Citations

OBJECTIVE We hypothesized that the minor allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a general Mediterranean population. RESEARCH DESIGN AND METHODS We genotyped a random sample of the residents of Ventimiglia di Sicilia, Sicily, for rs5068. RESULTS Genotype frequencies of rs5068 are AA, 93.5%; AG, 6.4%; and GG, 0.1%. All subsequent analyses are AA versus AG+GG. After adjusting for age and sex, the minor G allele is associated with lower BMI (estimate [SE]: −1.7 kg/m2 [0.8], P = 0.04). In the AG+GG group, males with HDL cholesterol levels <40 mg/dL are less frequent (P = 0.05) and obesity tends to be less prevalent (P = 0.07). Importantly, the G allele is associated with a lower prevalence of metabolic syndrome (P = 0.02). After adjusting for BMI, the above associations were attenuated. Independently of age, sex, and BMI, the minor allele is also associated with lower systolic blood pressure (−6.0 mmHg [2.5], P = 0.02) and lower prevalence of hypertension (odds ratio 0.41 [95% CI 0.20–0.83], P = 0.01). CONCLUSIONS The association between the minor allele of rs5068 and a favorable cardiometabolic phenotype that we previously reported in a U.S. population is now replicated in a Mediterranean population in which the G allele of rs5068 is associated with lower blood pressure, BMI, and prevalence of hypertension and metabolic syndrome. These findings may lead to a diagnostic strategy to assess cardiometabolic risk and lay the foundation for the future development of an ANP or ANP-like therapy for metabolic syndrome.

Abstract Background: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. Methods: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign. Results: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. Conclusions: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk. Cancer Epidemiol Biomarkers Prev; 22(7); 1239–51. ©2013 AACR.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) enhance insulin sensitivity and glucose homeostasis in rodent models of insulin resistance. These beneficial effects have been linked with anti-inflammatory properties, but emerging data suggest that the mechanisms may also converge on mitochondria. We evaluated the influence of dietary n-3 PUFAs on mitochondrial physiology and muscle lipid metabolites in the context of high-fat diet (HFD) in mice. Mice were fed control diets (10% fat), HFD (60% fat), or HFD with fish oil (HFD+FO, 3.4% kcal from n-3 PUFAs) for 10 wk. Body mass and fat mass increased similarly in HFD and HFD+FO, but n-3 PUFAs attenuated the glucose intolerance that developed with HFD and increased expression of genes that regulate glucose metabolism in skeletal muscle. Despite similar muscle triglyceride levels in HFD and HFD+FO, long-chain acyl-CoAs and ceramides were lower in the presence of fish oil. Mitochondrial abundance and oxidative capacity were similarly increased in HFD and HFD+FO compared with controls. Hydrogen peroxide production was similarly elevated in HFD and HFD+FO in isolated mitochondria but not in permeabilized muscle fibers, likely due to increased activity and expression of catalase. These results support a hypothesis that n-3 PUFAs protect glucose tolerance, in part by preventing the accumulation of bioactive lipid mediators that interfere with insulin action. Furthermore, the respiratory function of skeletal muscle mitochondria does not appear to be a major factor in sphingolipid accumulation, glucose intolerance, or the protective effects of n-3 PUFAs.

Abstract Background: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case–control design. Methods: There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institute's CHARRED database (Bethesda, MD). Logistic regression was used to calculate ORs and 95% confidence intervals (CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus. Results: Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer. Conclusions: The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies. Impact: These data contribute to evidence about pancreatic cancer and potentially carcinogenic compounds in meat. Cancer Epidemiol Biomarkers Prev; 22(7); 1336–9. ©2013 AACR.

Object In this paper the authors' goal was to review the clinical features and outcome of patients with intracranial dural arteriovenous fistulas (DAVFs) who presented with hemorrhage. Methods A retrospective study of 28 patients with DAVFs who presented with intracranial hemorrhage to 2 separate institutions was performed. The information reviewed included clinical presentation, location and size of hemorrhage, angiographic features, treatment, and clinical and radiologically documented outcomes. Clinical and radiological follow-up were available in 27 of 28 patients (mean follow-up 17 months). Results The vast majority of patients were male (86%), and the most common presenting symptom was sudden-onset headache. All DAVFs had cortical venous drainage, and about one-third were associated with a venous varix. The most common location was tentorial (75%). Treatment ranged from endovascular (71%), surgical (43%), Gamma Knife surgery (4%), or a combination of modalities. The majority of fistulas (75%) were completely obliterated, and most patients experienced excellent clinical outcome (71%, modified Rankin Scale score of 0 or 1). There were no complications in this series. Conclusions Case series, including the current one, suggest that the vast majority of patients who present with intracranial hemorrhage from a DAVF are male. The most common location for DAVFs presenting with hemorrhage is tentorial. Excellent outcomes are achieved with individualized treatment, which includes various therapeutic strategies alone or in combination. Despite the hemorrhagic presentation, almost two-thirds of patients experience a full recovery with no or minimal residual symptoms.

Abstract Purpose: We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens. Experimental Design: Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. Results: Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo. Conclusions: Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease. Clin Cancer Res; 19(9); 2368–80. ©2013 AACR.

Instability after arthroplasty of the shoulder is difficult to correct surgically. Soft-tissue procedures and revision surgery using unconstrained anatomical components are associated with a high rate of failure. The purpose of this study was to determine the results of revision of an unstable anatomical shoulder arthroplasty to a reverse design prosthesis. Between 2004 and 2007, 33 unstable anatomical shoulder arthroplasties were revised to a reverse design. The mean age of the patients was 71 years (53 to 86) and their mean follow-up was 42 months (25 to 71). The mean time to revision was 26 months (4 to 164). Pain scores improved significantly (pre-operative visual analogue scale (VAS) of 7.2 (sd 1.6); most recent VAS 2.2 (sd 1.9); p = 0.001). There was a statistically significant increase in mean active forward elevation from 40.2° (sd 27.3) to 97.0° (sd 36.2) (p = 0.001). There was no significant difference in internal (p = 0.93) or external rotation (p = 0.40). Radiological findings included notching in five shoulders (15%) and heterotopic ossification of the inferior capsular region in three (9%). At the last follow-up 31 shoulders (94%) were stable. The remaining two shoulders dislocated at 2.5 weeks and three months post-operatively, respectively. According to the Neer rating system, there were 13 excellent (40%), ten satisfactory (30%) and ten unsatisfactory results (30%). Revision of hemiarthroplasty or anatomical total shoulder replacement for instability using a reverse design prosthesis gives good short-term results. Cite this article: Bone Joint J 2013;95-B:668–72.

The detection of aneuploidy by fluorescence in situ hybridization (FISH) has revolutionized how laboratories diagnose cholangiocarcinoma and pancreatic adenocarcinoma using cytology specimens. Numerous clinical studies have demonstrated that FISH increases the diagnostic sensitivity of routine cytology for detecting pancreatobiliary tract malignancy with minimal decreases in clinical specificity. FISH also provides useful information in difficult clinical scenarios, including the assessment of patients with biliary strictures who have equivocal cytology results and the assessment of patients with primary sclerosing cholangitis who have clinical features suggestive of malignancy. The improved ability to detect pancreatobiliary tract cancers offers the possibility of earlier detection when patients are amenable to surgical intervention and can decrease health care costs by reducing the amount of clinical evaluation required to arrive at a cancer diagnosis. Cytopathology personnel should maintain familiarity with molecular cytology testing methodologies, because morphologic and aneuploidy assessment of tumors will continue to be an integral part of large‐scale genome analyses of individual tumors. Cancer (Cancer Cytopathol) 2013;121:610‐9. © 2013 American Cancer Society.