The bronze baby syndrome: evidence of increased tissue concentration of copper porphyrins

A case regarding a newborn infant with severe Rh haemolytic disease, who presented with the bronze baby syndrome and eventually died, is reported. The postmortem examination showed marked extramedullary haematopoiesis in the liver and spleen, heavy hepatic haemosiderosis and mild intralobular cholestasis. The porphyrin content, which was assayed in different tissues. was very high in the liver, suggesting that the increased erythropoiesis seen in Rh haemolytic disease leads to an increased synthesis of porphyrins as by-products of haem synthesis. Phototherapy causes photodestruction, sensitized by bilirubin, of porphyrins (mainly copper porphyrins), yielding brown photoproducts.     

江西省8所大学1348名大学生主观幸福感影响因素的调查

目的:对江西省8所大学部分学生主观幸福感进行调查分析,为进一步开展大学生心理健康教育工作提供依据。方法:于2005-10-20/11-30运用主观幸福感量表、青少年生活事件量表、领悟社会支持量表、内在-外在心理控制源量表对江西省8所大学的1348名大学生进行抽样调查。其中主观幸福感量表分数越高,幸福感越高。内在-外在心理控制源量表得分越低,越倾向内控,得分越高,越倾向外控。结果:共发放问卷1348份,收回有效问卷1231份,其中男生539名,女生692名,大一学生421名,大二学生390名,大三学生420名,城市452名,农村779名,平均年龄20.4岁。①男生主观幸福感的得分略低于女生的得分,但差异没有显著性(25.97±5.80,26.61±5.03,t=0.309,P>0.05)。②大一学生主观幸福感评分为26.97±4.61,大二学生为25.35±6.37,大三学生为25.92±5.75,3个年级之间的主观幸福感评分比较差异无显著性(F=2.769,P>0.05),两两比较发现,大一学生主观幸福感的得分显著高于大三学生(P<0.05)。③家庭经济收入低的大学生(家庭人均年收入≤2000元)主观幸福感评分显著低于普通大学生(21.58±3.97,26.30±5.43,t=3.015,P<0.01)。④生活事件与主观幸福感存在显著性负相关(r=-0.289,P<0.01),社会支持与主观幸福感存在显著性正相关(r=0.384,P<0.01)。生活事件、社会支持分别对主观幸福感的回归分析发现,生活事件、社会支持分别解释了主观幸福感变异的7.2%,11.7%。⑤按照控制感量表得分把分数由高到低进行排序,把分数处于最低点的30%的学生作为内控组的学生,分数处于最高点的30%的学生作为外控组的学生。内控组大学生的主观幸福感得分显著高于外控组(27.29±5.86,21.83±7.03,t=5.359,P<0.01)。结论:高年级学生、低收入家庭的学生幸福感水平低,负性生活事件能降低大学生的主观幸福感,而较多社会支持会产生较高的主观幸福感。     

Hepatotoxicity of 6-mercaptopurine (6-MP) and Azathioprine (AZA) in adult IBD patients

OBJECTIVE: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15% of pediatric patients and has been associated with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 x 10(8) RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients. METHODS: Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis. RESULTS: Eight patients (4.6%) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 x 10(8) RBC versus 3,452 pmol/8 x 10(8) RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4%vs 2.3%, P < 0.05); however, nearly 90% of all patients with 6-MMPR > 5,300 pmol/8 x 10(8) RBC had no hepatotoxicity, while almost 40% of subjects with hepatotoxicity had 6-MMPR levels below this cutoff. CONCLUSIONS: 6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.     

Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin

In comparison with peginterferon/ribavirin alone, boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of ≥ 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity = 33%) without sacrificing a single SVR among 475 successes (specificity = 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a ≥ 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR. CONCLUSION: Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels ≥ 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In boceprevir recipients, the combination of 2 stopping rules-an HCV RNA level ≥ 100 IU/mL at week 12 and detectable HCV RNA at week 24--maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation.     

Simeprevir,daclatasvir and sofosbuvir for hepatitis C virus‐infected patients with decompensated liver disease

Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1‐ or 4‐infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct‐acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment‐naïve or treatment‐experienced adults with Child‐Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7–9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS‐331007 (sofosbuvir metabolite) was 2.2‐, 1.5‐, 1.2‐ and 1.2‐fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.     

Long‐term safety and efficacy results in hepatitis C virus genotype 1‒infected patients receiving ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in the TOPAZ‐I and TOPAZ‐II trials

The 3‐DAA regimen consisting of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) has shown high sustained virologic response rates (~95%) in phase 3 clinical trials including >2300 HCV genotype 1–infected patients. Real‐world evidence studies have confirmed the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with chronic HCV genotype 1 infection and are consistent with clinical trial results. TOPAZ‐I and TOPAZ‐II are ongoing phase 3b trials, assessing safety, efficacy and long‐term progression of liver disease and clinical outcomes for up to 5 years post‐treatment in patients treated with OBV/PTV/r + DSV ± RBV. High rates of sustained virologic response (SVR) were achieved regardless of presence or absence of cirrhosis.In this report, we assessed the long‐term progression of liver disease and incidence of clinical outcomes up to 3 years of post‐treatment follow‐up in patients with chronic HCV GT1 infection who were treated with (OBV/PTV/r + DSV) ± RBV in the TOPAZ‐I and TOPAZ‐II studies. Improvements were observed in liver disease markers including FIB‐4, METAVIR and Child‐Pugh scores as well as platelet counts. Clinical outcomes related to long‐term progression of liver disease such as liver decompensation were infrequent (<1%). Hepatocellular carcinoma (HCC) occurred in 1.4% of cirrhotic patients.