Quarterly Journal of Medicine最新文献

Efficient antigen presentation requires the provision of a costimulatory signal, the best characterized of which is B7/BB1. It is unclear whether thyroid cells expressing class II molecules can present autoantigens to T cells, although this has been suggested as an important mechanism in the initiation of Graves' disease and Hashimoto's thyroiditis. We have found that thyroid cells from patients with thyroid autoimmunity do not express B7/BB1 in vivo or in vitro, even after activation with the cytokines interleukin-1 or gamma-interferon, or with a phorbol ester. Increased numbers of CD20+ B cells and CD14+ dendritic cells expressing B7/BB1 were found in intrathyroidal lymphocyte preparations from such patients compared to peripheral blood. These results suggest that conventional antigen-presenting cells rather than thyroid cells provide B7/BB1 costimulatory activity in autoimmune thyroid disease, and argue against a role for the thyroid cells themselves in autoantigen presentation to T cells via the B7/BB1 pathway.

We have previously shown that the 90 kDa heat-shock protein (hsp90) is notably elevated in lupus patients with active neuro-psychiatric (NP) and/or cardio-respiratory (CR) disease. This elevation is dependent upon enhanced transcription of the hsp90 beta gene. Serial studies have shown that changes in hsp90 levels have a high level of sensitivity for changes in activity of NP, CR, haematological and renal SLE. We now present evidence that overexpression of hsp90 in lupus patients is associated with the presence of the anti-phospholipid syndrome, and with the absence of the HLA allo-/haplotypes most commonly found in this particular cohort of patients. We conclude that the upregulation of hsp90 expression in SLE has a genetic basis, and that this may be directly involved in pathogenesis in subsets of patients with this disease.

The search for genes involved in the aetiology of primary biliary cirrhosis (PBC) has centred on the major histocompatibility complex (MHC) on chromosome 6. Genotyping studies have confirmed an association with HLA class II allele DR8. We investigated polymorphisms in two newly identified genes (TAP1 and TAP2) situated close to the DR locus and thought to encode membrane transporter molecules involved in endogenous antigen processing. Genomic DNA extracted from PBC patients was compared with local healthy controls. TAP1 was analysed by amplification refractory mutation system (ARMS) PCR, and two alleles (A and B) were identified. In 126 PBC patients and 116 controls, allele frequencies were (A:B) 81:19% and 79:21%, respectively (NS). TAP2 analysis was by PCR followed by Bfal restriction digest, and again two alleles (A and B) were identified. Their frequencies in 109 PBC patients and 96 controls were (A:B) 76:24% and 73:27%, respectively (NS). No TAP1-TAP2 haplotype was associated with PBC. TAP allele frequencies were estimated within the DR8 subgroups (22 PBC, 14 controls). B allele frequency for TAP1 was increased in both DR8-positive PBC patients and controls compared with DR8-negative patients and controls (41% vs. 14% in PBC; 43% vs. 18% in controls), but no disease association was found. However, the increased frequency of TAP1B in DR8-positive subjects (42% DR8-positive vs. 16% DR8-negative, p < 0.001) indicates linkage disequilibrium between these two loci.

It has been shown that myocardial infarction survivors are more likely to carry an insertion/deletion polymorphism (I/D) of the angiotensin-converting-enzyme (ACE) gene than age-matched population controls. To test whether the association with coronary risk had been under-estimated, the frequency of the ACE I/D was studied in 213 fatal cases of definite and possible myocardial infarction which came to autopsy in the Belfast MONICA Project area. In comparison to controls from the same population, the autopsy cases had an increased frequency of the ACE D allele (p < 0.02). The overall odds ratios were 2.2 for DD vs. II, and 1.8 for ID vs II (test for trend p = 0.01). The findings bear out the hypothesis that the ACE I/D polymorphism is a risk factor for fatal myocardial infarction and sudden cardiac death.

Twenty-one patients with membranous nephropathy, heavy proteinuria and progressive renal failure were treated with alternating monthly cycles of corticosteroids and chlorambucil for six months. Four patients received repeat courses. After a median period of follow-up of 39 months, three patients had died, six were receiving renal replacement therapy or had serum creatinine > 500 mumol/l, and one had progressive renal failure. Eleven patients had either stable or improved renal function, as judged by serum creatinine concentration. Of these eleven, four patients were in partial remission (daily protein excretion 0.2-2.0 g), and two were in complete remission. There was a tendency for those who received intravenous methylprednisolone to have a more favourable outcome. There was a high incidence of side-effects, with significant complications related to drug therapy observed in > 50% of subjects. Although individual patients appeared to respond well, sometimes dramatically, these results are less encouraging than other reports. We would urge caution in the use of this form of therapy, particularly in older patients who may have occult neoplasms, impaired glucose intolerance or pre-existing cardiac disease.

We studied 16 patients aged 77-88 years to determine whether elderly patients gain significant benefit from dual-chamber (DDD) compared with single-chamber ventricular demand (VVI) pacing. The study was designed as a double-blind randomized two-period crossover study--each pacing mode was maintained for 7 days. End points included: (i) overall symptoms scores; (ii) exercise tests related to daily activities; and (iii) perceived level of difficulty (Borg score). The mean symptom score in DDD mode was 7.07 (6.38) vs. 12.27 (7.29) in VVI mode (p < 0.006). Dizziness, breathlessness and fatigue were the most noticed symptoms during VVI pacing. One patient dropped out from follow-up and three patients requested early reprogramming, all from VVI mode. Overall, no patient preferred VVI mode, 11 preferred DDD mode and four expressed no preference. There were significant improvements in all objective test performances in DDD mode. Mean (SD) total Borg scores in DDD mode and VVI mode were 36.57 (5.85) and 41.93 (6.49), respectively (p < 0.002). Ventricular demand pacing in elderly patients with complete heart block is associated with higher symptom scores, reduced exercise ability and greater perceived exercise difficulty compared with dual-chamber pacing.