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Biomedical subjects

J J Cohen

Publications and source records attributed to J J Cohen.

At least 19 recordsLinked to original sources
PubMed1999

Calpain and calpastatin regulate neutrophil apoptosis.

The average polymorphonuclear neutrophil (PMN) lives only a day and then dies by apoptosis. We previously found that the calcium-dependent protease calpain is required for apoptosis in several mouse models of cell death. Here we identify calpain, and its endogenous inhibitor calpastatin, as regulators of human neutrophil apoptosis. Cell death triggered by the translation inhibitor cycloheximide is calpain-dependent, as evidenced using either a calpain active site inhibitor (N-acetyl-leucyl-leucyl-norleucinal) or agents that target calpain's calcium binding sites (PD150606, PD151746). No significant effect on cycloheximide-triggered apoptosis was found by using inhibitors of the proteasome or of other papain-like cysteine proteases, providing further evidence that the active site calpain inhibitor prevents apoptosis via its action on calpain. In addition, we find that potentiation of calpain activity by depleting its endogenous inhibitor, calpastatin, is sufficient to cause apoptosis of neutrophils. Nevertheless, apoptosis signalled via the Fas antigen proceeds regardless of the presence of calpain inhibitor. These experiments support a growing body of work, indicating an upstream regulatory role for calpain in many, but not all, forms of apoptotic cell death. They also identify calpastatin as a participant in apoptotic cell death and suggest that for at least one cell type, a decrease in calpastatin is a sufficient stimulus to initiate calpain-dependent apoptosis.

Acrylates↗
PubMed1999

Apoptosis: mechanisms of life and death in the immune system.

When normal cells die, it is almost always by the process of apoptosis, which is a morphologic description. Some cells die readily and are rapidly replaced; others live as long as we do. Because apoptotic morphology is similar from cell to cell, researchers have embarked on an intense search for a common underlying biochemical process. There is an apoptotic mechanism or cell death program, which is expressed in embryos and throughout life. Most tissues, and especially the skin, gut, and immune system, depend on well-ordered apoptosis and cell replacement. Apoptosis can fail to occur, as in the newly described autoimmune lymphoproliferative syndrome, or be turned on pathologically, as in degenerative diseases. We would like to induce apoptosis in dangerous cells or block it to preserve valuable cells. We need to know more about how apoptosis is regulated and what we can do to influence the process.

Animals↗
PubMed1999

Honoring the "E" in GME.

Medical educators should realize that the public's complaints about doctors--that they don't care enough about their patients, don't know enough to practice the best medicine, and don't do enough to maintain the public's trust--are exaggerations of the truth but highlight areas demanding improvement in the educational component of graduate medical education (GME). In addition to continuing to prepare residents for the demanding technical challenges they will face as physicians, those involved in GME need to (1) enrich significantly the educational content of residency programs; (2) promote the coordination, strengthening, and potential consolidation of the institutional responsibility for these programs; (3) reorder programs' priorities to make room for the added educational content, which means limiting service requirements to those necessary to meet prospectively defined educational goals; and (4) recognize the power of the hidden curriculum in communicating professional values, and thus modify significantly the way residents are treated. The author explains these recommendations in detail and notes a variety of ways that the Association of American Medical Colleges intends to help educators make these needed changes. He concludes by stating that a "time bomb" is ticking: many sectors of the public and many patients are becoming impatient with doctors. "Listening hard to their complaints and finding appropriate remedies is a must if we are going to ... answer our critics ... and continue to provide America with the world's best doctors."

Education, Medical↗
PubMed1999

Reovirus-induced apoptosis is preceded by increased cellular calpain activity and is blocked by calpain inhibitors.

The cellular pathways of apoptosis have not been fully characterized; however, calpain, a cytosolic calcium-activated cysteine protease, has been implicated in several forms of programmed cell death. Reoviruses induce apoptosis both in vitro and in vivo and serve as a model for studying virus-induced cell death. We investigated the potential role of calpain in reovirus-induced apoptosis in vitro by measuring calpain activity as well as evaluating the effects of calpain inhibitors. L929 cells were infected with reovirus type 3 Abney (T3A), and calpain activity, measured as cleavage of the fluorogenic calpain substrate Suc-Leu-Leu-Val-Tyr-AMC, was monitored. There was a 1.6-fold increase in calpain activity in T3A-infected cells compared to mock-infected cells; this increase was completely inhibited by preincubation with calpain inhibitor I (N-acetyl-leucyl-leucyl-norleucinal [aLLN]), an active-site inhibitor. Both aLLN and PD150606, a specific calpain inhibitor that interacts with the calcium-binding site, inhibited reovirus-induced apoptosis in L929 cells by 54 to 93%. Apoptosis induced by UV-inactivated reovirus was also reduced 65 to 69% by aLLN, indicating that inhibition of apoptosis by calpain inhibitors is independent of effects on viral replication. We conclude that calpain activation is a component of the regulatory cascade in reovirus-induced apoptosis.

Acrylates↗
PubMed1999

Improving the environment for women in nephrology.

Data on the representation and distribution of women in nephrology and internal medicine show why continuing efforts are required to ensure that women reach their potential in academic medicine. Some of the cumulative disadvantages that women face in their professional development are summarized, particularly those related to obtaining mentoring. Efforts on the part of the Association of American Medical Colleges and one department of medicine are described as examples of strategic interventions, and other actions are suggested, with the goal of increasing women's leadership in nephrology, as well as in academic medicine overall.

Faculty, Medical↗
PubMed1998

In vivo treatment with granulocyte colony-stimulating factor results in divergent effects on neutrophil functions measured in vitro.

We have studied the effects of granulocyte colony-stimulating factor (G-CSF) administration to normal individuals on a variety of functional and biochemical neutrophil characteristics that relate to host defense. G-CSF adversely affected neutrophil (polymorphonuclear leukocyte [PMN]) chemotaxis. While this could be partially explained by reduced assembly of neutrophil F-actin, we also recognized an elevated cytosolic calcium mobilization and a normal upregulation of neutrophil CD11b. G-CSF resulted in reduced PMN killing of Staphylococcus aureus with a 10:1 (bacteria:neutrophil) ratio and normal killing with a 1:1 ratio. In association with this, we demonstrated divergent effects on the respiratory burst of intact cells and divergent effects on the content of marker proteins for neutrophil granules. While G-CSF may have resulted in increased content of cytochrome b558 in the cell membrane, it did not alter the amounts of cytosolic oxidase components. After therapy, there was normal content of the azurophilic granule marker, myeloperoxidase, decreased content of the specific granule marker, lactoferrin, and normal content of lysozyme (found in both granules classes). Finally, G-CSF therapy markedly reduced the apoptotic rate of the isolated neutrophil. Therefore, considering disparate functional and biochemical activities, the real benefit of G-CSF therapy may lie in enhanced number and survival of neutrophils.

Adult↗
PubMed1998

Selective induction of apoptosis in mouse and human lung epithelial cell lines by the tert-butyl hydroxylated metabolite of butylated hydroxytoluene: a proposed role in tumor promotion.

Butylated hydroxytoluene (BHT) causes lung injury in mice and promotes tumor formation. Hydroxylation of a tert-butyl group on BHT to yield the metabolite, 6-tert-butyl-2-[2'-(2'-hydroxymethyl)-propyl]-4-methylphenol (BHTOH), may be required. BHTOH is more potent than BHT on an equimolar basis in causing lung damage, enhancing lung tumor development, killing isolated bronchiolar non-ciliated Clara cells, and inhibiting lung epithelial gap junctional intercellular communication. One mechanism proposed for tumor promoting agents is selective cytotoxicity; killing normal cells allows uninhibited clonal expansion of neighboring initiated cells. We compared the abilities of BHT, BHTOH, and other BHT metabolites to kill non-tumorigenic and tumorigenic mouse and human lung cell lines, and examined the contribution of apoptosis to this cytotoxicity. These cells lack the cytochrome P450 2B isozyme necessary for converting BHT to BHTOH. BHTOH and 4-hydroperoxy-4-methyl-2,6-di-tert-butyl-2,5-cyclohex-adienone+ ++ (BHTOOH) were most toxic, BHT and 2,6-di-tert-butyl-1,4-benzoquinone (BHTQu) were less potent, and 4-methyl BHT metabolites that are not pneumotoxic were ineffective. BHTOH most strongly induced apoptosis, based on nuclear condensation and transmission electron microscopy. Non-tumorigenic cells were as susceptible to cell death as the neoplastic cell lines when apoptosis and necrosis are not distinguished, but more sensitive to BHTOH-induced apoptosis. An apoptotic mechanism may underlie the lung tumor promoting actions of BHTOH.

Animals↗
PubMed1998

Leadership for medicine's promising future.

Leadership in improving the education of doctors, while impressive, is not happening fast enough. While there are many obstacles, there is no time to waste in restructuring medical education to repair its present deficiencies, for otherwise outside forces could overwhelm today's education leaders with imperatives to make improvements on their own terms. The first step in addressing present shortcomings is to establish measurable objectives for the education of doctors that are aligned with the legitimate expectations of society and the enduring precepts of the medical profession. To provide guidance in establishing these objectives, the AAMC launched the Medical School Objectives Project (MSOP) two years ago. This project is now close to completing its initial phase, which is to define the knowledge, skills, attitudes, and values every medical student must demonstrate before graduating. Phase Two will be concerned with implementation (e.g., establishing assessment methods; improving faculty development; etc.). As for aligning the outcomes of medical education with the precepts of the profession, nothing is more important: if doctors do not have high standards of professionalism--altruism, respect, compassion, honesty, integrity, and others--medicine's very survival is threatened. Medical educators must insist that their graduates demonstrate these attributes, through more careful admission criteria, more attention to medical professionalism in the curriculum and in the evaluation of students, more community service for students, and improved role modeling by faculty. Leadership for the changes that are needed will not come from a once-in-a-lifetime leader of heroic proportions but from everyone within academic medicine leading the profession to its promising future through quality education.

Altruism↗