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Biomedical subjects

M Kennedy

Publications and source records attributed to M Kennedy.

At least 181 records · Page 10Linked to original sources
PubMed1993

Disseminated trichosporonosis in a neutropenic murine model.

Life-threatening disseminated infection with Trichosporon beigelii (trichosporonosis) is a rare mycosis most commonly seen in patients with hematologic malignancies made neutropenic by cytotoxic therapy. This infection is usually resistant to conventional antifungal therapies. Poor correlation between therapeutic outcome of trichosporonosis and in vitro susceptibility of clinical isolates of T. beigelii to antifungal agents is often reported. To obtain a better understanding of its pathogenesis, and to aid in the future study of the therapy of this disease, a murine model of trichosporonosis was developed. The in vitro growth of clinical isolates of T. beigelii was first studied. Subsequently, mice made neutropenic with cyclophosphamide were inoculated intravenously with the fungus to produce the disease model. Inoculum size which produced 100% mortality, yet allowed an apparent therapeutic window (6 x 10(6)) was determined. Tissue distribution and burden of organism during the course of infection was examined by viability and histopathologic studies. T. beigelii disseminated rapidly in this model, involving numerous organs including the heart, brain, kidneys, lungs, and liver. The heart and kidneys of the infected animals showed evidence of infection as early as 6 hours following inoculation. Further understanding of the pathogenesis of trichosporonosis in the neutropenic host was imparted by this study. This will aid in the future study of antibiotic treatment of this disease and its untreated progression.

Animals↗
PubMed1993

Hematopoietic commitment during embryonic stem cell differentiation in culture.

We report that embryonic stem cells efficiently undergo differentiation in vitro to mesoderm and hematopoietic cells and that this in vitro system recapitulates days 6.5 to 7.5 of mouse hematopoietic development. Embryonic stem cells differentiated as embryoid bodies (EBs) develop erythroid precursors by day 4 of differentiation, and by day 6, more than 85% of EBs contain such cells. A comparative reverse transcriptase-mediated polymerase chain reaction profile of marker genes for primitive endoderm (collagen alpha IV) and mesoderm (Brachyury) indicates that both cell types are present in the developing EBs as well in normal embryos prior to the onset of hematopoiesis. GATA-1, GATA-3, and vav are expressed in both the EBs and embryos just prior to and/or during the early onset of hematopoiesis, indicating that they could play a role in the early stages of hematopoietic development both in vivo and in vitro. The initial stages of hematopoietic development within the EBs occur in the absence of added growth factors and are not significantly influenced by the addition of a broad spectrum of factors, including interleukin-3 (IL-3), IL-1, IL-6, IL-11, erythropoietin, and Kit ligand. At days 10 and 14 of differentiation, EB hematopoiesis is significantly enhanced by the addition of both Kit ligand and IL-11 to the cultures. Kinetic analysis indicates that hematopoietic precursors develop within the EBs in an ordered pattern. Precursors of the primitive erythroid lineage appear first, approximately 24 h before precursors of the macrophage and definitive erythroid lineages. Bipotential neutrophil/macrophage and multilineage precursors appear next, and precursors of the mast cell lineage develop last. The kinetics of precursor development, as well as the growth factor responsiveness of these early cells, is similar to that found in the yolk sac and early fetal liver, indicating that the onset of hematopoiesis within the EBs parallels that found in the embryo.

Animals↗
PubMed1993

The sports' clinic: a one year review of new referrals.

The new presentations to the Cork Sports' Clinic over a one year period 1.1.90 to 31.12.90 were examined. We looked at the age and sex distribution of the presenting population, the type and site of injury, the sport played and the treatment and outcome of the injury. 126 new cases presented in 1990. 107 (85%) were male. The three commonest sports featured were all contact ones. The knee was the commonest site of injury (46.8% of cases) with 73.1% of injuries occurring in the lower limb. 73% of cases presented between the ages of 15 to 29 years. The majority of patients had improved on follow-up. Nine were referred to an orthopaedic service-five fractures and four serious ligamental injuries. The Cork Sports' Clinic works adjacent to a busy accident and emergency department. There is a definite need for our clinic in conjunction with the casualty department.

Adolescent↗
PubMed1992

Factor-dependent erythroid cell lines derived from mice transplanted with hematopoietic cells expressing the v-src oncogene.

Transplantation of spleen cells from primary reconstituted mice expressing the v-src oncogene to secondary and tertiary irradiated recipients resulted in the emergence of erythroid precursors with a transformed phenotype. When cultured in methyl cellulose, these precursors generated colonies of undifferentiated cells that could be expanded into continuously growing factor-dependent cell lines in liquid culture. All lines tested had a similar phenotype and expressed the v-src oncogene. In addition they responded to factors that regulate normal erythroid development, namely erythropoietin (Epo), interleukin-3 (IL-3), and mast cell growth factor (MGF), the ligand to the c-kit encoded receptor. When cells from one of the lines were maintained in the absence of factor, a "factor independent" subpopulation emerged that appeared to grow in an autocrine fashion. Conditioned medium from these cells stimulated their own growth as well as the growth of broad spectrum of normal precursors. Studies with neutralizing antibodies indicated that the predominant colony-stimulating factor produced by these cells is IL-3.

Animals↗
PubMed1992

A roundtable discussion: hospital leaders discuss QI implementation issues.

To address critical questions regarding the practical application of quality improvement (QI) concepts within health care, the Joint Commission visited six hospitals that have been implementing QI for several years. After the site visits, the leaders of these hospitals participated in a roundtable discussion of QI issues. The discussion centered around nuts-and-bolts topics, such as leadership, implementing QI, barriers/resistances, medical staff involvement, cultural change, institutionalizing QI, and external environment. The roundtable discussion is excerpted in full from a new book, Striving Toward Improvement: Six Hospitals in Search of Quality, which tells the stories of the six hospitals and their transitions to QI.

Attitude↗
PubMed1992

Loss of the common "A" determinant of hepatitis B surface antigen by a vaccine-induced escape mutant.

A previous study (Carman, W. F., A. R. Zanetti, P. Karayiannis, J. A. Waters, G. Manzillo, E. Tanzi, A. J. Zuckerman, and H. C. Thomas. 1990. Lancet. 336:325-329) demonstrated a variant hepatitis B surface antigen (HBsAg) in a vaccinated child born to a hepatitis B virus-infected mother. A substitution of arginine for glycine at amino acid 145 in HBsAg was observed. In this study the effect of this substitution on the common "a" determinant of this protein, against which protective immunity is directed, is investigated. Using recombinant HBsAg with and without the amino acid substitution, the binding of monoclonal antibodies that recognize different epitopes of the "a" determinant, was shown to be destroyed by the presence of arginine at amino acid 145. In convalescent and vaccinee sera, antibody binding to HBsAg was not inhibited by the variant HBsAg. Immunization with the variant HBsAg, although eliciting a high titer antibody that recognized the variant, produced a low titer of antibody recognizing the native protein. Studies in mice demonstrate that the immunogenicity of the variant protein is also substantially altered. The data presented here demonstrate that this variant evades the known protective anti-HBs response and lends support to the suggestion that this mutation arose as the result of immune pressure.

Animals↗
PubMed1991

Evidence that hydrolysis of ethanolamine plasmalogens triggers synthesis of platelet-activating factor via a transacylation reaction.

Addition of 1-O-alk-1'-enyl-2-lyso-sn-glycero-3-phosphoethanolamine (alkenyl-lyso-GPE) to human neutrophil membrane preparations containing 1-O-[3H]hexadecyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (1-O-[3H]alkyl-2-arachidonoyl-GPC) resulted in rapid deacylation of the 1-O-[3H]alkyl-2-arachidonoyl-GPC to 1-O-[3H]alkyl-2-lyso-GPC (lyso-platelet-activating factor, lyso-PAF). When acetyl-CoA was included in the incubation mixture, the [3H]lyso-PAF was converted to [3H]PAF. Studies of [3H]arachidonate-labeled neutrophils permeabilized with Staphlococcus aureus alpha-toxin revealed a major shift of labeled [3H]arachidonate from the choline to the ethanolamine-containing phosphoglycerides upon addition of alkenyl-lyso-GPE. The studies indicated that lyso-PAF is formed in the system by the transfer of arachidonate from 1-O-alkyl-2-arachidonoyl-GPC to the alkenyl-lyso-GPE by a CoA-independent transacylase reaction. Mass measurements revealed a rapid loss of arachidonate from 1-radyl-2-acyl-GPE and a concomitant increase in alkenyl-lyso-GPE upon stimulation of the neutrophils by ionophore A23187. Based on these and other findings, a pathway is proposed that may play a significant, if not obligatory, role in the synthesis of PAF in intact stimulated neutrophils. It has been widely accepted that phospholipase A2 acts directly on 1-O-alkyl-2-arachidonoyl-GPC as the first step in the synthesis of PAF via formation of lyso-PAF. In the proposed scheme, phospholipase A2, upon stimulation, acts rapidly on ethanolamine plasmalogen selectively releasing arachidonic acid and generating alkenyl-lyso-GPE. The CoA-independent transacylase then selectively transfers arachidonate from 1-radyl-2-arachidonoyl-GPC to the alkenyl-lyso-GPE generating lyso-PAF, which is then acetylated to form PAF. The interactions outlined can account for the synthesis of 1-acyl-2-acetyl-GPC, 1-O-alk-1'-enyl-2-acetyl-GPE, and eicosanoids, in parallel with PAF.

Acylation↗
PubMed1991

A simple technique for generating probes for RNA in situ hybridization: an adjunct to genome mapping exemplified by the RAG-1/RAG-2 gene cluster.

Two major problems have to be solved in studies of genes near breakpoints of chromosome abnormalities and in large-scale genomic mapping projects: (i) the identification of genes within the large amount on nontranscribed DNA and (ii) the determination of the tissues in which the identified genes are transcribed. In situ hybridization to mRNA is ideally suited to assess gene expression in all tissues but probe preparation presents major difficulties for adapting the technique for rapid screening. Here, we present a procedure to easily generate strand-specific DNA probes for in situ hybridization. In this method, a DNA fragment to be tested in uniformly labeled, denatured, and prehybridized to an excess of competitor single-stranded DNA corresponding to either positive or negative strands of the test fragment. No sequence information is needed. The prehybridized mixture is used directly for hybridization to whole embryo or tissue sections. We demonstrate the utility of this approach for any nonrepetitive fragment by using cDNA probes, intronless genomic probes, or genomic probes comprising transcribed and nontranscribed DNA. As an example, we show that mRNA for the recombination-activating genes (RAG) RAG-1 and RAG-2 is found in thymus of dE16 mouse embryos. Within the thymus, high levels of expression of RAG-1 and RAG-2 are detectable in the cortex but not in the medullary region. This supports the view that RAG-1 and RAG-2 expression is associated with cells known to actively rearrange antigen receptor loci.

Animals↗
PubMed1991

A complex chromosome rearrangement forms the BCR-ABL fusion gene in leukemic cells with a normal karyotype.

Chromosome in situ hybridization studies showed that the normal karyotype of leukemic cells from a patient with Ph1-negative, BCR-positive chronic myeloid leukemia (CML) concealed a complex t(9;22;20)(q34;q11;p13). The close association of 5'-BCR and 3'-ABL was demonstrated by field inversion gel electrophoresis, and in situ hybridization showed that BCR-ABL was located on the short arm of chromosome 20. Our findings further indicate that chromosome rearrangement is the cause of BCR-ABL gene fusion in leukemic cells that show a normal karyotype. Results from in situ hybridization studies were consistent with formation of the t(9;22;20) by a two step chromosomal rearrangement, but field inversion gel electrophoresis results indicated a more complex rearrangement.

Aged↗
PubMed1991

The constitution of physicians' power: a theoretical framework for comparative analysis.

Drawing on literatures documenting the experience of physicians in both European and American societies, a new theoretical framework for explaining variations in the professional power of physicians is provided. Most studies of professions have used professional organization as the principal explanatory variable, with state policy and the organization of civil society as secondary mediating factors. Our approach instead treats strategies of state power and forms of civil society as central features shaping the ability of the profession to exert power. Such a three-dimensional approach not only allows us to make more powerful classifications explaining contemporary differences, but also allows us to trace historical shifts and anticipate alternative futures in professional power. For example, in those societies where the state's intervention is limited and civil society is pluralistic, professional power is potentially greatest. But increasing state power does not necessarily reduce professional power. Where the state is most powerful and organizes all groups in civil society, professionals and society can be united in common struggle against the state. In response to that, it is likely that such centralized states will opt for corporatist solutions to maximize the internal differentiation of society and pit those once allied against one another, and preclude the organization of powerful autonomous interest groups.

Europe↗
PubMed1991

An empirical evaluation of the performance of antibody identification tasks.

Four empirical studies were conducted for better understanding of the nature of problem-solving activities by medical technologists and medical technology students when performing antibody identification tasks. The results indicated the importance of strategies that ensure the collection of converging evidence, as these strategies protect against the fallibility of commonly used heuristics and against errors due to simple slips. The results also indicate that not only do students make significant numbers of errors, but so do practicing technologists. In one of the studies covering a 1-year period, for instance, a group of 16 technologists made a total of 41 errors in 1057 cases. On the basis of these findings, several alternatives are proposed to reduce errors.

Adult↗
PubMed1991

Determining the significance of anti-Kl in hemolytic disease of the newborn (HDN).

Anti-K1 is capable of causing severe hemolytic disease of the newborn (HDN), but few cases are seen due to the low frequency of the antigen. A total of 1,215 pregnancies from 1962 to 1989 were reviewed. There were 404 non-anti-D clinically significant antibodies, of which 103 (25%) were anti-K1. Anti-K1 was detected in nine of the women at delivery, of whom two had antigen-positive infants who were clinically unaffected. Antigen typing was done on 64 of the 85 fathers. Forty-seven were K - 1 and 17 were K1,2; 21 were unavailable. Antibody titers were done on the mothers in the latter two groups. Women with titers <32 were followed by titration studies; all delivered clinically unaffected infants, four of whom were K:1. Women with titers >32 had amniocentesis performed for optical density values (AOD450) or, after November 1987, were offered an alternative test, cordocentesis, to type the fetus and to do hemoglobins if the fetus was antigen-positive. Two women had severely affected infants requiring multiple intrauterine transfusions starting at 20-23 weeks. Six others delivered antigen-positive infants who did not require transfusions, although all had positive direct antiglobulin tests (DAB). We conclude that titration studies are reliable tools to evaluate anti-K1 sensitization when the titer is <32. Cordocentesis can detect antigen-negative fetuses, which then reduces the need for titrations and amniocentesis.

Journal Article↗
PubMed1990

CD4+ T cell-mediated killing of MHC class II-positive antigen-presenting cells. I. Characterization of target cell recognition by in vivo or in vitro activated CD4+ killer T cells.

Ag-specific as well as Ia-restricted killing of certain APC by CD4+ T cells was investigated. The CD4-mediated killing is not only a characteristic of in vitro long term cultured T cell lines or clones, but is also manifest after in vivo priming. Thus, CD4+ killer T cells are generated in vivo as well. CD4+ killer T cells are detected in the Th1, but not in the Th2 subset, and they do not appear to lyse Ia+ APC or bystander cells by a pathway mediated by secreted T cell factors. The latter observation is demonstrated by cold target inhibition experiments as well as by the failure of puromycin to inhibit killing, if applied in doses which completely block lymphokine secretion. Ia+ APC differ in their susceptibility to lysis. Transformed APC are usually better lysed than nontransformed APC. Unstimulated B cells are not killed, while LPS-stimulated B cell blasts are killed. The results of cold target inhibition and bystander killing experiments suggest that CD4+ killer T cells are activated by the common pathway, i.e., by Ag presented in the context of Ia, but killing requires the recognition of additional determinant(s) on APC. It is proposed that these killing-inducing determinants are continuously expressed on most transformed Ia+ cells and on nontransformed but stimulated APC.

Animals↗
PubMed1990

The rhombotin gene belongs to a class of transcriptional regulators with a potential novel protein dimerisation motif.

The derived protein sequence of the presumptive oncogene rhombotin is virtually identical between human and mouse (Boehm et al., 1990), rendering it difficult to identify functionally important regions or motifs. We have therefore sought to isolate and compare rhombotin sequences from disparate species. Here we show that a sequence which is highly homologous to that of human and mouse rhombotin exists in Drosophila DNA. Comparison of the sequences shows the main conserved feature to be a cysteine-rich region (CRR). The mammalian rhombotin gene has tandemly duplicated CRR's (CRR-1 and CRR-2) and comparison of CRR-1 and -2 with other known proteins shows close homology to the proposed LIM domains of the nematode cell lineage proteins lin-11 and mec-3 (Freyd et al., 1990), and of a vertebrate transcription factor (Isl-1) (Karlsson et al., 1990). The latter three proteins share a homeodomain, in addition to the LIM domains. These observations suggest that the LIM domain might facilitate protein-protein interactions in a manner analogous to the leucine zipper or the helix-loop-helix motifs. Thus, since rhombotin lacks a DNA-binding homeodomain, this protein might belong to a new class of transcriptional regulators which modulate transcription via intermolecular competitive binding to the LIM domains of certain DNA-binding transcription factors.

Amino Acid Sequence↗
PubMed1990

A scientific paradox--explosives that are safe for use in flammable atmospheres.

Explosives used in coal mines have to be efficient in blasting rock and coal but at the same time should not ignite the flammable atmosphere that can sometimes be encountered underground. When used, the explosives are placed in drilled holes and shot in rounds, with a short delay between each shot. Because the explosive is of low power, later shots in the round may fail to detonate but deflagrate instead. Any flammable atmosphere that might be present would then be ignited. This paper describes investigations of the initiation and propagation of detonation in low-power mining explosives. Qualitative studies show how detonation can fail in the vicinity of delay detonators when the explosive is precompressed prior to detonation. Analysis of X-ray photographs of detonation waves propagating in conditions near to failure enables estimates to be made of reaction-zone shapes, densities, pressures, and particle velocities. This information is used to devise a model of the reaction-zone processes, explain why compression of the explosive can lead to detonation failure, and to assess nearness to failure.

Coal Mining↗