Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers

Background The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. Objective We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. Methods We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell–derived IL-1β levels were measured by means of ELISA. Results Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator. Conclusions The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory

Association between Frequency Domain Heart Rate Variability and Unplanned Readmission to Hospital in Geriatric Patients

<p>Abstract</p> <p>Background</p> <p>An accurate prediction of unplanned readmission (UR) after discharge from hospital can facilitate physician's decision making processes for providing better quality of care in geriatric patients. The objective of this study was to explore the association of cardiac autonomic functions as measured by frequency domain heart rate variability (HRV) and 14-day UR in geriatric patients.</p> <p>Methods</p> <p>Patients admitted to the geriatric ward of a regional hospital in Chiayi county in Taiwan were followed prospectively from July 2006 to June 2007. Those with invasive tubes and those who were heavy smokers, heavy alcohol drinkers, on medications that might influence HRV, or previously admitted to the hospital within 30 days were excluded. Cardiac autonomic functions were evaluated by frequency domain indices of HRV. Multiple logistic regression was used to assess the association between UR and HRV indices adjusted for age and length of hospitalization.</p> <p>Results</p> <p>A total of 78 patients met the inclusion criteria and 15 of them were readmitted within 14 days after discharge. The risk of UR was significantly higher in patients with lower levels of total power (OR = 1.39; 95% CI = 1.04-2.00), low frequency power (LF) (OR = 1.22; 95% CI = 1.03-1.49), high frequency power (HF) (OR = 1.27; 95% CI = 1.02-1.64), and lower ratios of low frequency power to high frequency power (LF/HF ratio) (OR = 1.96; 95% CI = 1.07-3.84).</p> <p>Conclusion</p> <p>This is the first study to evaluate the association between frequency domain heart rate variability and the risk of UR in geriatric patients. Frequency domain heart rate variability indices measured on admission were significantly associated with increased risk of UR in geriatric patients. Additional studies are required to confirm the value and feasibility of using HRV indices on admission as a non-invasive tool to assist the prediction of UR in geriatric patients.</p

FADD phosphorylation is critical for cell cycle regulation in breast cancer cells

Anti-oestrogen therapy is effective for control of hormone receptor-positive breast cancers, although the detailed molecular mechanisms, including signal transduction, remain unclear. We demonstrated here that long-term tamoxifen treatment causes G2/M cell cycle arrest through c-jun N-terminal kinase (JNK) activation, which is dependent on phosphorylation of Fas-associated death domain-containing protein (FADD) at 194 serine in an oestrogen (ER) receptor-positive breast cancer cell line, MCF-7. Expression of a dominant negative mutant form of MKK7, a kinase upstream of JNK, or mutant FADD (S194A) in MCF-7 cells suppressed the cytotoxicity of long-term tamoxifen treatment. Of great interest, similar signallings could be evoked by paclitaxel, even in an ER-negative cell line, MDA-MB-231. In addition, immunohistochemical analysis using human breast cancer specimens showed a close correlation between phosphorylated JNK and FADD expression, both being significantly reduced in cases with metastatic potential. We conclude that JNK-mediated phosphorylation of FADD plays an important role in the negative regulation of cell growth and metastasis, independent of the ER status of a breast cancer, so that JNK/FADD signals might be promising targets for cancer therapy

Ecology and Transmission of Buruli Ulcer Disease: A Systematic Review

Buruli ulcer is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis. Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. Large lesions often result in scarring, contractual deformities, amputations, and disabilities, and in Africa, most cases of the disease occur in children between the ages of 4–15 years. This environmental mycobacterium, Mycobacterium ulcerans, is found in communities associated with rivers, swamps, wetlands, and human-linked changes in the aquatic environment, particularly those created as a result of environmental disturbance such as deforestation, dam construction, and agriculture. Buruli ulcer disease is often referred to as the “mysterious disease” because the mode of transmission remains unclear, although several hypotheses have been proposed. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. We discuss traditional and non-traditional methods for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens, and suggest an intellectual framework for establishing criteria for transmission. The application of these criteria to the transmission of M. ulcerans presents a significant challenge

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron