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Biomedical subjects

J M Stuart

Publications and source records attributed to J M Stuart.

At least 37 records · Page 2Linked to original sources
PubMed1999

Routine reporting or sentinel surveys for HIV/AIDS surveillance in resource-poor settings: experience in South Africa, 1991-97.

Information from routine and sentinel surveillance was used to monitor the HIV/AIDS epidemic in KwaZulu-Natal, South Africa between 1991 and 1997. Comparisons were made between data obtained from (1) sentinel surveillance for antenatal HIV infection, pulmonary tuberculosis (PTB), and AIDS in a single health district and (2) province-wide sentinel surveillance for antenatal HIV infection, legally required notification of cases of PTB, and voluntary notification of AIDS cases. HIV prevalence among antenatal clinic attenders in the sentinel district rose rapidly and at similar rates to provincial figures: 4.2% vs 4.8% in 1992 to 25.9% vs 26.9% in 1997. PTB incidence increased four-fold in the sentinel district over the study period, whereas provincial PTB figures from passive surveillance fluctuated widely and showed no clear increase (Chi-square for trend 425.5, P<0.00001). AIDS incidence in the sentinel district increased dramatically while provincial data from the voluntary reporting system showed a less consistent and much slower rise (Chi-square for trend 9.07, P=0.003). Incidence of AIDS in 1997 was estimated as 437/10(5) in the sentinel district compared to 32/10(5) in the provincial figures. Routine disease notification and voluntary reporting systems are likely to underestimate the impact of the HIV/AIDS epidemic in resource-poor settings. Sentinel surveillance at representative sites should be developed to validate or replace passive surveillance systems.

AIDS-Related Opportunistic Infections↗
PubMed1999

Practical guidelines for responding to an outbreak of meningococcal disease among university students based on experience in Southampton.

Six students at the University of Southampton developed meningococcal disease in October 1997, five of them with confirmed serogroup C infections, and three died. The outbreak had major organisational and financial implications for the agencies involved. Detailed planning and good working relationships with the management of higher educational institutions can prove invaluable in such situations. This paper summarises the management of the outbreak in Southampton and presents recommendations based on our experience.

Antibiotic Prophylaxis↗
PubMed1999

Automation of yeast two-hybrid screening.

We have developed an automated format for screening yeast two-hybrid libraries for protein-protein interactions. The format consists of a liquid array in which pooled library subsets of yeast, expressing up to 1000 different cDNAs, are mated to a yeast strain of the opposite mating type, expressing a protein of interest. Interactors are detected by a liquid assay for beta-galacsidase following prototrophic selection. The method is demonstrated by the detection of interactions between two encoded yeast RNA polymerase subunits in simulated libraries of varied complexity. To demonstrate its utility for large scale screening of complex cDNA libraries, two nuclear receptor ligand-binding domains were screened through two cDNA libraries arrayed in pooled subsets. Screening these libraries yielded clones which had previously been identified in traditional yeast two hybrid screens, as well as several new putative interacting proteins. The formatting of the cDNA library into pooled subsets lends itself to functional subtraction of the promiscuous positive class of interactor from the library. Also, the liquid arrayed format enables electronic handling of the data derived from interaction screening, which, together with the automated handling of samples, should promote large-scale proteome analysis.

Automation↗
PubMed1998

Characterization of a peptide analog of a determinant of type II collagen that suppresses collagen-induced arthritis.

Immunization of susceptible strains of mice with type II collagen (CII) elicits an autoimmune arthritis known as collagen-induced arthritis (CIA). One analogue peptide of the immunodominant T cell determinant, A9 (CII245-270 (I260-->A, A261-->B, F263-->N)), was previously shown to induce a profound suppression of CIA when coadministered at the time of immunization with CII. In the present study, A9 peptide was administered i.p., orally, intranasally, or i.v. 2 to 4 wk following CII immunization. We found that arthritis was significantly suppressed even when A9 was administered after disease was induced. To determine the mechanism of action of A9, cytokine responses to A9 and wild-type peptide A2 by CII-sensitized spleen cells were compared. An increase in IL-4 and IL-10, but not in IFN-gamma, was found in A9 culture supernatants. Additionally, cells obtained from A9-immunized mice produced higher amounts of IL-4 and IL-10 when cultured with CII compared with cells obtained from mice immunized with A2, which produced predominantly IFN-gamma. Suppression of arthritis could be transferred to naive mice using A9-immune splenocytes. Lastly, phosphorylation of TCRzeta was not altered in the immunoprecipitates from the lysates of cells exposed to analogue peptides (A9 and A10) together with wild-type A2 in a T cell line and two I-Aq-restricted, CII-specific T hybridomas. We conclude that analogue peptide A9 is effective in suppressing established CIA by inducing T cells to produce a Th2 cytokine pattern in response to CII.

Administration, Intranasal↗
PubMed1998

Characterization of signal transduction through the TCR-zeta chain following T cell stimulation with analogue peptides of type II collagen 260-267.

The immunodominant T cell determinant of type II collagen (CII) recognized by DBA/1 mice (I-Aq) is CII 260-267. The aims of this study were to determine the role of the amino acid residues within CII 245-270 in T cell signal transduction. To that end, we utilized I-Aq-restricted, CII-specific T cell hybridomas and examined tyrosine phosphorylation of TCR-zeta following stimulation with either wild-type CII 245-270 or a panel of analogue peptides. A variety of patterns occurred, ranging from increased phosphorylation of TCR-zeta to either partial or a complete abrogation of phosphorylation. Critical substitutions also completely abrogated the phosphorylation of ZAP70, a downstream molecule in TCR-zeta signaling. Evaluation of the supernatants of the T cell hybridomas for cytokine production in response to the peptides revealed a close correlation between the induction of phosphorylation of TCR-zeta and the amount of cytokine induced. Selected analogue peptides were tested as tolerogens in neonatal mice. Analogues that did not induce the phosphorylation of zeta chain, such as B3 (CII 251-270s263F-->N), were completely unable to induce tolerance, while analogues that caused a partial phosphorylation, such as B6 (CII 251-270s267Q-->T) and A3 (CII 245-270s269P-->A), induced partial tolerance judged by intermediate degrees of suppression of arthritis. We conclude that discrete alterations in specific amino acid residues of antigenic peptides had profound effects on T cell signaling and that the signaling correlated with T cell cytokine secretion and T cell function in the induction of tolerance and suppression of arthritis.

Amino Acid Sequence↗
PubMed1998

Induction of autoimmune arthritis in HLA-DR4 (DRB1*0401) transgenic mice by immunization with human and bovine type II collagen.

Although associations between the expression of particular HLA genes and the susceptibility to specific autoimmune diseases has been known for some time, the role that these HLA molecules play in the autoimmune response is unclear. Through the establishment of a chimeric HLA-DR/I-E transgene, we have examined the function of the rheumatoid arthritis (RA) susceptibility allele HLA-DR4 (DRB1*0401) in presenting antigenic peptides derived from the model Ag, type II collagen (CII), and in mediating an autoimmune response. As a transgene, the chimeric DR4 molecule conferred susceptibility to an autoimmune arthritis induced by immunization with human CII or bovine CII. These mice developed an inflammatory, autoimmune arthritis that was similar both histologically and in severity to that previously described for the collagen-induced arthritis model. The DR4-mediated autoimmune arthritis was accompanied by T cell and B cell responses to both the immunogen and the autoantigen, murine CII. The DR4-restricted T cell response to human CII was focused on an immunodominant determinant within CII263-270 and a minor determinant within CII286-300, the same CII determinants recently identified for yet another RA susceptibility allele, HLA-DR1 (DRB1*0101). Thus these data demonstrate that, like HLA-DR1, HLA-DR4 is capable of binding peptides derived from human CII and therefore probably plays a role in the autoimmune response to human CII observed in RA patients.

Amino Acid Sequence↗
PubMed1998

National outbreak of Salmonella senftenberg associated with infant food.

Eight cases of Salmonella senftenberg infection in infants were identified in the first half of 1995 in England, five were indistinguishable S. senftenberg strains. A case-control study showed an association between illness and consumption of one brand of baby cereal (P = 0.03). The cereal manufacturer reported isolating S. senftenberg in June 1994 from an undistributed cereal batch. Outbreak strains and the cereal strain were all plasmid-free in contrast to other human isolates of S. senftenberg in the same period. Changes in the production process were implemented to prevent further contamination. Surveillance centres should strengthen the detection and investigation of outbreaks of gastrointestinal infection in susceptible groups, especially young children. In this outbreak, the study of only five cases led to identification of the vehicle of infection. Even when few cases are reported, epidemiological investigation in conjunction with molecular typing may lead to public health action which prevents continuing or future outbreaks.

Case-Control Studies↗
PubMed1998

Outbreaks of waterborne infectious intestinal disease in England and Wales, 1992-5.

Following the introduction of an improved surveillance system for infectious intestinal disease outbreaks in England and Wales, the Public Health Laboratory Service Communicable Disease Surveillance Centre received reports of 26 outbreaks between 1 January 1992 and 31 December 1995 in which there was evidence for waterborne transmission of infection. In these 26 outbreaks, 1756 laboratory confirmed cases were identified of whom 69 (4%) were admitted to hospital. In 19 outbreaks, illness was associated with the consumption of drinking water from public supplies (10 outbreaks) or private supplies (9 outbreaks). The largest outbreak consisted of 575 cases. In 4 of the remaining 7 outbreaks, illness was associated with exposure to swimming pool water. Cryptosporidium was identified as the probable causative organism in all 14 outbreaks associated with public water supplies and swimming pools. Campylobacter was responsible for most outbreaks associated with private water supplies. This review confirms a continuing risk of cryptosporidiosis from chlorinated water supplies in England and Wales, and reinforces governmental advice to water utilities that water treatment processes should be rigorously applied to ensure effective particle removal. High standards of surveillance are important for prompt recognition of outbreaks and institution of control measures. As microbiological evidence of water contamination may be absent or insufficient to implicate a particular water supply, a high standard of epidemiological investigation is recommended in all outbreaks of suspected waterborne disease.

Communicable Diseases↗
PubMed1998

Characterization of recombinant type II collagen: arthritogenicity and tolerogenicity in DBA/1 mice.

Recombinant human type II collagen (rhCII) was produced using both the HT1080 mammalian cell expression system (rhCIIht) and a baculovirus expression system (rhCIIbac). The biosynthesis of CII requires extensive post-translational modifications, such as the hydroxylation of prolyl and lysyl residues and glycosylation of hydroxylysyl residues. Amino acid analyses indicated that the rhCIIbac was adequately hydroxylated at prolyl residues but underhydroxylated at lysyl residues and underglycosylated compared with tissue-derived hCII, while rhCIIht was hyperhydroxylated and hyperglycosylated at lysyl residues. When the murine collagen-induced arthritis (CIA) model was used to investigate the immunological properties of the two forms of recombinant CII, each induced a high incidence of arthritis following immunization of susceptible mice when emulsified with complete Freund's adjuvant (CFA). However, the severity of the arthritis, as assessed by the number of affected limbs, was significantly higher in mice immunized with rhCIIht than in mice immunized with rhCIIbac. These data indicate that the degree of hydroxylysine glycosylation may play a role in the induction of the arthritogenic response to CII. Each of the recombinant collagens was comparable to tissue-derived hCII in their ability to induce tolerance and suppress arthritis when given as intravenous or oral tolerogens. Taken together, our data suggest that recombinant CII can be prepared in adequate amounts for therapeutic uses and that the material is immunologically comparable to tissue-derived hCII when used to induce tolerance.

Administration, Oral↗
PubMed1997

Restricted TCR V alpha repertoire in the T cell response to a tolerogenic determinant of type II collagen.

Tolerization of B10.RIII mice (H-2r) with i.v.-injected type II collagen (CII) renders the animals resistant to induction of collagen-induced arthritis (CIA). The B10.RIII mouse is of particular interest, in that the T cell determinants that induce tolerance are different from those that induce arthritis. To characterize T cells that react with the tolerogenic determinant and play a role in regulation of arthritis, we have developed a panel of T cell hybridomas reactive with the tolerogenic T cell epitope, CII 607-621. None of the hybrids cross-reacted with either the arthritogenic CII 445-453 or murine CII. As determined by PCR and immunofluorescence, the T cell response to the tolerogenic determinant was oligoclonal, with evident preferential usage of V alpha. Through the analysis of a large panel of T cell hybridomas, preferential usage of V alpha2, J alpha44, J beta2.7, and D beta2.1 was observed. Characterization of T cells reactive with the immunodominant determinant, CII 607-621, responsible for the induction of tolerance should prove important in developing novel therapeutic approaches for the treatment of autoimmune diseases.

Amino Acid Sequence↗
PubMed1997

An HLA-DR1 transgene confers susceptibility to collagen-induced arthritis elicited with human type II collagen.

Rheumatoid arthritis (RA) is an autoimmune disease that is strongly associated with the expression of several HLA-DR haplotypes, including DR1 (DRB1*0101). Although the antigen that initiates RA remains elusive, it has been shown that many patients have autoimmunity directed to type II collagen (CII). To test the hypothesis that HLA-DR1 is capable of mediating an immune response to CII, we have generated transgenic mice expressing chimeric (human/mouse) HLA-DR1. When the DR1 transgenic mice were immunized with human CII (hCII), they developed a severe autoimmune arthritis, evidenced by severe swelling and erythema of the limbs and marked inflammation and erosion of articular joints. The development of the autoimmune arthritis was accompanied by strong DR1-restricted T and B cell responses to hCII. The T cell response was focused on a dominant determinant contained within CII(259-273) from which an eight amino acid core was defined. The B cell response was characterized by high titers of antibody specific for hCII, and a high degree of cross-reactivity with murine type II collagen. These data demonstrate that HLA-DR1 is capable of presenting peptides derived from hCII, and suggest that this DR1 transgenic model will be useful in the development of DR1-specific therapies for RA.

Adjuvants, Immunologic↗
PubMed1997

Management of clusters of meningococcal disease. PHIS Meningococcus Working Group and Public Health Medicine Environmental Group.

Guidance on the management of clustered cases of meningococcal disease has been revised following a review of the clusters that occurred in England and Wales between 1 April 1995 and 31 March 1996. Public health action is indicated for confirmed and probable cases but not in response to possible cases. The importance of microbiological confirmation is re-emphasised. Intervention is recommended for defined target groups when two or more confirmed or probable cases occur in a preschool group or school within a four week period. We present a framework to assist in the management of clusters of invasive serogroup C infections in larger and less defined communities.

Cluster Analysis↗
PubMed1997

Application of molecular methods to a nosocomial outbreak of Salmonella enteritidis phage type 4.

A nosocomial outbreak of Salmonella enteritidis phage type 4 occurred in July 1995. Seven definite cases were identified over 13 days affecting four wards in a London hospital. The outbreak strain was characterized by plasmid profile typing and pulsed-field gel electrophoresis (PFGE), and was unusual in that it did not possess a 38 MDa plasmid common to most isolates of S. enteritidis PT 4 made from humans and food animals in England and Wales. Seven asymptomatic excreters were identified on screening. No additional cases occurred on wards after standard isolation procedures were implemented. No common or continuing food or dietary source was identified. Results of epidemiological, microbiological and environmental investigations suggested that the outbreak was due to person-to-person transmission within the hospital. The source of the outbreak was not established but was probably due to admission of a patient with an unrecognized infection of S. enteritidis PT 4. The study highlights the importance of close collaboration between hospital staff, epidemiologists and microbiologists, and demonstrates the value of molecular techniques for strain subdivision in outbreak investigations.

Aged↗
PubMed1997

Suppression of murine collagen-induced arthritis by nasal administration of collagen.

DBA/1 mice were administered type II collagen (CII) or collagen peptides intranasally before systemic immunization to determine whether tolerance could be induced and autoimmune arthritis suppressed. Although prior experiments have demonstrated that collagen given intravenously or orally is effective, the respiratory mucosal route offers several theoretical advantages for dosing peptides, in addition to ease of use. Intact CII, CB11 and a synthetic peptide containing the immunodominant T-cell epitope recognized by H-2q mice were all effective in reducing the incidence and severity of arthritis and the immune response to CII. Since previous studies have demonstrated the importance of IgG2 antibody subclasses to the induction of collagen-induced arthritis, total immunoglobulin G (IgG), IgG1, and IgG2a and IgG2b were measured. IgG2 antibody subclasses were significantly downregulated by the treatment regimen, whereas a slight decrease in IgG1 antibodies was noted that was not significant. In an effort to determine the mechanism by which arthritis was attenuated, cervical lymph node and spleen cells from treated mice were cultured separately with CII and supernatants tested for the presence of T-cell lymphokines. The cells provided a T-helper 2 (Th2)-like response to CII, with T cells from lymph nodes secreting interleukin-4 (IL-4) and splenocytes secreting both IL-4 and IL-10, whereas a Th1-like response was detected in immunized mice not tolerized with CII. These findings indicate that the downregulation of arthritis that occurs with intranasal administration of CII is associated with Th2-type lymphokine profile and a decrease in complement-fixing antibody subclass.

Administration, Intranasal↗
PubMed1997

Community immunization programme in response to an outbreak of invasive Neisseria meningitidis serogroup C infection in the Trent region of England 1995-1996.

Between 8 December 1995 and 16 January 1996 seven laboratory confirmed cases of septicaemia owing to infection with Neisseria meningitidis serogroup C strains and one highly probable case of meningococcal septicaemia occurred in three electoral wards in south Rotherham and the Retford area of north Nottinghamshire. All cases occurred among children aged 1-17 years. One patient died. The public health response to this outbreak was the largest community prophylactic antibiotic and immunization programme against meningococcal infection, to date, in the United Kingdom. The target group for each Health Authority was 8900 for Rotherham Health Authorities and 8000 for North Nottinghamshire Health. Local logistical factors led to differences in the implementation of the programme by each Health Authority. At the completion of each programme, 8320 doses of vaccine had been administered (92.5 per cent coverage) during the Rotherham Health Authorities programme and 7660 (95.7 per cent coverage) during the North Nottinghamshire Health programme. The additional financial cost of the exercise amounted to approximately Pounds 125000 for each Health Authority. This paper describes the evolution of the outbreak, the decision-making process resulting in the immunization programme in each Health Authority, the implementation of each programme, problems identified and lessons learned.

Adolescent↗
PubMed1996

Marshmallows cause an outbreak of infection with Salmonella enteritidis phage type 4.

Thirty-six cases of Salmonella enteritidis phage type (PT) 4 infection, mainly in children, were notified in one local authority in the two weeks beginning on 23 October 1995. Twenty-four cases and 42 controls nominated by cases were included in a case control study, which showed a significant association between illness and the consumption of marshmallow confectionery from a bakery. S. enteritidis PT4 was isolated from samples of the marshmallow, and all isolates had the same plasmid and pulsed field gel electrophoresis profiles. The marshmallow had been made using raw egg white, which shows that not all caterers follow the Department of Health's advice.

Case-Control Studies↗
PubMed1996

Autoantibodies to murine type II collagen in collagen-induced arthritis: a comparison of susceptible and nonsusceptible strains.

Collagen-induced arthritis (CIA) is an experimental autoimmune disease elicited in genetically susceptible strains of mice by immunization with heterologous type II collagen. This experimental disease is mediated by the immune response of both T cells and B cells, and susceptibility is restricted by the class II molecules of the MHC. In this study we identify specific epitopes bound by autoantibodies elicited through immunization of several haplotypes of C57BL/10 mice with chick alpha1 (II)-CB11. ELISA analysis using a panel of 15-mer murine type II collagen peptides revealed a pattern of autoantibody epitope specificity that was remarkably similar among CIA-susceptible and nonsusceptible congenic strains, regardless of class II haplotype. However, one epitope was identified that was bound only by autoantibodies from CIA-susceptible strains bearing I-A(q) (B10.Q and B10.QbetaBR). In addition, this epitope was also present within affinity-purified Ab obtained from the CIA-susceptible strain DBA/1 (I-A(q)). Analyses of immune serum from B10.Q and B10.QbetaBR mice revealed that a subset of the antibodies binding this epitope were of the IgG2 subclass, and therefore efficient at fixing complement, a requirement for pathogenicity of the Abs in CIA.

Amino Acid Sequence↗