Effects of the H2-antagonists famotidine and nizatidine and the cytoprotectant misoprostol on human colonic and rat peritoneal mast cells

The H₂-antagonists famotidine and nizatidine produced a dose-dependent inhibition of histamine release from human colonic mucosal and muscle mast cells stimulated with anti-IgE. The IC₃₀ values were in the range 0.5–10 μM and the maximum inhibition approached 50%. The compounds showed similar efficacy against rat peritoneal mast cells but were more potent. The cytoprotectant misoprostol had a striking effect on the human colonic mast cells, producing more than 50% inhibition at concentrations of 0.1–1 nM, but was much less active against the rat cells.

     

Biological effects of histamine: An overview

Conclusion It is now some eighty years since the pioneering studies of Dale, Barger, Laidlaw and others defined the immediate pharmacological actions of histamine. In that period, it has become apparent that endogenous histamine is implicated in a diversity of physiological processes as well as in immediate hypersensitivity reactions and injury. Thus, the amine is intimately involved in the control of gastric acid secretion, acts as a neurotransmitter or modulator in the brain, and influences cell growth and immune function. The definition of distinct receptor subtypes for the autacoid has found therapeutic application in the treatment of allergy and peptic ulcer disease and holds promise for the management of problems of sleep and wakefulness. Indeed, the discovery of H₂-receptors, and more recently H₃-receptors, has led to a considerable resurgence in interest in histamine in biology and clinical medicine. It is hoped that this interest will continue and prosper.     

Long-term outcomes of myeloablation and autologous transplantation of relapsed acute myeloid leukemia in second remission: a British Society of Blood and Marrow Transplantation registry study.

Relapsed acute myeloid leukemia (AML) in adults has a poor prognosis if treated with chemotherapy alone. Case series have previously supported the role of myeloablation and autologous transplantation as a potentially curative treatment. This study aimed to use the large numbers and extended follow-up data in the British Society of Blood and Marrow Transplantation (BSBMT) registry database to establish long-term outcomes and relate these to biological and procedural factors. The BSBMT registry database was used to retrospectively identify 152 adult patients (age, 16-69 years) with AML in second remission treated with autologous transplantation in 1982-2003. Cytogenetic data were available for 68% of the patients; of these, at diagnosis, 42% had good risk features, 57% had standard risk features, and 1% had poor risk features. Conditioning regimens varied; autologous rescue was provided with bone marrow (BM) (71%), peripheral blood stem cells (PBSCs) (18%), or both (11%), which were harvested during first complete remission (CR1) and/or second CR (CR2). Median follow-up was 84 months (range, 2-200 months). At 10 years, actuarial overall survival (OS) was 32%, progression-free survival (PFS) was 28%, and relapse rate (RR) was 57%. The 100-day nonrelapse mortality (NRM) was 7%, rising to 11% at 1 year and to 14% at 10 years. OS was significantly related to M3 subtype (5-year OS, 66%; P = .005), patient age at diagnosis (P = .005) and transplantation (P = .026), and length of CR1, with greatest significance if the patient was dichotomized at CR1 duration of < 8 months or > or = 8 months (P = .0001). There was no difference in OS between regimens containing total body irradiation (TBI) and chemotherapy alone (P = .7). In relation to the nature of autologous graft material, there was improved OS (P = .025) and PFS (P = .009) with the use of cells harvested entirely in CR1 compared with cells harvested in CR2 or in both CR1 and CR2. Engraftment times were significantly shortened with the use of PBSCs alone or in combination with BM compared with BM alone (P = .0001), but there was no significant long-term impact on OS, PFS, RR, or NRM. This study provides long-term follow-up data in one of the largest series of patients with standard-risk and good-risk AML in CR2 treated with autologous transplantation and supports earlier observations that long-term survival is achievable in about 1/3 of patients overall and in about 2/3 of patients with M3 with a relatively low NRM. Outcomes are better in patients with CR1 > or = 8 months by use of grafts obtained entirely in CR1 and use of PBSCs. TBI conditioning did not confer an advantage. Randomized studies against unrelated donor transplantation are warranted.     

Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis

Schistosoma mansoni-infected wild-type (WT) mice develop a Th2 response and chronic disease. In contrast, infected interleukin-4 double-deficient (IL-4(-/-)) mice develop a Th1-like response and an acute, lethal syndrome. Disease severity in these animals correlates with excessive and prolonged production of nitric oxide (NO) associated with enhanced antigen-driven gamma interferon (IFN-gamma) production in the absence of IL-4. Strikingly, splenic lymphocytes from infected IL-4(-/-) mice failed to proliferate as well as those from infected WT mice following stimulation in vitro with antigen or anti-CD3 antibody. Contrary to antigen-driven IFN-gamma responses, anti-CD3 antibody stimulation of splenocytes resulted in significantly less IFN-gamma being produced by CD8 cells from infected IL-4(-/-) mice than by those from infected WT mice or normal mice. NO is largely responsible for the impaired T-cell functions in infected IL-4(-/-) mice, as inhibition of iNOS significantly enhanced proliferation and IFN-gamma production.     

Antigen presentation by macrophages is enhanced by the uptake of necrotic, but not apoptotic, cells

The aim of this study was to determine whether phagocytosis of necrotic or apoptotic cells affects antigen presentation by murine bone marrow-derived macrophages. After uptake of necrotic neutrophils, macrophages were able to stimulate significantly higher T cell proliferation in vitro against both the recall antigen albumin and the mitogen concanavalin A. No such effect was seen following phagocytosis of apoptotic neutrophils. Flow cytometry revealed that, within 4h of ingestion, macrophages that had taken up the necrotic cells expressed higher levels of CD40 than those that had phagocytosed apoptotic cells. Macrophage cultures pulsed with apoptotic, but not necrotic, neutrophils contained higher levels of transforming growth factor beta1, but lower concentrations of tumour necrosis factor alpha, compared to untreated controls. Our interpretation of these results is that macrophages that have taken up necrotic neutrophils co-stimulate T cells with greater efficiency due to rapid CD40 up-regulation, whereas those that have ingested apoptotic cells are not only ineffective in co-stimulation, but also secrete inhibitory cytokine.     

Effect of cyclic AMP on histamine release induced by compound 48/80.

Bu2 cAMP(N6, O2'-dibutyryl adenosine-3',5'-cyclic monophosphate) inhibited the response of rat peritoneal mast cells to compound 48/80 in the presence of calcium ions. In the absence of calcium, the nucleotide partially prevented the desensitization induced by chelating agents. The response of cells, allowed to accumulate Bu2 cAMP in the presence of calcium (to avoid depletion of intracellular stores of the ion) and then challenged in the absence of extracellular calcium, was also inhibited. These results are discussed in terms of the postulated effects of Bu2 cAMP on the calcium-gatubg mechanism operative in histamine secretion.     

Leucocyte Migration Test and Hypersensitivity to Glafenin

The leucocyte migration test (LMT) was performed on 20 patients with an intolerance to glafenin--a non-narcotic analgesic drug. LMT was found to be positive in 50% of the subjects with intolerance, a highly significant percentage as compared with the control groups. HSA-glafenin was found to be the most appropriate method for presenting the antigen, but glafenin and its hydroxylated metabolites were only found to induce a migration inhibition in the subjects intolerant to glafenin.     

Knowledge mobilization tool to promote,protect, and support breastfeeding during COVID-19

SettingThis knowledge mobilization project was conceptualized to increase awareness among breastfeeding mothers and the general public on safe infant feeding practices during the COVID-19 pandemic by addressing myths and misconceptions associated with breastfeeding practices, guiding breastfeeding mothers to make informed decisions around child feeding practices, and offering meaningful guidance in simple language through a short online animated video.InterventionThis project was undertaken in four phases. During phase 1, an informal discussion was held with the breastfeeding mothers, service providers, and community partner in identifying issues surrounding lactation counselling facilities during the COVID-19 pandemic. During phase 2, recommendations from 23 organizations with regard to breastfeeding during COVID-19 were reviewed and analyzed. During phase 3, using evidence from reliable sources, a 5-minute animated e-resource on breastfeeding during COVID-19 was conceptualized and developed. During phase 4, the e-resource was disseminated to the breastfeeding mothers, general public, post-secondary institutions, and organizations providing services to breastfeeding mothers in Canada.OutcomesThis evidence-based e-resource facilitated addressing misconceptions around breastfeeding during COVID-19 and raising public awareness on safe infant feeding practices during this pandemic. Overall, the video was described as an informative, user-friendly, useful, and easily accessible resource by breastfeeding mothers who were in self-isolation with little access to healthcare services during the pandemic.ImplicationsThis project highlighted the importance of patient engagement and collaboration with the community partner in protecting breastfeeding during the COVID-19 pandemic. It further illustrated how informational e-resources can protect breastfeeding in situations where breastfeeding mothers’ access to healthcare services is compromised.