Clinical and molecular implications of mosaicism in FMR1 full mutations

Expansions of more than 200 CGG repeats (full mutation) in the FMR1 gene give rise to fragile X syndrome (FXS) through a process that generally involves hypermethylation of the FMR1 promoter region and gene silencing, resulting in absence of expression of the encoded protein, FMRP. However, mosaicism with alleles differing in size and extent of methylation often exist within or between tissues of individuals with FXS. In the current work, CGG-repeat lengths and methylation status were assessed for eighteen individuals with FXS, including 13 mosaics, for which peripheral blood cells (PBMCs) and primary fibroblast cells were available. Our results show that for both PBMCs and fibroblasts, FMR1 mRNA and FMRP expression are directly correlated with the percent of methylation of the FMR1 allele. In addition, Full Scale IQ (FSIQ) scores were inversely correlated with the percent methylation and positively correlated with higher FMRP expression. These latter results point toward a positive impact on cognition for full mutation, methylation mosaics with lower methylation compared to individuals with fully methylated, full mutation alleles. However, we did not observe a significant reduction in the number of seizures, nor in the severity of hyperactivity or autism spectrum disorder, among individuals with mosaic genotypes in the presentation of FXS.These observations suggest that low, but non-zero expression of FMRP may be sufficient to positively impact cognitive function in individuals with FXS, with methylation mosaicism (lowered methylation fraction) contributing to a more positive clinical outcome

Barriers to PrEP uptake among Black female adolescents and emerging adults

HIV/AIDS disproportionately impacts Black cisgender female adolescents and emerging adults. Pre-Exposure Prophylaxis (PrEP) reduces the risk of HIV infection; however, structural barriers may exacerbate resistance to PrEP in this population. The purpose of this paper is to understand the characteristics of age, race, gender, history, and medical mistrust as barriers to PrEP uptake among Black female adolescents and emerging adults (N = 100 respondents) between the ages of 13–24 years in Chicago. Between January and June of 2019, participants completed the survey. We used directed content analysis to examine reported barriers to PrEP uptake. The most commonly identified barriers to PrEP uptake were side effects (N = 39), financial concerns (N = 15), and medical mistrust (N = 12). Less frequently reported barriers included lack of PrEP knowledge and misconceptions (N = 9), stigma (N = 2), privacy concerns (N = 4). We describe innovative multi-level strategies to provide culturally safe care to improve PrEP acceptability among Black female adolescents and emerging adults in Chicago. These recommendations may help mitigate the effect of medical mistrust, stigma, and misconceptions of PrEP within Black communities

Cytokine-mediated degradation of the transcription factor ERG impacts the pulmonary vascular response to systemic inflammatory challenge

BACKGROUND: During infectious diseases, proinflammatory cytokines transiently destabilize interactions between adjacent vascular endothelial cells (ECs) to facilitate the passage of immune molecules and cells into tissues. However, in the lung, the resulting vascular hyperpermeability can lead to organ dysfunction. Previous work identified the transcription factor ERG (erythroblast transformation-specific-related gene) as a master regulator of endothelial homeostasis. Here we investigate whether the sensitivity of pulmonary blood vessels to cytokine-induced destabilization is due to organotypic mechanisms affecting the ability of endothelial ERG to protect lung ECs from inflammatory injury. METHODS: Cytokine-dependent ubiquitination and proteasomal degradation of ERG were analyzed in cultured HUVECs (human umbilical vein ECs). Systemic administration of TNFα (tumor necrosis factor alpha) or the bacterial cell wall component lipopolysaccharide was used to cause a widespread inflammatory challenge in mice; ERG protein levels were assessed by immunoprecipitation, immunoblot, and immunofluorescence. Murine Erg deletion was genetically induced in ECs (Ergfl/fl;Cdh5[PAC]-CreERT2), and multiple organs were analyzed by histology, immunostaining, and electron microscopy. RESULTS: In vitro, TNFα promoted the ubiquitination and degradation of ERG in HUVECs, which was blocked by the proteasomal inhibitor MG132. In vivo, systemic administration of TNFα or lipopolysaccharide resulted in a rapid and substantial degradation of ERG within lung ECs but not ECs of the retina, heart, liver, or kidney. Pulmonary ERG was also downregulated in a murine model of influenza infection. Ergfl/fl;Cdh5(PAC)-CreERT2 mice spontaneously recapitulated aspects of inflammatory challenges, including lung-predominant vascular hyperpermeability, immune cell recruitment, and fibrosis. These phenotypes were associated with a lung-specific decrease in the expression of Tek-a gene target of ERG previously implicated in maintaining pulmonary vascular stability during inflammation. CONCLUSIONS: Collectively, our data highlight a unique role for ERG in pulmonary vascular function. We propose that cytokine-induced ERG degradation and subsequent transcriptional changes in lung ECs play critical roles in the destabilization of pulmonary blood vessels during infectious diseases

Smoking duration before first childbirth: an emerging risk factor for breast cancer? Results from 302,865 Norwegian women

This article is part of Eivind Bjerkaas' doctoral thesis which is available in Munin at http://hdl.handle.net/10037/6799Purpose: Recently, The International Agency for Research on Cancer classified cigarette smoking as possibly carcinogenic to the human breast. Since some new cohort studies have suggested that this risk is confined to women who started to smoke before first childbirth, we wanted to examine the association between smoking and breast cancer, with a focus on time of smoking initiation in relation to the first childbirth. Methods: We followed 302,865 Norwegian women born between 1899 and 1975, recruited from 1974 to 2003, by linkage to national registries through December 2007. We used Cox proportional hazard models to estimate hazard ratios (HR) and 95 % confidence intervals (CI). Results: During more than 4.1 million person-years of follow-up, we ascertained 7,490 cases of primary invasive breast cancer. Compared with never smokers, ever smokers had a 15 % (HR = 1.15, 95 % CI 1.10–1.21) increased risk of breast cancer overall and also a significantly increased risk of breast cancer in the three most exposed categories of age at smoking initiation (parous women), number of cigarettes smoked per day, years of smoking duration and number of pack-years. Ever smokers who started to smoke more than 1 year after the first childbirth had not an increased risk (HR = 0.93, 95 % CI 0.86–1.02), while those who initiated smoking more than 10 years before their first childbirth had a 60 % (HR = 1.60, 95 % CI 1.42–1.80) increased risk of breast cancer, compared with never smokers

Metabolite-related dietary patterns and the development of islet autoimmunity

The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in theYoung) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts

Calibrating and adjusting expectations in life: A grounded theory on how elderly persons with somatic health problems maintain control and balance in life and optimize well-being

Aim: This study aims at exploring the main concern for elderly individuals with somatic health problems and what they do to manage this. Method: In total, 14 individuals (mean = 74.2 years; range = 68–86 years) of both gender including hospitalized and outpatient persons participated in the study. Open interviews were conducted and analyzed according to grounded theory, an inductive theory-generating method. Results: The main concern for the elderly individuals with somatic health problems was identified as their striving to maintain control and balance in life. The analysis ended up in a substantive theory explaining how elderly individuals with somatic disease were calibrating and adjusting their expectations in life in order to adapt to their reduced energy level, health problems, and aging. By adjusting the expectations to their actual abilities, the elderly can maintain a sense of that they still have the control over their lives and create stability. The ongoing adjustment process is facilitated by different strategies and result despite lower expectations in subjective well-being. The facilitating strategies are utilizing the network of important others, enjoying cultural heritage, being occupied with interests, having a mission to fulfill, improving the situation by limiting boundaries and, finally, creating meaning in everyday life. Conclusion: The main concern of the elderly with somatic health problems was to maintain control and balance in life. The emerging theory explains how elderly people with somatic health problems calibrate their expectations of life in order to adjust to reduced energy, health problems, and aging. This process is facilitated by different strategies and result despite lower expectation in subjective well-being

Metabolite-related dietary patterns and the development of islet autoimmunity

The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in theYoung) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts