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Biomedical subjects

J F Kerr

Publications and source records attributed to J F Kerr.

At least 19 recordsLinked to original sources
PubMed2001

Impact of a toxicology service on a metropolitan teaching hospital.

OBJECTIVE: To evaluate the impact of a toxicology service on a major metropolitan teaching hospital. METHOD: A descriptive comparative study of all patients presenting with poisoning or suspected poisoning 12 months before and after the commencement of a toxicology service. Data on length of stay in the emergency department, disposition, length of stay of admitted patients and substance(s) involved were examined. RESULTS: A total of 1,316 poisoned patients were studied. There was a statistically significant increase in self-poisonings from 612 to 704 (P = 0.002) and in the number of admissions from 113 to 192 (P < 0.05). There was no significant change in emergency department length of stay. The average length of stay for patients admitted under the care of the toxicology service decreased, especially for complicated patients. CONCLUSION: In the first 12 months of operation the toxicology service treated more patients than the 12-month period prior to commencement, achieving a decrease in average length of stay for those patients admitted to the service. The emergency department length of stay was not altered. We surmise that by decreasing average length of stay for the patients under the care of the toxicology service, the net increase in the general pool of unoccupied beds improves bed access for all emergency department patients.

Emergency Service, Hospital↗
PubMed1995

Neglected opportunities in apoptosis research.

Interest in apoptosis is currently growing rapidly, and previous articles in this series in TCB have described a number of recent advances in the field. Certain aspects of the process, however, have been relatively neglected. In this article, John Kerr draws attention to some of them, with the hope that he may indicate potentially productive areas for future research.

Journal Article↗
PubMed1994

Apoptosis. Its significance in cancer and cancer therapy.

Apoptosis is a distinct mode of cell death that is responsible for deletion of cells in normal tissues; it also occurs in specific pathologic contexts. Morphologically, it involves rapid condensation and budding of the cell, with the formation of membrane-enclosed apoptotic bodies containing well-preserved organelles, which are phagocytosed and digested by nearby resident cells. There is no associated inflammation. A characteristic biochemical feature of the process is double-strand cleavage of nuclear DNA at the linker regions between nucleosomes leading to the production of oligonucleosomal fragments. In many, although not all of the circumstances in which apoptosis occurs, it is suppressed by inhibitors of messenger RNA and protein synthesis. Apoptosis occurs spontaneously in malignant tumors, often markedly retarding their growth, and it is increased in tumors responding to irradiation, cytotoxic chemotherapy, heating and hormone ablation. However, much of the current interest in the process stems from the discovery that it can be regulated by certain proto-oncogenes and the p53 tumor suppressor gene. Thus, c-myc expression has been shown to be involved in the initiation of apoptosis in some situations, and bcl-2 has emerged as a new type of proto-oncogene that inhibits apoptosis, rather than stimulating mitosis. In p53-negative tumor-derived cell lines transfected with wild-type p53, induction of the gene has, in rare cases, been found to cause extensive apoptosis, instead of growth arrest. Finally, the demonstration that antibodies against a cell-surface protein designated APO-1 or Fas can enhance apoptosis in some human lymphoid cell lines may have therapeutic implications.

Animals↗
PubMed1993

Spontaneous apoptosis in NS-1 myeloma cultures: effects of cell density, conditioned medium and acid pH.

Apoptosis is a form of cell death which plays an important role in many biological processes including the regulation of B and T lymphocyte functions. We report here the spontaneous development of extensive apoptosis in cultures of the NS-1 mouse myeloma cell line following overgrowth. The apoptosis was identified by both its ultrastructural features and its DNA fragmentation pattern. High cell density and conditioned medium, but not acid pH, were found to be major inducers of apoptosis in this experimental system.

Animals↗
PubMed1993

Ethionine-induced atrophy of rat pancreas involves apoptosis of acinar cells.

The mechanism of acinar cell loss occurring during ethionine-induced atrophy of the pancreas was investigated. Rats were given a standard diet, a protein-depletion diet (PDD), or a PDD with low- (0.04 g/kg body wt; LDE) or high- (0.4 g/kg; HDE) dose ethionine administered intraperitoneally daily for 10 days. Changes were most extensive in the animals given a PDD and HDE: After 10 days, pancreatic weight was reduced by 72%, and most of the acinar cells had disappeared. Prior to their deletion, these cells showed cytoplasmic vacuolation and enhanced autophagy. The main mechanism involved in their deletion was apoptosis, the apoptotic bodies being phagocytosed and degraded by adjacent acinar cells and intraepithelial macrophages. In contrast, necrosis of acinar cells was rare. Interstitial inflammation and apoptosis of capillary endothelial cells were also observed. In animals given a PDD and LDE, enhanced apoptosis occurred later and was more limited in extent, and additional manifestations of cell injury were not evident. As in other circumstances where glandular atrophy is effected by apoptosis, the basic tissue architecture was preserved, thus explaining the known capacity for the pancreas to regenerate after ethionine is discontinued.

Animals↗
PubMed1992

Ultrastructure of the rat pancreas after experimental duct ligation. II. Duct and stromal cell proliferation, differentiation, and deletion.

Ligation of the pancreas in rats was followed by rapid atrophy of the distal part of the gland, where deletion of the acinar cells by apoptosis and simultaneous extensive proliferation of duct cells resulted in the lobules being converted into groups of closely packed small ducts within 5 days. We found no ultrastructural evidence that cells lining these small ducts arose from acinar cells by a process of dedifferentiation, as has been suggested by some investigators. During the succeeding weeks, some of the ductal lining cells developed islet cell or partial acinar cell differentiation. The latter soon died by apoptosis, and some ductlike and islet cells were also deleted by this means. Most of the apoptotic bodies formed in the ducts were phagocytosed by intraepithelial macrophages. In the longer term, continuing apoptosis eventually resulted in the disappearance of many ducts, only their thickened basal laminae remaining. Differentiation of stromal fibroblasts into contractile myofibroblasts may have contributed to shrinkage of the duct-obstructed glandular tissue, and apoptosis of endothelial cells probably accounted for the associated reduction of the capillary bed.

Analysis of Variance↗
PubMed1991

Apoptosis induced by mild hyperthermia in human and murine tumour cell lines: a study using electron microscopy and DNA gel electrophoresis.

Mild hyperthermia is known to enhance apoptosis in a range of normal and neoplastic cell populations. Studies of tumours previously shown to respond to heating in this manner might be expected to provide insights not only into the mechanism of hyperthermic cell killing, but also into the apoptotic process in general. In the present study, cell death induced by 43 degrees C heating for 30 min in two human Burkitt's lymphoma lines, BM 13674 and WW1, and in murine mastocytoma P-815 x 2.1 was found to be exclusively apoptotic in type, identification being based on light and electron microscopic appearances and on the presence of internucleosomal cleavage of DNA into fragments that are multiples of 180-200 base pairs, which was demonstrated by agarose gel electrophoresis. The heat-induced apoptosis was prevented by the presence of zinc sulphate, an inhibitor of the endonuclease considered to be responsible for the DNA cleavage, but was not suppressed by the protein synthesis inhibitor cycloheximide. The findings question the validity of the widely held view that active protein synthesis is an invariable prerequisite for the execution of apoptosis. It is suggested that an inositol triphosphate-mediated increase in cytosolic Ca2+, resulting from limited membrane damage, might be the critical event responsible for activation of apoptosis by mild hyperthermia.

Animals↗
PubMed1991

Apoptosis in the nervous system in experimental allergic encephalomyelitis.

We report here for the first time the occurrence of apoptosis of cells in the spinal cord in experimental allergic encephalomyelitis (EAE), an autoimmune, T-cell-mediated demyelinating disease. Four different forms of EAE were studied in the Lewis rat: (i) acute EAE induced by inoculation with whole spinal cord and adjuvants; (ii) acute EAE induced by inoculation with myelin basic protein (MBP) and adjuvants; (iii) acute EAE induced by the passive transfer of MBP-sensitized spleen cells; (iv) chronic relapsing EAE induced by inoculation with whole spinal cord and adjuvants followed by treatment with low-dose cyclosporin A. Cells undergoing apoptosis were recognized at light and electron microscopy by the presence of either crescentic masses of condensed chromatin lying against the nuclear envelope or rounded masses of uniformly dense chromatin. They were found in both the white and grey matter of the spinal cord in all 4 forms of this disease. Although it was not possible to identify definitively the types of cells undergoing apoptosis, the size and location of some of the affected cells suggested that they were oligodendrocytes. As there is now a large body of evidence that T-cell-induced target cell death takes the form of apoptosis, it is attractive to hypothesize that oligodendrocyte apoptosis is occurring in EAE as a result of oligodendrocyte-directed T-cell cytotoxicity. However, other apoptotic cells were located within the myelin sheath, meninges and perivascular spaces and were clearly not oligodendrocytes but were most likely blood-derived mononuclear cells. The sparsity of their cytoplasm and the absence of phagocytosed material suggested that they were mainly lymphocytes rather than macrophages. Apoptosis has been shown to be involved in deleting autoreactive T-cells during the normal development of tolerance. Thus apoptotic deletion of myelin/oligodendrocyte-specific lymphocytes in the central nervous system in EAE might explain both the subsidence of inflammation and the acquisition of tolerance in this autoimmune disease.

Animals↗
PubMed1991

Effects of cycloheximide on B-chronic lymphocytic leukaemic and normal lymphocytes in vitro: induction of apoptosis.

A number of reports indicate that protein synthesis is a requirement for the occurrence of apoptosis. In this study, the effect of the protein synthesis inhibitor cycloheximide (CHM) on spontaneous apoptosis of B-chronic lymphocytic leukaemia (B-CLL) cells, previously shown to occur when they are cultured in RPMI-1640 medium with autologous or heterologous serum, was examined. No definite inhibition of apoptosis was observed. Indeed, CHM-treatment augmented apoptosis in the B-CLL cultures and also induced apoptosis of cultured normal peripheral blood lymphocytes. Augmentation was dose-dependent for B-CLL cells over the concentration range 10(-6) M (0.28 micrograms ml-1) to 10(-2) M (2800 micrograms ml-1), resulting in 9% to 98% apoptosis respectively by 24 h of culture (r = 0.619, P = 0.0008). Normal lymphocytes were affected by CHM over the range 10(-4) M to 10(-2) M, resulting in 7% to 74% apoptosis respectively (r = 0.794, P = 0.0001). Inhibition of protein synthesis in these cells by CHM was virtually complete at a concentration of 10(-3) M. The findings are in accord with some recent reports indicating that suppression of protein synthesis by CHM does not inhibit apoptosis in all circumstances. They also illustrate the marked susceptibility of B-CLL cells, compared with normal lymphocytes, to the induction of apoptosis by this drug. The manner in which CHM triggers apoptosis of some cell types is at present uncertain.

Antigens, CD↗
PubMed1990

Cell death induced in a murine mastocytoma by 42-47 degrees C heating in vitro: evidence that the form of death changes from apoptosis to necrosis above a critical heat load.

The pathogenesis of heat-induced cell death is controversial. Categorizing the death occurring after various heat loads as either apoptosis or necrosis might help to elucidate this problem, since it has been shown that these two processes differ in their mode of initiation as well as in their morphological and biochemical features. Log-phase cultures of mastocytoma P-815 x 2.1 were heated at temperatures ranging from 42 to 47 degrees C for 30 min. After 42 degrees C heating a slight increase in apoptosis was observed morphologically. However, after heating at 43, 43.5 and 44 degrees C, there was marked enhancement of apoptosis, and electrophoresis of DNA showed characteristic internucleosomal cleavage. With heating at 45 degrees C both apoptosis and necrosis were enhanced, whereas at 46 and 47 degrees C only necrosis was produced. DNA extracted from the 46 and 47 degrees C cultures showed virtually no degradation, which contrasts with the random DNA breakdown observed in necrosis produced by other types of injury; lysosomal enzymes released during heat-induced necrosis may be inactivated at the higher temperatures. It is suggested that apoptosis following heating may be triggered either by a limited increase in cytosolic calcium levels resulting from mild membrane changes or by DNA damage. Necrosis, on the other hand, is likely to be a consequence of severe membrane disruption.

Animals↗
PubMed1989

Cell death by apoptosis during involution of the lactating breast in mice and rats.

The role of cell death in involution of lactating breast was investigated in mice and rats by light and electron microscopy. Apoptosis, recognized by sharply demarcated compaction of chromatin against the nuclear envelope and by shrinkage and budding of the whole cell to form membrane-bounded apoptotic bodies, was responsible for major loss of cells in both species. In the mouse, rapid involution during the first 2 days was associated with shedding of large numbers of apoptotic bodies derived from alveolar epithelial cells into alveolar lumens. This was followed by more gradual regression, during which the bodies were mostly phagocytosed by macrophages within the epithelium. In the rat, glandular involution was a more gradual and uniform process, with shedding of apoptotic epithelial cells into alveolar lumens being much less conspicuous. Apoptosis of myoepithelial cells was observed in mice, the resulting apoptotic bodies being phagocytosed by intraepithelial macrophages, but was not detected in rats. Apoptosis of capillary endothelial cells caused rapid regression of the capillary beds in both mice and rats. Intraepithelial macrophages increased in number during involution, developed cytoplasmic lipofuscin pigment, and either remained within the epithelium or migrated to the interstitium and regional nodes. Cell loss by apoptosis has been demonstrated during involution and atrophy of a variety of other glands. It characteristically results in shrinkage of a tissue without disruption of its basic architecture.

Animals↗
PubMed1989

Spontaneous programmed death (apoptosis) of B-chronic lymphocytic leukaemia cells following their culture in vitro.

When B-chronic lymphocytic leukaemia (B-CLL) cells derived from peripheral blood were cultured in vitro, a substantial proportion of them spontaneously died by apoptosis. This type of cell death is morphologically and biochemically distinct from necrosis and has previously been found to occur under physiologic and certain pathologic conditions where cell deletion appears controlled and biologically meaningful. By 30 h of culture, approximately 20% of the unfractionated B-CLL cells were affected. There was no significant difference in the incidence of apoptosis in T-cell depleted and undepleted cultures or when either autologous or normal human serum was used. Furthermore, seeding densities of 2 x 10(6) and 5 x 10(5) cells/ml resulted in a similar incidence of apoptosis, indicating that cell density was unlikely to be a contributing factor in producing the death. The finding that B-CLL cells spontaneously die in vitro has at least two important implications. Firstly, previous work relating to some of the functions of B-CLL cells and their interactions with T cells may require re-evaluation. Secondly, an understanding of the mechanisms involved in the induction of apoptosis in this disease may have therapeutic consequences.

Blood Cell Count↗
PubMed1988

Patterns of cell death.

Cell death takes two distinct forms, necrosis and apoptosis. Necrosis is a degenerative phenomenon that follows irreversible injury. Apoptosis, in contrast, appears to be an active process requiring protein synthesis for its execution; it is implicated in physiological regulation of tissue size, and, where it occurs pathologically, a homeostatic role for the death is often evident. Morphologically, apoptosis involves condensation of the nuclear chromatin and cytoplasm, fragmentation of the nucleus, and budding of the whole cell to produce membrane-bounded bodies in which organelles are initially intact. These bodies are disposed of by adjacent cells without inflammation. Biochemically, there is distinctive internucleosome cleavage of DNA in apoptosis, which is quite different from the random DNA degradation observed in necrosis.

Adult↗
PubMed1985

Apoptosis, lymphocytotoxicity and the containment of viral infections.

It is generally agreed that cellular immunity plays an important role in limiting certain primary viral infections. Morphological studies indicate that cell death induced by T cells, K cells and NK cells takes the form of apoptosis, not classical necrosis. Killing of a virus-infected cell by either of these means prior to the assembly of infectious virus would clearly contain the infection. Our hypothesis is that the exclusive involvement of apoptosis in lymphocytotoxicity may have additional advantages in preventing virus dissemination. Firstly, a very early event in apoptosis is activation of endogenous, non-lysosomal endonuclease, and this might destroy virus. Secondly, apoptosis results in the formation of membrane-bounded cell fragments, which are phagocytosed intact and digested within the lysosomes of adjacent cells. In contrast, necrosis is characteristically associated with rupture of the cell membrane and release of cellular contents; its induction by non-budding viruses aids in spread of the infection.

Cytotoxicity, Immunologic↗