Clevudine therapy with vaccine inhibits progression of chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck hepatitis virus infection

We examined a rational approach to therapy of chronic hepatitis B virus (HBV) infection that utilized the reduction of viral load combined with appropriately timed immune modulation/stimulation. In a placebo-controlled study, chronic woodchuck hepatitis virus (WHV) carrier woodchucks received clevudine (L-FMAU), previously shown to have especially potent and sustained antiviral activity in woodchucks, for 32 weeks followed by WHV surface antigen (WHsAg) alum-adjuvanted vaccine at 32, 36, 40 and 48 weeks. Clevudine induced significant reductions in viraemia, surface antigenaemia, hepatic WHV nucleic acids, and hepatic core and surface antigens. Viral replication markers remained markedly suppressed in 75% of the clevudine-treated woodchucks following drug withdrawal, but remained at high levels in the vaccine monotherapy and placebo groups. Combination drug and vaccine therapy had benefits based on sustained reduction of viraemia, antigenaemia, and hepatic WHV DNA and RNA; inhibition of progression of chronic hepatitis; reduced frequency of chronic liver injury; and delayed onset of hepatocellular carcinoma (HCC). Combination therapy contributed to prevention of HCC in up to 38% of treated carriers, although the growth rate of established HCC was not affected. This study demonstrates enhanced benefits of combination chemo-immunotherapy against viral load and disease progression in chronic hepadnaviral infection, and provides a platform for further development of such treatment regimens.     

Renal replacement therapy and the kidney: minimizing the impact of renal replacement therapy on recovery of acute renal failure

PURPOSE OF REVIEW: Although renal replacement therapy is the mainstay of supportive care in patients with severe acute renal failure, its performance can have untoward effects that contribute to the prolongation of renal failure or impede the ultimate recovery of renal function. In this review, we categorize the major complications associated with renal replacement therapy and assess their impact on recovery of renal function. RECENT FINDINGS: The major mechanisms by which renal replacement therapy is postulated to delay renal recovery include treatment-associated hemodynamic instability, vascular catheter-related bacteremia and sepsis, and cytokine activation by bioincompatible membranes. Clinical data regarding the role of dialysis catheter infections in delay of renal recovery are lacking. The data regarding the role of membrane biocompatibility and the modality and dose of renal replacement therapy are limited and conflicting. SUMMARY: Clinical recommendations must be limited to the broad admonishment that complications during renal replacement therapy, including hemodynamic instability and catheter-related bacteremia, be minimized by using best clinical practices, while recognizing that the impact of specific practices on recovery of renal function have not been evaluated. The data do not support recommendations regarding utilization of specific membranes or the modality or dose of renal replacement therapy on the basis of their impact on recovery of renal function.     

血管紧张素原基因5’端启动子区A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压的相关性

目的:分析血管紧张素原基因启动子区A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压的相关性。方法:实验于2005-08/2006-01在北京华大实验室完成。选取对象均为生活在内蒙古乌拉特后旗的蒙古族牧民,三代血亲内无其他民族。采用基因测序技术对内蒙古蒙古族人群中107例原发性高血压患者和108例正常对照者进行A-20C和A-6G基因分型,观察高血压组和正常对照组不同基因型的分布和等位基因频率的差异。结果:①两组受试者在性别、年龄及吸烟、饮酒、体质量指数和临床化验检查指标有较好的匹配(P均>0.05)。②两组血管紧张素原基因A-20C位点AA,AC,CC基因型频率比较差异无显著性意义(高血压组分别为0.51,0.29,0.20;正常对照组分别为0.49,0.28,0.23,χ2=0.395,P=0.529)。A,C等位基因频率比较差异无显著性意义(高血压组分别为0.65,0.35;正常对照组分别为0.63,0.37,χ2=0.015,P=0.904)。③两组血管紧张素原基因A-6G位点AA,AG,GG基因型频率比较差异无显著性意义(高血压组分别为0.50,0.33,0.17;正常对照组分别为0.55,0.34,0.11,χ2=1.924,P=0.165)。A,G等位基因频率比较差异无显著性意义(高血压组分别为0.66,0.34;正常对照组分别为0.72,0.28,χ2=1.728,P=0.189)。④高血压组协同存在血管紧张素原基因A-20C基因型CC时,血管紧张素原基因A-6G基因型GG频率稍高于正常对照组,但差异无显著性意义(χ2=2.395,P=0.122,OR=7.52,95%CI0.014～1.250),高血压组G等位基因明显高于正常对照组(分别为0.37,0.22,χ2=4.658,P=0.034),携带该等位基因的蒙古族人群发生原发性高血压的相对危险度升高(OR=2.80,95%CI1.087～7.271)。结论:血管紧张素原基因A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压相关,并可能具有协同作用。     

重庆居民与流动人口结核病就诊及诊断的延迟因素：隐蔽性调查分析

目的:调查重庆居民及流动人口结核病就诊及诊断延迟情况,探索在其过程中存在的问题,分析问题产生的原因。方法:在重庆市主城区按照经济发展水平的不同选取了两个区Y和J,采用方便抽样的方法在Y区抽取了一家综合性医院的呼吸科门诊R,在J区抽取了一家综合性医院的一般基层门诊P,于2005-10-10/14和2005-10-17/21,采用隐蔽性观察法对门诊情况进行了观察,主要观察医生和患者的相关语言、行为,了解结核病就诊及诊断延迟情况。实验得到了利物浦大学热带医学院伦理委员会的许可,并通过了重庆市卫生局的批准。资料分析采用主题框架分析法。结果:重庆居民和流动人口都存在结核病就诊延迟的情况,主要与患者的经济状况、健康意识和社会支持等因素有关;医院在结核病的诊断方面具备基本的技术和条件,诊断延迟则主要与医务人员对结核病的意识和责任心有关;另外患者自身在诊疗过程中的中途退出现象不容忽视,也是导致延迟的一个重要因素。结论:一方面综合医院缺乏对结核病患者的管理措施和意识,对结核患者重治轻管,另一方面特殊人群的患者卫生保健支付能力差,缺乏相关结核病防控知识,应依据目前的形势对相关领域进行政策倾斜和调控,积极开展对人群行之有效的健康教育。     

JNK potentiates TNF-stimulated necrosis by increasing the production of cytotoxic reactive oxygen species

The c-Jun NH(2)-terminal kinase (JNK) has been implicated in both cell death and survival responses to different stimuli. Here we reexamine the function of JNK in tumor necrosis factor (TNF)-stimulated cell death using fibroblasts isolated from wild-type, Mkk4(-/-) Mkk7(-/-), and Jnk1(-/-) Jnk2(-/-) mice. We demonstrate that JNK can act to suppress TNF-stimulated apoptosis. However, we find that JNK can also potentiate TNF-stimulated necrosis by increasing the production of reactive oxygen species (ROS). Together, these data indicate that JNK can shift the balance of TNF-stimulated cell death from apoptosis to necrosis. Increased necrosis may represent a contributing factor in stress-induced inflammatory responses mediated by JNK.     

Effect of Medicare coverage on use of invasive colorectal cancer screening tests

BACKGROUND: Colorectal cancer is the second leading cause of cancer death in the United States. Screening for colorectal cancer is now widely recommended but underused. Lack of insurance coverage for screening tests may be one reason patients do not undergo these procedures. OBJECTIVE: To determine the effect of Medicare reimbursement on utilization rates of invasive screening tests. Use of fecal occult blood testing was not studied before 1998. METHODS: We performed a retrospective analysis of ambulatory claims data for Washington State Medicare beneficiaries in 1994, 1995, and 1998. We determined the proportion of patients undergoing diagnostic and screening flexible sigmoidoscopy, colonoscopy, or double-contrast barium enema in 1994, 1995, and 1998 and the proportion receiving fecal occult blood testing in 1998. RESULTS: Use of diagnostic and screening colon tests was low in all years. Fewer than 6% of beneficiaries received any colon test, and fewer than 4% received a screening test. Although more patients underwent diagnostic testing after Medicare coverage began, use of screening tests did not significantly change (odds ratio, 0.99; 95% confidence interval, 0.97-1.01 comparing 1994 and 1998 [P =.33]). Women, individuals older than 80 years, and nonwhite patients were statistically significantly less likely to be screened in all 3 years (P<.001). In 1998, fewer than 7% of patients underwent fecal occult blood testing, with men and nonwhites statistically significantly less likely to have this test (P<.001). CONCLUSIONS: Colorectal cancer screening tests are underused in the Washington State Medicare population, and insurance coverage for these tests did not substantially affect utilization rates in the period studied.     

Patient preference for chronic obstructive pulmonary disease (COPD) treatment inhalers: a discrete choice experiment in France

Objectives: Understanding inhaler preferences may contribute to improving adherence in COPD patients and improving long-term outcomes. This study aims to identify and quantify preferences for convenience-related inhaler attributes in French moderate-to-severe COPD patients, with discrete choice experiment (DCE) methodology.

Methods: Attributes were defined from a literature search, clinician and patient interviews: shape, dose insertion, dose preparation, dose release, dose confirmation, dose counter and reusability. An online DCE was conducted in respondents with self-reported COPD stage 2–4 recruited through a panel. The study questionnaire included twelve choice scenarios per respondent and questions on patient characteristics, treatment and disease severity. Statistical analyses used a mixed logit regression model with random effects. Utility scores were estimated for four types of inhalers: Inhaler A – soft mist inhaler; Inhaler B – reusable soft mist inhaler; Inhaler C – multi-dose dry powder inhaler; and Inhaler D – single dose dry powder inhaler.

Results: The study was completed by 153 patients (50 females); respondents were 50.4?years old on average; 13 different inhaler devices were reported. The most preferred inhaler is L-shaped, has dose preparation with capsule insertion and a dose counter, and is reusable. Inhaler profiles A and B had the highest utilities (mean of 1.2533 and 0.9578 respectively) compared to inhaler C (0.6315) and D (0.2200).

Conclusions: This study showed statistically significant results that the strongest drivers of preference in French users of inhalation devices for COPD are shape, dose counter and reusability. Convenience-related characteristics are important to patients and should be taken into account by clinicians prescribing these devices.