. Louis MO 63110; {Departments of Artherosclerosis Therapeutics, }Biochemistry and }Chemistry Parke-Davis, Ann Arbor MI 48105 and #Department of Pharmacology, Columbia University, New York, NY 10032, U.S.A.1 15-Lipoxygenase (15-LO) has been implicated in the pathogenesis of atherosclerosis because of its localization in lesions and the many biological activities exhibited by its products. To provide further evidence for a role of 15-LO, the e ects of PD 146176 on the development of atherosclerosis in cholesterol-fed rabbits were assessed. This novel drug is a speci®c inhibitor of the enzyme in vitro and lacks signi®cant non speci®c antioxidant properties. 2 PD 146176 inhibited rabbit reticulocyte 15-LO through a mixed noncompetitive mode with a K i of 197 nM. The drug had minimal e ects on either copper or 2,2'-azobis(2-amidinopropane)hydrochloride (ABAP) induced oxidation of LDL except at concentrations 2 orders higher than the K i . 3 Control New Zealand rabbits were fed a high-fat diet containing 0.25% wt./wt. cholesterol; treated animals received inhibitor in this diet (175 mg kg 71 , b.i.d.). Plasma concentrations of inhibitor were similar to the estimated K i (197 nM). During the 12 week study, there were no signi®cant di erences in weight gain, haematocrit, plasma total cholesterol concentrations, or distribution of lipoprotein cholesterol. 4 The drug plasma concentrations achieved in vivo did not inhibit low-density lipoprotein (LDL) oxidation in vitro. Furthermore, LDL isolated from PD 146176-treated animals was as susceptible as that from controls to oxidation ex vivo by either copper or ABAP. 5 PD 146176 was very e ective in suppressing atherogenesis, especially in the aortic arch where lesion coverage diminished from 15+4 to 0% (P50.02); esteri®ed cholesterol content was reduced from 2.1+0.7 to 0 mg mg 71 (P50.02) in this region. Immunostainable lipid-laden macrophages present in aortic intima of control animals were totally absent in the drug-treated group. 6 Results of these studies are consistent with a role for 15-LO in atherogenesis.
The risk of acquiring cytomegalovirus (CMV) from infected infants concerns pediatric health-care workers, particularly those who may be pregnant. We determined the prevalence of CMV antibody, and thus of past infection, in groups of medical students and house staff, nurses, and physicians, and in groups of pregnant and nonpregnant young women in the community. Although age, sex, and race influenced the results, occupation did not. We then estimated the exposure of the health-care workers by determining the prevalence of CMV infection in three groups of asymptomatic infants for whom they provided care; CMV was shed in urine or saliva of 1.6 per cent of newborns, 13 per cent of premature infants hospitalized for over a month, and 5 per cent of older infants seen in outpatient settings. When we determined the incidence of primary infection in the adult groups by retesting the seronegative members about two years later, we found that the annual attack rates in the medical students (0.6 per cent), house staff (2.7 per cent), and nurses (3.3 per cent) were not higher than in young women in the community (2.5 per cent during pregnancy and 5.5 per cent between pregnancies). We conclude that although pediatric health-care workers frequently and unknowingly care for infants shedding CMV, this occupational contact confers no greater risk than that faced by young women in the community at large.
Hyperventilation (respiratory alkalosis) is an important treatment for persistent pulmonary hypertension in neonates. The precise way that hyperventilation attenuates hypoxic pulmonary vasoconstriction is unclear. We studied the effect of alkalosis on hypoxia-induced pulmonary vasoconstriction in 13 acutely instrumented, pentobarbital anesthetized, neonatal lambs. We specifically examined the relative effects of a metabolic alkalosis versus a respiratory alkalosis on hypoxic pulmonary vasoconstriction and compared these results to the control response to hypoxia without alkalosis. Hypoxic pulmonary vasoconstriction was significantly milder whenever the animal was alkalotic, regardless of whether the alkalosis was respiratory of metabolic. Thus, the elevated pHa rather than decreased PaCO2 during hyperventilation appears to be the major factor in moderating the response of the pulmonary vessels to acute hypoxia in this neonatal lamb model.
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