Citations

AbstractFrontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD‐TDP). Recently, a genome‐wide association study identified the first FTLD‐TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD‐TDP risk. Intriguingly, the most significant association was in FTLD‐TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD‐TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B‐specific antibody for investigation of this protein. Enzyme‐linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over‐expression. However, over‐expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N‐glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD‐TDP risk. image We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations. Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B, potentially due to differences in glycosylation. These findings suggest that low TMEM106B levels might protect against FTLD‐TDP in these patients.

Accumulating pre-clinical data suggests that matrix metalloproteinase (MMP) expression plays a critical role in the pathophysiology of secondary brain injury. We conducted a prospective multimodal monitoring study in order to characterize the temporal MMP response after severe traumatic brain injury (TBI) in eight critically ill humans and its relationship with outcomes. High-cutoff, cerebral microdialysis ( n =8); external ventricular drainage ( n =3); and arterial and jugular venous bulb catheters were used to collect microdialysate, cerebrospinal fluid, and arterial and jugular bulb blood over 6 days. Levels of MMP-8 and -9 were initially high in microdialysate and then gradually declined over time. After these MMPs decreased, a spike in the microdialysate levels of MMP-2 and -3 occurred, followed by a gradual rise in the microdialysate concentration of MMP-7. Use of generalized estimating equations suggested that MMP-8 concentration in microdialysate was associated with mortality ( p =0.019) and neurological outcome at hospital discharge ( p =0.013). Moreover, the mean microdialysate concentration of MMP-8 was 2.4-fold higher among those who died after severe TBI than in those who survived. Mean microdialysate levels of MMP-8 also rose with increasing intracranial pressure (ICP), whereas those of MMP-7 decreased with increasing cerebral perfusion pressure (CPP). Significant changes in the mean microdialysate concentrations of MMP-1, -2, -3, and -9 and MMP-1, -2, -3, -7, and -9 also occurred with increases in microdialysate glucose and the lactate/pyruvate ratio, respectively. These results imply that monitoring of MMPs following severe TBI in humans is feasible, and that their expression may be associated with clinical outcomes, ICP, CPP, and cerebral metabolism.

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

Background— Implantable cardioverter-defibrillator (ICD) therapy in children and congenital heart disease patients is hampered by poor long-term lead survival. Lead extraction is technically difficult and carries substantial morbidity. We sought to determine the outcomes of ICD leads in pediatric and congenital heart disease patients. Methods and Results— The Pediatric Lead Extractability and Survival Evaluation (PLEASE) is a 24-center international registry. Pediatric and congenital heart disease patients with ICD lead implantations from 2005 to 2010 were eligible. Study subjects comprised 878 ICD patients (44% congenital heart disease). Mean±SD age at implantation was 18.6±9.8 years. Of the 965 total leads, 54% were thin (≤7F), of which 57% were Fidelis, and 23% were coated with expanded polytetrafluoroethylene. There were 139 ICD lead failures (14%) in 132 patients (15%) at a mean lead age of 2.0±1.4 years, causing shocks in 53 patients (40%). Independent predictors of lead failure included younger implantation age and Fidelis leads. Actuarial analysis showed an incremental risk of lead failure with younger age at implantation: <8 years compared with >18 years ( P =0.015). The actuarial yearly failure rate was 2.3% for non-Fidelis and 9.1% for Fidelis leads. Extraction was performed on 143 leads (80% thin, 7% expanded polytetrafluoroethylene coated), with lead age as the only independent predictor for advanced extraction techniques. There were 6 major extraction complications (4%) but no procedural mortality. Conclusions— This study demonstrates that ICD leads in children and congenital heart disease patients have an age-related suboptimal performance, further compounded by a high failure rate of Fidelis leads. Advanced extraction techniques were common and correlated with older lead age. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00335036.

Background— The risks of sports participation for implantable cardioverter-defibrillator (ICD) patients are unknown. Methods and Results— Athletes with ICDs (age, 10–60 years) participating in organized (n=328) or high-risk (n=44) sports were recruited. Sports-related and clinical data were obtained by phone interview and medical records. Follow-up occurred every 6 months. ICD shock data and clinical outcomes were adjudicated by 2 electrophysiologists. Median age was 33 years (89 subjects <20 years of age); 33% were female. Sixty were competitive athletes (varsity/junior varsity/traveling team). A pre-ICD history of ventricular arrhythmia was present in 42%. Running, basketball, and soccer were the most common sports. Over a median 31-month (interquartile range, 21–46 months) follow-up, there were no occurrences of either primary end point—death or resuscitated arrest or arrhythmia- or shock-related injury—during sports. There were 49 shocks in 37 participants (10% of study population) during competition/practice, 39 shocks in 29 participants (8%) during other physical activity, and 33 shocks in 24 participants (6%) at rest. In 8 ventricular arrhythmia episodes (device defined), multiple shocks were received: 1 at rest, 4 during competition/practice, and 3 during other physical activity. Ultimately, the ICD terminated all episodes. Freedom from lead malfunction was 97% at 5 years (from implantation) and 90% at 10 years. Conclusions— Many athletes with ICDs can engage in vigorous and competitive sports without physical injury or failure to terminate the arrhythmia despite the occurrence of both inappropriate and appropriate shocks. These data provide a basis for more informed physician and patient decision making in terms of sports participation for athletes with ICDs.

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.

Atrial fibrillation ( AF ) is a cardiac arrhythmia associated with significant morbidity and mortality, affecting more than 3 million people in the United States and 1–2% of the population worldwide. Its estimated prevalence is expected to double within the next 50 years. During the past decade, there have been significant advances in the treatment of AF . Studies have demonstrated that a rate control strategy, with a target resting heart rate between 80 and 100 beats/minute, is recommended over rhythm control in the vast majority of patients. The CHA 2 DS 2 ≥ (congestive heart failure, hypertension, age ≥ 65 yrs, diabetes mellitus, stroke or transient ischemic attack, vascular disease, female gender) scoring system is a potentially useful stroke risk stratification tool that incorporates additional risk factors to the commonly used CHADS 2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke transient ischemic attack) scoring tool. Similarly, a convenient scheme, termed HAS ‐ BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), to assess bleeding risk has emerged that may be useful in select patients. Furthermore, new antithrombotic strategies have been developed as potential alternatives to warfarin, including dual‐antiplatelet therapy with clopidogrel plus aspirin and the development of new oral anticoagulants such as dabigatran, rivaroxaban, and apixaban. Vernakalant has emerged as another potential option for pharmacologic conversion of AF , whereas recent trials have better defined the role of dronedarone in the maintenance of sinus rhythm. Finally, catheter ablation represents another alternative to manage AF , whereas upstream therapy with inhibitors of the renin‐angiotensin‐aldosterone system, statins, and polyunsaturated fatty acids could potentially prevent the occurrence of AF . Despite substantial progress in the management of AF , significant uncertainty surrounds the optimal treatment of this condition.

A growing body of research is investigating the potential contribution of mitochondrial function to the etiology of type 2 diabetes. Numerous in vitro, in situ, and in vivo methodologies are available to examine various aspects of mitochondrial function, each requiring an understanding of their principles, advantages, and limitations. This review provides investigators with a critical overview of the strengths, limitations and critical experimental parameters to consider when selecting and conducting studies on mitochondrial function. In vitro (isolated mitochondria) and in situ (permeabilized cells/tissue) approaches provide direct access to the mitochondria, allowing for study of mitochondrial bioenergetics and redox function under defined substrate conditions. Several experimental parameters must be tightly controlled, including assay media, temperature, oxygen concentration, and in the case of permeabilized skeletal muscle, the contractile state of the fibers. Recently developed technology now offers the opportunity to measure oxygen consumption in intact cultured cells. Magnetic resonance spectroscopy provides the most direct way of assessing mitochondrial function in vivo with interpretations based on specific modeling approaches. The continuing rapid evolution of these technologies offers new and exciting opportunities for deciphering the potential role of mitochondrial function in the etiology and treatment of diabetes.

Abstract Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.