Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis.

The bisdichloroacetyldiamine WIN 18,446 reversibly inhibits spermatogenesis in many species, including humans; however, the mechanism by which WIN 18,446 functions is unknown. As retinoic acid is essential for spermatogenesis, we hypothesized that WIN 18,446 might inhibit retinoic acid biosynthesis from retinol (vitamin A) within the testes by inhibiting the enzyme aldehyde dehydrogenase 1a2 (ALDH1a2). We studied the effect of WIN 18,446 on ALDH1a2 enzyme activity in vitro, and on spermatogenesis and fertility in vivo, in mature male rabbits for 16 weeks. WIN 18,446 markedly inhibited ALDH1a2 enzyme activity in vitro with an IC(50) of 0.3 µM. In vivo, the oral administration of 200 mg/kg WIN 18,446 to male rabbits for 16 weeks significantly reduced intratesticular concentrations of retinoic acid, severely impaired spermatogenesis, and caused infertility. Reduced concentrations of intratesticular retinoic acid were apparent after only 4 weeks of treatment and preceded the decrease in sperm counts and the loss of mature germ cells in tissue samples. Sperm counts and fertility recovered after treatment was discontinued. These findings demonstrate that bisdichloroacetyldiamines such as WIN 18,446 reversibly suppress spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2. These findings suggest that ALDH1a2 is a promising target for the development of a reversible, nonhormonal male contraceptive.

NIRS monitoring of pilots subjected to +Gz acceleration and G-induced loss of consciousness (G-LOC).

With the increasing maneuverability of modern aircraft, there is an increased frequency of pilots losing consciousness due to high +Gz acceleration. This phenomena is defined as "G-induced loss of consciousness" (G-LOC). We used an NIRS system of our design to monitor cerebral oxygenation changes of pilots subjected to high +Gz acceleration and G-LOC. During the +Gz pulse, delta HbO2, and delta TotalHb decreased, with lesser changes of delta Hb. The maximum decrease of delta HbO2 and delta TotalHb usually occurred at the onset of G-LOC. After G-LOC, delta HbO2 and delta TotalHb increased rapidly for the first few seconds, beginning the reactive hyperemic recovery phase. delta HbO2 and delta TotalHb peaked, and then began to decrease towards baseline. The subjects were unconscious for 3-10 seconds after the onset of G-LOC. Upon returning to consciousness, the subjects were disoriented for another 4-11 seconds. NIRS provides an additional means of studying physiological mechanisms leading to and recovery from G-LOC.

Correlation of NIRS determined cerebral oxygenation with severity of pilot +Gz acceleration symptoms.

Pilots commonly experience decreased peripheral vision, confusion & disorientation, and/or unconsciousness when exposed to high +Gz acceleration. We correlated NIRS determined delta Hb, delta HbO2, and delta TotalHb with the resultant +Gz stress symptoms that subjects reported after experiencing a 6 to 10 +Gz amplitude pulse. During the hyperemic response phase following the +Gz pulses, an increase of the averaged peak values of delta HbO2 and delta TotalHb as a function of the severity of the subjects' symptoms was observed. Significant increases were found for the averaged peak values of delta HbO2 and delta TotalHb between high vision loss, confusion and disorientation while remaining conscious (A-LOC), and unconsciousness (G-LOC). The results suggest that the confusion and disorientation associated with A-LOC is physiologically based and that A-LOC is an intermediate +Gz stress symptom between high peripheral vision loss and G-LOC. Like G-LOC, pilots who experience A-LOC symptoms momentarily do not have full control of their aircraft.

Adapting and validating a NIRS device to measure in utero fetal sheep cerebral oxygenation.

NIRS has provided us with a reliable and sensitive method to monitor in utero fetal cerebral oxygenation in the surgically-recovered pregnant sheep. Our preliminary results indicate that monitoring fetal cerebral oxygenation may be important to understanding how maternal drug exposure can affect the fetal brain.

Change in plasma glutamate concentration during cardiac surgery is a poor predictor of cognitive outcome.

OBJECTIVE: To develop a simple and reliable method for quantitating plasma glutamate concentration and apply this method to monitor systemic glutamate levels during coronary artery bypass graft (CABG) surgery, a procedure associated with neurologic deficits. DESIGN: Prospective serial investigation of cardiac surgery patients. SETTING: Tertiary-care university teaching hospital. PARTICIPANTS: Patients undergoing CABG surgery (n = 33). INTERVENTIONS: Preoperative and postoperative neurologic and neurocognitive testing were done. Intraoperative blood samples for glutamate quantitation were obtained from jugular bulb and pulmonary artery catheters before, during, and after cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Glutamate concentrations were determined using a reverse-phase high-pressure liquid chromatography method coupled to precolumn derivatization of the analyte with o-phthalaldehyde. The mean prebypass plasma glutamate concentration was 79.4 +/- 41.8 micromol/L. Plasma glutamate levels fluctuated during surgery with considerable degrees of temporal and quantitative interpatient variability. Neurologic and neurocognitive deficits were observed after CABG surgery. However, neither the occurrence nor the severity of cognitive decline could be predicted by the magnitude of increase in plasma glutamate concentration. CONCLUSION: Fluctuations in intraoperative systemic glutamate levels do not predict post-CABG surgery neurologic outcome.

Neuroprotection is associated with beta-adrenergic receptor antagonists during cardiac surgery: evidence from 2,575 patients.

OBJECTIVE: To determine the impact of perioperative beta-adrenergic receptor (betaAR) antagonist administration on neurologic complications. DESIGN: Observational database analysis. SETTING: A clinical investigation at a single tertiary academic medical center. PARTICIPANTS: Elective coronary artery bypass graft surgical patients operated on in the period 1994-1996. INTERVENTIONS: Patients were divided into 2 groups: (1) patients given betaAR antagonist-blocking drugs in the perioperative period, including during operation, and (2) patients not given betaAR antagonists. MEASUREMENTS AND MAIN RESULTS: betaAR antagonist use in 2,575 consecutive patients undergoing coronary artery bypass graft surgery (1994-1996) was determined using the Cardiovascular Database and Anesthesia Information System Database. Outcome variables were postoperative stroke, coma, and transient ischemic attack. Of patients, 113 (4.4%) had postoperative neurologic complications, including stroke (n = 44), coma (n = 12), and transient ischemic attack (n = 3). Of patients, 2,296 (89%) received perioperative betaAR antagonist therapy, and 279 (11%) did not. Adverse neurologic events occurred in 3.9% (n = 90) of patients who received perioperative betaAR antagonists and 8.2% (n = 23) of patients who did not receive betaAR antagonists (odds ratio, 0.45; 95% confidence interval, 0.28 to 0.73; p = 0.003, unadjusted.) Severe neurologic outcomes (stroke and coma) occurred in 1.9% (n = 44) of patients who received betaAR antagonists and 4.3% (n = 12) of patients who did not receive betaAR antagonists (odds ratio, 0.43; 95% confidence interval, 0.23 to 0.83; p = 0.016). CONCLUSION: Use of beta-adrenergic antagonists was associated with a substantial reduction in the incidence of postoperative neurologic complications. A prospective randomized trial is needed to verify this potentially important neuroprotective strategy in cardiac surgery.