Survival of AA and ANA rats during lifelong ethanol exposure

BACKGROUND: Study of the long-term effects of chronic alcohol consumption in human populations is confounded by genetic and environmental factors. METHODS: The study was intended to investigate the effects on morbidity and survival of lifetime forced ethanol consumption in male and female AA (Alko, Alcohol) and ANA (Alko, Non-Alcohol) rats. The ethanol-exposed rats had 12% ethanol as the only available fluid from 3 to 24 months of age. The control groups had water. Rats that died during the experiment and those that were killed at 24 months of age were all autopsied, and the pathologic findings were recorded. RESULTS: Lifelong ethanol consumption did not change the survival rate of the rats, and had no significant effect on the rates of any of the pathologic measures in either the AA or ANA line of rats, suggesting that this may not be a good animal model for studying the detrimental effects of chronic alcohol. An unexpected, highly significant finding was observed: the AA rats, bred for high voluntary ethanol drinking, lived much longer than the ANA rats, bred for ethanol avoidance. The death rate by 24 months in the AA line was less than one-third of that in the ANA line. This difference was found regardless of whether the animals were maintained on alcohol or water, and in both genders. The AA rats had significantly lower rates of kidney disease, benign tumors, and cardiovascular disease than the ANA animals. CONCLUSIONS: Lifelong ethanol consumption increased neither the mortality nor the morbidity of AA and ANA line of rats. Genes selected in the development of the high drinking AA line have additional effects producing rats that are healthier and living longer than the ANA rats possessing genes resulting in alcohol avoidance.     

抗核抗体检测的临床价值评估

目的:初步评估抗核抗体(ANA)检测的临床价值。方法:回顾分析872例ANA检测患者资料,作统计学分析。结果:皮肤病变、关节症状、肾脏病变3类临床征象组ANA阳性率明显高于其他临床征象组,ANA检测有较高的灵敏度(P<0.05);ANA检测对皮肤病变、肾脏病变2类临床征象组有较高特异性,明显高于其他组(阴阳性组百分率u检验,P<0.05)。ANA检测时对SLE和其他风湿性疾病的灵敏度、特异性、阳性率分别为94.5%、66.7%、15.3%和63.7%、52.6%、11.4%。其总体阳性率较低,仅为26.7%。结论:就临床征象而言,ANA检测对于皮肤病变、关节症状、肾脏病变具有较高的灵敏度,对皮肤病变、肾脏病变具有较高的特异性,但对除此之外的其他征象(如发热等)灵敏度和特异性较差。就疾病而言,ANA检查对SLE和其他风湿性疾病特异性较高,而仅对SLE有较高的灵敏度。ANA检测的阳性检出率强烈地依赖于受检对象的选择,而且具有一定的假阳性率,不宜作为普通人群的风湿性疾病筛选检查。     

Differential development of behavioral tolerance and the subsequent hedonic effects of alcohol in AA and ANA rats

RATIONALE: There at least two ways in which tolerance development to alcohol's behavioral effects could interact with its subsequent intake: 1) tolerance to alcohol's reward or reinforcing effects per se could lead to increased consumption, and 2) tolerance to alcohol's aversive effects could unmask alcohol's rewarding effects. These two mechanisms may differentially interact with preexisting genetic traits underlying alcoholism. OBJECTIVES: Alcohol's subjective attributes were assessed in selectively bred AA and ANA rats after the development of tolerance to alcohol's behaviorally disruptive effects on lever-press performance. METHODS: Rats were trained to press a lever under an FR30 schedule of food presentations. Group-dependent differential access to intoxicated practice, using a typical pre-post drug administration design, was utilized to promote the development of alcohol tolerance in only the group receiving intoxicated practice sessions. Subsequently, rats were trained to associate alcohol with unique place and taste stimuli in order to assess the relative changes in the approach towards, or avoidance of alcohol-related cues in each group. RESULTS: Groups of AA and ANA rats given access to intoxicated practice demonstrated tolerance development. These groups subsequently conditioned place preferences and failed to develop conditioned taste aversions to alcohol. Passive alcohol exposure in the ANA rats set the occasion for the development of a place preference and delayed taste conditioning. AA rats exposed to passive alcohol exposure failed to condition place preferences and developed rapid taste aversions. Saline control rats failed to develop tolerance or place preferences but did condition a robust alcohol-induced taste aversion. CONCLUSIONS: AA and ANA rats differ in their behavioral and pharmacokinetic response to chronic alcohol exposure. Compensatory responses interacting with approach-avoidance behaviors appear to be learned during intoxicated practice in the AA rats and during both intoxicated practice and passive exposure in the ANA rat line.     

Toxic oxygen products alter calcium homeostasis in an asthma model

After anaphylactic or synthetic leukotriene C4 contractions in guinea pig trachealis muscle, an accelerated initial rate and greater total myorelaxation are induced in these muscle preparations when they are immersed in calcium-free medium, O(Ca++)E. Inhibition of the late phase of anaphylaxis (ANA) by FPL 55712 (10(-5) mol/L) eliminated the post-ANA O(Ca++)E-augmented myorelaxation, suggesting a causal role for SRS-A products. Hypoxia or superoxide dismutase/catalase pretreatment also abolished the post-ANA or leukotriene C4 O(Ca++)E-augmented myorelaxation. The data support the hypothesis that toxic oxygen products generated with SRS-A and/or LTC4 induce an alteration in Ca++ homeostasis in airway smooth muscle. In this model of allergic asthma, airway smooth muscle alteration after ANA may contribute to the pathogenesis of asthma and/or airway hypersensitivity associated with allergic asthma.     

Thrombotic Complications Associated With Early and Late Nonadherence to Dual Antiplatelet Therapy

ObjectivesThis study sought to assess the frequency and clinical impact of dual antiplatelet therapy (DAPT) nonadherence.BackgroundThere are limited data on the impact of DAPT nonadherence during the first year after a second-generation drug-eluting stent placement.MethodsAfter successful Endeavor zotarolimus-eluting stent implantation, 2,265 patients were enrolled in a registry with limited exclusions and monitored during 12 months of prescribed DAPT. Predictors of any nonadherence (ANA) at 6 months were analyzed by multivariable analysis, and the association between ANA at 6 or 12 months with the endpoints of death, myocardial infarction, and stent thrombosis was assessed.ResultsThe study population included 30% female patients, 34% with diabetes and 36% with acute coronary syndromes. ANA occurred in 208 patients (9.6%) before 6 months and 378 patients (18.5%) before 1 year. Major bleeding (odds ratio [OR]: 12.83, 95% confidence interval [CI]: 7.55 to 21.80, p < 0.001) was the only predictor of ANA at 6 months. In time-dependent analyses, ANA before 6 months was associated with an increased risk of death or myocardial infarction (7.6% vs. 3.0%, p < 0.001) and a numerical increase in stent thrombosis (2.0% vs. 0.9%, p = 0.12). After adjustment for baseline differences, ANA within 6 months remained associated with death or MI (OR: 1.95, 95% CI: 1.02 to 3.75). ANA occurring after 6 months did not increase the risk of subsequent ischemic events.ConclusionsDAPT ANA occurs frequently and is associated with increased risk for thrombotic complications if it occurs within the first 6 months. Major bleeding was a significant correlate of DAPT ANA within 6 months. (EDUCATE: The MEDTRONIC Endeavor Drug Eluting Stenting: Understanding Care, Antiplatelet Agents and Thrombotic Events; NCT01069003)     

Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis

BACKGROUND & AIMS: The mechanism for development of primary biliary cirrhosis (PBC) remains enigmatic, but molecular mimicry has been implicated because of well-known cross-reactivity of human mitochondrial autoantigens and equivalent bacterial antigens. Virtually all patients with PBC have antimitochondrial autoantibodies (AMA), but, interestingly, approximately 50% also manifest antinuclear antibodies (ANA). METHODS: To determine whether generation of ANA are due to molecular mimicry of mitochondrial peptides, we established 6 T-cell clones selected by a peptide corresponding to the E2 subunit of mitochondrial pyruvate dehydrogenase complex and analyzed for reactivity to mimicry peptides derived from mitochondrial and nuclear autoantigens, including control sequences. RESULTS: For mitochondrial autoantigens, 1 peptide from the E2 subunit of the pyruvate dehydrogenase complex, 1 peptide from the E2 subunit of the oxo-glutarate dehydrogenase complex, 1 peptide from the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, and 1 peptide from the E3-binding protein cross-reacted with these T-cell clones. For the nuclear autoantigens, 5 peptides from gp210 and 1 from Sp100 cross-reacted with these clones. Furthermore, 1 of 3 T-cell clones selected by recombinant gp210 protein reacted with a mimicry peptide corresponding to amino acids 188-201 of gp210, indicating that this part of the protein is a naturally processed immunodominant T-cell epitope. CONCLUSIONS: These results demonstrate molecular mimicry between mitochondrial and nuclear autoantigens in PBC and that a mimicry peptide may become an immunodominant T-cell epitope. These data have significance not only for PBC but also for the production of ANA in other disease processes.     

5971例抗核抗体阴性病例的抗核抗体谱分析

目的探讨抗核抗体（Antinuclear antibody,ANA）与ANA谱联合检测对自身免疫性疾病的诊断价值。方法对5971例ANA阴性的标本进行ANA谱检测。ANA检测采用欧蒙间接免疫荧光法,ANA谱检测采用欧蒙免疫印迹法。结果在5971例ANA阴性样本中,ANA谱阳性的标本为422例,占7.07%。其中抗SSA抗体、抗SSB抗体、抗Scl-70抗体、抗PM-Scl抗体、抗JO-1抗体、抗细胞周期蛋白抗体（抗PCNA）、抗dsDNA抗体、抗组蛋白抗体（抗His）、抗核糖体P蛋白抗体（抗ARPA）、抗线粒体抗体M2型（抗AMA-M2）阳性率分别为1.46%、0.33%、0.35%、0.35%、0.28%、0.32%、0.83%、0.63%、0.60%和0.75%。抗Ro-52阳性率最高（2.04%）,抗SSA次之（1.46%）。不同年龄组间抗PCNA阳性率差异有统计学意义（P〈0.05）。ANA谱阳性的病例中单项抗体阳性者,女性阳性率高于男性,差异有统计学意义（P〈0.05）。结论为了更准确地诊断自身免疫性疾病,应用ANA进行筛查,并联合应用ANA谱。两者的联合应用有助于对疾病的早期诊断和治疗。     

Use of panel testing for detection of antinuclear antibody in a resource-limited setting: an appraisal

Objectives: Despite an increase in the incidence of systemic connective tissue diseases (CTD), panel testing for detection of antinuclear antibodies (ANA) is not a routine practice in many health centers of the Indian subcontinent. Consequently, the data on its significance is scanty.

Methods: To evaluate utility of panel testing, line immunoassay (LIA) and indirect immunofluorescence antinuclear antibody test (IIF-ANA) were performed in 321 cases of CTD.

Results: Out of 321 serum samples screened by the above tests, 227 were positive and 18 were negative by both LIA and IIF-ANA. Additional 11/321 (3.4%) cases were picked up by LIA. SSA was most common specificity in these cases followed by SSA/SSB, SSB, Ro-52, Jo-1, dsDNA and nRNP/Sm.

Conclusion: Use of LIA along with IF-ANA and ELISA improves sensitivity of CTD screening.