Biomedical subjects
Publications and source records attributed to M D'Souza.
A case of multiple trichoepitheliomas associated with epidermal cysts is reported. The trichoepithelioma lesions were florid and extensive with large nodulo-cystic lesions on the face and a new variant simulating hidradenitis suppurativa near the gluteal cleft.
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3'-Phosphoadenosine 5'-phosphosulfate (PAPS) functions as the high-energy sulfate donor for sulfate ester synthesis in all higher organisms. This activated sulfate, like its adenosine 5'-phosphosulfate precursor, is both chemically labile and vulnerable to sulfohydrolase degradation. These obstacles have limited the utility of the native PAPS in the purification and mechanistic description of the numerous PAPS-utilizing enzymes. This paper describes the synthesis of the 2'- and 3'-isomers of a nonhydrolysable, and thus stable, PAPS analog, beta-methylene-PAPS, from the previously described beta-methylene-APS (L. Callahan et al., Anal. Biochem. 177, 67-71, 1989). The method involves phosphorylation of beta-methylene-APS with trimetaphosphate and separation of the resulting mixed 2'(3')-isomers by ion-pair reverse-phase HPLC. The utilization of this analog as an inhibitor of APS kinase and PAPS translocase, two of the numerous PAPS-utilizing activities, as well as an affinity ligand for purification of APS kinase, is described.
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We examined the polymorphism of DR2,DQw1 haplotypes in Epstein-Barr virus-transformed B-lymphoblastoid cell lines (HTCs) and unrelated (32 Canadian Caucasians and 24 Asian Indians) individuals by restriction fragment length polymorphism (RFLP) and oligonucleotide typing. The data demonstrate that three subtypes of DR2,DQw1 haplotypes, DRw15(B1.1501).DQw6a(A1.0102,B1.0602),DRw15(B1.1502). DQw6b(A1.0103,B1.0601), DRw16(B1.1601).DQw5(A1.0102,B1.0502) are present in HTCs and Canadian Caucasians. Of these, DRw15(B1.1501).DQw6a (A1.0102,B1.0602) haplotype was present in majority (81.3%) of Caucasians. Among Asian Indians, this haplotype was present only in one DR2,DQw1-positive individual. In addition, three new haplotypes representing different combinations of DRB1, DQA1 and DQB1 genes were demonstrable in Asian Indians. These new haplotypes are DRw15(B1.1501).DQw6b(A1.0103,B1.0601),DRw15(B1.1501). DQw5(A1.0102,B1.0502), and DRw15(B1.1501).DQw6c(A1.0102, B1.0601). The most frequent haplotypes among Asian Indians were DRw15(B1.1502).DQw6b(A1.0103,B1.0601) and DRw15(B1.1501). DQw6b(A1.0103,B1.0601). The distribution of subtypes of DR2,DQw1 haplotypes in Asian Indians was significantly different from that in Canadian Caucasians. The results in the present study have important implications for HLA and for HLA-disease associations.
A strong association between HLA-DR4 and rheumatoid arthritis (RA) has been found in a number of populations. In contrast, the incidence of DR2 is decreased in patients with RA, suggesting that this specificity may confer some protection against the disease. A number of subtypes of DR2 have been defined by serology, by responses in mixed lymphocyte culture reaction, and, more recently, by restriction fragment length polymorphism. These subtypes of DR2 are in linkage disequilibrium with different subspecificities of DQw1. It is thus likely that the distribution of these subtypic DR,DQ haplotypes in DR2 positive patients with RA may be important in understanding the genetic basis of susceptibility/resistance to RA. In this paper a study of the subtypes of DR2,DQw1 haplotypes in 18 patients with RA, who required sodium aurothiomalate as a disease remitting drug, and unrelated healthy individuals is reported. Three subtypes of DR2 haplotypes, DRw15 (Dw2),DQw1.2(DQw6), DRw15(Dw12),DQw1.12(DQw6), and DRw16(Dw21),DQw1, AZH (DQw5), were analysed with a cDNA probe for the DQ beta gene. The data show that DR2 positive patients with RA carried either the DRw15(Dw2),DQw6 or DRw15(Dw12),DQw6 haplotype. No patient with RA was positive for the DRw16(Dw21),DQw5 subspecificity. In contrast, six of 29 (21%) normal healthy DR2,DQw1 positive individuals carried the DRw16(Dw21),DQw5 haplotype. These data together with earlier results on the distribution of the DR4,DQw7 haplotype in patients with RA support the hypothesis that DQB1 chain polymorphism may be important in determining susceptibility to severe RA.
The distribution of DR3 and of extended haplotypes bearing DR3 was studied in three groups of subjects: 35 patients with rheumatoid arthritis (RA) with gold induced thrombocytopenia or proteinuria, 185 patients with RA without these side effects, and 300 normal healthy controls. The extended haplotypes bearing DR3 were analysed with cDNA probes for DR alpha, DR beta, DQ alpha, and DQ beta genes. The data showed that the prevalence of DR3 was significantly higher in patients who developed gold induced thrombocytopenia or proteinuria than in normal controls or patients with RA without these side effects. Distribution of three extended haplotypes bearing DR3 (B8, DR3; B18,DR3; non-B8,non-B18,DR3) in patients with RA with thrombocytopenia or proteinuria was significantly different from that in normal controls, but not from that in patients with RA without these toxic reactions. Southern blot analysis of DR, DQ genes with cDNA probes showed that the extended haplotype bearing B8,DR3, which carries DQA2.1 and DQB2.1 genes, was present in a significantly higher proportion of patients with RA with gold induced thrombocytopenia or proteinuria (22/24, 92%) than in patients with RA without these side effects (32/45, 71%) or normal subjects (40/61, 66%). The data suggest that the genomic region on chromosome 6 involved in susceptibility to gold induced thrombocytopenia or proteinuria should be extended to the DQA2, DQB2 gene loci.
There is controversy about whether allergic disease has increased in recent decades. This study compared the prevalence of atopy, as shown by allergy skin prick testing among adults in 1988 (n = 74) with a similar study carried out in 1974 (n = 1359). Both study groups were drawn from the general population in south west London, but the 1988 sample specifically excluded people with rhinitis. The proportion of subjects with at least one positive reaction to a panel of three common allergens increased significantly from 23% in 1974 to 46% in 1988 (P less than 0.01). If allowance was made for the exclusion of rhinitis subjects from the 1988 sample, the current prevalence of atopy may be higher still. The increase in prevalence was significant in older subjects (aged 55-59 years) and women but not in other age groups or in men. This small study raises the possibility that atopy has increased in prevalence in the UK over recent decades and additional studies are needed to evaluate the validity of this hypothesis.
Cyclosporine (CyA) is a potent immunosuppressant, but possesses toxicities which prohibit its unrestricted dosing in patients. The topical administration of CyA could serve to localize the immunosuppressive effect, or could serve as an administration route for patients who cannot tolerate the oral route of administration. We evaluated the potential for transdermal delivery of cyclosporine in rabbits. We sensitized six rabbits to dinitrochlorobenzene (DNCB), treated them topically with either 100 mg CyA or the vehicle, and repeated the DNCB skin testing at 15 and 28 days at the site of administration and at a distal site. In the CyA treated rabbits, significant increases in the suppression of the reaction to DNCB were observed from the control to the 15 day test, and from the 15 to the 28 day testing. Significant differences were also observed between reaction to DNCB at the site of CyA administration and at the distal site. While blood concentrations demonstrated slow and variable absorption of the topically administered CyA, concentrations greater than 1000 ng/ml were frequently observed in blood. We conclude that the local versus a systemic dermatologic effect of CyA can be achieved, and that high blood concentrations are present after topical CyA administration in this model.
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We have studied the complexity of HLA class II region in DR7 bearing extended haplotypes by restriction fragment length polymorphism (RFLP). Genomic DNA from homozygous cell lines and from unrelated individuals was digested with a number of restriction endonucleases and probed with DR alpha, DR beta, DQ alpha and DQ beta cDNA probes. We detected RFLPs that distinguished subspecificities of DRA, DRB1, DQA1 and DQB1 chain genes. On the basis of polymorphism in these genes, three distinct types of DR7 bearing extended haplotypes could be identified: (1) B44 or Bw47 or B14, DR7a (DRA1, B1.1), DRw53a (DRA1,B4), DQw2 (DQA1.1, B1.1); (2) B13 or B40, DR7b (DRA1, B1.2), DRw53a (DRA1, B4), DQw2 (DQA1.1, B1.1); and (3) Bw57, DR7c (DRA2, B1.2), DRw53b (DRA2, B4), DQw9 (DQA1.2, B1.2). Available evidence indicates that independent examples belonging to a haplotype were similar in RFLP patterns, suggesting that most examples of an extended haplotype belonging to a subtype are similar. The results in the present study have important implications for immune function and disease susceptibility.
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With a cDNA probe for the DQ beta gene, two variants of the DR4-linked DQw3 (3.1 and 3.2) allele were analysed in patients with rheumatoid arthritis (RA), healthy individuals, and homozygous cell lines. The DQw3.1 allele, identified by 3.4 kb (HindIII), 2.3 kb (SstI), and 3.7 kb and 6.9 kb (BamHI) restriction fragment lengths, was expressed in 100% (of 18) DR4-positive patients, compared with only 19% (of 16) of DR4-positive controls including one of five homozygous cell lines. This DQ beta variant showed a highly significant association (relative risk = 78; p less than 10(-6) with RA and may therefore play an important part in susceptibility to RA.