Citations

Abstract Prior genome-wide association (GWA) studies have identified 10 susceptibility loci for risk of chronic lymphocytic leukemia (CLL). To identify additional loci, we performed a GWA study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls. Moreover, given the strong familial risk of CLL, we further subset our GWA analysis to the CLL cases with a family history of CLL to identify loci specific to these familial CLL cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values ≤ 3.37 × 10−8), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 × 10−9). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Finally, we evaluated the 10 previously reported SNPs in the overall sample and replicated 8 of them. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. Additional loci among familial CLL cases may be identified through larger studies.

Rationale: The exact etiology of sporadic Alzheimer disease (AD) is unclear, but it is interesting that several cardiovascular risk factors are associated with higher incidence of AD. The link between these risk factors and AD has yet to be identified; however, a common feature is endothelial dysfunction, specifically, decreased bioavailability of nitric oxide (NO). Objective: To determine the relationship between endothelial derived NO and the expression and processing of amyloid precursor protein (APP). Methods and Results: We used human brain microvascular endothelial cells to examine the role of NO in modulating APP expression and processing in vitro. Inhibition of endothelial nitric oxide synthase (eNOS) with the specific NOS inhibitor L-NAME ( N G -nitro- l -arginine methyl ester) led to increased APP and BACE1 (β-site APP-cleaving enzyme1) protein levels, as well as increased secretion of the amyloidogenic peptide amyloid β (Aβ) (control 10.93±0.70 pg/mL; L-NAME 168.21±27.38 pg/mL; P <0.001). To examine the role of NO in modulation of APP expression and processing in vivo, we used brain and cerebral microvessels from eNOS-deficient (eNOS −/− ) mice. Brain tissue from eNOS −/− mice had statistically higher APP and BACE1 protein levels, as well as increased BACE1 enzyme activity and Aβ (Aβ 1 - 42 wild-type control, 0.737pg/mg; eNOS −/− , 1.475 pg/mg; P <0.05), compared with wild-type controls (n=6 to 8 animals per background). Brain microvessels from eNOS −/− mice also showed statistically higher BACE1 protein levels as compared with wild-type control. Conclusions: Our data suggest that endothelial NO plays an important role in modulating APP expression and processing within the brain and cerebrovasculature. The NO/cGMP pathway may be an important therapeutic target in preventing and treating mild cognitive impairment, as well as AD.

ABSTRACT We compared two commercial PCR assays, the Prodesse ProGastro CD assay and the BD GeneOhm Cdiff assay, with a laboratory-developed Clostridium difficile toxin PCR assay with previously established performance characteristics. Results of all methods were in agreement for 333 (96%) of 346 stool specimens. No significant difference in performance among the assays was found ( P values, >0.05).

abstract Context: Large increases in systemic free fatty acid (FFA) availability in the absence of a corresponding increase in fatty acid oxidation can create a host of metabolic abnormalities. These adverse responses are thought to be the result of fatty acids being shunted into hepatic very low-density lipoprotein-triglyceride production and/or intracellular lipid storage and signaling pathways because tissues are forced to increase nonoxidative FFA disposal. Objective: The objective of the study was to examine whether variations in postabsorptive nonoxidative FFA disposal within the usual range predict insulin resistance and hypertriglyceridemia. Design: We measured: systemic FFA turnover using a continuous iv infusion of [9–10, 3H]palmitate; substrate oxidation with indirect calorimetry combined with urinary nitrogen excretion; whole-body and peripheral insulin sensitivity with the labeled iv glucose tolerance test minimal model. Setting: the study was conducted at the Mayo Clinic General Clinical Research Center. Participants: Participants included healthy, postabsorptive, nonobese adults (21 women and 21 men). Interventions: There were no interventions. Main Outcome Measures: Nonoxidative FFA disposal (micromoles per minute), defined as the FFA disappearance rate minus fatty acid oxidation. Results: Women had 64% greater nonoxidative FFA disposal rate than men but a better lipid profile and similar insulin sensitivity. There was no significant correlation between nonoxidative FFA disposal and whole-body sensitivity, peripheral insulin sensitivity, or fasting serum triglyceride concentrations in men or women. Conclusions: Healthy nonobese women have greater rates of nonoxidative FFA disposal than men, but this does not appear to relate to adverse health consequences. Understanding the sex-specific interaction between adipose tissue lipolysis and peripheral FFA removal will help to discover new approaches to treat FFA-induced abnormalities.

Abstract Background Progressive familial intrahepatic cholestasis (PFIC) results in liver cirrhosis during the disease course, although the etiology includes unknown mechanisms. Some PFIC patients require liver transplantation (LT). Methods In this study, 11 patients with PFIC type 1 (PFIC1) and 3 patients with PFIC type 2 (PFIC2) who underwent living‐donor LT (LDLT) were evaluated. Results Digestive symptoms after LDLT were confirmed in 10 PFIC1 recipients (90.9%); 8 PFIC1 recipients showed steatosis after LDLT (72.7%), which began during the early postoperative period (71.5 ± 55.1 days). Seven of the eight steatosis‐positive PFIC1 recipients (87.5%) showed a steatosis degree of ≥80%, which was complicated with steatohepatitis and resulted in fibrosis. Cirrhotic findings persisted in six PFIC1 recipients even after LDLT (54.5%), and three PFIC1 recipients finally died. The survival rates of the PFIC1 recipients at 5, 10, and 15 years were 90.9%, 72.7%, and 54.5%, respectively. In contrast, the PFIC2 recipients showed good courses and outcomes without any steatosis after LDLT. Conclusions The clinical courses and outcomes after LDLT are still not sufficient in PFIC1 recipients owing to steatosis/steatohepatitis and subsequent fibrosis, in contrast to PFIC2 recipients. PFIC2 is good indication for LDLT. PFIC1 patients require LT during the disease course; therefore, we suggest that the therapeutic strategies for PFIC1 patients, including the timing of LDLT, under the donor limitation should be reconsidered. The establishment of more advanced treatments for PFIC1 patients is required to improve the long‐term prognosis of these patients.

Abstract The contribution of emphysema to lung cancer risk has been recognized, but the effect size needs to be further defined. In this study, 565 primary lung cancer cases were enrolled though a prospective lung cancer cohort at Mayo Clinic, and 450 controls were smokers participating in a lung cancer screening study in the same institution using spiral computed tomography (CT). Cases and controls were frequency matched on age, gender, race, smoking status, and residential region. CT imaging using standard protocol at the time of lung cancer diagnosis (case) or during the study (control) was assessed for emphysema by visual scoring CT analysis as a percentage of lung tissue destroyed. The clinical definition of emphysema was the diagnosis recorded in the medical documentation. Using multiple logistic regression models, emphysema (≥5% on CT) was found to be associated with a 3.8-fold increased lung cancer risk in Caucasians, with higher risk in subgroups of younger (&lt;65 years old, OR = 4.64), heavy smokers (≥40 pack-years, OR = 4.46), and small-cell lung cancer (OR = 5.62). When using &gt;0% or ≥10% emphysema on CT, lung cancer risk was 2.79-fold or 3.33-fold higher than controls. Compared with CT evaluation (using criterion ≥5%), the sensitivity, specificity, positive and negative predictive values, and the accuracy of the clinical diagnosis for emphysema in controls were 19%, 98%, 73%, 84%, and 83%, respectively. These results imply that an accurate evaluation of emphysema could help reliably identify individuals at greater risk of lung cancer among smokers. Cancer Prev Res; 4(1); 43–50. ©2010 AACR.