Characterization of the 12C4 survivin monoclonal antibody and insight into the expression of survivin in human adult tissues.

AIMS: To elucidate the expression and regulation of survivin in normal tissues. METHODS AND RESULTS: A novel monoclonal antibody (12C4) to survivin was generated. Application of this antibody to determine survivin expression in human normal adult tissues revealed that most adult tissues do not express survivin and, where it is present, survivin is largely restricted to a small subset of epithelial cells and cells with proliferative potential such as thymus. Survivin expression among positive tissues showed individual variations, ranging from zero to < 5% positive cells in epithelial cell populations. Testis is the only human adult tissue highly expressing survivin, with 60-70% positivity in the nuclei of spermatogonia. Consistent with deregulated expression of survivin associated with oncogenesis, we found that certain ligands and transcription factors differentially modulate survivin promoter activity in cancer cells versus normal/untransformed cells. CONCLUSION: Deregulation of survivin transcription controls in individual epithelial cells may contribute to oncogenesis in various human adult tissues.

Modification of lidocaine protein binding with CO2.

Using new, specially designed ultrafiltration devices and an enzyme immunoassay technique, the authors determined the effect of carbon dioxide tension on the fractional binding of lidocaine to human plasma proteins. Identical samples of serum at therapeutic (2.2 micrograms X ml-1) and toxic (6.8 micrograms X ml-1) lidocaine concentrations were tonometered at 37 degrees C to CO2 tensions between 0.13 and 10.7 kPa (1.0 to 80.5 mmHg). The fraction of unbound lidocaine increased linearly with increasing pCO2 (r = 0.93, p less than 0.001). These changes help to explain the increased central nervous system toxicity of lidocaine associated with hypercarbia.

Comparison of the ventilatory effects of etomidate and methohexital.

Using a dual-isohypercapnic technique, the authors determined the effect of equipotent doses of methohexital (1.5 mg/kg) and etomidate (0.3 mg/kg) on the ventilatory response to CO2 (VERCO2) in six healthy volunteers. Speed of induction and duration of hypnosis did not differ significantly between the two drugs. Within 2 min after injection, the slope of VERCO2 decreased significantly after both methohexital (from 2.52 to a minimum of 0.15 l . min-1 . mmHg-1, P less than 0.05) and etomidate (from 2.56 to a minimum of 0.62 l . min-1 . mmHg-1, P less than 0.05); the magnitude of this depression did not differ significantly between the drugs. Methohexital also caused a significant decrease in minute ventilation at end-tidal PCO2 of 46 mmHg (VE 46) from 14.6 to 4.3 l . min-1 within 60 s after injection (P less than 0.05). In contrast, after etomidate VE 46 gradually increased from 17.9 1 . min-1 to a maximum of 31.6 l . min-1 at 3.5 min after injection (P less than 0.05); respiratory rate increased significantly, while changes in tidal volume were not significant. Effects of etomidate and methohexital on VE 46 differed significantly (P less than 0.001). These data indicate that, while etomidate and methohexital similarly depress the medullary centers that modify ventilatory drive in response to changing CO2 tensions, ventilation at any given CO2 tension is greater after etomidate than after methohexital. This indicates that etomidate may cause a CO2-independent stimulation of ventilation, suggesting its use for induction of anesthesia in cases where maintenance of spontaneous ventilation is desirable.

The effect of physostigmine on diazepam-induced ventilatory depression: a double-blind study.

The authors conducted a double-blind crossover study to determine the effects of physostigmine salicylate on hyperoxic ventilatory response to carbon dioxide (VE RCO2) and on awareness in healthy subjects previously sedated with diazepam. Diazepam 0.4 mg/kg iv decreased the slope of VE RCO2 from 2.41 +/- 0.19 to 1.30 +/- 0.15 1 . min-1 . mmHg-1 (mean +/- SEM, P less than 0.001). Subsequent injection of physostigmine 2.0 mg iv was associated with a 0.20 +/- 0.28 1 . min-1 . mmHg-1 decrease in slope; this was significantly different from the 0.56 +/- 0.22 1 . min-1 . mmHg-1 increase in slope associated with saline placebo (P less than 0.05). Level of consciousness, on the other hand, increased more after physostigmine than after saline (P less than 0.01). The authors conclude that despite an apparent increase in awareness resulting from physostigmine administration, the accompanying decrease in ventilatory drive may contraindicate its use in patients who previously have received diazepam.