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THE COUNCIL FOR TOBACCO RRSE ARCH-U.S.A., INC. MEMORANDUM TO: FROM: Dr. S. C. Sommers and Staff D.H. Ford RE: Site visit with Dr. A. McLaughlin, University of Pennsylvania, Phila. Jan. 14, 1986 Site visitors: Drs. D.H. Ford, A. Maudsley (outside reviewer) and S.C. Sommers. Grant proposal No. 1493A entitled "NMR studies of cerebral metabolism" History: This application was deferred at the October 1985 SAB meeting for an outside review and site visit. The major premise of the original proposal was that NMR techniques could provide information that would be useful in diagnosing cerebral infarction and in designing therapeutic protocols. o~ Current directionYproposal• Dr. McLauglin now appears to be focusing his investigation on determing what happens to cell membrane and cytoplasmic function of brain cells following or during hypoxia or ischemia, including differing degrees of ischemia. Thus, the study will be directed toward evaluating the effect of ischemia on CA++ influx into cells and its subsequent role in increasing phospholipases, arachadonic acid and its metabolites, which products could damage the cell membrane to permit a further increase in intracellular CA++ and damage to the cell. Further, the investigation will evaluate, in relation to time after infarction, the effect on P04~ Na+ and lactate by examining P and proton spectra. The derived data will establish levels of ATPa,P and :15, phosphocreatine, inorganic phosphate and phosphate monoester as well as tissue pYl. He further believes he will soon be able to measure K levels. Thus, he believes the study will determine how ischemia causes damage to brain cells and if the disrupted metabolism can return to normal if the degree of ischemia is not too severe or of short duration. As a final aspect of the ~roblem, Dr. McLaughlin plans to determine the effect of Ca+ blocking agents and endogenous opiates (shown to increase following exposure to hypoxia). Imaging studies on the brains will be undertaken by Dr. Haselgrove. Comment: An addendum which better describes the specific goals of the proposal as well as a modified budget t"b

cover an unexpected increase in equipment costs will be submitted. The proposal, as currently described by Dr. McLaughlin appears more in line with his earlier studies on Ca++ effects on membrane function,with the current focus being on how Ca++ cation flux into cells is influenced by hypoxia and ischemia to effect cell membrane and cytoplasmic component function, possibly leading to cell death. Since reports in the literature link smoking to increases in atherosclerosis and increased thrombosis, which could relate to stroke, the investigation seems relevant to the interests of CTR. Further, the study should provide information relevant to membrane and cell energy functions following varying degrees of ischemia as well as possibilities of return of function. Dr. McLaughlin appears well informed in this area of research. He is enthusiastic concerning the use of NMR to measure cell metabolism and how changes in such metabolism might be influenced by environmental factors. He seems capable of undertaking the investigation. As discussed at this visit, I would judge the proposal to merit serious consideration for support. DHF 2