Growth and functional maturation of beta-cells in implants of endocrine cells purified from prenatal porcine pancreas

The development of islet cell transplantation as a cure for diabetes is limited by the shortage of human donor organs. Moreover, currently used grafts exhibit a marginal beta-cell mass with an apparently low capacity for beta-cell renewal and growth. Although duct-associated nonendocrine cells have often been suggested as a potential source for beta-cell production, recent work in mice has demonstrated the role of beta-cells in postnatal growth of the pancreatic beta-cell mass. The present study investigated whether the beta-cell mass can grow in implants that are virtually devoid of nonendocrine cells. Endocrine islet cells were purified from prenatal porcine pancreases (gestation >110 days) and implanted under the kidney capsule of nude mice. beta-Cells initially presented with signs of immaturity: small size, low insulin content, undetectable C-peptide release, and an inability to correct hyperglycemia. They exhibited a proliferative activity that was highest during posttransplant week 1 (2.6 and 5% bromodeoxyuridine [BrdU]-positive beta-cells 4 and 72 h posttransplant) and then decreased over 20 weeks to rates measured in the pancreas (0.2% BrdU-positive cells). beta-Cell proliferation in implants first compensated for beta-cell loss during posttransplant week 1 and then increased the beta-cell number fourfold between posttransplant weeks 1 and 20. Rates of alpha-cell proliferation were only shortly and moderately increased, which explained the shift in cellular composition of the implant (beta-cell 40 vs. 90% and alpha-cell 40 vs. 7% at the start and posttransplant week 20, respectively). beta-Cells progressively matured during the 20 weeks after transplantation, with a twofold increase in cell volume, a sixfold increase in cellular insulin content, plasma C-peptide levels of 1-2 ng/ml, and an ability to correct diabetes. They became structurally organized as homogenous clusters with their secretory vesicles polarized toward fenestrated capillaries. We concluded that the immature beta-cell phenotype provides grafts with a marked potential for beta-cell growth and differentiation and hence may have a potential role in curing diabetes. Cells with this phenotype can be isolated from prenatal organs; their presence in postnatal organs needs to be investigated.     

Disambiguation and mapping of new word meanings by individuals with intellectual/ developmental disabilities

Wilkinson and Green (1998) reported that differences in the procedure by which new words were introduced to learners with cognitive impairments significantly affected their accuracy in later tests of receptive understanding of word meanings. However, a limited sample and no control group rendered the data preliminary. Here, I replicated and extended the research. First, a control group of preschool children, matched on receptive vocabulary age, was compared to individuals with intellectual disability of unspecified origin. Second, performance was also evaluated in three matched groups of varying etiology: unspecified, Down syndrome, and autism spectrum disorders. Performance on receptive word matching differed between preschool children and their matched experimental groups as well as among matched etiological groups.     

Leptin induces cell migration and the expression of growth factors in human prostate cancer cells

BACKGROUND: The adipocyte hormone leptin has been shown to increase migration and angiogenesis in epithelial cells. Therefore, we hypothesized that leptin would induce prostate cancer cell migration and growth factor expression in vitro. METHODS: Prostate cancer cell lines DU145 and PC-3 (androgen-resistant) were treated with leptin over time. Supernatants were assayed for growth factor expression via enzyme-linked immunosorbent assay (ELISA). Becton Dickinson-Falcon Transwell systems were used to assay leptin-induced migration. RESULTS: Leptin significantly induced expression of vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), and basic fibroblast growth factor (bFGF) in DU145 and PC-3 cells. Prostate cancer cell migration was enhanced by leptin and inhibited 50% to 70% with the addition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) inhibitors. CONCLUSIONS: The mitogenic effects of leptin on cancer cells, in combination with the increased migration and expression of growth factors, overall likely contributes to the progression of prostate cancer. Therefore, obesity associated with high leptin levels should be considered a risk factor in prostate cancer patients.     

Kupffer cell-derived fas ligand plays a role in liver injury and hepatocyte death

Liver injury is an important prognostic indicator during acute pancreatitis. The aim of this study was to determine the role of Fas ligand (FasL) in hepatocyte injury. Liver parenchymal enzymes were measured in cocultures of hepatocytes and Kupffer cells treated with elastase. FasL and FasL mRNA were measured in elastase-treated Kupffer cells. Hepatocytes were treated with FasL and their viability was assessed by monotetrazolium (MTT), apoptosis by flow cytometry, as well as caspase-3 and p38-mitogen-activated protein kinase (MAPK) by immunoblotting. Elastase increased aspartate aminotransferase and lactate dehydrogenase in cocultures of hepatocyte and Kupffer cells (P < 0.040). Elastase increased FasL production from Kupffer cells (P = 0.02) and upregulated FasL mRNA (FasL/beta-2 microglobulin (BMG): 0.23 ± 0.03 vs. 0.11 ± 0.003; P = 0.04). FasL increased alanine aminotransferase and lactate dehydrogenase (P < 0.03) and reduced hepatocyte viability by 45% (P = 0.01). FasL increased the number of dually labeled cells with AnnexinV/7AAD (P = 0.03) while upregulating cleavage of caspase-3 and the phosphorylation of p38-MAPK. FasL antibody attenuated the FasL-related increase in dually labeled cells (P = 0.02), the cleavage of caspase-3, and phosphorylation of p38-MAPK. Pancreatic elastase upregulates FasL within Kupffer cells. FasL induces hepatocyte injury and death and upregulates p38-MAPK and caspase-3 within hepatocytes. The ability to manipulate interactions between Kupffer cells and hepatocytes may have important therapeutic implications. Presented at the Forty-Fourth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Florida, May 18–21, 2003 (poster presentation) and published as an abstract in Gastroenterology 2003. Supported by SSAT Career Development Award (M.M.), Dr. Bob Haines Pancreatitis Research Fund (M.M.), VA Merit Award (J.N.) and a VA Merit Award (P.K.E.-B.).     

The epidemiology, treatment patterns, and costs of cytomegalovirus retinitis in the post-haart era among a national managed-care population

To examine the epidemiology, treatment patterns, and costs of cytomegalovirus (CMV) retinitis treatment in the post-HAART (highly active antiretroviral therapy) era, a retrospective cohort study was performed using data from US managed-care plans from 1997-2002. Cases with CMV retinitis were defined by requiring diagnosis codes for HIV (or AIDS), CMV, and retinitis and claims for anti-CMV treatment. Costs of oral, intravenous, and intraocular treatment periods were examined. The incidence of enrolled HIV or AIDS cases increased from 7 per million members in 1997 to 150 per million members in 2001. The incidence of CMV retinitis decreased from 23 per 10,000 HIV or AIDS cases in 1997 to 8 per 10,000 HIV or AIDS cases in 2001. The average duration of a CMV episode was 192 days and the average cost was 19,576 US dollars. In a multiple linear regression model adjusting for age, gender, insurance type, geographic region, HAART use, and co-existing AIDS-defining illnesses, intraocular and oral treatment periods saved 7135 and US dollars and 6866 US dollars, respectively, per treatment period compared with intravenous treatment (P < 0.05). The incidence of CMV retinitis decreased in this managed-care population during the post-HAART era. Use of oral or intraocular treatment saves costs compared with intravenous treatment in a managed-care environment.     

Reaching out to see: arm position can attenuate human visual loss

Electrophysiological recordings in monkeys have now revealed several brain regions that contain bimodal visuotactile neurons capable of responding to either tactile or visual stimuli placed on or near the hands, arms, and face. These cells have now been found in frontal, parietal, and subcortical areas of the monkey brain, suggesting a cortical network of neurons that preferentially represent near peripersonal space. The degree to which the visual responses of such cells rely on input from the primary visual cortex and the extent to which they may contribute to visual perception is not completely understood. Nonetheless, recent neuropsychological studies suggest that a similar representation of near space may be bimodally coded in humans as well. Given the accumulating evidence for specialized processing of visual stimuli placed near the hands and arms, we hypothesized that arm position may be capable of modulating human visual ability. Here we report the case of WM, who lost his ability to see in his left visual hemifield after sustaining damage to his right primary visual cortex. Interestingly, the placement of WM's left arm into his "blind" field resulted in significantly better detection of left visual field stimuli compared to when his hand was placed in his lap at midline. Moreover, we found this attenuation to be confined to stimuli presented within reaching distance (unless a tool that extended WM's reach was held while he performed the test). These findings are highly consistent with the characteristics of the bimodal visuo-tactile neurons that have been described in monkeys. Thus, it seems that arm position can modulate human visual ability, even after damage to the primary visual cortex. This study provides an exciting bridge between monkey neurophysiology and human visual capacity while also offering a novel approach for improving visual defects acquired via cortical injury.