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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
PubMed1992

Roles of various organizations in internal medicine curriculum reform.

The curriculum in internal medicine for medical students and residents is being driven increasingly by the service demands of our teaching hospitals and is badly in need of fundamental reform. In reasserting the primacy of education as the driving force for the curriculum, numerous tasks must be done to achieve successful reform. These tasks are well within the scope of the several organizations that command leadership positions in the discipline of internal medicine and that represent the spectrum of activities required to discharge the specialty's public responsibility. These organizations include the Association of Professors of Medicine (APM), the Association of Program Directors in Internal Medicine (APDIM), the Society of General Internal Medicine (SGIM), The Residency Review Committee for Internal Medicine (RRC-IM), the American Board of Internal Medicine (ABIM), the American College of Physicians (ACP), the American Society of Internal Medicine (ASIM), and the Federated Council of Internal Medicine (FCIM). The challenge posed by the need for curriculum reform is to rouse these organizations to concerted action. Each of the seven organizations must assume a specific role and a unique set of responsibilities in the epic reforms envisioned.

Curriculum↗
PubMed1992

Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.

During normal tissue remodeling, macrophages remove unwanted cells, including those that have undergone programmed cell death, or apoptosis. This widespread process extends to the deletion of thymocytes (negative selection), in which cells expressing inappropriate Ag receptors undergo apoptosis, and are phagocytosed by thymic macrophages. Although phagocytosis of effete leukocytes by macrophages has been known since the time of Metchnikoff, only recently has it been recognized that apoptosis leads to surface changes that allow recognition and removal of these cells before they are lysed. Our data suggest that macrophages specifically recognize phosphatidylserine that is exposed on the surface of lymphocytes during the development of apoptosis. Macrophage phagocytosis of apoptotic lymphocytes was inhibited, in a dose-dependent manner, by liposomes containing phosphatidyl-L-serine, but not by liposomes containing other anionic phospholipids, including phosphatidyl-D-serine. Phagocytosis of apoptotic lymphocytes was also inhibited by the L isoforms of compounds structurally related to phosphatidylserine, including glycerophosphorylserine and phosphoserine. The membranes of apoptotic lymphocytes bound increased amounts of merocyanine 540 dye relative to those of normal cells, indicating that their membrane lipids were more loosely packed, consistent with a loss of membrane phospholipid asymmetry. Apoptotic lymphocytes were shown to express phosphatidylserine (PS) externally, because PS on their surfaces was accessible to derivatization by fluorescamine, and because apoptotic cells expressed procoagulant activity. These observations suggest that apoptotic lymphocytes lose membrane phospholipid asymmetry and expose phosphatidylserine on the outer leaflet of the plasma membrane. Macrophages then phagocytose apoptotic lymphocytes after specific recognition of the exposed PS.

Animals↗
PubMed1992

Identification of genes involved in programmed cell death.

Three modes of activation of apoptosis are described: induction, in which new gene expression occurs after the stimulus is applied; transduction, in which gene expression is unnecessary at the time of stimulation; and release, in which apoptosis is activated by the inhibition of gene expression. Genes activated in the induction mechanism were identified by a process of subtractive hybridization, whereby newly transcribed messenger RNAs could be isolated. Progress in characterizing some of these genes is described. There are many difficulties and conceptual problems associated with such a gene cloning approach, but the results will be worth the effort.

Animals↗
PubMed1992

Cell-mediated cytotoxicity.

Progress is being made in determining how cytotoxic cells are activated, the way the lethal hit is delivered and the subsequent events in the target cell. Several factors cloud the issue, including the heterogeneity of cytotoxic cells, differences between fresh cells and cell lines, and the possibility of single cells using multiple cytotoxic mechanisms. The most difficult task will be to define which cytotoxic mechanisms are significant in vivo.

Animals↗
PubMed1992

Apoptosis and programmed cell death in immunity.

Death of some cells in the mammalian body is clearly programmed. In the immune system there are many examples of programmed cell death, during development of lymphocytes as well as at later stages, after interaction with antigen. Many of these examples display the morphology of apoptosis: They undergo shrinkage and zeiosis, the nucleus collapses, and chromatin is cleaved into nucleosomal fragments. The cell is rapidly recognized by phagocytes and disposed of without releasing its contents. In some but not all cases of apoptosis, new macromolecular synthesis is required. Cytotoxic T cells induce changes in their targets that are morphologically apoptotic. The mechanism of apoptosis is currently under active investigation.

Animals↗
PubMed1992

Glucocorticoid-induced apoptosis in the thymus.

Destruction of thymus cells was one of the earliest observed properties of adrenal glucocorticoids. The cells affected are primarily immature, CD4/CD8 double-positive lymphocytes. This process has been clearly shown in vivo and in vitro to be apoptosis, as characterized by cell shrinkage, membrane alterations, nuclear collapse and chromatin fragmentation into oligonucleosomes. Glucocorticoid-induced thymocyte death requires new mRNA and protein synthesis. A beginning has been made in identifying the genes involved in thymocyte apoptosis. A case is made for the death of unselected thymocytes in vivo being regulated by endogenous glucocorticoids.

Animals↗
PubMed1991

Cytotoxic T lymphocytes induce different types of DNA damage in target cells of different origins.

Nuclear changes may be important in the mechanism of CTL-mediated lysis. Rapid cleavage of target cell DNA into oligonucleosomes has been demonstrated as a very early event in CTL-mediated killing of murine hematopoietic targets. However, the results presented herein and by other investigators have shown that this extensive dsDNA fragmentation does not occur in all CTL targets. In terms of actual DNA damage, there is a wide range in the extent and type of DNA cleavage in various targets. Differences exist at both the species and the cell lineage level. The extent of DNA damage generally corresponds to the efficiency of lysis; thus, murine hematopoietic cells, which undergo dsDNA fragmentation, are killed more rapidly and at lower E/T cell ratios than are murine nonhematopoietic cells, which sustain single-stranded nicks. Experiments using cloned CTL demonstrate that the same effector cell kills both hematopoietic and nonhematopoietic targets, producing different types of DNA damage. These observations indicate that the fate of the target cell DNA is determined by the nature of the target cell and not by the CTL. We propose that DNA damage results from an enzyme pathway inherent to the target, which is activated by, not transferred from, the CTL.

Animals↗
PubMed1991

Programmed cell death in terminally differentiating keratinocytes: role of endogenous endonuclease.

Mammalian epithelium is a tissue with a very high turnover rate. It consists of a rapidly proliferating compartment comprising basal and suprabasal keratinocytes, from which cells move upwards while differentiating into granular keratinocytes. The end product is shed as an enucleate corneocyte, which has a mechanically rigid, chemically resistant cross-linked keratinous envelope. The loss of the nucleus occurs specifically in the granular keratinocyte layer; here, cells with the classical apoptotic morphology of clumped and marginated condensed chromatin may be observed. This morphology is characteristic of "programmed" cell death in other systems, of which the lymphocyte has been most extensively studied, and is associated with the cleavage of nuclear DNA into nucleosome-sized fragments. In the present investigation we separated newborn mouse skin into basal and granular keratinocyte fractions and examined the state of the DNA in each fraction. Our results indicate that cells in the basal layer, while their DNA is perfectly intact, are preparing to die. DNA fragmentation is initiated in the granular keratinocyte layer and is identical in pattern to that seen in other examples of programmed cell death.

Animals↗
PubMed1991

Chloride-depletion metabolic alkalosis induces ECF volume depletion via internal fluid shifts in nephrectomized dogs.

We recently reported that chloride-depletion metabolic alkalosis (CDMA) results in renal losses of Na, K, and water. In these studies we investigated whether CDMA (induced using a new model that avoids external changes in Na and water balance) was also associated with internal Na and water shifts out of the ECF. CDMA was induced using haemofiltration in functionally nephrectomized dogs. Plasma ultrafiltrate was substituted quantitatively with a solution duplicating each dog's plasma electrolyte composition in control animals, and with a solution containing HCO3 as the sole anion in CDMA animals. ECF volume was estimated as the space of distribution of [3H]-mannitol. Plasma composition and [3H]-mannitol distribution space were unchanged in control dogs. In CDMA dogs metabolic alkalosis developed; despite the absence of external changes in Na and water balance, the space of distribution of [3H]-mannitol decreased by 335 +/- 46 ml (equivalent to 8% of baseline ECF volume), calculated chloride space fell by 304 +/- 50 ml, and haematocrit increased from 45.6 to 48.5 vol%. We conclude that CDMA causes an internal shift of fluid out of the ECF. The resulting ECF volume contraction appears to be an inherent feature of CDMA.

Alkalosis↗
PubMed1991

Identification of mRNAs associated with programmed cell death in immature thymocytes.

Programmed cell death is an essential cellular process that occurs in epithelial turnover, neural development, and regulation of cell populations of the immune system. Thymocytes undergo programmed cell death in response to several inductive stimuli, including exposure to glucocorticoids or radiation. This program can be blocked by inhibitors of RNA or protein synthesis; this implies that new proteins are required to execute the death programs. To search for possible death-associated mRNAs, we directionally cloned cDNA representing mRNA from control and dexamethasone-treated thymocytes. These libraries were used to produce ample amounts of DNA and RNA used in subtractive hybridization for the removal of sequences present in both control and induced cells. The remaining unhybridized sequences were selectively amplified by polymerase chain reaction and cloned to produce a library enriched for sequences expressed in death-induced cells. From this library we isolated cDNAs of death-associated mRNAs. One of these mRNAs, RP-8, appears within 1 h after exposure to gamma radiation, and a second mRNA, RP-2, is observed within 2 h. Both of these mRNAs accumulate during a period when a reference mRNA, actin, is declining. RP-2 and RP-8 are no longer detectable after 6 h postinduction, when apoptosis and mRNA degradation are evident in the culture. Sequence analysis of RP-8 cDNA indicates the presence of a zinc finger domain suggestive of a possible DNA regulatory role for the RP-8 protein. cDNA sequence results on RP-2 classify the corresponding protein as an integral membrane protein. We conclude that RP-2 and RP-8 are death-associated mRNAs that should be functionally evaluated in the context of the death process. As previously suggested, it may be that a family of "death genes" is activated by various stimuli depending on the type of cell, in a manner somewhat analogous to the induction of heat shock (stress) protein genes.

Amino Acid Sequence↗
PubMed1991

Hyperthermia induces apoptosis in thymocytes.

Mild hyperthermia (43 degrees C for 1 h) induces extensive double-stranded DNA fragmentation and, at a later time, cell death in murine thymocytes. The cleavage of DNA into oligonucleosome-sized fragments resembles that observed in examples of apoptosis including radiation-induced death of thymocytes. Following hyperthermia, incubation at 37 degrees C is necessary to detect DNA fragmentation, although protein and RNA synthesis do not seem to be required. Two protein synthesis inhibitors, cycloheximide and emetine, and two RNA synthesis inhibitors, actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, do not inhibit DNA fragmentation or cell death in heated thymocytes at concentrations which significantly block these effects in irradiated thymocytes. We have used this difference in sensitivity to show that the DNA fragmentation induced in thymocytes which are irradiated and then heated seems to be caused only by the heating and not by the irradiation.

Animals↗
PubMed1990

Behavioral and immunological consequences of brief mother-infant separation: a species comparison.

The immediate behavioral and immunological consequences of a single 2-week maternal separation experience were studied in socially housed 7-month old bonnet and pigtail macaques. Maternal separation was associated with species dependent behavioral changes. Both species showed significant increases in ingestive behaviors associated with separation. Separated and matched controls showed an increase in disturbance behaviors (vocalization, startles, shaking, temper-tantrums) that subsided after 24-36 hours in control subjects, but continued, albeit with species-dependent patterns, in the separated monkeys. Allomaternal care of the separated bonnet infants but not the pigtail infants was associated with a progressive reduction of these disturbance behaviors during the separation period. Following a period of agitation, pigtail infants showed a depressive phase characterized by slouched, withdrawn postures and reduced motor activity. As a group, the separated infants of both species were not different from controls with respect to lymphocyte activation by mitogens, a measure of immunocompetence. However, when individual behavioral responses were considered, the change in lymphocyte activation during separation was significantly related to behavioral responses which reflected disturbance, such that the change in lymphocyte activation following in vitro stimulation with the mitogens phytohemagglutinin and Concanavalin A (markers of the immunocompetence of T lymphocytes) was related to levels of vocalization and time spent in slouched postures. The activation of B lymphocytes by pokeweed mitogen was not influenced by the separation experience nor was it associated with specific behavioral responses to separation. The importance of assessing the affective consequences of stressor is discussed.

Animals↗
PubMed1990

Direct effects of endotoxin on the function of the isolated perfused rat kidney.

When the endotoxin-lipopolysaccharide (LPS) derived from the cell wall of gram-negative bacteria is given to the rat in vivo, there are prompt, marked decreases in glomerular filtration rate (GFR), renal blood flow (RBF) and % Na+ reabsorption (%T-Na+). However, it has not been determined whether the endotoxin itself has a direct effect on these renal functions. To test whether endotoxin has a direct renal effect, isolated rat kidneys (N = 8) were perfused for 160 minutes with a Krebs-Ringer-HCO3- solution containing substrate-free albumin (40 g/liter), glucose (5 mM) and L(+) lactate (7.5 mM). After control observations (20 to 80 min) were made, purified LPS from E. coli was added (N = 4) to the perfusate to achieve [endotoxin] of 0.01 micrograms/ml (80 to 120 min) and 0.1 micrograms/ml (120 to 160 min). Endotoxin had no effect on GFR, Na+ reabsorption or tissue K+ content when compared to timed-control perfusions (N = 4). There was a small (approximately 10%) but significant decrease in mean perfusion flow rate (PFR) at the highest [endotoxin] when compared to the low [endotoxin]p but no change in GFR occurred. When the same LPS was given to four rats in vivo at a dose which achieved an [endotoxin] of approximately 0.08 micrograms/ml plasma, there were prompt decreases in GFR and %T-Na+ and an increase in body temperature when compared with timed-controls; there also was a large loss of K+ from the kidney tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1990

Influence of acute and chronic respiratory alkalosis on preexisting chronic metabolic alkalosis.

The severity of the alkalemia produced by a reduction in arterial carbon dioxide tension (PaCO2) in normal humans and animals is ameliorated by buffer and renal responses that diminish the levels of plasma bicarbonate concentration ([HCO3-]p). These adjustments have even greater potential importance in preventing extreme degrees of alkalemia when hypocapnia occurs in the presence of an initially elevated [HCO3-]p (mixed respiratory and metabolic alkalosis). The aim of the present study was to characterize the acute (approximately 3 h) and chronic (5 days) acid-base effects of respiratory alkalosis when superimposed on chronic metabolic alkalosis. Ten dogs were made alkalotic by the repeated administration of ethacrynic acid and the provision of a chloride-restricted diet. Hypocapnia (delta PaCO2 = 10 mmHg) was then superimposed by exposing the animals to 11% O2 in an environmental chamber. A large fall in [HCO3-]p occurred in the acute hypocapnic phase that was further augmented in the chronic phase; the corresponding delta [HCO3-]p/delta PaCO2 slopes were 0.43 and 0.71 meq.l-1.mmHg-1, respectively, values substantially larger than those previously reported for hypocapnia in normals as well as in animals with preexisting HCl acidosis. Hyperlactatemia was responsible, on average, for 43% of the decrement in [HCO3-]p during acute hypocapnia but for only 20% of the delta [HCO3-]p during the chronic phase of the study. The striking decrement in [HCO3-]p observed in response to the chronic reduction in PaCO2 was sufficient not only to prevent the development of extreme alkalemia but also to offset entirely the effect of hypocapnia on plasma [H+].

Acute Disease↗
PubMed1979

A redefinition of normal acid-base equilibrium in man: carbon dioxide tension as a key determinant of normal plasma bicarbonate concentration.

It has been shown recently that normal acid-base equilibrium in the dog is characterized by a strong positive correlation between plasma bicarbonate concentration and PCO2. The present study was undertaken to examine the possibility that a similar relationship between normal levels of PCO2 and plasma bicarbonate might be present in man. The results indicate that values for bicarbonate within the normal range are highly dependent upon the prevailing level of PCO2 ([HCO3-] = 0.36 PaVCO2 + 10.4; r = 0.73). Thus, approximately 50% of the normal variance in bicarbonate concentration is explained simply by the variance in PCO2. The joint confidence region for bicarbonate concentration and PCO2, that can be derived from these data provides a new and more rigorous definition of normal acid-base equilibrium in man.

Acid-Base Equilibrium↗