Intracellular S-glutathionyl adducts in murine lung and human bronchoepithelial cells after exposure to diisocyanatotoluene.

Diisocyanatotoluene (toluene diisocyanate, TDI), a 4:1 mixture of 2, 4- and 2,6-isomers used in the preparation of polyurethanes, causes occupational asthma by an as yet unknown mechanism. We previously showed that it forms adducts with the apical surface of the bronchoepithelium in vivo, and with ciliary microtubules in cultured human bronchoepithelial (HBE) cells. These results suggested that TDI may not enter HBE cells. In vitro studies, however, showed that TDI avidly forms bis adducts with glutathione (GSH) and that these adducts transfer monoisocyanato-monoglutathionyl-TDI to a sulfhydryl-containing peptide. This study sought to elucidate intracellular reactions of TDI. Using an electron paramagnetic resonance spectrometric (EPR) method, we established that the level of thiol-dependent quenching of phenoxyl radicals of etoposide was decreased >40% in pulmonary tissue of mice that received TDI intrabronchially. Similarly, HBE cells exposed to 100 ppb TDI vapor experienced a >30% reduction in thiol levels as determined with a thiol-specific fluorescent probe (ThioGlo 1). HPLC/UV analysis of lysates from HBE cells exposed to 200 and 500 ppb TDI vapor suggested a dose-related formation of S-glutathionyl adducts. Data from the 500 ppb TDI-treated HBE cells verified the identity of the 2-monoglutathionyl-4-monoisocyanato adduct. The results provide firm evidence that TDI enters pulmonary cells and reacts with GSH. This rapid reaction leading to formation of S-glutathionyl adducts of TDI suggests the importance of cellular thiols in TDI-induced pulmonary disease.     

A robust structure-activity relationship (SAR) model for esters that cause skin irritation in humans.

A structure-activity relationship (SAR) model has been developed to discriminate skin irritant from nonirritant esters. The model is based on the physicochemical properties of 42 esters that were tested in humans for skin irritation. Nineteen physicochemical parameters that represent transport, electronic, and steric properties were calculated for each chemical. Best subsets regression analysis indicated candidate models for further analysis. Regression analyses identified significant models (p < 0.05) that had variables that were also significant (p < 0.05). These candidate models were evaluated using linear discriminant analysis to determine if the irritant esters could be discriminated from nonirritant esters. The stability of the model was evident from the consistency of parameters among ten submodels generated using multiple random sampling of the database. The sensitivity of the ten models, evaluated by "leave-one-out" cross-validation, ranged from 0. 846 to 0.923, with a mean of 0.885 +/- 0.025 (95% CI). The specificity ranged from 0.615 to 0.923, with a mean of 0.738 +/- 0.06 (CI). Compared with nonirritant esters, irritant esters had lower density, lower water solubility, lower sum of partial positive charges, higher Hansen hydrogen bonding parameter, and higher Hansen dispersion parameter. The results indicate that physicochemical features of esters contribute to their ability to cause skin irritation in humans, and that chemical partitioning into the epidermis and intermolecular reactions are likely important components of the response. This model is applicable for prediction of human irritation of esters yet untested.     

Influence of cardiac output on dexmedetomidine pharmacokinetics

Dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, reduces the requirements for anesthetic, analgesic, sedative, and hypnotic drugs. Dexmedetomidine pharmacokinetics were characterized in healthy subjects after intravenous administration by means of a computer-controlled infusion pump. A series of seven stepwise increasing pseudo-steady-state plasma concentrations were targeted. The influence of cardiac output on the pharmacokinetics was investigated by use of a compartmental modeling approach in which the elimination clearance was characterized as being either cardiac output independent or dependent. At dexmedetomidine concentrations of 0, 0.6, and 1.2 ng/mL, mean (SD) estimated cardiac outputs were 5. 6 (0.85), 5.1 (0.67), and 4.5 (0.83) L/min, and mean (SD) clearances were 40 (10), 38 (9.0), and 35 (8.5) L/h, respectively. Dexmedetomidine V(SS) and elimination half-life were 72 (19) L and 1. 9 (0.62) h, respectively. The approximately 3 to 19% decrease in cardiac output observed within the anticipated therapeutic range of 0.3 to 1.2 ng/mL was similar to that observed for clonidine. The decrease in cardiac output with increasing plasma concentrations of dexmedetomidine resulted in a corresponding decrease in drug elimination clearance of < or =12% within the therapeutic range; however, this decrease in dexmedetomidine clearance is likely not clinically relevant.     

Robot-assisted laparoscopic prostatectomy in a 68-year-old patient with previous heart transplantation and pelvic irradiation

We report the case of a 68-year-old man who had previously undergone heart transplantation and pelvic irradiation for Hodgkin’s lymphoma and who was under active surveillance for prostate cancer. In response to his increased prostate-specific antigen levels and elevated Gleason score, he was offered robot-assisted laparoscopic prostatectomy.     

Cerebral nocardiosis in immunosuppressed patients: five cases

Five cases of 'primary' cerebral nocardiosis are described. All occurred in patients already affected by factors carrying a poor prognosis for nocardial infections. These included primary immune dysfunction, immunosuppressive drug therapy including high-dose prednisolone and the presence of cerebral nocardial abscesses. Three of the five patients died, but only two had evidence of continued nocardial infection at necropsy. This compares with mortality of 90 per cent reported in other studies. Therefore aggressive surgical and antibiotic treatment of cerebral nocardial abscesses may reduce the mortality rate in the immunocompromised to the rate seen in immunocompetent patients. We suggest that investigations of non-specific pulmonary symptoms in the immunocompromised should include a search for nocardial colonization as this is indicative of infection. Diagnosis of nocardial infection at the pulmonary stage rather than when central nervous system abscesses are present would lead to an improvement in prognosis.     

Effect of haemolysate preparation on measurement of red cell folate by a radioisotopic method.

The effects of varying the method of preparation of haemolysates on the measurement of red cell folate concentration were investigated using the Simultrac kit. The concentration of ascorbic acid did not have any significant effect on the assayed concentrations of folate, but lower concentrations were obtained when the incubation time was increased. Folate was stable for 14 days in cells when they were stored at 4 degrees C and for seven days at -25 degrees C, but instability was increased by storage in ascorbic acid, by the use of stored (4 degrees C) ascorbic acid, and by preparing the haemolysates by freeze-thaw cycling. It is recommended that haemolysates should be diluted in fresh ascorbic acid, at a concentration of 10 g/l, incubated for 60 minutes in the dark and stored at -20 degrees/25 degrees C before being assayed.     

The quality of life after aortic valve replacement with homografts or prosthetic valves.

BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the quality of life in patients after homograft or prosthetic aortic valve implantation. Evaluation was based on clinical and echocardiographic examinations, and on analysis of data from patient questionnaires. METHODS: Patients undergoing either homograft (HV, n = 220) or prosthetic (PV, n = 220) aortic valve replacement were investigated. The patients groups were similar in age, sex, follow up period, risk factors and type of heart defect, and did not demonstrate any dysfunction of the replacement valve. RESULTS: During both pre- and postoperative periods, no significant inter-group differences were identified with regard to the occurrence of retrosternal pain, dyspnea, palpitation, fear reaction and circulatory efficiency based on NYHA classification, and self-evaluation of physical activity assessed by patient questionnaires. The majority of patients in both groups noticed on increase in their quality of life and physical activity. The reduced sexual activity (50%) and fear reaction (30%) in both groups did not correlate with their improved sense of well-being. Up to 14.6% of PV patients did not accept the implanted valve, and 65 (29.5%) would have preferred an HV, despite the need for reoperation. Following surgery, 21% of HV patients resumed work, compared with only 7.7% of PV patients. The frequency of claims for disability pension after surgery did not correlate with the considerate clinical and subjective improvement. CONCLUSIONS: In patients receiving either homograft or prosthetic valves, the subjective evaluation of life quality is comparable with the clinical evaluation, though the homograft valve was better accepted than its prosthetic counterpart.