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Biomedical subjects

J Barratt

Publications and source records attributed to J Barratt.

At least 19 recordsLinked to original sources
PubMed2002

Expression of T cell receptor variable region families by bone marrow gammadelta T cells in patients with IgA nephropathy.

IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA (pIgA). Abnormalities of the IgA system include reduced mucosal and increased bone marrow (BM) pIgA production. Gammadelta T cells are regulators of mucosal IgA production and oral tolerance. We have described previously a deficiency of gammadelta T cells expressing Vgamma3 and Vdelta3 from the duodenal mucosa in IgAN. Since pIgA production is displaced to the BM, we have now studied BM gammadelta T cells in IgAN. Peripheral blood and BM aspirates were obtained from 14 patients with IgAN and 15 controls. Expression of TCR gamma and delta V region families was analysed by semiquantitative RT-PCR, and CDR3 spectratyping of Vgamma1-4 and Vdelta3 genes was performed. We found no difference between IgAN and controls in the V region usage of blood gammadelta T cells. However, in the BM of patients with IgAN, there was significantly reduced expression of the V region families Vgamma3 and Vdelta3, with the decrease in Vdelta3 being particularly striking. CDR3 spectratyping showed no abnormalities in blood or BM samples. Vgamma3 and Vdelta3 are underexpressed in the duodenum and the BM in IgAN. The combination of imbalanced mucosal and systemic pIgA production with deficient expression of gammadelta T cells using Vgamma3 and Vdelta3 in both sites may imply a role for these gammadelta T cells in the normal regulation of IgA immune responses, and in the complex immunopathogenesis of IgAN.

Adult↗
PubMed2001

Diet-related knowledge, beliefs and actions of health professionals compared with the general population: an investigation in a community Trust.

BACKGROUND: Dietary change is advocated for the prevention and treatment of a number of major diseases, and the implicit and explicit assumption is that health professionals have a major role in promoting diet change. Previous studies of doctors and nurses have shown their knowledge to be inadequate. Other health professionals have not been investigated. METHODS: Parts of a questionnaire used in a national study of the general public were administered to groups of health professionals from a variety of disciplines working in a community Trust. The results were compared with those from the study of the general public, for which the questionnaire had been devised. RESULTS: 358 questionnaires were completed. There was little difference between the knowledge, beliefs and actions of health professionals and the general public. CONCLUSION: If health professionals are to continue to be expected to promote healthy eating messages there will need to be a more systematic approach to their training about nutrition.

Adult↗
PubMed2001

Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients.

BACKGROUND: In IgA nephropathy (IgAN), circulating IgA1 molecules display an abnormal pattern of O-glycosylation. This abnormality may potentially contribute to mesangial IgA1 deposition, but this is unproven because the O-glycosylation of mesangial IgA1 has not been analyzed. METHODS: IgA1 was eluted from glomeruli isolated from the kidneys of three IgAN patients obtained after nephrectomy or at postmortem. Serum from these patients, other patients with IgAN, and controls was subjected to the same treatment as the glomerular eluates. The O-glycosylation of eluted and serum IgA1 was measured by lectin binding using an enzyme-linked immunosorbent assay-based system. RESULTS: In all three cases, the lectin binding of IgA1 eluted from the glomeruli of IgAN patients was markedly higher than that of the serum IgA1 of the same individual, and also all but one of a series of serum IgA1 samples from other patients and controls. CONCLUSIONS: The higher lectin binding of glomerular compared with serum IgA1 suggests that O-glycosylated IgA1 molecules abnormally and selectively deposit in the kidney. These results provide the first evidence that mesangial IgA1 is abnormally O-glycosylated, and support a direct role for abnormal IgA1 O-glycosylation in the mechanism of mesangial IgA deposition in IgAN.

Adult↗
PubMed2000

Identification of a novel Fcalpha receptor expressed by human mesangial cells.

BACKGROUND: IgA nephropathy (IgAN) is characterized by mesangial deposits of polymeric IgA (pIgA). The pathological consequences of IgA deposition are believed to center on direct interaction between IgA and the glomerular mesangial cell (MC). We have characterized a novel mesangial receptor that recognizes the Fc portion of IgA. METHODS: Five primary MC cultures were evaluated for IgA binding by flow cytometry, and specificity of binding was determined by competitive inhibition. Relative affinities of the receptor for all IgA isoforms were also determined, and binding of pIgA1 was compared to monomer. The identified Fc receptor was then compared with CD89, hitherto the only other Fcalpha receptor reported. CD89 protein and mRNA expression were detected by conventional and intracellular flow cytometry, sequencing of reverse transcription-polymerase chain reaction (RT-PCR) products, and Northern blotting. RESULTS: All MCs constitutively expressed a receptor that bound IgA in an Fcalpha-dependent fashion. The receptor recognized secretory and serum IgA1 and IgA2 equally, but pIgA bound with much greater affinity than monomer. At no time were we able to detect CD89 synthesis, although three novel CD89-related mRNA transcripts were identified by RT-PCR. CONCLUSIONS: We have clearly demonstrated that MCs consistently express an FcalphaR distinct from the myeloid FcalphaR CD89. This novel receptor binds pIgA with high affinity and may therefore mediate the mesangial injury that follows IgA deposition in IgAN. While immunogenically distinct, the mesangial Fcalpha receptor may share some molecular homology with CD89, as mRNA transcripts with partial identity to CD89 were found in all five MC cultures.

Antigens, CD↗
PubMed2000

Outcome of acute renal failure following surgical repair of ruptured abdominal aortic aneurysms.

OBJECTIVES: to establish the mortality of ARF following surgical repair of ruptured abdominal aortic aneurysms (AAAs) and to identify clinical variables which might assist in predicting outcome. DESIGN, MATERIALS AND METHODS: all cases of ARF complicating repair of ruptured AAAs treated at Leicester General Hospital between 1984 and 1996 were identified in a retrospective study based on review of clinical records. The main outcome measures were overall mortality, duration of hospital treatment and renal function in survivors. RESULTS: in 65 cases identified, overall hospital mortality was 75%. Six patients did not receive RRT, since their clinical state was judged irreversible; all died. Of the 16 survivors, 11 were left with irreversible renal impairment and one patient required maintenance dialysis. Over half of the survivors had died at 5 years>> follow-up. Non-survivors had more vascular disease (p=0.048), required more surgery during AAA repair (p=0.042) and were more likely to have developed multiple organ failure (p=0.01). A clinical severity score based on these three variables allowed stratification into prognostic groups. CONCLUSIONS: ARF following surgical repair of ruptured AAA has an overall hospital mortality of 75%. A clinical severity score, calculated at the time dialysis was considered, may assist in prediction of outcome.

APACHE↗
PubMed1999

Exaggerated systemic antibody response to mucosal Helicobacter pylori infection in IgA nephropathy.

Numerous studies in the literature report aberrant immune responsiveness in immunoglobulin A (IgA) nephropathy. However, all these studies investigate immune responses invoked by an artificially engineered antigen challenge. For the first time in IgA nephropathy, we report the systemic humoral responses generated as part of an active mucosal immune response against a common environmental pathogen, Helicobacter pylori (Hp). We studied 22 patients with IgA nephropathy and 9 controls without renal disease who were shown to be infected with Hp, using a 13C-urea breath test. Hp antigen-specific enzyme-linked immunosorbent assays were established to measure the anti-Hp IgA, IgG, and IgA and IgG subclass antibody levels. In addition, anti-Hp responses in the monomeric and polymeric (pIgA) fractions of serum IgA were measured after separation by gel filtration high-performance liquid chromatography. IgA nephropathy was associated with both a greater rate of IgA anti-Hp seropositivity (P < 0.05) and a more pronounced IgA anti-Hp antibody response (P < 0.01). In almost all cases, IgA anti-Hp was IgA1, and more than 90% was polymeric. There was no difference in the frequency of IgG anti-Hp seropositivity, but patients produced a much greater IgG anti-Hp response (P < 0.01). In addition, the IgG subclass responses were markedly different, with IgG1 predominant in controls and IgG2 and IgG3 the major subclasses produced in IgA nephropathy. We have shown an exaggerated systemic antibody response to mucosal infection caused by Hp in patients with IgA nephropathy, predominantly consisting of pIgA1, IgG2, and IgG3. This suggests that in IgA nephropathy, not only is pIgA1 production poorly controlled, but regulation of IgG isotype switching in response to mucosal pathogens is also deranged.

Adolescent↗
PubMed1999

Analysis of IgA1 O-glycans in IgA nephropathy by fluorophore-assisted carbohydrate electrophoresis.

Abnormal O-glycosylation of IgA1 may contribute to pathogenic mechanisms in IgA nephropathy (IgAN). Observations of altered lectin binding to IgA1 in IgAN suggest that the O-glycan chains may be undergalactosylated, but precise structural definition of the defect has proved technically difficult, and it remains unconfirmed. This is the first study using fluorophore-assisted carbohydrate electrophoresis (FACE) to analyze IgA1 O-glycans in IgAN and controls. IgA1 was purified from serum, and the intact O-glycans were released by hydrazinolysis at 60 degrees C. After re-N-acetylation, the glycans were fluorophore-labeled and separated by polyacrylamide gel electrophoresis. Sequential exoglycosidase digestions of IgA1 allowed identification of the different O-glycan bands on FACE gels, and their relative frequencies in IgA1 samples were measured by ultraviolet densitometry. Lectin binding of the IgA1 samples was also measured. In some patients with IgAN, FACE analysis demonstrated a significant increase in the percentage of IgA1 O-glycan chains consisting of single N-acetyl galactosamine (GalNAc) units rather than the more usual galactosylated and sialylated forms. This finding was confirmed using both desialylated IgA1 and enzymatically released O-glycans. Good correlation was also found between O-glycan agalactosylation on FACE analysis and IgA1 lectin binding in IgAN, supporting the value of lectins as tools for detection of this abnormality. This is the first study in which all of the predicted O-glycan forms of IgA1 have been analyzed simultaneously, and demonstrates that in IgAN, the IgA1 Oglycan chains are truncated, with increased terminal GalNAc. This abnormality has the potential to significantly affect IgA1 behavior and handling with pathogenic consequences in IgAN.

Adult↗
PubMed1998

The nucleotide sequence of the IgA1 hinge region in IgA nephropathy.

BACKGROUND: Mesangial IgA1 deposition is characteristic of IgA nephropathy (IgAN). Structural abnormalities of the IgA1 glycoprotein may play a key role in its mesangial deposition, particularly the recently described abnormalities of O-glycosylation of the IgA1 hinge region. The mechanism of abnormal O-glycosylation has not yet been elucidated; it is not clear whether there is an alteration in the amino acid sequence of the hinge region, modifying the number of O-glycosylation sites available, or whether there is a post-translational defect in the glycosylation process. METHODS: The O-glycosylation of serum IgA1 from a series of patients with IgAN and matched controls was assessed by lectin binding assay. We then used dideoxy-sequencing of the PCR-amplified hinge region of the alpha1 heavy chain gene to compare the hinge region nucleotide sequence in IgAN and controls. We also compared cDNA transcripts of alpha1 hinge region mRNA to look for evidence for a transcriptional abnormality in IgAN. RESULTS: Lectin binding assays confirmed that the IgAN subjects used in this study did indeed display the previously reported abnormality of IgA1 O-glycosylation. However, the hinge region nucleotide sequence of the alpha1 gene was identical in IgAN and controls. There was also no difference in the sizes of cDNA transcripts of hinge region mRNA from patients with IgAN and controls. CONCLUSIONS: We found no evidence for any nucleotide sequence alteration or transcriptional abnormality of the alpha1 hinge region in IgAN, and we conclude that the O-glycosylation defect is post-translational.

Adolescent↗
PubMed1994

Extramedullary hemopoiesis arising in the gut mimicking carcinoma of the cecum.

A patient initially treated for iron deficiency anemia was later found to have myelofibrosis. She developed increasing splenomegaly and then a mass in the right iliac fossa for which a right hemicolectomy was performed. Histopathology demonstrated extramedullary hemopoiesis in the spleen and cecum. The patient subsequently developed a protein-losing enteropathy and she deteriorated and died 14 mths later. Autopsy was not performed.

Bone Marrow↗
PubMed1992

Putative immunolocalization of the mechanoelectrical transduction channels in mammalian cochlear hair cells.

Hair cells bear an apical bundle of stereocilia arranged in serried rows. Deflection of the bundle controls the opening and closing of mechanoelectrical transduction channels, thereby altering the conductance across the apical plasma membrane. Two locations for these channels have been proposed in the bundle, either near the bases of the stereocilia or towards their tips. One hypothesis that is consistent with the latter possibility suggests that fine extracellular filaments, which run between the tips of the shorter stereocilia and the sides of the taller stereocilia behind, operate the channels. Determining the precise position of the channels is essential to test this hypothesis. We have therefore attempted to localize them immunocytochemically. Because hair-cell transduction is amiloride sensitive, the channels may have an amiloride-binding site associated with them. We have therefore used a polyclonal antibody raised against another amiloride-sensitive ion channel to hunt for them. This antibody recognizes a 62-64 kDa band in immunoblots of cochlear tissue, and produces discrete labelling in the hair bundle. This is most concentrated just below the tips of the shorter stereocilia, coinciding with a region of specialization in the closely apposed membranes of the short and tall stereocilia but not with either end of the tip link.

Amiloride↗
PubMed1992

Trial of intensive compared with weekly speech therapy in preschool children.

Forty two preschool children referred to a speech therapy department were randomly allocated to receive intensive individual speech therapy or the more traditional once weekly approach. Boys and minority ethnic groups were referred most frequently. Speech therapy improved expression more than comprehension, as measured on Reynell scales. The mean improvements were 0.5 SDs (95% confidence intervals (CI) 0.3 to 0.7) and 0.3 (95% CI 0.1 to 0.5) respectively. There was a greater improvement in children receiving intensive compared with weekly therapy in the expression scores (0.8 SDs (95% CI 0.5 to 1.1) v 0.2 SDs (95% CI -0.1 to 0.5]. White and non-white children had similar improvements in comprehension scores but white children had greater improvement in expression scores (1.1 SDs v 0.3 SDs). This difference was seen in both therapy groups. Randomised trials are useful in the evaluation of speech therapy in children.

Child, Preschool↗
PubMed1986

Metabolic activity of erosions in rheumatoid arthritis.

The hands of 10 patients with rheumatoid arthritis were investigated with diphosphonate scanning and radiology. Increased uptake of isotope can be associated with some erosions but not all and also reflects other processes more linked to acute inflammatory areas unassociated with the development of erosions. If the latter are the hallmark of active rheumatoid arthritis then bone scans are not.

Adult↗
PubMed1982

Circulating immune complexes in cutaneous and systemic vasculitis: clinicopathological correlations.

A high incidence of raised levels of circulating immune complexes has found in a group of patients with idiopathic vasculitis. Serial measurements in 8 patients with systemic vasculitis showed a good correlation between clinical status and circulating immune complex levels. Some correlation existed between the constituents of circulating and tissue-bound complexes in 6 patients so studied. However, there was no correlation between apparent organ involvement and hypocomplementaemia and the levels of size of circulating immune complexes. It is concluded that the measurement of circulating immune complexes may be clinically useful in vasculitis, but that no direct evidence is yet available that they are pathogenetically related to those which are tissue-bound.

Antigen-Antibody Complex↗
PubMed1981

Infective endocarditis-associated glomerulonephritis in rabbits: evidence of a pathogenetic role for antiglobulins.

Serial studies of circulating immune complexes, serum complement, proteinuria and renal histology and immunofluorescence have been undertaken in infective endocarditis glomerulonephritis in rabbits. Eighteen of 24 rabbits developed evidence of glomerulonephritis and 13 of 18 had circulating immune complexes. Gel filtration studies showed the immune complexes to have a size range of ca 4.10(6)--3.10(5) daltons. Direct immunofluorescence staining of glomeruli showed that IgM was the predominant immunoglobulin present and that antiglobulin activity was associated with IgM deposition. Intraglomerular localization of antiglobulin was closely associated with evidence of glomerulonephritis. Streptococcal antigen(s) were not demonstrable in glomeruli, even after acid elution of sections.

Animals↗