Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate

We observed that pretreatment of male F344 rats with benzyl selenocyanate, a versatile organoselenium chemopreventive agent in several animal model systems, decreases the levels of DNA and RNA modifications produced in the liver by the hepatocarcinogen 2- nitropropane. To clarify the mechanisms involved, we pretreated male F344 rats with either benzyl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450. We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane- induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen. Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microsomes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excretion of nitrate by 157 and 209%, respectively. Pretreatment with benzyl thiocyanate had no significant effect on any of these parameters. Pretreatment with cobalt protoporphyrin IX decreased liver P4502B 1 by 87%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increased the extent of 2-nitropropane-induced liver nucleic acid modifications by 17-67%. These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modifications does not involve the removal of the nitro group. Moreover, they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic acid modifications in part by increasing its detoxication through induction of denitrification, although it is evident that other mechanisms must also be involved.      

Renal Function and Bone Loss in a Cohort of Afro‐Caribbean Men

Poor renal function is associated with increased rates of bone loss and osteoporotic fractures in Caucasian men. The importance of kidney function for skeletal health in African ancestry men, who are a population segment with a high prevalence of chronic kidney disease as well as high peak bone mass, is not well known. We examined the relationship between estimated glomerular filtration rate (eGFR) and rates of bone loss in a large population cohort of otherwise healthy Afro‐Caribbean men aged 40 years and older. Dual X‐ray absorptiometry of the proximal femur and quantitative computed tomography of the proximal radius and tibia were obtained approximately 6 years apart. We calculated eGFR from serum creatinine that was measured in fasting samples in 1451 men. Impaired kidney function (IKF, eGFR<60 ml/min/1.7 m²) was observed in 8.6% of the cohort. The relationship between IKF and baseline BMD and annualized rate of change in BMD was analyzed controlling for potentially important confounders. IKF was not associated with baseline BMD. In contrast, men with IKF experienced a rate of decline in areal BMD at the total hip, femoral neck and trochanter and cortical volumetric BMD compared to those with normal kidney function (p<0.05 for all). Impaired kidney function was not associated with changes in trabecular volumetric BMD. In conclusion, poorer kidney function is associated with accelerated bone loss among otherwise healthy Afro‐Caribbean men even after controlling for age and other important medical and lifestyle related variables. © 2015 American Society for Bone and Mineral Research.     

B-cell lymphoma after angioimmunoblastic lymphadenopathy: a case with oligoclonal gene rearrangements associated with Epstein-Barr virus

We describe a patient with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), who subsequently developed large-cell immunoblastic lymphoma of B-cell immunophenotype. At the time of the initial diagnosis, histologic examination of an inguinal lymph node showed typical features of AILD, and there was no evidence of a monoclonal B-cell population by immunohistochemical analysis. In situ hybridization and Southern blot analysis for Epstein-Barr virus (EBV) were negative. At autopsy 2 years later, the patient had widespread lymph node and organ involvement by large-cell immunoblastic lymphoma of B-cell immunophenotype. Southern blot analysis performed on DNA extracted from lymph nodes, liver, and spleen showed two patterns of Ig heavy chain and kappa light chain gene rearrangements. The T-cell receptor beta chain gene was in the germline configuration. Analysis with an EBV terminal repeat region probe showed two clonal populations that paralleled the Ig gene rearrangement studies. Double-labeling immunohistochemistry and in situ hybridization confirmed the presence of EBV within the neoplastic B cells. The data support the hypothesis that EBV was not etiologically related to AILD in this case, and that EBV proliferation may occur after the onset of the disease. Further, the data suggest that some B-cell lymphomas that arise in the setting of AILD resemble EBV-associated B-cell lymphomas that arise in other immunodeficiency states.     

Reductions in arterial stiffness with weight loss in overweight and obese young adults: Potential mechanisms

ObjectiveArterial stiffness decreases with weight loss in overweight/obese young adults. We aimed to determine the mechanisms by which this occurs.MethodsWe evaluated carotid-femoral pulse wave velocity (cfPWV) and brachial-ankle pulse wave velocity (baPWV) in 344 young adults (23% male, BMI 25–40 kg/m²) at baseline, 6, and 12 months in a behavioral weight loss intervention. Linear mixed models were used to evaluate associations between weight loss and arterial stiffness and to examine whether improvements in obesity-related factors explained these associations.ResultsAt 6 months (7% mean weight loss), there was a significant median decrease of 47.5 cm/s in cfPWV (p < 0.0001) and a mean decrease of 11.7 cm/s in baPWV (p = 0.049). At 12 months (6% mean weight loss), only cfPWV remained reduced. In models adjusting for changes in mean arterial pressure and obesity-related factors, changes in BMI (p = 0.01) and common carotid artery diameter (p = 0.003) were positively associated with change in cfPWV. Reductions in heart rate (p < 0.0001) and C-reactive protein (p = 0.02) were associated with reduced baPWV and accounted for the association between weight loss and reduced baPWV.ConclusionsWeight loss is associated with reduced cfPWV independently of changes in established hemodynamic and cardiometabolic risk factors, but its association with reduced baPWV is explained by concurrent reductions in heart rate and inflammation.