Prostate cancer in fathers with fewer male offspring: the Jerusalem Perinatal Study cohort

Recent studies have suggested the involvement of loci on the Y chromosome in prostate cancer. We studied the relative risk (RR) of prostate cancer in relation to sex ratio of offspring in a cohort of 38,934 Israeli men who were followed from the birth of their offspring (in 1964 through 1976) until 2005. Cox models were used to adjust for changes in incidence over time, age, the man's year of birth, and social and ethnic variables. A total of 712 men were diagnosed with prostate cancer. Compared with men who had at least one son, men with only daughters had an increased risk of prostate cancer (adjusted RR = 1.40, 95% confidence interval [CI] = 1.20 to 1.64, P<.0001). In men with one, two, or three or more offspring, the relative risks associated with absence of sons were 1.25 (95% CI = 1.00 to 1.56), 1.41 (95% CI = 1.04 to 1.91), and 1.60 (95% CI = 1.05 to 2.43), respectively. Men with no daughters showed no statistically significantly altered risk, compared with men who had offspring of both sexes. The relative risk of prostate cancer decreased as the number of sons increased (P(trend)<.0001) but did not change with the number of daughters. These findings suggest that a Y chromosome locus may be involved in prostate cancer risk in this population.     

Range of movement in the wrist as a diagnostic tool in radial-sided wrist pain.

Kienb?ck disease is diagnosed by imaging studies, and is often difficult to diagnose in its early stages. Our clinical impression is that wrist movement is more limited in Kienb?ck disease than when radial-sided wrist pain is caused by other conditions. The purpose of this study was to determine the use of wrist movement in differentiating between early Kienb?ck disease and radial-sided sprained wrist. We retrospectively reviewed 62 cases of Kienb?ck disease and 49 patients with radial-sided wrist sprain. Wrist movement at presentation was recorded. The two groups differed significantly in flexion and extension (p<0.001). The ability of movement of the affected wrist relative to the normal side to distinguish between the groups was excellent (AUC = 0.96, 0.97, respectively). The ability of wrist movement measurements to differentiate between early Kienb?ck disease and radial-sided wrist sprain emphasises that wrist movement should be measured prior to invasive or expensive testing.     

Low-dose mirtazapine: a new option in the treatment of antipsychotic-induced akathisia. A randomized, double-blind, placebo- and propranolol-controlled trial.

BACKGROUND: Preliminary evidence indicates a beneficial effect of serotonin 2A (5-HT(2A)) receptor antagonists in antipsychotic-induced akathisia (AIA). We investigated the antiakathisia effect, safety, and tolerability of low-dose mirtazapine, an agent with marked 5-HT(2A) antagonism. METHODS: In a 7-day double-blind trial, 90 antipsychotic-treated patients meeting DSM-IV criteria for AIA were randomly assigned to mirtazapine (n = 30; 15 mg), propranolol (n = 30; 80 mg), or placebo (n = 30). Primary outcome measures were between-group differences in Barnes Akathisia Scale (BAS) global scores and in the proportion of responders (reduction of > or = 2 points on BAS). Analysis was by intention to treat. RESULTS: Twenty-four patients (26.6%) who were assigned treatment did not complete the study (7 mirtazapine, 8 propranolol, 9 placebo), due to lack of response (n = 19) and adverse events (n = 5). Both mirtazapine and propranolol significantly reduced AIA severity (BAS: -34% mirtazapine and -29% propranolol vs. placebo -11%; p = .012 and p = .023, respectively). Thirteen (43.3%) mirtazapine and 9 (30.0%) propranolol-treated patients versus 2 (6.7%) placebo-treated patients responded (the corresponding odds ratios 10.7 [95% confidence interval (CI), 2.1-53.3] and 6.0 [95% CI, 1.1-30.7]). Five (16.7%) of 30 propranolol-treated patients and none in the mirtazapine and placebo groups (p = .0195 for both) prematurely discontinued the study due to clinically significant hypotension or bradycardia. CONCLUSIONS: The comparable efficacy and better tolerability of low-dose mirtazapine versus propranolol, the current first-line treatment for AIA, position mirtazapine as a favorable candidate for the treatment of acute AIA and may improve current therapeutic practices.     

Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer

Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO'90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cells in vitro and in vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cells in vitro and in vivo. However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor-induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation.     

Birthweight of offspring and mortality of parents: the Jerusalem perinatal study cohort

PURPOSE: We sought to examine the association between birthweight in offspring and mortality in their parents. Distinguishing between risks of outcomes in mothers from fathers potentially provides clues as to the relative roles of genetic versus nongenetic mechanisms underlying these associations. METHODS: We studied total and cause-specific mortality in a population-based cohort of 37,718 mothers and 38,002 fathers whose offspring were delivered in West Jerusalem during 1964-1976, after an average follow-up of 34.12 years. RESULTS: Hazard models controlling for sociodemographic and lifestyle characteristics indicated a U-shaped relationship between offspring's birthweight and overall mortality, deaths from coronary heart disease, circulatory and other non-neoplastic causes in their mothers. Greater rates of mortality from coronary heart disease were observed among mothers who gave birth to babies with low (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.40-3.25) and high birthweight (HR, 1.98; 95% CI, 1.36-2.88), as compared with mothers whose offspring weighed 2500-3999 g at birth. Adjustment for maternal pre-eclampsia slightly attenuated these results. Multivariate models indicated a negative linear relationship (HR, 0.95; 95% CI, 0.91-0.99) between offspring's birthweight and overall mortality in their fathers. Unlike the association in mothers, the relation was noted primarily with deaths from "other causes." CONCLUSIONS: Birthweight of offspring is associated with parental mortality although the relation differs for fathers and mothers. These findings broaden previous observations that intra-uterine events have long-term consequences for adult health and support the need to explore genetic and/or environmental mechanisms underlying these associations.     

Biotin deficiency inhibits heme synthesis and impairs mitochondria in human lung fibroblasts

Four of the 5 biotin-dependent carboxylases (BDC) are in the mitochondria. BDC replace intermediates in the Krebs [tricarboxylic acid (TCA)] cycle that are regularly removed for the synthesis of key metabolites such as heme or amino acids. Heme, unlike amino acids, is not recycled to regenerate these intermediates, is not utilized from the diet, and must be synthesized in situ. We studied whether biotin deficiency (BD) lowers heme synthesis and whether mitochondria would be disrupted. Biotin-deficient medium was prepared by using bovine serum stripped of biotin with charcoal/dextran or avidin. Biotin-deficient primary human lung fibroblasts (IMR90) lost their BDC and senesced before biotin-sufficient cells. BD caused heme deficiency; there was a decrease in heme content and heme synthesis, and biotin-deficient cells selectively lost mitochondrial complex IV, which contains heme-a. Loss of complex IV, which is part of the electron transport chain, triggered oxidant release and oxidative damage, hallmarks of heme deficiency. Restoring biotin to the biotin-deficient medium prevented the above changes. Old cells were more susceptible to biotin shortage than young cells. These findings highlight the biochemical connection among biotin, heme, and iron metabolism, and the mitochondria, due to the role of biotin in maintaining the biochemical integrity of the TCA cycle. The findings are discussed in relation to aging and birth defects in humans.     

Relationship between human herpesvirus 8 loads and disease stage in classic Kaposi sarcoma patients

Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma (KS)-associated herpesvirus, is causally implicated in all forms of KS, including the classic form. Our objective was to investigate the relationship between HHV-8 load in peripheral blood mononuclear cells (PBMCs) and the stage of the disease in classic KS (CKS) patients. HHV-8 loads were measured in 41 PBMC samples from CKS patients with different Krigel-based classification stages using a quantitative real-time polymerase chain reaction assay. Low HHV-8 DNA loads reaching a maximum of 75.5 copies/10(5) cells were detected in 73.2% of the patients. HHV-8 loads in patients with stages I and II were similarly distributed. An increased detection rate of HHV-8 DNA, although not statistically significant, was evident in patients diagnosed with CKS stages III and IV. We conclude that the measurements of HHV-8 load in PBMCs provide a limited correlation with the clinical stage of KS.     

Suppression of lung cancer tumor growth in a nude mouse model by the Ras inhibitor salirasib (farnesylthiosalicylic acid)

Aberrant Ras pathway functions contribute to the malignant phenotype of lung cancers. Inhibitors of Ras might therefore be considered as potential drugs for lung cancer therapy. Here, we show that the Ras inhibitor farnesylthiosalicylic acid (salirasib) inhibits proliferation of human lung cancer cells harboring a mutated K-ras gene (A549, H23, or HTB54) or overexpressing a growth factor receptor (H1299 or HTB58) and enhances the cytotoxic effect of the chemotherapeutic drug gemcitabine. Salirasib inhibited active K-Ras in A549 cells, reversed their transformed morphology, and inhibited their anchorage-independent growth in vitro. Tumor growth in A549 and HTB58 cell nude mouse models was inhibited by i.p. administration of salirasib. P.o. formulated salirasib also inhibited A549 cell tumor growth. Our results suggest that p.o. salirasib may be considered as a potential treatment for lung cancer therapy.     

Cystatin-C and inflammatory markers in the ambulatory elderly

Purpose

Inflammatory factors are elevated in persons with severe renal dysfunction, but their association across all levels of renal function is unclear. We compared cystatin-C, a novel marker of renal function, with creatinine and estimated glomerular filtration rate (eGFR) as predictors of C-reactive protein and fibrinogen levels.

Methods

This study is a cross-sectional analysis to evaluate cystatin-C, creatinine, and eGFR as predictors of the inflammatory markers C-reactive protein and fibrinogen. Participants included 4637 ambulatory elderly patients from the Cardiovascular Health Study. Multivariate linear regression was used to determine the independent associations of each renal function measurement with the inflammatory marker outcomes.

Results

After adjustment for confounding factors, cystatin-C was correlated with both C-reactive protein (coefficient = 0.13; 95% confidence interval: 0.10-1.16, P <.0001) and fibrinogen levels (0.15; 0.13-0.18, P <.0001). Associations were larger than those for creatinine and C-reactive protein (0.05; 0.02-0.07, P = .003) or fibrinogen (0.07; 0.04-0.10, P <.0001). Adjusted levels of C-reactive protein increased incrementally across quintiles of cystatin-C, from a median of 2.2 mg/L in quintile 1 to 3.7 mg/L in quintile 5. In contrast, both C-reactive protein and fibrinogen had U-shaped associations with quintiles of creatinine and eGFR, because the inflammatory markers were equivalently elevated in quintiles 1 and 5.

Conclusions

The finding of a significant linear association of cystatin-C and inflammation markers suggests that even small reductions in renal function may be associated with adverse pathophysiologic consequences.     

Peritoneal Equilibration Test and Patient Outcomes

Background and objectives

Although a peritoneal equilibration test yields data on three parameters (4-hour dialysate/plasma creatinine, 4- to 0-hour dialysate glucose, and 4-hour ultrafiltration volume), all studies have focused on the prognostic value of dialysate/plasma creatinine for patients undergoing peritoneal dialysis. Because dialysate 4- to 0-hour glucose and ultrafiltration volume may be superior in predicting daily ultrafiltration, the likely mechanism for the association of peritoneal equilibration test results with outcomes, we hypothesized that they are superior to dialysate/plasma creatinine for risk prediction.

Design, setting, participants, & measurements

We examined unadjusted and adjusted associations of three peritoneal equilibration test parameters with all-cause mortality, technique failure, and hospitalization rate in 10,142 patients on peritoneal dialysis treated between January 1, 2007 and December 31, 2011 in 764 dialysis facilities operated by a single large dialysis organization in the United States, with a median follow–up period of 15.8 months; 87% were treated with automated peritoneal dialysis.

Results

Demographic and clinical parameters explained only 8% of the variability in dialysate/plasma creatinine. There was a linear association between dialysate/plasma creatinine and mortality (adjusted hazards ratio per 0.1 unit higher, 1.07; 95% confidence interval, 1.02 to 1.13) and hospitalization rate (adjusted incidence rate ratio per 0.1 unit higher, 1.05; 95% confidence interval, 1.03 to 1.06). Dialysate/plasma creatinine and dialysate glucose were highly correlated (r=−0.84) and yielded similar risk prediction. Ultrafiltration volume was inversely related with hospitalization rate but not with all-cause mortality. None of the parameters were associated with technique failure. Adding 4- to 0-hour dialysate glucose, ultrafiltration volume, or both did not result in any improvement in risk prediction with dialysate/plasma creatinine alone.

Conclusions

This analysis from a large contemporary cohort treated primarily with automated peritoneal dialysis validates dialysate/plasma creatinine as a robust predictor of outcomes in patients treated with peritoneal dialysis.