Grip strength and subjective fatigue in patients with primary biliary cirrhosis.
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Fatigue↗
Biomedical subjects
D E Jones
Publications and source records attributed to D E Jones.
Aural abscesses in wild-caught box turtles (Terapene carolina): possible role of organochlorine-induced hypovitaminosis A.
Wild-caught box turtles (Terapene carolina carolina) with aural abscesses were observed over a period of several years. Histopathologic evaluation of epithelial tissues (conjunctiva, pharynx, trachea, auditory tube) revealed mucosal hyperplasia and squamous metaplasia, and accumulated keratin-like material in the middle ear cavity. These manifestations suggested the possibility of vitamin A deficiency. A nonsignificant trend toward reduced serum and hepatic vitamin A levels was observed in turtles with abscesses (mean serum and hepatic vitamin A levels 71 and 49% of respective levels in turtles without abscesses). Three organochlorine (OC) compounds (alpha-benzene hexachloride, heptachlor epoxide, and oxychlordane) and total (microg/g) OC compounds were significantly higher in turtles with abscesses compared with turtles without abscesses. No OC compounds were higher in turtles without abscesses compared with turtles with abscesses. These data suggest a possible effect of environmental chemicals on metabolism or utilization of vitamin A in wild box turtles, resulting in hypovitaminosis A.
Abscess↗
IL-4-independent inhibition of IL-12 responsiveness during Leishmania amazonensis infection.
Leishmania amazonensis induces a nonhealing infection in C3H mice, whereas infection with Leishmania major is self-healing. We found that C3H mice infected with L. amazonensis exhibited decreased IL-12 production, which could account for the susceptibility to this organism. However, exogenous IL-12 administration failed to induce a healing immune response. The failure of L. amazonensis-infected C3H mice to respond to IL-12 was associated with a specific defect in IL-12 receptor beta2 (IL-12Rbeta2) mRNA expression by CD4+ T cells. Furthermore, decreased IL-12Rbeta2 mRNA expression correlated with a decrease in the IL-12-signaling capacity of the lymph node (LN) cells. IL-4 did not contribute to susceptibility or down-regulation of the IL-12Rbeta2 subunit, because IL-4-/- mice remained susceptible to L. amazonensis infection, even after IL-12 administration, and CD4+ cells from infected IL-4-/- mice also had reduced expression of IL-12Rbeta2 mRNA. These results demonstrate that regulation of the IL-12 receptor, independent of IL-4, is a point of control for the immune response to leishmaniasis. In contrast to experimental L. major infections, where host genetics control susceptibility, these studies demonstrate that the lack of IL-12 responsiveness may be dictated by the pathogen, rather than the host.
Animals↗
Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis.
Genetic susceptibility to type 1 autoimmune hepatitis is indicated by a preponderance of female subjects and strong associations with human leukocyte antigens (HLA) DRB1*0301 and DRB1*0401. The gene encoding cytotoxic T-lymphocyte antigen-4 (CTLA-4) on chromosome 2q33 may also influence autoimmunity. To determine the frequency and significance of the exon 1 adenine (A)-guanine (G) base-exchange polymorphism for CTLA-4 in patients with type 1 autoimmune hepatitis, 155 northern European Caucasoid patients and 102 ethnically-matched control subjects were tested by polymerase chain reaction. The genotype distribution was significantly different in patients compared to controls (AA = 50/155 patients vs. 51/102 controls; AG = 84/155 patients vs. 38/102 controls; GG = 21/155 patients vs. 13/102 controls, chi(2) = 8.94, P =.011). This difference was caused by a significant over-representation of the G allele in patients compared to controls (105/155 patients vs. 51/102 controls, chi(2) = 8.34, P =.004, odds ratio = 2.12). The GG genotype was associated with a significantly higher mean serum aspartate transaminase level (P =. 03), greater frequency of antibodies to thyroid microsomal antigens (P =.004) and was found more commonly in patients with HLA DRB1*0301 (P =.02). Treatment outcomes, however, were not affected by the genotype. The CTLA-4 G allele is more common in patients with type 1 autoimmune hepatitis and may represent a second susceptibility allele. Furthermore, there may be synergy between the HLA-DRB1*0301 and the GG genotype in terms of disease risk.
Abatacept↗
CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis.
BACKGROUND/AIM: Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease thought to develop through a complex interaction of genetic and environmental factors. It is characterised by T-cell-mediated non-suppurative destructive cholangitis. We have studied the polymorphic cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene, which encodes a molecule that is a vital negative regulator of T-cell activation, as a candidate susceptibility locus for PBC. This gene on chromosome 2q33 (designated IDDM12) is associated with susceptibility to both type 1 diabetes and autoimmune thyroid disease. METHODS: The CTLA-4 exon 1 polymorphism (A/G encoding for threonine or alanine, respectively) was genotyped via polymerase chain reaction in 200 Caucasoid PBC patients and 200 non-related geographically matched Caucasoid controls. RESULTS: There was significant overrepresentation of the G/A and G/G genotypes in PBC patients compared to controls (G/A 53% vs 40%; G/G 18.5% vs 10.5%, Odds Ratio (OR)=2.45 [95% CI 1.6-3.7], p=0.00006, chi2=19.4). Likewise, there was a significant difference in allele frequencies (G encoding alanine at codon 17, PBC 0.45 vs controls 0.305: OR=1.9 [1.4-2.5], p<0.0002). This association remained significant (p=0.00027) when patients with autoimmune thyroid disease were excluded from the analysis. CONCLUSIONS: The CTLA-4 exon 1 polymorphism is the first non-major histocompatibility complex gene to be identified as a susceptibility locus for PBC. Our data support the hypothesis that clinically distinct autoimmune disease may be controlled by a common set of susceptibility genes.
Abatacept↗
Fetal microchimerism: an aetiological factor in primary biliary cirrhosis?
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Animals↗
Validation of a fatigue impact score in primary biliary cirrhosis: towards a standard for clinical and trial use.
BACKGROUND/AIMS: Fatigue is the commonest symptom of the chronic liver disease primary biliary cirrhosis (PBC). PBC is increasingly being diagnosed earlier in its natural history at a stage when concerns about progression to liver failure may be less prominent than current symptoms. The importance of symptomatic treatment is therefore increasingly being recognised. Research into the aetiology and treatment of fatigue in PBC has been hampered by the lack of relevant, reproducible measures of fatigue severity. The aim of this study was to validate the Fisk Fatigue Severity Score (FFSS), a measure of the impact of fatigue on daily living, for use in PBC and to use the FFSS to study the severity and correlates of fatigue in this condition. METHODS: Fifty-eight patients with PBC and 31 matched control patients attending hospital for nonhepatic disease were studied. The reproducibility of FFSS was assessed over periods from 1 hour to 1 month. Fatigue, as measured by FFSS, was compared in PBC patients and controls. The severity of fatigue in the patients with PBC was correlated with other symptoms and with established biochemical and histological markers of severity. RESULTS: The FFSS questionnaire was acceptable to patients and had reasonable intra-observer variation (coefficient of reproducibility 13% of mean value at 1 hour). The FFSS was more reproducible than a visual analogue scale. FFSSs varied over 4 weeks by up to 36%. Median FFSS's were 2.3 times higher in PBC patients than controls (p<0.005). There were no associations between FFSS and patient age, disease duration, or histological or biochemical markers of severity. CONCLUSIONS: The FFSS is a highly acceptable, internally consistent and reproducible measure of fatigue severity in PBC. We advocate its use in clinical assessment of patients, in studies of the aetiology of fatigue in PBC and, most importantly, in therapeutic trials of symptomatic treatment.
Clinical Trials as Topic↗
Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by immune-mediated destruction of the biliary epithelial cells (BEC) lining the intrahepatic bile ducts (non-suppurative destructive cholangitis (NSDC)). Autoantibody and autoreactive T-cell responses specific for the self-antigen pyruvate dehydrogenase complex (PDC) are almost ubiquitous in PBC patients, leading to the view that the disease has an autoimmune aetiology. Autoreactive responses in PBC appear to be directed at the E2 and at the E3-binding protein (E3BP) (protein X) components of PDC, with the dominant B-cell and T-cell epitopes in E2 (fewer data are available for E3BP) spanning the inner (of two) lipoic acid-binding domains. The causal link between the breakdown of self-tolerance to PDC (particularly at the T-cell level) and the development of NSDC has been emphasised by the demonstration, in a murine model (experimental autoimmune cholangitis), that sensitisation with PDC of mammalian origin results in a breakdown of both B-cell and T-cell tolerance to murine PDC accompanied by the development of NSDC. An increasing understanding of the role played by PDC-specific autoreactive T cells in the pathogenesis of PBC has led us to examine the role played by the target cells in PBC (BEC) in both the inducer and effector mechanisms responsible for PBC.
Acyltransferases↗
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↗
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↗
Presentation and mortality of primary biliary cirrhosis in older patients.
OBJECTIVES: many patients with primary biliary cirrhosis present for the first time aged over 65, but it is unclear whether the disease is different in older patients. We have examined presentation and mortality in relation to age at which primary biliary cirrhosis was first suspected clinically. DESIGN: we identified 1023 patients from our regional primary biliary cirrhosis database with definite or probable primary biliary cirrhosis (689 definite); 397 (39%) presented aged > or =65. Definite primary biliary cirrhosis was defined as a positive antimitochondrial antibody titre > or =1/40, abnormal liver enzymes and compatible/diagnostic histology; probable as the presence of two of these indications. RESULTS: there was no difference in presenting clinical features between the older and younger groups. Older patients were significantly less likely than younger to have had liver biopsy (50% vs 78%; P < 0.001). The 1023 patients had been followed for 8561 patient years. Follow-up was shorter (5.9+/-4 vs 9.8+/-5.5 years; P < 0.001) in the older group because of higher cumulative mortality (59% vs 33%; P < 0.001). Liver-related deaths were significantly commoner in the older group (18% vs 13%; P < 0.05). The mortality ratio for liver deaths (liver deaths per year of follow-up) was 2.4 times higher in the older group (0.031 vs 0.013). CONCLUSIONS: patients with primary biliary cirrhosis who are over and under 65 have similar features on presentation. The annual risk of liver death is 2.4 times higher in those presenting over 65, reaffirming the importance of age as an independent prognostic factor in an unselected primary biliary cirrhosis population.
Adult↗
Autoantigens in primary biliary cirrhosis.
The automimmune liver disease primary biliary cirrhosis (PBC) is characterised by serum autoantibodies directed at mitochondrial and nuclear antigens (seen in most patients and a subset of patients, respectively). The antimitochondrial antibodies (AMA) characteristic of PBC are directed at members of the 2-oxoacid dehydrogenase components of multienzyme complexes; in particular, the E2 and E3 binding protein (E3BP) components of the pyruvate dehydrogenase complex (PDC). The presence of autoantibodies reactive with PDC-E2 and/or E3BP is strongly predictive of the presence of PBC. Therefore, the detection of these antibodies plays a very important role in the diagnosis of PBC. Originally demonstrated using immunofluorescence approaches, AMA can now be detected by the use of commercially available enzyme linked immunosorbent assays (ELISAs). Although the ELISA based approaches have advantages in terms of laboratory practicality, they are slightly less sensitive for the diagnosis of PBC than immunofluorescence (occasional patients with PBC show reactivity with PDC related antigens not present in the antigen preparations available for use with ELISA). Therefore, immunofluorescence should continue to be available as a complementary diagnostic test for use in occasional patients. In a subset of patients with PBC, autoantibodies are directed at increasingly well characterised nuclear antigens. Antinuclear antibody (ANA) positive patients are typically AMA negative. There are no significant differences in disease phenotype between AMA positive and AMA negative groups. At present, the clinical detection of ANA is mostly by Hep2 immunofluorescence, although ELISA kits for individual nuclear antigens are increasingly becoming available.
Antigens, Nuclear↗
Primary biliary cirrhosis: new perspectives in diagnosis and treatment.
Primary biliary cirrhosis (PBC) is a chronic autoimmune disease characterised by cholestatic liver function tests, antimitochondrial antibodies, and abnormal liver histology. Early descriptions of a rare rapidly progressive disease no longer reflect the more indolent progress often seen today. Many patients have significant long term morbidity through symptoms such as fatigue and itch with a minority progressing to liver failure and need for transplantation. The current data on the diagnosis, clinical progression, and treatment of PBC are reviewed.
Humans↗
Multi-step polymer-assisted solution-phase (PASP) library synthesis of functionalized diaminobenzamides.
A parallel solution-phase library synthesis of functionalized diaminobenzamides is described. The four-step library synthesis is accomplished using polymer-assisted solution-phase (PASP) synthesis techniques. This high-yielding, multi-step sequence utilizes sequestering resins for the removal of reactants, reactant by-products, and employs a resin capture/release strategy as a key library synthesis step. Step one of the sequence relies on the displacement of an activated fluoro-group from the aromatic ring of 1a, b with a variety of primary amines to introduce the first diversity position. Step two is hydrolysis of the benzoate ester to a benzoic acid which is subsequently captured on a polyamine resin, washed, and released to give 4a, b in pure form. Step three utilizes PASP resins to mediate the amide coupling of a benzoic acid with a variety of primary amines to give the aminonitrobenzamides 5a, b and introduces the second diversity position. Step four is the parallel reduction of the aminonitrobenzamides 5a, b to the functionalized diaminobenzamides 6a, b. This library synthesis proceeds with high overall purities which average 80 % over the 4-step sequence.
Amines↗
Neurodevelopmental effects: making the case for biologic plausibility.
It has been suggested that the most critical missing link between science and policy is causality; that is, the establishment of a definite cause-effect relationship between exposure and adverse health effects. As has been clearly demonstrated by the decades-long tobacco debate, causality is extremely difficult to establish with absolute certainty, particularly in the minds of scientists. Because of this, it has been suggested that a "weight of evidence" approach based on biologic plausibility should be used as a surrogate for causality when translating science into policy and public health practice. In the case of neurodevelopmental effects, the case for biologic plausibility is supported by scientific findings from three broad areas consisting of wildlife biology, toxicology, and epidemiology. A striking example of this is provided by research findings from the Great Lakes Basin, an area which has been the focus of significant scientific research for the last thirty years in these three broad areas. In this paper, we examine relevant findings from the Great Lakes Basin and elsewhere as they relate to establishing and supporting the biologic plausibility of neurodevelopmental effects associated with environmental exposures to persistent toxic substances.
Animals↗
The integral divalent cation within the intermolecular purine*purine. pyrimidine structure: a variable determinant of the potential for and characteristics of the triple helical association.
In vitro assembly of an intermolecular purine*purine.pyrimidine triple helix requires the presence of a divalent cation. The relationships between cation coordination and triplex assembly were investigated, and we have obtained new evidence for at least three functionally distinct potential modes of divalent cation coordination. (i) The positive influence of the divalent cation on the affinity of the third strand for its specific target correlates with affinity of the cation for coordination to phosphate. (ii) Once assembled, the integrity of the triple helical structure remains dependent upon its divalent cation component. A mode of heterocyclic coordination/chelation is favorable to triplex formation by decreasing the relative tendency for efflux of integral cations from within the triple helical structure. (iii) There is also a detrimental mode of base coordination through which a divalent cation may actively antagonize triplex assembly, even in the presence of other supportive divalent cations. These results demonstrate the considerable impact of the cationic component, and suggest ways in which the triple helical association might be positively or negatively modulated.
Base Pairing↗
Development of autoimmune hepatitis following liver transplantation for primary biliary cirrhosis.
Two patients undergoing liver transplantation for classical end-stage primary biliary cirrhosis (PBC) are described, who went on to develop de novo autoimmune hepatitis (AIH) in the transplanted liver. The presentation, in both instances, was with malaise and lethargy. Markedly elevated serum transaminases were found, together with a raised serum IgG and/or globulin fraction and histological features on liver biopsy typical of AIH. Both cases had had changes in their immunosuppressive therapy before the onset of AIH episodes, and both rapidly responded to reinstitution of steroid therapy. The finding, in each case, of a coincidental multiple HLA class I allele match between the recipient and their liver donor suggests that HLA class I-restricted mechanisms may play an important role in the pathogenesis of AIH.
Female↗
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↗