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Enterotoxigenic Escherichia coli (ETEC) encoding heat-stable enterotoxin (ST) alone or with heat-labile enterotoxin (LT) cause moderate-to-severe diarrhea (MSD) in developing country children. The Global Enteric Multicenter Study (GEMS) identified ETEC encoding ST among the top four enteropathogens. Since the GEMS objective was to provide evidence to guide development and implementation of enteric vaccines and other interventions to diminish diarrheal disease morbidity and mortality, we examined colonization factor (CF) prevalence among ETEC isolates from children age <5 years with MSD and from matched controls in four African and three Asian sites. We also assessed strength of association of specific CFs with MSD. MSD cases enrolled at healthcare facilities over three years and matched controls were tested in a standardized manner for many enteropathogens. To identify ETEC, three E. coli colonies per child were tested by polymerase chain reaction (PCR) to detect genes encoding LT, ST; confirmed ETEC were examined by PCR for major CFs (Colonization Factor Antigen I [CFA/I] or Coli Surface [CS] antigens CS1-CS6) and minor CFs (CS7, CS12, CS13, CS14, CS17, CS18, CS19, CS20, CS21, CS30). ETEC from 806 cases had a single toxin/CF profile in three tested strains per child. Major CFs, components of multiple ETEC vaccine candidates, were detected in 66.0% of LT/ST and ST-only cases and were associated with MSD versus matched controls by conditional logistic regression (p≤0.006); major CFs detected in only 25.0% of LT-only cases weren't associated with MSD. ETEC encoding exclusively CS14, identified among 19.9% of 291 ST-only and 1.5% of 259 LT/ST strains, were associated with MSD (p = 0.0011). No other minor CF exhibited prevalence ≥5% and significant association with MSD. Major CF-based efficacious ETEC vaccines could potentially prevent up to 66% of pediatric MSD cases due to ST-encoding ETEC in developing countries; adding CS14 extends coverage to ~77%.

BackgroundThe ratio of von Willebrand Factor to platelets (VITRO) reflects the severity of fibrosis and portal hypertension and might thus hold prognostic value.MethodsPatients with compensated cirrhosis were recruited. VITRO, Child–Pugh score (CPS) and MELD were determined at study entry. Hepatic decompensation was defined as variceal bleeding, ascites or hepatic encephalopathy. Liver transplantation and death were recorded.ResultsOne hundred and ninety-four patients with compensated cirrhosis (CPS-A 89%, B 11%; 56% male; median age 56 years; 50% with varices) were included. During a median follow-up of 45 months (IQR 29–61), decompensation occurred in 35 (18%) patients and 14 (7%) patients deceased. The risk of hepatic decompensation was significantly increased in the n = 88 (45%) patients with a VITRO ≥ 2.5 (p < 0.001). Patients with a VITRO ≥ 2.5 had a higher probability of decompensation at 1-year 9% (95% CI 3–16) vs. 0% (95% CI 0–0) and at 2-years 18% (95% CI 10–27%), vs. 4% (95% CI 0–8%) as compared to patients with VITRO < 2.5. Patients with VITRO ≥ 2.5, the estimated 1-year/2-year survival rates were at 98% (95% CI 95–100%) and 94% (95% CI 88–99%) as compared to 100% (95% CI 100–100%) both in the patients with a VITRO < 2.5 (p < 0.001). After adjusting for age, albumin and MELD, VITRO ≥ 2.5 remained as significant predictor of transplant-free mortality (HR 1.38, CI 1.09–1.76; p = 0.007). Patients with compensated cirrhosis and VITRO > 2.1 after hepatitis C eradication remained at significantly increased risk for decompensation (p = 0.033).ConclusionsVITRO is a valuable prognostic tool for estimating the risk of decompensation and mortality in patients with compensated cirrhosis—including the setting after hepatitis C eradication.

Highlights • ETVAX induces cross-reactive antibodies that bind to related, non-vaccine colonisation factors. • ETVAX may protect against a wider range of ETEC strains than previously appreciated. • A novel approach to determine antibody avidity based on limiting antigen dilution is described. • Repeat ETVAX vaccination induces vaccine-specific antibodies with increased avidity.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1 – 4 . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5 – 8 . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9 , 10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3 , 4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2 , CBFA2T3 , PRDM6 , UTX and OTX2 . CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens , and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES + KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB. Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour. 

We aimed to study the endothelial dysfunction among children and adolescents with transfusion-dependent β-thalassemia using von Willebrand factor antigen (VWF:Ag) and flow cytometric analysis of circulating CD144+ endothelial microparticles (EMPs) and endothelial progenitor cells (CD34+VEGFR2+) and assess their relation to iron overload, erythropoietin and chelation therapy as well as echocardiographic parameters and carotid intima–media thickness. The VWF:Ag, EMPs, and CD34+VEGFR2+ cells were significantly higher among patients with β-thalassemia than controls (P < .001). The type of chelation and patients’ compliance did not influence the results. No significant correlations were found between the studied vascular markers. Patients with evident heart disease had higher VWF: Ag, EMPs, and CD34+VEGFR2+ cells than those without. Carotid intima–media thickness was increased among patients but not correlated with vascular markers. We suggest that procoagulant EMPs and VWF: Ag are involved in cardiovascular complications in patients with young β-thalassemia. CD34+VEGFR2+ cells were further increased in response to tissue injury contributing to reendothelialization and neovascularization.

Background/Objectives: Teosinte branched1/Cycloidea/Proliferating cell nuclear antigen factors (TCPs) are plant-specific transcription factors involved in leaf development, flowering, branching, hormone signaling, and stress responses. Prunus a key temperate fruit tree with ornamental spring blooms, still lacks comprehensive TCP gene studies across many species. Methods: We identified 154 TCP genes in eight Prunus species: 19 in Prunus tenella var. tenella, 19 in P. amygdalus, 17 in P. armeniaca ‘Rojo Pasion’, 19 in P. mira, 20 in P. jamasakura var. jamasakura, 19 in P. fruticosa, 19 in P. mume var. tortuosa, and 22 in P. × yedoensis ‘Somei-yoshino’. These genes were classified into PCF, CIN, and CYC/TB1 groups. We examined segmental duplication, conserved motifs, and cis-acting elements. Expression patterns of 12 TCPs in P. tenella var. tenella were tested under low-temperature stress (25 °C, 5 °C, −5 °C, and −10 °C), and PtTCP9’s subcellular localization was determined. Results: TCP genes within the same groups showed similar motifs and cis-acting elements. Cold stress analysis identified multiple low-temperature-responsive elements in gene promoters. Four genes (PtTCP2, PtTCP6, PtTCP14, and PtTCP16) increased expression under cold stress, while six genes (PtTCP1, PtTCP5, PtTCP8, PtTCP9, PtTCP17, and PtTCP19) decreased. PtTCP9 was localized to the nucleus. Conclusions: This was the first genome-wide study of the TCP gene family in these eight Prunus species, providing valuable insights into the characteristics and functions of TCP genes within this important genus.

Background: Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality and is an independent risk factor for hypertension. Novel circulating cardiovascular risk markers enabling a more accurate prediction of cardiovascular risk have been identified. Examination of these markers may clarify the increased risk in OSA and contribute to an analysis of the benefits of treatment. Methods: Plasma levels of total cholesterol and triglyceride and activated coagulation factors XIIa and VIIa, factors VII, VIII, XII, fibrinogen, thrombin-antithrombin (TAT), von Willebrand factor antigen (vWFAg), soluble P-selectin (sP-sel), and homocysteine were measured before and after treatment for 1 month with therapeutic or subtherapeutic (control) continuous positive airways pressure (CPAP) in 220 patients with OSA. Results: Levels of activated coagulation factors XIIa, VIIa, TAT and sP-sel were higher in OSA patients at baseline than in unmatched controls, but did not fall with 1 month of therapeutic CPAP treatment. The raised sP-sel levels correlated only with body mass index (p = 0.002). There was a trend towards a significant fall in total cholesterol with therapeutic CPAP (p = 0.06) compared with the control group. In the therapeutic group there was a clinically significant mean fall in total cholesterol of 0.28 mmol/l (95% confidence interval 0.11 to 0.45, p = 0.001) which may reduce cardiovascular risk by about 15%. Conclusion: A number of activated coagulation factors are increased in untreated OSA patients, potentially contributing to vascular risk, but they do not fall with 1 month of CPAP treatment. Nasal CPAP may produce a clinically relevant fall in total cholesterol level, potentially reducing cardiovascular risk, but this needs to be verified in a larger prospective study.

We evaluated the accuracy and precision of von Willebrand disease (vWD) testing performed by up to 50 North American Specialty Coagulation Laboratories from 2004 through 2009, using proficiency samples from healthy subjects (n = 7) and patients with type 1 vWD (n = 7) or type 2 vWD (n = 3). We analyzed 2,212 submitted results. Precision was highest for von Willebrand factor (vWF) antigen assays (coefficient of variation, 14%), which were performed predominantly by latex immunoassays, and lowest for ristocetin cofactor assays (coefficient of variation, 28%), which were increasingly replaced by collagen binding and immunofunctional methods during the 6-year evaluation period. Overall interpretation error rates ranged from 3% for normal samples, 28% for type 1 vWD, and 60% for type 2 vWD. Type 2 vWD samples were correctly identified by all laboratories using collagen binding/antigen ratios but by only one third of laboratories using ristocetin cofactor/antigen or immunofunctional/antigen ratios. In 2009, only 27% (12/45) of laboratories performed vWF multimer analysis, with error rates ranging from 7% to 22%.

We have previously reported clinical data to suggest that colonization factor I (CFA/I) fimbriae of enterotoxigenic Escherichia coli (ETEC) can bind to Lewis a (Le a ), a glycan epitope ubiquitous in the small intestinal mucosa of young children (<2 years of age), and individuals with a genetic mutation of FUT2 . To further elucidate the physiological binding properties of this interaction, we engineered Chinese Hamster Ovary (CHO-K1) cells to express Le a or Le b determinants on both N - and O -glycans. We used our glyco-engineered CHO-K1 cell lines to demonstrate that CfaB, the major subunit of ETEC CFA/I fimbriae, as well as four related ETEC fimbriae, bind more to our CHO-K1 cell-line expressing Le a , compared to cells carrying Le b or the CHO-K1 wild-type glycan phenotype. Furthermore, using in-silico docking analysis, we predict up to three amino acids (Glu 25 , Asn 27 , Thr 29 ) found in the immunoglobulin (Ig)-like groove region of CfaB of CFA/I and related fimbriae, could be important for the preferential and higher affinity binding of CFA/I fimbriae to the potentially structurally flexible Le a glycan. These findings may lead to a better molecular understanding of ETEC pathogenesis, aiding in the development of vaccines and/or anti-infection therapeutics.

von Willebrand factor ristocetin cofactor activity (VWF:RCo) is the standard functional assay used for von Willebrand disease (VWD) diagnosis. However, it has some drawbacks including being time consuming and labor intensive and having high inter-laboratory variability. The HemosIL VWF activity assay has the advantages of both high speed and automation. The purpose of this study was to prospectively compare these two functional assays for type 1 VWD detection. Plasma samples from 108 subjects were assessed in this study. HemosIL VWF activity was measured with the HemosIL latex immunoturbidimetric commercial kits by the ACL TOP coagulation analyzer. VWF:RCo was measured by platelet aggregation method. Pearson correlation analyses were performed to estimate the correlation of HemosIL VWF activity with VWF:RCo. Receiver-operator characteristic (ROC) curve analysis was used to evaluate the performance of the two diagnostic tests. The correlation coefficient between VWF:RCo and HemosIL VWF activity was 0.874 overall and was 0.761 and 0.811 in the cohorts of type 1 VWD and non-VWD, respectively. The sensitivity and specificity of HemosIL VWF activity assay for type 1 VWD identification were 94.7% and 80.0%, respectively, and the ROC curve of HemosIL VWF activity was larger than that of VWF:RCo (0.928 vs 0.863, p=0.0138). Finally, the positive and negative predictive values of the HemosIL VWF activity assay for type 1 VWD detection were 72.0% and 96.6%, respectively. Our results demonstrate that the HemosIL VWF activity assay was an effective method for type 1 VWD screening and diagnosis. It carried good sensitivity and specificity and had a higher ROC curve than VWF:RCo besides showing good correlation with VWF:RCo. With its advantages of greater speed and automated performance, these results suggest that the HemosIL VWF activity assay was reliable and precise in the clinical setting.