There is limited evidence whether being on fludrocortisone prevents vasovagal syncope.
The authors sought to determine whether treatment with fludrocortisone reduces the proportion of patients with ...recurrent vasovagal syncope by at least 40%, representing a pre-specified minimal clinically important relative risk reduction.
The multicenter POST 2 (Prevention of Syncope Trial 2) was a randomized, placebo-controlled, double-blind trial that assessed the effects of fludrocortisone in vasovagal syncope over a 1-year treatment period. All patients had >2 syncopal spells and a Calgary Syncope Symptom Score >-3. Patients received either fludrocortisone or matching placebo at highest tolerated doses from 0.05 mg to 0.2 mg daily. The main outcome measure was the first recurrence of syncope.
The authors randomized 210 patients (71% female, median age 30 years) with a median 15 syncopal spells over a median of 9 years equally to fludrocortisone or placebo. Of these, 96 patients had ≥1 syncope recurrences, and only 14 patients were lost to follow-up before syncope recurrence. There was a marginally nonsignificant reduction in syncope in the fludrocortisone group (hazard ratio HR: 0.69: 95% confidence interval CI: 0.46 to 1.03; p = 0.069). In a multivariable model, fludrocortisone significantly reduced the likelihood of syncope (HR: 0.63; 95% CI: 0.42 to 0.94; p = 0.024). When the analysis was restricted to outcomes after 2 weeks of dose stabilization, there was a significant benefit due to fludrocortisone (HR: 0.51; 95% CI: 0.28 to 0.89; p = 0.019).
The study did not meet its primary objective of demonstrating that fludrocortisone reduced the likelihood of vasovagal syncope by the specified risk reduction of 40%. The study demonstrated a significant effect after dose stabilization, and there were significant findings in post hoc multivariable and on-treatment analyses. (A randomised clinical trial of fludrocortisone for the prevention of vasovagal syncope; ISRCTN51802652; Prevention of Syncope Trial 2 POST 2; NCT00118482).
In inflammatory diseases such as rheumatoid arthritis (RA), steroid metabolism is a central component mediating the actions of immuno-modulatory glucocorticoids and sex steroids. However, the ...regulation and function of cellular steroid metabolism within key leukocyte populations such as macrophages remain poorly defined. In this study, the inflammatory regulation of global steroid metabolism was assessed in RA macrophages.
Bulk RNA-seq data from RA synovial macrophages was used to assess transcripts encoding key enzymes in steroid metabolism and signalling. Changes in metabolism were assessed in synovial fluids, correlated to measures of disease activity and functionally validated in primary macrophage cultures.
RNA-seq revealed a unique pattern of differentially expressed genes, including changes in genes encoding the enzymes 11β-HSD1, SRD5A1, AKR1C2 and AKR1C3. These correlated with disease activity, favouring increased glucocorticoid and androgen levels. Synovial fluid 11β-HSD1 activity correlated with local inflammatory mediators (TNFα, IL-6, IL-17), whilst 11β-HSD1, SRD5A1 and AKR1C3 activity correlated with systemic measures of disease and patient pain (ESR, DAS28 ESR, global disease activity). Changes in enzyme activity were evident in inflammatory activated macrophages in vitro and revealed a novel androgen activating role for 11β-HSD1. Together, increased glucocorticoids and androgens were able to suppress inflammation in macrophages and fibroblast-like-synoviocytes.
This study underscores the significant increase in androgen and glucocorticoid activation within inflammatory polarized macrophages of the synovium, contributing to local suppression of inflammation. The diminished profile of inactive steroid precursors in postmenopausal women may contribute to disturbances in this process, leading to increased disease incidence and severity.
Schematic of changes in steroid metabolism in inflammatory activated macrophages that favour increased synthesis of the active androgen Dihydrotestosterone (DHT) and the active glucocorticoid cortisol (F). The local activation suppresses pro-inflammatory profiles in macrophages and attenuates TNFα driven synovial fibroblast hyperproliferation. Display omitted
•In patients with rheumatoid arthritis, inflammatory macrophages are engines of steroid metabolism, generating androgens and glucocorticoids•These glucocorticoids and androgens are immunomodulatory, suppressing inflammatory cytokine profiles and attenuating synoviocyte hyperproliferation.•The glucocorticoid activating enzyme 11beta-HSD1 plays a novel role in this context bridging androgen activation from circulating precursors.•A diminished profile of inactive steroid precursors metabolites in postmenopausal women may contribute to increased disease incidence and severity.
Shortly before I was elected President of ASCO, I attended the 65th birthday party of a current patient. She had been diagnosed 10 years earlier with metastatic breast cancer and hadn't been sure she ...wanted to move forward with further treatment. With encouragement, she elected to participate in a clinical trial of an investigational drug that is now widely used to treat breast cancer. Happily, here we were, celebrating with her now-married daughters, their husbands, and three beautiful grandchildren, ages 2, 4, and 8. Such is the importance of clinical trials and promising new therapies.Clinical research is about saving and improving the lives of individuals with cancer. It's a continuing story that builds on the efforts of untold numbers of researchers, clinicians, caregivers, and patients. ASCO's
report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology.ASCO's 2020 Advance of the Year-Refinement of Surgical Treatment of Cancer-highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery.Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer.While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can't rest on our laurels. With ASCO's Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we've identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress.Of course, the effectiveness or number of new treatments is meaningless if patients don't have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge.Sincerely,Howard A. "Skip" Burris III, MD, FACP, FASCOASCO President, 2019-2020.
Aims The recent development of a rat model that closely resembles the metabolic syndrome allows to study the mechanisms of amelioration of the syndrome by exercise training. Here, we compared the ...effectiveness for reducing cardiovascular risk factors by exercise training programmes of different exercise intensities. Methods and results Metabolic syndrome rats were subjected to either continuous moderate-intensity exercise (CME) or high-intensity aerobic interval training (AIT). AIT was more effective than CME at reducing cardiovascular disease risk factors linked to the metabolic syndrome. Thus, AIT produced a larger stimulus than CME for increasing maximal oxygen uptake (VO2max; 45 vs. 10%, P < 0.01), reducing hypertension (20 vs. 6 mmHg, P < 0.01), HDL cholesterol (25 vs. 0%, P < 0.05), and beneficially altering metabolism in fat, liver, and skeletal muscle tissues. Moreover, AIT had a greater beneficial effect than CME on sensitivity of aorta ring segments to acetylcholine (2.7- vs. 2.0-fold, P < 0.01), partly because of intensity-dependent effects on expression levels of nitric oxide synthase and the density of caveolae, and a greater effect than CME on the skeletal muscle Ca2+ handling (50 vs. 0%, P < 0.05). The two exercise training programmes, however, were equally effective at reducing body weight and fat content. Conclusion High-intensity exercise training was more beneficial than moderate-intensity exercise training for reducing cardiovascular risk in rats with the metabolic syndrome. This was linked to more superior effects on VO2max, endothelial function, blood pressure, and metabolic parameters in several tissues. These results demonstrate that exercise training reduces the impact of the metabolic syndrome and that the magnitude of the effect depends on exercise intensity.
Abstract Background Exercise is recommended as a cornerstone of treatment for type 2 diabetes mellitus (T2DM), however, it is often poorly adopted by patients. Even in the absence of apparent ...cardiovascular disease, persons with T2DM have an impaired ability to carry out maximal and submaximal exercise and these impairments are correlated with cardiac and endothelial dysfunction. Glucagon-like pepetide-1 (GLP-1) augments endothelial and cardiac function in T2DM. We hypothesized that administration of a GLP-1 agonist (exenatide) would improve exercise capacity in T2DM. Methods and Results. Twenty-three participants (64 ± 4 years; mean ± SE) with uncomplicated T2DM were randomized in a double-blinded manner to receive either 10mcg BID of exenatide or matching placebo after baseline measurements. Treatment with exenatide did not improve VO2peak (P = 0.1464) or VO2 kinetics (P = 0.2775). Diastolic function, assessed via resting lateral E:E’, was improved with administration of exenatide compared with placebo (Placebo Pre: 7.6 ± 1.0 vs. Post: 8.4 ± 1.2 vs. Exenatide Pre: 8.1 ± 0.7 vs. Post: 6.7 ± 0.6; P = 0.0127). Additionally, arterial stiffness measured by pulse wave velocity, was reduced with exenatide treatment compared with placebo (Placebo Pre: 10.5 ± 0.8 vs. Post: 11.5 ± 1.1 seconds vs. Exenatide Pre: 11.4 ± 1.8 vs. Post: 10.2 ± 1.4 seconds; P = 0.0373). Exenatide treatment did not improve endothelial function (P = 0.1793). Conclusions. Administration of exenatide improved cardiac function and reduced arterial stiffness, however, these changes were not accompanied by improved functional exercise capacity. In order to realize the benefits of this drug on exercise capacity, combining exenatide with aerobic exercise training in participants with T2DM may be warranted. Clinical Trials Registration. www.clinicaltrials.gov NCT01364584
We present measurements of the cross section for anti-neutrino charged-current quasielastic-like scattering on hydrocarbon using the medium energy NuMI wide-band neutrino beam peaking at antineutrino ...energy $\langle E_\bar{v} \rangle$ 6 GeV. The measurements are presented as a function of the longitudinal momentum ($p_{||}$) and transverse momentum ($p_{T}$) of the final state muon. This work complements our previously reported high statistics measurement in the neutrino channel and extends the previous anti-neutrino measurement made in the low energy beam at $\langle E_\bar{v} \rangle$ ~ 3.5 GeV out to $p_{T}$ of 2.5 GeV/c. Current theoretical models do not completely describe the data in this previously unexplored high $p_{T}$ region. The single differential cross section as a function of four momentum transfer ($Q^{2}_{QE}$) now extends to 4 GeV2 with high statistics. The cross section as a function of $Q^{2}_{QE}$ shows that the tuned simulations developed by the MINERvA collaboration that agreed well with the low energy beam measurements do not agree as well with the medium energy beam measurements. Newer neutrino interaction models such as the GENIE 3 tunes are better able to simulate the high $Q^{2}_{QE}$.
Neutron production in antineutrino interactions can lead to bias in energy reconstruction in neutrino oscillation experiments, but these interactions have rarely been studied. MINERvA previously ...studied neutron production at an average antineutrino energy of ~3 GeV in 2016 and found deficiencies in leading models. In this paper, the MINERvA 6 GeV average antineutrino energy dataset is shown to have similar disagreements. A measurement of the cross section for an antineutrino to produce two or more neutrons and have low visible energy is presented as an experiment-independent way to explore neutron production modeling. This cross section disagrees with several leading models’ predictions. Neutron modeling techniques from nuclear physics are used to quantify neutron detection uncertainties on this result.
Abstract Introduction Prenatal ethanol exposure compromises fetal growth by impairing placentation. Invasive trophoblastic cells, which mediate placentation, express the insulin-IGF regulated gene, ...aspartyl-asparaginyl β-hydroxylase (ASPH), which has a critical role in cell motility and invasion. The aims of this study were to characterize effects of ethanol on trophoblastic cell motility, and assess ethanol dose-dependent impairments in placentation and fetal development. Methods Pregnant Long Evans dams were fed with isocaloric liquid diets containing 0%, 8%, 18% or 37% ethanol (caloric content) from gestation day (GD) 6 to GD18. Fetal development, placental morphology, density of invasive trophoblasts at the mesometrial triangle, as well as placental and mesometrial ASPH and Notch-1 protein expression were evaluated. Directional motility of control and ethanol-exposed HTR-8/SVneo cells was assessed by ATP Luminescence-Based assay. Results Severity of fetal growth impairment correlated with increasing doses of ethanol. Ethanol exposure produced dose-dependent alterations in branching morphogenesis at the labyrinthine zone, and inhibited physiological transformation of maternal arteries. ASPH and Notch-1 protein expression levels were reduced, corresponding with impairments in placentation. Discussion Prenatal ethanol exposure compromises fetal growth and placentation in a dose-responsive manner. Ethanol's adverse effects on placental development are mediated by: 1) altered branching morphogenesis in labyrinthine zone; 2) suppression of invasive trophoblastic precursor cells; and 3) inhibition of trophoblastic cell adhesion and motility, corresponding with reduced ASPH and Notch-1 protein expression.
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