Endocrine risk factors for COVID-19: Endogenous and exogenous glucocorticoid excess.
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ABSTRACT:
SUBMITTER: Vogel F
PROVIDER: S-EPMC8267234 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:An increase in early-onset colorectal cancers (eoCRC), defined as a CRC before 50 years, is confirmed globally.
CRC pathogenesis has been associated with several risk factors (family history, germline pathogenic variants, obesity, alcohol, physical activity, red meat, and a Western diet).
Design: an international, multicenter, retrospective case-control study of prospectively enrolled patients; low-risk intervention study as it will perform a fecal occult blood test Endpoint: predictive power of a semi-quantitative food frequency questionnaire (SQFFQ) developed for eoCRC.
Cases: Patients with a recent diagnosis of eoCRC (within 2 years from enrollment).
Controls: matched by age (matching range ± 5 years) and sex. Healthy volunteers will be mainly enrolled among workers within the participating hospital center. The enrolled healthy volunteers will perform a fecal occult blood test.
Variables of interest: age, sex, ethnicity, BMI at the time of eoCRC diagnosis and at 18 years old, country, tobacco smoking at the time of eoCRC diagnosis and at 18 years old, sitting time, TV-viewing time, moderate-to-vigorous physical activity (MVPA), waist circumference (cm), home blood pressure levels (mmHg), fasting blood glucose (mg/dl), regular consumption of aspirin/NSAID, calcium and folate supplements, oral contraceptive agents, post-menopausal hormones and years of consumptions, if the filled questionnaire reflects diet for the last 5-10 years before.
Cases only: date of eoCRC diagnosis, symptoms at diagnosis, eoCRC localization, eoCRC stage, histological diagnosis, type of surgery, and date (if performed), chemotherapy and radiotherapy (if performed), vital status and duration of follow-up, family history of CRC and other cancers (uterus, ovary, stomach, small intestine, urinary tract/bladder/kidney, bile ducts, brain, pancreas, skin tumors), type of germline pathogenetic variant (if performed).
Before the case-control study, three non-consecutive 24-hour Dietary Recalls (24hDRs) will validate the SQFFQ.
The SQFFQ will be administered to the validation study group during three non-consecutive calls, including one non-weekday (30-minute 24-h-recall computer-aided personal interview).
Primary Objective To measure the relative risk of specific dietary and lifestyle factors (smoking habit, alcohol intake, physical activity) for early-onset colorectal cancer in countries where eoCRC incidence is increasing versus stable/decreasing
| 8689 | ecrin-mdr-crc
Project description:BackgroundThe glucocorticoid receptor (GR) consists of two alternatively spliced isoforms: GR?, which activates gene transcription, and GR?, a dominant-negative receptor. Theoretically, inactivating variants of GR? could result in glucocorticoid hypersensitivity.DesignA 46-year-old woman presented for evaluation of adrenal insufficiency prompted by low plasma cortisol levels and multiple unexplained symptoms but without clinical evidence of glucocorticoid insufficiency. To explain these findings, extensive clinical, genetic, and molecular studies were performed.MethodsStandard clinical methods assessed the patient's hypothalamic-pituitary-adrenal axis. Validated molecular techniques were used for receptor sequencing, stable transfections, stimulation of candidate genes, cDNA arrays, Ingenuity Pathway Analysis, volcano analysis, and isolation and analysis of the patient's mononuclear cells.ResultsClinical studies excluded primary or secondary adrenal insufficiency, established consistently low basal cortisol levels, and demonstrated hypersensitivity to ultra-low-dose dexamethasone. Receptor sequencing identified two variants of GR9? (A3669G and G3134T) as well as the known Bcl1 polymorphism. Reductionist studies using stable osteosarcoma cell lines transfected with the GR? variants demonstrated glucocorticoid hypersensitivity of transcribed genes on cDNA array analysis. The patient's monocytes responded to hydrocortisone with exaggerated stimulation of the candidate genes GILZ and FKBP5.ConclusionTwo variants of the dominant-negative GR?, in conjunction with a common Bcl1 intron variant, resulted in hypersensitivity to endogenous and exogenous glucocorticoids and, as a reflection of severity, low circulating cortisol levels without clinical evidence of glucocorticoid insufficiency. This prismatic case exemplifies the unique effects of variants of a dominant-negative receptor.
| S-EPMC6179182 | biostudies-literature
Project description:ContextGlucocorticoid excess exhibits multiple detrimental effects by its catabolic properties. Metformin was recently suggested to protect from adverse metabolic side-effects of glucocorticoid treatment. Whether metformin is beneficial in patients with endogenous glucocorticoid excess has not been clarified.ObjectiveTo evaluate the phenotype in patients with endogenous Cushing's syndrome (CS) treated with metformin at the time of diagnosis.Patients and methodsAs part of the German Cushing's Registry we selected from our prospective cohort of 96 patients all 10 patients who had been on pre-existing metformin treatment at time of diagnosis (CS-MET). These 10 patients were matched for age, sex and BMI with 16 patients without metformin treatment (CS-NOMET). All patients had florid CS at time of diagnosis. We analyzed body composition, metabolic parameters, bone mineral density and bone remodeling markers, muscle function and quality of life.ResultsAs expected, diabetes was more prevalent in the CS-MET group, and HbA1c was higher. In terms of comorbidities and the degree of hypercortisolism, the two groups were comparable. We did not observe differences in terms of muscle function or body composition. In contrast, bone mineral density in metformin-treated patients was superior to the CS-NOMET group at time of diagnosis (median T-Score -0.8 versus -1.4, p = 0.030). CS-MET patients showed decreased β-CTX levels at baseline (p = 0.041), suggesting reduced bone resorption under metformin treatment during glucocorticoid excess.ConclusionThis retrospective cohort study supports potential protective effects of metformin in patients with endogenous glucocorticoid excess, in particular on bone metabolism.
| S-EPMC8578886 | biostudies-literature
Project description:PurposeBone and vascular diseases are considered to share pathogenic mechanisms. Excess glucocorticoids, key regulators of cardiovascular and metabolic homeostasis, may promote both diseases simultaneously. We used endogenous Cushing's syndrome (CS) to investigate whether glucocorticoid excess underlies coexisting bone and vascular diseases.MethodsWe included 194 patients with adrenal tumors (ATs): autonomous cortisol secretion (ACS, n = 97) and non-functional AT (n = 97). ACS was further classified into overt CS (n = 17) and subclinical CS (SCS, n = 80). Arterial stiffness was defined as a brachial-ankle pulse wave velocity (baPWV) ≥ 1800 cm/s.ResultsPatients with ACS had higher coexistence rates of vertebral fracture and arterial stiffness (23 % vs. 2 %; p < 0.001) and vertebral fracture and abdominal aortic calcification (22 % vs. 1 %; p < 0.001) than those with non-functional AT. In patients with ACS, baPWV was negatively correlated with trabecular bone score (TBS, r = -0.33; p = 0.002), but not with bone mineral density, and vertebral fracture was associated with arterial stiffness in the logistic regression analysis. In the multivariate analysis of variance, the degree of cortisol excess (defined as CS, SCS, and non-functional AT) determined the correlation between TBS and baPWV (partial η2 = 0.07; p < 0.001). In the analysis of covariance, patients with coexisting vertebral fracture and arterial stiffness had higher levels of serum cortisol after the 1-mg dexamethasone suppression test than those without.ConclusionIn endogenous glucocorticoid excess, bone and vascular diseases frequently coexisted, and deteriorated bone quality, not bone loss, was related to arterial stiffness. Thus, glucocorticoid excess may perturb the bone-vascular axis.
| S-EPMC9398912 | biostudies-literature
Project description:Gender is one of the factors influencing the intestinal microbial composition in mammals, but whether fish also have gender-specific intestinal microbial patterns remains unknown. In this decade, endocrine disrupting chemicals in surface and ground water of many areas and increasing observation of freshwater male fish displaying female sexual characteristics have been reported. Here we identified the difference in intestinal microbiota between male and female zebrafish, and revealed the influence of endocrine disrupting chemicals on zebrafish intestinal microbiota by using high-throughput sequencing. The results indicated that Fusobacteria, Bacteroidetes and Proteobacteria were dominant in the gut of zebrafish and there were no obvious gender-specific intestinal microbial patterns. Two endocrine disrupting chemicals, Estradiol (E2) and Bisphenol A (BPA), were selected to treat male zebrafish for 5 weeks. E2 and BPA increased vitellogenin expression in the liver of male zebrafish and altered the intestinal microbial composition with the abundance of the phylum CKC4 increased significantly. Our results suggested that because of the developmental character and living environment, gender did not influence the assembly of intestinal microbiota in zebrafish as it does in mammals, but exposure extra to endocrine disrupting chemicals disturbed the intestinal microbial composition, which may be related to changes in host physiological metabolism.
| S-EPMC5049800 | biostudies-literature
Project description:Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
2022-02-01 | E-MTAB-10129 | biostudies-arrayexpress
Project description:Understanding is still developing about spatial risk factors for COVID-19 infection or mortality. This is a secondary analysis of patient records in a confined area of eastern England, covering persons who tested positive for SARS-CoV-2 through end May 2020, including dates of death and residence area. We obtained residence area data on air quality, deprivation levels, care home bed capacity, age distribution, rurality, access to employment centers, and population density. We considered these covariates as risk factors for excess cases and excess deaths in the 28 days after confirmation of positive Covid status relative to the overall case load and death recorded for the study area as a whole. We used the conditional autoregressive Besag-York-Mollie model to investigate the spatial dependency of cases and deaths allowing for a Poisson error structure. Structural equation models were applied to clarify relationships between predictors and outcomes. Excess case counts or excess deaths were both predicted by the percentage of population age 65 years, care home bed capacity and less rurality: older population and more urban areas saw excess cases. Greater deprivation did not correlate with excess case counts but was significantly linked to higher mortality rates after infection. Neither excess cases nor excess deaths were predicted by population density, travel time to local employment centers, or air quality indicators. Only 66% of mortality was explained by locally high case counts. Higher deprivation clearly linked to higher COVID-19 mortality separate from wider community prevalence and other spatial risk factors.
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Project description:A fundamental question in ecology is whether vegetation oscillations are merely a result of periodic environmental variability, or rather driven by endogenous factors. We address this question using a mathematical model of dryland vegetation subjected to annual rainfall periodicity. We show that while spontaneous oscillations do not exist in realistic parameter ranges, resonant response to periodic precipitation is still possible due to the existence of damped oscillatory modes. Using multiple time-scale analysis, in a restricted parameter range, we find that these endogenous modes can be pumped by the exogenous precipitation forcing to form sustained oscillations. The oscillations amplitude shows a resonance peak that depends on model parameters representing species traits and mean annual precipitation. Extending the study to bistability ranges of uniform vegetation and bare soil, we investigate numerically the implications of resonant oscillations for ecosystem function. We consider trait parameters that represent species with damped oscillatory modes and species that lack such modes, and compare their behaviors. We find that the former are less resilient to droughts, suffer from larger declines in their biomass production as the precipitation amplitude is increased, and, in the presence of spatial disturbances, are likely to go through abrupt collapse to bare soil, rather than gradual, domino-like collapse.
| S-EPMC6344492 | biostudies-literature
Project description:Although the pro-adipogenic effect of glucocorticoid (GC) on adipose tissue (AT) precursor cell differentiation is openly accepted, the effect of chronically high peripheral levels of GC on AT mass expansion is not fully understood. In the present study, we aim to assess the in vitro adipogenic capacity of AT precursor cells isolated from retroperitoneal (RP) AT pads of the hypercorticosteronaemic, adult neonatally treated monosodium L-glutamate (MSG) male rat. To ascertain this issue, we explored the in vitro adipogenic process of stromal-vascular fraction (SVF) cells isolated from RPAT pads of 60-day-old MSG rats. The data recorded indicated that RPAT-SVF cells from hypercorticosteronaemic MSG rats, although displaying an enhanced proliferation capacity, differentiated slower than normal cells. This dysfunction was associated with a reduction in key parameters indicative of precursor cell commitment, differentiation capacity and the percentage of fully differentiated adipocytes, with a retarded maturation process. The distorted adipogenic capacity was highly conditioned by RPAT-SVF cells displaying a low committed population and both excessive and reduced expression of anti- (Pref-1 and Wnt-10b) and pro-adipogenic (mineralocorticoid receptor) signals respectively. Notably, the normalization of peripheral corticosterone levels in MSG rats, as a result of bilateral adrenalectomy combined with GC replacement therapy, fully prevented reduced RPAT precursor cell commitment and overall impaired adipogenesis. Our study strongly supports that the impaired adipogenic process observed in the adult hypertrophic obese MSG male rat is a GC-dependent mechanism, thus explaining the unhealthy RPAT expansion observed in human hypertrophic obese phenotypes, such as in the Cushing's syndrome.
| S-EPMC4190901 | biostudies-literature
Project description:The COVID-19 pandemic has had a detrimental impact on the healthcare system. Our study armed to assess the extent and the disparity in excess acute myocardial infarction (AMI)-associated mortality during the pandemic, through the recent Omicron outbreak. Using data from the CDC's National Vital Statistics System, we identified 1 522 669 AMI-associated deaths occurring between 4/1/2012 and 3/31/2022. Accounting for seasonality, we compared age-standardized mortality rate (ASMR) for AMI-associated deaths between prepandemic and pandemic periods, including observed versus predicted ASMR, and examined temporal trends by demographic groups and region. Before the pandemic, AMI-associated mortality rates decreased across all subgroups. These trends reversed during the pandemic, with significant rises seen for the youngest-aged females and males even through the most recent period of the Omicron surge (10/2021-3/2022). The SAPC in the youngest and middle-age group in AMI-associated mortality increased by 5.3% (95% confidence interval [CI]: 1.6%-9.1%) and 3.4% (95% CI: 0.1%-6.8%), respectively. The excess death, defined as the difference between the observed and the predicted mortality rates, was most pronounced for the youngest (25-44 years) aged decedents, ranging from 23% to 34% for the youngest compared to 13%-18% for the oldest age groups. The trend of mortality suggests that age and sex disparities have persisted even through the recent Omicron surge, with excess AMI-associated mortality being most pronounced in younger-aged adults.
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