Larry Dial

Tissue distribution, subcellular localization and covalent binding of 2-chloroaniline and 4-chloroaniline in Fischer 344 rats

Chloroanilines (CA) are widely used chemical intermediates which induce numerous toxicities including hematotoxicity, splenotoxicity, hepatotoxicity and nephrotoxicity. Although chloroaniline-induced hematotoxicity has been studied in detail, little information is available on the organ-directed toxicity seen following exposure to these agents. The purpose of this study was to examine and compare the excretion and distribution of two nephrotoxicant and hepatotoxicant chloroanilines (2- and 4-chloroaniline) to liver, kidney, spleen, plasma and erythrocytes. Subcellular distribution and covalent binding in kidney and liver were also determined. Male Fischer 344 rats (four per group) were administered [14C]-2-chloroaniline or [14C]-4-chloroaniline (0.5 or 1.0 mmol/kg; approximately 50 microCi/rat) intraperitoneally (i.p.). Urine, feces, blood and tissues were collected at 3 and 24 h. Both 2- and 4-chloroaniline-derived radioactivity were primarily renally excreted with < 1% excretion in the feces by 24 h post-treatment. Both chloroanilines accumulated mainly in liver (percentage of administered dose/total tissue), but kidney generally had similar or higher equivalent concentrations (micromol/g tissue) compared to liver. Subcellular distribution revealed that for both chloroanilines, the cytosolic fraction generally had the highest level of radioactivity independent of time or dose. Covalent binding was detected in both liver and kidney, with the highest concentration (pmol/mg protein) of binding observed in the hepatic microsomal fraction regardless of compound, dose or time studied. In general, 2-chloroaniline derived radioactivity was excreted faster, reached peak tissue concentrations earlier, disappeared from tissues faster and had less covalent binding in target tissue at 24 h than 4-chloroaniline-derived radioactivity. These results suggest that the increased toxic potential of 4-chloroaniline as compared to 2-chloroaniline may be due in part to a more prolonged and persistent accumulation of 4-chloroaniline and/or its metabolites in target tissue.

Cardiotonic Steroids in Adaptation to Dietary Salt Intake

For many years the concept relating salt to blood pressure (BP) changes has been debated and the concept of natriuretic hormone eliminating excessive sodium by direct inhibition of Na/K-ATPase has raised controversy. However, a recently discovered Na/K-ATPase signaling function has been widely confirmed and provided a novel mechanism to explain the relationship between sodium and blood pressure. Recently, we have demonstrated that activation of this Na/KATPase signaling function regulates sodium reabsorption in renal proximal tubules (RPTs) to correct sodium retention related volume expansion and BP increase. This mechanism demonstrates that rather than contributing to development and maintenance of hypertension, a properly regulated RPT Na/K-ATPase signaling has a protective effect by stimulating renal sodium excretion. A clear understanding of molecular mechanisms whereby the Na/K-ATPase signaling axis counterbalance volume expansion would have major pathophysiological and therapeutic implications for volume expansion mediated hypertension. In this review, we will focus on the effect of the newly appreciated cardiotonic steroids (CTS)-Na/K-ATPase signaling on RPT-mediated sodium handling by coordinated regulation of the Na/K-ATPase and sodium/proton exchanger isoform 3 (NHE3).

How Safe Is Unilateral Nephrectomy

See related article, pp 1458–1463 In this issue of Hypertension , Rodriguez-Gomez et al1 report on their studies of the long-term consequences of uninephrectomy (UNx) in male and female rats. This is an excellent study with very interesting implications to science, as well as clinical practice. The investigators studied the effects of UNx over 18 months, a long period of time given the relatively short life span of the rat. They noted that the males appeared to be more sensitive to the UNx as evidenced by earlier salt-sensitive hypertension, as well as greater pathological changes when animals were studied at the 18-month time point. We point out that the methods used by the authors to determine salt sensitivity were quite clever. Both acute and chronic salt loading were used to assess the relationships between blood pressure and natriuresis, the Guytonian renal function curves. Interestingly but not surprisingly, the authors observed that the presence of salt-sensitive hypertension corresponded quite well with renal pathology in the …

Femoral Neck Bone Mineral Density in Persons Over 50 Years Performing Shiftwork: An Epidemiological Study.

Objective: Shiftwork has been associated with bone loss due to hormonal fluctuations. Our aim was to assess the femoral neck bone mineral density and content in persons over 50 years performing shiftwork. Methods: We performed analysis on the femoral neck bone mineral parameters in persons over age 50 years from the National Health and Nutrition Examination Survey cross-sectional data for 2010 to 2011 in regular and shiftworkers. We also assessed the degree of moderate physical activity and smoking in both groups. Results: Middle-aged men performing shiftwork had significantly higher total femur bone mineral content (37.33 ± 11.00 vs 34.09 ± 10.45, P = 0.01) and femoral neck bone mineral content (4.57 ± 1.07 vs 4.29 ± 1.0, P = 0.03). This difference was not seen in middle aged women. Conclusions: Shiftwork does not seem to affect bone mineral density in those performing moderate physical activity.

Predictors of systolic blood pressure in post-menopausal euthyroid women: A study of the NHANES continuous survey data 2007–2012

There is an increased risk of cardiovascular disease and higher rate of hypertension in post-menopausal (compared to pre-menopausal women). We analysed the cross-sectional National Health and Nutritional Examination and Survey 2007–2012 to look at the factors that affect systolic blood pressure in post-menopausal women. We also performed a linear regression with systolic blood pressure as the dependent variable and age, body mass index, total cholesterol, triglycerides, A1C and serum creatinine as independent variables. In the regression model, only body mass index was a significant predictor of systolic blood pressure (adjusted r2 of 0. 100, F(6, 740) = 14.74, standard error β = 0.08, standardized coefficient B = 0.31, p < 0.01).

Systematic review of nephrotoxicity of drugs of abuse, 2005–2016

BackgroundThe United States is faced with an unprecedented epidemic of drug abuse. Every year thousands of Americans visit the emergency departments all over the country with illicit drug related complaints. These drugs have been known to be associated with a range of renal pathologies, from reversible acute kidney injuries to debilitating irreversible conditions like renal infarction. So far, no comprehensive study or systematic review has been published that includes the commonly used street drugs and designer drugs with potential nephrotoxic outcomes.MethodsWe conducted a systematic review of published case reports, case series, and cross sectional studies of nephrotoxicities related to drugs of abuse. Literature review was conducted using PubMed/Medline from January 1, 2005 -December 31, 2016 to search for publications related to drug abuse with a defined renal outcome. Publications which reported renal injury in relation to the use of illicit drugs were selected, specifically those cases with raised creatinine levels, clinically symptomatic patients, for instance those with oliguria and proven renal biopsies.ResultsA total of 4798 publications were reviewed during the search process and PRISMA flow chart and Moose protocol regarding systematic reviews were followed. 110 articles were shortlisted for the review. A total of 169 cases from case reports and case series, and 14 case studies were analyzed. Renal manifestations of specific illicit drug abuse were included in this review.ConclusionBased on the evidence presented, a wide range of renal manifestations were found to be associated with drug abuse. If the trend of increasing use of illicit drug use continues, it will put a significant percentage of the population at an elevated risk for poor renal outcomes. This study is limited by the nature of the literature reviewed being primarily case reports and case series.

Apolipoprotein B and Insulin Resistance in Hypertensive Compared With Normotensive Patients: An Epidemiological Study

To the Editor: Cross-sectional studies performed recently have suggested that the prevalence of type 2 diabetes in persons with familial hypercholesterolemia might be lower than unaffected individuals (1.75% vs 2.93%, respectively; P<.01). Moreover, statin therapy might increase the risk of type 2 diabetes by 46% with substantial decreases in insulin secretion and resistance as reported by the researchers in the Metabolic Syndrome in Men (METSIM) cohort. The exact relationship between cholesterol and insulin resistance remains unclear in persons with hypertension. We have attempted to evaluate the relationship between Apolipoprotein B (Apo B) and insulin resistance in hypertensive patients. We performed an analysis of the cross-sectional data from the National Health and Nutrition Examination Survey1 for the period 2008–2012 to evaluate the relationship between Apo B and insulin resistance in both a normotensive and hypertensive population. We stratified the serum Apo B levels into low (<100 mg/dL) and high (≥100 mg/dL) groups. Data on variables including age at screening, body mass index (kg/m), waist circumference (cm), mean systolic blood pressure (mm Hg), and cholesterol (mg/dL) were tabulated. We excluded persons 18 years or younger from our analysis. Blood pressure (BP) was categorized as normotensive (systolic BP <140 mm Hg) and hypertensive (systolic BP ≥140 mm Hg). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using the formula (–fasting insulin (lU/mL)9fasting blood glucose (mg/dL)/405). We performed the independent sample t test comparing variables between the two groups. Additionally, we performed nonparametric (spearman) correlation between Apo B and HOMA-IR, Apo B and fasting serum insulin level(s) (lU/mL), and Apo B and fasting blood glucose (mg/dL) in both normotensive and hypertensive patients. SPSS version 21 (IBM, Armonk, NY) was used for statistical analysis. There were 3557 persons with normal BP and 497 with hypertension in the study population. Persons with low Apo B and high Apo B levels were equally distributed between normotensive and hypertensive patients (chi-square, 0.89). There was no difference in the mean Apo B level between normotensives and hypertensive patients (87.8 [ 25.1] vs 87.5 [ 25.3], P=.80). The results of the comparison (Student t test) between the low Apo B group and the high Apo B group in persons with hypertension is summarized in the Table. The high Apo B group had significantly higher fasting insulin, insulin resistance (HOMA-IR), and fasting blood glucose levels (P=.04, P<.01, and P<.01, respectively). There was a significant positive correlation between Apo B, fasting insulin, and fasting blood glucose levels, as well as HOMA-IR in both the normotensive and hypertensive groups. However, the relationship between Apo B and fasting insulin levels was stronger in hypertensive patients (Spearman correlation coefficient (q)=0.198, P<.01) as compared with persons without hypertension (Spearman correlation coefficient (q)=0.148, P<.01). This greater correlation was also seen in the relationship between Apo and HOMA-IR (q=0.214, P<.01 vs q=0.180, P<.01). Recently, higher insulin resistance was associated with lower lipoprotein (a) levels in persons with hypertension. The results of our cross-sectional study show that higher Apo B levels are associated with increased insulin resistance. A meta-analysis published last year showed that statin-induced cardiovascular risk reduction is more closely associated with Apo B levels than lowdensity lipoprotein cholesterol. Prospective studies may be needed to better describe the underlying relationship.

Self-reported weight perceptions in euthyroid individuals across different levels of free thyroxine and BMI.

ypothyroidism is commonly associated with sympoms of weight gain (especially lean body mass), atigue and poor concentration ability [1,2]. Howver, on achieving euthyroidism (i.e. normalization f TSH (thyrotropin) — within reference range of .5—4.5, as per the NHANES III CDC data) in primary ypothyroidism due to autoimmune disease, many ersons continue to experience persistent fatigue nd weight gain in clinical practice. We performed n analysis on the self-reported weight concerns in ealthy euthyroid individuals across different thyoxine (ft4) levels.