating mutations in the subunit genes can result in monogenic diabetes, whereas inactivating mutations are the most common cause of congenital hyperinsulinism of infancy (CHI). Twenty-six Norwegian probands with CHI were analyzed for alterations in ABCC8 and KCNJ11 . Fifteen probands (58%) had mutations in the ABCC8 gene. Nine patients were homozygous or compound heterozygous for the mutations, indicating diffuse pancreatic disease. In five patients, heterozygous and paternally inherited mutations were found, suggesting focal disease. One patient had a de novo mutation likely to cause a milder, dominant form of CHI. Altogether, 16 different ABCC8 mutations (including the novel alterations W231R, C267X, IVS6-3C>G, I462V, Q917X and T1531A) were identified. The mutations IVS10+1G>T, R1493W and V21D occurred in five, three and two families, respectively. KCNJ11 mutations were not found in any patients. Based on our mutation screening, we estimate the minimum birth prevalence of ABCC8 -CHI in Norway to 1:70,000 during the past decade. Our results considerably extend the knowledge of the molecular genetics behind CHI in Scandinavia.     

Second‐line treatment in the Malawi antiretroviral programme: high early mortality,but good outcomes in survivors,despite extensive drug resistance at baseline*

Objectives

The Malawi antiretroviral therapy (ART) programme uses the public health approach to identify ART failure. Advanced disease progression may occur before switching to second‐line ART. We report outcomes for patients evaluated and initiated on second‐line treatment in Malawi.

Methods

Patients meeting Malawi immunological or clinical criteria for ART failure in two large urban ART clinics were evaluated for virological failure (viral load >400 HIV‐1 RNA copies/mL) and, if failure was confirmed, initiated on second‐line ART (zidovudine/lamivudine/tenofovir/lopinavir/ritonavir). Patients were seen monthly and laboratory evaluations were performed quarterly and as needed. We performed logistic regression modelling to identify factors associated with mortality, mortality or new HIV illnesses, and virological suppression at 12 months.

Results

Of the 109 patients with confirmed virological failure, five patients died prior to initiation, three declined switching and 101 patients initiated second‐line treatment. Over 12 months, 10 additional patients died, 34 patients experienced 45 HIV‐related events, and 19 patients experienced grade 3 or 4 toxicities. Among survivors, 85.2% had HIV‐1 RNA<400 copies/mL at 12 months. While power to distinguish differences was limited, response rates were similar regardless of baseline resistance level. The median CD4 count increase was 142 cells/μL. World Health Organization clinical failure at baseline [odds ratio (OR) 3.47; 95% confidence interval (CI) 1.14–10.59] and body mass index <18.5 (OR 4.43; 95% CI 1.15–17.12) were risk factors for death. Baseline CD4 count <50 cells/μL was associated with increased risk for death or morbidity at 12 months (OR 2.57; 95% CI 1.01–6.52).

Conclusions

Second‐line treatment in Malawi was associated with substantial mortality, morbidity and toxicity but, among survivors, virological outcomes were favourable.     

Plasma concentrations of individual tea catechins after a single oral dose in humans

1. Ten healthy volunteers ingested 1.5 mmole epicatechin gallate (ECg), epigallocatechin (EGC) or epigallocatechin gallate (EGCg) in a randomized crossover design. After deconjugation, catechins in plasma and 24-h urine samples were determined by high-performance liquid chromatography (HPLC). Antioxidant activity was measured in plasma by determining ferric reducing activity (FRAP). 2. The catechin levels in plasma after ingestion were significantly different: EGC rose quickly with a short elimination half-life (t 1/2 elim = 1.7?h), ECg was intermediate in rise but slowest in decline (t 1/2 elim = 6.9h), EGCg was slowest in rise but intermediate in decline (t 1/2 elim = 3.9?h). At 24?h, EGC and EGCg had returned to base levels, but ECg was still elevated. Peak maximum varied between 1.3 (EGCg) and 5.0 µmol?l -1 (EGC). 3. Very limited interconversion (ECg → epicatechin, EGCg → EGC) occurred indicating that degallation is not required for uptake. 4. Up to 13.6% of the ingested EGC (partly methylated) was excreted in the urine, but ECg or EGCg were not detected. 5. EGC and ECg produced an increase in antioxidant activity in plasma, but with EGCg, no statistically significant effect was found. 6. The pattern of uric acid in plasma showed a clear resemblance with that of FRAP and linear regression analysis indicated a very significant relationship (R 2 = 0.88, p < 0.0001). 7. It is concluded that tea catechins differ significantly in their pharmacokinetic behaviour.     

Evaluation of surveillance case definition in the diagnosis of leptospirosis, using the Microscopic Agglutination Test: a validation study

Background  

Leptospirosis is endemic in both urban and rural areas of Sri Lanka and there had been many out breaks in the recent past. This study was aimed at validating the leptospirosis surveillance case definition, using the Microscopic Agglutination Test (MAT).     

Regional differences in the vasorelaxant effects of nicorandil and amlodipine on isolated porcine coronary arteries

Summary— The vasorelaxant effects of nicorandil, a K⁺-channel opener, and amlodipine, a dihydropyridine-type Ca²⁺-channel blocker, were investigated on partially and maximally K⁺-depolarized ring preparations from the porcine left anterior descending coronary artery. By comparing vascular responses in the proximal and distal parts of the epicardial segment, the scope of the study was to evaluate regional differences in the action of nicorandil and amlodipine. Nicorandil (10 ⁷- 10^-4 M) shifted the K⁺ concentration-response curves to the right and depressed the maximal contractile responses in a concentration-dependent manner, consistent with K⁺-channel opening and secondary non-K⁺-channel opening mechanisms of action. Nicorandil had a significantly more potent relaxant effect in the proximal compared to the distal arterial rings contracted with 85 mM K⁺. Pretreatment with methylene blue (10^-5 M) did not significantly influence the regional difference in the action of nicorandil. Amlodipine (10⁹- 10^-6 M) had a significantly more potent and effective inhibitory and relaxant effect than nicorandil under the same conditions. In contrast to nicorandil, the effect of amlodipine was more prominent in the distal compared to the proximal vessel rings. The cumulative addition of extracellular Ca²⁺ exhibited a more potent contractile response in the distal rather than in the proximal rings. Nicorandil totally and amlodipine partly eliminated the contractile responses to the lowest concentration of Ca²⁺. The inhibitory effect of amlodipine on the contractile responses to higher Ca²⁺ concentrations was more pronounced than that of nicorandil. The results show that there are regional differences in the responsiveness of porcine coronary arteries to Ca²⁺, nicorandil and amlodipine. Our findings indicate that the regional difference in nicorandil-induced vasodilation was caused neither by the K⁺-channel opening nor by the nitrate-like mechanism of action, but could be due to a direct Ca²⁺-influx blocking effect of the drug.     

哌拉西林钠／舒巴坦钠（2：1）体内抗菌活性研究

目的：评价哌拉西林钠／舒巴坦钠（2：1）的体内抗菌活性。方法：用产酶的金黄色葡萄球菌，大肠埃希菌、肺炎克雷伯菌及铜绿假单胞菌建立感染动物模型，用哌拉西林钠／舒巴坦钠（2：1）及单用派拉西林钠，舒巴坦钠及对照药阿莫西林钠／舒巴坦钠（2：1）通过静脉注射，皮下注射进行感染动物的治疗，评价对感染小鼠的保护作用。结果：舒巴坦钠对感染小鼠的抗菌保护作用极弱，ED50均＞400mg/kg，哌拉西林钠静脉注射单用对四种菌感染动物的ED50分别为55．7mg/kg,6.54mg/kg,24.09mg/kg与11．07mg/kg，哌拉西林钠／舒巴坦钠（2：1）者为27．96mg/kg，2.49mg/kg,6.75mg/kg与6.36mg/kg，分别比哌拉西林钠强2，2．5，3．6与1．8倍，哌拉西林钠皮下注射单用对四种菌感染动物的ED50分别为哌拉西林钠，哌拉西林钠／舒巴坦钠（2：1）皮下注射对四种产酶菌感染小鼠的保护作用弱于静脉注射者，ED50分别为51．95mg/kg,4.41mg/kg,8.19mg/kg,10.58mg/kg，但仍比哌拉西林钠强1．2，2，3．6与1．5倍。结论：无论静脉注射或皮下注射，哌拉西林钠／舒巴坦钠（2：1）对上述四种产酶菌株感染小鼠的体内抗菌活性（DE50）均明显优于哌拉西林钠，舒巴坦钠单用，也强于阿莫西林／舒巴坦钠（2：1）。静脉注射是临床应用较恰当的给药途径。     

Treatment of Diamond-Blackfan anemia with recombinant human interleukin- 3 [see comments]

This report describes the response of eighteen Diamond-Blackfan anemia (DBA) patients to recombinant human interleukin-3 (rhIL-3). rhIL-3 was administered subcutaneously once daily on an escalating dose schedule (0.5 to 10 micrograms/kg/d). The rhIL-3 dose was escalated every 21 days until erythroid response was attained, grade III or IV nonhematologic toxicity was observed, or the maximum rhIL-3 dose was reached. Four patients experienced clinically significant erythroid responses. Two of the responders were steroid-dependent and transfusion- independent, while two were steroid-independent and transfusion- dependent. Baseline clinical or laboratory parameters, in particular in vitro bone marrow erythroid progenitor assays, were not useful in predicting rhIL-3 response. rhIL-3 administered at 5 to 10 micrograms/kg/d was associated with an increase in total white blood cell count, secondary to increases in neutrophils, eosinophils, and lymphocytes. Patients experienced a dose-dependent elevation in absolute eosinophils across the entire dose range. Two of the responding patients remain on maintenance rhIL-3, without diminution of effect at 244 and 370 + days. rhIL-3 was discontinued in the other two responders, because of the development of deep venous thrombi.