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Biomedical subjects

P D Smith

Publications and source records attributed to P D Smith.

At least 19 recordsLinked to original sources
PubMed1992

Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa.

The mechanism by which Helicobacter pylori, a noninvasive bacterium, initiates chronic antral gastritis in humans is unknown. We now show that H. pylori releases products with chemotactic activity for monocytes and neutrophils. This chemotactic activity was inhibited by antisera to either H. pylori whole bacteria or H. pylori-derived urease. Moreover, surface proteins extracted from H. pylori and purified H. pylori urease (a major component of the surface proteins) exhibited dose-dependent, antibody-inhibitable chemotactic activity. In addition, a synthetic 20-amino acid peptide from the NH2-terminal portion of the 61-kD subunit, but not the 30-kD subunit, of urease exhibited chemotactic activity for monocytes and neutrophils, localizing the chemotactic activity, at least in part, to the NH2 terminus of the 61-kD subunit of urease. The ability of leukocytes to chemotax to H. pylori surface proteins despite formyl-methionyl-leucyl-phenylalanine (FMLP) receptor saturation, selective inhibition of FMLP-mediated chemotaxis, or preincubation of the surface proteins with antiserum to FMLP indicated that the chemotaxis was not FMLP mediated. Finally, we identified H. pylori surface proteins and urease in the lamina propria of gastric antra from patients with H. pylori-associated gastritis but not from uninfected subjects. These findings suggest that H. pylori gastritis is initiated by mucosal absorption of urease, which expresses chemotactic activity for leukocytes by a mechanism not involving N-formylated oligopeptides.

Antibodies, Bacterial↗
PubMed1992

NIH conference. Gastrointestinal infections in AIDS.

As the largest lymphoid organ in the body, the gastrointestinal tract is a potential reservoir for human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS), and it is an important site for HIV-induced immunodeficiency. The resulting defects in cellular and humoral defense mechanisms predispose the gastrointestinal tract to a spectrum of viral, fungal, bacterial, and protozoan pathogens that cause relentless morbidity and, in some cases, death. With a thorough diagnostic evaluation, physicians can identify one or more of these pathogens in a majority of patients with AIDS who have gastrointestinal symptoms. The identification of enteric pathogens in patients with AIDS is important because an increasing array of therapeutic regimens is becoming available to treat many of these infections.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Alleles of the rat T-cell receptor beta chain gene complex.

Inbred rat strains provide a rich source of genetic diversity in immunologically relevant genes. We have characterized the alleles of one of these genes, encoding the rat T-cell receptor C beta 1 chain, by Southern blots and nucleic acid sequencing. The Cb1 gene segments from DA and LEW rats display complex allotypic variation: both coding and noncoding regions contain multiple nucleotide substitutions. In addition, there is a polymorphic insertion of a rat repetitive LINE element 3' to the coding region. The Cb1 alleles are one part of larger Tcrb haplotypes, containing V beta, D beta, and J beta elements; complete Cb1 genomic nucleotide sequences, and a partial list of the strain distribution of the two alleles, are described in this report.

Alleles↗
PubMed1992

Amino acid composition of dentine in permanent human teeth.

Dentine of permanent mandibular incisors from nine individuals was hydrolysed and the amino acid composition determined by ion-exchange chromatography against a standard calibrant of 41 amino acids. Nineteen amino acids were detected, including small quantities of 1-methylhistidine and asparagine, two amino acids whose existence had apparently not been recorded before in human dentine. The total content of hydroxylysine plus lysine varied between 2.6 and 3.3 residues per 100 (SD, 0.74) in different teeth, which therefore did not support previous studies that had proposed a constant total value. This and other quantifiable differences between present and previous findings may be the result of the different methods and the influence of dietary and other regional factors on dentinogenesis.

Amino Acids↗
PubMed1992

Pulsed laser and thermal ablation of atherosclerotic plaque: morphometrically defined surface thrombogenicity in studies using an annular perfusion chamber.

Although clinical trials using laser and thermal angioplasty devices have been underway, the effects of pulsed laser and thermal ablation of atherosclerotic plaque on surface thrombogenicity are poorly understood. This study examined the changes in platelet adherence and thrombus formation on freshly harvested atherosclerotic aorta segments from Watanabe-heritable hyperlipidemic rabbits after ablation by two pulsed laser sources (308-nm xenon chloride excimer and 2,940-nm erbium:yttrium-aluminum-garnet [YAG] lasers) and a prototype catalytic hot-tip catheter. Specimens were placed in a modified Baumgartner annular chamber and perfused with citrated whole human blood, followed by quantitative morphometric analysis to determine the percent surface coverage by adherent platelets and thrombi in the treated and contiguous control areas. Pulsed excimer laser ablation of plaque did not change platelet adherence or thrombus formation in the treated versus control zones. However, photothermal plaque ablation with a pulsed erbium:YAG laser resulted in a 67% reduction in platelet adherence, compared with levels in control areas (from 16.7 +/- 2.2% to 5.5 +/- 1.8%; p less than 0.005). Similarly, after plaque ablation using a catalytic thermal angioplasty device, there was a 74% reduction in platelet adherence (from 29.2 +/- 5.1% to 7.7 +/- 1.6%; p less than 0.005) and a virtual absence of platelet thrombi (from 8.6 +/- 2.3% to 0.03 +/- 0.03%; p less than 0.005). This reduced surface thrombogenicity after plaque ablation with either an erbium:YAG laser or a catalytic hot-tip catheter suggests that thermal modifications in the arterial surface ultrastructure or thermal denaturation of surface proteins, or both, may be responsible for reduced platelet adherence. These in vitro findings indicate that controlled thermal plaque ablation by catheter-based techniques may elicit endovascular responses that can reduce early thrombus formation during angioplasty procedures.

Angioplasty, Laser↗
PubMed1992

Leg ulceration in venous disease.

We have given a brief summary of the scale of the problem caused by venous ulceration in the UK, and have then reviewed the various theories of causation, including a historical survey, and presented the evidence for and against the two main current theories of fibrin cuffs and white cell trapping. We also outline previous hypotheses of the aetiology of venous ulceration, including arteriovenous microanastomoses, stasis and oedema. The contribution of superficial venous incompetence in the pathogenesis of ulceration is also examined.

Arteriovenous Fistula↗
PubMed1992

Cytomegalovirus induction of tumor necrosis factor-alpha by human monocytes and mucosal macrophages.

Cytomegalovirus (CMV) is a major cause of inflammatory organ disease in immunosuppressed persons. To elucidate the mechanisms of CMV-induced inflammation, we investigated whether tumor necrosis factor-alpha (TNF-alpha) was involved in the pathogenesis of CMV colitis in patients with AIDS. In in situ hybridization experiments, TNF-alpha mRNA was shown to be abundantly present in colonic mucosa from AIDS patients with CMV colitis but not in colonic mucosa from control (AIDS and normal) subjects. The TNF-alpha transcripts, identified in macrophage-like cells containing cytomegalic inclusions, were positively associated with CMV, but not HIV-1, within the mucosa. In in vitro experiments, a patient-derived isolate of CMV, but not HIV-1Ba-L, induced human monocytes to express TNF-alpha mRNA and to release increased levels of TNF-alpha peptide following stimulation. CMV induction of TNF-alpha may play a critical role in CMV-induced inflammation and, since TNF-alpha upregulates expression of HIV-1, offers a mechanism by which CMV could serve as a co-factor for HIV-1 expression without both viruses infecting the same cell.

Colitis↗
PubMed1992

Immunopathophysiology of gastrointestinal disease in HIV infection.

In summary, gastrointestinal manifestations are a major complication of HIV infection. These manifestations present clinically as early, intermediate, and late-phase enteric illness due to HIV itself or the acquisition of opportunistic infections and neoplasms. HIV-induced defects in lymphocytes and mononuclear phagocytes, which circulate through and populate the gastrointestinal mucosa, and a sequence of HIV-dependent alterations in mucosal integrity represent the fundamental immunopathophysiologic basis for these clinical manifestations.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Medial calf perforators in venous disease: the significance of outward flow.

The role of medial calf perforators in the initiation or promotion of venous disease is incompletely understood. The purpose of this study was to define the direction of blood flow in the perforating vein of the calf in normal limbs and in those limbs of patients with venous disease under defined laboratory conditions. Both lower limbs of 57 patients, (32 women and 25 men, median age, 56 years; range, 40 to 62 years) were examined by duplex ultrasonography. In 10 patients no clinical or duplex evidence existed of venous disease. In 60 legs we found evidence of superficial venous insufficiency, complicated by lipodermatosclerosis in 29. In 15 limbs we found deep venous insufficiency. Finally, in 19 limbs no evidence existed of venous disease, but venous reflux was present in the contralateral limb. The direction of blood flow in the medial calf perforators was assessed during compression of the foot and calf, by a cuff that inflated to 60 mm Hg. Blood flow was also assessed during deflation of the cuff. We found that the direction of blood flow within medial calf perforators can be both inward or outward, even in limbs without evidence of venous disease. Outward flow could be demonstrated in 21% of perforators in normal limbs. Flow on release of distal compression occurred in 33% to 44% of perforators in limbs with evidence of venous disease but in none of the perforators in limbs without evidence of venous disease. We found that flow, during the relaxation phase, within medial calf perforators was associated with venous disease elsewhere in the limb.

Adult↗
PubMed1991

Inhibitors of reactive oxygen intermediates suppress bacterial cell wall-induced arthritis.

Peritoneal and peripheral blood monocyte-macrophages from inbred Lewis (LEW) rats generate higher levels of reactive oxygen intermediates (ROI) in response to group A streptococcal cell walls (SCW) than do similar populations of cells from histocompatible Fischer rats. This differential sensitivity of the phagocytes to SCW is reflected in differences in susceptibility of the two strains to the development of arthritis in response to SCW. After systemic administration of the SCW, LEW rats develop acute and chronic erosive polyarthritis, whereas the Fischer rats are arthritis resistant. Inasmuch as these data suggested that the SCW-induced release of inflammatory cell products such as ROI might be an important contributory factor in the pathogenesis of arthritis in the LEW rats, the animals were injected with SCW and treated with ROI inhibitors. A single intraarticular injection of superoxide dismutase or catalase significantly reduced the SCW-induced inflammatory response and evolution of erosive arthritis in the treated animals (articular index 3.6 +/- 0.36 for SCW only vs 1.4 +/- 0.3 for SCW + SOD; p less than 0.001; n = 6). These data indicate that ROI play a pivotal role in synovitis and, furthermore, that suppression of these inflammatory mediators modulates both acute and chronic SCW-induced inflammation of the joint.

Animals↗
PubMed1991

Humoral recall responses in HIV infection. Levels, specificity, and affinity of antigen-specific IgG.

To evaluate the integrity of humoral immunologic memory among persons with HIV infection, we measured the levels, specificity, and functional affinity of circulating antibodies to vaccine-related recall Ag, tetanus (TT) and diphtheria toxoids (DT), and to naturally acquired measles virus, in sera from 17 HIV-seronegative control subjects, 17 asymptomatic HIV-seropositive patients, and 10 patients with AIDS. Preimmunization levels of TT- and measles-specific IgG were similar in all groups, although DT-specific IgG was lower in AIDS patients. Four wk after immunization with TT3 and DT, all groups showed significantly increased specific antibody levels (p less than 0.02). The asymptomatic HIV+ patients and control subjects achieved similar peak serum levels of TT-specific IgG (102 +/- 32 and 169 +/- 36 micrograms/ml, respectively). In contrast, the AIDS patients had lower peak values of both TT- and DT- specific IgG (p less than 0.05). Peak levels correlated directly with the number of CD4+ T cells (p less than 0.05). However, 80 to 100% of all participants tested, independent of HIV status, showed higher levels of TT- and DT-specific IgG 6 mo after immunization compared with preimmunization levels. The antitoxoid antibodies were specific as they did not cross-react with other Ag in competitive inhibition experiments. In addition, all groups exhibited antibodies to TT and DT both pre- and postimmunization of equivalent functional affinity (avidity) (Kd = 10(-10)-10(-11) mol/liter). We conclude that, in contrast to the profoundly depressed humoral responses to new Ag, persons with asymptomatic HIV infection retain humoral immunity to certain recall Ag. These levels of specific IgG to three recall Ag are not proportional to elevated levels of total serum IgG in HIV-infected patients. In addition, many patients with HIV respond to challenge with recall Ag by producing significant amounts of high affinity IgG that may persist over time.

Antibody Affinity↗
PubMed1991

Microwave cyclodestruction for glaucoma in a rabbit model.

Microwave thermotherapy was used to treat experimentally induced glaucoma. Microwave-induced cyclodestruction was successful in reducing intraocular pressure in all treated glaucomatous eyes for 4 weeks. Two additional glaucomatous eyes were left untreated to serve as controls, and were noted to have persistently elevated intraocular pressures. Six additional eyes were then subjected to an equivalent treatment (50 degrees C in five 1-minute applications), which resulted in approximately 180 degrees of heat treatment just posterior to the corneoscleral limbus. These specimens were evaluated with light microscopy at baseline, 24 hours, and 7 days after treatment. Our clinical and histopathologic evaluations suggested that microwave thermotherapy (delivered under thermometry control) allowed for chorioretinal/ciliary body destruction that resulted in reductions of intraocular pressure in glaucomatous eyes.

Animals↗
PubMed1991

Technique of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. Phase I study.

Patients with disseminated intraperitoneal malignant neoplasms were given intra-abdominal photodynamic therapy. Patients received dihematoporphyrin ethers intravenously 48 to 72 hours before laparotomy at doses of 1.5 to 3.0 mg/kg. At operation, as much tumor as possible was resected. Red light (630 nm) was delivered to all peritoneal surfaces from an argon-pumped dye laser at doses ranging from 0.2 to 3.0 J/cm2 in an escalating fashion. Viscera and peritoneal surfaces were anatomically isolated and exposed to light for intervals calculated to deliver the prescribed energy. Light was delivered to mesentery and bowel by a flat-cut optical fiber, while other areas, including diaphragm, viscera, omental bursa, gutters, and pelvis, were delivered light through a diffusing wand. Twenty-three patients (13 with ovarian cancer, eight with sarcoma, and two with pseudomyxoma peritoneii) underwent photodynamic therapy. Five of eight patients cleared positive peritoneal cytologies after treatment. Six patients remained clinically free of disease for up to 18 months, and five patients had treatment-related complications. Intraperitoneal phototherapy is technically feasible and deserving of clinical evaluation.

Adrenal Gland Neoplasms↗
PubMed1991

Genetic differences in the T cell receptor alleles of LEW rats and their encephalomyelitis-resistant derivative, LER, and their impact on the inheritance of EAE resistance.

Experimental allergic encephalomyelitis (EAE) is an animal model for the human disease, multiple sclerosis. The LEW rat strain is very susceptible to induction of EAE, whereas the closely related, major histocompatibility complex (MHC)-identical, inbred strain LER is resistant. In this report, the two rat strains have been compared for differences at a number of immunologically relevant loci by restriction fragment length analysis and by nucleotide sequencing. A major difference between the two strains was discovered at the T cell receptor beta chain locus (TcR beta). Both variable (V beta 8) and constant (C beta 1) region elements of TcR beta showed allelic variation between LEW and LER. The known genetic influences in rat models of autoimmunity are currently limited to those encoded by the rat MHC, RT-1. In this study we report our characterization of the allelic differences in TcR beta chains between two rats which differ in their susceptibility to induced EAE, with the goal of understanding the role played by these allelic forms of TcR in the pathogenesis of EAE. The importance of the TcR beta allelic difference in resistance or susceptibility to EAE was assessed in a study of backcross rats scored for both EAE and for the novel LER TcR beta allele. We found that the TcR beta allele from the susceptible strain was present in three out of four susceptible rats, suggesting that it is an important, but not the only, genetic factor in EAE. Supporting this conclusion were the observations that 12 of 13 rats with homozygous LER-derived TCR beta alleles were resistant to EAE.

Alleles↗
PubMed1991

Adenovirus colitis in the acquired immunodeficiency syndrome.

Adenovirus was identified in colonic tissue by transmission electron microscopy or culture in 5 of 67 (7.4%) homosexual men seropositive for human immunodeficiency virus (51 with the acquired immunodeficiency syndrome) with diarrhea. Colonoscopy showed the mucosa to be normal in 3 cases and mildly inflamed in 2. Light microscopy showed foci of mucosal necrosis that contained chronic inflammatory cells and degenerating and necrotic epithelial cells with amphophilic nuclear inclusions. By transmission electron microscopy, hexagonal viral particles characteristic of adenovirus were identified within the inclusions. Only 1 patient was concomitantly infected by a second potential enteric pathogen. It was concluded that adenovirus, an uncommon enteric pathogen in immunocompetent adults, causes intestinal pathology and may be associated with diarrheal illness in persons with the acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1991

In vitro and in vivo analysis of somatic and germline mutability of 2-amino-N6-hydroxyadenine in Drosophila melanogaster.

Two complementary assays were employed to examine the mutagenicity of 2-amino-N6-hydroxyadenine (AHA) in Drosophila melanogaster. A lambda phage-based shuttle vector system, utilizing the supF transfer RNA gene of Escherichia coli, questioned the mutagenicity of AHA in established cell cultures derived from somatic tissue while the standard sex-linked recessive lethal assay measured mutational events in vivo. Consistent with studies in other systems, AHA appears strongly mutagenic when cells are exposed directly. Conversely, in vivo studies suggest that AHA is not a strong mutagen. Further studies will determine if AHA is weakly or not mutagenic in vivo and, using the supF system, what the nature of the mutational events at the molecular level is.

Adenine↗