The impact of islet mass, number of transplants, and time between transplants on graft function in a national islet transplant program.

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3-8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291-15 417] vs. 6442 [5156-7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta -0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.

Characterization of pre-transplant psychosocial burden in an integrated national islet transplant program.

The psychological burden experienced by people with diabetes prior to islet transplantation is recognized but has not been studied comprehensively, especially in relation to glycemia. Therefore, we conducted a rigorous pre-operative psychosocial profile of UK islet transplant recipients, and compared groups with higher/lower HbA1 c to test the null hypothesis that pre-transplant hypoglycemia awareness and psychosocial burden would not be related to baseline HbA1 c in this high-risk cohort. Pre-transplant, recipients (n = 44) completed validated hypoglycemia awareness questionnaires and generic/diabetes-specific measures of psychological traits and states. Scores were compared in groups, dichotomized by HbA1 c (≤8% versus >8%). Participants were aged (mean±SD) 53 ± 10 years; 64% were women; with HbA1 c 8.3 ± 1.7%. Median rate of severe hypoglycemia over the preceding 12 months was 13 events/person-year and 90% had impaired awareness of hypoglycemia (Gold/Clarke score ≥4). Participants had elevated fear of hypoglycemia (HFS-II Worry), impaired diabetes-specific quality of life (DQoL) and low generic health status (SF-36; EQ-5D). One quarter reported scores indicating likely anxiety/depression (HAD). Dispositional optimism (LOT-R) and generalized self-efficacy (GSE) were within published 'norms.' Despite negative perceptions of diabetes (including low personal control), participants were confident that islet transplantation would help (BIPQ). Hypoglycemia awareness and psychosocial profile were comparable in lower (n = 24) and higher (n = 20) HbA1 c groups. Islet transplant candidates report sub-optimal generic psychological states (anxiety/depressive symptoms), health status and diabetes-specific psychological states (fear of hypoglycemia, diabetes-specific quality of life). While their generic psychological traits (optimism, self-efficacy) are comparable with the general population, they are highly optimistic about forthcoming transplant. HbA1 c is not a proxy measure of psychosocial burden, which requires the use of validated questionnaires to systematically identify those who may benefit most from psychological assessment and support.

Mutation spectra induced by alpha-acetoxytamoxifen-DNA adducts in human DNA repair proficient and deficient (xeroderma pigmentosum complementation group A) cells.

Tamoxifen, a breast cancer drug, has recently been approved for the chemoprevention of this disease. However, tamoxifen causes hepatic carcinomas in rats through a genotoxic mechanism and increases the risk of endometrial tumors in women. DNA adducts have been detected at low levels in human endometrium, and there is much interest in determining whether DNA damage plays a role in tamoxifen-induced endometrial carcinogenesis. This study investigates the mutagenicity of tamoxifen DNA adducts formed by alpha-acetoxytamoxifen, a reactive ester producing the major DNA adduct formed in livers of tamoxifen-treated rats. pSP189 plasmid DNA containing the supF gene was treated with alpha-acetoxytamoxifen and adduct levels (0.5-8.0 adducts per plasmid) determined by (32)P-postlabeling. Adducted plasmids were transfected into nucleotide excision repair proficient (GM00637) or deficient (GM04429, XPA) human fibroblasts. After replication, plasmids were recovered and screened in indicator bacteria. Relative mutation frequencies increased with the adduct level, with 1.3-3.6-fold higher numbers of mutations in the XP cells compared to the GM00637 cells, indicating that NER plays a significant role in the removal of these particular tamoxifen DNA adducts. The majority of sequence alterations (91-96%) occurred at GC base pairs, as did mutation hotspots, although the type and position of mutations was cell-specific. In both cell lines, as the adduct level increased, the proportion of GC --> AT transitions decreased and GC --> TA transversions, mutations known to arise from the major tamoxifen adducts, increased. Given the high mutagenicity of dG-N(2)-tamoxifen adducts, if not excised, they may potentially contribute to the initiation of endometrial cancer in women.