HERV-K Gag RNA and Protein Levels Are Elevated in Malignant Regions of the Prostate in Males with Prostate Cancer

Heightened expression of human endogenous retrovirus (HERV) sequences has been associated with a range of malignancies, including prostate cancer, suggesting that they may serve as useful diagnostic or prognostic cancer biomarkers. We analysed the expression of HERV-K (Gag and Env/Np9 regions), HERV-E 4.1 (Pol and Env regions), HERV-H (Pol) and HERV-W (Gag) sequences in prostate cancer cells lines and normal prostate epithelial cells using qRT-PCR. HERV expression was also analysed in matched malignant and benign prostate tissue samples from men with prostate cancer (n = 27, median age 65.2 years (range 47–70)) and compared to prostate cancer-free male controls (n = 11). Prostate cancer epithelial cell lines exhibited a signature of HERV RNA overexpression, with all HERVs analysed, except HERV-E Pol, showing heightened expression in at least two, but more commonly all, cell lines analysed. Analysis of primary prostate material indicated increased expression of HERV-E Pol but decreased expression of HERV-E Env in both malignant and benign regions of the prostate in men with prostate cancer as compared to those without. Expression of HERV-K Gag was significantly higher in malignant regions of the prostate in men with prostate cancer as compared to matched benign regions and prostate cancer-free men (p < 0.001 for both), with 85.2% of prostate cancers donors showing malignancy-associated upregulation of HERV-K Gag RNA. HERV-K Gag protein was detected in 12/18 (66.7%) malignant tissues using immunohistochemistry, but only 1/18 (5.6%) benign tissue sections. Heightened expression of HERV-K Gag RNA and protein appears to be a sensitive and specific biomarker of prostate malignancy in this cohort of men with prostate carcinoma, supporting its potential utility as a non-invasive, adjunct clinical biomarker.     

Is occupational or leisure physical activity associated with low back pain? Insights from a cross-sectional study of 1059 participants

BackgroundLow back pain is a highly prevalent and disabling musculoskeletal disorder. Physical activity is widely used as a prevention strategy for numerous musculoskeletal disorders; however, there is still conflicting evidence as to whether physical activity is a protective or risk factor for low back pain or whether activity levels differ between people with and without low back pain.ObjectiveTo investigate the association between low back pain and different types (occupational and leisure) and intensities (moderate and vigorous) of physical activity.MethodsThis is cross-sectional observational study. We included in this study a total of 1059 individuals recruited from a Spanish twin registry with data available on low back pain. Outcome: Self-reported leisure and occupational physical activity were the explanatory variables. The low back pain outcome used in this study was recurrent low back pain.ResultsOur results indicate that leisure physical activity is associated with a lower prevalence of recurrent low back pain. In contrast, occupational physical activity, such as carrying, lifting heavy weight while inclined, awkward postures (e.g. bending, twisting, squatting, and kneeling) are associated with a higher prevalence of recurrent low back pain. There was no statistically significant association between other occupational physical activities, such as sitting or standing, and low back pain.ConclusionLeisure and occupational physical activity are likely to have an opposed impact on low back pain. While leisure physical activity appears to be protective, occupational physical activity appears to be harmful to low back pain. Future longitudinal studies should assist in formulating guidelines addressing specific types and intensity of physical activity aimed at effectively preventing low back pain.     

Detection of proarrhythmia in the female rabbit heart: blinded validation

INTRODUCTION: Reliable detection of drug-induced proarrhythmia, especially the potential for polymorphic ventricular tachycardia, is of great importance in the development of new compounds that are safe for the heart and was evaluated in a blinded study. METHODS AND RESULTS: In 142 female rabbits, the monophasic action potential was used to determine intraventricular conduction, action potential duration (APD), triangulation (APD30 to APD90), reverse use-dependence, instability and presence of chaotic behavior, early afterdepolarizations, torsades de pointes (TdP), and ventricular fibrillation. In addition, 31 coded drugs were tested in a blinded fashion in another 150 hearts. Prototype cardiovascular agents [quinidine (IA), lidocaine (IB), flecainide (IC), propranolol (II), sotalol (IIIB), amiodarone (IIIAB) and verapamil (IV)] were correctly characterized in terms of their effects upon conduction and APD. Agents documented in clinical practice to have proarrhythmic potential (droperidol, sotalol, mibefradil, bepridil, lidoflazine, ketanserin, sertindole, terfenadine, haloperidol, astemizole, cisapride, ziprasidone, lubeluzole, dofetilide, quinidine, ibutilide) were identified as such. Pimozide is reported to rarely produce TdP and was also found to elicit Class III action with few adverse effects. Equally important, agents believed not to be proarrhythmic (two solvents, atenolol, propranolol, fenoximone, cetirizine, verapamil, sildenafil, lidocaine, diltiazem) were identified as having no proarrhythmic activity. CONCLUSION: The SCREENIT method properly characterized and quantified prototype cardiovascular drugs and correctly identified proarrhythmic noncardiovascular agents of various mechanisms, but it did not produce false-positive results.     

“Dog ear” formation after double-stapled low anterior resection as a risk factor for anastomotic disruption

PURPOSE: The aim of this study was to investigate the possible deleterious effect of the lateral intersecting margins (so-called dog ears) on anastomotic disruption after experimentally performed double-stapled anastomoses. METHODS: Two groups of double-stapled side-to-end anastomoses were performed using pig small intestines. Group A consisted of 35 circular anastomoses and Group B of 32 double-stapled anastomoses with a bilateral dog ear. In both groups bursting pressures were tested using a water-filled, pressure-controlled automatic pumping system (Hamou Endomat®), and special attention was paid to the location(s) in the anastomoses were the disruption(s) occurred. RESULTS: In Group A bursting pressures were significantly higher than in Group B (median pressure, 90vs. 60 mmHg;P<0.001, Mann-WhitneyU test). Remarkably, in Group B in 13 cases (42 percent) the first disruption occurred at the corner of a dog ear. CONCLUSIONS: We conclude that the lateral intersections of double-stapled anastomoses are a structural weak spot and that the currently most often applied double-stapled anastomosis is a less effective type of anastomosis than a complete circular one. Resolving this technical problem might help to reduce the number of anastomotic disruptions after low anterior resections.Equipment supplied by Ethicon Endosurgery-Johnson & Johnson, the Netherlands.Presented at the meeting of the Dutch Surgical Society, Leiden, the Netherlands, November 27, 1998.     

Multifactorial Genetic and Environmental Hedgehog Pathway Disruption Sensitizes Embryos to Alcohol-Induced Craniofacial Defects

Background

Prenatal alcohol exposure (PAE) is perhaps the most common environmental cause of human birth defects. These exposures cause a range of structural and neurological defects, including facial dysmorphologies, collectively known as fetal alcohol spectrum disorders (FASD). While PAE causes FASD, phenotypic outcomes vary widely. It is thought that multifactorial genetic and environmental interactions modify the effects of PAE. However, little is known of the nature of these modifiers. Disruption of the Hedgehog (Hh) signaling pathway has been suggested as a modifier of ethanol teratogenicity. In addition to regulating the morphogenesis of craniofacial tissues commonly disrupted in FASD, a core member of the Hh pathway, Smoothened, is susceptible to modulation by structurally diverse chemicals. These include environmentally prevalent teratogens like piperonyl butoxide (PBO), a synergist found in thousands of pesticide formulations.

Methods

Here, we characterize multifactorial genetic and environmental interactions using a zebrafish model of craniofacial development.

Results

We show that loss of a single allele of shha sensitized embryos to both alcohol- and PBO-induced facial defects. Co-exposure of PBO and alcohol synergized to cause more frequent and severe defects. The effects of this co-exposure were even more profound in the genetically susceptible shha heterozygotes.

Conclusions

Together, these findings shed light on the multifactorial basis of alcohol-induced craniofacial defects. In addition to further implicating genetic disruption of the Hh pathway in alcohol teratogenicity, our findings suggest that co-exposure to environmental chemicals that perturb Hh signaling may be important variables in FASD and related craniofacial disorders.

     

Determinants of longer time from HIV result to enrollment in publicly funded care and treatment in California by race/ethnicity and behavioral risk

The Early Intervention Program (EIP) is California's publicly funded human immunodeficiency virus (HIV) care and treatment program with 30 sites throughout the state. Our objective for this study was to examine the number of days from first HIV-positive result until enrollment into EIP by race/ethnicity, behavioral risk, and other characteristics, with data from clients who enrolled in an EIP site after the availability of highly active antiretroviral therapies. For Model I, logistic regression distinguished clients diagnosed with HIV and enrolled in EIP on the same day (0 days) from those with values of 1+ days; linear regression was then used on the log transformation of days for the majority of clients not diagnosed and enrolled on the same day. For Model II, logistic regression was used to identify client characteristics related to enrollment in EIP over 6 weeks from the date of HIV diagnosis. We found that Latinos were more likely than whites to enroll in EIP on the day they were diagnosed with HIV. For clients not diagnosed and enrolled in EIP on the same day, no differences across racial and ethnic groups were found for days until enrollment in HIV care and treatment. However, clients with a history of injection drug use took longer from the day they were diagnosed with HIV to enroll in EIP. The California EIP represents a model for programs seeking equity in access to HIV care and treatment across racial and ethnic groups. Getting injectors into timely HIV care and treatment represents a challenge.     

Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group

We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P < .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.