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Biomedical subjects

N Savage

Publications and source records attributed to N Savage.

At least 19 recordsLinked to original sources
PubMed2001

Syndromes with salivary dysfunction predispose to tooth wear: Case reports of congenital dysfunction of major salivary glands, Prader-Willi, congenital rubella, and Sjögren's syndromes.

Four cases-of congenital dysfunction of the major salivary glands as well as of Prader-Willi, congenital rubella, and Sjögren's syndromes-were identified in a series of 500 patients referred for excessive tooth wear. Although there was evidence of consumption of highly acidic drinks, some occlusal parafunction, and unacceptable toothbrushing habits, salivary dysfunction was the salient factor predisposing a patient to tooth wear in these syndromal cases. The 500 subjects have been characterized either as having medical conditions and medications that predispose them to xerostomia or lifestyles in which workplace- and sports-related dehydration lead to reduced salivary flow. Normal salivation, by buffering capacity, clearance by swallowing, pellicle formation, and capacity for remineralization of demineralized enamel, protects the teeth from extrinsic and intrinsic acids that initiate dental erosion. Thus, the syndromes, unrelated in many respects, underline the importance of normal salivation in the protection of teeth against tooth wear by erosion, attrition, and abrasion.

Adult↗
PubMed2000

Immunogenicity of Ty-VLP bearing a CD8(+) T cell epitope of the CS protein of P. yoelii: enhanced memory response by boosting with recombinant vaccinia virus.

We characterized the immunogenicity of the hybrid Ty-virus-like carrying the CD8(+) T cell epitope (SYVPSAEQI) of the circumsporozoite (CS) protein of Plasmodium yoelii (TyCS-VLP), a rodent malaria parasite. Balb/c mice were immunized with hybrid TyCS-VLP, and their CS-specific CD8(+) T cell response was quantitatively evaluated with the ELISPOT assay, based on the enumeration of epitope specific gamma-interferon secreting CD8(+) T cell. A single immunization with the TyCS-VLP by a variety of routes and doses indicated that the maximal response occurred in mice, which were immunized with 50 micrograms of these particles, administered via intramuscular. Combined immunization of mice with this TyCS-VLP followed by recombinant vaccinia virus expressing the entire P. yoelii CS protein (VacPyCS) or irradiated sporozoites, induced high levels of IFN-gamma-producing cells. The immunization regime, priming with TyCS-VLP and boosting with VacPyCS generated a potent protective immune response, which strongly inhibited P. yoelii liver stages development and protected 62% of the mice against a subsequent live P. yoelii sporozoite challenge.

Animals↗
PubMed2000

Rhythmic patterns in the expression of the ras oncogene in proliferating and differentiating erythroleukaemia cells.

Temporal variations in the expression of the ras oncogene, and its protein product, were investigated during hexamethylene bisacetamide (HMBA)-induced differentiation of murine erythroleukaemic (MEL) cells. We highlight the fact that when comparisons were made between untreated, proliferating cells and HMBA-treated, differentiating cells using only one time-point, differences, both for the expression of the gene and the protein, were in most cases insignificant; standard deviations were high and the interpretation could be made that HMBA had little effect. Such interpretation fails to take account of the dynamic nature of the system, with single time-point studies giving incomplete information, which can be misleading. Multiple time analyses showed clearly that rhythmic patterns of expression were modulated by the differentiating agent. Time-dependent changes in the expression of mRNA specific to H- ras and N- ras, as well as in the expression of the Ras protein, when measured over periods of minutes or hours, were apparent. HMBA affected frequency and phasing of the rhythms. Regulation of the dynamics in this way may be crucial to the control of cell function and transformation.

Acetamides↗
PubMed2000

Protein kinase c in erythroleukaemia cells: temporal variations in the expression of the alpha, epsilon and zeta isoforms.

Determinations of mRNA and enzyme protein analyses for the protein kinase C (PKC) isoforms, alpha, epsilon and zeta, representing the classical, novel and atypical groups, respectively, in murine erythroleukaemic (MEL) cells revealed the occurrence of cyclic behaviour in expression. Such rhythmicity was not apparent when multiple analyses using only a single time-point were considered; the importance of incorporating a time component into experimental design was demonstrated. On induction of differentiation over a period of five days with hexamethylene bisacetamide, changes in the patterns of expression of mRNA and protein were apparent, as compared with those of untreated, proliferating cells. Modulation of the dynamics of the various PKC isoforms may represent a regulatory mechanism for the control of a diversity of cellular functions.

Acetamides↗
PubMed1999

CD4(+) T cells induced by virus-like particles expressing a major T cell epitope down-regulate IL-5 production in an ongoing immune response to Der p 1 independently of IFN-gamma production.

It has been previously demonstrated that hybrid Ty virus-like particles (VLP) prime effective CD8(+) and CD4(+) T cell responses. In this study, we investigated the effect of treating mice with Ty VLP carrying the immunodominant epitope of Der p 1 after sensitizing them to the group 1 allergen of the house dust mite Dermatophagoides pteronyssinus (Der p 1), under conditions that induce T(h)2 immunity. We show that i.p. treatment with the hybrid VLP abrogated allergen-specific IL-5 production and reduced allergen-specific cell proliferation. This suppression of the response was mediated by CD4(+) T cells and was not accompanied by an increase in IFN-gamma production.

Allergens↗
PubMed1999

Intratype sequence variation among clinical isolates of the human papillomavirus type 6 L1 ORF: clustering of mutations and identification of a frequent amino acid sequence variant.

Human papillomavirus type 6 (HPV-6) is the causative agent of condyloma acuminata, a common sexually transmitted disease. Virus-like particles (VLPs) assembled from the L1 major capsid protein represent promising candidates for prophylactic vaccines. However, any intratype sequence variation among HPV-6 L1 ORFs will influence which sequence is used for a vaccine according to its prevalence in the population and its propensity for VLP production. Therefore, we have analysed the entire L1 nucleotide sequence of 17 clinical isolates of HPV-6 from the London area. We found 28 positions where changes from the prototype HPV-6b L1 occurred, showing that HPV-6 L1 intratype variation is greater than previously reported. The most frequently observed substitutions are clustered into three discrete regions: R1 (nt 5920-6075), R2 (nt 6590-6670) and R3 (nt 7070-7230). Indeed, most of the nucleotide substitutions within the HPV-6 L1 reported worldwide also map to these regions. The R3 region contains predominantly non-silent substitutions, the most common of which is a G-to-C substitution at position 7079. This results in a Glu-to-Gln change at aa 431, although this change had no effect on VLP yield or stability. This substitution defines a new HPV-6 L1 amino acid sequence that is more abundant in the isolates examined than any other reported sequence.

Amino Acid Sequence↗
PubMed1998

Treatment of normal skeletal muscle with FK506 or rapamycin results in halothane-induced muscle contracture.

BACKGROUND: FKBP12 is a protein that is closely associated with the ryanodine receptor type 1 of skeletal muscle and modulates Ca2+ release by the channel. The immunosuppressants FK506 and rapamycin both bind to FKBP12 and in turn dissociate the protein from the ryanodine receptor. By treating healthy human skeletal muscle strips with FK506 or rapamycin and then subjecting the strips to the caffeine-halothane contracture test, this study determined that FK506 and rapamycin alter the sensitivity of the muscle strip to halothane, caffeine, or both. METHODS: Skeletal muscle strips from 10 healthy persons were incubated in Krebs medium equilibrated with a 95% oxygen and 5% carbon dioxide mixture, which contained either 12 microM FK506 (n = 8) or 12 microM rapamycin (n = 6), for 15 min at 37 degrees C. The strips were subjected to the caffeine-halothane contracture test for malignant hyperthermia according to the European Malignant Hyperthermia Group protocol. RESULTS: Treatment of normal skeletal muscle strips with FK506 and rapamycin resulted in halothane-induced contractures of 0.44+/-0.16 g and 0.6+/-0.49 g, respectively, at 2% halothane. CONCLUSIONS: The results obtained show that pre-exposure of healthy skeletal muscle strips to either FK506 or rapamycin is sufficient to give rise to halothane-induced contractures. This is most likely caused by destabilization of Ca2+ release by the ryanodine receptor as a result of the dissociation of FKBP12. This finding suggests that a mutation in FKBP12 or changes in its capacity to bind to the ryanodine receptor could alter the halothane sensitivity of the skeletal muscle ryanodine receptor and thereby predispose the person to malignant hyperthermia.

Adolescent↗
PubMed1997

Prediction of murine MHC class I epitopes in a major house dust mite allergen and induction of T1-type CD8+ T cell responses.

The group I (Der p 1) allergen of Dermatophagoides pteronyssinus (house dust mite, HDM) contains several T helper (Th) epitopes recognized by C57BL/6 mice, with the peptide (111-139) containing a dominant MHC class II-restricted epitope (113-127). Since CD8+ T cells are thought to play a role in the regulation of allergic disease, we examined the Der p 1 sequence for potential MHC class I-binding motifs and observed that residues 111-119 (FGISNYCQI) contain motifs for H-2Db and Kb. Furthermore, immunization of C57BL/6 mice with unadjuvanted Ty virus-like particles (VLP) carrying Der p 1 (111-139), a method known to induce murine cytotoxic T lymphocyte (CTL) responses, primed Der p 1 (111-119)-specific Db-restricted CTL which produce high levels of IFN-gamma and low levels of IL-5 and IL-6 in vitro (T1-type CTL). VLP carrying the minimal epitope (FGISNYCQI) also induced a CTL response following immunization without adjuvant by various routes. Der p 1 (111-139)-VLP adjuvanted with alum did not prime CTL in C57BL/6 mice but were found to prime Th1-type CD4+ T cells that recognize the overlapping peptide (113-127) and native protein. The ability to successfully predict allergen-specific CD8+ T cell epitopes and prime CD8+ and/or CD4+ T cell responses provides an opportunity to dissect the relative roles of these T cells in the regulation of allergic responses and may offer therapeutic potential for reprogramming Th2-type allergic responses.

Administration, Intranasal↗
PubMed1995

Patterns of cytokine expression in community-acquired pneumonia.

BACKGROUND: Pneumonia continues to be a major cause of disease and death among patients worldwide. Aspects of the host response to infection, such as the release of cytokines, may be contributing to the persistent morbidity and mortality. METHODS: Plasma levels of cytokines interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) were measured in critically ill patients with pneumonia (ICUP; n = 12) and less severely ill patients with pneumonia (NONICUP; n = 8), and in 2 additional control groups of patients, viz, severely ill postoperative patients without evidence of infection (POSTOP; n = 11) and less severely ill patients with nonpneumonia infections (NONP; n = 9). All four groups of patients were studied in a multivariate one-way analysis of variance using the parameter vector: plasma IL-1 beta, IL-6, TNF-alpha, systolic blood pressure, diastolic blood pressure, plasma urea, creatinine, and temperature. Thereafter the significance of individual parameters were assessed by univariate analysis and pairwise comparisons. RESULTS: All cytokine concentrations were highest in the ICUP group. In the case of IL-1 beta, levels were significantly higher in the ICUP group when compared with the noninfected POSTOP group. The acute physiology and chronic health evaluation (APACHE) II scores were identical in these two groups (17 +/- 3 [SD] and 10 +/- 1, respectively, not significantly different). Intermediate levels were found in those groups with intermediate levels of infection. The IL-6 levels were not significantly different between the groups and in particular, the levels in the ICUP and POSTOP groups were similar. The TNF-alpha levels tended to mimic those of IL-1 beta, although the significant difference found was between the ICUP and NONICUP groups which had significantly different APACHE II scores (17 +/- 3 vs 4.4 +/- 1, respectively). No association between cytokine levels and patient mortality was demonstrated. CONCLUSION: Among the cytokines, IL-1 beta appeared to be associated with the severity of infection, IL-6 appears to reflect severity of stress whether of infection or noninfective origin, and TNF-alpha may be a marker of severity of pneumonia.

APACHE↗
PubMed1994

Cloning of an antibody binding DNA sequence: pitfalls of DNA/protein immunoprecipitation reactions.

This paper presents evidence of cross-reactivity of a normal genomic DNA sequence to a number of antibodies raised against common proteins. This DNA fragment was inadvertently isolated during DNA-protein immunoprecipitation cloning experiments and was found to bind not only to the antibody used in the immunoprecipitation experiment, but to several different antibodies in gel-shift assays. This data demonstrates the ability of certain DNA sequences to bind non-specifically to antibodies and highlights the danger of DNA/antibody binding which can produce artifacts. Possible means of overcoming these reactions are discussed.

Animals↗
PubMed1994

Circulating cytokine concentrations and cytokine production by monocytes from newborn babies and adults.

As a possible factor responsible for reduced fever responses in the newborn, we measured plasma cytokine concentrations and cytokine production by neonatal monocytes after lipopolysaccharide or IL (interleukin)-1 alpha stimulation in vitro and compared these data with those obtained from adult plasma and monocytes. Whole blood was collected from afebrile adults (n = 12) and the umbilical cord of normal term infants (n = 12). Plasma and peripheral blood monocytes were prepared by conventional techniques. Significantly lower concentrations of IL-1 alpha, IL-1 beta (P < 0.05, t-test) and IL-6 (P < 0.01, t-test) were found in the plasma of newborn babies compared with that of adults. There was no significant difference in plasma tumour necrosis factor (TNF) concentrations between the adults and newborn babies. Monocytes from newborn babies had the capacity to produce IL-1 alpha and IL-1 beta as readily as adult cells after stimulation with lipopolysaccharide or IL-1 alpha, and produced significantly lower concentrations of TNF and IL-6 than those produced by stimulated adult monocytes (P < 0.01, ANOVA). Our results suggest that the reduced production of IL-6 by monocytes of the newborn during infection could be partly responsible for attenuated fever responses observed in the neonate.

Adult↗
PubMed1994

BCL-2 proto-oncogene expression in prostate cancer and its relationship to the prostatic neuroendocrine cell.

Prostatic adenocarcinoma has a divergent response to androgen ablation and a varied long-term prognosis. BCL-2 is a proto-oncogene that prevents programmed cell death. Since androgen withdrawal induces apoptosis, it has been postulated that BCL-2 may play a role in androgen resistance. Neuroendocrine cells have been demonstrated in prostate cancer and have an adverse influence on long-term prognosis. This study demonstrates a proportional relationship between the tissue levels of BCL-2 and the neuroendocrine marker, neuron-specific enolase in 11 of 13 cases of primary prostate cancer. This relationship does not appear to exist in metastatic prostate cancer or in most nonprostate cancers. Direct immunohistochemical staining confirmed BCL-2 in six of the primary tumors, and these BCL-2-containing cells appeared to be intimately associated with tumor neuroendocrine cells.

Adenocarcinoma↗
PubMed1993

Cyclic adenosine 3',5'-monophosphate, a second messenger in interleukin-1 mediated K562 cytostasis.

This study evaluates intracellular cAMP concentrations, in interleukin-1 (IL-1) mediated cytostasis of K562 cells. Dibutyryl-cAMP, forskolin, staurosporine and phorbol 12-myristate 13-acetate were all found to mimic the cytostatic action of IL-1 on K562 cells. IL-1 was found to elicit a dose-dependent rise in adenyl cyclase activity in isolated K562 membranes, as well as increasing cAMP concentrations in whole cells. cAMP concentrations were found to peak within 3 minutes of IL-1 stimulation. A 27-29% reduction in proliferative activity elicited by IL-1, forskolin and staurosporine, correlated with a 6 fold increase in adenyl cyclase activity, in each case.

Adenylyl Cyclases↗
PubMed1993

Interleukin-1 receptor antagonist in newborn babies and pregnant women.

We have investigated the possible role of the interleukin-1 receptor antagonist (IL-1ra) in the attenuated fever response in the newborn. Umbilical cord blood was collected from normal full-term infants (n = 12), and venous blood was obtained from afebrile, non-pregnant adults, of both genders (n = 12) and women in late pregnancy (n = 12). Plasma IL-1ra, and IL-1ra produced in vitro by peripheral blood monocytes stimulated with IL-1 alpha or LPS, were assayed by ELISA. Significantly higher concentrations of IL-1ra (P < 0.01, t test) were found in umbilical cord plasma than in plasma of non-pregnant adults. Furthermore concentrations of IL-1ra in the plasma of women in late pregnancy were significantly higher than in the plasma of neonates and non-pregnant adults (P < 0.01, Mann-Whitney rank-sum test). Neonatal monocytes failed to produce significant amounts of IL-1ra upon stimulation in vitro. The monocytes of pregnant women produced much higher concentrations of IL-1ra than the monocytes of non-pregnant adults (P < 0.01 Mann-Whitney rank-sum test). We speculate that IL-1ra may attenuate the febrile response to Gram-negative pyrogens in women in late pregnancy, and by crossing the placenta, also in the newborn.

Enzyme-Linked Immunosorbent Assay↗