A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection

Beliefs About Dementia: Development and Validation of the Representations and Adjustment to Dementia Index (RADIX)

YesThe Self-Regulation Model (SRM) identifies that the beliefs people hold about an illness can influence their responses to that illness. Although there are generic measures of illness representations, there is a need for a brief tailored measure to use with people with dementia. The aim of this study was to develop and validate a brief measure called the Representations and Adjustment to Dementia Index (RADIX). The RADIX contains questions on the SRM elements: Identity, Cause, Timeline, Control, and Consequences. The RADIX validation was conducted with a sample of 385 community-dwelling people with mild to moderate dementia who were taking part in the IDEAL cohort study. Test-retest reliability was conducted over a 4-week period with a separate sample of 20 people with dementia. The validation process resulted in a reduction in the number of items in the Timeline, Control, and Consequences items. The resulting RADIX demonstrated good acceptability, internal reliability, and test-retest reliability. All the RADIX items had low missing data, indicating good acceptability. The factor analysis confirmed that the Consequences items formed two subscales (practical and emotional consequences) that had Cronbach's α of 8 and 0.91 respectively. Test-retest reliability indicated that the Identity, Timeline, and Control items had moderate reliability and the practical and emotional consequences scales had good reliability. The RADIX demonstrates acceptable psychometric properties, proves to be a useful measure for exploring people's beliefs about dementia, and could aid the provision of tailored information and support to people with dementia

Genetic and Non-Genetic Influences during Pregnancy on Infant Global and Site Specific DNA Methylation: Role for Folate Gene Variants and Vitamin B12

Inter-individual variation in patterns of DNA methylation at birth can be explained by the influence of environmental, genetic and stochastic factors. This study investigates the genetic and non-genetic determinants of variation in DNA methylation in human infants. Given its central role in provision of methyl groups for DNA methylation, this study focuses on aspects of folate metabolism. Global (LUMA) and gene specific (IGF2, ZNT5, IGFBP3) DNA methylation were quantified in 430 infants by Pyrosequencing®. Seven polymorphisms in 6 genes (MTHFR, MTRR, FOLH1, CβS, RFC1, SHMT) involved in folate absorption and metabolism were analysed in DNA from both infants and mothers. Red blood cell folate and serum vitamin B12 concentrations were measured as indices of vitamin status. Relationships between DNA methylation patterns and several covariates viz. sex, gestation length, maternal and infant red cell folate, maternal and infant serum vitamin B12, maternal age, smoking and genotype were tested. Length of gestation correlated positively with IGF2 methylation (rho = 0.11, p = 0.032) and inversely with ZNT5 methylation (rho = −0.13, p = 0.017). Methylation of the IGFBP3 locus correlated inversely with infant vitamin B12 concentration (rho = −0.16, p = 0.007), whilst global DNA methylation correlated inversely with maternal vitamin B12 concentrations (rho = 0.18, p = 0.044). Analysis of common genetic variants in folate pathway genes highlighted several associations including infant MTRR 66G>A genotype with DNA methylation (χ2 = 8.82, p = 0.003) and maternal MTHFR 677C>T genotype with IGF2 methylation (χ2 = 2.77, p = 0.006). These data support the hypothesis that both environmental and genetic factors involved in one-carbon metabolism influence DNA methylation in infants. Specifically, the findings highlight the importance of vitamin B12 status, infant MTRR genotype and maternal MTHFR genotype, all of which may influence the supply of methyl groups for DNA methylation. In addition, gestational length appears to be an important determinant of infant DNA methylation patterns

Meta‐Analysis of Genome‐wide Linkage Studies in BMI and Obesity

Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI‐defined obesity using a nonparametric genome scan meta‐analysis. Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome‐wide logarithm of the odds (LOD) scores, non‐parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI‐defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Results: Bins at chromosome 13q13.2‐ q33.1, 12q23‐q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3‐22.3 were also observed for BMI‐defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1‐qter and 12p11.21‐q23 (p < 0.01). Conclusion: Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93663/1/oby.2007.269.pd

Pulmonary Embolism complicated Acute Chest Syndrome due to SARS-CoV-2 in adolescents with Sickle Cell Disease

info:eu-repo/semantics/publishe

First Documented Transmission of Trypanosoma cruzi Infection through Blood Transfusion in a Child with Sickle-Cell Disease in Belgium.

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A pilot study of manual chronic partial exchange transfusion in children with sickle disease

Objective: Red cell exchange transfusion is frequently used in the management of patients with sickle cell disease (SCD) either electively or chronically to maintain hemoglobin S (HbS) <30%. The purpose of this retrospective study was to evaluate the results of manual chronic partial exchange transfusion (MCPET) on level of Hb and HbS, on iron load and on the need for chelation, on risk of immunization, monitoring transfusion-transmitted viral infection, and clinical outcome. Methods: We reviewed the long-term effect of MCPET in 10 children (six men and four women) with SCD and evaluated the iron balance during a median follow-up of 20 months (range: 6–36) in which 248 exchanges were performed. Results: The pre-exchange median Hb value was 9.5 g/dl (range: 7.7–10.9 g/dl) and the median postexchange value was 9.4 g/dl (range: 8.4–11.1 g/dl).The majority of patients reached an HbS of <50% with a median HbS value of 40.04% (range: 30–54). At start of the MCPET program, the median ferritin was 439 ng/ml (range: 80–1704 ng/ml). In the final evaluation, the median value of ferritin was 531 ng/ml (range: 84–3840 ng/ml). The annual calculated iron balance was 0. 28 ± 0.08 mg/kg/day. MCPET was well tolerated, and adverse effects were limited. Discussion: MCPET in children with SCD is safe to prevent iron overload, and is effective and easy to use in our cohort. Conclusion: Indication for chronic exchange blood transfusion is essential for patients with SCD with recurrent and frequent crises who do not respond to hydroxyurea. However, there is no consensual study for the period at which chronic transfusion can safely be stopped and further research in large population of patients with SCD will need to clarify this question.SCOPUS: ar.jSCOPUS: ar.jSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Sodium-dependent multivitamin transporter defect (SMVT), a successfully treated cardiac decompensation with vitamins

Biallelic pathogenic variants in SLC5A6 gene, resulting in sodium-dependent multivitamin transporter (SMVT) defect, is a recently described inborn error of metabolism mimicking biotinidase deficiency. SMVT is a transmembrane protein expressed in multiple tissues including, kidney, liver, heart and brain. SMVT plays a key role in water-soluble vitamins biotin and pantothenic acid as well as α-lipoic acid intestinal absorption, regulating their cellular uptake and transport across the blood-brain barrier. Biotin is a known cofactor of carboxylases involved in various metabolic reactions including fatty acid synthesis, gluconeogenesis and lipid and branched-chain amino acid (BCAA) catabolism. Pantothenic acid is a coenzyme A precursor involved, for example, in glycolysis, Krebs cycle, fatty acid oxidation and BCAA catabolism. α–lipoic acid is a cofactor of several enzymes of the intermediary metabolism and has antioxidative and anti-inflammatory effects. Only 16 patients have been reported so far with various clinical phenotypes such as neuropathy and other neurologic impairment (neurodevelopmental delay, microcephaly but also thin corpus callosum), gastro-intestinal dysfunction and failure to thrive, osteopenia, immunodeficiency, metabolic acidosis with hypoglycemia and recently optic nerves atrophy. Only four patients have been reported to have cardiac involvement. We report a new presentation of SMVT defect in a 5-month-old girl. Familial history was marked by consanguinity and the unexplained death of a brother at the age of 8 months after a flu. Patient had normal parameters at birth and a normal psychomotor development but microcephaly and failure to thrive. She was initially admitted for neurological distress, hemodynamic shock, ketoacidosis and lactic acidosis (pH 7.33, BE -5 mmol/L, lactate 6 mmol/L) associated with a refusal to eat and without hypoglycemia. She was quickly transferred to the pediatric intensive care unit (PICU) for invasive ventilation, inotropic support and intravenous saline and glucose infusion. Heart failure with a reduced left ventricular ejection fraction (LVEF) 32% (N > 60%) was rapidly identified. After two weeks of cardiac support, the baby was discharged with a complete normalisation of cardiac function. Two weeks later, she relapsed with a refusal to eat and vomiting. She was promptly readmitted to the PICU with severe metabolic acidosis (pH 7.1, base excess -16.1 mmol/L), hyperlactatemia up to 8.8 mmol/L and a severe haemodynamic shock associated with severe cardiac dysfunction (LVEF 17%, elevated troponin and NT-pro-BNP). A rapid normalisation of lactic acidosis was observed with saline and glucose (up to 10mg/kg/min) infusion, L-carnitine 100mg/kg and a multivitamin cocktail (B1 100mg, B2 1mg, biotin 10mg and B12 50mg) supplementation. Due to feeding problems and chronic diarrhea, she developed poor weight gain and required temporary nasogastric tube feeding. Later, the patient developed persistent severe refractory cardiac dysfunction despite cardiotonics and diuretics. Rapid trio WES identified a homozygous potentially pathogenic missense variant in SLC5A6 gene (NM_021095.4): c.1310C>T p.(Pro437Leu). Under treatment with biotine 15 mg and pantothenic acid 100 mg we observed an improvement in neurodevelopment, gradual enteral refeeding and an impressive and complete cardiac function recovery with normalization at 3-months follow-up. Biallelic pathogenic variants in SLC5A6 are responsible for the sodium-dependent multivitamin transporter (SMVT) defect, a recently described inborn error of metabolism. The presence of elevated 3-hydroxyisovaleric acid on urinary organic acid chromatography may indicate a defect in the symporter of biotin, pantothenic acid and α-lipoic acid in the absence of biotinidase deficiency. Rapid sequencing of the whole exome allowed for an accurate diagnosis and further a highly effective treatment. In parallel to recently and only one case published with cardiac recovery, our patient presented with severe cardiac decompensation that was successfully treated with biotin and pantothenic acid and normalisation of cardiac function on water soluble vitamins supplementation