Plasma cysteine, cystine, and glutathione in cirrhosis

Plasma contains three forms of cyst(e)ine: cysteine, cystine, and protein-bound cysteine. The former is a thiol and the latter two are disulfides. The levels of all three types of cyst(e)ine, as well as the cysteinyl tripeptide glutathione, were measured in the plasma of 14 normal and 10 cirrhotic individuals. All subjects ate mixed foods. Some cirrhotic patients were studied during nasogastric hyperalimentation with Vivonex (Norwich Eaton Pharmaceuticals, Norwich, N.Y.) as well as during total parenteral nutrition with FreAmine III (American McGaw, Irvine, Calif.); neither formula contains cyst(e)ine. Regardless of the nature of the diet, cirrhotic patients had significantly subnormal values for cysteine, glutathione, and albumin. In addition, the following significant changes were found to be diet-dependent: (a) elevated methionine during Vivonex, (b) subnormal taurine during mixed foods and total parenteral nutrition, (c) depressed protein-bound cysteine during total parenteral nutrition, (d) depressed cyst(e)ine thiol/disulfide ratio during mixed foods, and (e) depressed total thiol during Vivonex and total parenteral nutrition. The data indicate multiple abnormalities in sulfur metabolism in cirrhosis.     

Significance of false-positive serologic tests for histoplasmosis and blastomycosis in an endemic area

False-positive serologic tests for histoplasmosis (H) and blastomycosis (B) are common in populations from endemic areas. In order to determine the significance of false-positive test results, we reviewed the final diagnoses of all patients whose sera were submitted to our laboratory for radioimmunoassay (RIA) and immunodiffusion (ID) during a 3-yr period. Of the 263 patients whose sera were examined, 29 (11%) had H or B; 41 (17.5%) of the remaining 234 patients had false-positive test results. Of these 41 patients, 31 were positive for H alone, and 10 had antibodies to both H and B. All three patients with false-positive ID tests for histoplasmosis also had positive titers (greater than or equal to 1:16) on RIA. No patient had a false-positive ID result for blastomycosis. The percentage of patients in each of five major diagnostic categories with and without false-positive serologic tests was similar (p greater than 0.05). The majority of patients had pulmonary infections, almost half of which were granulomatous infections other than H or B; this reflects the clinical indications for requesting fungal serologic tests. A positive fungal serology is not useful in suggesting the presence of a pulmonary disease other than H or B in patients from an endemic area suspected of having a pulmonary mycosis.     

Efficacy of Lactulose in Cirrhotic Patients with Subclinical Hepatic Encephalopathy

To investigate the role of lactulose in the treatment of cirrhotic patients with subclinical hepatic encephalopathy (SHE), 40 cirrhotic patients, 33 males and 7 females, were included in the study. The diagnosis of SHE was made by quantitative psychometric tests including the number connection test (NCT), figure connection test (FCT) parts A and B, and two performance subtests of Wechsler adult intelligence scale, ie, picture completion (PC) and block design (BD) tests. SHE was diagnosed in 26 (65%) of 40 patients. Of these 26 patients, 14 patients were randomized to treatment group (lactulose 30–60 ml/day for three months, SHE-L) and 12 patients to no treatment group (no lactulose, SHE-NL). Psychometric tests were repeated in all patients in both groups and in six patients with no SHE (group NSHE, N = 14) after three months. The mean scores and number of the abnormal psychometric tests at entry were significantly higher in patients in groups SHE-L and SHE-NL than in patients in group NSHE; however, there was no significant difference between SHE-L and SHE-NL. The mean number of the abnormal psychometric tests decreased in patients in group SHE-L after three months of treatment with lactulose (2.9 ± 0.9 vs 0.8 ± 1.2; P = 0.004); however, there was no change in patients in group SHE-NL after three months (3.7 ± 1.5 vs 3.5 ± 1.3; P = NS). While SHE improved in 8 of 10 patients in group SHE-L, none of the patients in group SHE-NL improved after three months of follow-up (P < 0.001). Two patients in group SHE-NL also developed overt encephalopathy during the study period. We conclude that lactulose treatment in cirrhotic patients with SHE is effective.     

Hepatitis E virus antigen detection as an early diagnostic marker: Report from India

Hepatitis E virus (HEV) is implicated in many outbreaks of viral hepatitis in the Indian subcontinent. The conventional diagnosis of such outbreaks rests on the detection of anti‐HEV IgM antibodies. However, IgM antibodies develop after 4–5 days of infection. An early‐diagnostic marker is imperative for timely diagnosis of the outbreak and also initiation of control measures. This study aimed to determine the use of hepatitis E virus antigen detection as an early diagnostic marker in an outbreak in comparison to anti‐HEV IgM and RT‐PCR analyses. Forty samples were collected during a suspected outbreak of viral hepatitis due to HEV. A total of 36 samples were positive for one or more HEV markers. The positivity for anti‐HEV IgM, HEV antigen, and RT‐PCR was 91.6%, 69.4%, and 47.2% respectively. RT‐PCR and HEV antigen detection gave the highest positive results (100%) in the first 3 days of illness. Positive HEV PCR declined to 54% by Days 4–7, whereas HEV antigen and IgM detection were 88% and 100%, respectively. Sequencing of representative HEV samples indicated that the strains responsible for this outbreak belonged to genotype I, subtype 1a. HEV antigen was found to be an early diagnostic marker of acute infection. HEV antigen was detected in three additional cases in the early phase (1–3 days), and they had no detectable anti‐HEV IgM antibodies. These three samples were also positive for HEV RNA. After Day 7, anti‐HEV IgM was the main diagnostic indicator of infection. J. Med. Virol. 85:823–827, 2013. © 2013 Wiley Periodicals, Inc.     

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1–2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex‐influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre‐symptomatic diagnosis has the greatest clinical utility.     

Hyperammonemic coma in a post-partum patient with undiagnosed urea cycle defect

Urea cycle disorders (UCD) are common during neonatal period, and it is rarely reported in adults. We are reporting a patient presenting with post-partum neuropsychiatric symptoms rapidly progressing to coma. Markedly raised serum ammonia level on presentation with an initial normal magnetic resonance imaging (MRI) of brain and normal liver function tests led to the suspicion of UCD, which was confirmed on the basis of urine orotic acid and elevated serum amino acid levels. We had to resort to hemodialysis to correct the hyperammonemic coma, which was unresponsive to conventional anti-ammonia measures. She exhibited remarkable improvement with a progressive decline in serum ammonia with repeated hemodialysis and made a full recovery. Timely diagnosis and early institution of hemodialysis in the setting of a poor neurological status maybe considered a suitable treatment option.     

LC-MS/MS测定人血浆中对乙酰氨基酚及其人体药动学和生物等效性研究

目的 建立一种快速、灵敏的高效液相色谱-串联质谱（HPLC-MS/MS）方法以测定人血浆中对乙酰氨基酚浓度,并应用于两种对乙酰氨基酚制剂的人体药代动力学和生物等效性研究。方法 以替硝唑为内标,200μL血浆样品经5倍于其体积的乙酸乙酯液液萃取,再经Waters XBridge? C18柱等度洗脱分离后导入串联质谱,以正离子多反应监测模式进行定量分析,对乙酰氨基酚和内标的选择性反应离子对分别是m/z 152→110和248→121。方法经验证后应用于19名健康受试者单剂量空腹口服两种对乙酰氨基酚制剂500mg后药代动力学和生物等效性的研究。结果 血浆中对乙酰氨基酚在0.1～8.0 μg·mL-1范围内线性良好（r2 > 0.99）,最低检测限为 0.1 μg·mL-1,提取回收率为91.0%～98.7%,日内和日间准确度分别为98.8%～111.3% （精密度：CV ? 9.03%）和94.9%～102.6% （精密度：CV ? 10.68%）。生物等效性试验中,受试制剂与参比制剂的主要药代动力学参数Cmax、AUC0-t和AUC0-∞ 几何均值比的90%置信区间分别为83.50%～105.79%,94.25%～101.54%和93.24%～101.02%,均落在生物等效可接受标准80.00%～125.00%范围内。结论 所建立测定人血浆中对乙酰氨基酚浓度的HPLC-MS/MS法具有快速灵敏、回收率高、选择性好的特点,适用于对乙酰氨基酚片人体药代动力学和生物等效性研究。受试制剂与参比制剂在人体内吸收速度和程度相似,两种制剂生物等效。