Citations

Genomewide association studies (GWAS) and candidate‐gene studies have implicated single‐nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case‐control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate‐gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate‐gene studies was associated in the full case‐control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate‐gene approach lay in selecting both appropriate genes and relevant SNPs within these genes.

ObjectivesThe clinical severity of aortic stenosis (AS) is based largely on symptoms. However, AS severity is primarily determined by estimating the aortic valve area (AVA) and pressure gradients (ΔP). Conditions may arise in which there is a mismatch in severity between AVA and ΔP determinations secondary to errors in measurement and/or assumption, alterations of flow, or variations in the magnitude of pressure recovery. The cause of discrepancy between area and gradient determinations must be deciphered so as to best counsel patients on the most ideal treatment strategy. (J Interven Cardiol 2013;26:183–194)

Background— Despite complete interruption of antegrade coronary artery flow in the setting of a chronic total occlusion (CTO), clinical recognition of myocardial infarction is often challenging. Using cardiac MRI, we investigated the frequency and extent of myocardial infarction in patients with CTO, and assessed their relationship with regional systolic function and the extent of angiographic collateral flow. Methods and Results— We included 170 consecutive patients (median age, 62 years) with angiographically documented CTO. Regional late gadolinium enhancement and wall motion score index were assessed by cardiac MRI with the use of a 17-segment model. Angiographic collateral flow was assessed by the collateral connection grade and the Rentrop score. Evidence of previous myocardial infarction was found in 25% of patients by ECG Q waves, in 69% by regional wall motion abnormality, and in 86% of patients by late gadolinium enhancement. Increased angiographic collateral flow was associated with a lower frequency of Q waves on ECG, and a lower regional wall motion score index, late gadolinium enhancement volume (%), and degree of late gadolinium enhancement transmurality (all P <0.001), as well. Conclusions— The frequency of myocardial infarction in territories subtended by CTO is significantly higher than previously recognized. The degree of myocardial injury downstream epicardial CTO is inversely correlated with the degree of angiographic collaterals.

Patients with pulmonary arterial hypertension (PAH) and heart failure (HF) display many abnormalities in respiratory gas exchange. These abnormalities are accentuated with exercise and track with disease severity. However, use of gas exchange measures in day-to-day clinical practice is limited by several issues, including the large number of variables available and difficulty in data interpretation. Moreover, maximal exercise testing has limitations in clinical populations due to their complexity, patient anxiety and variability in protocols and cost. Therefore, a multivariable gas exchange index (MVI) that integrates key gas exchange variables obtained during submaximal exercise into a severity score that ranges from normal to severe-very-severe is proposed. To demonstrate the usefulness of this index, we applied this to 2 groups (PAH,n=42and HF,n=47) as well as to age matched healthy controls (n=25). We demonstrate that this score tracks WHO classification and right ventricular systolic pressure in PAH (r=0.53and 0.73,P≤0.01) and NYHA and cardiac index in HF (r=0.49and 0.74,P≤0.01). This index demonstrates a stronger relationship than any single gas exchange variable alone. In conclusion, MVI obtained from light, submaximal exercise gas exchange is a useful approach to simplify data interpretation in PAH and HF populations.

Purpose The purpose of this study was to evaluate whether transporting insulin aspart FlexPens via a pneumatic tube system affects the dosing accuracy of the pens. Methods A total of 115 Novo Nordisk FlexPens containing insulin aspart were randomly assigned to be transported via a pneumatic tube system (n = 92) or to serve as the control (n = 23). Each pen was then randomized to 10 international unit (IU) doses (n = 25) or 30 IU doses (n = 67), providing 600 and 603 doses, respectively, for the pneumatic tube group. The control group also received random assignment to 10 IU doses (n = 6) or 30 IU doses (n = 17), providing 144 and 153 doses, respectively. Each dose was expelled using manufacturer instructions. Weights were recorded, corrected for specific gravity, and evaluated based on acceptable International Organization for Standardization (ISO) dosing limits. Results In the group of pens transported through the pneumatic tube system, none of the 600 doses of 10 IU (0.0%; 95% CI, 0.0 to 0.6) and none of the 603 doses of 30 IU (0.0%; 95% CI, 0.0 to 0.6) fell outside of the range of acceptable weights. Correspondingly, in the control group, none of the 144 doses at 10 IU (0.0%; 95% CI, 0.0 to 2.5) and none of the 153 doses at 30 IU (0.0%; 95% CI, 0.0 to 2.4) were outside of acceptable ISO limits. Conclusion Transportation via pneumatic tube system does not appear to compromise dosing accuracy. Hospital pharmacies may rely on the pneumatic tube system for timely and accurate transport of insulin aspart FlexPens.

Constitutively active nuclear factor-κB (NF-κB) is integral to the survival of Hodgkin/Reed-Sternberg cells (H/RS) in Hodgkin lymphoma (HL). To investigate NF-κB pathway proteins in pediatric HL, we utilized a tissue microarray compiled from 102 children enrolled in the Children's Oncology Group intermediate-risk clinical trial AHOD0031 (56 male, 78 Caucasian, median age 15 years (range 1–20 years), 85 nodular sclerosing subtype, 23 Epstein-Barr virus (EBV) positive, and 24 refractory/relapsed disease). We examined the intensity, localization, and pathway correlations of NF-κB pathway proteins (Rel-A/p65, Rel-B, c-Rel, NF-κB1, NF-κB2, IκB-α, IKK-α, IKK-β, IKK-γ/NEMO, NIK, and A20), as well as their associations with EBV status and clinical outcome. NF-κB pathway proteins were overexpressed in pediatric HL patients compared to controls. Patients with EBV− tumors, or with rapid early therapy response, had tightly coordinated regulation of NF-κB pathway proteins, whereas patients with EBV+ tumors, or slow early therapy response, had little coordinated NF-κB pathway regulation. High NIK expression was associated with a slow response to therapy and decreased EFS. Elevated Rel-B, NIK, and the NF-κB inhibitor A20 were associated with decreased EFS in multivariate analysis. These studies suggest a pivotal role for the NF-κB pathway in therapy response and patient survival in Hodgkin lymphoma.

Plasma free fatty acid (FFA) kinetics in humans are often measured with only one tracer. In study 1, healthy volunteers received infusions of [U-13C]linoleate, [U-13C]oleate, and [U-13C]palmitate during continuous feeding with liquid meals low (n = 12) and high (n = 5) in palmitate and containing three labeled fatty acids to measure FFA appearance and fractional spillover of lipoprotein lipase–generated fatty acids. Study 2 used an intravenous lipid emulsion to increase FFA concentrations during infusion of linoleate and palmitate tracers. In study 1, there were no differences in spillover of the three fatty acids for the low-palmitate meal, but linoleate spillover was greater than oleate or palmitate for the high-palmitate meal. In studies 1 and 2, clearance was significantly greater for linoleate than for the other FFAs. There was a negative correlation between clearance and concentration for each fatty acid in the two studies. In study 1, concentration and spillover correlated positively for oleate and palmitate but negatively for linoleate. In conclusion, linoleate spillover is greater than that of other fatty acids under some circumstances. Linoleate clearance is greater than that of palmitate or oleate, indicating a need for caution when using a single FFA to infer the behavior of all fatty acids.