Heterozygous mis-sense mutations in Prkcb as a critical determinant of anti-polysaccharide antibody formation

To identify rate-limiting steps in T cell-independent type 2 (TI-2) antibody production against polysaccharide antigens, we performed a genome-wide screen by immunizing several hundred pedigrees of C57BL/6 mice segregating ENU-induced mis-sense mutations. Two independent mutations, Tilcara and Untied, were isolated that semi-dominantly diminished antibody against polysaccharide but not protein antigens. Both mutations resulted from single amino acid substitutions within the kinase domain of Protein Kinase C Beta (PKCβ). In Tilcara, a Ser552>Pro mutation occurred in helix G, in close proximity to a docking site for the inhibitory N-terminal pseudosubstrate domain of the enzyme, resulting in almost complete loss of active, autophosphorylated PKCβI whereas the amount of alternatively spliced PKCβII protein was not markedly reduced. Circulating B cell subsets were normal and acute responses to BCR-stimulation such as CD25 induction and initiation of DNA synthesis were only measurably diminished in Tilcara homozygotes, whereas the fraction of cells that had divided multiple times was decreased to an intermediate degree in heterozygotes. These results, coupled with evidence of numerous mis-sense PRKCB mutations in the human genome, identify Prkcb as a genetically sensitive step likely to contribute substantially to population variability in anti-polysaccharide antibody levels

Protrusion of the carotid canal into the sphenoid sinuses: evaluation before endonasal endoscopic sinus surgery

Background: Many reports have previously indicated the vast number of anatomical variations of the sphenoid sinuses, e.g. presence of the recesses. Notwithstanding, there are a few crucial neurovascular structures directly neighbouring with the sinuses. The following research aimed to evaluate frequency prevalence of the carotid canal’s protrusion into the sphenoid sinuses in adult population.Materials and methods: Computed tomography (CT) scans of the paranasal sinuses of 296 patients (147 females, 149 males) were analysed in this retrospective study. The patients did not present any pathology in the sinuses. Spiral CT scanner Siemens Somatom Sensation 16 was used in the standard procedure in the option Siemens CARE Dose 4D.Results: Protrusion of the carotid canal was found in the majority of the patients — 55.74%, more frequently in males (65.1% of the patients) than in females (46.26% of the patients). The said variant — regardless of gender — was noted more often bilaterally (41.55% of the cases: 29.93% females, 53.02% males) than unilaterally (14.19% of the cases: 16.33% females, 12.08% males). In the unilateral type (regardless of gender), the protrusion was more common for the left sphenoid sinus — 10.81% of the patients (12.24% females, 9.4% males) than for the right — 3.38% of the patients (4.08% females, 2.68% males).Conclusions: Complicated structure of the paranasal sinuses, derived from the high prevalence of their anatomical variations, may perplex routine surgical interventions. Henceforth, referral for a CT scan is imperative in order to abate the risks associated with an invasive procedure in the said region

Operationalizing Frailty in the Atherosclerosis Risk in Communities Study Cohort

Background: Factors that may contribute to the development of frailty in late life have not been widely investigated. The Atherosclerosis Risk in Communities (ARIC) Study cohort presents an opportunity to examine relationships of midlife risk factors with frailty in late life. However, we first present findings on the validation of an established frailty phenotype in this predominantly biracial population of older adults. Methods: Among 6,080 participants, we defined frailty based upon the Cardiovascular Health Study (CHS) criteria incorporating measures of weight loss, exhaustion, slow walking speed, low physical activity, and low grip strength. Criterion and predictive validity of the frailty phenotype were estimated from associations between frailty status and participants' physical and mental health status, physiologic markers, and incident clinical outcomes. Results: A total of 393 (6.5%) participants were classified as frail and 50.4% pre-frail, similar to CHS (6.9% frail, 46.6% pre-frail). In age-adjusted analyses, frailty was concurrently associated with depressive symptoms, low self-rated health, low medication adherence, and clinical biomarker levels (ie, cholesterol, hemoglobin A1c, white blood cell count, C-reactive protein, and hemoglobin). During 1-year follow-up, frailty was associated with falls, low physical ability, fatigue, and mortality. Conclusions: These findings support the validity of the CHS frailty phenotype in the ARIC Study cohort. Future studies in ARIC may elucidate early-life exposures that contribute to late-life frailty

Variation in Rates of Fatal Coronary Heart Disease by Neighborhood Socioeconomic Status: The Atherosclerosis Risk in Communities Surveillance (1992–2002)

Racial and gender disparities in out-of-hospital deaths from coronary heart disease (CHD) have been well-documented, yet disparities by neighborhood socioeconomic status have been less systematically studied in US population-based surveillance efforts

Role of BMI in the Association of the TCF7L2 rs7903146 Variant with Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study

We examined the association of variation in the type 2 diabetes risk-conferring TCF7L2 gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean ( BMI < 25 kg/m2) individuals homozygous for the T allele of the TCF7L2 rs7903146 gene risk variant (hazard ratio 1.42; 95% CI 1.03,1.97; P = .01). No association was found among 3,631 blacks, regardless of BMI status. An attenuated hazard ratio was observed among the nondiabetic ARIC cohort members. This study suggests that body mass modifies the association of the TCF7L2 rs7903146 T allele with CHD risk

Electrocardiographic Predictors of Coronary Heart Disease and Sudden Cardiac Deaths in Men and Women Free From Cardiovascular Disease in the Atherosclerosis Risk in Communities Study

BackgroundWe evaluated predictors of coronary heart disease (CHD) death and sudden cardiac death (SCD) in the Atherosclerosis Risk in Communities (ARIC) study.Methods and ResultsThe study population included 13 621 men and women 45 to 65 years of age free from manifest cardiovascular disease at entry. Hazard ratios from Cox regression with 95% confidence intervals were computed for 18 dichotomized repolarization‐related ECG variables. The average follow‐up was 14 years. Independent predictors of CHD death in men were TaVR‐ and rate‐adjusted QTend (QTea), with a 2‐fold increased risk for both, and spatial angles between mean QRS and T vectors and between Tpeak (Tp) and normal R reference vectors [θ(Rm|Tm) and θ(Tp|Tref), respectively], with a >1.5‐fold increased risk for both. In women, independent predictors of the risk of CHD death were θ(Rm|Tm), with a 2‐fold increased risk for θ(Rm|Tm), and θ(Tp|Tref), with a 1.7‐fold increased risk. Independent predictors of SCD in men were θ(Tp|Tref) and QTea, with a 2‐fold increased risk, and θ(Tinit|Tterm), with a 1.6‐fold increased risk. In women, θ(Tinit|Tterm) was an independent predictor of SCD, with a >3‐fold increased risk, and θ(Rm|Tm) and TV1 were >2‐fold for both.Conclusionsθ(Rm|Tm) and θ(Tp|Tref), reflecting different aspects of ventricular repolarization, were independent predictors of CHD death and SCD, and TaVR and TV1 were also independent predictors. The risk levels for independent predictors for both CHD death and SCD were stronger in women than in men, and QTea was a significant predictor in men but not in women

SH3BP4 Regulates Intestinal Stem Cells and Tumorigenesis by Modulating β-Catenin Nuclear Localization

SUMMARY Wnt signals at the base of mammalian crypts play a pivotal role in intestinal stem cell (ISC) homeostasis, whereas aberrant Wnt activation causes colon cancer. Precise control of Wnt signal strength is governed by a number of negative inhibitory mechanisms acting at distinct levels of the cascade. Here, we identify the Wnt negative regulatory role of Sh3bp4 in the intestinal crypt. We show that the loss of Sh3bp4 increases ISC and Paneth cell numbers in murine intestine and accelerates adenoma development in Apcmin mice. Mechanistically, human SH3BP4 inhibits Wnt signaling downstream of b-catenin phosphorylation and ubiquitination. This Wnt inhibitory role is dependent on the ZU5 domain of SH3BP4. We further demonstrate that SH3BP4 is expressed at the perinuclear region to restrict nuclear localization of b-catenin. Our data uncover the tumor-suppressive role of SH3BP4 that functions as a negative feedback regulator of Wnt signaling through modulating b-catenin’s subcellular localization

Medication Adherence Based on Part D Claims for Patients With Heart Failure After Hospitalization (from the Atherosclerosis Risk in Communities Study)

Medication non-adherence is a common precipitant of heart failure (HF) hospitalization and is associated with poor outcomes. Recent analyses of national data focus on long-term medication adherence. Little is known about adherence of HF patients immediately following hospitalization. Hospitalized HF patients were identified from the Atherosclerosis Risk in Communities (ARIC) study. ARIC data were linked to Medicare inpatient and Part D claims from 2006–2009. Inclusion criteria were: a chart adjudicated diagnosis of acute decompensated or chronic HF; documentation of angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), beta-blocker (BB), or diuretic prescription at discharge; Medicare Part D coverage. Proportion ambulatory days covered (PADC) was calculated for up to twelve 30-day periods after discharge. Adherence was defined as ≥80% PADC. We identified 402 participants with Medicare Part D: mean age 75, 30% male, 41% black. Adherence at 1, 3 and 12 months was 70%, 61%, 53% for ACEI/ARB, 76%, 66%, 62% for BB, and 75%, 68%, 59% for diuretic. Adherence to any single drug class was positively correlated with being adherent to other classes. Adherence varied by geographic site/race for ACEI/ARB and BB but not diuretics. In conclusion, despite having Part D coverage, medication adherence post discharge for all three medication classes declined over 2–4 months after discharge, followed by a plateau over the subsequent year. Interventions should focus on early and sustained adherence