Hypoxia enhances proliferation and generation of IP3 in pulmonary artery fibroblasts but not in those from the mesenteric circulation.
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Animals↗
Biomedical subjects
P Scott
Publications and source records attributed to P Scott.
The 1 alpha-hydroxylase locus is not linked to calcium stone formation or calciuric phenotypes in French-Canadian families.
Calcium urolithiasis is often associated with increased intestinal absorption and urine excretion of calcium, and has been suggested to result from increased vitamin D production. The role of the enzyme 1 alpha-hydroxylase, the rate-limiting step in active vitamin D production, was evaluated in 36 families, including 28 sibships with at least a pair of affected sibs, using qualitative and quantitative trait linkage analyses. Sibs with a verified calcium urolithiasis passage (n = 117) had higher 24-h calciuria (P = 0.03), oxaluria (P = 0.02), fasting and postcalcium loading urine calcium/creatinine (Ca/cr) ratios (P = 0.008 and P = 0.002, respectively), and serum 1,25(OH)2 vitamin D levels (P = 0.02) compared with nonstone-forming sibs (n = 120). Markers from a 9-centiMorgan interval encompassing the VDD1 locus on chromosome 12q13-14 (putative 1 alpha-hydroxylase) were analyzed in 28 sibships (146 sib pairs) of single and recurrent stone formers and in 14 sibships (65 sib pairs) with recurrent-only (> or = 3 episodes) stone-forming sibs. Two-point and multipoint analyses did not reveal excess in alleles shared among affected sibs at the VDD1 locus. Linkage of stone formation to the VDD1 locus could be excluded, respectively, with a lambda d of 2.0 (single and recurrent stone formers) and 3.25 (recurrent stone formers). Quantitative trait analyses revealed no evidence for linkage to 24-h calciuria and oxaluria, serum 1,25(OH)2 vitamin D levels, and Ca/cr ratios. This study shows absence of linkage of the putative 1 alpha-hydroxylase locus to calcium stone formation or to quantitative traits associated with idiopathic hypercalciuria. In addition, there is coaggregation of calciuric and oxaluric phenotypes with stone formation.
25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
Partnership for excellence in asthma care: evidence-based disease management.
Our experience with developing and implementing the outpatient component of an evidence-based disease management initiative has been a positive one. Involvement of respected practicing physicians in the planning phase, recommendation of evidence-based guidelines, and the supportive relationship between the hospital and participating practices have been essential to the successful launching of an asthma disease management program by a children's healthcare system. As the implementation phase continues to progress, we are preparing for the 6 month data collection stage, including outcomes measurement and practice pattern feedback. After 1 year of implementation we will analyze the data and report on the effects of the Partnership. We expect that physicians will continue to use the guidelines, and therefore sustain the improved health status of children with asthma. We will continue to invite pediatricians' participation in the Partnership so that more children in our community can benefit from high-quality cost-effective care that results in superior health outcomes.
Ambulatory Care↗
Setting up a risk management programme in a small, private birth unit.
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Adult↗
A day in the life of a school health nurse.
Registered nurses Daria Del Prete, Cheryl Schroeder, Clare Sullivan, and Patti Scott all work with the Vanderbilt University School of Nursing School Health Program. They work in two Nashville elementary schools that serve primarily inner-city children who face many barriers to health care. Many of these school-children have special needs, including complex medical, social, emotional, and learning problems that require a variety of nursing and case management services during the school day. Current staffing at the health centers allows for full-time nursing coverage at each site. Some days, a school nurse and nurse practitioner work together. Other days, there is just a nurse or nurse practitioner working alone. This article is a composite of a typical day at the Fall-Hamilton Elementary School with a school nurse (Cheryl Schroeder) and pediatric nurse practitioner (Patti Scott) working together. (All students names have been changed.)
Child↗
Interferon-gamma and interleukin 4 gene expression in cows infected with Mycobacterium paratuberculosis.
OBJECTIVE: To determine whether clinical progression of paratuberculosis in cattle was associated with alterations in cytokine gene expression in affected tissues. ANIMALS: 5 uninfected adult Holstein cows, 7 adult Holstein cows naturally infected with Mycobacterium paratuberculosis that did not have clinical signs of disease, and 4 adult Holstein cows naturally infected with M paratuberculosis that had progressive clinical signs of infection. PROCEDURE: Samples of ileum and cecal lymph nodes were obtained from each animal at the time of slaughter. A reverse transcriptase-competitive polymerase chain reaction assay was used to determine mRNA expression of interferon-gamma (IFN-gamma) and interleukin 4 in each sample. RESULTS: Interferon-gamma gene expression was significantly higher in ileum and cecal lymph node samples from subclinically infected cows than from clinically infected cows. CONCLUSIONS AND CLINICAL RELEVANCE: Progression of paratuberculosis to clinical stages is associated with reduced expression of IFN-gamma at site of infection. If immune response to M paratuberculosis can be manipulated so that IFN-gamma expression is increased, resistance to infection in cattle might be enhanced.
Animals↗
Leishmania major-infected C3H mice treated with anti-IL-12 mAb develop but do not maintain a Th2 response.
Leishmania major-infected C3H mice develop a Th1 response, but studies have shown that treatment of C3H mice with anti-IL-12 or anti-IFN-gamma mAb promotes the development of a Th2 response and susceptibility. However, we discovered that C3H mice treated for 3 wk with either anti-IL-12 or anti-IFN-gamma mAb eventually resolved their lesions and switched from a Th2 to a Th1 response. No significant differences in IL-4, IL-10, or IFN-gamma levels or in the parasite burden could be detected between BALB/c and anti-IL-12-treated C3H mice early after infection, suggesting that the instability of the Th2 response in anti-IL-12-treated C3H mice was unrelated to levels of these cytokines and parasite numbers. However, anti-IL-12-treated C3H mice continued to produce IL-12 in spite of exhibiting a Th2 phenotype. To determine whether the production of IL-12 was associated with the healing observed in these animals, we treated C3H mice with anti-IL-12 continuously for 12 wk. In contrast to C3H mice given anti-IL-12 for 3 wk, C3H mice continuously treated with anti-IL-12 failed to heal. These results suggest that qualitative differences in Th2-type responses may influence their stability and that the presence of IL-4, IL-10, or high parasite numbers is not sufficient to maintain a Th2 response in mice with certain genetic backgrounds.
Animals↗
Metacyclogenesis modulates the ability of Leishmania promastigotes to induce IL-12 production in human mononuclear cells.
Immunity against the intracellular protozoan Leishmania species is highly dependent on Th1 development. We have previously shown that IL-12 is a powerful and probably obligatory factor for Th1 cell generation and proliferation. We also observed that the experimental infection of C3H and BALB/c mice with Leishmania major is associated with IL-12 production in vivo. Now we demonstrate that metacyclic L. major promastigotes are poor inducers of IL-12 in vitro in fresh human PBMC and monocytes. In addition, we show that the ability of this pathogen to induce IL-12 and other cytokines is modulated by the metacyclogenic process, which had previously not been recognized. In contrast to the infective parasites (metacyclic promastigotes), the procyclic promastigotes collected at the logarithmic phase of the culture displayed a striking ability to induce IL-12, IFN-gamma, TNF-alpha, and IL-10. Despite this differential effect of procyclic and metacyclic parasites in terms of IL-12 induction, both stages were inhibitory for IL-12 production induced by Staphylococcus aureus. The ability of procyclic promastigotes and, to a much lesser extent, that of metacyclic promastigotes to induce IL-12 were enhanced by pretreatment of monocytes in a cytokine milieu containing IFN-gamma, IL-4, IL-13, or granulocyte-macrophage CSF or by neutralization of endogenous IL-10. Our results suggest the development of an evasion mechanism as the Leishmania promastigotes mature to infectious forms and the possibility of using Ags derived from procyclic promastigotes for immunization procedures.
Animals↗
Choline monooxygenase, an unusual iron-sulfur enzyme catalyzing the first step of glycine betaine synthesis in plants: prosthetic group characterization and cDNA cloning.
Plants synthesize the osmoprotectant glycine betaine via the route choline --> betaine aldehyde --> glycine betaine. In spinach, the first step is catalyzed by choline monooxygenase (CMO), a ferredoxin-dependent stromal enzyme that has been hypothesized to be an oligomer of identical subunits and to be an Fe-S protein. Analysis by HPLC and matrix-assisted laser desorption ionization MS confirmed that native CMO contains only one type of subunit (Mr 42,864). Determination of acid-labile sulfur and nonheme iron demonstrated that there is one [2Fe-2S] cluster per subunit, and EPR spectral data indicated that this cluster is of the Rieske type--i.e., coordinated by two Cys and two His ligands. A full-length CMO cDNA (1,622 bp) was cloned from spinach using a probe generated by PCR amplification for which the primers were based on internal peptide sequences. The ORF encoded a 440-amino acid polypeptide that included a 60-residue transit peptide. The deduced amino acid sequence included two Cys-His pairs spaced 16 residues apart, a motif characteristic of Rieske-type Fe-S proteins. Larger regions that included this motif also showed some sequence similarity (approximately 40%) to Rieske-type proteins, particularly bacterial oxygenases. Otherwise there was very little similarity between CMO and proteins from plants or other organisms. RNA and immunoblot analyses showed that the expression of CMO in leaves increased several-fold during salinization. We conclude that CMO is a stress-inducible representative of a new class of plant oxygenases.
Amino Acid Sequence↗
IL-12 as an adjuvant for cell-mediated immunity.
Recent studies have shown that IL-12 initiates the development of cell-mediated immunity following infection with certain infectious agents. This attribute of IL-12 makes it a potentially effective adjuvant for vaccines. This review summarizes our findings in the Leishmania system, outlining the role of endogenous IL-12 in resistance to L. major and the use of exogenous IL-12 in a vaccine against L. major, and also describes other examples in which IL-12 has been shown to be effective as an adjuvant at inducing protective immunity. The potential use of IL-12 as an adjuvant in therapeutic vaccines is also discussed.
Adjuvants, Immunologic↗
DNA replication asynchrony between the paternal and maternal alleles of imprinted genes does not straddle the R/G transition.
Imprinted autosomal loci apparently reside in very large chromosomal domains that exhibit asynchrony in replication of homologous alleles during the DNA synthesis phase. Replication asynchrony can be cytogenetically visualized by a replication-banding discordance between homologous bands of a given pair of chromosomal homologs. The replication time of a chromosomal band at high resolution can be determined by blocking DNA synthesis at the R/G-band transition and using replication banding. The R/G transition reflects the transition from early (R-) to late (G- and C-) band DNA replication. We studied discordance between two groups of homologous chromosomal bands: (a) four bands, 6q26-27, 11p13, 11p15.5 and 15q11.2-12, each containing at least one imprinted gene; and (b) nine bands containing no known imprinted genes. Fifty pairs of chromosomes were analyzed at high resolution after R/G transition blocking and late 5-bromo-2'-deoxyuridine incorporation. The rate of discordance was the same for bands containing imprinted genes and for control bands. Both homologous bands of a pair replicate either before or after the R/G transition and do not straddle the R/G transition. Repression associated with imprinting does not appear to involve late replication at the band level of resolution. Tissue-specific inactivation is associated with DNA methylation and late replication, whereas allele-specific inactivation is associated with DNA methylation but not with delayed or late replication.
Adult↗
Dust mite allergen avoidance in the treatment of hospitalized children with asthma.
BACKGROUND: Asthma is a leading cause of hospital admission in children. The majority of children with asthma are sensitized and exposed to inhalant allergens that may contribute to chronic airway inflammation. OBJECTIVE: To evaluate the practicality and effects of dust mite (D. farinae and D. pteronyssinus) allergen avoidance in homes of children hospitalized with acute asthma. METHODS: Children 5 to 18 years of age who were admitted with asthma to a suburban Atlanta hospital were randomly assigned, without knowledge of allergen sensitization or exposure in their houses, to active (n = 13) or placebo (n = 10) treatment group. Active treatment included encasing mattress, box springs, and pillows in allergen impermeable covers; weekly hot water wash of bed linens; replacement of bedroom carpet with polished flooring; and 3% tannic acid spray to living room carpet. Placebo treatment included permeable encasing for bedding, cold water wash, and water spray for carpet. Dust samples were analyzed for dust mite, cockroach, and cat allergens, while serum samples were analyzed for IgE antibodies to the same allergens. Outcome measures included daily peak expiratory flow rates, spirometry, methacholine inhalation challenge, and hospital readmission. RESULTS: Children in both groups were similar by demographics, sensitization, and exposure to dust mite allergen. Allergen levels fell > 3-fold in many active and placebo homes. Children in the active group had improved PEFR at 3 and 6 months after intervention (P < .04, P < .05, respectively). Six of seven children in the study who were sensitized and exposed to dust mite allergen demonstrated improved PEFR at 3 months when allergen levels fell in both bedding and bedroom floor. There was no difference in FEV1 or methacholine challenge, although a few children in either group could tolerate methacholine because of bronchial hyperreactivity. Six children (four active and two placebo) were readmitted to hospital during the study. CONCLUSION: Increases in PEFR were recorded among children in the active treatment group and also among sensitized patients whose dust mite allergens fell. These results support the hypothesis that avoidance can be effective even among children admitted to hospital. The study was complicated by insufficient numbers of mite-allergic children and poor compliance with diaries and the protocol. Recruitment from the hospital resulted in participants with more severe asthma than anticipated. The results also suggest that many of the patients in this group will continue to have exacerbations triggered by upper or lower respiratory tract infections.
Adolescent↗
Development of children's understanding of basic-subordinate inclusion relations.
Four studies focused on developmental differences in the representation of basic-subordinate inclusion relations. Tests of comprehension and production of category names, induction, and responses to direct questions pertaining to inclusion revealed a marked developmental gap between the production of subordinate category names and complete understanding of basic-subordinate inclusion relations. However, even 3-year-olds showed rudimentary knowledge of the asymmetry of inclusion. Discrepancies between children's performance on categorization tasks involving familiar and unfamiliar subordinate categories suggest that understanding of the logical nature of inclusion relations is constructed through the integration of categorical knowledge from familiar domains. Interactions among the knowledge base, pragmatic sensitivity, and information processing efficiency in the development of inclusion are discussed.
Age Factors↗
IL-12 eliminates the Th-2 dependent protective immune response of mice to larval Strongyloides stercoralis.
The goal of the present study was to determine if immune-mediated killing of S. stercoralis L3 in mice could be modulated by shifting from a Th-2 to a Th-1 type immune response. L3 killing in immunized mice was ablated in CD4+ T cell-depleted animals, but not in CD8+ T cell-depleted or beta 2-microglobulin-deficient mice. Treatment of immunized mice with IL-4 or IL-5 neutralizing MoAb significantly reduced the protective effects of vaccination against S. stercoralis, while protective immunity was unimpaired in IFN-gamma knockout mice. Recombinant IL-12 was administered to infected mice to switch the immune response from a Th-2 to a Th-1 type response. Protective immunity was ablated in immunized mice that received IL-12 therapy. Eosinophil numbers, eosinophil peroxidase levels, and parasite-specific IgG1 levels were lowered in IL-12 treated immunized animals, and parasite-specific IgG2a levels were increased in these animals. The data indicate that eosinophils are important as mediators of larval killing, and that the establishment of Th-2 type immunity results in killing of infective S. stercoralis L3, while a shift to Th-1 type immunity abrogates protective responses.
Animals↗
The role of IL-12 in regulation of T helper cell subsets in vivo. Lessons from experimental cutaneous leishmaniasis.
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Animals↗
Leishmania major metacyclogenesis modulates ability to induce IL-12.
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Animals↗
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↗