New onset diabetes mellitus (NODM) is a serious complication of transplantation. This meta-analysis evaluates the reported incidence of NODM after solid organ transplantation in patients receiving CNI treatment.Databases from January 1992 to April 2002 were searched. Fifty-six publications providing NODM incidence data were reviewed. Sixteen prospective, randomized comparative studies providing information on incidence of insulin-dependent diabetes mellitus (IDDM) were subjected to meta-analysis.New onset diabetes mellitus was reported in 13.4% of patients after solid organ transplantation, with a higher incidence in patients receiving tacrolimus than cyclosporine (16.6% vs. 9.8%). This trend was observed across renal, liver, heart and lung transplant groups. Meta-analysis of 16 studies included patients receiving either tacrolimus (n = = 1636) or cyclosporine (n = = 1407). The incidence of IDDM was significantly higher among tacrolimus-treated patients (10.4% vs. 4.5%, p < 0.00001), an effect observed in renal (9.8% vs. 2.7% p < 0.00001) and nonrenal (11.1% vs. 6.2%; p < 0.003) groups, and among patients receiving equal doses of concomitant medication in both treatment arms (12.0% vs. 3.0%; p < 0.00001).The reported incidence of NODM during the past decade was significantly higher among patients receiving tacrolimus than cyclosporine. These data provide a quantitative foundation for studies designed to reduce the rates of NODM following solid organ transplantation.

Fractalkine has been identified as a novel chemokine that exhibits cell adhesion and chemoattractive properties in the central nervous system (CNS), and the fractalkine receptors, CX3CR1, are also expressed in the CNS. In the present study, the expression of fractalkine and fractalkine receptors was investigated in enriched populations of human CNS neurons, astrocytes, and microglia. In addition, the regulatory role played by protein kinase C (PKC) in fractalkine secretion in neurons was determined in A1 human hybrid neuronal cell line produced between a human cerebral neuron and a human neuroblastoma cell. Human neurons and astrocytes expressed fractalkine mRNA as determined by the revserse transcriptasepolymerase chain reaction (RT-PCR) analysis, while human microglia preparation did not express the fractalkine message. Human neurons and microglia expressed CX3CR1 mRNA, but astrocytes did not. These results suggest that fractalkine secreted by CNS neurons and astrocytes produce biological effects in neurons and microglia. Although phorbol ester did not change the expression of fractalkine mRNA level in A1 hybrid neurons, it did upregulate fractalkine secretion over unstimulated controls. This upregulation of fractalkine production was suppressed by the treatment with Ro32-0432, a PKC inhibitor. These results indicate that intracellular signals transduced by PKC play an important role in the regulation of soluble fractalkine at the post-transcriptional level in human neurons. As for the biological function of fractalkine, extracellularly applied fractalkine increased the number of bromodeoxyuridine-labeled microglia 3-fold over the untreated controls, indicating fractalkine induces proliferation of human microglia. These observations suggest that fractalkine released by injured neurons could induce proliferation, activation and/or migration of microglia at the injured brain sites.

Human neural stem cells (NSCs) grown in culture responded to extracellularly applied adenosine triphosphate (ATP), and the rate of proliferation increased as shown by immunocytochemical and RT-PCR analysis. Activation of P2 purinoceptors by ATP is coupled to the release of intracellular calcium ([Ca 2ϩ ] i ) from thapsigargin-sensitive intracellular stores. ATP-induced proliferation was blocked by thapsigargin, an inhibitor of the endoplasmic reticulum Ca 2ϩ -ATPase. Neither EGTA, a calcium chelator, nor caffeine had any effect on ATP-induced [Ca 2ϩ ] i increases. Multiblot kinase analysis, by which activation of 24 different kinases could be determined, showed that application of ATP to NSCs predominantly activated p70 ribosomal protein S6 kinase (p70 S6 kinase). As well, rapamycin, a p70 S6 kinase inhibitor, blocked the ATP-mediated proliferative response in NSCs. After outlining a role for p70 S6 kinase in ATP-mediated NSC proliferation, we examined the possibility that phosphatidylinositol 3-kinase (PI3-kinase) acts upstream of p70 S6 kinase. The application of wortmannin, a PI3-kinase inhibitor, decreased both ATP-mediated p70 S6 kinase activation and NSC proliferation. From these results, we conclude that ATP application to NSCs induces release of Ca 2ϩ from intracellular Ca 2ϩ stores and that this increase in intracellular Ca 2ϩ in turn promotes NSC proliferation. The increase in NSC proliferation observed following ATP application can also be mediated by PI3-kinasedependent p70 S6 kinase activation.

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