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J Smith

Publications and source records attributed to J Smith.

At least 415 records · Page 23Linked to original sources
PubMed1997

Influence of acute rejection episodes, HLA matching, and donor/recipient phenotype on the development of 'early' transplant-associated coronary artery disease.

BACKGROUND: Transplant-associated coronary artery disease (TxCAD) is the manifestation of chronic rejection in the cardiac allograft. Both immunological and nonimmunological factors contribute to its development. Stratification by the time of development of TxCAD has not been considered previously for an extensive transplant series and may provide a means for apportioning relative risk factors appropriately. Specifically, TxCAD that develops early may have a pathogenesis different from TxCAD that develops later; ie, immunological factors play a more significant role in early development of TxCAD compared with later forms of the disease or in recipients where it has not been found. METHODS AND RESULTS: Between 1980 and 1994, 550 heart transplant recipients with postmortem data or yearly angiograms, donor:recipient serological HLA typing, and biopsy data were reviewed. Recipients were divided into four groups: Very Early (<1 year), Early (1-2 years), Late (3-14 years), and None (clear angio >3 years). There was a significant association between the number of histologically proven acute rejection episodes within 3 months and at 1 year and the development of early TxCAD. The number of acute rejection episodes within 3 months and 1 year is also significantly related to freedom of development of TxCAD. There was no significant association between the mean number of mismatches for Class I or Class II antigens, nor could any Class I/II phenotype for recipient or donor be identified that exerted a protective or deleterious effect. A lack of any association or trend with HLA data is demonstrated. CONCLUSIONS: These differences in pathogenesis between early and late TxCAD help define the importance of acute rejection in the etiology of chronic cardiac rejection. Stratification by time of development of TxCAD may provide further insight into defining the relative importance of other risk factors associated with the development of TxCAD. The lack of association with HLA data is discussed.

Acute Disease↗
PubMed1997

Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy.

OBJECTIVES: To provide Canadian physicians with a standard definition of hypertension in pregnancy, recommendations for laboratory investigations and tests for the assessment and management of hypertensive disorders in pregnancy, and a classification of such disorders. OPTIONS: To improve or not improve Canadian uniformity and standardization in the investigation and classification of hypertensive disorders in pregnancy. OUTCOMES: 1) Accuracy, reliability and practicality of diagnostic clinical criteria for hypertensive disorders in pregnancy. 2) Laboratory tests useful to determine severity and prognosis of disorders as measured by maternal and neonatal adverse outcomes. 3) A classification of disorders for use by Canadian physicians to facilitate uniformity and diffusion of research through a common language. EVIDENCE: Articles on hypertensive disorders in pregnancy published from 1966 to 1996, retrieved through MEDLINE search, related to definitions, tests, diagnostic criteria and classification, as well as documents on diagnosis and classification from authorities in the United States, Europe and Australia and from special interest groups. VALUES: High priority was given to the principle of preventing adverse maternal and neonatal outcomes through the provision of diagnostic criteria for severity and prognosis and through dissemination of reliable and pertinent information and research results using a common language. BENEFITS, HARMS AND COST: Higher degree of vigilance in diagnosing hypertensive disorders in pregnancy, allowing for earlier assessment and intervention, and more efficient dissemination of comparative information through common language. No harm or added cost is perceived at this time. RECOMMENDATIONS: (1) A diastolic blood pressure of 90 mm Hg or more should be the criterion for a diagnosis of hypertension in pregnancy and should trigger investigation and management. Except for very high diastolic readings (110 mm Hg or more), all diastolic readings of 90 mm Hg or more should be confirmed after 4 hours. (2) A regularly calibrated mercury sphygmomanometer, with an appropriate-sized cuff, is the instrument of choice. A rest period of 10 minutes should be allowed before taking the blood pressure. The woman should be sitting upright and the cuff positioned at the level of the heart. (3) Both Korotkoff phase IV and V sounds should be recorded, but the phase IV sound should be used for initiating clinical investigation and management. (4) A urine protein level of more than 0.3 g/d should be the criterion for a diagnosis of proteinuria; 24-hour urine collection should be the standard method for determining proteinuria. (5) Edema and weight gain should not be used as diagnostic criteria. (6) Hypertensive disorders diagnosed during pregnancy should be classified as pre-existing hypertension; gestational hypertension with or without proteinuria; pre-existing hypertension with superimposed gestational hypertension with proteinuria; and unclassifiable antenatally but final classification 42 days after delivery. VALIDATION: Except for expert opinions and reviews solicited for this project, these recommendations need to be field tested and validated in Canada. Guidelines endorsed by the Canadian Hypertension Society and the Society of Obstetricians and Gynaecologists of Canada.

Blood Pressure Determination↗
PubMed1997

Developmental pathways of dendritic cells in vivo: distinct function, phenotype, and localization of dendritic cell subsets in FLT3 ligand-treated mice.

We have recently shown that Flt3 ligand administration dramatically increases dendritic cell (DC) numbers in various mouse tissues. This has enabled the identification of distinct mature DC subpopulations. These have been designated: population C (CD11c(bright) CD11b(bright)), D (CD11c(bright) CD11b(dull)), and E (CD11c(bright) CD11b(negative)) This report demonstrates that the mature DC subsets (C, D, and E) from Flt3 ligand-treated mice differ with respect to phenotype, geographic localization, and function. The myeloid Ags CD11b, F4/80, and Ly-6C are predominantly expressed by population C, but not D or E. In addition, a subset of population C-type DC expresses 33D1 and CD4. In contrast, DC within population D and E selectively express the lymphoid-related DC markers CD8alpha, DEC 205, CD1d, as well as CD23, elevated levels of CD117 (c-kit), CD24 (HSA), CD13, and CD54. Immunohistology indicates that the different DC subsets reside in distinct microenvironments, with populations D and E residing in the T cell areas of the white pulp, while DC within population C localize in the marginal zones. These DC subpopulations showed different capacities to phagocytose FITC-zymosan and to secrete IL-12 upon stimulation with Staphylococcus aureus cowan I strain + IFN-gamma + granulocyte-macrophage-CSF. Population C-type DC were more phagocytic but secreted little inducible IL-12 while population D- and E-type DC showed poor phagocytic capacity and secreted considerably higher levels of IL-12. These results underscore the importance of viewing DC development in vivo, as an interplay between distinct lineages and a maturational dependence on specific microenvironmental signals.

Animals↗
PubMed1997

The angiotensin-II receptor antagonist, losartan, inhibits LDL lipid peroxidation and atherosclerosis in apolipoprotein E-deficient mice.

The potential antiatherogenic actions of the angiotensin II receptor antagonist, losartan were investigated in apolipoprotein (apo) E deficient mice, an animal model with severe hypercholesterolemia and extensive atherosclerosis. In these animals accelerated atherosclerosis is associated with increased lipid peroxidation which may play a crucial role in the build up of the atherosclerotic lesions. Administration of losartan (25mg/kg/d) to the apo E deficient mice for a 3-month period increased the plasma renin activity 3.5-fold compared to the placebo group. Losartan increased the resistance of LDL to CuSO4-induced oxidative modification as shown by a significant reduction in the LDL content of malondialdehyde by 55% compared to placebo, as well as by the prolongation of the lag time required for LDL oxidation, from 60 min in the placebo-treated mice to more than 140 min in the losartan-treated mice. Losartan reduced significantly the mean atherosclerotic lesion area by 80% compared to the placebo group. We conclude that losartan inhibits LDL lipid peroxidation in the apo E deficient mice and this effect may have an important role in the attenuation of the accelerated atherosclerosis.

Angiotensin Receptor Antagonists↗
PubMed1997

Toward development of a non-viral gene therapeutic.

Gene therapy is an emerging field that has reached the early clinical stages of development for some disease states. However, the demonstration of safety in animals and the introduction of gene-based formulations in humans hides the fact that numerous developmental and basic research questions remain. This article highlights progress and emerging issues in the area of liposome-based non-viral gene delivery. The colloidal nature of these formulations render them complicated at the physico-chemical and biological levels. Instrumentation and methodologies need to be developed to better understand the subtleties of plasmid DNA, complexing agents, delivery mode and the route of entry into the cell and the nucleus. Major hurdles to entry include membrane binding, endosomal release, nuclear uptake and decomplexation. Each 'stage' is poorly understood but numerous approaches are being directed to increase cellular delivery. These research efforts, coupled with sensible formulation research and a multi-disciplinary, long-term effort, are necessary for success.

Journal Article↗
PubMed1997

Removal of polymerase-produced mutant sequences from PCR products.

Heteroduplex DNA lacking d(GATC) methylation is subject to mismatch-provoked double-strand cleavage at d(GATC) sites in a reaction dependent on MutH, MutL, MutS, and ATP. We have exploited this reaction to develop a method for removal of polymerase-produced mutant sequences that arise during sequence amplification by PCR. After denaturation and reannealing, the PCR product pool is subjected to MutH, MutL, and MutS mismatch repair proteins under double-strand cleavage conditions, followed by isolation of uncleaved product by size selection. Use of an Escherichia coli lac forward mutation assay has shown that this procedure reduces the incidence of polymerase-induced mutant sequences by an order of magnitude. Twenty mutants that originated from three independent PCR amplification reactions and survived MutHLS treatment all were found to contain an infrequently occurring A.T --> T.A transversion mutation at a unique position within the product. By contrast, the majority of mutations in untreated PCR products were transitions occurring throughout the amplified region, although frameshifts and transversions also were observed. The MutHLS method thus can be used to effectively remove the majority of mutant sequences produced by polymerase errors during PCR amplification.

Escherichia coli↗
PubMed1997

Rat basophilic leukaemia (RBL) cells overexpressing Rab3a have a reversible block in antigen-stimulated exocytosis.

The rat basophilic leukaemia (RBL) cell line has been widely used as a convenient model system to study regulated secretion in mast cells. Activation of these cells through the high-affinity receptor for IgE (Fcepsilon-RI) results in degranulation and the extracellular release of mediators. There is good evidence of a role for GTPases in mast cell degranulation, and a number of studies with peptides derived from the Rab3a effector domain have suggested that Rab3a may function in this process. However, in neuroendocrine cells, overexpression of Rab3a can act as a negative regulator of stimulated exocytosis [Holz, Brondyk, Senter, Kuizon and Macara (1994) J. Biol. Chem. 269, 10229-10234; Johanes, Lledo, Roa, Vincent, Henry and Darchen (1994) EMBO J. 13, 2029-2037]. In order to study the function of Rab3a in RBL degranulation, we have generated clones of RBL cells stably expressing Rab3a, and show that in these haematopoietic cells Rab3a can also function as a negative regulator of exocytosis. Overexpression of a mutant form of Rab3a (Asn-135 to Ile), which is predicted to be predominantly GTP-bound, also inhibited degranulation. However, overexpression of a mutant form of Rab3a that was truncated at the C-terminus to remove the sites for geranylgeranylation failed to inhibit degranulation. The effect of Rab3a is specific to secretion, and we observe no effect of Rab3a on receptor-mediated endocytosis. The Rab3a-induced block in degranulation can be bypassed by stimulation of streptolysin-O-permeabilized cells with guanosine 5'-[gamma-thio]triphosphate. We conclude from these studies that Rab3a is implicated in an early stage of granule targeting, whereas fusion of granules with the plasma membrane is regulated by a distinct downstream GTP-binding protein or proteins.

Animals↗
PubMed1997

Early-response gene signalling is induced by angiogenic oligosaccharides of hyaluronan in endothelial cells. Inhibition by non-angiogenic, high-molecular-weight hyaluronan.

The degradation products of hyaluronan are known to stimulate endothelial-cell proliferation and to promote neovascularization associated with angiogenesis, whilst native high-molecular-weight hyaluronan is inhibitory to these processes. To investigate the cellular signalling pathways coupled to hyaluronan-induced responses in angiogenesis, we have analyzed early-response gene expression in vitro, in cultured bovine aortic endothelial cells. Angiogenic oligosaccharides of hyaluronan induced rapid transient up-regulation of the immediate early genes c-fos, c-jun, jun-B, Krox-20 and Krox-24. In contrast, native hyaluronan when used alone failed to elicit a significant change in expression of any of the genes tested, and when used in combination with angiogenic oligosaccharides of hyaluronan, gave a dose-dependent inhibition of induced gene expression. However, prior addition of angiogenic hyaluronan, as little as one minute before addition of high-molecular-weight hyaluronan, abrogated this inhibition, suggesting that positive or negative responses associated with hyaluronan signalling are integrated at a very early stage following receptor binding. Conversely, prior addition of high-molecular-weight hyaluronan led to an irreversible block in gene expression and proliferative response. These data are consistent with native hyaluronan antagonizing the angiogenic response in part by blocking a signalling cascade at or immediately following ligand-receptor interaction. Finally, we demonstrated that chronic exposure to oligosaccharides of hyaluronan is essential for cell proliferation, indicating that short-term immediate early-gene signalling is insufficient to elicit the proliferation of endothelial cells.

Animals↗
PubMed1997

Streptococcus pyogenes type 5 M protein is an antigen, not a superantigen, for human T cells.

M proteins are coiled-coil dimers expressed on group A streptococcal cell surfaces. They have an important role in host antistreptococcal immunity and in poststreptococcal autoimmune sequelae. Controversy has arisen regarding whether type 5 M proteins are superantigenic for human T cells. To investigate this, we have produced and tested M5 in the form of two novel recombinant proteins. We found no evidence of superantigenicity using either recombinant whole M5 protein (rM5) or recombinant pep M5 protein (rpepM5) to activate peripheral blood mononuclear cells (PBMC) from healthy adult volunteers. Short-term, rM5-specific T-cell lines from different subjects were uniformly self-APC restricted and showed no consistent pattern of TCR V beta usage. A synthetic peptide of M5 residues 217-237 was found to contain epitope(s) recognized by some rM5-specific human T cells. PBMC responses to rM5 and rpepM5 in 3- and 7-day proliferation assays were characteristic of antigenic rather than superantigenic stimulation. We conclude that type 5 M protein activates human T cells as a conventional antigen.

Adult↗
PubMed1997

The efficiency of CD4 recruitment to ligand-engaged TCR controls the agonist/partial agonist properties of peptide-MHC molecule ligands.

One hypothesis seeking to explain the signaling and biological properties of T cell receptor for antigen (TCR) partial agonists and antagonists is the coreceptor density/kinetic model, which proposes that the pharmacologic behavior of a TCR ligand is largely determined by the relative rates of (a) dissociation ofligand from an engaged TCR and (b) recruitment oflck-linked coreceptors to this ligand-engaged receptor. Using several approaches to prevent or reduce the association of CD4 with occupied TCR, we demonstrate that consistent with this hypothesis, the biological and biochemical consequence of limiting this interaction is to convert typical agonists into partial agonist stimuli. Thus, adding anti-CD4 antibody to T cells recognizing a wild-type peptide-MHC class II ligand leads to disproportionate inhibition of interleukin-2 (IL-2) relative to IL-3 production, the same pattern seen using a TCR partial agonist/antagonist. In addition, T cells exposed to wild-type ligand in the presence of anti-CD4 antibodies show a pattern of TCR signaling resembling that seen using partial agonists, with predominant accumulation of the p21 tyrosine-phosphorylated form of TCR-zeta, reduced tyrosine phosphorylation of CD3epsilon, and no detectable phosphorylation of ZAP-70. Similar results are obtained when the wild-type ligand is presented by mutant class II MHC molecules unable to bind CD4. Likewise, antibody coligation of CD3 and CD4 results in an agonist-like phosphorylation pattern, whereas bivalent engagement of CD3 alone gives a partial agonist-like pattern. Finally, in accord with data showing that partial agonists often induce T cell anergy, CD4 blockade during antigen exposure renders cloned T cells unable to produce IL-2 upon restimulation. These results demonstrate that the biochemical and functional responses to variant TCR ligands with partial agonist properties can be largely reproduced by inhibiting recruitment of CD4 to a TCR binding a wild-type ligand, consistent with the idea that the relative rates of TCR-ligand disengagement and of association of engaged TCR with CD4 may play a key role in determining the pharmacologic properties of peptide-MHC molecule ligands. Beyond this insight into signaling through the TCR, these results have implications for models of thymocyte selection and the use of anti-coreceptor antibodies in vivo for the establishment ofimmunological tolerance.

Amino Acid Sequence↗
PubMed1997

Sucralfate for radiation mucositis: results of a double-blind randomized trial.

PURPOSE: To determine if addition of the ulcer-coating polysaccharide sucralfate could improve symptomatic relief of radiation mucositis over a popular combination of antacid, diphenhydramine, and viscous lidocaine alone. METHODS AND MATERIALS: A double-blind study was conducted in which nurses and pharmacists coded patient groups and distributed medication in a manner blinded to both the patients and physicians. Eligible patients receiving radiation to the head and neck and/or chest sites that included the esophagus were randomized to a standard combination of antacid, diphenhydramine, and viscous lidocaine vs. the same solution plus sucralfate. Eligible patients were those receiving >40 Gy at 1.8 Gy/fraction, one fraction/day, five fractions/week. Participating patients were stratified between chest, small field head and neck, and large field head and neck. The patients subjective evaluation of throat soreness and relief with medication was elicited as well as physician observations and smears for Candidiasis screening. Medication was prescribed when the patient became symptomatic and concomitant use of other locally effective nonstudy agents was not allowed. The ability to eat various consistency of foods was graded 0-5, with 5 indicating no compromise of ability to ingest a food compared to baseline. Statistical analysis included mean + SD for food and soreness scores, paired t-test, and two-way analyses of variance to evaluate effects of site and treatment group on the changes in scores. RESULTS: Over 2 years, 111 patients were entered. Because some withdrew and others did not require medication, results are presented for evaluable patients in each category. Mild adverse effects from the medication solution (usually mouth discomfort) were reported by <10% of patients in each treatment group among 106 patients evaluable for toxicity. There was a comparable incidence of mild-moderate mucositis for the two treatment groups. Severe mucositis was noted in two patients of the standard medication group and none among patients receiving sucralfate. The groups were comparable for indicators including degree of soreness, dietary changes, and objective measures or mucosal irritation or infection. For the head and neck patients there was a significant worsening in soreness and in the ability to eat in both treatment groups, whereas patients treated to the chest had less nutritional change. Multivariate analysis including control for confounding factors did not detect treatment effects for any of the response measures. No patient had occult fungal infection detected by oral pathology evaluation of routine mucosal scrapings. CONCLUSIONS: A trend (that was not statistically significant) of less severe radiation mucositis was noted for patients receiving sucralfate in addition to the combination of viscous lidocaine, diphenhydramine, and antacid for nonulcerative radiation mucositis.

Anti-Ulcer Agents↗
PubMed1997

Ezrin is a cyclic AMP-dependent protein kinase anchoring protein.

cAMP-dependent protein kinase (A-kinase) anchoring proteins (AKAPs) are responsible for the subcellular sequestration of the type II A-kinase. Previously, we identified a 78 kDa AKAP which was enriched in gastric parietal cells. We have now purified the 78 kDa AKAP to homogeneity from gastric fundic mucosal supernates using type II A-kinase regulatory subunit (RII) affinity chromatography. The purified 78 kDa AKAP was recognized by monoclonal antibodies against ezrin, the canalicular actin-associated protein. Recombinant ezrin produced in either Sf9 cells or bacteria also bound RII. Recombinant radixin and moesin, ezrin-related proteins, also bound RII in blot overlay. Analysis of recombinant truncations of ezrin mapped the RII binding site to a region between amino acids 373 and 439. This region contained a 14-amino-acid amphipathic alpha-helical putative RII binding region. A synthetic peptide containing the amphipathic helical region (ezrin409-438) blocked RII binding to ezrin, but a peptide with a leucine to proline substitution at amino acid 421 failed to inhibit RII binding. In mouse fundic mucosa, RII immunoreactivity redistributed from a predominantly cytosolic location in resting parietal cells, to a canalicular pattern in mucosa from animals stimulated with gastrin. These results demonstrate that ezrin is a major AKAP in gastric parietal cells and may function to tether type II A-kinase to a region near the secretory canaliculus.

Amino Acid Sequence↗
PubMed1997

Analysis of carbohydrate deficient transferrin by capillary zone electrophoresis.

We report a capillary zone electrophoresis method to separate the various sialylated isoforms of transferrin. The separation is carried out under nondenaturing conditions and at basic pH. Under these conditions, transferrin exhibits two major and three minor peaks. Plasma samples from a population consuming varying amounts of alcohol at different intervals were studied. A cut-off value of 3% carbohydrate deficient transferrin (CDT: disialo, monosialo, and asialo transferrin), results in a clinical sensitivity of 88% in a population consuming at least 70 g/day alcohol for a minimum of two weeks. The sensitivity dropped significantly in a population consuming less than 70 g/day. This confirms previous reports of CDT as a specific marker for significant and chronic use of alcohol. Capillary electrophoresis offers an alternative method with respect to analysis time and throughput in the clinical laboratory.

Animals↗
PubMed1997

Group hydrotherapy versus group land-based treatment for chronic low back pain.

Sixty subjects with chronic low back pain (LBP) were sequentially allocated to either hydrotherapy treatment or land treatment groups in order of presentation. Subjects acted as their own controls for a period of three weeks, after which they attended their respective group sessions twice weekly for six weeks. Twenty-eight subjects from each group attended all treatment and assessment sessions. Results indicated that both groups improved significantly in functional ability and in decreasing pain levels. Thoracolumbar mobility did not improve significantly in either group. Overall there was no significant difference found between the two types of treatment, although results should be viewed as encouraging for the advocates of both hydrotherapy and land-based exercise as a treatment for chronic LBP.

Activities of Daily Living↗
PubMed1997

Community mental health program efficiency.

Six urban community mental health centers participated in a capitated payment system designed for persons with severe mental illness who frequently used the state hospital. The centers and their funding agency agreed that a chief outcome measure would be the length of time clients were able to remain enrolled in the outpatient program. Clients of the six agencies were quite similar to one another. During the 18-month study length of enrollment in the outpatient program did not vary among the agencies whereas agency expenditures varied by more than three-fold. Although some of this expenditure variation was due to economies of scale at larger agencies, different practice styles also contributed to variable efficiency.

Adult↗
PubMed1997

Nutritional and economic benefits of Leucaena and Gliricidia as feed supplements for small ruminants in humid West Africa.

Considering leguminous trees Leucaena and Gliricidia as good sources of quality food, on-station and on-farm studies were conducted in the humid zone of West Africa to establish animal responses to levels, times and forms of browse supplementation, to develop alternative feeding strategies for utilising limited feed supply and to assess the economic benefits of feed supplements as against the use of tree foliage as mulch for crop production. Results indicate that at any level of supplement, sheep grew twice as fast as goats. The main benefits of supplementation came through increased growth and survival. Form and level of supplementation had significant effect on intake. Economic analyses showed that crop response to mulching was the principal competing determinant of whether the use of tree foliage as feed supplement was economic.

Africa, Western↗