Interaction of the hepatitis C virus (HCV) core with cellular genes in the development of HCV-induced steatosis

Hepatitis C virus (HCV) has chronically infected a large number of patients, leading to the development of steatosis, cirrhosis and, ultimately, hepatocellular carcinoma. The pathogenesis of HCV has not been fully explained, although steatosis is considered to contribute greatly to liver fibrosis progression, modulating host-cell lipid metabolism. Suspected underlying molecular mechanisms include interactions between HCV proteins and intracellular lipid metabolic pathways. Recent studies have suggested that the nucleocapsid of HCV (core) acts as a pathogenic factor involved in lipid droplet accumulation, changes in lipogenic gene expression and/or the activity of lipogenic proteins in a genotype-specific manner. In this review, we have tried to summarize the current knowledge regarding HCV-induced steatosis and the regulation of expression of host genes and receptors that aid in the viral life cycle and promote liver diseases.     

The association of the Friesinger score and pulse pressure in an urban South Asian patient population: pulse pressure,an independent predictor of coronary artery disease

Increase in pulse pressure has been shown to be predisposing factor for Coronary Artery Disease (CAD) in diverse patient populations but its relationship with the severity of CAD, particularly in the South Asians immigrant population of United States has not been demonstrated. We performed a single-center, cross-sectional study. Pulse pressure was calculated by the difference between the systolic and diastolic brachial blood pressures, and the Friesinger score (FS) was used to quantify the severity of CAD with the score of 5 used as a cutoff for extensive disease. We also sought to assess the correlation between the Friesinger score and the 10-year cardiovascular event (CVD) risk as calculated by the Framingham score. Odds ratios and 95% confidence intervals for the associations between explanatory variables and a high Friesinger score were estimated using multivariate logistic regression models. P values below .05 were considered to be statistically significant. Statistical analysis was performed using STATA version 10 software package (College Station, TX). The mean pulse pressure was significantly higher in participants with an FS of ≥5 compared with participants with an FS of <5 (63 vs. 46 mm Hg; P = .004). In univariate analysis, a pulse pressure ≥40 mm Hg was associated with a five-fold increased odds of a higher FS compared with a pulse pressure <40 mm Hg (P = .039), which was unchanged in multivariate analysis. In multivariate analysis, even after adjustment for presence of hypertension, a 10 mm Hg increase in pulse pressure was associated with a 1.97-fold increased odds of a higher FS (95% CI 1.22–3.71, P = .009). The mean Framingham score was higher in participants with a higher FS, but this difference was not significant (32.7 vs. 20.3; P = .1139). Our study demonstrates that pulse pressure, a well-established marker of vascular health, is a significant independent predictor of the severity of CAD as assessed by coronary angiography in South Asians.     

Performance indicators to measure dementia risk reduction activities in primary care

The increasing burden of chronic diseases including cardiovascular and cerebrovascular disease, diabetes and dementia has led to greater emphasis on health promotion, prevention and early intervention (PPEI) activities within primary care. At the same time, there is growing recognition of the importance of measuring and benchmarking health‐care system performance. This includes the measurement of PPEI activities. This paper considers the issue of measuring PPEI activities that are relevant to reducing the risk of dementia within the Australian primary care system. Although Australia does not currently have a comprehensive data collection regarding primary health‐care services, there are a number of national, state and other data sources. These sources could be utilised, either in their current format or modified to provide data regarding PPEI activities in primary care that may reduce the risk of dementia and we have made recommendations regarding the development of such indicators.     

Clinical study of the recurrent flaps of the arm for resurfacing of elbow defects

Defects around the elbow region are often irregular with exposed nerves, tendons, bones/joint, and implants. Skin grafts, though possible in some cases, must be avoided, as it requires prolonged splintage and physiotherapy to prevent recurrence and elbow stiffness. Distant flaps require multiple stages, and free flaps are rarely indicated for elbow defects. Muscle flaps are bulky. To overcome these problems, distally based fasciocutaneous flaps from medial and lateral sides of the arm based on posterior ulnar recurrent artery and radial recurrent artery, respectively, were used. Ten patients were studied. Age of the patients ranged from 10 to 40 years. Five were male, and five were female. Radial and ulnar recurrent flaps were used in five patients each. The largest flap size was 18 × 8 cm, and the smallest was 10 × 6 cm. The flaps were islanded in four cases, and in six cases, they were used as pedicled flaps. Skin grafts were used in 90% of the patients because large flaps were required for resurfacing; also, our patients had thinner arms with less girth. All flaps survived well. One island flap had venous congestion and marginal necrosis, which eventually healed. A significant improvement of mobility and elbow movement was noted in all patients. These flaps can be raised even from the previously burnt skin, as the pedicle is located deep. These flaps have the following advantages: The flap is reliable (deeply located consistent vascular pedicle), can cover both the flexor and extensor surface of the elbow joint, avoids prolonged splintage, elbow stiffness, and recurrence, good aesthetic, and has functional results.     

The application of controlled intracranial hypertension in slit ventricle syndrome patients with obstructive hydrocephalus and shunt malfunction.

When a shunted patient with slit-ventricle syndrome (SVS) presents with a shunt malfunction or infection, the third ventricle may not be of sufficient caliber, despite the shunt malfunction, to allow atraumatic passage of an endoscope to the floor of the third ventricle. We describe four slit ventricle syndrome patients with respectively 24, 12, 18 and 2 prior shunt revisions who presented with shunt infection. In each patient the shunt was externalized and controlled intracranial hypertension (CIH) was applied over an average of 5.8 days by raising the height of the external ventricular drain (EVD) bag to a mean height of 18.8 cm above EAM. This increased the mean transverse third ventricular diameter from an average of 0.28 cm on admission to 1.13 cm after application of CIH. Endoscopic third ventriculocisternostomy (ETV) was satisfactorily performed in three of the four patients who remain shunt free after a mean follow-up of 21.3 months. CIH followed by ETV is an option in selected SVS patients who present with shunt malfunction or infection.     

Assessment of microvascular endothelial function in human skin.

Endothelial dysfunction is an important factor in many cardiovascular diseases, and is commonly associated with impaired endothelium-mediated vasodilatation. Information about the mechanisms behind this dysfunction has come largely from animal studies or, in humans, through invasive techniques that are not specific to one vascular bed. We have developed protocols to assess endothelial function non-invasively in the cutaneous microcirculation by measuring blood flow responses to four receptor-specific vasoactive compounds. Cumulative doses of acetylcholine, methacholine, bradykinin and substance P were administered iontophoretically to the forearm skin of healthy volunteers on two to three occasions. Dose-dependent increases in skin microvascular blood flow in response to these drugs were measured with laser Doppler imaging. Vascular responses to acetylcholine and methacholine were reasonably consistent, with coefficients of variation of approx. 17%. The coefficients of variation for bradykinin and substance P were much poorer, as high as 70% for some doses. This might partly be a consequence of the more unpredictable effects of histamine release in the vasoactive behaviour of these two agonists. Although it might be advantageous to find other agonists with which to test the function of different receptor pathways, we have shown that just acetylcholine and methacholine can currently be used with iontophoresis to allow sensitive and reproducible assessment of endothelial function.     

Intracranial Dural Sinus Thrombosis: Novel Use of a Mechanical Thrombectomy Catheter and Review of Management Strategies

Management of intracranial dural sinus thrombosis with involvement of multiple sinuses is complex, often involving not only the primary problem (thrombosis) but acute adverse events consequent to the disease. We highlight the novel use of an endovascular device (typically for suction thrombectomy in the peripheral vascular system) used in our patient with a life-threatening multi-sinus thrombosis. As there is no standard treatment yet for cranial sinus thrombosis, our review of the literature highlights some effective management strategies. A 35-year-old woman developed associated complications of cranial sinus thrombosis that included intracranial hypertension caused by an expanding intracranial hematoma, pulmonary embolism treated by placement of filters in superior and inferior vena cava to eliminate intra- and extracranial sources of emboli, and procedure-related retroperitoneal hematoma that necessitated peripheral vascular intervention. After failure of several common devices during mechanical thrombolysis, a thrombectomy catheter (typically for peripheral vascular intervention to aide in the clot removal) was used. Our case highlights the fine balance of anticoagulation and thrombolysis and the proactive, aggressive approach used by our multispecialty team to manage concurrent factors.     

Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome.

PURPOSE: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. RESULTS: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.