Alpha2 Macroglobulin-Like Is Essential for Liver Development in Zebrafish

Background: Alpha 2 Macroglobulin family members have been studied extensively with respect to their roles in physiology and human disease including innate immunity and Alzheimer’s disease, but little is known about a possible role in liver development loss-of-function in model systems. Principal Findings: We report the isolation of the zebrafish a2 macroglobulin-like (A2ML) gene and its specific expression in the liver during differentiation. Morpholino-based knock-down of A2ML did not block the initial formation of the liver primordium, but inhibited liver growth and differentiation. Significance: This report on A2ML function in zebrafish development provides the first evidence for a specific role of an A2M family gene in liver formation during early embryogenesis in a vertebrate

The Complexity of Computing Minimal Unidirectional Covering Sets

Given a binary dominance relation on a set of alternatives, a common thread in the social sciences is to identify subsets of alternatives that satisfy certain notions of stability. Examples can be found in areas as diverse as voting theory, game theory, and argumentation theory. Brandt and Fischer [BF08] proved that it is NP-hard to decide whether an alternative is contained in some inclusion-minimal upward or downward covering set. For both problems, we raise this lower bound to the Theta_{2}^{p} level of the polynomial hierarchy and provide a Sigma_{2}^{p} upper bound. Relatedly, we show that a variety of other natural problems regarding minimal or minimum-size covering sets are hard or complete for either of NP, coNP, and Theta_{2}^{p}. An important consequence of our results is that neither minimal upward nor minimal downward covering sets (even when guaranteed to exist) can be computed in polynomial time unless P=NP. This sharply contrasts with Brandt and Fischer's result that minimal bidirectional covering sets (i.e., sets that are both minimal upward and minimal downward covering sets) are polynomial-time computable.Comment: 27 pages, 7 figure

Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia?

A previous report suggested that 88% of individuals in the general population with total cholesterol (TC)>9.3mmol/L have familial hypercholesterolaemia (FH). We tested this hypothesis in a cohort of 4896 UK civil servants, mean (SD) age 44 (±6) years, using next generation sequencing to achieve a comprehensive genetic diagnosis. 25 (0.5%) participants (mean age 49.2 years) had baseline TC>9.3mmol/L, and overall we found an FH-causing mutation in the LDLR gene in seven (28%) subjects. The detection rate increased to 39% by excluding eight participants with triglyceride levels over 2.3mmol/L, and reached 75% in those with TC>10.4mmol/L. By extrapolation, the detection rate would be ~25% by including all participants with TC>8.6mmol/L (2.5 standard deviations from the mean). Based on the 1/500 FH frequency, 30% of all FH-cases in this cohort would be missed using the 9.3mmol/L cut-off. Given that an overall detection rate of 25% is considered economically acceptable, these data suggest that a diagnostic TC cut-off of 8.6mmol/L, rather than 9.3mmol/L would be clinically useful for FH in the general population

Subjects with Molecularly Defined Familial Hypercholesterolemia or Familial Defective apoB-100 Are Not Being Adequately Treated

To study whether subjects with a molecular genetic diagnosis of familial hypercholesterolemia (FH) or familial defective apoB-100 (FDB) are being adequately treated.A questionnaire regarding medical history was sent to 2611 subjects who had been provided with a molecular genetic diagnosis of FH or FDB, and a blood sample was obtained for lipid measurements.956 (36.6%) of the 2611 subjects participated. The mean age for starting lipid-lowering therapy was 33.4 (±12.1) years. Among those below 18 years of age, only 20.4% were on lipid-lowering drugs, whereas 89.1% of those aged 18 and above were on lipid-lowering drugs. The mean levels of total serum cholesterol and LDL-cholesterol were 5.7 (±1.5) mmol/l and 3.9 (±1.3) mmol/l, respectively. Among those who were on lipid-lowering drugs, 29.0% and 12.2% had levels of LDL cholesterol below 3.0 mmol/l and 2.6 mmol/l, respectively. Only 47.3% of the 956 subjects were considered as being adequately treated largely due to a failure to titrate their drug regimens. From the use of cholesterol-years score, lipid-lowering therapy must start before the age of 20 in order to prevent the subjects from contracting premature coronary heart disease.The majority of FH/FDB subjects are being diagnosed late in life and are not being adequately treated. In order to prevent them from contracting premature coronary heart disease, it is key that levels of LDL cholesterol are normalized from a young age and that sufficient doses of lipid-lowering drugs are being used

Prognostic value of temporal patterns of global longitudinal strain in patients with chronic heart failure

BACKGROUND: We investigated whether repeatedly measured global longitudinal strain (GLS) has incremental prognostic value over repeatedly measured left ventricular ejection fraction (LVEF) and N-terminal pro B-type natriuretic peptide (NT-proBNP), and a single “baseline” GLS value, in chronic heart failure (HF) patients. METHODS: In this prospective observational study, echocardiography was performed in 173 clinically stable chronic HF patients every six months during follow up. During a median follow-up of 2.7 years, a median of 3 (25th–75th percentile:2–4) echocardiograms were obtained per patient. The endpoint was a composite of HF hospitalization, left ventricular assist device, heart transplantation, cardiovascular death. We compared hazard ratios (HRs) for the endpoint from Cox models (used to analyze the first available GLS measurements) with HRs from joint models (which links repeated measurements to the time-to-event data). RESULTS: Mean age was 58 ± 11 years, 76% were men, 81% were in New York Heart Association functional class I/II, and all had LVEF < 50% (mean ± SD: 27 ± 9%). The endpoint was reached by 53 patients. GLS was persistently decreased over time in patients with the endpoint. However, temporal GLS trajectories did not further diverge in patients with versus without the endpoint and remained stable during follow-up. Both single measurements and temporal trajectories of GLS were significantly associated with the endpoint [HR per SD change (95%CI): 2.15(1.34–3.46), 3.54 (2.01–6.20)]. In a multivariable model, repeatedly measured GLS maintained its prognostic value while repeatedly measured LVEF did not [HR per SD change (95%CI): GLS:4.38 (1.49–14.70), LVEF:1.14 (0.41–3.23)]. The association disappeared when correcting for repeatedly measured NT-proBNP. CONCLUSION: Temporal evolution of GLS was associated with adverse events, independent of LVEF but not independent of NT-proBNP. Since GLS showed decreased but stable values in patients with adverse prognosis, single measurements of GLS provide sufficient information for determining prognosis in clinical practice compared to repeated measurements, and temporal GLS patterns do not add prognostic information to NT-proBNP

Prospective multicentre study of indications for surgery in patients with idiopathic acute pancreatitis following endoscopic ultrasonography (PICUS)

Background:Cholecystectomy in patients with idiopathic acute pancreatitis (IAP) is controversial. A randomized trial found cholecystectomy to reduce the recurrence rate of IAP but did not include preoperative endoscopic ultrasonography (EUS). As EUS is effective in detecting gallstone disease, cholecystectomy may be indicated only in patients with gallstone disease. This study aimed to determine the diagnostic value of EUS in patients with IAP, and the rate of recurrent pancreatitis in patients in whom EUS could not determine the aetiology (EUS-negative IAP).Methods:This prospective multicentre cohort study included patients with a first episode of IAP who underwent outpatient EUS. The primary outcome was detection of aetiology by EUS. Secondary outcomes included adverse events after EUS, recurrence of pancreatitis, and quality of life during 1-year follow-up.Results:After screening 957 consecutive patients with acute pancreatitis from 24 centres, 105 patients with IAP were included and underwent EUS. In 34 patients (32 per cent), EUS detected an aetiology: (micro)lithiasis and biliary sludge (23.8 per cent), chronic pancreatitis (6.7 per cent), and neoplasms (2.9 per cent); 2 of the latter patients underwent pancreatoduodenectomy. During 1-year follow-up, the pancreatitis recurrence rate was 17 per cent (12 of 71) among patients with EUS-negative IAP versus 6 per cent (2 of 34) among those with positive EUS. Recurrent pancreatitis was associated with poorer quality of life.Conclusion:EUS detected an aetiology in a one-third of patients with a first episode of IAP, requiring mostly cholecystectomy or pancreatoduodenectomy. The role of cholecystectomy in patients with EUS-negative IAP remains uncertain and warrants further study

Serum uric acid does not predict incident metabolic syndrome in a population with high prevalence of obesity

To evaluate whether uric acid (UA) predicts 4-yr incidence of metabolic syndrome (MetS) in non-diabetic participants of the Strong Heart Study (SHS) cohort

BMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells

Naive mouse embryonic stem cells (mESCs) are in a metastable state and fluctuate between inner cell mass- and epiblast-like phenotypes. Here, we show transient activation of the BMP-SMAD signaling pathway in mESCs containing a BMP-SMAD responsive reporter transgene. Activation of the BMP-SMAD reporter transgene in naive mESCs correlated with lower levels of genomic DNA methylation, high expression of 5-methylcytosine hydroxylases Tet1/2 and low levels of DNA methyltransferases Dnmt3a/b. Moreover, naive mESCs, in which the BMP-SMAD reporter transgene was activated, showed higher resistance to differentiation. Using double Smad1;Smad5 knockout mESCs, we showed that BMP-SMAD signaling is dispensable for self-renewal in both naive and ground state. These mutant mESCs were still pluripotent, but they exhibited higher levels of DNA methylation than their wild-type counterparts and had a higher propensity to differentiate. We showed that BMP-SMAD signaling modulates lineage priming in mESCs, by transiently regulating the enzymatic machinery responsible for DNA methylation