The Hepatitis B Virus Ribonuclease H Is Sensitive to Inhibitors of the Human Immunodeficiency Virus Ribonuclease H and Integrase Enzymes

Nucleos(t)ide analog therapy blocks DNA synthesis by the hepatitis B virus (HBV) reverse transcriptase and can control the infection, but treatment is life-long and has high costs and unpredictable long-term side effects. The profound suppression of HBV by the nucleos(t)ide analogs and their ability to cure some patients indicates that they can push HBV to the brink of extinction. Consequently, more patients could be cured by suppressing HBV replication further using a new drug in combination with the nucleos(t)ide analogs. The HBV ribonuclease H (RNAseH) is a logical drug target because it is the second of only two viral enzymes that are essential for viral replication, but it has not been exploited, primarily because it is very difficult to produce active enzyme. To address this difficulty, we expressed HBV genotype D and H RNAseHs in E. coli and enriched the enzymes by nickel-affinity chromatography. HBV RNAseH activity in the enriched lysates was characterized in preparation for drug screening. Twenty-one candidate HBV RNAseH inhibitors were identified using chemical structure-activity analyses based on inhibitors of the HIV RNAseH and integrase. Twelve anti-RNAseH and anti-integrase compounds inhibited the HBV RNAseH at 10 μM, the best compounds had low micromolar IC50 values against the RNAseH, and one compound inhibited HBV replication in tissue culture at 10 μM. Recombinant HBV genotype D RNAseH was more sensitive to inhibition than genotype H. This study demonstrates that recombinant HBV RNAseH suitable for low-throughput antiviral drug screening has been produced. The high percentage of compounds developed against the HIV RNAseH and integrase that were active against the HBV RNAseH indicates that the extensive drug design efforts against these HIV enzymes can guide anti-HBV RNAseH drug discovery. Finally, differential inhibition of HBV genotype D and H RNAseHs indicates that viral genetic variability will be a factor during drug development. © 2013 Tavis et al

A perspective on SIDS pathogenesis. The hypotheses: plausibility and evidence

Several theories of the underlying mechanisms of Sudden Infant Death Syndrome (SIDS) have been proposed. These theories have born relatively narrow beach-head research programs attracting generous research funding sustained for many years at expense to the public purse. This perspective endeavors to critically examine the evidence and bases of these theories and determine their plausibility; and questions whether or not a safe and reasoned hypothesis lies at their foundation. The Opinion sets specific criteria by asking the following questions: 1. Does the hypothesis take into account the key pathological findings in SIDS? 2. Is the hypothesis congruent with the key epidemiological risk factors? 3. Does it link 1 and 2? Falling short of any one of these answers, by inference, would imply insufficient grounds for a sustainable hypothesis. Some of the hypotheses overlap, for instance, notional respiratory failure may encompass apnea, prone sleep position, and asphyxia which may be seen to be linked to co-sleeping. For the purposes of this paper, each element will be assessed on the above criteria

Exercise therapy in Type 2 diabetes

Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity

Early supportive medication use and end-of-life care among Medicare beneficiaries with advanced breast cancer

PURPOSE: A randomized controlled trial of cancer patients has linked early supportive care with improved hospice use and less aggressive end-of-life care. In practice, the early use of supportive interventions and potential impact on end-of-life care are poorly understood. We sought to describe early use of medications to treat common breast cancer symptoms (pain, insomnia, anxiety, and depression) and to assess the relationship between early use of these treatments and end-of-life care. METHODS: Secondary analysis of 2006–2012 SEER-Medicare data. Women included had stage IV breast cancer and died within the observation period. We used modified Poisson regression to assess the relationship between supportive medication use in the 90 days post-diagnosis and several end-of-life care measures (hospice use, in-hospital death, chemotherapy receipt within 14 days of death, ICU admission or >1 hospitalization or emergency department/ED visit 30 days before death). RESULTS: Among the 947 women included, 68% of women used at least one supportive medication in the 90 days following their diagnosis: 60.3% used opioid pain medications, and 28.3% received non-opioid psychotropic medications. Early use of any supportive medications was not associated with end-of-life care. Similarly, we found no differences in end-of-life care between opioid pain medication users and non-users. However, we found that non-opioid psychotropic medication users were less likely to receive chemotherapy in the last 14 days of life (aRR: 0.33, 95% CI: 0.12–0.88). CONCLUSIONS: Non-opioid psychotropic use was associated with some aspects of end-of-life care. Future research should consider alternative measures of palliative and supportive care use using administrative data sources

O manejo não medicamentoso da hipertensão arterial sistêmica no Sul do Brasil Non-pharmacological management of hypertension in Southern Brazil

Foi realizado um estudo transversal com base populacional entre os indivíduos de 20 a 69 anos, residentes na zona urbana de Pelotas, Rio Grande do Sul, Brasil. O objetivo foi avaliar o manejo da hipertensão e descrever as características dos indivíduos classificados com cuidados inadequados. Entre os 1.968 entrevistados, 380 eram hipertensos (19,3%), 44,1% consultaram sempre com o mesmo médico. Entre os hipertensos, 85,5% eram sedentários, 48,2% consumiam gordura em excesso e 47,4% eram fumantes. As recomendações adequadas mais realizadas pelos médicos foram restringir o sal (98,4%), interromper o consumo de bebidas alcoólicas (93,7%), aconselhar dieta para emagrecer e reduzir a ingestão de gorduras (88,2%), parar de fumar (73,2%) e praticar atividades físicas (68,9%). O manejo da hipertensão foi classificado como inadequado em 284 indivíduos (74,7%; IC95%: 70,4-79,1). Constatou-se maior probabilidade de manejo adequado nas mulheres, nos indivíduos a partir dos cinqüenta anos, nas pessoas pertencentes à classe econômica A e B, em não fumantes, e nos indivíduos com diabetes mellitus. Alguns achados traduziram aspectos positivos da atenção, contudo as diferenças de cuidados de acordo com a classe social evidenciaram a falta de eqüidade assistencial.<br>A cross-sectional population-based study was carried out among individuals aged 20 to 69 years in the urban area of Pelotas, Rio Grande do Sul, Brazil. The objective was to analyze characteristics of hypertensive patients in relation to management of arterial hypertension. Among the 1,968 interviewees, 380 were hypertensive (19.3%), and 44.1% of these always consulted the same physician. Of the entire sample, 85.5% were sedentary, 48.2% showed excessive fat consumption, and 47.4% smoked. Most physicians recommend the following: lowering salt consumption (98.4%), cessation of alcohol consumption (93.7%), for losing weight, diet and consumption of low-fat food (88.2%), smoking cessation (73.2%), and physical activity (68.9%). The clinical management was classified as inadequate in 284 individuals (74.7%). Increased probability of adequate management was found among: women, individuals > 50 years, upper and middle-class patients, non-smokers, and patients with diabetes mellitus. Some findings showed positive aspects, but differences according to socioeconomic status evidenced lack of equity in care