The early evolving sex hormone environment is associated with significant outcome and inflammatory response differences after injury.
ABSTRACT: Clinical research characterizing the mechanisms responsible for sex-based outcome differences after injury remains conflicting. Currently lacking is an understanding of the early sex hormone milieu of the injured patient and the effects these early hormone differences have on clinical outcomes and the innate immune response following injury.A prospective cohort study was performed over a 20-month period. Blunt injury patients requiring intensive care unit admission were enrolled. Samples were collected within 6 hours and at 24 hours after injury and were analyzed for total testosterone (TT) and estradiol concentrations. Outcomes of interest included multiple-organ failure (MOF; Marshall Multiple Organ Dysfunction Score [MODScore] > 5), nosocomial infection (NI), mortality, and serial cytokine/chemokine measurements. Multivariate logistic regression was used to determine the independent risks associated with early sex hormone measurements.In 288 prospectively enrolled patients, 69% were male, with a median Injury Severity Score (ISS) of 16 (interquartile range 10-21). Elevated TT levels at 6 hours were associated with elevated interleukin 6 levels and cytokine/chemokine measurements (18 of 24 measured). Rising TT levels were significantly associated with more than a fivefold and twofold higher independent risk of MOF and NI, respectively (odds ratio [OR], 5.2; p = 0.02; 95% confidence interval [CI], 1.2-22.3; and OR, 2.1; p = 0.03; 95% CI, 1.02-4.2). At 24 hours, TT levels were no longer associated with poor outcome, while estradiol levels were significantly associated with nearly a fourfold higher independent risk of MOF (OR, 3.9; p = 0.04, 95% CI, 1.05-13).Early elevations and increasing testosterone levels over initial 24 hours after injury are associated with an exaggerated inflammatory response and a significantly greater risk of MOF and NI. High estrogen levels at 24 hours are independently associated with an increased risk of MOF. The current analysis suggests that an early evolving testosterone to estrogen hormonal environment is associated with a significantly higher independent risk of poor outcome following traumatic injury.Prognostic/epidemiologic study, level II.
Project description:Vapor-assisted dry-gel synthesis of the metal-organic framework-74 (MOF-74) structure, specifically Ni-MOF-74 produced from synthetic precursors using an organic-water hybrid solvent system, showed a very high yield (>90% with respect to 2,5-dihydroxyterepthalic acid) and enhanced performance. The Ni-MOF-74 obtained showed improved sorption characteristics towards CO2 and the refrigerant fluorocarbon dichlorodifluoromethane. Unlike conventional synthesis, which takes 72?hours using the tetrahydrofuran-water system, this kinetic study showed that Ni-MOF-74 forms within 12?hours under dry-gel conditions with similar performance characteristics, and exhibits its best performance characteristics even after 24?hours of heating. In the dry-gel conversion method, the physical separation of the solvent and precursor mixture allows for recycling of the solvent. We demonstrated efficient solvent recycling (up to three times) that resulted in significant cost benefits. The scaled-up manufacturing cost of Ni-MOF-74 synthesized via our dry-gel method is 45% of conventional synthesis cost. Thus, for bulk production of the MOFs, the proposed vapor-assisted, dry-gel method is efficient, simple, and inexpensive when compared to the conventional synthesis method.
Project description:Objective:Pharmacokinetic and efficacy data from a phase 3 testosterone nasal gel (TNG) study were stratified by baseline endogenous testosterone level in patients with testosterone deficiency. Total testosterone (TT), LH, and FSH levels, as well as erectile function, mood, and lean body mass for each group were compared. In a subset of patients with very low baseline endogenous testosterone levels (<100 ng/dL), we investigated whether TNG is a suitable treatment option. Materials and Methods:Patients with testosterone deficiency (serum TT <300 ng/dL) were treated with TNG for 3 months, followed by safety extension periods of 90 and/or 180 days. Pharmacokinetic parameters were calculated from serum hormone levels on days 30 and 90, along with efficacy measurements, which were analyzed by comparison with baseline values. Baseline and/or predose TT values were used for patient stratification. Results:Prestudy and predose endogenous testosterone concentrations correlated. The maximal concentration of TT was nearly identical across all cohorts at days 30 and 90, whereas the average concentration over 24 hours had a slight positive dependence relative to predose levels. LH levels remained in the normal range but were decreased more in patients with higher starting baseline levels. These findings indicate that TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period. Patients with the lowest endogenous testosterone levels received maximum exposure impact from each TNG dose. Patients with severe testosterone deficiency had similar efficacy improvements as the remainder of the study population. Conclusion:All testosterone-deficient cohorts were successfully treated with TNG.
Project description:BACKGROUND: Both trauma-induced coagulopathy (TIC) and transfusion strategies influence early outcome in hemorrhagic trauma patients. Their impact on late outcome is less well characterized. This study systematically reviews risk factors for TIC- and transfusion-associated multiple organ failure (MOF) in severely injured trauma patients. MATERIALS AND METHODS: A systematic search was conducted in PubMed and Embase. Studies published from 1986 to 2013 on adult trauma patients with an injury severity score ?16, investigating TIC or transfusion strategies with MOF as primary or secondary outcome, were eligible for inclusion. Results of the included studies were evaluated with meta-analyses of pooled data. RESULTS: In total, 50 studies were included with a total sample size of 63,586 patients. Due to heterogeneity of the study populations and outcome measures, results from 7 studies allowed for pooling of data. Risk factors for TIC-associated MOF were hypocoagulopathy, hemorrhagic shock, activated protein C, increased histone levels, and increased levels of markers of fibrinolysis on admission. After at least 24?h after admission, the occurrence of thromboembolic events was associated with MOF. Risk factors for transfusion-associated MOF were the administration of fluids and red blood cell units within 24?h post-injury, the age of red blood cells (>14?days) and a ratio of FFP:RBC???1:1 (OR 1.11, 95% CI 1.04-1.19). CONCLUSION: Risk factors for TIC-associated MOF in severely injured trauma patients are early hypocoagulopathy and hemorrhagic shock, while a hypercoagulable state with the occurrence of thromboembolic events later in the course of trauma predisposes to MOF. Risk factors for transfusion-associated MOF include administration of crystalloids and red blood cells and a prolonged storage time of red blood cells. Future prospective studies investigating TIC- and transfusion-associated risk factors on late outcome are required.
Project description:The beneficial effects of testosterone treatment (TT) are debated.Double-blinded, placebo-controlled study of six months TT (gel) in 54 men aged 60-78 with bioavailable testosterone (BioT) <7.3 nmol/L and waist >94 cm randomized to TT (50-100 mg/day, n = 20), placebo (n = 18), or strength training (ST) (n = 16) for 24 weeks. Moreover, the ST group was randomized to TT (n = 7) or placebo (n = 9) after 12 weeks.Chemokines (MIF, MCP-1, and MIP-1 α ) and lean body mass (LBM), total, central, extremity, visceral, and subcutaneous (SAT) fat mass established by DXA and MRI. Results. From 0 to 24 weeks, MIF and SAT decreased during ST + placebo versus placebo, whereas BioT and LBM were unchanged. TT decreased fat mass (total, central, extremity, and SAT) and increased BioT and LBM versus placebo. MIF levels increased during TT versus ST + placebo. ST + TT decreased fat mass (total, central, and extremity) and increased BioT and LBM versus placebo. From 12 to 24 weeks, MCP-1 levels increased during TT versus placebo and MCP-1 levels decreased during ST + placebo versus placebo.ST + placebo was associated with decreased MIF levels suggesting decreased inflammatory activity. TT may be associated with increased inflammatory activity.
Project description:Male BRCA mutation carriers are at risk for an early onset aggressive prostate cancer. No data exist on the association of testosterone levels among these patients. We aimed to analyze testosterone and associated hormonal levels among male BRCA carriers and non-carriers.Overall 87 male carriers and 43 non-carriers aged 40-70 were prospectively enrolled. Clinical data were collected and all patients were tested for total testosterone (TT), prostate specific antigen (PSA), follicle stimulating hormone (FSH), luteinizing hormone (LH), free androgen index (FAI), sex hormone binding globulin (SHBG) and prolactin. Multivariate linear regression analysis was performed to predict TT levels.The median age, mean BMI, comorbidities, PSA, FSH, LH and SHBG levels in both groups were similar. However, mean TT and FAI were higher in the carriers (16.7 nmol/l vs 13.5 nmol/l, p=0.03 and 39.5 vs 34.8, p=0.05, respectively), while prolactin was significantly lower. Multivariate analysis demonstrated that while BMI was inversely correlated to TT levels in both groups, LH was a predictor only in non-carriers.Carriers have higher TT and FAI levels and lower prolactin levels; but LH does not predict their TT levels. Further research in a larger cohort of BRCA carriers with and without prostate cancer should be performed.
Project description:Microvascular injury early after hypoxic ischemia (HI) may contribute to neonatal brain damage. N-methyl-D-aspartate receptor overstimulation activates neuronal nitric oxide synthases (nNOS). We hypothesized that microvascular damage occurs early post-HI via nNOS activation and contributes to brain injury. Postpartum day-7 rat pups were treated with 7-nitroindazole (7-NI) or aminoguanidine (AG) before or after HI. Electron microscopy was performed to measure neuronal and endothelial cell damage. There were vascular lumen narrowing at 1 hour, pyknotic neurons at 3 hours, and extensive neuronal damage and loss of vessels at 24 hours post HI. Early after reoxygenation, there were neurons with heterochromatic chromatin and endothelial cells with enlarged nuclei occluding the lumen. There was also increased 3-nitrotyrosin in the microvessels and decreased cerebral blood perfusion. 7-NI and AG treatment before hypoxia provided complete and partial neuroprotection, respectively. Early post-reoxygenation, the AG group showed significantly increased microvascular nitrosative stress, microvascular interruptions, swollen nuclei that narrowed the vascular lumen, and decreased cerebral perfusion. The 7-NI group showed significantly decreased microvascular nitrosative stress, patent vascular lumen, and increased cerebral perfusion. Our results indicate that microvascular damage occurs early and progressively post HI. Neuronal nitric oxide synthases activation contributes to microvascular damage and decreased cerebral perfusion early after reoxygenation and worsens brain damage.
Project description:BACKGROUND:Reduced total hours of sleep and low quality of sleep have been suggested to be associated with low levels of male hormones. Few studies have examined the association between excessive sleep and male reproductive hormones. OBJECTIVE:To investigate the association of total hours of sleep and quality of sleep with serum levels of total-, bioavailable- and free testosterone (tT, bT and fT), sex hormone binding globulin (SHBG) and dehydroepiandrosteron-sulfat (DHEAS). METHODS:Serum levels of tT, SHBG and DHEAS were measured with immunoassays in a cross-sectional population-based study of 2,095 males. bT and fT were calculated in accordance with Vermeulens method. Information on total hours of sleep and sleep quality was obtained by questionnaire. Linear regression as used to calculate hormones according to total hours of sleep and the results were expressed as β-estimates and 95% confidence intervals (CI). The adjustment in the multivariable models was constructed taking age, bmi, smoking, alcohol intake and physical activity into account. RESULTS:Excessive sleep (> 9 hours) compared to 7-9 hours of sleep was significantly associated with lower tT, bT and fT, but not with SHBG or DHEAS. These significant associations were also found in our analyses with hormones as continuous variables but no associations were found in our general additive model analyses. CONCLUSIONS:In this cross-sectional study in men, excessive sleep, associated with lower levels of male reproductive hormones. Longitudinal studies are needed to determine the causal direction of the observed association between excessive sleep and lower male reproductive hormones levels.
Project description:<h4>Objectives</h4>Serum testosterone (T) levels in men decline with age. Low T levels are associated with sarcopenia and frailty in men aged <u>></u>80 years. T levels have not previously been directly associated with disability in older men. We explored associations between T levels, frailty and disability in a cohort of octogenarian men.<h4>Setting</h4>Data from all men from Life and Living in Advanced Age Cohort Study in New Zealand, a longitudinal cohort study in community-dwelling older adults.<h4>Participants</h4>Community-dwelling (<u>></u>80 years) adult men excluding those receiving T treatment or with prostatic carcinoma.<h4>Outcomes measures</h4>Associations between baseline total testosterone (TT) and calculated free testosterone (fT), frailty (Fried scale) and disability (Nottingham Extended Activities of Daily Living scale (NEADL)) (baseline and 24?months) were examined using multivariate regression and Wald's ?<sup>2</sup> techniques. Subjects with the lowest quartile of baseline TT and fT values were compared with those in the upper three quartiles.<h4>Results</h4>Participants: 243 men, mean (SD) age 83.7 (2.0) years. Mean (SD) TT=17.6 (6.8) nmol/L and fT=225.3 (85.4) pmol/L. On multivariate analyses, lower TT levels were associated with frailty: ?=0.41, p=0.017, coefficient of determination (R<sup>2</sup>)=0.10?and disability (NEADL) (?=-1.27, p=0.017, R<sup>2</sup>=0.11), low haemoglobin (?=-7.38, p=0.0016, R<sup>2</sup>=0.05), high fasting glucose (?=0.38, p=0.038, R<sup>2</sup>=0.04) and high C reactive protein (CRP) (?=3.57, p=0.01, R<sup>2</sup>=0.06). Low fT levels were associated with frailty (?=0.39, p=0.024, R<sup>2</sup>=0.09) but not baseline NEADL (?=-1.29, p=0.09, R<sup>2</sup>=0.09). Low fT was associated with low haemoglobin (?=-7.83, p=0.0008, R<sup>2</sup>=0.05) and high CRP (?=2.86, p=0.04, R<sup>2</sup>=0.05). Relationships between baseline TT and fT, and 24-month outcomes of disability and frailty were not significant.<h4>Conclusions</h4>In men over 80 years, we confirm an association between T levels and baseline frailty scores. The new finding of association between T levels and disability is potentially relevant to debates on T supplementation in older men, though, as associations were not present at 24 months, further work is needed.
Project description:Higher levels of testosterone have been associated with better lung function in cross-sectional population-based studies. The role of testosterone in lung function in women and in lung function decline in men or women is unclear. We studied 5114 men and 5467 women in the UK Biobank with high-quality spirometry at baseline (2006–2010) and 8.4?years later. We studied cross-sectional associations of total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI) and sex hormone-binding globulin (SHBG) with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC using linear regression and associations of baseline markers with lung function decline using linear mixed-effects regression. Men with higher levels of TT had higher FEV1 (27.56?mL per interquartile range increase TT, 95% CI 5.43–49.68) and FVC (48.06?mL, 95% CI 22.07–74.06) at baseline. Higher cFT levels were associated with higher FEV1 and FVC among physically active men only. In women, higher FAI and cFT levels were associated with lower lung function at baseline and higher levels of TT, cFT and FAI were associated with slightly attenuated FEV1 and FVC decline. Higher levels of SHBG were associated with better lung function in both sexes but slightly accelerated decline in men. In this population-based sample, higher levels of TT were associated with better lung function in men and higher levels of cFT with better lung function in physically active men. A small attenuation of lung function decline with higher levels of TT, cFT and FAI was seen in women only. Higher levels of testosterone are associated with better lung function in men, especially if physically active, but not in women. A small attenuation of lung function decline with higher testosterone levels is seen in women only.https://bit.ly/382d0xT
Project description:UNLABELLED: BACKGROUND: Increased prenatal testosterone exposure has been hypothesized as a mechanism underlying autism spectrum disorders (ASD). However, no studies have prospectively measured prenatal testosterone exposure and ASD. The current study sought to determine whether testosterone concentrations in umbilical cord blood are associated with a clinical diagnosis of ASD in a small number of children and with autistic-like traits in the general population. METHODS: Umbilical cord blood was collected from 707 children. Samples were analyzed for total (TT) and bioavailable (BioT) testosterone concentrations. Parent report indicated that five individuals had a clinical diagnosis of ASD. Those participants without a diagnosis were approached in early adulthood to complete the Autism-Spectrum Quotient (AQ), a self-report measure of autistic-like traits, with 184 males (M = 20.10 years; SD= 0.65 years) and 190 females (M = 19.92 years; SD=0.68 years) providing data. RESULTS: The BioT and TT concentrations of the five children diagnosed with ASD were within one standard-deviation of the sex-specific means. Spearman's rank-order coefficients revealed no significant correlations between TT levels and scores on any AQ scale among males (rho range: -.01 to .06) or females (rho value range: -.07 to .01). There was also no significant association between BioT or TT concentrations and AQ scores among males (rho value range: -.07 to .08) or females (rho value range: -.06 to .12). Males were more likely than females to have 'high' scores (upper decile) on the AQ scale relating pattern and detail processing. However, the likelihood of a high score on this scale was unrelated to BioT and TT concentrations in both males and females. CONCLUSIONS: These findings indicate that testosterone concentrations from umbilical cord blood are unrelated to autistic-like traits in the general population. However, the findings do not exclude an association between testosterone exposure in early intrauterine life and ASD.