Background-The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery. Methods and Results-We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level Ն10ϫ upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted PϽ0.05; false discovery rate Ͻ10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 Ϫ572GϾC; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98GϾT; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703). Conclusions-Functional

No abstract

No abstract

Topics: Pharmacology P regnant women may require sedation, anesthesia, or pain control for nonobstetric-related care. The a 2adrenergic receptor (a 2 AR) agonist dexmedetomidine (DEX) has sedative, anxiolytic, and analgesic actions and can reduce the dose requirements for other sedative and analgesic drugs through synergistic effects with opioids and benzodiazepines. Clinical investigations of DEX have not included significant numbers of pregnant patients; in fact, most studies have excluded pregnant women. This study was designed to determine the maternal and fetal responses to an intravenous infusion of DEX in sheep.The study was performed on 9 preterm pregnant ewes at gestational day 92, a time relatively equivalent to the end of the second trimester in humans. Surgical anesthesia was induced with IV sodium thiopental and maintained with isoflurane in oxygen. Standard surgical techniques were used to insert catheters into maternal femoral artery and jugular vein as well as bilateral fetal femoral arteries. A flow probe was placed around the left uterine artery to record uterine blood flow (UBF). The fetal head was exteriorized to install near-infrared spectroscopy probes to assess changes in fetal cerebral oxygenation during and after drug administration to the mother. The fetus was then returned to the uterus. After the procedure, infiltration of the surgical incision with bupivacaine and intramuscular nalbuphine hydrochloride were used to control postoperative pain. Animals recovered for 48 hours before the DEX-exposure experiment was conducted. Maternal and fetal cardiovascular data along with UBF were recorded. Fetal cerebral oxygenation, measured by changes in oxygenated, deoxygenated, and total hemoglobin (Hb) (oxyHb, deoxyHb, and totalHb, respectively), was quantitated with the near-infrared spectroscopy monitor. After a baseline recording period of 30 to 60 minutes, drug exposure was begun using human-dosing guidelines. Each ewe received an IV bolus injection of DEX, 1.0 mg/kg followed by a constant IV infusion of 1.0 mg/kg/h. The infusion was stopped after 3 hours and the experiment halted 2 hours later. Hemodynamic and fetal cerebral oxygenation data were continuously recorded during the study; maternal and fetal arterial blood samples were obtained at 30-minute intervals.The statistical analyses focused on the 3 primary endpoints: changes in fetal cerebral oxygenation, maternal and fetal cardiovascular status, and arterial blood gas status.All animals tolerated the DEX infusion with no complications during or after drug exposure. Profound sedation occurred within minutes of starting the infusion; consciousness returned within 30 to 60 minutes after discontinuation of the infusion. During the infusion, the sheep were unresponsive to painful stimuli. The ewes had a normal respiratory pattern throughout the exposure period, as evidenced by the arterial blood gas values that remained normal throughout the study. Only blood glucose levels in both the ewe and fetus continued to rise during DEX infusion, p...

No abstract

No abstract

No abstract

No abstract