Identification and characterization of EBP, a novel EEN binding protein that inhibits Ras signaling and is recruited into the nucleus by the MLL-EEN fusion protein

The chimeric MLL-EEN fusion protein is created as a result of chromosomal translocation t(11;19)(q23;p13). EEN, an Src homology 3 (SH3) domain-containing protein in the endophilin family, has been implicated in endocytosis, although little is known about its role in leukemogenesis mediated by the MLL-EEN fusion protein. In this study, we have identified and characterized EBP, a novel EEN binding protein that interacts with the SH3 domain of EEN through a proline-rich motif PPERP. EBP is a ubiquitous protein that is normally expressed in the cytoplasm but is recruited to the nucleus by MLL-EEN with a punctate localization pattern characteristic of the MLL chimeric proteins. EBP interacts simultaneously with EEN and Sos, a guanine-nucleotide exchange factor for Ras. Coexpressoin of EBP with EEN leads to suppression of Ras-induced cellular transformation and Ras-mediated activation of Elk-1. Taken together, our findings suggest a new mechanism for MLL-EEN-mediated leukemogenesis in which MLL-EEN interferes with the Ras-suppressing activities of EBP through direct interaction. © 2004 by The American Society of Hematology.postprin

Rabbit Production in Selected Urban Areas of Southern Ghana: Status and Implications for Policy and Research

A survey was conducted to elicit information on rabbit keeping in 26 urban areas of southern Ghana. The average age of the rabbit keepers was 44.3 years, and 95.5% of the keepers had formal education. Most of the producers got into rabbit keeping for money to meet urgent family needs, while household consumption was a major factor influencing the decision for rearing rabbits. Personal savings was the main source of income for the establishment of the rabbit enterprises. The major breeds of rabbits kept were the California White, New Zealand White and crossbreds of varied genetic variations. Backyard, small-scale and medium-scale commercial rabbit holdings were held by 18.2, 51.7 and 30.2% of the keepers respectively. The average rabbit population per farm was 77.8, with an average of 8.4 bucks, 21.6 does. Young rabbits formed 70.0% of the rabbit population. Owners of rabbitries usually cared for their animals as hired labour was expensive and often not available. High cost of feed was the most significant constraint to rabbit keeping, and mange was the most common disease affecting the rabbits. Marketing of rabbits was not organized, and this served as a disincentive to expanding the holdings. The rabbits were mostly sold either life or as fresh carcasses at the farm gate. To ensure a rapid growth of the rabbit industry, research should be undertaken to address the identified constraints to production while appropriate policies are put in place to enhance the growth of the industry

Occult alpha globin gene mutations are the commonest causes of red cell microcytosis unexplained by phenotypic testing

HAA: Haematology Society of Australia and New Zealand, The Australian & New Zealand Society of Blood Transfusion and The Australasian Society of Thrombosis and HaemostasisAIM: Hypochromic microcytic anaemia is the hallmark phenotype of thalassaemia. Current phenotypic tests do not provide a diagnosis in a small proportion of patients with red cell microcytosis. We investigated the genetic basis of microcytosis in a cohort of such subjects. METHOD: We identified from a large cohort of 1684 unselected requests for thalassaemia testing 25 Chinese subjects who had unexplained microcytosis after phenotypic haemoglobin studies. Extensive genotypic analysis of the α and β globin gene cluster was performed in 20 of these subjects who had adequate DNA. Techniques employed included gap-polymerase chain reaction, amplification-refractory mutation system, Sanger sequencing and multiplex ligation-dependent …postprin

Robust Association Tests Under Different Genetic Models, Allowing for Binary or Quantitative Traits and Covariates

The association of genetic variants with outcomes is usually assessed under an additive model, for example by the trend test. However, misspecification of the genetic model will lead to a reduction in power. More robust tests for association might therefore be preferred. A useful approach is to consider the maximum of the three test statistics under additive, dominant and recessive models (MAX3). The p-value however has to be adjusted to maintain the type I error rate. Previous studies and software on robust association tests have focused on binary traits without covariates. In this study we developed an analytic approach to robust association tests using MAX3, allowing for quantitative or binary traits as well as covariates. The p-values from our theoretical calculations match very well with those from a bootstrap resampling procedure. The methodology is implemented in the R package RobustSNP which is able to handle both small-scale studies and GWAS. The package and documentation are available at http://sites.google.com/site/honcheongso/software/robustsnp

Stated preferences for attributes of a CYP2C19 pharmacogenetic test among the general population presented with a hypothetical acute coronary syndrome scenario

Background: Pharmacogenetic (PGx) testing identifies pharmacotherapeutic risks to permit personalized therapy. Identifying the genetic profile of patients with acute coronary syndrome (ACS) who are considered for therapy with clopidogrel (P2Y12 receptor blockers) and acetylsalicylic acid (ASA) contributes to the treatment paradigm. Patient preferences would inform a collaborative framework and by extension inform healthcare policy formulation. Purpose: To quantify stated preferences (willingness to pay) for attributes of a novel point-of-care PGx (CYP2C19) test using a discrete choice experiment (DCE) from the general public in Ontario, Canada, and to identify starting point bias of the cost attribute. Methods: A web survey was created and included a questionnaire, decision board, and a DCE. DCE choice sets include the following attributes (levels): sample collection (blood, finger prick, and cheek swab), turnaround time for results (1 hr, 3 days, and 1 week), and cost in additional insurance premiums. The presence of starting point bias (cost attribute levels of $0,$1, $5 or$0, $2,$10) in the estimation of willingness to pay (WTP) was tested. Results: Estimates for turnaround time and cost attributes were statistically significant. Coefficients related to the starting point bias were also significant. Approximately 67% of survey participants chose the PGx test compared to status quo treatment options. WTP for a 1 hr turnaround time compared to a 1-week turnaround time was $10.77 (95% CI 9.58-12.25). Conclusion: This translational study shows preference for a point of care PGx test

Crude incidence in two-phase designs in the presence of competing risks.

BackgroundIn many studies, some information might not be available for the whole cohort, some covariates, or even the outcome, might be ascertained in selected subsamples. These studies are part of a broad category termed two-phase studies. Common examples include the nested case-control and the case-cohort designs. For two-phase studies, appropriate weighted survival estimates have been derived; however, no estimator of cumulative incidence accounting for competing events has been proposed. This is relevant in the presence of multiple types of events, where estimation of event type specific quantities are needed for evaluating outcome.MethodsWe develop a non parametric estimator of the cumulative incidence function of events accounting for possible competing events. It handles a general sampling design by weights derived from the sampling probabilities. The variance is derived from the influence function of the subdistribution hazard.ResultsThe proposed method shows good performance in simulations. It is applied to estimate the crude incidence of relapse in childhood acute lymphoblastic leukemia in groups defined by a genotype not available for everyone in a cohort of nearly 2000 patients, where death due to toxicity acted as a competing event. In a second example the aim was to estimate engagement in care of a cohort of HIV patients in resource limited setting, where for some patients the outcome itself was missing due to lost to follow-up. A sampling based approach was used to identify outcome in a subsample of lost patients and to obtain a valid estimate of connection to care.ConclusionsA valid estimator for cumulative incidence of events accounting for competing risks under a general sampling design from an infinite target population is derived

Protein profiling in hepatocellular carcinoma by label-free quantitative proteomics in two west african populations.

Background Hepatocellular Carcinoma is the third most common cause of cancer related death worldwide, often diagnosed by measuring serum AFP; a poor performance stand-alone biomarker. With the aim of improving on this, our study focuses on plasma proteins identified by Mass Spectrometry in order to investigate and validate differences seen in the respective proteomes of controls and subjects with LC and HCC. Methods Mass Spectrometry analysis using liquid chromatography electro spray ionization quadrupole time-of-flight was conducted on 339 subjects using a pooled expression profiling approach. ELISA assays were performed on four significantly differentially expressed proteins to validate their expression profiles in subjects from the Gambia and a pilot group from Nigeria. Results from this were collated for statistical multiplexing using logistic regression analysis. Results Twenty-six proteins were identified as differentially expressed between the three subject groups. Direct measurements of four; hemopexin, alpha-1-antitrypsin, apolipoprotein A1 and complement component 3 confirmed their change in abundance in LC and HCC versus control patients. These trends were independently replicated in the pilot validation subjects from Nigeria. The statistical multiplexing of these proteins demonstrated performance comparable to or greater than ALT in identifying liver cirrhosis or carcinogenesis. This exercise also proposed preliminary cut offs with achievable sensitivity, specificity and AUC statistics greater than reported AFP averages. Conclusions The validated changes of expression in these proteins have the potential for development into high-performance tests usable in the diagnosis and or monitoring of HCC and LC patients. The identification of sustained expression trends strengthens the suggestion of these four proteins as worthy candidates for further investigation in the context of liver disease. The statistical combinations also provide a novel inroad of analyses able to propose definitive cut-offs and combinations for evaluation of performance

Diffuse duodenal nodular lymphoid hyperplasia: a large cohort of patients etiologically related to Helicobacter pylori infection

Abstract Background Nodular lymphoid hyperplasia of gastrointestinal tract is a rare disorder, often associated with immunodeficiency syndromes. There are no published reports of its association with Helicobacter pylori infection. Methods From March 2005 till February 2010, we prospectively followed all patients with diffuse duodenal nodular lymphoid hyperplasia (DDNLH). Patients underwent esophagogastroduodenoscopy with targeted biopsies, colonoscopy, and small bowel video capsule endoscopy. Duodenal nodular lesions were graded from 0 to 4 based on their size and density. Patients were screened for celiac sprue (IgA endomysial antibody), immunoglobulin abnormalities (immunoglobulin levels & serum protein electrophoresis), small intestine bacterial overgrowth (lactulose hydrogen breath test), and Helicobacter pylori infection (rapid urease test, and histological examination of gastric biopsies). Patients infected with Helicobacter pylori received sequential antibiotic therapy and eradication of infection was evaluated by 14C urea breath test. Follow up duodenoscopies with biopsies were performed to ascertain resolution of nodular lesions. Results Forty patients (Males 23, females 17; mean age ± 1SD 35.6 ± 14.6 years) with DDNLH were studied. Patients presented with epigastric pain, vomiting, and weight loss. Esophagogastroduodenoscopy showed diffuse nodular lesions (size varying from 2 to 5 mm or more) of varying grades (mean score ± 1SD 2.70 ± 0.84) involving postbulbar duodenum. Video capsule endoscopies revealed nodular disease exclusively limited to duodenum. None of the patients had immunoglobulin deficiency or small intestine bacterial overgrowth or positive IgA endomysial antibodies. All patients were infected with Helicobacter pylori infection. Sequential antibiotic therapy eradicated Helicobacter pylori infection in 26 patients. Follow up duodenoscopies in these patients showed significant reduction of duodenal nodular lesions score (2.69 ± 0.79 to 1.50 ± 1.10; p Helicobacter pylori infection showed no significant reduction of nodular lesions score (2.71 ± 0.96 to 2.64 ± 1.15; p = 0.58). Nodules partially regressed in score in 2 patients, showed no interval change in 10 patients and progressed in 2 patients. Conclusions We report on a large cohort of patients with DDNLH, etiologically related to Helicobacter pylori infection.</p

Institutional Mergers in Ireland

The importance of knowledge as a driver of social and economic growth and prosperity, and the increasingly competitive “global race for knowledge and talent” (Hazelkorn, Higher Educ Manage Policy 21(1):55–76, 2009) have combined to transform the higher education landscape, forcing national governments and higher education institutions (HEIs) to pursue new ways of addressing the challenges of a multi-polar world order. Rising demand for higher education (HE), as part of the broader shift from elite to mass to universal participation, has led to the emergence of new models of provision. At the same time, many governments face restrictions on public resources due to high levels of public and private debt; accordingly, system-level and institutional restructuring has been contemplated as a way to enhance quality, performance and efficiency