The development of hepatocellular carcinoma (HCC) in persons who are persistently infected with hepatitis C virus (HCV) is a growing problem worldwide. Current antiviral therapies are not effective ...in many patients with chronic hepatitis C, and a greater understanding of the factors leading to progression of HCC will be necessary to design novel approaches to prevention of HCV-associated HCC. The lack of a small animal model of chronic HCV infection has hampered understanding of these factors. As HCV is an RNA virus with little potential for integration of its genetic material into the host genome, the mechanisms underlying HCV promotion of cancer are likely to differ from other models of viral carcinogenesis. In patients persistently infected with HCV, chronic inflammation resulting from immune responses against infected hepatocytes is associated with progressive fibrosis and cirrhosis. Cirrhosis is an important risk factor for HCC independent of HCV infection, and a majority of HCV-associated HCC arises in the setting of cirrhosis. However, a significant minority arises in the absence of cirrhosis, indicating that cirrhosis is not a prerequisite for cancer. Other lines of evidence suggest that direct, virus-specific mechanisms may be involved. Transgenic mice expressing HCV proteins develop cancer in the absence of inflammation or immune recognition of the transgene. In vitro studies have revealed multiple interactions of HCV-encoded proteins with cell cycle regulators and tumor suppressor proteins, raising the possibility that HCV can disrupt control of cellular proliferation, or impair the cell's response to DNA damage. A combination of virus-specific, host genetic, environmental and immune-related factors are likely to determine the progression to HCC in patients who are chronically infected with HCV. Here, we summarize current knowledge of the virus-specific mechanisms that may contribute to HCV-associated HCC.
The cellular DEAD-box protein DDX3 was recently shown to be essential for hepatitis C virus (HCV) replication. Prior to that, we had reported that HCV core binds to DDX3 in yeast-two hybrid and ...transient transfection assays. Here, we confirm by co-immunoprecipitation that this interaction occurs in cells replicating the JFH1 virus. Consistent with this result, immunofluorescence staining of infected cells revealed a dramatic redistribution of cytoplasmic DDX3 by core protein to the virus assembly sites around lipid droplets. Given this close association of DDX3 with core and lipid droplets, and its involvement in virus replication, we investigated the importance of this host factor in the virus life cycle. Mutagenesis studies located a single amino acid in the N-terminal domain of JFH1 core that when changed to alanine significantly abrogated this interaction. Surprisingly, this mutation did not alter infectious virus production and RNA replication, indicating that the core-DDX3 interaction is dispensable in the HCV life cycle. Consistent with previous studies, siRNA-led knockdown of DDX3 lowered virus production and RNA replication levels of both WT JFH1 and the mutant virus unable to bind DDX3. Thus, our study shows for the first time that the requirement of DDX3 for HCV replication is unrelated to its interaction with the viral core protein.
This study was designed to investigate the effect of posture on oxygen saturation during fibre-optic bronchoscopy (FOB). Thirty-eight consecutive patients requiring diagnostic FOB were randomized ...into two groups according to the initial posture in which the FOB was performed. In group 1 (20 patients), FOB was commenced supine, and in group 2 (18 patients) in a semi-recumbent position (45° from horizontal). Sedation with midazolam was titrated according to clinical response. All patients received atropine 0·6 mg intravenously and topical lignocaine. Observations of peak, trough and plateau oxygen saturation and pulse rate were recorded during six study periods, each lasting 3 min. Periods 1 and 2 were pre- and post-sedation without supplemental oxygen, respectively. The bronchoscope was then inserted into the distal end of the trachea and observations taken during periods 3 and 4 (no supplemental oxygen) and periods 5 and 6 (2 l oxygen by nasal cannulae).
In group 1, posture was changed from supine to semi-recumbent from periods 3–4 and reversed in periods 5 and 6. In group 2, posture changes were in reverse sequence. Patients with initial oxygen saturation of less than 90% or showing a fall below 85% during FOB were excluded. Five patients from each group were withdrawn because of hypoxia. In both groups, oxygen saturation fell significantly (P<0·001) following sedation. There was no significant change in saturation (peak, trough or plateau) with change in posture from supine to semi-recumbency (group 1) or the reverse (group 2). These correspond to periods 3–4 and 5–6 in both groups. Supplemental oxygen was associated with a significant rise in oxygen saturation in both postures, attaining levels close to presedation levels.
There has never been a more critical time for the development of cadres of younger, better-prepared nurse researchers. The following 3 current factors underscore this need: the current and prolonged ...nursing shortage that affects practice, research, and teaching; the increased emphasis on health promotion, disease prevention, and reduction in health disparities as articulated in
Healthy People 2010; and the renewed effort to advance the image of nursing as an intellectual as well as compassionate enterprise.
There are a limited number of institutions equipped to prepare these nurse scholars with undergraduate and graduate education and postdoctoral training in an accelerated manner, to provide mentoring throughout their education by funded faculty researchers, and to protect the focus of this career preparation and trajectory.
Schools of nursing that have baccalaureate, master’s, and doctoral programs and are highly ranked with respect to their National Institutes of Health funding have the opportunity and responsibility to create accelerated research-intensive tracks that link the baccalaureate through doctoral programs and move the graduates to postdoctoral training. These schools of nursing will have to identify which students to recruit and how the development of the research-intensive track will modify their schools’ curricula and the institutions themselves.
The profession will have to identify and create the environment that sanctions the legitimacy of scholars prepared in this way.
BACKGROUND In acute asthma the optimal duration of treatment with combination β agonist and anticholinergic nebuliser solutions is unknown; most studies have investigated single doses or treatment ...for up to 12 hours. To determine whether longer treatment with ipratropium bromide might aid recovery a study was undertaken in 106 patients with acute asthma. METHODS A double blind, randomised, placebo controlled, three group study was performed with all patients receiving ipratropium for 12 hours and salbutamol for 60 hours after admission (both nebulised four hourly), systemic steroids and, if necessary, theophylline. At 12 hours ipratropium was stopped in group I (n = 35) but was continued in the other two groups, and at 36 hours ipratropium was also stopped in group II (n = 35) while patients in group III (n = 36) continued with ipratropium for 60 hours. Spirometric tests were performed before and after salbutamol, and again 30 and 60 minutes after ipratropium or placebo at 12, 36 and 60 hours. Peak flow rates (PEFR) were measured before and after each nebulisation. RESULTS There were no differences between the groups in PEFR on admission (group I: 214 l/min, group II: 198 l/min, group III: 221 l/min), or mean forced expiratory volume in one second (FEV1) at 12 hours (group I: 1.8 l, group II: 2.0 l, group III: 2.2 l), 36 hours (group I: 2.1 l, group II: 2.3 l, group III: 2.4 l), or at 60 hours (group I: 2.2 l, group II: 2.3 l, group III 2.5 l). Despite this, median time to discharge was significantly higher for patients in group I (5.4 days) than for those in groups II (4.1 days) and III (4.0 days). CONCLUSIONS Combination nebulised therapy can be continued beyond 12 hours and up to 36 hours after admission with improved recovery time. Lung function testing may not reflect the full benefit of treatment.
Loan modifications have been heavily advertised both inside and outside bankruptcy, and, unfortunately, many borrowers believe that they can solve most of their problems if they can just qualify for ...a modification. However, loan modifications are often less helpful to debtors than the typical maintain-and-cure treatment of a mortgage in a chapter 13. This has not slowed the high numbers of applications submitted, as it is seldom that one sees a chapter 13 case where there has not been at least one loan modification application submitted. In the author's experience, the majority of chapter 13 cases have been filed to stop a foreclosure proceeding on the debtor's residence. The mortgages were typically six to 12 months in default, due to the short timeframes for the foreclosure process pre-financial crisis, and the default could easily be cured within a reasonable period of time, regardless of one's region's definition of "reasonable."
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