9 research outputs found
Steroid metabolism in normal and rheumatoid arthritic human subjects
The nature of the quantitative relationship
between progesterone secretion and urinary pregnanediol
excretion had been investigated by the
quantitative determination of the metabolite
after continued daily administration of progesterone to normal post-menopausal women, normal
men, hysterectomised-ovariectomised women and
hysterectomised post-menopausal women. These
experiments prove that when the human body is
subjected to the influence of progesterone for
more than a few days, a progressive change in the
relationship of hormone to metabolite occurs so that an increasing proportion of the administered
hormone is recovered from the urine as the
metabolite. This progesterone "priming"
phenomenon has been shown to be attributable to a role of the uterus in the metabolism of
progesterone. Pregnane -3a,20a-diol has been administered to post-menopausal women and the
biochemical mechanism and clinical implications
of these findings have been discussed.(2) The claim by de datteville et al. (1948)
that pre-treatment with a-tocopherol augments the
conversion of administered progesterone to urinary
pregnanediol has been investigated. An identical
experimental procedure has been adopted but normal
human subjects have been studied in place of
patients with carcinoma of the uterus or breast
and the method of Sommerville, Gough and Marrian
(1948) has been used instead of the modified
method of Huber (1947). The results clearly indicate that a-tocopherol does not have the effect
observed by de Watteville et al. when normal
subjects are studied by the former method. Explanations are offered for these contradictory
results.(3) A synthetic orally active progestogen-ethinyltestosterone - has been administered to
normal men and the urine investigated for the
presence of pregnanediol. Significant amounts
of pregnanediol were not recovered from the urine
but large amounts of an unidentified crystalline
precipitate were observed. Excretion of this
substance - which may be metabolite of ethinyltestosterone - as a glucuronide would account for
the results obtained by Allen, Viergiver and
Soule (1944) . The clinical implications of a progestogen which is not metabolised to pregnanediol have been discussed.(4)
The excretion of urinary pregnanediol has
been studied during normal pregnancy and the
results have been compared with those obtained by
less specific methods for the quantitative determination of the steroid. The results emphasise
the necessity to establish values of pregnanediol
excretion in normal pregnancy.(5) It has been shown that the method of
Sommerville, Gough and Marrian (1948) is applicable to the determination of small amounts of
pregnanediol in rabbit urine. The accuracy of
the method when used for this purpose has been
assessed and it is concluded that as little as 0.25 mg. of the steroid can be determined in one half of a twenty -four hour urine specimen.(6) «n analogy has been drawn between the
intermediary metabolisms of progesterone and
cortisone (17-hydroxy-11-dehydrocorticosterone)
and it was anticipated on theoretical grounds that
an abnormality of progesterone metabolism might be
associated with rheumatoid arthritis. Such an
abnormality was demonstrated in a large series of
women and men with rheumatoid
arthritis, and consisted in the conversion of an
abnormally high proportion of administered
progesterone to urinary pregnanediol.The abnormality was not observed in a series
of patients suffering from diseases which
resemble rheumatoid arthritis in one or more of
their clinical features.The belief in the possibility that the pathology of rheumatoid arthritis is associated with
an abnormality of steroid metabolism rather than
with a deficiency of endogenous steroid secretion
was strengthened by the observation that the abnormality is not affected by the administration
of the adrenocorticotrophic hormone of the
anterior pituitary gland.The biochemical mechanism and clinical implications of the abnormality of steroid
metabolism have been considered and the rational
of attempts to modify this abnormality has been
discussed
Near-Infrared Integral Field Spectroscopy of Damped Lyman-alpha Systems
We assess the feasibility of detecting star formation in damped Lyman-alpha
systems (DLAs) at z>1 through near-infrared spectroscopy using the forthcoming
integral field units on 8m-class telescopes. Although their relation to
galaxies is not well established, high-z DLAs contain most of the neutral gas
in the Universe, and this reservoir is depleted with time - presumably through
star formation. Line emission should be an indicator of star formation
activity, but searches based on Lyman-alpha are unreliable because of the
selective extinction of this resonant UV line. Using more robust lines such as
H-alpha forces a move to the near-infrared at z>1. For line emission searches,
spectroscopy is more sensitive than imaging, but previous long-slit
spectroscopic searches have been hampered by the likelihood that any star
forming region in the DLA galaxy disk would fall outside the narrow slit. The
new integral field units such as CIRPASS on Gemini will cover sufficient solid
angles to intercept these, even in the extreme case of large galactic disks at
high redshift. On an 8m-class telescope, star formation rates of <1M_sun/yr
will be reached at z~1.4 with H-alpha in the H-band. Such star formation rates
are well below L* for the high-z Lyman-break population, and are comparable
locally to the luminous giant HII complexes in M101. It appears that
instruments such as CIRPASS on Gemini will have both the sensitivity and the
survey area to measure star formation rates in z>1 DLAs. These observations
will probe the nature of damped Lyman-alpha systems and address their relation
to galaxies.Comment: To appear in the proceedings of the ESO/ECF workshop on "Deep
Fields", 9-12 October 2000, Garching. 4 page
The Effect of Iron Limitation on the Transcriptome and Proteome of Pseudomonas fluorescens Pf-5
One of the most important micronutrients for bacterial growth is iron, whose bioavailability in soil is limited. Consequently, rhizospheric bacteria such as Pseudomonas fluorescens employ a range of mechanisms to acquire or compete for iron. We investigated the transcriptomic and proteomic effects of iron limitation on P. fluorescens Pf-5 by employing microarray and iTRAQ techniques, respectively. Analysis of this data revealed that genes encoding functions related to iron homeostasis, including pyoverdine and enantio-pyochelin biosynthesis, a number of TonB-dependent receptor systems, as well as some inner-membrane transporters, were significantly up-regulated in response to iron limitation. Transcription of a ribosomal protein L36-encoding gene was also highly up-regulated during iron limitation. Certain genes or proteins involved in biosynthesis of secondary metabolites such as 2,4-diacetylphloroglucinol (DAPG), orfamide A and pyrrolnitrin, as well as a chitinase, were over-expressed under iron-limited conditions. In contrast, we observed that expression of genes involved in hydrogen cyanide production and flagellar biosynthesis were down-regulated in an iron-depleted culture medium. Phenotypic tests revealed that Pf-5 had reduced swarming motility on semi-solid agar in response to iron limitation. Comparison of the transcriptomic data with the proteomic data suggested that iron acquisition is regulated at both the transcriptional and post-transcriptional levels
The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report
The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument
The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report
The Habitable Exoplanet Observatory, or HabEx, has been designed to be the
Great Observatory of the 2030s. For the first time in human history,
technologies have matured sufficiently to enable an affordable space-based
telescope mission capable of discovering and characterizing Earthlike planets
orbiting nearby bright sunlike stars in order to search for signs of
habitability and biosignatures. Such a mission can also be equipped with
instrumentation that will enable broad and exciting general astrophysics and
planetary science not possible from current or planned facilities. HabEx is a
space telescope with unique imaging and multi-object spectroscopic capabilities
at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities
allow for a broad suite of compelling science that cuts across the entire NASA
astrophysics portfolio. HabEx has three primary science goals: (1) Seek out
nearby worlds and explore their habitability; (2) Map out nearby planetary
systems and understand the diversity of the worlds they contain; (3) Enable new
explorations of astrophysical systems from our own solar system to external
galaxies by extending our reach in the UV through near-IR. This Great
Observatory science will be selected through a competed GO program, and will
account for about 50% of the HabEx primary mission. The preferred HabEx
architecture is a 4m, monolithic, off-axis telescope that is
diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two
starlight suppression systems: a coronagraph and a starshade, each with their
own dedicated instrument.Comment: Full report: 498 pages. Executive Summary: 14 pages. More information
about HabEx can be found here: https://www.jpl.nasa.gov/habex
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Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (nâ=â143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (nâ=â152), or no hydrocortisone (nâ=â108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (nâ=â137), shock-dependent (nâ=â146), and no (nâ=â101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial
Background:
Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke.
Methods:
We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30â50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515.
Findings:
Patients were screened between July 1, 2015, and Nov 24, 2016. 10â793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68â0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group.
Interpretation:
In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes.
Funding:
GlaxoSmithKline
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570