Faculty Bibliography

BM stem cells may have regenerative effects on islet function through angiogenesis. Human islets (100islet equivalent/mL) were cultured alone (control) or co-cultured (experimental group) with whole human BM (1 x 10(6) cells/mL) for 210 days. A protein array measuring angiogenesis factors found upregulated (experimental vs control, day 210) proteins levels of VEGF-a (535 vs 2 pg/mL), PDGF (280.79 vs 0 pg/mL), KGF (939 vs 8 pg/mL), TIMP-1 (4592 vs 4332 pg/mL) and angiogenin (506 vs 97 pg/mL). Lower protein levels of angiopoietin-2 (5 vs 709 pg/mL) were observed. Depletion of pro-angiogenesis factors in co-culture decreased the effects of BM-induced islet vascularization. Depletion of VEGF-a, eKGF and PDGF significantly reduced islet vascularization but individual depletion of KGF and PDGF had less effects overall on vessel formation. BM-induced vascularization showed significant endothelial cell distribution. Islet vascularization was linked to islet growth. A decrease in islet size indicated poor vascularization. Insulin release was evident in the tissues generated from human islet-BM co-culture throughout the entire culture period. Significant increase in insulin (28.66-fold vs control) and glucagon (24.4-fold vs control) gene expression suggest BM can induce endocrine cell regeneration. In conclusion, BM promotes human islet tissue regeneration via regulation of angiogenesis factors.

Adult T-cell leukemia/lymphoma is a T-cell malignancy caused by the human T-cell lymphotropic virus type 1. The aggressive forms of the disease carry a poor prognosis with standard therapies. The role of high-dose treatment with blood and marrow transplantation has, therefore, been examined mainly by Japanese groups in the form of retrospective studies. In this study, we review the literature, discuss some of the challenges facing successful transplantation approaches and stress the need for more innovative studies including in the Western hemisphere.

BACKGROUND: Venous thromboembolism (VTE) prophylaxis in medically ill patients has received a level 1A recommendation in previously published clinical guidelines. Pharmacologic prophylaxis for VTE includes unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux. Few direct comparisons between anticoagulants exist in medically ill patients. OBJECTIVE: This meta-analysis was conducted to assess UFH and LMWH (including the selective factor Xa inhibitor fondaparinux) in the reduction of in-hospital VTE in unselected medically ill patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Registry databases from January 1981 through September 2007 (English language) for randomized controlled trials using the following terms: dalteparin, enoxaparin, fondaparinux, nadroparin, and heparin. References of included articles and key review papers for additional studies were also searched. Data from studies were included in the analysis if the studies included medically ill patients with risk factors for VTE who had been followed up for 7 to 21 days. RESULTS: A total of 12,391 patients (of whom 8357 were in placebo-controlled trials) from 9 studies were included. Mean age for the entire cohort was 72.8 years; mean (SD) body mass index, 25.6 kg/m2; and mean (SD) actual body weight, 68.2 kg. Deep vein thrombosis (DVT) was significantly reduced with the addition of an LMWH compared with placebo (odds ratio [OR], 0.60; 95% CI, 0.47-0.75; P < or = 0.001), but rates of DVT were similar when comparing LMWH with UFH (OR, 0.92; 95% CI, 0.56-1.52). No significant differences in pulmonary embolism (PE) or death were found among the UFH, LMWH, and placebo groups. LMWH was associated with a significant increased risk for minor bleeding compared with placebo (OR, 1.64; 95% CI, 1.18-2.29; P = 0.003). However, no significant difference was found between LMWH and UFH (OR, 0.68; 95% CI, 0.27-1.70). Major bleeding events were similar among all groups: LMWH/fondaparinux versus placebo, OR, 1.65 (95% CI, 0.8-3.4); LMWH/fondaparinux versus UFH, OR, 0.69 (95% CI, 0.29-1.68); LMWH/fondaparinux versus UFH or placebo, OR, 1.16 (95% CI, 0.66-2.04). CONCLUSIONS: This analysis suggests that VTE prophylaxis with an LMWH (including fondaparinux) or UFH is effective in reducing the rate of DVT, but this benefit did not extend to enhanced protection against PE. Additionally, LMWH and UFH had similar bleeding outcomes.

To assess the frequency and molecular polymorphism of malignancy-associated latent membrane protein 1 (LMP1) variants in human immunodeficiency virus type 1 (HIV-1) infection, 94 B-lymphoblastoid cell lines spontaneously derived from peripheral blood mononuclear cells (PBMC) and 30 PBMC samples at seroconversion and later (mean, 55 months) were analyzed by longitudinal comparative sequence analysis in 8 patients progressing to non-Hodgkin's lymphoma (AIDS-NHL), 7 patients to opportunistic infections, and 2 patients with long-term asymptomatic HIV-1 infection. The sequence polymorphism in the C-terminus of LMP1 was characteristic for strains harbored by individual patients, with high fidelity for strain identification. In 14 of the 17 patients, two different but characteristic LMP1 variants were identified. At HIV seroconversion in 8 of 15 patients, a 30-bp deletion (LMP1Delta) was present. Though serial analysis revealed a shift to LMP1Delta in some individuals, statistical analysis of the cohort does not support the hypothesis that accumulation of LMP1Delta variants in PBMC accounts for their observed high incidence in AIDS-NHL.

EBNA-2 is the first protein to be detected after infection of primary B lymphocytes by Epstein-Barr virus (EBV) and plays an essential role as transcriptional activator in EBV-induced lymphocyte transformation. We analysed by PCR and sequencing regions of the EBNA-2 type 1 gene from isolates from 13 children with infectious mononucleosis (IM), 6 children with tonsillar hyperplasia (TH), and 9 patients with HIV infection followed longitudinally. We found in all three groups of patients frequent non-silent point mutations at positions 48990, 48991, 49021, 49057, 49083, 49089, 49091, 49113, 49119, 49140, 49156, and a triplet insertion at position 49136. While 4 out of 13 samples from patients with IM showed a mosaic pattern suggesting co-existence of more than 1 substrain of EBNA-2 type 1, none of the samples from TH showed this pattern consistent with substrain selection during clinical latency. No sequence changes were noted over time in samples derived from patients with HIV infection. We conclude that in analogy to the coexistence of several subtypes of EBNA-1 in healthy EBV carriers, samples from IM can harbor more than one subtype of the EBNA-2 type 1 gene.