Nonprogression of subclinical beta-cell dysfunction among first-degree relatives of IDDM patients. 5-yr follow-up of the Seattle Family Study

It is unknown among first-degree relatives of individuals with insulin-dependent diabetes mellitus (IDDM) whether the disease process occurs in relatively few but always progresses to clinical IDDM or whether subclinical disease is more common but remains nonprogressive in many cases. Islet cell antibodies (ICAs) were found in 21 of 724 (2.9%) first-degree relatives during screening in the greater Seattle area between 1983 and 1988. Measures of beta-cell function (glucose disappearance rate [Kg], fasting insulin, acute insulin response to intravenous arginine [AIRarg], acute insulin response to intravenous glucose [AIRgluc], slope of glucose potentiation of AIRarg) and insulin sensitivity were obtained. Twenty individuals, 9 ICA+ relatives and 11 ICA- relatives, were evaluated prospectively. When expressed in relation to the expected AIRgluc based on each subject's sensitivity index, AIRgluc in 18 of 20 relatives fell below 100%, indicating inappropriately low insulin secretion (subclinical beta-cell dysfunction). After a median follow-up of 42 mo, 10 of 11 ICA- relatives remained ICA-. None showed deteriorating beta-cell dysfunction, and none developed diabetes. Five ICA+ relatives showed persistent immunologic positivity. beta-Cell function remained remarkably stable in all except 2 relatives. One was a 15-yr-old boy who developed IDDM shortly after screening and before evaluation of beta-cell function could be carried out. The other was an 18-yr-old monozygotic twin who developed IDDM after 27 mo. Both of these individuals had ICAs of 80 Juvenile Diabetes Foundation U and had been discordant for less than 5 yr.(ABSTRACT TRUNCATED AT 250 WORDS)     

Further study on the vascular basis for the reimplantation of the hand amputated through the palm

Summary Based on the anatomic data obtained from earlier studies on the vascular anatomy of the hand, the vascular architecture in the palm of the hand was studied on 60 sides of unembalmed adult upper extremities. Each palm was divided into 64 squares by 8 sagittal and 8 transverse sections. The vascular architecture in these squares and the arterial relations between them were observed and measured by angiography, operative microscopic dissection and computerised three-dimensional reconstruction. According to the pattern of the blood-vessels, the amputated palms can be classified into 4 types. The anatomic basis for the vascular anastomosis in each type is defined. There are three key-areas for the blood-supply of the palm and their significance is discussed. Apart from the 4 types of transversely amputated palms, the repair programe of the blood-vessles in 4 types of common obliquely amputated palms are also discussed.

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Etude complémentaire de l'anatomie vasculaire de la main pour la réimplantation des amputations transpalmaires

Résumé Sur la base de données anatomiques obtenues lors de précédents travaux sur l'anatomie vasculaire de la main, l'architecture vasculaire palmaire a été étudiée sur 60 extrémités supérieures de cadavres d'adultes, non embaumés. Chaque paume a été divisée en 64 carrés par 8 sections sagittales et 8 sections transversales. L'architecture vasculaire à l'intérieur des carrés et les relations artérielles entre eux ont été étudiées et mesurées par angiographie, dissection au microscope opérateur et reconstruction computérisée en 3D. Les paumes amputées ont été regroupées en 4 types d'après la distribution des vaisseaux sanguins. Les données anatomiques concernant les anastomoses vasculaires sont précisées. Il existe trois zones clés pour l'irrigation de la paume. Leur importance quant à l'irrigation de la main est exposée. Outre la division des paumes amputées transversalement en 4 types, le programme de réparation de vaisseaux dans les 4 types d'amputations obliques communes de la paume et aussi discuté.

     

T-cell receptor V beta selectivity in T-cell clones alloreactive to HLA-Dw14.

The HLA-DR4 subtypes Dw14 and Dw4 are T-cell-defined allospecificities encoded by the DRB1*0404 and DRB1*0401 genes, respectively. Although these allelic subtypes differ in only two amino acids, allorecognition between Dw14 and Dw4-positive individuals is brisk. This provides an opportunity to analyze T-cell receptor (TCR) usage in a very limited and specifically targeted case, namely the Dw4 anti-Dw14 allogeneic T-cell response. The variable (V), diversity (D), and joining (J) region sequences of the TCR beta chain from two different Dw14-specific alloreactive T-cell clones derived from a Dw4 donor were examined. Clone EMO25 recognized the Dw14.1, Dw14.2, and Dw15 subtypes, which share a DRB1 polymorphism at codon 71 on a DR4 background, while clone EMO36 reacted with only the Dw14.1 subtype associated with polymorphisms at codons 71 and 86. TCR beta cDNA from each clone was amplified using an anchored polymerase chain reaction (PCR) and subsequently expanded with V beta- and C beta-specific primers for asymmetric PCR and direct DNA sequencing. Both clones were found to express the same TCR V beta 8.2 gene segment; however, they have several different residues within the V beta-D beta-J beta junctional regions. V beta 8 usage was also enriched in polyclonal cells obtained from mixed lymphocyte cultures performed between the Dw4 and Dw14 responder-stimulator combination from which EMO25 and EMO36 were derived.     

A deletion mutant defines DQ beta variants with DR4 positive DQw3 positive haplotypes

We describe the production of an HLA deletion mutation by radiation mutagenesis of a DR4- and DQw3-homozygous, Dw4- and Dw14-heterozygous cell line designed to analyze polymorphisms associated with DR4 and DQw3. Southern blot analysis confirms a deletion of class I and class II genes on one haplotype. Variation in DQ beta alleles associated with DQw3 was previously described by characteristic RFLP patterns for a DQ beta bene. One pattern, which correlated precisely with A-10-83 monoclonal antibody reactivity (TA10), defined an allele which we call DQ"3.1". The mutant cell line has lost the polymorphic bands on Southern blots corresponding to the DQ"3.1" allele, while the intact Dw14 haplotype retains the alternate allele at DQ beta which is DQw-3 positive. TA10-negative. These data demonstrate the segregation of two DQw3 positive DQ beta allelic variants, both associated with DR4, which can be distinguished on the basis of both RFLP and monoclonal antibody reactivity.     

Identification and modulation of a naturally processed T cell epitope from the diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65)

T cell recognition of autoantigens is critical to progressive immune-mediated destruction of islet cells, which leads to autoimmune diabetes. We identified a naturally presented autoantigen from the human islet antigen glutamic acid decarboxylase, 65-kDa isoform (GAD65), by using a combination of chromatography and mass spectrometry of peptides bound by the type I diabetes (insulin-dependent diabetes mellitus, IDDM)-associated HLA-DR4 molecule. Peptides encompassing this epitope-stimulated GAD65-specific T cells from diabetic patients and a DR4-positive individual at high risk for developing IDDM. T cell responses were antagonized by altered peptide ligands containing single amino acid modifications. This direct identification and manipulation of GAD65 epitope recognition provides an approach toward dissection of the complex CD4(+) T cell response in IDDM.     

Association of HLA-Dw16 with rheumatoid arthritis in Yakima Indians. Further evidence for the "shared epitope" hypothesis.

Rheumatoid arthritis (RA) is prevalent in Yakima Indians, a Native American tribe. HLA-DR4, the HLA specificity commonly associated with RA in Caucasians, is rare among the Yakima. Using a specific oligonucleotide probe that recognizes DR4 nucleotide sequences associated with RA, a rare HLA-Dw16 gene was identified in 83% of Yakima patients with RA and in 60% of Yakima control subjects. This shared sequence encodes a discrete class II epitope that is highly correlated with RA in both DR4 positive and DR4 negative individuals.     

Electrophoretic analysis of human HLA-DR antigens from HLA-DR4 homozygous cell lines: correlation between beta-chain diversity and HLA-D.

Two-dimensional gel electrophoresis of immunoprecipitated human HLA-DR antigens from cells expressing the HLA-DR4 haplotype shows distinct clustering of beta-chain patterns. Six unique electrophoretic variants were observed among 17 HLA-DR4 homozygous cell lines (HCL) analyzed. These patterns correlate precisely with the HLA-D phenotype of the HCL donor as determined by reactivity in mixed lymphocyte culture. All DR4 HCL that belong to one of the well-defined HLA-D antigen groups (Dw4, Dw10, LD "40", LD "DYT", LD "KT2", or LD "TAS") have identical DR beta-chain patterns; DR4 HCL belonging to different HLA-D antigen groups do not. The concordance of the functional expression in mixed lymphocyte culture of a specific D phenotype with a distinct DR beta-chain pattern on gel analysis provides a direct structural basis for understanding the genetic control of HLA-D polymorphisms; HLA-D specificities as revealed by T-cell recognition in mixed lymphocyte culture thus might be accounted for by DR beta-chain polymorphisms. The extent of this beta-chain diversity within a single DR haplotype may aid in understanding variations in Ia-regulated functions, such as Ir gene control and certain disease susceptibilities.     

Radiographic hand joint space width assessed by computer is a sensitive measure of change in early rheumatoid arthritis

OBJECTIVE: To compare changes in the computerized measurement of radiographic hand joint space width (JSW) to changes in modified Sharp scores in a retrospective 2-year study of early rheumatoid arthritis (RA). METHODS: First and last standard clinical hand radiographs of 245 patients with RA were analyzed blind using purpose-written computer software to measure changes in JSW for proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints in the 3 middle fingers of each hand. Before measurement, the radiographs were scored independently by 2 radiologists using a modification of Sharp scoring. RESULTS: The paired changes in JSW (-0.051 +/- 0.005 mm) and Sharp score (+3.81 +/- 0.50) were both significant over the study duration. In measured joints showing an increase in joint space narrowing (JSN) score, 92% had a corresponding reduction in JSW. In patients with an increase in total score, including JSN and erosion scores in fingers and wrists, 84% had a corresponding reduction in mean (PIP + MCP) JSW. Patients with no change in Sharp score (47%) still experienced a significant reduction in measured JSW (-0.027 +/- 0.006 mm). HLA-DR genetic markers of severe disease progression were associated with significantly greater reductions in JSW but not increases in Sharp score. (Values: mean +/- standard error of mean). CONCLUSION: Measured JSW averaged over 6 PIP and 6 MCP joints was a valid and more sensitive measure of change than total Sharp score in this study of early RA.