Type 1, or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease associated with loss of tolerance to several pancreatic islet cell molecules, including insulin, glutamic acid decarboxylase (GAD), ICA69 and the tyrosine phosphatase IA-2 (refs 1-3). Among several predisposing loci, IDDM2 maps to the insulin gene (INS) VNTR (variable number of tandem repeats) minisatellite on chromosome 11p15 (refs 4-9). Allelic variation at this VNTR locus correlates with steady-state levels of INS mRNA in pancreas and transfected rodent cell lines, but it is difficult to reconcile the association of lower INS mRNA levels in the pancreas with class III VNTRs that are dominantly protective from IDDM. We show that during fetal development and childhood, mRNAs for insulin and other islet cell autoantigens (GAD, ICA69, IA-2) are expressed at low levels in the human thymus. Critically, we also detect proinsulin and insulin protein. VNTR alleles correlate with differential INS mRNA expression in the thymus where, in contrast to the pancreas, protective class III VNTRs are associated with higher steady-state levels of INS mRNA expression. This finding provides a plausible explanation for the dominant protective effect of class III VNTRs, and suggests that diabetes susceptibility and resistance associated with IDDM2 may derive from the VNTR influence on INS transcription in the thymus. Higher levels of (pro)insulin in the thymus may promote negative selection (deletion) of insulin-specific T-lymphocytes which play a critical role in the pathogenesis of type-1 diabetes.

We report a prospective series evaluating the incidence and degree of tunnel widening in a well-matched series of patients receiving a hamstring or patella tendon graft for anterior cruciate ligament (ACL) deficiency. We correlated tunnel widening with clinical factors, knee scores, KT-1000 and isokinetic muscle strength to determine the clinical significance of this finding. Seventy-three patients at least 12 months post-ACL reconstruction were evaluated. Thirty-eight patients had received a doubled semitendinous and gracilis graft and 35 a bone-patella tendon-bone graft. All patients underwent a similar endoscopic procedure and accelerated postoperative rehabilitation. Tunnel widening was determined using standardized anteroposterior (AP) and lateral X-rays adjusted for magnification. A limited series of MRIs was performed to validate these measurements. There was a significant difference in the degree of tunnel widening between the two groups. The mean increase in femoral tunnel area in the hamstring group was 100.4% compared with a decrease of 25% in the patella tendon group (P = < 0.0001). In the tibial tunnel the mean increase in the hamstring group was 73.9% compared with a decrease of 2.1% in the patella tendon group (P = < 0.0001). The MRIs validated the plain film measurements. Tunnel widening did not correlate with the clinical findings, knee scores, KT-1000 or isokinetic muscle strength. Tunnel widening is marked in the hamstring group. Tunnel widening does not correlate with instability or a poor clinical outcome in the short term. The long-term implications of this finding are still to be determined.

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