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Notes: 1. Myocarditis may be an early indicator of or may subsequently lead to dilated cardiomyopathy in humans. This hypothesis has evolved from research on viruses that induce myocarditis, wherein the coxsackie B group viruses (CVB) in the family Picornaviridae are the most common known viral infectants of heart muscle.2. Many competing hypotheses exist as to the pathogenesis of CVB3-induced myocarditis, including direct virus-induced myocyte damage and immunopathological disease with autoimmune sequelae. Evidence to support the direct-damage and viral RNA-persistence hypothesis is derived from in situ hybridization and gene amplification studies.3. Recent use of terminal deoxynucleotidyl transferase-mediated nick-end labelling indicates that this injury in target organs is largely non-apoptotic in nature. Most apoptotic bodies in cardiac tissue are derived from immune cells.4. Beyond infection of heart muscle, CVB3 can also associate with, infect and persist in cells of immune origin. The CVB3 localizes to follicles in spleens and lymph nodes of the murine host and this particular localization may continue in mice susceptible to more aggressive myocarditis. Whether virus-immune cell association in these compartments is advantageous (or essential) to the host in the evolution of anti-viral immune responses or whether it is more advantageous to the virus in immunosuppression of the host is not known.5. We suggest that CVB3 can directly perturb or alter the immune response, thereby delaying viral clearance from vulnerable systemic organs. Both host and viral genetic factors can influence susceptibility, persistance and disease progression.6. Picornaviruses use a unique method for the initiation of translation, involving the internal binding of the ribosome on a sequence element of the 5′ untranslated region, termed an internal ribosome entry sit. (IRES).7. The IRES of CVB3 is located at approximately stem loops G, H and I, spanning nucloetides 530 and 630. Arrest of host translation is also a feature of picornavirus infection. Such regulation of host cell translation machinery no doubt fosters viral replication at the expense of the host cell.8. Differences between cell types in the mechanisms, along with those at other key steps in the viral life cycle and in signalling via kinase pathways, may determine viral tropism and cellular destruction and the physiological outcome of neighbourin. cells.

Notes: Describes how two US hospitals, members of an integrated health system, took different routes to achieve radical constructive change, one of them - an urban community hospital - through what is described in detail as core process redesign; the other - a full-service, research and teaching hospital - devised and implemented a process described, again in step-by-step detail, as re-engineering of clinical services and business operations.

Notes: Abstract  The effects of subcutaneous administration of 5-benzylacyclouridine (BAU), a uridine phosphorylase (UrdPase, EC 2.4.2.3) inhibitor, on uridine concentration in plasma and urine were evaluated in rhesus monkeys. Administration of BAU at 50, 100 and 250 mg/kg increased the plasma uridine baseline concentration 1.5-, 2.9-, and 3.2-fold, respectively. The basis for this moderate perturbation of plasma uridine by BAU was investigated using a tracer dose of 500 μCi 3H-uridine. Administration of 3H-uridine alone led to its rapid catabolism to uracil and dihydrouracil. Administration of 83.3 mg/kg BAU with 500 μCi 3H-uridine resulted in a 2.5-fold enhancement of 3H-uridine plasma levels and a substantial decrease in the plasma levels of uridine catabolites, suggesting inhibition of UrdPase activity by BAU in rhesus monkeys. Coadministration of 83.3 mg/kg BAU with 83.3 mg/kg uridine also reduced the plasma concentration of uracil and dihydrouracil, but it did not increase plasma uridine concentration above that of control animals receiving 83.3 mg/kg uridine alone. In animals receiving uridine alone at 83.3 or 25 mg/kg, approximately 10% of the administered dose was recovered in the urine within 6 h, with unchanged uridine being the major component. In contrast, administration of 83.3 mg/kg BAU increased the excretion of unchanged uridine to more than 32% of the total dose administered, even when the urinary excretion ratio of uracil to uridine was reduced ten-fold. Administration of multiple doses (three times per day) of BAU alone (83.3 mg/kg) or in the presence of uridine (83.3 mg/kg) did not enhance plasma uridine concentration further. In addition, uridine pharmacokinetics were associated with a time-dependent relationship as evidenced by an increased total plasma clearance, renal clearance and volume of distribution, resulting in a substantial decrease in uridine peak concentration with time. These results indicate that administration of BAU inhibits UrdPase activity in rhesus monkeys as manifested by decreased uracil and dihydrouracil plasma levels, as well as a lower urinary excretion ratio of uracil to uridine, as compared to control animals. However, plasma levels of unchanged uridine were not substantially enhanced by BAU in spite of the large increase in urinary excretion of unchanged uridine. This phenomenon was also observed when uridine was coadministered with BAU, suggesting that plasma uridine concentration in monkeys may be strongly regulated by the renal system as evidenced by the “spillover” of excess plasma uridine into urine. In addition, the pharmacokinetics of uridine were dose-independent, but time-dependent. This investigation may provide insights into the clinical usefulness of BAU to protect against or rescue from host toxicity induced by FUra and other chemotherapeutic pyrimidine analogues whose toxicity can be alleviated by uridine.

Notes: Abstract The effects of subcutaneous administration of 5-benzylacyclouridine (BAU), a uridine phosphorylase (UrdPase, EC 2.4.2.3) inhibitor, on uridine concentration in plasma and urine were evaluated in rhesus monkeys. Administration of BAU at 50, 100 and 250 mg/kg increased the plasma uridine baseline concentration 1.5-, 2.9-, and 3.2-fold, respectively. The basis for this moderate perturbation of plasma uridine by BAU was investigated using a tracer dose of 500 μCi3H-uridine. Administration of3H-uridine alone led to its rapid catabolism to uracil and dihydrouracil. Administration of 83.3 mg/kg BAU with 500 μCi3H-uridine resulted in a 2.5-fold enhancement of3H-uridine plasma levels and a substantial decrease in the plasma levels of uridine catabolites, suggesting inhibition of UrdPase activity by BAU in rhesus monkeys. Coadministration of 83.3 mg/kg BAU with 83.3 mg/kg uridine also reduced the plasma concentration of uracil and dihydrouracil, but it did not increase plasma uridine concentration above that of control animals receiving 83.3 mg/kg uridine alone. In animals receiving uridine alone at 83.3 or 25 mg/kg, approximately 10% of the administered dose was recovered in the urine within 6 h, with unchanged uridine being the major component. In contrast, administration of 83.3 mg/kg BAU increased the excretion of unchanged uridine to more than 32% of the total dose administered, even when the urinary excretion ratio of uracil to uridine was reduced ten-fold. Administration of multiple doses (three times per day) of BAU alone (83.3 mg/kg) or in the presence of uridine (83.3 mg/kg) did not enhance plasma uridine concentration further. In addition, uridine pharmacokinetics were associated with a time-dependent relationship as evidenced by an increased total plasma clearance, renal clearance and volume of distribution, resulting in a substantial decrease in uridine peak concentration with time. These results indicate that administration of BAU inhibits UrdPase activity in rhesus monkeys as manifested by decreased uracil and dihydrouracil plasma levels, as well as a lower urinary excretion ratio of uracil to uridine, as compared to control animals. However, plasma levels of unchanged uridine were not substantially enhanced by BAU in spite of the large increase in urinary excretion of unchanged uridine. This phenomenon was also observed when uridine was coadministered with BAU, suggesting that plasma uridine concentration in monkeys may be strongly regulated by the renal system as evidenced by the “spillover” of excess plasma uridine into urine. In addition, the pharmacokinetics of uridine were dose-independent, but time-dependent. This investigation may provide insights into the clinical usefulness of BAU to protect against or rescue from host toxicity induced by FUra and other chemotherapeutic pyrimidine analogues whose toxicity can be alleviated by uridine.