THE IMPACT OF GEL ELECTROPHORESIS UPON OUR UNDERSTANDING OF THE ESTERASES *

The impact of gel electrophoresis upon our understanding of the esterases has been formidable in that it has provided us with new insights and understanding concerning the number and biochemical characteristics of the many esterase-active proteins found in biological material. The relationships between the esterases within a species and among species still remains largely to be determined. With regard to the function of esterases it is to be expected that there will be several. One promising possibility is suggested by the work of Allen and Hunter, which illustrated a dependent relationship between male sex hormone and the esterases in the mouse epididymis. Supporting this work is the observation by Shaw and Koen (1963) demonstrating the presence of an esterase in the mouse kidney, which also was dependent on male sex hormone. The change observed in the serum esterase of the pregnant rabbit reported here and in women by Friedman and Lapman (1961) may also relate to hormone changes associated with pregnancy, although this relationship remains to be demonstrated. A second area where the esterases are likely to be functioning is in relation to protein synthetic activity of the endoplasmic reticulum. The only evidence supporting this suggestion is the abundant presence of esterases found in this location. The seven experiments described and discussed here along with those included in the references may serve as illustrations of the kind of work that can be accomplished by the use of these methods.*Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75632/1/j.1749-6632.1964.tb14224.x.pd

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) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). 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 (n = 137), shock-dependent (n = 146), and no (n = 101) 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

"The End of Immortality!" Eternal Life and the Makropulos Debate

Responding to a well-known essay by Bernard Williams, philosophers (and a few theologians) have engaged in what I call “the Makropulos debate,” a debate over whether immortality—“living forever”—would be desirable for beings like us. Lacking a firm conceptual grounding in the religious contexts from which terms such as “immortality” and “eternal life” gain much of their sense, the debate has consisted chiefly in a battle of speculative fantasies. Having presented my four main reasons for this assessment, I examine an alternative and neglected conception, the idea of eternal life as a present possession, derived in large part from Johannine Christianity. Without claiming to argue for the truth of this conception, I present its investigation as exemplifying a conceptually fruitful direction of inquiry into immortality or eternal life, one which takes seriously the religious and ethical surroundings of these concepts

Body mass index and age at natural menopause: an international pooled analysis of 11 prospective studies

Current evidence on the association between body mass index (BMI) and age at menopause remains unclear. We investigated the relationship between BMI and age at menopause using data from 11 prospective studies. A total of 24,196 women who experienced menopause after recruitment was included. Baseline BMI was categorised according to the WHO criteria. Age at menopause, confirmed by natural cessation of menses for ≥ 12 months, was categorised as < 45 years (early menopause), 45–49, 50–51 (reference category), 52–53, 54–55, and ≥ 56 years (late age at menopause). We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CI) for the associations between BMI and age at menopause. The mean (standard deviation) age at menopause was 51.4 (3.3) years, with 2.5% of the women having early and 8.1% late menopause. Compared with those with normal BMI (18.5–24.9 kg/m2), underweight women were at a higher risk of early menopause (RRR 2.15, 95% CI 1.50–3.06), while overweight (1.52, 1.31–1.77) and obese women (1.54, 1.18–2.01) were at increased risk of late menopause. Overweight and obesity were also significantly associated with around 20% increased risk of menopause at ages 52–53 and 54–55 years. We observed no association between underweight and late menopause. The risk of early menopause was higher among obese women albeit not significant (1.23, 0.89–1.71). Underweight women had over twice the risk of experiencing early menopause, while overweight and obese women had over 50% higher risk of experiencing late menopause

Improving Teaching Effectiveness: Access to Effective Teaching, The Intensive Partnerships for Effective Teaching Through 20132014

This report attends to the distribution of effective teachers within and across schools in the sites, collectively known as the Intensive Partnership sites. We examine the trends in the distribution of effective teachers between LIM students and other students. We also examine whether any of a variety of mechanisms can explain changes in LIM students' access to effective teaching. These mechanisms include increasing the percentage of LIM students whom effective teachers teach, increasing the effectiveness of teachers with large percentages of LIM students, and replacing less effective teachers of LIM students with more-effective teachers