Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations

We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n ∼ 350,000) and height (n ∼ 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the variation in BMI in Dutch adults from the LifeLines DEEP study (n = 750) but did not account for any BMI variation in adolescents from the Brisbane Systems Genetic Study (BSGS, n = 403). Methylation profiles based on the Dutch sample explained 4.9% and 3.6% of the variation in BMI in the LBCs and BSGS, respectively. Methylation profiles predicted BMI independently of genetic profiles in an additive manner: 7%, 8%, and 14% of variance of BMI in the LBCs were explained by the methylation predictor, the genetic predictor, and a model containing both, respectively. The corresponding percentages for LifeLines DEEP were 5%, 9%, and 13%, respectively, suggesting that the methylation profiles represent environmental effects. The differential effects of the BMI methylation profiles by age support previous observations of age modulation of genetic contributions. In contrast, methylation profiles accounted for almost no variation in height, consistent with a mainly genetic contribution to inter-individual variation. The BMI results suggest that combining genetic and epigenetic information might have greater utility for complex-trait prediction.     

Flavonols and an indole alkaloid skeleton bearing identical acylated glycosidic groups from yellow petals of Papaver nudicaule

From yellow petals of Iceland poppy, besides the known flavonoid gossypitrin, seven kaempferol derivatives were isolated. In addition to kaempferol 3-O-beta-sophoroside and kaempferol 3-O-beta-sophoroside-7-O-beta-glucoside, known from other plants, the mono- and dimalonyl conjugates of the latter were identified by MS and NMR spectroscopy. Structure analyses of a set of co-occurring pigments, the nudicaulins, revealed that they have the identical acylated glycoside moieties attached to a pentacyclic indole alkaloid skeleton for which the structure of 19-(4-hydroxyphenyl)-10H-1,10-ethenochromeno[2,3-b]indole-6,8,18-triol was deduced from MS and NMR as well as chemical and chiroptical methods.     

Detection of Antibody against Fungal Glucosylceramide in Immunocompromised Patients: A Potential New Diagnostic Approach for Cryptococcosis

We have developed an ELISA to determine the value of anti-glucosylceramide antibody for the prediction of disseminated cryptococcosis in immunocompromised subjects and performed a clinical prospective study at the Medical University of South Carolina. The study enrolled a total of 53 patients who were free of active fungal diseases at the time of enrollment but at risk of developing one because they were all immunocompromised, e.g., (1) patients positive for HIV and (2) patients post- or awaiting solid organ transplantation. Among 53 patients enrolled, two patients developed invasive cryptococcosis, and in both patients, IgM anti-GlcCer was detected in sera using the ELISA at least 6 weeks prior to the clinical presentation of the brain disease. These results were corroborated by a cryptococcal antigen lateral flow assay, which was also positive in serum prior to the development of meningoencephalitis. However, a high number of positive results were also detected in patients with no evidence of cryptococcosis. This study highlights the potential utility of this new assay in early diagnostic testing algorithms for patients at risk for cryptococcosis, but further investigations are needed to validate the sensitivity and specificity of the glucosylceramide ELISA as a predictor of cryptococcosis.     

Cognitive function and behavioural status in paediatric heart and heart-lung transplant recipients: the Harefield experience.

OBJECTIVE--To assess the psychological impact of cardiac and cardiopulmonary transplantation on children. DESIGN--Retrospective cross sectional study. SETTING--One British centre performing paediatric heart and heart-lung transplant operations, four cardiac units in London, three London schools, two London health centres, and the dental department of a London children''s hospital. SUBJECTS--65 children who had been given heart or heart-lung transplants and two reference groups of 52 children who had had other types of cardiac surgery and 45 healthy children. MAIN OUTCOME MEASURES--Development, cognition, and behaviour at home and at school as assessed by measures with proved validity and reliability. RESULTS--Developmental and cognitive measures indicated that children given transplants had significantly lower scores on several parameters, particularly in terms of development in children under 4 1/2 years of age. Performance on all tests, however, was within the normal range. There were no significant differences in behavioural ratings between the transplant and reference groups, though problem behaviour at home was more prevalent in the transplant group. CONCLUSIONS--Though cognitive development may be within the normal range, there are adverse psychological effects associated with cardiac and cardiopulmonary transplantation. These data indicate the need for a controlled prospective study in which children and their families are seen before and at regular intervals after transplantation. Interventions should be developed that are tailored to the particular needs of this very specialised group of paediatric patients and their families.