A possible mechanism of action of danazol and an ethinylestradiol/ norgestrel combination used as postcoital contraceptive agents

Twenty-seven women requesting postcoital contraception were randomly allocated to take an ethinylestradiol/dl-norgestrel combination or danazol. Urine specimens were assayed for luteinising hormone (LH) and pregnanediol-3-glucuronide (P3G) levels from the day of the postcoital treatment to the next period. In addition, the urine samples of these recruits and 12 additional women were assayed for the Beta-subunit of human chorionic gonadotropin (B-hCG). A consistent pattern of alteration in urinary steroids was lacking, indicating a heterogenous effect on ovarian function. There was no evidence of early pregnancy in successfully treated cases. We suggest that the main mechanism of action of these drugs is at the endometrial level.     

Significance of Histological Response to Preoperative Chemoradiotherapy for Pancreatic Cancer

Background Neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection. Methods Since 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods.Results The estimated overall survival (median±SE) in the entire group of patients undergoing resection was 23±4.2 months, with an estimated 3-year survival of 37%±6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation.Conclusions Histological response to neoadjuvant CRT—as measured by residual tumor load—may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.     

Clinical outcomes after upgrading from pacemakers to cardiac resynchronization therapy

1 Background and aims

Right ventricular pacing may lead to heart failure (HF). Upgrades from pacemakers to cardiac resynchronization therapy (CRT) were excluded from most randomized, controlled trials. We sought to determine the long‐term outcomes of upgrading from pacemakers to CRT with (CRT‐D) or without (CRT‐P) defibrillation in patients with no history of sustained ventricular arrhythmias.

2 Methods and results

In this observational study, clinical events were quantified in relation to the type of implant (de novo or upgrade) and device type at upgrade (CRT‐P or CRT‐D). Patients underwent CRT implantation (n = 1,545; 1,314 [85%] de novo implants and 231 [15%] upgrades) over a median of 4.6 years [interquartile range: 2.4–7.0]. In analyses of crude event rates, upgrades had a higher total mortality (adjusted hazard ratio [aHR]: 1.33; 95% confidence interval [CI] 0.10–1.61), a higher total mortality or HF hospitalization (aHR: 1.26; 95% CI 1.05–1.51), but similar mortality or hospitalization for major adverse cardiac events (MACEs, aHR: 1.15; 95% CI 0.96–1.38). No group differences emerged in any of these endpoints after propensity score matching. After inverse probability weighting in upgrades, total mortality (HR: 0.55; 95% CI 0.36–0.73), total mortality or HF hospitalization (HR: 0.56; 95% CI 0.34–0.79), and total mortality or hospitalization for MACEs (HR: 0.61; 95% CI 0.40–0.82) were lower after CRT‐D than after CRT‐P.

3 Conclusion

Upgrading from pacemakers to CRT was associated with a similar long‐term risk of mortality and morbidity to de novo CRT. After upgrade, CRT‐D was associated with a lower mortality than CRT‐P.     

Global thinking,local action

This article examines the risk of proliferation of nuclear weapons to several Third World countries, exemplified by recent events in Iraq, and the possibility of rapid acquisition of a nuclear weapons capability in developed countries. It considers the role of the International Atomic Energy Agency and the United Nations in preventing proliferation and calls for wider powers for the latter. The role of the civil nuclear power industry and of reprocessing of nuclear fuel to produce plutonium is stressed, with emphasis on the part played by nuclear power in Japan and the THORP reprocessing plant at Sellafield.     

Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.     

Effect of histamine H1-and H2-receptor blockade on canine gastric acid secretion

In dogs with gastric fistulae and Heidenhain pouches, inhibition of histamine-stimulated gastric acid secretion by the histamine H₂-receptor antagonist metiamide is not increased by the addition of a histamine H₁-receptor antagonist (mepyramine maleate). Under the conditions of this study there is no evidence for the presence of histamine H₁-receptor sites on the gastric parietal cell.Financial assistance was provided by the South African Medical Research Council.     

Gluten-sensitive recurrent aphthous stomatitis

Twenty selected patients with recurrent aphthous stomatitis in whom celiac disease had been specifically excluded were placed on a gluten-free diet. Five patients (25%) showed a favorable response to gluten withdrawal and a positive gluten challenge. Jejunal morphology was normal in all patients indicating gluten sensitivity without enteropathy. Gluten withdrawal provides a further method of treating some patients with recurrent aphthous stomatitis.