A comparison of PBDE serum concentrations in Mexican and Mexican-American children living in California.

BackgroundPolybrominated diphenyl ethers (PBDE), which are used as flame retardants, have been found to be higher in residents of California than of other parts of the United States.ObjectivesWe aimed to investigate the role of immigration to California on PBDE levels in Latino children.MethodsWe compared serum PBDE concentrations in a population of first-generation Mexican-American 7-year-old children (n = 264), who were born and raised in California [Center for Health Analysis of Mothers and Children of Salinas (CHAMACOS) study], with 5-year-old Mexican children (n = 283), who were raised in the states in Mexico where most CHAMACOS mothers had originated (Proyecto Mariposa).ResultsOn average, PBDE serum concentrations in the California Mexican-American children were three times higher than their mothers' levels during pregnancy and seven times higher than concentrations in the children living in Mexico. The PBDE serum concentrations were higher in the Mexican-American children regardless of length of time their mother had resided in California or the duration of the child's breast-feeding. These data suggest that PBDE serum concentrations in these children resulted primarily from postnatal exposure.ConclusionsLatino children living in California have much higher PBDE serum levels than their Mexican counterparts. Given the growing evidence documenting potential health effects of PBDE exposure, the levels in young children noted in this study potentially present a major public health challenge, especially in California. In addition, as PBDEs are being phased out and replaced by other flame retardants, the health consequences of these chemical replacements should be investigated and weighed against their purported fire safety benefits

Dysregulated B cell function and disease pathogenesis in systemic sclerosis

Systemic sclerosis (SSc) is a complex, immune-mediated rheumatic disease characterised by excessive extracellular matrix deposition in the skin and internal organs. B cell infiltration into lesional sites such as the alveolar interstitium and small blood vessels, alongside the production of defined clinically relevant autoantibodies indicates that B cells play a fundamental role in the pathogenesis and development of SSc. This is supported by B cell and fibroblast coculture experiments revealing that B cells directly enhance collagen and extracellular matrix synthesis in fibroblasts. In addition, B cells from SSc patients produce large amounts of profibrotic cytokines such as IL-6 and TGF-β, which interact with other immune and endothelial cells, promoting the profibrotic loop. Furthermore, total B cell counts are increased in SSc patients compared with healthy donors and specific differences can be found in the content of naïve, memory, transitional and regulatory B cell compartments. B cells from SSc patients also show differential expression of activation markers such as CD19 which may shape interactions with other immune mediators such as T follicular helper cells and dendritic cells. The key role of B cells in SSc is further supported by the therapeutic benefit of B cell depletion with rituximab in some patients. It is notable also that B cell signaling is impaired in SSc patients, and this could underpin the failure to induce tolerance in B cells as has been shown in murine models of scleroderma

Ten Years In: Implementing Strategic Approaches to Cyberspace

This book represents a look beyond theories and analogies to examine the challenges of strategy implementation. In the essays that follow, practitioners who are building cyberspace forces at-scale join scholars who study power and force in this new domain to collectively offer a unique perspective on the evolution and future of cyber strategy and operations.https://digital-commons.usnwc.edu/usnwc-newport-papers/1044/thumbnail.jp

An implementation study of the crisis resolution team model in Norway: Are the crisis resolution teams fulfilling their role?

Background The establishment of crisis resolution teams (CRTs) is part of the national mental health policy in several Western countries. The purpose of the present study is to describe characteristics of CRTs and their patients, explore the differences between CRTs, and examine whether the CRTs in Norway are organized according to the international CRT model. Methods The study was a naturalistic study of eight CRTs and 680 patients referred to these teams in Norway. Mental health problems were assessed using the Health of the Nation Outcome Scales (HoNOS), Global Assessment of Functioning Scales (GAF) and the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). Results None of the CRTs operated 24 hours a day, seven days a week (24/7 availability) or had gate-keeping functions for acute wards. The CRTs also treated patients who were not considered for hospital admission. Forty per cent of patients waited more than 24 hours for treatment. Fourteen per cent had psychotic symptoms, and 69% had affective symptoms. There were significant variations between teams in patients' total severity of symptoms and social problems, but no variations between teams with respect to patients' aggressive behaviour, non-accidental self-injury, substance abuse or psychotic symptoms. There was a tendency for teams operating extended hours to treat patients with more severe mental illnesses. Conclusions The CRT model has been implemented in Norway without a rapid response, gate-keeping function and 24/7 availability. These findings indicate that the CRTs do not completely fulfil their intended role in the mental health system

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease