Role of cytochrome P4503A in cysteine S-conjugates sulfoxidation and the nephrotoxicity of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A) in rats

The volatile anesthetic sevoflurane is degraded to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) in anesthesia machines. FDVE is nephrotoxic in rats. FDVE undergoes glutathione conjugation, subsequent conversion to cysteine and mercapturic acid conjugates, and cysteine conjugate metabolism by renal beta-lyase, which is a bioactivation pathway mediating nephrotoxicity in rats. Recent in vitro studies revealed cytochrome P4503A-catalyzed formation of novel sulfoxide metabolites of FDVE cysteine-S and mercapturic acid conjugates in rat liver and kidney microsomes. FDVE-mercapturic acid sulfoxides were more toxic than other FDVE conjugates to renal proximal tubular cells in culture. Nevertheless, the occurrence and toxicological significance of FDVE sulfoxides formation in vivo remain unknown. This investigation determined, in rats in vivo, the existence, role of P4503A, and nephrotoxic consequence of FDVE conjugates sulfoxidation. Rats were pretreated with dexamethasone, phenobarbital, troleandomycin, or nothing (controls) before FDVE, and then, nephrotoxicity, FDVE-mercapturate sulfoxide urinary excretion, and FDVE-mercapturate sulfoxidation by liver microsomes were assessed. The formation of FDVE-mercapturic acid sulfoxide metabolites in vivo and their urinary excretion were unambiguously established by mass spectrometry. Dexamethasone and phenobarbital increased, and troleandomycin decreased (i) liver microsomal FDVE-mercapturic acid sulfoxidation in vitro, (ii) FDVE-mercapturic acid sulfoxide urinary excretion in vivo, and (iii) FDVE nephrotoxicity in vivo assessed by renal histology, blood urea nitrogen concentrations, and urine volume and protein excretion. Urine 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, reflecting beta-lyase-dependent FDVE-cysteine S-conjugates metabolism, was minimally affected by the pretreatments. These results demonstrate that FDVE S-conjugates undergo P4503A-catalyzed sulfoxidation in rats in vivo, and this sulfoxidation pathway contributes to nephrotoxicity. FDVE S-conjugates sulfoxidation constitutes a newly discovered mechanism of FDVE bioactivation and toxicification in rats, in addition to beta-lyase-catalyzed metabolism of FDVE-cysteine S-conjugates.     

Sulfoxidation of cysteine and mercapturic acid conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A)

The volatile anesthetic sevoflurane is degraded in anesthesia machines to the haloalkene fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), which can cause renal and hepatic toxicity in rats. FDVE is metabolized to S-[1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl)ethyl]-L-cysteine (DFEC) and (E) and (Z)-S-[1-fluoro-2-fluoromethoxy-2-(trifluoromethyl)vinyl]-L-cysteine [(E,Z)-FFVC], which are N-acetylated to N-Ac-DFEC and (E,Z)-N-Ac-FFVC S-conjugates. Some haloalkene S-conjugates undergo sulfoxidation. This investigation tested the hypothesis that FDVE S-conjugates can also undergo sulfoxidation, by evaluating sulfoxide formation by human and rat liver and kidney microsomes and expressed P450s and flavin monooxygenases. Rat, and at lower rates human, liver microsomes oxidized (Z)-N-Ac-FFVC and N-Ac-DFEC to the corresponding sulfoxides. Much lower rates of (Z)-N-Ac-FFVC, but not N-Ac-DFEC, sulfoxidation occurred with rat and human kidney microsomes. In human liver microsomes, the P450 inhibitor 1-aminobenzotriazole completely inhibited S-oxidation, while heating to inactivate FMO decreased (Z)-N-Ac-FFVC and N-Ac-DFEC sulfoxidation only 0 and 30%, respectively. Of the various cytochrome P450s examined, P450s 3A4 and 3A5 had the highest S-oxidase activity toward (Z)-N-Ac-FFVC; P450 3A4 was the predominant enzyme forming N-Ac-DFEC-SO. The P450 3A inhibitors troleandomycin and ketoconazole inhibited >95% of (Z)-N-Ac-FFVC sulfoxidation by P450 3A4 and 3A5 and 40-100% of (Z)-N-Ac-FFVC sulfoxidation by human liver microsomes and 15-85% of N-Ac-DFEC sulfoxidation by human liver microsomes. Sulfoxidation of DFEC was also examined in human liver microsomes. Substantial amounts of sulfoxide were observed, even in the absence of NADPH or protein, while enzymatic formation was comparatively minimal. These results show that FDVE S-conjugates undergo P450-catalyzed and nonenzymatic sulfoxidation and that enzymatic sulfoxidation of (Z)-N-Ac-FFVC and N-Ac-DFEC is catalyzed predominantly by P450 3A. The extent of FDVE sulfoxidation in vivo and the toxicologic significance of FDVE sulfoxides remain unknown and merit further investigation.     

Maternal deaths and their causes in Ankara, Turkey, 1982-2001

This study was carried out to determine the incidence and causes of maternal deaths about a 20-year period at the Zekai Tahir Burak Women's Health Education and Research Hospital (ZTBWHERH), Ankara, Turkey. All maternal deaths from January 1982 to July 2001 were reviewed and classified retrospectively. Using a computer-generated list, 348 patients admitted to the Labour Department of ZTBWHERH during 1982-2001 were selected as controls. Medical records were reviewed for demographic data, history of antenatal care, route of delivery, referral history, and perinatal mortality. Cases and controls were compared, and standard tests were used for calculating odds ratio (OR) and 95% confidence interval (CI) for the association of demographic and delivery characteristics. During this period, there were 174 maternal deaths and 430,559 livebirths, giving a maternal mortality ratio of 40.4/100,000 livebirths. The mortality rate declined from 85.1/100,000 in 1982 to 11.6/100,000 in 2001. One hundred thirty (74.7%) deaths were due to direct obstetric causes and 24 (13.7%) were abortion-related, while 20 (11.4%) were due to indirect obstetric causes. The most common cause of direct obstetric deaths was pre-eclampsia/eclampsia, followed by obstetric haemorrhage and embolism. Abortion-related sepsis and haemorrhage, anesthesia-related deaths, obstetric sepsis, acute fatty liver of pregnancy, and ectopic pregnancy accounted for other causes of deaths. Cardiovascular disease was the leading indirect cause of death. Referral, lack of antenatal care, and foetal death at admittance were associated with 8-, 3-, and 6-fold increased risk of maternal mortality respectively (OR 8.89, 95% CI 5.7-13.8; OR 3.74, 95% CI 2.5-5.5; OR 6.38, 95% CI 3.1-13.1). Although maternal mortality ratios have declined at the hospital, especially in the past five years, the rate is still high, and further improvements are needed. The problem of maternal mortality remains multifactorial. Short-term objectives should be focused on improving both medical and administrative practices. Improving the status of women will necessarily remain a long-term objective.     

Cervical hematomyelia: a rare entity in a neonate with cesarean section and surgical recovery

Spinal cord injury with or without trauma has been reported in the perinatal period. The prognosis depends primarily on diagnosis of the level, extent and nature of the lesion, established by correlations between clinical, imaging and electrophysiological data. A 25-day-old boy with normal birth weight delivered at term by cesarean section was transferred to In?nü University Turgut Ozal Medical Center because of respiratory distress and brachial diplegia. A suspicious medullary lesion on cervical computerized tomography was confirmed as an intramedullary lesion extending from C3 to D1 on magnetic resonance imaging (MRI). Emergent surgery consisting of exposure of the lesion site and interlaminar direct puncture of the lesion under fluoroscopy revealed that the pathology was an intramedullary hematoma. The partial evacuation of the lesion with direct puncture, the patient's neurological improvement and close follow-up of the patient with ultrasonography, electrophysiology and MRI are discussed in the light of recent literature.     

An unusual case of primary nasal tuberculosis with epistaxis and epilepsy

Primary nasal tuberculosis is rare. We report a case that was all the more extraordinary because of the age and sex of the patient (an 11-year-old boy), the unusual associated symptoms (epistaxis and grand and seizures), and the presence of intracranial extension. Clinical and radiologic findings on our initial evaluation suggested that the patient had a large sinonasal malignancy. The patient manifested no evidence of pulmonary tuberculosis. The diagnosis of primary nasal tuberculosis was established only after we obtained the results of histopathology of the excised mass and a subsequent tuberculin skin test; the diagnosis was confirmed by the patient's rapid response to antituberculosis drug therapy. We also review the relevant literature on this rare condition.     

Ethnic differences and determinants of proteinuria among South Asian subgroups in Pakistan

BACKGROUND: Hypertension, diabetes, increasing age, and smoking are known risk factors for proteinuria. Prevalence of proteinuria is high in South Asians. However, ethnic subgroup differences and determinants of proteinuria within the South Asian population have not been explored. METHODS: The National Health Survey of Pakistan conducted between 1990 and 1994 was used to explore ethnic subgroup variation in proteinuria. Distinct ethnic subgroups, the Muhajir, the Punjabi, the Sindhi, the Pashtun, and the Baluchi, were defined by mother tongue. We report results in individuals aged >or=15 years (N = 9442). Proteinuria was defined as dipstick positive for protein on random urine sample. RESULTS: Increasing age, high consumption of meat, and presence of hypertension and diabetes were each independently associated with proteinuria. The age-standardized prevalence of proteinuria was 4.6% (4.2% to 5.1%) and varied among ethnic subgroups (P < 0.001). The highest was among the Sindhi (men 9.5%, women 10.3%), then the Muhajir (men 8.2%, women 4.7%), the Punjabi (men 3.2% women 3.5%), and lowest among the Baluchi (men 2.4%, women 4.2%) and the Pashtun (men 2.7%, women 1.2%). The ethnic differences persisted after adjusting for the above-mentioned sociodemographic, dietary, and clinical risk factors [adjusted odds ratio (OR) (95% CI)] were 6.42 (3.97 to 10.38) for the Sindhis, 3.58 (2.22 to 5.79) for the Muhajirs, 2.03 (1.25 to 3.29) for the Punjabis, and 1.75 (0.79 to 3.88) for the Baluchis compared to the Pashtuns). CONCLUSION: We conclude that unmeasured environmental or genetic factors account for ethnic variations in proteinuria, and deserve further study.     

Bilateral petrous internal carotid artery pseudoaneurysms presenting with sensorineural hearing loss

We present a case of an 85-year-old woman with a 40-year history of progressive bilateral sensorineural hearing loss. Imaging studies demonstrated bilateral pseudoaneurysms of the petrous portion of the internal carotid arteries eroding into both cochleas. To our knowledge, this is the first case report of such lesions.     

Increased vasoconstrictor reactivity and decreased endothelial function in high grade varicocele; functional and morphological study

The pathophysiology of human varicocele is not fully understood. We investigated vasoconstrictor reactivity, endothelial function and morphological changes in different grades of varicocele to clarify the pathophysiology. Contractile responses to phenylephrine, norepinephrine, serotonin and histamine were determined in isolated human varicose spermatic veins using the organ bath technique. Endothelial function was tested with acetylcholine-induced relaxation after phenylephrine-induced precontraction in the absence and presence of nitric oxide synthase inhibitor, L-NAME, and cyclooxygenase inhibitor, indomethacin. The cyclic guanosine monophosphate (cGMP) level was measured in the spermatic vein and peripheral plasma. Morphological changes were evaluated with light microscopy. Phenylephrine, norepinephrine, serotonin and histamine induced concentration-dependent contractions. The maximum contractions for all of these agents except norepinephrine were significantly higher in grade III than grade I and II (P<0.05). The sensitivity to phenylephrine was significantly higher in grades II and III than in grade I (P<0.05). In the presence of L-NAME and indomethacin, the difference from respective control phenylephrine-induced contractions was higher in grade I and II than grade III. Acetylcholine did not induce stable relaxation but the level of cGMP, which is responsible for the vasorelaxant effect of NO, in veins was lower in grades II and III than grade I (P<0.05). Vessel wall thickness increased in grade II and dilatation developed in grade III when compared to grade I (P<0.05). Our findings suggest that endothelium produces less vasorelaxant which results in the more enhanced effects of vasoconstrictor substances in grade III, indicating that endothelial dysfunction develops at high grades of varicocele.