Influence of Maternal Lifestyle and Diet on Perinatal DNA Methylation Signatures Associated With Childhood Arterial Stiffness at 8 to 9 Years

Increases in aortic pulse wave velocity, a measure of arterial stiffness, can lead to elevated systolic blood pressure and increased cardiac afterload in adulthood. These changes are detectable in childhood and potentially originate in utero, where an adverse early life environment can alter DNA methylation patterns detectable at birth. Here, analysis of epigenome-wide methylation patterns using umbilical cord blood DNA from 470 participants in the Southampton’s Women’s Survey identified differential methylation patterns associated with systolic blood pressure, pulse pressure, arterial distensibility, and descending aorta pulse wave velocity measured by magnetic resonance imaging at 8 to 9 years. Perinatal methylation levels at 16 CpG loci were associated with descending aorta pulse wave velocity, with identified CpG sites enriched in pathways involved in DNA repair (P=9.03×10−11). The most significant association was with cg20793626 methylation (within protein phosphatase, Mg2+/Mn2+ dependent 1D; β=−0.05 m/s/1% methylation change, [95% CI, −0.09 to −0.02]). Genetic variation was also examined but had a minor influence on these observations. Eight pulse wave velocity-linked dmCpGs were associated with prenatal modifiable risk factors, with cg08509237 methylation (within palmitoyl-protein thioesterase-2) associated with maternal oily fish consumption in early and late pregnancy. Lower oily fish consumption in early pregnancy modified the relationship between methylation and pulse wave velocity, with lower consumption strengthening the association between cg08509237 methylation and increased pulse wave velocity. In conclusion, measurement of perinatal DNA methylation signatures has utility in identifying infants who might benefit from preventive interventions to reduce risk of later cardiovascular disease, and modifiable maternal factors can reduce this risk in the child

Altered H19/miR‐675 expression in skeletal muscle is associated with low muscle mass in community‐dwelling older adults

Background: Despite increasing knowledge of the pathogenesis of muscle ageing, the molecular mechanisms are poorly understood. Based on an expression analysis of muscle biopsies from older Caucasian men, we undertook an in-depth analysis of the expression of the long non-coding RNA, H19, to identify molecular mechanisms that may contribute to the loss of muscle mass with age. Methods: We carried out transcriptome analysis of vastus lateralis muscle biopsies from 40 healthy Caucasian men aged 68–76 years from the Hertfordshire Sarcopenia Study (HSS) with respect to appendicular lean mass adjusted for height (ALMi). Validation and replication was carried out using qRT-PCR in 130 independent male and female participants aged 73–83 years recruited into an extension of the HSS (HSSe). DNA methylation was assessed using pyrosequencing. Results: Lower ALMi was associated with higher muscle H19 expression (r2 = 0.177, P < 0.001). The microRNAs, miR-675-5p/3p encoded by exon 1 of H19, were positively correlated with H19 expression (Pearson r = 0.192 and 0.182, respectively, P < 0.03), and miR-675-5p expression negatively associated with ALMi (r2 = 0.629, P = 0.005). The methylation of CpGs within the H19 imprinting control region (ICR) were negatively correlated with H19 expression (Pearson r = −0.211 to −0.245, P ≤ 0.05). Moreover, RNA and protein levels of SMAD1 and 5, targets of miR-675-3p, were negatively associated with miR-675-3p (r2 = 0.792 and 0.760, respectively) and miR-675-5p (r2 = 0.584 and 0.723, respectively) expression, and SMAD1 and 5 RNA levels positively associated with greater type II fibre size (r2 = 0.184 and 0.246, respectively, P < 0.05). Conclusions: Increased expression profiles of H19/miR-675-5p/3p and lower expression of the anabolic SMAD1/5 effectors of bone morphogenetic protein (BMP) signalling are associated with low muscle mass in older individuals

DNA methylation signatures associated with cardiometabolic risk factors in children from India and The Gambia: results from the EMPHASIS study.

BACKGROUND: The prevalence of cardiometabolic disease (CMD) is rising globally, with environmentally induced epigenetic changes suggested to play a role. Few studies have investigated epigenetic associations with CMD risk factors in children from low- and middle-income countries. We sought to identify associations between DNA methylation (DNAm) and CMD risk factors in children from India and The Gambia. RESULTS: Using the Illumina Infinium HumanMethylation 850 K Beadchip array, we interrogated DNAm in 293 Gambian (7-9 years) and 698 Indian (5-7 years) children. We identified differentially methylated CpGs (dmCpGs) associated with systolic blood pressure, fasting insulin, triglycerides and LDL-Cholesterol in the Gambian children; and with insulin sensitivity, insulinogenic index and HDL-Cholesterol in the Indian children. There was no overlap of the dmCpGs between the cohorts. Meta-analysis identified dmCpGs associated with insulin secretion and pulse pressure that were different from cohort-specific dmCpGs. Several differentially methylated regions were associated with diastolic blood pressure, insulin sensitivity and fasting glucose, but these did not overlap with the dmCpGs. We identified significant cis-methQTLs at three LDL-Cholesterol-associated dmCpGs in Gambians; however, methylation did not mediate genotype effects on the CMD outcomes. CONCLUSION: This study identified cardiometabolic biomarkers associated with differential DNAm in Indian and Gambian children. Most associations were cohort specific, potentially reflecting environmental and ethnic differences

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p

Molecular and epigenetic changes associated with age-related skeletal muscle loss and sacropenia

Sarcopenia is defined as the age-related loss of muscle mass and function and is common in both men and women over the age of 65, with a worldwide prevalence estimated at between 3-30%. As the population is becoming more aged, the prevalence of sarcopenia in the community is increasing and with that, an increase in the number of adverse physical and metabolic outcomes including frailty, disability, metabolic disorders and osteoporosis. However, the molecular pathways altered during muscle ageing and how they contribute to sarcopenia are poorly understood. Previous studies have investigated the mechanisms contributing to muscle ageing and the pathogenesis of sarcopenia. However to date, there have been no investigations into the variability in skeletal muscle mass and function in the elderly, using age-matched controls to investigate the pathogenesis of sarcopenia. Using both genome-wide and candidate gene approaches, skeletal muscle tissue and myoblasts from participants of the Hertfordshire Sarcopenia Study were utilized and the signalling pathways that contribute to the variability in muscle mass and function among community-dwelling older people were investigated. Genome-wide transcriptome analysis highlighted mitochondrial function, DNA damage and myogenesis as the major pathways altered in sarcopenia. RT-PCR validation of the RNAseq data confirmed an association between reduced muscle mass and higher expression of the long non-coding RNA H19, with a concomitant increase in miR-675-3p/5p expression and decreased SMAD1/5 expression, resulting in reduced muscle hypertrophy. Singlecell transcriptomics of the isolated myoblasts from the muscle biopsies showed that many of the pathways altered with respect to muscle mass were intrinsic to the muscle cells. Changes in transcription were also accompanied by genome wide changes in DNA methylation with pathways related to calcium signalling, denervation/muscle atrophy and muscle development being changed and enriched for the polycomb regulator EZH2. Moreover, the epigenetic signatures related to muscle mass and strength were conserved in primary myoblasts after culture. Skeletal muscle myoblasts isolated from sarcopenic muscle also exhibited altered mitochondrial respiration, with reduced ATP production and maximal respiration compared to healthy elderly people, as well as increased levels of senescence in myoblasts as suggested by an increase in p16INK4a expression and a decrease in ANRIL expression.Taken together, these findings suggest an impairment in the balance between muscle hypertrophy and atrophy in sarcopenia. This impairment is intrinsic to myogenic cells, with increased cell death, in combination with increased mitochondrial dysfunction, cellular senescence and DNA damage. This may result in the impaired regenerative capacity of skeletal muscle, and together with reduced hypertrophic signalling, a reduced capability to efficiently repair skeletal muscle in the elderly. Understanding these mechanisms may provide better insight into the development of therapeutics for the treatment of sarcopenia, while the muscle-derived myoblasts provide an in vitro model system to investigate the efficacy of new treatments. The methylation changes associated with the measures of muscle mass and function may also provide potential biomarkers to identify those at increased risk of developing sarcopenia, allowing early intervention for prevention and treatment

No English title available

Cette thèse traite le thème de l’agriculture traditionnelle et ses techniques dans le cadre socio-culturel de ‘Araya, village du Mont Liban, situé à 10 km environ à l’est de Beyrouth. Le sujet, d’orientation ethnoarchéologique, basé sur l’enquête orale, est abordé d’une manière rétrospective ; il s’agit de reconstruire le modèle actuel de l’agriculture afin d’interpréter des phénomènes agricoles passés. Le texte aborde en premier lieu les types de culture divisés en cultures sèches et irriguées ainsi que les travaux nécessaires liés à leur croissance, comme l’essartage, l’épierrement, la fertilisation, etc. ; de même, le texte décrit les activités agro-industrielles, comme la transformation du blé en farine, la fabrication de la mélasse et l’extraction de l’huile d’olive... Les terrasses constituent l’un des points essentiels traités ; elles sont composées d’une plateforme soutenue par un mur de soutènement en pierre assemblé à sec. Avec des outillages rudimentaires, le paysan de la montagne a pu transformer des terrains pentus et incultes en jardins verdoyants. Parmi les activités agricoles étudiées, l’irrigation occupe une place privilégiée. Elle est pratiquée durant la saison sèche qui s’étend entre les mois d’avril et de septembre. Les installations d’irrigation sont des captages constitués de galeries souterraines qui déversent l’eau d’une nappe dans un bassin. L’eau emmagasinée est ensuite partagée entre les propriétaires. La dernière rubrique concerne les outillages agricoles classés, selon leurs fonctions, en outils de coupe, du travail de la terre, de cueillette, de dépiquage, de vannage et d’attelage. Certains remontent à la haute antiquité ; d’autre, beaucoup plus récents, datent du XIXe s. .The traditional agriculture in the village of 'Araya is the subject treated. It is an ethnoarchaeological approach dealt in a retrospective method. It aims at reconstructing the agriculture model in order to develop an accurate interpretation of the ancient agricultural process. At the start, the farming metho divided into two types, namely dry and irrigated, are studied followed by the activities needed in the growing process such as clearing, soil treatment and fertilization, etc. Otheragricultural processes are concerned such as the transformation of wheat into flour. The farming methods on terraces, which are platforms sustained by dried up walls; the transformations of ga rdens into fields with the use of rudimentary tools;the irrigation during two seasons, spring and summer, which consists of trapping the water in basins in underground galleries, are developed. Finally, the tools are classified according to their functions such as cutting, picking, trimming. Some of them go back to Antiquity other originated in the nineteenth century

Complete Disappearance of Choroidal Metastasis from Lung Adenocarcinoma Treated with Bevacizumab and Chemotherapy

Choroidal metastasis from lung cancer is uncommon. We report a case of choroidal metastasis as an inaugural manifestation of lung adenocarcinoma, successfully treated by docetaxel, cisplatinum, and intravenous bevacizumab as an antiangiogenesis therapy. A complete remission was obtained after 4 cycles and maintained after six cycles. This case report demonstrates the importance of the systemic bevacizumab and chemotherapy in the treatment of choroidal metastasis from adenocarcinoma of the lung

Folic acid induces intake-related changes in the mammary tissue transcriptome of C57BL/6 mice

Folic acid (FA) intake has been associated with increased breast cancer risk in some studies. Although underlying mechanisms are unknown, epigenetic modifications that persistently alter transcription have been suggested. We tested the hypothesis that high FA (HFA) intake alters the adult mammary transcriptome in a manner consistent with increased potential for carcinogenesis, detectable beyond the period of intake. C57BL/6 mice were fed control FA (CFA) (1 mg/kg diet) or HFA (5 mg/kg diet) diets for 4 weeks, followed by AIN93M maintenance diet for 4 weeks. Plasma 5-methyltetrahydrofolate, p-aminobenzoylglutamate and unmetabolised FA concentrations were greater (1.62, 1.56, 5.80-fold, respectively) in HFA compared to CFA mice. RNA sequencing of the mammary transcriptome (~20 million reads) showed 222 transcripts (191 upregulated) differentially expressed between groups. Gene Set Enrichment showed upregulated genes significantly enriched in Epithelial Mesenchymal Transition, Myogenesis and Apical Junction and downregulated genes in E2F targets, MYC targets and G2M checkpoint. Cancer was the most altered Disease and Disorder pathway, with Metastasis, Mammary Tumour and Growth of Tumour the most upregulated pathways. ChIP-seq enrichment analysis showed that targets of histone methyltransferase EZH2 were enriched in HFA mice. This study demonstrates HFA intake during adulthood induces mammary transcriptome changes, consistent with greater tumorigenic potential.</p

Unveiling Dandy-Walker syndrome: A surprising twist in the tale of acute hydrocephalus and Down syndrome child

The correlation between Down syndrome and Dandy-Walker syndrome is an exceptionally uncommon occurrence. To date, only four cases have been documented. All previously reported cases involved individuals under the age of 37 months, with prenatal or birth diagnoses. Additionally, most of these cases displayed a limited life expectancy and experienced poor developmental outcomes. In this report, we present the first-ever instance of an 11-year-old male patient, previously undiagnosed with Dandy-Walker syndrome, who presented with acute intracranial hypertension. Magnetic Resonance Imaging revealed an active hydrocephalus caused by a Dandy-Walker malformation. The patient's condition was effectively managed through the implementation of a ventriculo-cysto-peritoneal shunt. This case highlights the coexistence of Dandy-Walker syndrome and Down syndrome in an asymptomatic young patient. Furthermore, it demonstrates that active hydrocephalus in such cases can be successfully addressed through either endoscopic third ventriculostomy or ventriculo-cysto-peritoneal shunt procedures

Osteonecrosis of the jaw during biyearly treatment with zoledronic acid for aromatase inhibitor associated bone loss in early breast cancer: A literature review

Osteonecrosis of the jaw (ONJ) is one of the most relevant and specific complication of biphosphonates. ONJ in patients receiving zoledronic acid every 3 to 4 weeks is frequently described, but the ONJ biyearly regimen used to reduce aromatase inhibitor associated bone loss (AIBL), is rarely reported. A literature review, focusing on the important trials using zoledronic acid to reduce AIBL, found that the mean risk of developing ONJ when zoledronic acid is used biyearly varies between 0.12% and 0.7%