Contribution of Clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation.

BACKGROUND: Lower gastrointestinal (GI) adverse events (LGAE) are common afflictions of patients undergoing stem cell transplantation (SCT). Unfortunately, the pathophysiology remains poorly characterized. Emerging data suggest a prominent role of intestinal microbiota; however, contributions of pathogenic gut microbiota such as Clostridium difficile are not well defined. We performed a genome-wide association study (GWAS) to investigate clinical and genetic factors associated with development of LGAE. METHODS: A total of 972 patients undergoing autologous SCT were graded for LGAE based on Common Terminology Criteria for Adverse Events (v 4.0). Germline DNA material was obtained from leukapharesis products and genotyped using Illumina(®) Whole Genome Genotyping Infinium chemistry and HumanOmni1-Quad Bead chips containing over 1.1 million single nucleotide polymorphisms (SNPs) (Illumina, San Diego, California, USA). Statistical models incorporating clinical factors, genetic factors, and a combination of clinical plus genetic factors were utilized to compare patients who developed severe LGAE (grade 2 or above) and others. RESULTS: Among 972 patients, 459 (47.2%) developed severe LGAE. Baseline hemoglobin and hematocrit, estimated glomerular filtration rate, ß2-microglobulin, protocol type, and C. difficile infection (CDI) were associated with severe LGAE on univariate analysis, Genomic comparisons between groups did not reveal any SNPs associated with severe LGAE and neither did incorporation of genetic factors into the clinical model. In addition, 11 candidate SNPs associated with upper GI mucositis were evaluated, alongside clinical factors in a multivariate model. Only CDI was found to be associated with severe LGAE in all models. CONCLUSION: CDI is a prominent factor in the development of LGAE in patients undergoing autologous SCT.

The reversal of diabetes in rat model using mouse insulin producing cells - a combination approach of tissue engineering and macroencapsulation.

Type 1 diabetes is a chronic disorder resulting from the autoimmune destruction of insulin-producing cells, a leading cause of morbidity and mortality all over the world. In this study a tissue engineering approach was compared with a macroencapsulation approach to reverse type 1 diabetes in a rat model, using mouse pancreatic progenitor cell (PPC)-derived islet-like clusters and mouse islets. For the tissue engineering approach the cells were cultured on gelatin scaffolds cross-linked with EDC in the presence of polyvinylpyrrolidone in vitro (GPE scaffolds), while for the macroencapsulation approach the cells were encapsulated in polyurethane-polyvinylpyrrolidone semi-interpenetrating networks. In the combination approach the cells cultured on GPE scaffolds were further encapsulated in a polyurethane-polyvinylpyrrolidone capsule. Real time PCR studies and the glucose challenge assay have shown that cells on GPE scaffolds could express and secrete insulin and glucagon in vitro. However, under in vivo conditions the animals treated by the tissue engineering approach died within 15-20 days and showed no reversal of their diabetes, due to infiltration of immune cells such as CD4 and CD8 cells and macrophages. In the macroencapsulation approach the animals showed euglycemia within 25 days, which was maintained for further 20 days, but after that the animals died. Interestingly, in the combination approach the animals showed reversal of hyperglycemia, and remained euglycemic for up to 3 months. The time needed to achieve initial euglycemia was different with different cell types, i.e. the combination approach with mouse islets achieved euglycemia within 15 days, whereas with PPC-derived islet-like clusters euglycemia was achieved within 25 days. This study confirmed that a combination of tissue engineering and macroencapsulation with mouse islets could reverse diabetes and maintain euglycemia in an experimental diabetes rat model for 90 days.

Prognostic factors influencing pregnancy rate after stimulated intrauterine insemination.

To determine the prognostic factors such as age, diagnosis, number of cycle attempts and semen parameters on the pregnancy rate of controlled ovarian hyperstimulation (COH) /intrauterine insemination (IUI). Three hundred and seventeen women who underwent 507 consecutive COH/IUI cycles were recruited from 1st January 2002 to 31st December 2005 inclusively. This retrospective study was done in University Malaya Medical Centre, a tertiary care academic centre. The main outcome measure was pregnancy rate according to age, infertility diagnosis, duration of infertility, semen parameters, and the number of treatment cycles. The overall pregnancy rates were 16.9% per cycle and 25.9% per couple. Pregnancy rates decreased with advancing maternal age. Pregnancy rate was also significantly lower in patient with postwash total motile sperm count (TMSC) < or = 20 million/ml compared to those with TMSC >20 million/ml. The cumulative pregnancy rates varied greatly by diagnosis from 16% for patients with male factor infertility to 60% for patients with ovulatory disorder. Pregnancies among patients with male infertility, tubal factors infertility and endometriosis were achieved during the first three cycles. There is a clear age-related decline in fecundity associated with COH/IUI treatment. Women of > 40 years old, couple with postwash TMSC < or = 20 million/ml, severe endometriosis and tubal factors have a particularly poor prognosis.