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BACKGROUNDCross‐sectional data on inpatient glucose control in a large sample of US hospitals are now available, but little is known about changes in glycemic control over time in these institutions.OBJECTIVETo evaluate trends in glycemic control in US hospitals over 2 years.DESIGNRetrospective analysis.METHODSPoint‐of‐care blood glucose (POC‐BG) test results at 126 hospitals during January to December 2007 and January to December 2009 were extracted using the Remote Automated Laboratory System‐Plus (Medical Automation Systems, Charlottesville, VA), and patient‐day‐weighted mean glucose levels were compared.SETTING/PATIENTSHospitalized patients.RESULTSA total of 12,541,929 POC‐BG measurements from 1,010,705 patients were analyzed for 2007, and 10,659,418 POC‐BG measurements from 656,206 patients were analyzed for 2009. Patient‐day‐weighted mean POC‐BG in 2009 decreased by 5 mg/dL in the non‐intensive care unit (non‐ICU) data compared with that in 2007 (154 mg/dL vs 159 mg/dL, respectively; P < 0.001). However, POC‐BG values were clinically unchanged in intensive care unit (ICU) data from 2009 vs 2007 (167 mg/dL vs 166 mg/dL; P < 0.001). From 2007 to 2009, the proportion of patient‐day‐weighted mean POC‐BGs that were >180 mg/dL declined from 28% to 25% in non‐ICU patients (P < 0.001), but not in ICU. Decreases in patient‐day‐weighted mean POC‐BG values in non‐ICU patients were significant regardless of hospital size, type, and geographic region (all P < 0.001), but similar decreases were not found in ICU data.CONCLUSIONSIn this first analysis of glucose changes in US hospitals, improvements over 2 years occurred in non‐ICU patients. Ongoing analysis will determine whether this trend continues. Journal of Hospital Medicine 2013;8:121–125. © 2012 Society of Hospital Medicine

Abstract Cancer-associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAFs are “activated” and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma as a desmoplastic tumor model, we investigated the sensitivity of liver CAFs to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells but lacked similar effects in quiescent fibroblasts or cholangiocarcinoma cells. Unlike cholangiocarcinoma cells, neither CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAFs or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAFs appeared to be due, in part, to upregulation of the proapoptotic protein Bax. Short hairpin RNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors, and apoptotic cell death. In a syngeneic rat model of cholangiocarcinoma, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth, and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAFs in the tumor microenvironment as a general strategy to attack solid tumors. Cancer Res; 73(2); 897–907. ©2012 AACR.

Background and Purpose— Previous studies have suggested that family members with intracranial aneurysms (IAs) often harbor IAs in similar anatomic locations. IA location is important because of its association with rupture. We tested the hypothesis that anatomic susceptibility to IA location exists using a family-based IA study. Methods— We identified all affected probands and first-degree relatives (FDRs) with a definite or probable phenotype in each family. We stratified each IA of the probands by major arterial territory and calculated each family’s proband-FDR territory concordance and overall contribution to the concordance analysis. We then matched each family unit to an unrelated family unit selected randomly with replacement and performed 1001 simulations. The median concordance proportions, odds ratios (ORs), and P values from the 1001 logistic regression analyses were used to represent the final results of the analysis. Results— There were 323 family units available for analysis, including 323 probands and 448 FDRs, with a total of 1176 IAs. IA territorial concordance was higher in the internal carotid artery (55.4% versus 45.6%; OR, 1.54 [1.04–2.27]; P =0.032), middle cerebral artery (45.8% versus 30.5%; OR, 1.99 [1.22–3.22]; P =0.006), and vertebrobasilar system (26.6% versus 11.3%; OR, 2.90 [1.05–8.24], P =0.04) distributions in the true family compared with the comparison family. Concordance was also higher when any location was considered (53.0% versus 40.7%; OR, 1.82 [1.34–2.46]; P <0.001). Conclusions— In a highly enriched sample with familial predisposition to IA development, we found that IA territorial concordance was higher when probands were compared with their own affected FDRs than with comparison FDRs, which suggests that anatomic vulnerability to IA formation exists. Future studies of IA genetics should consider stratifying cases by IA location.

Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but poses a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD defined by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC), 610 women participating in the Kronos Early Estrogen Prevention Study (KEEPS), a clinical trial of MHT to prevent progression of CVD, were genotyped for 13,229 single nucleotide polymorphisms (SNPs) within 764 genes from anticoagulant, procoagulant, fibrinolytic, or innate immunity pathways. According to linear regression, proportion of European ancestry correlated negatively, but age at enrollment and pulse pressure correlated positively with CIMT. Adjusting for these variables, two SNPs, one on chromosome 2 for MAP4K4 gene (rs2236935, β = 0.037, P value = 2.36 × 10−06) and one on chromosome 5 for IL5 gene (rs739318, β = 0.051, P value = 5.02 × 10−05), associated positively with CIMT; two SNPs on chromosome 17 for CCL5 (rs4796119, β = −0.043, P value = 3.59 × 10−05; rs2291299, β = −0.032, P value = 5.59 × 10−05) correlated negatively with CIMT; only rs2236935 remained significant after correcting for multiple testing. Using logistic regression, when we adjusted for waist circumference, two SNPs (rs11465886, IRAK2, chromosome 3, OR = 3.91, P value = 1.10 × 10−04; and rs17751769, SERPINA1, chromosome 14, OR = 1.96, P value = 2.42 × 10−04) associated positively with a CAC score of >0 Agatston unit; one SNP (rs630014, ABO, OR = 0.51, P value = 2.51 × 10−04) associated negatively; none remained significant after correcting for multiple testing. Whether these SNPs associate with CIMT and CAC in women randomized to MHT remains to be determined.

AbstractBackgroundThere is epidemiological evidence that cardiovascular risk factors (CVRF) also are risk factors for Alzheimer's disease, but there is limited information on this from neuropathological studies, and even less from in vivo studies. Therefore, we examined the relationship between CVRF and amyloid‐β (Aβ) brain burden measured by Pittsburgh Compound B‐positron emission tomography (PiB‐PET) studies in the Alzheimer's Disease Neuroimaging Initiative.MethodsNinety‐nine subjects from the Alzheimer's Disease Neuroimaging Initiative cohort who had a PiB‐PET study measure, apolipoprotein E genotyping data, and information available on CVRF (body mass index [BMI], systolic blood pressure, diastolic blood pressure [DBP], and cholesterol and fasting glucose test results) were included. Eighty‐one subjects also had plasma cortisol, C‐reactive protein, and superoxide dismutase 1 measurements. Stepwise regression models were used to assess the relation between the CVRF and the composite PiB‐PET score.ResultsThe first model included the following as baseline variables: age, clinical diagnosis, number of apolipoprotein ε4 alleles, BMI (P = .023), and DBP (P = .012). BMI showed an inverse relation with PiB‐PET score, and DBP had a positive relation with PiB‐PET score. In the second adjusted model, cortisol plasma levels were also associated with PiB‐PET score (P = .004). Systolic blood pressure, cholesterol, or impaired fasting glucose were not found to be associated with PiB‐PET values.ConclusionIn this cross‐sectional study, we found an association between Aβ brain burden measured in vivo and DBP and cortisol, indicating a possible link between these CVRF and Aβ burden measured by PiB‐PET. These findings highlight the utility of biomarkers to explore potential pathways linking diverse Alzheimer's disease risk factors.

SummaryBackgroundThe optimal methadone dosing regimen for children undergoing spinal surgery is uncertain because of sparse pediatric pharmacokinetic data and a paucity of analgesic effect data. The minimum effective analgesic concentration of methadone in opioid naïve adults is 58 mcg·L−1.MethodsAdolescents aged 12–19 years undergoing idiopathic scoliosis correction were administered 0.25 mg·kg−1 racemic methadone IV prior to surgical incision. Arterial blood samples for methadone assay were obtained at 0 min, 5 min, 10 min, 15 min, 20 min, 40 min, 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. Compartment analysis was undertaken using nonlinear mixed effects models. Parameter estimates were standardized to a 70‐kg person using allometric models.ResultsA three‐compartment linear disposition model best described observed time–concentration profiles. Population parameter estimates (between‐subjects variability) were central volume (V1) 19.1 (126%) L 70 kg−1, peripheral volumes of distribution V2 65.5 (60%) L 70 kg−1, V3 485 (23%) L 70 kg−1, clearance (CL) 9.3 (11%) L·h−1·70 kg−1, and inter‐compartment clearances Q2 282 (95%) L·h−1 70 kg−1, Q3 139 (42%) L·h−1 70 kg−1. The terminal elimination half‐life was 44.4 h. The mean observed methadone concentration was <58 mcg·L−1 by the first hour after administration.ConclusionsCurrent pharmacokinetic parameter estimates in adolescents are similar to those reported in adults. Methadone undergoes rapid redistribution after bolus administration. This may result in plasma concentrations that provide inadequate analgesia postoperatively. We would suggest following the bolus (0.25 mg.kg‐1) with an infusion (0.1–0.15 mg·kg−1·h−1 for 4 h) during spinal surgery to ensure adequate plasma concentrations for 24 h.