Conjugation of hydrophobic moieties enhances potency of antisense oligonucleotides in the muscle of rodents and non-human primates.

We determined the effect of attaching palmitate, tocopherol or cholesterol to PS ASOs and their effects on plasma protein binding and on enhancing ASO potency in the muscle of rodents and monkeys. We found that cholesterol ASO conjugates showed 5-fold potency enhancement in the muscle of rodents relative to unconjugated ASOs. However, they were toxic in mice and as a result were not evaluated in the monkey.

Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts.

High affinity antisense oligonucleotides (ASOs) containing bicylic modifications (BNA) such as locked nucleic acid (LNA) designed to induce target RNA cleavage have been shown to have enhanced potency along with a higher propensity to cause hepatotoxicity. In order to understand the mechanism of this hepatotoxicity, transcriptional profiles were collected from the livers of mice treated with a panel of highly efficacious hepatotoxic or non-hepatotoxic LNA ASOs. We observed highly selective transcript knockdown in mice treated with non-hepatotoxic LNA ASOs, while the levels of many unintended transcripts were reduced in mice treated with hepatotoxic LNA ASOs.

The future of nuclear power: value orientations and risk perception.

Since the turn of the 21st century, there has been a revival of interest in nuclear power. Two decades ago, the expansion of nuclear power in the United States was halted by widespread public opposition as well as rising costs and less than projected increases in demand for electricity. Can the renewed enthusiasm for nuclear power overcome its history of public resistance that has persisted for decades? We propose that attitudes toward nuclear power are a function of perceived risk, and that both attitudes and risk perceptions are a function of values, beliefs, and trust in the institutions that influence nuclear policy.

Impact of chronic liver disease and cirrhosis on health utilities using SF-6D and the health utility index.

Assessment of health-related quality of life (HRQL) and health utilities have become important aspects of clinical research. Patient-derived utility adjustments are frequently used in economic analysis. Although HRQL has been frequently studied among patients with liver disease, extensive data on the health utilities of patients with liver disease are not available.

Health-related quality of life in patients with chronic hepatitis B.

Unlabelled: Although chronic hepatitis C (CH-C) has consistently been shown to impair patients' health-related quality of life (HRQL), the impact of chronic hepatitis B (CH-B) on HRQL has not been fully explored.

Aim: Compare HRQL between patients with CH-B, CH-C, primary biliary cirrhosis (PBC) and healthy controls.

Design: Three HRQL questionnaires [Chronic Liver Disease Questionnaire (CLDQ), Short Form 36 (SF-36) and the Health Utility Index (HUI Mark-2 and Mark-3)] were administered prospectively.

Anger experiences among hepatitis C patients: relationship to depressive symptoms and health-related quality of life.

The authors examined anger among hepatitis C (HCV) patients and its relationship to health-related quality of life (HRQL) and depression. Eighty-seven HCV patients who received pegylated interferon-alpha(2b) and ribavirin were included. Patients' mean age was 48 years; 42% were women, and 60% were white.

Development of siRNA for therapeutics: efficient synthesis of phosphorothioate RNA utilizing phenylacetyl disulfide (PADS).

Efficient synthesis of phosphorothioate RNA (PS-RNA) is demonstrated by using phenylacetyl disulfide (PADS) in a mixture of pyridine and acetonitrile (1:1, v/v) for 3 min. Sulfurization is achieved with >99.8% stepwise efficiency.

Depression, anemia and health-related quality of life in chronic hepatitis C.

Background/aims: Hepatitis C (HCV) infected patients have significant health-related quality of life (HRQL) impairment which worsens during anti-viral therapy. Our aim was to examine the association of HRQL with treatment-induced depression and anemia.

Methods: Two hundred and seventy-one HCV patients who received pegylated interferon alfa 2b and ribavirin were included.

The personal and social context of planning for end-of-life care.

Objectives: To examine the potential facilitators of or deterrents to end-of-life planning for community-dwelling older adults, including personal (health-related and sociodemographic) and social (physician and family) influences.

Design: In-person interviews with older adults, telephone interviews with physicians and family members.

Setting: Cleveland, Ohio.