New recommendations from the 1999 American College of Cardiology/American Heart Association acute myocardial infarction guidelines

OBJECTIVE: To review literature relating to significant changes in drug therapy recommendations in the 1999 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treating patients with acute myocardial infarction (AMI). DATA SOURCES: 1999 ACC/AHA AMI guidelines, English-language clinical trials, reviews, and editorials researching the role of drug therapy and primary angioplasty for AMI that were referenced in the guidelines were included. Additional data published in 2000 or unpublished were also included if relevant to interpretation of the guidelines. STUDY SELECTION: The articles selected influence AMI treatment recommendations. DATA SYNTHESIS: Many clinicians and health systems use the ACC/AHA AMI guidelines to develop treatment plans for AMI patients. This review highlights important changes in AMI drug therapy recommendations by reviewing the results of recent clinical trials. Insights into evolving drug therapy strategies that may impact future guideline development are also described. CONCLUSIONS: Several changes in drug therapy recommendations were included in the 1999 AMI ACC/AHA guidelines. There is emphasis on administering fibrin-specific thrombolytics secondary to enhanced efficacy. Selection between fibrin-specific agents is unclear at this time. Low response rates to thrombolytics have been noted in the elderly, women, patients with heart failure, and those showing left bundle-branch block on the electrocardiogram. These patient groups should be targeted for improved utilization programs. The use of glycoprotein (GP) IIb/IIIa receptor inhibitors in non-ST-segment elevation MI was emphasized. Small trials combining reduced doses of thrombolytics with GP IIb/IIIa receptor inhibitors have shown promise by increasing reperfusion rates without increasing bleeding risk, but firm conclusions cannot be made until the results of larger trials are known. Primary percutaneous coronary intervention (PCI) trials suggest lower mortality rates for primary PCI when compared with thrombolysis alone. However, primary PCI, including coronary angioplasty, is only available at approximately 13% of US hospitals, making thrombolysis the preferred strategy for most patients. Clopidogrel has supplanted ticlopidine as the recommended antiplatelet agent for patients with aspirin allergy or intolerance following reports of a better safety profile. The recommended dose of unfractionated heparin is lower than previously recommended, necessitating a separate nomogram for patients with acute coronary syndromes. Routine use of warfarin, either alone or in combination with aspirin, is not supported by clinical trials; however, warfarin remains a choice for antithrombotic therapy in patients intolerant to aspirin. Beta-adrenergic receptor blockers continue to be recommended, and emphasis is placed on improving rates of early administration (during hospitalization), even in patients with moderate left ventricular dysfunction. New recommendations for drug treatment of post-AMI patients with low high-density lipoprotein cholesterol and/or elevated triglycerides are included, with either niacin or gemfibrozil recommended as an option. Supplementary antioxidants are not recommended for either primary or secondary prevention of AMI, with new data demonstrating lack of efficacy vitamin E in primary prevention. Estrogen replacement therapy or hormonal replacement therapy should not be initiated solely for prevention of cardiovascular disease, but can be continued in cardiovascular patients already taking long-term therapy for other reasons. Bupropion has been added as a new treatment option for smoking cessation. As drug therapy continues to evolve in treating AMI, more frequent updates of therapy guidelines will be necessary.     

Mutation of ataxia–telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia

Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia–telangiectasia (A–T), a disease caused by mutations in the ataxia–telangiectasia mutated (ATM) gene. A hallmark of A–T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A–T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione‐S‐transferase. We also found decreased levels of intercellular and secreted GSH in A–T astroglia. Metabolic labeling of l ‐cystine, the major precursor for GSH, revealed that a key component of the defect in A–T astroglia is an impaired ability to import this rate‐limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT‐dependent import of l ‐cystine through addition of N‐acetyl‐l ‐cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A–T mutant astroglia providing a possible future avenue for targeted therapeutic intervention. GLIA 2016;64:227–239     

Direct identification of Yersinia enterocolitica in blood by polymerase chain reaction amplification

Primers based on the nucleotide sequence of the virF gene in the pYV plasmid and the chromosomal ail gene were used in polymerase chain reaction (PCR) amplifications to directly identify Yersinia enterocolitica in blood. Approximately 500 bacteria seeded into 100 microL of blood can be extracted and amplified by PCR to yield positive results. PCR analyses of seven Y. enterocolitica isolates previously implicated in blood contaminations showed that only one isolate harbored the plasmid-borne virF gene; however, all seven isolates were identified effectively by the PCR product amplified from the chromosomal gene. The PCR assay has the potential for use in the identification of Y. enterocolitica contamination in stored units of blood or in the rapid diagnosis of transfusion-related bacteremia caused by Y.     

Response to cardiac resynchronization therapy predicts survival in heart failure: a single-center experience

Objective: To determine whether survival after cardiac resynchronization therapy (CRT) is related to improvement in clinical or echocardiographic parameters.
Background: In clinical trials, CRT improved symptoms, left ventricular (LV) structure, function, and survival. In clinical practice, response to CRT is highly variable and whether survival benefit is confined to those patients who experience improvement in clinical status or cardiac structure and function is unclear.
Methods: This is a single-center study of patients receiving clinically indicated CRT between January 2002 and December 2004.
Results: Of 309 patients (age 68 ± 11 years, 83% male) receiving CRT at our institution during the study period, 174 returned for follow-up and 127 had repeat echocardiography. Baseline clinical characteristics and survival were similar among those who did or did not return for follow-up. In paired analyses, New York Heart Association (NYHA) class (−0.56 ± 0.07, p < 0.0001), ejection fraction (EF, 6.3 ± 0.7%, P < 0.0001), LV dimension (−2.7 ± 0.6 mm, P < 0.0001), pulmonary artery systolic pressure (PASP, −4.6 ± 1.3 mm Hg, P = 0.0007), and MR severity grade (−0.20 ± 0.05, P = 0.0002) improved after CRT. Survival after CRT was associated with decrease in NYHA class (risk ratio [RR]= 0.43, P = 0.0004), increase in EF (RR = 0.94, P = 0.02), and decrease in PASP (RR = 0.96, P = 0.03). Change in EF and NYHA class were correlated (r =−0.46, P < 0.0001) and, adjusting for this covariance, change in NYHA (P = 0.04) but not EF (P = 0.12) was associated with improved survival.
Conclusion: Patients who experience improved symptoms, ventricular function, and/or hemodynamics have better survival after CRT. These data enhance understanding of the relationship between CRT clinical response and survival benefit in clinical practice.     

Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors

As discussed in Part I of this review, the geographic distribution of multiple sclerosis (MS) and the change in risk among migrants provide compelling evidence for the existence of strong environmental determinants of MS, where "environmental" is broadly defined to include differences in diet and other behaviors. As we did for infections, we focus here primarily on those factors that may contribute to explain the geographic variations in MS prevalence and the change in risk among migrants. Among these, sunlight exposure emerges as being the most likely candidate. Because the effects of sun exposure may be mediated by vitamin D, we also examine the evidence linking vitamin D intake or status to MS risk. Furthermore, we review the evidence on cigarette smoking, which cannot explain the geographic variations in MS risk, but may contribute to the recently reported increases in the female/male ratio in MS incidence. Other proposed risk factors for MS are mentioned only briefly; although we recognize that some of these might be genuine, evidence is usually sparse and unpersuasive.     

Antihypertensive efficacy of the oral direct renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy

This study investigated the addition of the direct renin inhibitor aliskiren to amlodipine in patients with mild to moderate hypertension that was inadequately controlled with amlodipine alone. Following once-daily treatment with amlodipine 5 mg for 4 weeks, patients whose hypertension responded inadequately to therapy (mean sitting diastolic blood pressure [DBP] 90-109 mm Hg) (n=545) were randomized to 6 weeks of double-blind treatment with amlodipine 5 mg plus aliskiren 150 mg, amlodipine 5 mg, or amlodipine 10 mg. At the study's end, mean systolic blood pressure and DBP reductions with the combination of aliskiren 150 mg and amlodipine 5 mg (11.0/8.5 mm Hg) were significantly greater (P<.0001) than with amlodipine 5 mg (5.0/4.8 mm Hg)--the comparator group--but similar to amlodipine 10 mg (9.6/8.0 mm Hg). All treatments were well tolerated. Edema occurred more frequently with amlodipine 10 mg (11.2%) than with combination therapy (2.1%) or amlodipine 5 mg (3.4%). In conclusion, aliskiren 150 mg plus amlodipine 5 mg shows similar but not better blood pressure-lowering efficacy when compared with amlodipine 10 mg in patients not completely responsive to amlodipine 5 mg; less edema was noted with combination therapy.     

2,3-吲哚醌在大鼠体内的药代动力学研究

目的考察单次静脉注射和口服给予大鼠2,3-吲哚醌后的药代动力学,为该药的新药开发提供依据。方法大鼠给药后经眼眶静脉采大约0.25 ml血液,采集时间点为：给予受试物前（0hr）和给予受试物后5 min,15min,30 min,1 h,2 h,4 h,6 h,8 h和24 h。血液样本采集后置于冰上,并立即取出50μl全血采用甲醇蛋白沉淀进行预处理,奎硫平作为内标。预处理后样品采用LC/MS/MS法进行测定,并用药动学处理软件WinNonlin 5.2采用非房室模型计算相关药代动力学参数。结果 Sprague Dawley大鼠静脉注射和口服两种制剂的药动学参数（平均值±标准偏差）如下。静脉注射：Tmax为0.83±0.29 hr,Cmax为141.53±10.99μg/L,T1/2为1.68±0.84 hr,AUC0-t为1068.15±389.06μg.hr/L,AUC0-∞为1211.19±469.18μg.hr/L,Vz为4.13±1.41 L/kg,CLz为1.89±0.94 L/hr/kg;口服：Tmax为0.05±0.00 hr,Cmax为1725.53±469.70 ng/ml,t 1/2为4.21±2.78 hr,AUC0-t为7711.21±2533.12μg.hr/L,AUC0-∞为7986.07±2623.38μg.hr/L,以AUC0-t计算,生物利用度平均为57.75±18.97%。结论 2,3-吲哚醌大鼠体内消除较快,可能存在非线性消除,口服吸收较好。     

X‐linked markers in the Duchenne muscular dystrophy gene associated with oral clefts

As part of an international consortium, case–parent trios were collected for a genome‐wide association study of isolated, non‐syndromic oral clefts, including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP). Non‐syndromic oral clefts have a complex and heterogeneous etiology. Risk is influenced by genes and environmental factors, and differs markedly by gender. Family‐based association tests (FBAT) were used on 14,486 single nucleotide polymorphisms (SNPs) spanning the X chromosome, stratified by type of cleft and racial group. Significant results, even after multiple‐comparisons correction, were obtained for the Duchenne muscular dystrophy (DMD) gene, the largest single gene in the human genome, among CL/P (i.e. both CL and CLP combined) trios. When stratified into groups of European and Asian ancestry, stronger signals were obtained for Asian subjects. Although conventional sliding‐window haplotype analysis showed no increase in significance, selected combinations of the 25 most significant SNPs in the DMD gene identified four SNPs together that attained genome‐wide significance among Asian CL/P trios, raising the possibility of interaction between distant SNPs within the DMD gene.     

老年性痴呆与血管性痴呆患者睡眠障碍的对照研究

目的:研究老年性痴呆(AD)和血管性痴呆(VD)患者睡眠障碍的特点及相关性。方法:对31例AD患者和30例VD患者采用阿森斯(Athens)失眠量表调查评分及临床资料比较分析。对研究对象进行筛选分组。从8个方面详细记录睡眠情况,按量表现规定进行评定。结果:AD患者和VD患者总体睡眠状况比较有显著性差异(t=2.251,P<0.05)。睡眠状况各因子比较,在总睡眠质量、白天情绪、白天思睡等3个方面无显著性差异(P>0.05)。在早醒、白天身体功能方面,两者有极显著差异(P<0.01)。在入睡时间、夜间苏醒、总睡眠时间等两者存在显著性差异(P<0.05)。结论:AD患者和VD患者都有睡眠障碍,AD患者在早醒、白天身体功能、夜间苏醒、总睡眠时间等方面都比VD患者差,而VD患者在入睡时间上比AD患者明显延迟。