PubMed Health⌕ Search

Biomedical subjects

P Scott

Publications and source records attributed to P Scott.

At least 19 recordsLinked to original sources
PubMed1996

Mice lacking the TNF receptor p55 fail to resolve lesions caused by infection with Leishmania major, but control parasite replication.

TNF is involved in host resistance to several pathogens. Recently it was found that mice lacking the p55 receptor for TNF (TNFRp55 -/-) do not control growth of the intracellular bacteria, Listeria monocytogenes and Mycobacterium tuberculosis. Here we report that the course of infection in TNFRp55 -/- mice with another intracellular pathogen, the protozoan parasite Leishmania major, is also quite different from normal mice. TNFRp55 -/- mice developed larger lesions than control mice and failed to resolve these lesions. However, they were able to eliminate parasites within the lesions. Histologic analysis indicated that at late stages lesions from TNFRp55 -/- mice appeared similar to lesions associated with cutaneous graft-vs-host disease. Both TNFRp55 -/- and control mice developed a normal Th1-type response during infection. We also found that IFN-gamma-activated macrophages from TNFRp55 -/- mice produced nitric oxide and killed L. major in vitro, which correlated with the ability of TNFRp55 -/- mice to eliminate the parasites in vivo. The production of nitric oxide by macrophages from TNFRp55 -/- mice required the presence of the parasites, however, since in their absence TNF could only synergize with IFN-gamma for nitric oxide production when added to normal, but not TNFRp55 -/-, macrophages. These results indicate that neither macrophage microbicidal activity nor nitric oxide production is absolutely dependent on the p55 receptor for TNF. Furthermore, they uncover a previously undefined role for TNFRp55 in resolution of parasite-induced inflammatory lesions.

Animals↗
PubMed1996

Fetal growth and cardiovascular risk factors in Jamaican schoolchildren.

OBJECTIVE: To determine relation between schoolchildren's blood pressure, glycated haemoglobin level, and cholesterol concentration and their anthropometry, socioeconomic status, and birth measurements. DESIGN: Retrospective cohort study. SETTING: 27 schools closest to University Hospital of the West Indies, Kingston, Jamaica. SUBJECTS: 2337 children aged 6-16 years who were born at university hospital were recruited, and their birth records were recovered: 1610 had suitable records, 659 had records including birth length, and 610 of these were prepubertal. MAIN OUTCOME MEASURES: Blood pressure, glycated haemoglobin level, serum cholesterol concentration, anthropometry at birth, current anthropometry, and socioeconomic status. RESULTS: Multiple regression analysis showed that children's systolic blood pressure was inversely related to their birth weight (P < 0.0001) and directly related to their current weight. Glycated haemoglobin level was higher in children with thicker triceps skinfolds (P < 0.001) and who had been shorter at birth (P = 0.003). Serum cholesterol concentration was inversely related to current height (P = 0.001) and to length at birth (P = 0.09) and was directly related to triceps skinfold thickness and higher socioeconomic status (P < 0.001). CONCLUSIONS: Blood pressure in childhood was inversely related to birth weight and directly to current weight. Glycaemic control and serum cholesterol were related to short length at birth, height deficit in childhood, and childhood obesity.

Adolescent↗
PubMed1996

Early IL-4 production does not predict susceptibility to Leishmania major.

Leishmania major in mice can be self-limiting or fatal, depending upon the inbred mouse strain. It is well established that the outcome of infection is dependent upon the Th cell subset that dominates after infection. This has led to intense study of the early events associated with infection, in order to better understand the factors that determine Th1/2 cell development. In the present report, we have analyzed the kinetics of IL-4 and IL-4 mRNA production in three mouse strains: BALB/c, C3H, and C57BL/6. We found that in the first week IL-4 is absent in the C3H mice, but present in the susceptible BALB/c and relatively resistant C57BL/6 mouse. These data indicate that the presence of IL-4 by itself does not determine whether the immune response will be dominated by Th2 cells, since C57BL/6 mice will eventually develop a Th1 response and heal. We suggest that the critical cytokine that determines susceptibility in experimental leishmaniasis is IL-12, rather than IL-4. Thus, in C3H mice IL-12 is evident soon after infection, and IL-4 responses are not observed. In C57BL/6 mice, IL-12 production is delayed, but once evident, the IL-4 response is ablated. Further, we show that addition of IL-12 can block early IL-4 production in BALB/c mice, and neutralization of IL-12 in C3H mice uncovers IL-4 production in response to L. major infection. Taken together, these data indicate that susceptibility to L. major, while possibly requiring IL-4, is not determined by the presence or absence of IL-4.

Animals↗
PubMed1996

Breast cancer angiogenesis--new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting.

Several groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGF beta 1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suramin in vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize. New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.

Angiogenesis Inducing Agents↗
PubMed1996

The research in semantics behind the OpenLabs coding system.

The OpenLabs coding system is an established, comprehensive, dynamic, flexible, open, multilingual European system which is tailored to meet the electronic data interchange (EDI) needs of medical laboratory users. The OpenLabs coding system, having many specific, independent classes and considerable flexibility, serves two different objectives: (i) unambiguous coding of entities present in messages used for EDI in clinical pathology; and (ii) interfacing with other nomenclatures and coding schemes to map concepts between different systems.

Classification↗
PubMed1996

Production of interleukin-10 in human fracture soft-tissue hematomas.

Clinical trauma suppresses immunity and experimental wound fluids have been shown to be immunosuppressive. To ascertain whether human wounds contain immunosuppressive cytokines, we assayed serum from fracture/soft-tissue hematomas (FSTH) of 22 patients for interleukin (IL)-10, transforming growth factor (TGF)-beta 1, and IL-4. Results were correlated to concurrent plasma cytokine concentrations in the same patients and in volunteer plasma. IL-10 was present in high concentration (1376 +/- 539 pg/mL) in all (7/7) FSTH < 24 h old. In FSTH > 24 h old, IL-10 was found intermittently and at lower levels (239 +/- 106 pg/mL, p = .011 vs. FSTH < 24 h old). IL-10 was rarely detectable in fracture patient plasma and never detectable (< 20 pg/mL) in normal plasma. No significant variations of IL-4 or total TGF-beta 1 were found in FSTH or plasma. FSTH are significant potential sources of IL-10 activity in trauma patients, which may be overlooked when only plasma is assayed. The potential for a relationship between cytokines found locally at sites of injury and clinical immune modulation in trauma requires further study.

Adult↗
PubMed1996

In vivo alterations in cytokine production following interleukin-12 (IL-12) and anti-IL-4 antibody treatment of CB6F1 mice with chronic cutaneous leishmaniasis.

CB6F1 mice exhibit intermediate resistance to infection with Leishmania major compared to their highly susceptible (BALB/c) and resistant (C57BL/6) parental strains. Unlike the C57BL/6 and BALB/c strains, which rapidly develop dominant Th1- or Th2-type responses, respectively, after infection, CB6F1 mice develop responses in which both Th1- and Th2-type cytokines are elevated through at least the first month of infection before Th1 responses become dominant as cutaneous lesions gradually heal. We have examined the effects of interleukin-12 (IL-12) and/or anti-IL-4 antibody treatment on cytokine production and the course of disease in CB6F1 mice with chronic L. major infections. When administered at 1 month of infection, IL-12 treatment led to a rapid decrease in mRNA levels for IL-4 within parasitized lesions and a moderate increase in gamma interferon (IFN-gamma) transcript levels in lymph nodes draining the site of infection. When IL-12 and anti-IL-4 antibody were administered together, they induced a marked decrease in IL-4 and transforming growth factor beta mRNA expression within lesions and a more dramatic increase in lymph node IFN-gamma transcript levels within 4 days after treatment. In comparison, similar treatment of infected BALB/c mice led to only a moderate increase in IFN-gamma transcripts but no decrease in mRNA levels for Th2-type cytokines. Treatment of CB6F1 mice with either IL-12 or anti-IL-4 antibody had no significant effect on the subsequent course of infection, whereas combined IL-12 plus anti-IL-4 treatment resulted in a decrease in lesion size and parasite numbers and a shift towards a Th1-dominant response. These results suggest that the immediate effects of cytokine or anti-cytokine therapy may be predictive of the long-term effects on the course of infection and that down-regulation of Th-2 type cytokines may be critical to the development of a Th1-dominant response.

Animals↗
PubMed1996

Sensory dysfunction associated with repetitive strain injuries of tendinitis and focal hand dystonia: a comparative study.

Repetitive strain injuries are reaching epidemic levels among workers who perform heavy schedules of rapid alternating movements (eg., computer programmers, data entry workers) or repetitive, sustained, coordinated movements (eg., editors, writers, salespeople). The purpose of this study was to determine if patients with repetitive strain injury demonstrated degraded sensory motor performance with their hands. Sixty age-matched adults were recruited, with 15 each assigned to a healthy adult control group, a healthy musician control group, a tendinitis group, or a focal dystonia group. Four sensory motor subtests from the Sensory Integration and Praxis Test were given to the subjects according to a standardized protocol. Using multiple one-factor analyses of variance in the parametric or nonparametric mode followed by post hoc pairwise testing, no significant differences were found between the healthy controls and the musician controls. On the test of kinesthesia, using the left hand, subjects with tendinitis performed significantly worse than controls and subjects with focal dystonia. Compared with controls, subjects with focal dystonia did significantly worse on graphesthesia and manual form perception (part 1 and part 2). Subjects with focal dystonia also did significantly worse than subjects with tendinitis when using the left hand on graphesthesia and manual form perception (part 2). When treating patients with repetitive strain injury, discriminative sensory motor skills must be carefully assessed and may need to be addressed as part of an effective treatment program.

Adult↗
PubMed1995

A second-generation YAC contig map of human chromosome 3.

A map of human chromosome 3 which integrates both physical and genetic data has been developed from the fusion of two large collections of markers and corresponding yeast artificial chromosome (YAC) clones. The map contains 972 megabase-sized YACs identified with 593 primary markers, of which 162 are highly polymorphic sequence-tagged sites (STSs) and form a closely spaced genetic linkage map; the remaining markers are hybridization-based. Chromosome 3 is now represented by 24 large YAC contigs whose order and orientation is largely known. The map generated by fusion of these hybridization- and STS-based datasets covers about 80% (over 160 megabases) of the chromosome and will provide the foundation necessary for rapid development of a detailed genetic understanding for this large autosome.

Chromosome Mapping↗
PubMed1995

IL-12 is required for natural killer cell activation and subsequent T helper 1 cell development in experimental leishmaniasis.

Infection of mice with the protozoan Leishmania major is an established in vivo model for the definition of factors that contribute to CD4+ T helper cell subset development. In the current study, a central role for IL-12 in directing both the innate and adaptive immune responses to L. major is established. We show that in vivo neutralization of IL-12 eliminates the NK cell cytotoxic response and IFN-gamma production by lymph node cells from 2-day L. major-infected C3H mice. Moreover, anti-IL-12 treatment abrogated Th1 cell development and enhanced Th2 cell development. Consistent with these results, elevated IL-12 p40 production and an increase in the number of IL-12 p40-producing cells were observed within 1 day of infection in C3H mice. Because BALB/c mice lack an early NK cell response or a Th1-type immune response after L. major infection, we investigated the possibility that they had a defect in the ability to produce IL-12. Surprisingly, L. major infection stimulated IL-12 p40 production in BALB/c mice early after infection. Further studies suggest that BALB/c mice are unable to generate an early IFN-gamma response because of the simultaneous production of IL-12 and cytokines that inhibit IL-12 function, such as TGF-beta, IL-4, and IL-10. Together, these data show that IL-12 regulates the immune response to L. major, but that even when IL-12 is induced, Th1 cell development may be interrupted by simultaneous production of inhibitory cytokines.

Animals↗
PubMed1995

Switch from a type 2 to a type 1 T helper cell response and cure of established Leishmania major infection in mice is induced by combined therapy with interleukin 12 and Pentostam.

Successful treatment in allergic, autoimmune, and infectious diseases often requires altering the nature of a detrimental immune response mediated by a particular CD4+ T helper (Th) cell subset. While several factors contribute to the development of CD4+ Th1 and Th2 cells, the requirements for switching an established response are not understood. Here we use infection with Leishmania major as a model to investigate those requirements. We report that treatment with interleukin 12 (IL-12), in combination with the antimony-based leishmanicidal drug Pentostam, induces healing in L. major-infected mice and that healing is associated with a switch from a Th2 to a Th1 response. The data suggest that decreasing antigen levels may be required for IL-12 to inhibit a Th2 response and enhance a Th1 response. These observations are important for treatment of nonhealing forms of human leishmaniasis and also demonstrate that in a chronic infectious disease an inappropriate Th2 response can be switched to an effective Th1 response.

Animals↗
PubMed1995

Presentation without proteolytic cleavage of endogenous precursors in the MHC class I antigen processing pathway.

The antigen presentation pathway yields peptide-MHC class I complexes on the antigen presenting cell (APC) surface for recognition by appropriate T-cells. Expression of the peptide-MHC complex on APC surface is preceded by several steps that include the generation of peptide fragments in the cytoplasm and their assembly with MHC molecules in the endoplasmic reticulum. It is now clear that MHC binding to optimally processed peptides in the endoplasmic reticulum is obligatory for their stable expression on the cell surface. However, whether a similar obligatory relationship exists between generation of processed peptides and their expression as peptide-MHC on APC surface is not known. Here, we addressed this question by analyzing the processing of ovalbumin (aa257-264, SL8) or influenza nucleoprotein (aa366-374, AM9) analogs. We examined the generation of naturally processed peptides using precursors that did, or did not, contain residues flanking the optimal MHC-binding peptides. By characterizing the peptides generated from these precursors by T-cell stimulation assays and by high performance liquid chromatography analysis, we established that intracellular assembly of peptide-MHC complexes and their expression on the cell surface can occur with peptides that lack flanking residues. The presentation of these endogenously synthesized perfect fit peptides demonstrates that the cleavage of precursor polypeptides is an independent step in the antigen presentation pathway.

ATP Binding Cassette Transporter, Subfamily B, Mem↗