Regulation of the Interaction of Inosine Monophosphate Dehydrogenase with Mycophenolic Acid by GTP

Inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in the de novo synthesis of guanine nucleotides, is a major therapeutic target. A prototypic uncompetitive inhibitor of IMPDH, mycophenolic acid (MPA), is the active form of mycophenolate mofeteil (CellCept), a widely used immunosuppressive drug. We have found that MPA interacts with intracellular IMPDH in vivo to alter its mobility on SDS-polyacrylamide gels. MPA also induces a striking conformational change in IMPDH protein in intact cells, resulting in the formation of annular aggregates of protein with concomitant inhibition of IMPDH activity. These aggregates are not associated with any known intracellular organelles and are reversible by incubating cells with guanosine, which repletes intracellular GTP, or with GTPgammaS. GTP also restores IMPDH activity. Treatment of highly purified IMPDH with MPA also results in the formation of large aggregates of protein, a process that is both prevented and reversed by the addition of GTP. Finally, GTP binds to IMPDH at physiologic concentrations, induces the formation of linear arrays of tetrameric protein, and prevents the aggregation of protein induced by MPA. We conclude that intracellular GTP acts as an antagonist to MPA by directly binding to IMPDH and reversing the conformational changes in the protein

Overview of the National Occupational Mortality Surveillance (NOMS) System: Leukemia and Acute Myocardial Infarction Risk by Industry and Occupation in 30 US States 1985–1999, 2003–2004, and 2007

Background Cancer and chronic disease are leading causes of death in the US with an estimated cost of $46 billion. Methods We analyzed 11 million cause-specific deaths of US workers age 18–64 years in 30 states during 1985–1999, 2003–2004, and 2007 by occupation, industry, race, gender, and Hispanic origin. Results The highest significantly elevated proportionate leukemia mortality was observed in engineers, protective service, and advertising sales manager occupations and in banks/savings &loans/credit agencies, public safety, and public administration industries. The highest significantly elevated smoking-adjusted acute myocardial infarction mortality was noted in industrial and refractory machinery mechanics, farmers, mining machine operators, and agricultural worker occupations; and wholesale farm supplies, agricultural chemical, synthetic rubber, and agricultural crop industries. Conclusions Significantly elevated risks for acute myocardial infarction and leukemia were observed across several occupations and industries that confirm existing reports and add new information

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The Effect of Ageing on Function and Quality of Life in Ileal Pouch Patients: A Single Cohort Experience of 409 Patients With Chronic Ulcerative Colitis

OBJECTIVE: To evaluate in what manner ageing affects functional outcome and quality of life (QoL) in patients with chronic ulcerative colitis (CUC) after ileal pouch-anal anastomosis (IPAA). SUMMARY BACKGROUND DATA: Short-term function and QoL after IPAA is good. However, patients are usually young, and little is known about the influence of time and ageing on long-term outcomes after IPAA. METHODS: Using a standardized questionnaire, functional outcome, QoL, and complications were assessed prospectively in a cohort of 409 patients followed annually for 15 years after IPAA. RESULTS: Follow-up was complete in the single cohort of 409 patients and functional and QoL outcomes summarized at 5, 10, and 15 years. Daytime stool frequency changed little (mean 6), while nighttime frequency increased from 1 stool to 2 stools. Incontinence for gas and stool increased from 1% to 10% during the day and from 2% to 24% at night over 15 years. The cumulative probability of pouchitis increased from 28% at 5 years to 38% at 10 years and to 47% at 15 years. Bowel obstruction and stricture were other principal long-term complications. At 15 years, 91% of patients had kept the same job. Work was not affected by the surgery in 83%, while social activities, sports, traveling, and sexual life all improved after surgery and did not deteriorate over time. CONCLUSIONS: These long-term results in a single cohort of 409 IPAA patients are unique and are likely a more accurate reflection of long-term outcome than has been previously reported. These data support the conclusion that IPAA is a durable operation for patients requiring proctocolectomy for CUC; functional and QoL outcomes are good, predictable, and stable for 15 years after operation