The Stanley Foundation Bipolar Network: Results of the naturalistic follow-up study after 2.5 years of follow-up in the German centres

The Stanley Foundation Bipolar Network (SFBN) is an international, multisite network investigating the characteristics and course of bipolar disorder. Methods (history, ratings and longitudinal follow-up) are standardized and equally applied in all 7 centres. This article describes demographics and illness characteristics of the first 152 German patients enrolled in them SFBN as well as the results of 2.5 years of follow-up. Patients in Germany were usually enrolled after hospitalisation. More than 72% of the study population suffered from bipolar I disorder and 25% from bipolar 11 disorder. The mean +/- SD age of the study participants was 42.08 +/- 13.5 years, and the mean SD age of onset 24.44 +/- 10.9 years. More than 40% of the sample reported a rapid-cycling course in history, and even more a cycle acceleration overtime. 37% attempted suicide at least once. 36% had an additional Axis I disorder, with alcohol abuse being the most common one, followed by anxiety disorders. During the follow-up period, only 27% remained stable, 56% had a recurrence, 12.8% perceived subsyndromal symptoms despite treatment and regular visits. 27% suffered from a rapid-cycling course during the follow-up period. Recurrences were significantly associated with bipolar I disorder, an additional comorbid Axis I disorder, rapid cycling in history, a higher number of mood stabilizers and the long-term use of typical antipsychotics. Rapid cycling during follow-up was only associated with a rapidcycling course in history, a higher number of mood stabilizers and at least one suicide attempt in history. Copyright (c) 2003 S. Karger AG, Basel

Metabolic imprinting, programming and epigenetics - a review of present priorities and future opportunities

Metabolic programming and metabolic imprinting describe early life events, which impact upon on later physiological outcomes. Despite the increasing numbers of papers and studies, the distinction between metabolic programming and metabolic imprinting remains confusing. The former can be defined as a dynamic process whose effects are dependent upon a critical window(s) while the latter can be more strictly associated with imprinting at the genomic level. The clinical end points associated with these phenomena can sometimes be mechanistically explicable in terms of gene expression mediated by epigenetics. The predictivity of outcomes depends on determining if there is causality or association in the context of both early dietary exposure and future health parameters. The use of biomarkers is a key aspect of determining the predictability of later outcome, and the strengths of particular types of biomarkers need to be determined. It has become clear that several important health endpoints are impacted upon by metabolic programming/imprinting. These include the link between perinatal nutrition, nutritional epigenetics and programming at an early developmental stage and its link to a range of future health risks such as CVD and diabetes. In some cases, the evidence base remains patchy and associative, while in others, a more direct causality between early nutrition and later health is clear. In addition, it is also essential to acknowledge the communication to consumers, industry, health care providers, policy-making bodies as well as to the scientific community. In this way, both programming and, eventually, reprogramming can become effective tools to improve health through dietary intervention at specific developmental points

Geographic and seasonal patterns and limits on the adaptive response to temperature of European Mytilus spp. and Macoma balthica populations

Seasonal variations in seawater temperature require extensive metabolic acclimatization in cold-blooded organisms inhabiting the coastal waters of Europe. Given the energetic costs of acclimatization, differences in adaptive capacity to climatic conditions are to be expected among distinct populations of species that are distributed over a wide geographic range. We studied seasonal variations in the metabolic adjustments of two very common bivalve taxa at European scale. To this end we sampled 16 populations of Mytilus spp. and 10 Macoma balthica populations distributed from 39° to 69°N. The results from this large-scale comprehensive comparison demonstrated seasonal cycles in metabolic rates which were maximized during winter and springtime, and often reduced in the summer and autumn. Studying the sensitivity of metabolic rates to thermal variations, we found that a broad range of Q10 values occurred under relatively cold conditions. As habitat temperatures increased the range of Q10 narrowed, reaching a bottleneck in southern marginal populations during summer. For Mytilus spp., genetic-group-specific clines and limits on Q10 values were observed at temperatures corresponding to the maximum climatic conditions these geographic populations presently experience. Such specific limitations indicate differential thermal adaptation among these divergent groups. They may explain currently observed migrations in mussel distributions and invasions. Our results provide a practical framework for the thermal ecophysiology of bivalves, the assessment of environmental changes due to climate change and its impact on (and consequences for) aquaculture

Metabolite ratios as potential biomarkers for type 2 diabetes:a DIRECT study

Aims/hypothesis Circulating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes. Methods We measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case–control studies of prevalent (n = 4925) and incident (n = 4277) diabetes. The data were analysed using regression models with adjustment for potential confounders. Results There were dynamic changes in metabolite levels in response to the different secretagogues. Furthermore, several fasting pairwise metabolite ratios were associated with one or multiple clamp-derived measures of insulin secretion (all p Conclusion/interpretation In this study we have shown that the Val_PC ae C32:2 metabolite ratio is associated with an increased risk of type 2 diabetes and measures of insulin secretion and resistance. The observed effects were stronger than that of the individual metabolites and independent of known risk factors.</p

Children's erythrocyte fatty acids are associated with the risk of islet autoimmunity

Our aim was to investigate the associations between erythrocyte fatty acids and the risk of islet autoimmunity in children. The Environmental Determinants of Diabetes in theYoung Study (TEDDY) is a longitudinal cohort study of children at high genetic risk for type 1 diabetes (n = 8676) born between 2004 and 2010 in the U.S., Finland, Sweden, and Germany. A nested case-control design comprised 398 cases with islet autoimmunity and 1178 sero-negative controls matched for clinical site, family history, and gender. Fatty acids composition was measured in erythrocytes collected at the age of 3, 6, and 12 months and then annually up to 6 years of age. Conditional logistic regression models were adjusted for HLA risk genotype, ancestry, and weight z-score. Higher eicosapentaenoic and docosapentaenoic acid (n - 3 polyunsaturated fatty acids) levels during infancy and conjugated linoleic acid after infancy were associated with a lower risk of islet autoimmunity. Furthermore, higher levels of some even-chain saturated (SFA) and monounsaturated fatty acids (MUFA) were associated with increased risk. Fatty acid status in early life may signal the risk for islet autoimmunity, especially n -3 fatty acids may be protective, while increased levels of some SFAs and MUFAs may precede islet autoimmunity

Maternal smoking during pregnancy and offspring overweight : is there a dose–response relationship? An individual patient data meta-analysis

We want to thank the funders of the individual studies: the UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol, the Danish National Research Foundation, Pharmacy Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation, the US NICHD (contracts no. 1-HD-4-2803 and no. 1-HD-1-3127, R01 HD HD034568), the NHMRC, the CNPq (Portuguese acronym for the National Research Council—grant 523474/96-2) and FAPESP (Portuguese acronym for the São Paulo State Research Council—grant 00/0908-7). We would like to thank the participating families of all studies for the use of data. For the ASPAC study, we want to thank the midwives for their help in recruiting families, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. This work was supported by the Deutschen Forschungsgesellschaft (German Research Foundation, DFG) [KR 1926/9-1, KU1443/4-1]. Dr. Gilman’s contribution was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.Peer reviewedPostprin

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Engineered human pluripotent stem cell-derived natural killer cells with PD-L1 responsive immunological memory for enhanced immunotherapeutic efficacy

Adoptive chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have shown promise in treating various cancers. However, limited immunological memory and access to sufficient numbers of allogenic donor cells have hindered their broader preclinical and clinical applications. Here, we first assess eight different CAR constructs that use an anti-PD-L1 nanobody and/or universal anti-fluorescein (FITC) single-chain variable fragment (scFv) to enhance antigen-specific proliferation and anti-tumor cytotoxicity of NK-92 cells against heterogenous solid tumors. We next genetically engineer human pluripotent stem cells (hPSCs) with optimized CARs and differentiate them into functional dual CAR-NK cells. The tumor microenvironment responsive anti-PD-L1 CAR effectively promoted hPSC-NK cell proliferation and cytotoxicity through antigen-dependent activation of phosphorylated STAT3 (pSTAT3) and pSTAT5 signaling pathways via an intracellular truncated IL-2 receptor β-chain (ΔIL-2Rβ) and STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif. Anti-tumor activities of PD-L1-induced memory-like hPSC-NK cells were further boosted by administering a FITC-folate bi-specific adapter that bridges between a programmable anti-FITC CAR and folate receptor alpha-expressing breast tumor cells. Collectively, our hPSC CAR-NK engineering platform is modular and could constitute a realistic strategy to manufacture off-the-shelf CAR-NK cells with immunological memory-like phenotype for targeted immunotherapy

Epigenome-wide association study reveals methylation loci associated with offspring gestational diabetes mellitus exposure and maternal methylome

Abstract Objective: Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure. Research Design and Methods: We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring. Results: We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10⁻²) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. Conclusions: Our study reveals the potential complexity of the epigenetic transmission between GDM mothers and their offspring, likely determined by not only GDM exposure, but also other factors indicated by maternal epigenetic status, such as maternal metabolic history