Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric ...gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.
During development, visual photoreceptors, bipolar cells and other neurons establish connections within the retina enabling the eye to process visual images over approximately 7 log units of ...illumination. Within the retina, cells that respond to light increment and light decrement are separated into ON- and OFF-pathways. Hereditary diseases are known to disturb these retinal pathways, causing either progressive degeneration or stationary deficits. Congenital stationary night blindness (CSNB) is a group of stable retinal disorders that are characterized by abnormal night vision. Genetic subtypes of CSNB have been defined and different disease actions have been postulated. The molecular bases have been elucidated in several subtypes, providing a better understanding of the disease mechanisms and developmental retinal neurobiology. Here we have studied 22 families with 'complete' X-linked CSNB (CSNB1; MIM 310500; ref. 4) in which affected males have night blindness, some photopic vision loss and a defect of the ON-pathway. We have found 14 different mutations, including 1 founder mutation in 7 families from the United States, in a novel candidate gene, NYX. NYX, which encodes a glycosylphosphatidyl (GPI)-anchored protein called nyctalopin, is a new and unique member of the small leucine-rich proteoglycan (SLRP) family. The role of other SLRP proteins suggests that mutant nyctalopin disrupts developing retinal interconnections involving the ON-bipolar cells, leading to the visual losses seen in patients with complete CSNB.
The ability to compare incremental changes in Quality Adjusted Life Years (QALYs) generated by different condition-specific preference-based measures (CSPBMs), or indeed between generic measures, is ...often criticised even where the valuation methods and source of values are the same. A key concern is the impact of excluding key dimensions from a descriptive system. This study examines the impact of adding a generic pain/discomfort dimension to a CSPBM, the AQL-5D (an asthma-specific CSPBM), by valuing samples of states from the AQL-5D with and without the new dimension using an interviewer administered time trade-off with a sample of the UK general public. 180 respondents provided 720 valuations for states with and without pain/discomfort. As expected the additional pain/discomfort dimension was found to have a significant and relatively large coefficient. More importantly for comparing changes in QALYs across populations the addition of pain/discomfort significantly impacts on the coefficients of the other dimensions and the degree of impact differs by dimension and severity level. The net effect on the utility value depends on the severity of their state: the addition of pain/discomfort at level 1 (no pain/discomfort) or 2 (moderate pain/discomfort) significantly increased the mean health state values in an asthma patient population; whereas level 3 pain/discomfort (extreme) reduced values. Comparability between measures requires that the impact of different dimensions on preferences is additive, whether or not they are included in the classification system. Our results cast doubt on this assumption, implying that the chosen measure must contain all important and relevant dimensions in its classification system.
► As expected the additional pain or discomfort dimension was associated with significant coefficients for levels 2 and 3 in the model of the health state valuation data. ► The additional dimension had a significant impact on the coefficients of other dimensions, but this differed by dimension and level. ► The net impact on the health state value depended on the level of the pain or discomfort dimension, with level 1 or 2 being associated with higher values and level 3 with lower values. ► This has important implications for the strategy of adding dimensions to existing instruments and for the achievement cross instrument comparability.
Impaired myocardial contractile function is a hallmark of heart failure (HF), which may present under resting conditions and/or during physiological stress. Previous studies have reported that high ...fat feeding in mild to moderate HF/left ventricular (LV) dysfunction is associated with improved contractile function at baseline. The goal of this study was to determine whether myocardial function is compromised in response to physiological stress and to evaluate the global gene expression profile of rats fed high dietary fat after infarction. Male Wistar rats underwent ligation or sham surgery and were fed normal chow (NC; 10% kcal fat; Sham + NC and HF + NC groups) or high-fat chow (SAT; 60% kcal saturated fat; Sham + SAT and HF + SAT groups) for 8 wk. Myocardial contractile function was assessed using a Millar pressure-volume conductance catheter at baseline and during inferior vena caval occlusions and dobutamine stress. Steady-state indexes of systolic function, LV +dP/dt(max), stroke work, and maximal power were increased in the HF + SAT group versus the HF + NC group and reduced in the HF + NC group versus the Sham + NC group. Preload recruitable measures of contractility were decreased in HF + NC group but not in the HF + SAT group. beta-Adrenergic responsiveness change in LV +dP/dt(max) and change in cardiac output with dobutamine (0-10 microg x kg(-1) x min(-1)) was reduced in HF, but high fat feeding did not further impact the contractile reserve in HF. The contractile reserve was reduced by the high-fat diet in the Sham + SAT group. Microarray gene expression analysis revealed that the majority of significantly altered pathways identified contained multiple gene targets correspond to cell signaling pathways and energy metabolism. These findings suggest that high saturated fat improves myocardial function at rest and during physiological stress in infarcted hearts but may negatively impact the contractile reserve under nonpathological conditions. Furthermore, high fat feeding-induced alterations in gene expression related to energy metabolism and specific signaling pathways revealed promising targets through which high saturated fat potentially mediates cardioprotection in mild to moderate HF/LV dysfunction.
Despite recent significant achievements in controlling hepatitis B virus (HBV) infection, immunizing high-risk groups against the disease remains a public health challenge in the United States. The ...aims of this article are to evaluate the projected cost effectiveness of hepatitis B vaccination of adults attending two major types of publicly funded HIV counseling and testing sites (CTSs)—freestanding HIV CTSs and sexually transmitted disease (STD) clinics, and to compare the cost-effectiveness of alternative vaccination and testing strategies in different subgroups in this population.
A decision model was developed to determine the economic and clinical consequences, from a societal perspective, of the following strategies in two hypothetical cohorts of 100,000 adults attending each type of site: (1) routine vaccination without screening, (2) screening for antibody to hepatitis B core antigen with an initial vaccine dose during the first visit, (3) screening and vaccination based on screening results, and (4) no intervention. Life expectancy, expected quality-adjusted life years (QALYs), and medical care costs were estimated for each strategy and at each site.
Routine vaccination was both more effective and more cost-effective than either screening strategy; under base-case assumptions, routine vaccination would cost $4400 both per QALY and per life year saved. Results for STD clinics were very similar in magnitude to those for freestanding CTSs. Results were most sensitive to clients’ time and travel costs for return visits and the time-discount rate.
Routine provision of hepatitis B vaccine at major HIV CTSs would be a highly effective and cost-effective approach to preventing hepatitis B among high-risk adults in the United States.
Intracardiac accumulation of lipid and related intermediates (e.g., ceramide) is associated with cardiac dysfunction and may contribute to the progression of heart failure (HF). Overexpression of ...nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARalpha) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPARalpha agonist increases myocardial triglyceride and/or ceramide and exacerbates LV dysfunction in HF. Rats with infarct-induced HF (n = 38) or sham-operated rats (n = 10) were either untreated (INF, n = 10), fed a high-fat diet (45% kcal fat, INF + Fat, n = 15), or fed the PPARalpha agonist fenofibrate (150 mg.kg(-1).day(-1), INF + Feno, n = 13) for 12 wk. LV ejection fraction was significantly reduced with HF (49 +/- 6%) compared with sham operated (86 +/- 2%) with no significant differences in ejection fraction (or other functional or hemodynamic measures) among the three infarcted groups. Treatment with the PPARalpha agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPARalpha-regulated genes, as well as protein expression and activity of medium chain acyl-CoA dehydrogenase (compared with INF and INF + Fat groups). Myocardial ceramide content was elevated in the INF group compared with sham-operated rats, with no further change in the INF + Fat or INF + Feno groups. Myocardial triglyceride was unaffected by infarction but increased in the INF + Fat group. In conclusion, LV dysfunction and dilation are not worsened despite upregulation of the fatty acid metabolic pathway and LV hypertrophy or accumulation of myocardial triglyceride in the rat infarct model of HF.
Lower body and core muscular strength are essential for optimal performance in many sports and competitive surfers have similar strength demands when maneuvering a surfboard to achieve competition ...success. Presently, the use of unstable surfaces is excessively utilized by surf coaches and trainers and to date, research does not support this as an effective training method for long-term improvements. Therefore, the purpose of this study was to determine the effectiveness of an 8-week Core Strength Training Program (CSTP) on a battery of field tests specific to assessing core musculature and lower body strength for junior competitive surf athletes. Nineteen American junior competitive surf athletes (age:15.7±1.01yrs, height:1.77±0.007m, mass:64.67±9.08kg) completed pre- and post-tests with a transitional pre-season to in-season 8-week CSTP intervention. The battery of tests included: rotational power (RP), time to peak acceleration (TP), maximal acceleration (Ma), maximal countermovement jump (CMJ), estimated peak power (PP), core strength (CS), core endurance (CE), and rotational flexibility (RF). Means, standard deviations, RMANOVA with a significance level of p < 0.05, and effect sizes were computed. Results demonstrated significant improvements in L.RP, TP, CMJ, PP, CS, and RF. Based on the results, the CSTP is an effective training program for surf coaches and strength and conditioning professionals to improve strength in the core musculature and lower body. In addition, we conclude implementation of the CSTP enhances athletic performance measurements which will likely increase competition success.
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