Biomedical subjects

J M Palmer

Publications and source records attributed to J M Palmer.

At least 19 recordsLinked to original sources

PubMed2002

The immunology of primary biliary cirrhosis: the end of the beginning?

The chronic liver disease primary biliary cirrhosis (PBC) is characterised by autoreactive B-cell and T-cell responses directed against mitochondrial antigens. In recent years these responses have been extensively characterised and the principal PBC associated autoantigen identified as pyruvate dehydrogenase complex (PDC). The identification of anti-PDC responses (present in over 95% of PDC patients) has given rise to important questions pertinent to our understanding of the pathogenesis of PBC. What specific role to anti-PDC responses play in target cell damage? How and why does immune tolerance break down to as highly conserved and ubiquitously expressed self-antigen as PDC? Why does breakdown in tolerance to an antigen present in all nucleated cells result in damage restricted to the intra-hepatic bile ducts? In attempting to answer these key questions we have, in this review, proposed a unifying hypothesis for the pathogenesis of PBC.

Animals↗

PubMed2001

Mutation analysis of the CDKN2A promoter in Australian melanoma families.

Approximately 50% of all melanoma families worldwide show linkage to 9p21-22, but only about half of these have been shown to contain germ line CDKN2A mutations. It has been hypothesized that a proportion of these families carry mutations in the noncoding regions of CDKN2A. Several Canadian families have been reported to carry a mutation in the 5' UTR, at position -34 relative to the start site, which gives rise to a novel AUG translation initiation codon that markedly decreases translation from the wild-type AUG (Liu et al., 1999). Haplotype sharing in these Canadian families suggested that this mutation is of British origin. We sequenced 1,327 base pairs (bp) of CDKN2A, making up 1,116 bp of the 5' UTR and promoter, all of exon 1, and 61 bp of intron 1, in at least one melanoma case from 110 Australian families with three or more affected members known not to carry mutations within the p16 coding region. In addition, 431 bp upstream of the start codon was sequenced in an additional 253 affected probands from two-case melanoma families for which the CDKN2A mutation status was unknown. Several known polymorphisms at positions -33, -191, -493, and -735 were detected, in addition to four novel variants at positions 120, -252, -347, and -981 relative to the start codon. One of the probands from a two-case family was found to have the previously reported Q50R mutation. No family member was found to carry the mutation at position -34 or any other disease-associated mutation. For further investigation of noncoding CDKN2A mutations that may affect transcription, allele-specific expression analysis was carried out in 31 of the families with at least three affected members who showed either complete or "indeterminate" 9p haplotype sharing without CDKN2A exonic mutations. Reverse transcription polymerase chain reaction and automated sequencing showed expression of both CDKN2A alleles in all family members tested. The lack of CDKN2A promoter mutations and the absence of transcriptional silencing in the germ line of this cohort of families suggest that mutations in the promoter and 5' UTR play a very limited role in melanoma predisposition.

Australia↗

PubMed2001

Longitudinal study of daily intake and excretion of lead in newly born infants.

As an adjunct to a study of lead mobilization during pregnancy and lactation, we have obtained estimates of the daily lead intake and excretion/intake for 15 newly born infants monitored for at least 6 months postpartum. The longitudinal data presented reflect the far lower levels of environmental contribution to lead in blood in the 1990's than that in the earlier studies from the 1970's and early 1980's, the last period for which such dietary information is available in newly born infants. Infants were breast-fed or formula-fed or both and, in the second quarter, were usually fed solid foods (beikost). Lead concentrations were as follows: lead in breast milk, ranged from 0.09 to 3.1 microg/kg with a geometric mean of 0.55 microg/kg, lead in infant formula ranged from 0.07 to 11.4 microg/kg with a geometric mean of 1.6 microg/kg, and lead in beikost ranged from 1.1 to 27 microg/kg with a geometric mean of 2.9 microg/kg. Daily lead intakes ranged from 0.04 to 0.83 microg/kg body weight/day with a geometric mean of 0.23 microg Pb/kg body weight/day, and excretion/intake ranged from 0.7 to 22 with a geometric mean of 2.6. There was no significant difference at the 5% level in lead concentration in daily intakes and excretion/intake for the first quarter versus the second quarter for this small number of subjects. Assuming that there was no contribution from environmental samples such as house dust and ambient air, the contribution of diet to blood has been estimated from lead isotopic measurements with the following ranges: for breast milk only as the dietary source, 40 to 65%; for breast milk and infant formula as the dietary sources, 15 to 70%; and for infant formula and beikost, 20 to 80%. The geometric mean value of the dietary contribution to blood over the 6-month period of approximately 35% is consistent with earlier estimates of uptake of lead in blood in newly born infants when environmental lead concentrations were much higher. Other sources such as air, soil, and dust are considered to contribute minimally to blood lead in these infants because of the low 206Pb/204Pb ratios in environmental media. Thus, we consider that the increased excretion over intake, along with other evidence, reflects mobilization of infant tissues arising especially from rapid bone turnover at this stage of life; the tissue lead has been identified isotopically in urine.

Adolescent↗

PubMed2001

Contribution of lead from calcium supplements to blood lead.

We conducted a case-control study to determine the contribution of lead to blood from consumption of calcium supplements approximating the recommended daily intakes over a 6-month period. Subjects were males and females ages 21 to 47 years (geometric mean 32 years) with a geometric mean blood lead concentration of 2.5 microg/dL. They were subdivided into three groups. One treatment group (n = 8) was administered a complex calcium supplement (carbonate/phosphate/citrate) and the other treatment group (n = 7) calcium carbonate. The control group (n = 6) received no supplement. The lead isotopic compositions of the supplements were completely different from those of the blood of the subjects, allowing us easily to estimate contribution from the supplements. The daily lead dose from the supplements at 100% compliance was about 3 microg Pb. Three blood samples were taken at 2-month intervals before treatment to provide background values, and three were taken during treatment. Subjects in the treatment group were thus their own controls. Lead isotopic compositions for the complex supplement showed minimal change during treatment compared with pretreatment. Lead isotopic compositions in blood for the calcium carbonate supplement showed increases of up to 0.5% in the (206)Pb/(204)Pb ratio, and for all isotope ratios there was a statistically significant difference between baseline and treatment (p < 0.005). The change from baseline to treatment for the calcium carbonate supplement differed from that for both the control group and the group administered the complex supplement. Blood lead concentrations, however, showed minimal changes. Variations in blood lead levels over time did not differ significantly between groups. Our results are consistent with earlier investigations using radioactive and stable lead tracers, which showed minimal gastrointestinal absorption of lead in the presence of calcium (+/- phosphorus) in adults. Even though there is no discernible increase in blood lead concentration during treatment, there are significant changes in the isotopic composition of lead in blood arising from the calcium carbonate supplement, indicating a limited input of lead from diet into the blood. Because calcium carbonate is overwhelmingly the most popular calcium supplement, the changes we have observed merit further investigation. In addition, this type of study, combined with a duplicate diet, needs to be repeated for children, whose fractional absorption of lead is considerably higher than that of adults.

Adult↗

PubMed2001

Integrative neuroimmunomodulation of gastrointestinal function during enteric parasitism.

Enteric helminths have a significant impact on the structure, function, and neural control of the gastrointestinal (GI) tract of the host. Interactions between the host's nervous and immune systems redirect activity in neuronal circuits intrinsic to the gut into an alternative repertoire of defensive and adaptive motor programs. Gut inflammation and activation of the enteric neuroimmune axis play integral roles in the dynamic interaction between host and parasite that occurs at the mucosal surface. Three inter-related themes are stressed in this review to underscore the pivotal role that neural control mechanisms play in the host's GI tract functional responses to enteric parasitism. First, we address the discovery that signaling molecules of both parasite and host origin can reorient the dynamic ecology of enteric host-parasite interactions. Second, we explore what has been learned from investigations of altered gut propulsive and secretomotor reflex activities that occur during enteric parasitic infections and the emerging picture derived from these studies that elucidates how nerves help facilitate and orchestrate functional reorganization of the parasitized gut. Third, we provide an overview of the direct impact that enteric parasitism has on nerve cell function and neurotransmission pathways in both the enteric and central nervous systems of the host. In summary, this review highlights and clarifies the complex mechanisms underlying integrative neuroimmunophysiological responses to the presence of both invasive and noninvasive enteric helminths and identifies directions for future research investigations in this highly important but understudied area.

Animals↗

PubMed2000

Urinary excretion of lead during pregnancy and postpartum.

We have compared lead isotopic ratios and lead concentrations in 53 spot urine and 59 24-h urine samples from 13 subjects covering the interval from pre-pregnancy through 180 days postpartum to estimate the amount of lead excreted in urine and renal clearance relative to blood. The total amount of lead excreted in 24-h urine samples ranges from 0.8 to 5.9 microg Pb with an arithmetic mean of 2.2+/-1.1 microg (geometric mean 1.90 microg). This compares with amounts of 0.9-10 microg of extra lead per day estimated to be released into blood from the skeleton during pregnancy and postpartum. There were no differences in excretion rates during the trimesters of pregnancy and between pregnancy and postpartum time periods. The renal clearance relative to blood ranged from 0.8 to 10 g/h (arithmetic mean 3.2+/-1.9; geometric mean 2.7). Renal clearance relative to blood was somewhat higher in trimesters 2 and 3 compared with postpartum 150-180 days (P = 0.004, 0.006, respectively). Reassessment of earlier published blood and dietary data for Australian pregnant controls indicates there is no increased gastrointestinal absorption of lead during pregnancy and postpartum. This differs from calcium, which shows increased absorption during late pregnancy. In light of the inconvenience of sampling and potential contamination at the low levels of lead found in most of these subjects, we do not consider the 24 h urines to provide sufficient useful information.

Adolescent↗

PubMed2000

Respiratory pathways and oxygen toxicity in Phanerochaete chrysosporium.

Phanerochaete chrysosporium maintained on glucose as the carbon source contained severely impaired mitochondria that were characterised by the loss of both succinate dehydrogenase and cytochrome oxidase activities. These cells maintained a constant value for energy charge using anaerobic metabolism. Cells with these properties express lignin peroxidase when supplied with a pure oxygen atmosphere, which may reflect a response to accumulating reactive oxygen species. Cells maintained on cellulose retained fully functional mitochondria, but expressed lignin peroxidase without being exposed to a pure oxygen atmosphere. In the cells maintained on cellulose, mitochondrial function may be limited by the supply of glucose, leading to the accumulation of reactive oxygen species.

Cellulose↗

PubMed2000

Effects of allogeneic bone marrow transplantation on recipient bone mineral density: A prospective study.

Allogeneic bone marrow transplant (BMT) recipients have many known risk factors for developing decreased bone mineral density (BMD) after transplantation. We performed a prospective sequential evaluation of BMD in the lumbar spine and nondominant hip using dual-energy x-ray absorptiometry (DEXA) in a cohort of 47 adult patients (median age, 43 years) who were undergoing radiation-based BMT for hematologic malignancies. Baseline DEXA studies were performed before BMT and repeated at 3 to 4 months, 6 to 8 months, and 12 to 14 months after BMT. The majority of patients (60%) had been minimally treated with combination cytotoxic chemotherapy, having received no more than 1 treatment regimen before BMT. Graft-versus-host disease prophylaxis consisted of cyclosporine in combination with either methotrexate or prednisone, or both. Mean lumbar spine and hip BMD were normal before BMT (spine: 1.01 g/cm2, z score = 96%; hip: 0.86 g/cm2, z score = 100%) and gradually decreased (spine: 0.98 g/cm2, z score = 94%; hip: 0.76 g/cm2, z score = 91%) at 12 to 14 months. These declines were statistically significant (P < .006 and < .002 for lumbar spine; P < .001 and < .001 for hip). In addition, the sharpest decline occurred during the first 6 months after BMT and was more marked in the hip than the lumbar spine. These data suggest that BMT adversely affects BMD in this patient population.

Absorptiometry, Photon↗

PubMed2000

Experimental autoimmune cholangitis: a mouse model of immune-mediated cholangiopathy.

BACKGROUND: Primary biliary cirrhosis (PBC) is characterised by intra-hepatic immune-mediated cholangiopathy (non-suppurative destructive cholangitis (NSDC)). Although auto-reactive immune responses against pyruvate dehydrogenase complex (PDC) have been characterised in PBC, the lack of an animal model of the disease has limited study of the mechanisms of disease induction and the development of novel approaches to therapy. AIMS: To develop and validate a mouse model of immune-mediated cholangiopathy relevant for future use in the study of the aetio-pathogenesis and therapy of PBC. METHODS: Female SJL/J, C57BL/6, NOD and BALB/c mice were sensitised with PDC, its purified E2/E3BP component, and a PDC-E2 derived peptide p163 (a dominant T-cell epitope in humans) in complete Freund's adjuvant (CFA). Morphological changes were assessed under light microscopy by a hepatic histopathologist blinded to the experimental details. Antibody responses to PDC were studied by ELISA and PDC inhibition assay. RESULTS: An initial series of experiments was performed to survey the susceptibility of female mice of a range of strains to the induction of NSDC by i.p. sensitisation with PDC, PDC-E2/E3BP or p163 in CFA. Although each animal showed a specific antibody response following sensitisation, it was found that NSDC development (assessed at 30 weeks post-sensitisation) was restricted to SJL/J mice following sensitisation with any of the mitochondrial antigen preparations. A subsequent series of experiments was performed to examine the specificity and aetiology of this disease. Significant bile duct lesions were only seen in SJL/J animals following sensitisation with CFA containing PDC, and were absent from CFA only and un-sensitised controls. Kinetic analysis revealed that this pathology developed slowly, but a high incidence of animals with severe lesions was observed after 30 weeks. CONCLUSIONS: We have described a model of experimental autoimmune cholangitis (EAC) with immunological (anti-PDC antibodies) and histological (immune-mediated cholangiopathy) features suggestive of PBC. This model may be useful in further defining the role of self-tolerance breakdown in the development of this condition.

Animals↗

PubMed2000

Secretory autoantibodies in primary biliary cirrhosis (PBC).

It is unclear how breakdown in immune tolerance to the ubiquitous self-antigen pyruvate dehydrogenase complex (PDC), seen in the autoimmune liver disease PBC, gives rise to tissue damage with such a limited distribution (restricted to the liver and salivary and lachrymal glands). One property shared by these tissues is the ability to export secretory IgA by the process of transcytosis. The aim of this study was to address whether active transcytosis of anti-PDC IgA occurs across epithelial surfaces in PBC, a finding that might implicate mucosal specific immune mechanisms in the pathogenesis of this disease. Parotid saliva was collected from PBC patients (n = 44), normal controls (n = 28) and PBC patients post-liver transplantation (n = 11). IgA and secretory component-positive antibodies specific for human PDC were quantified by ELISA and immunoblotting. PBC patients (but not control subjects) had anti-PDC IgA in their saliva. The strong correlation seen between titres detected using anti-IgA and anti-secretory component antibodies suggests that this is predominantly secretory IgA reaching the saliva by the active process of epithelial transcytosis. Titres of anti-PDC IgA remain high in PBC patients saliva post-liver transplant. Findings from studies of IgA in viral infection models raise the possibility that anti-PDC IgA could, whilst undergoing transcytosis, bind to newly translated PDC components in the cytoplasm of the epithelial cells transporting them out of the cell and inducing metabolic damage. This model would, if correct, help to explain the mechanism and tropism of tissue damage in PBC and the aberrant pattern of expression of PDC on the apical surface of biliary and salivary epithelial cells reported in this disease.

Adult↗

PubMed2000

Urinary lead isotopes during pregnancy and postpartum indicate no preferential partitioning of endogenous lead into plasma.

We have compared lead isotopic ratios and lead concentrations in 51 matched blood and spot urine samples from 13 subjects covering the interval from before pregnancy through 180 days postpartum to evaluate whether mobilization of lead from the maternal skeleton is preferentially partitioned into plasma; we have used urine as an isotopic proxy for plasma. There was no statistically significant difference in the lead 206/lead 204 and lead 207/lead 206 ratios over pregnancy. The urine data for the postpartum period are in the opposite relationships to that predicted for a preferential partitioning hypothesis. These data provide no support for the hypothesis that lead released from the skeleton is preferentially partitioned into plasma.

Adolescent↗

PubMed2000

Suppression of food intake is linked to enteric inflammation in nematode-infected rats.

Our aim was to investigate the cause-effect relationship between intestinal inflammation induced by infection with enteric stages of Trichinella spiralis and decreased host food intake. A suppression of food intake in T. spiralis-infected rats occurred within the first 24 h postinfection (PI) and was maximized by day 6 PI. Food intake, cumulated over an 8-day PI period, decreased by 59% compared with uninfected animals. The anti-inflammatory glucocorticoid betamethasone 21-phosphate was orally administered to rats in their drinking water to suppress T. spiralis-induced jejunal inflammation. When treated with a low dose of glucocorticoid (5.2 microg/ml), food intake in infected rats was still significantly reduced, but only by 21% compared with glucocorticoid-treated, uninfected rats. At the highest glucocorticoid dose (10.4 microg/ml) administered, infection-induced reduction in food intake was not different from that of glucocorticoid-treated, uninfected counterparts. The elevation in jejunal myeloperoxidase activity caused by infection was also significantly blunted by oral glucocorticoid treatment. Our results suggest that suppressed host food intake during enteric T. spiralis infection is directly linked to intestinal inflammation.

Administration, Oral↗

PubMed1999

Enhanced ultrasensitive detection of structurally diverse antigens using a single immuno-PCR assay protocol.

Our studies of DNA damage and repair in autoimmune disease, lymphomagenesis, and carcinogenesis, require identification of an immunoassay approach that is capable of ultrasensitive detection in a routine human tissue biopsy of several physicochemically diverse antigens, some of which will be present at very low level. Immuno-polymerase chain reaction (immuno-PCR) is a recently described method for ultrasensitive antigen detection that combines the amplification power of PCR with a method similar to a standard antibody capture, enzyme-linked immunosorbent assay (ELISA). As a test of the universality of immuno-PCR, and as an assessment of the suitability of this method for our studies, we used a single immuno-PCR protocol to assay purified forms of the following physicochemically diverse antigens: oligomeric pyruvate dehydrogenase complex (PDC; Mr 8.5 x 10(6)), the promutagenic DNA base adduct O(6)-methylguanosine (Mr 298) and its monomeric repair enzyme, O(6)-methylguanine-DNA methyltransferase (MGMT; Mr 22,000), and a peptide from the N-terminus of MGMT (Mr 2310). We found that all antigens could be ultrasensitively assayed using the single immuno-PCR protocol. Assay limits observed using antigen-specific (primary) antibodies at 1 microg/ml, were in the approximate range of 10(2)-10(9) molecules, with O(6)-methylguanosine being detected most sensitively. Sensitivity of the antigen assay appeared to positively correlate with primary antibody titres determined by ELISA. Furthermore, we observed a substantial increase in detection sensitivity for all antigens by the use of primary antibodies at the higher level of 10 microg/ml. The latter approach permitted antigen assay within the approximate range of 10(0)-10(7) molecules. The combination of higher titre primary antibodies and their use at higher input level, produced an increase of immuno-PCR assay sensitivity of up to four orders of magnitude greater than those previously reported through the use of this assay to measure other antigens. This represents up to a nine order of magnitude increase in immunoassay sensitivity compared to ELISA. Our findings provide compelling evidence that immuno-PCR is indeed a universal ultrasensitive antigen detection method. Using the indicated assay enhancements. immuno-PCR performed as detailed here can offer greatly increased sensitivity for antigen measurement compared to other methods. Thus, our findings suggest that parallel quantitation of several different antigens in very small samples of human tissue will be readily attainable using immuno-PCR.

Amino Acid Sequence↗

PubMed1999

Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis.

Autoantibodies to the pyruvate dehydrogenase complex (PDC) are present in the serum of more than 95% of patients with primary biliary cirrhosis (PBC), the major epitope being the inner lipoyl domain of the E2 component. Immunoblotting suggests a similar prevalence of antibodies to a tightly associated lipoic acid-containing protein, E3 binding protein (E3BP). Attempts to resolve E3BP from E2 have been unsuccessful, restricting study of the nature and significance of antibody responses to the individual proteins. In particular, it is unclear (1) whether there is true cross-reactivity between E3BP and E2 and, if so, which is the originating response and (2) whether autoantibodies preferentially bind a lipoylated epitope on E3BP as is the case with PDC-E2. In this study, complementary DNAs encoding rE2, full-length rE3BP, its single lipoyl domain (rLip), and core domain (rE3BPCore) were cloned, and the proteins were expressed in Escherichia coli. Sera from 47 PBC patients were studied by immunoblotting and enzyme-linked immunosorbent assay (ELISA) against rE2, rE3BP, rE3BPCore, and both unlipoylated (U) and lipoylated (L) rLip. All sera were reactive by ELISA to some degree with all recombinant proteins except rE3BPCore, to which only 6 of 47 showed any reactivity. Significant correlations (P <.0001) were observed when comparing absorbance values for rE3BP with both rLip (U) (r = 0.793) and (L) (r = 0.963). The mean absorbance for rLip (U, 0.26 +/- 0.05) was, however, significantly lower than the absorbance for rLip (L) (0.78 +/- 0.12; P <.0001). After probing by immunoblotting and elution of antibodies from rE2 and rE3BP, subsequent reprobing against the components in whole PDC revealed true cross-reactivity. In summary, the response to E3BP is primarily directed against the lipoylated domain of the protein. It still remains unclear, however, whether the initial breakdown of tolerance is to E2 or E3BP.

Antibody Formation↗

PubMed1999

Breakdown of tolerance to pyruvate dehydrogenase complex in experimental autoimmune cholangitis: a mouse model of primary biliary cirrhosis.

The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by autoreactive responses to a highly conserved self-antigen, pyruvate dehydrogenase complex (PDC). We recently reported the development of PBC-like lesions in SJL mice sensitized with PDC and have named this model disease experimental autoimmune cholangitis (EAC). In the present study, the breakdown of tolerance to PDC has been investigated in animals sensitized for EAC. Splenic mononuclear cells from SJL mice sensitized with bovine heart PDC (bPDC) in adjuvant showed T-cell proliferative and mixed Th1/Th2 cytokine secretory responses following in vitro stimulation with bPDC. Despite the likelihood of extensive sequence homology with mouse PDC (there is a greater than 95% sequence identity between rat and human PDC-E2 subunits), bPDC was highly immunogenic inducing significant T- and B-cell responses in the absence of any form of adjuvant. The multi-subunit quaternary structure of intact PDC was critical for this immunostimulatory activity because no response was produced by sensitization with monomeric recombinant PDC-E2 inner lipoyl domain. Mice sensitized with bPDC and CFA developed, within 2 weeks of sensitization, high-titer antibody responses reactive with bPDC that were fully cross-reactive with the murine homologue. Breakdown of T-cell tolerance to self-PDC took significantly longer, not being seen until 20 weeks postsensitization; a similar length of time to that previously shown to be required for EAC lesion development. Conclusions drawn from these data may have important implications for our understanding, and therapeutic manipulation, of PBC in humans.

Animals↗

PubMed1999

Ethnicity and attitudes towards life sustaining technology.

The ethical and legal implications of decisions to withhold and withdraw life support have been widely debated. Making end-of-life decisions is never easy, and when the cultural background of doctor and patient differ, communication about these issues may become even more difficult. In this study, we examined the attitudes of people aged 65 and older from different ethnic groups toward foregoing life support. To this end, we conducted a survey of 200 respondents from each of four ethnic groups: European-American, African-American, Korean-American and Mexican-American (800 total), followed by in-depth ethnographic interviews with 80 respondents. European-Americans were the least likely to both accept and want life-support (p < 0.001). Mexican-Americans were generally more positive about the use of life-support and were more likely to personally want such treatments (p < 0.001). Ethnographic interviews revealed that this was due to their belief that life-support would not be suggested if a case was truly hopeless. Compared to European-Americans, Korean-Americans were very positive regarding life-support (RR = 6.7, p < 0.0001); however, they did not want such technology personally (RR = 1.2, p = 0.45). Ethnographic interviews revealed that the decision of life support would be made by their family. Compared to European-Americans, African-Americans felt that it was generally acceptable to withhold or withdraw life-support (RR = 1.6, p = 0.06), but were the most likely to want to be kept alive on life-support (RR = 2.1, p = 0.002). Ethnographic interviews documented a deep distrust towards the health care system and a fear that health care was based on one's ability to pay. We concluded that (a) ethnicity is strongly related to attitudes toward and personal wishes for the use of life support in the event of coma or terminal illness, and (b) this relationship was complex and in some cases, contradictory.

Black or African American↗

PubMed1999

T cell responses to the putative dominant autoepitope in primary biliary cirrhosis (PBC).

PBC is characterized by T cell-mediated destruction of the biliary epithelial cells lining the small intrahepatic bile ducts. The E2 and E3 binding protein (E3BP (protein X)) components of pyruvate dehydrogenase complex (PDC) are disease-specific autoantigens in PBC. Attempts to localize the T cell autoepitopes within PDC-E2 have, however, generated contradictory results. One study has suggested the presence of T cell epitopes throughout PDC-E2, whilst another has identified a single dominant 14 amino acid T cell epitope (p163) spanning the lipoic acid binding lysine residue in the inner lipoyl domain (ILD) of PDC-E2. The aim of the current study was to determine the prevalence of T cell responses to p163 and PDC-E2 ILD, and the role played by lipoylation of these antigens in their immunogenicity, in a UK PBC population. We found that the majority of the PBC patients showing a 6-day peripheral blood T cell proliferative response to native human PDC also responded, in a MHC class II-restricted fashion, to biochemically purified PDC-E2 and E3BP (which co-purify) (9/10 positive (SI > 2.76), mean SI 5.74 +/- 5.04 (PDC-E2/E3BP) versus 6.67 +/- 3.84 (PDC), P = NS), implying that the important PBC-specific T cell epitopes are contained within the PDC-E2 or E3BP components of PDC. Only a minority of patients responsive to PDC, however, responded to either lipoylated recombinant PDC-E2 ILD (4/10 positive, mean SI 1.98 +/- 1.24, P < 0.005 versus PDC response) or lipoylated p163 (4/12 positive, mean SI 1.90 +/- 1.58, P < 0.001). The lipoylation state did not affect the T cell response to either ILD or p163. Our findings suggest that in some UK patients with PBC there are immunodominant T cell autoepitopes within PDC-E2/E3BP which are outside the ILD of PDC-E2.

Autoantigens↗

PubMed1999

Psychometric properties of a Chinese translation of the SF-36 health survey questionnaire in the Well Elderly Study.

OBJECTIVES: To evaluate the psychometric properties of a Chinese translation of the 36-item Short Form Health Survey (SF-36) in the Well Elderly Study--a randomized clinical trial designed to evaluate the effectiveness of preventive occupational therapy services specifically tailored for multiethnic, independent-living, older adults. METHODS: Translation and back-translation procedures were used to obtain appropriate meanings for the SF-36 survey questions and to ensure face, functional, and conceptual equivalence. RESULTS: Statistical analyses demonstrated satisfactory reliability and validity, with the results generally similar to those reported for older Anglo adults. DISCUSSION: As the percentage of older adults of diverse ethnicity increases, the need for health care research and service strategies that can effectively include multiple ethnicities becomes paramount. The results of this study suggest that a Chinese-translated SF-36 can be used to assess multiple dimensions of health in a Mandarin-speaking population of older adults.

Aged↗