Immunochemical characterization of cytochrome P-450 isozymes responsible for benzene oxidation in the rat liver

The contribution of cytochrome P-450 isozymes to benzene metabolismin liver microsomes from fed, fasted, pyrazole-, pbenobarbital(PB)- and ethanol-treated rats and in respective isocaloriccontrols was investigated using monoclonal antibodies (mAbs).Clone 1-7-1 mAb did not inhibit benzene metabolism, whereasclone 2-66-3 inhibited only in PB-induced microsomes at a highconcentration of benzene (6.26 mM), and clone 1-91-3 mAb inhibitedbenzene metabolism in all cases. The degree of inhibition wasas follows: fed isocaloric control PB < fasted < pyrazole ethanol. The pattern of inhibition was similar with clone 1-91-3for low (0.23 mM) and high concentrations of benzene, exceptin PB-induced mkrosomes. Western blot analysis showed that clone1-7-1 mAb did not bind any liver mkrosomal protein in the regionof cytochrome P-450s, whereas with clone 2-66-3 a clear-cutband was seen only in liver microsomes from PB-treated rats,with clone 1-98-1, a band was detected in mkrosomes from alltreated groups, in the following order: PB = isocaloric control< fed < fasted < pyrazole < ethanol. These resultsindicate that (i) cytochromes P-450b,e and P-450J contributeto benzene metabolism in rat liver; (ii) the former has a lowaffinity to benzene and is induced by PB; and (iii) P-450J hasa high affinity to benzene and is induced by 1-day fasting,pyrazole and ethanol, but decreased by PB treatment.     

Exposure to 1-bromopropane causes ovarian dysfunction in rats.

Although 1-bromopropane has been used in chemical and electronic industries as an alternative to ozone layer-depleting solvents, its toxicity on female reproductive organs has not been fully elucidated. The aim of this experiment was to determine the effect of 1-bromopropane on female reproductive function in rats. Forty female Wistar rats were divided into four equal groups. Each group was exposed daily to 0, 200, 400, or 800 ppm of 1-bromopropane for eight h a day. After exposure for 7 weeks, all rats in the 800-ppm group became seriously ill and were sacrificed during the 8th week. The other dose groups were exposed for 12 weeks. In the 800-ppm group, but not in the other two exposed groups, body weight was significantly less than the control at each time point from 2 to 7 weeks after the beginning of exposure. Tests of vaginal smears showed a significant increase in the number of irregular estrous cycles with extended diestrus in the 400- and 800-ppm groups. Histopathological examination of the ovary showed a significant dose-dependent reduction of the number of normal antral follicles and a decrease in the number of normal growing follicles in the 400-ppm group. No significant change was found in plasma concentrations of LH or FSH in any group when compared with the control. Our results indicate that 1-bromopropane can induce a dose-dependent ovarian dysfunction in nonpregnant female rats associated with disruption in follicular growth process.     

Spatial Performance Is More Sensitive to Ethanol Than Nonspatial Performance Regardless of Cue Proximity

In rodents, ethanol produces a greater impact on the ability to perform spatial reference memory tasks than nonspatial reference memory tasks. Such evidence may reflect a selective disruption in the use of previously acquired spatial information. However, a rtonmnemonic explanation has yet to be ruled out Tasks used to study ethanol's effects on spatial memory commonly require subjects to utilize distal, or ex-tramaze, cues to respond correctly. In contrast, many previously used nonspatial tasks could be solved using cues located on the maze itself. Because ethanol has been shown to disrupt sensory processing, it is possible that previously observed differences in the effects of ethanol on spatial and nonspatial performance were actually due to differences in the proximity of relevant cues in the spatial and nonspatial tasks and not to a selective disruption in spatial memory. The present study compares the effects of ethanol on the performance of spatial and nonspatial reference memory tasks that require subjects to discriminate among extramaze cues for correct responding. Subjects were trained while sober to navigate to a goal arm on a 12-arm maze. In the spatial task, the goal arm was defined by its location with respect to a number of extramaze cues. In the nonspatial task, the goal arm was defined by the presence of a single extramaze cue located directly beyond the end of the arm. Subjects were tested under 1 of 4 doses of ethanol (0.0, 0.7, 1.4, and 2.1 g/kg). Performance on the nonspatial task was more resistant to the effects of ethanol than performance on the spatial task. The results suggest that differences in the effects of ethanol on spatial and nonspatial performance are not due to differences in the proximity of relevant cues in previously used spatial and nonspatial tasks. Key Words: Ethanol, Spatial, Nonspatial, Memory, Maze.     

A review of hazardous chemical toxicity studies utilizing genetically-modified animals--their applications for risk assessment

Studies on the mechanisms of chemical toxicity carried out using knockout mice lacking genes of enzymes for drug metabolism or nuclear receptor proteins were reviewed, and the studies were compared with the respective conventional mechanistic studies. While the toxicity of many hazardous chemicals was observed only in wild-type or knockout mice, which clearly showed that their toxicity was involved in the enzyme or receptor, some chemicals exhibited the same degree of toxicity in two genotypes, i.e., in both the wild strain and knockout mice, demonstrating that the enzymes or receptors are not involved in their toxicity. The use of genetically-modified animals presents not only the advantage of simultaneous evaluation of toxicity endpoints and mechanisms, but also suggests significant benefits over conventional methods using several chemicals to elucidate toxicity mechanisms. Elucidation of the mechanism of toxicity will provide useful information for risk assessment, and the use of genetically-modified animals for this purpose will lead to the advancement of this assessment.     

Nasal resistance for determinant factor of nasal surgery in CPAP failure patients with obstructive sleep apnea syndrome

OBJECTIVES: Given that criteria for nasal surgery in individuals with obstructive sleep apnea syndrome (OSAS) have not been proposed, we investigated the effectiveness of nasal surgery for CPAP failure in patients with both severe OSAS and nasal obstruction. PATIENTS AND METHODS: Conventional nasal surgery was performed in 12 patients who were refractory to treatment by CPAP. The subject group consisted of 12 males (mean age, 54.2 +/- 9.2 years; range 39-66 years). The effect of nasal surgery was evaluated with data from preoperative and postoperative polysomunography. The nasal resistance value was first deduced to determine which OSAS patients with CPAP failure should undergo nasal surgery, compared to control values. RESULTS: Nasal surgery resulted in a significant decrease in nasal resistance, as measured by rhinomanometry, from 0.57 +/- 0.31 Pa/cm3 /sec to 0.16 +/- 0.03 Pa/cm3/sec and rendered all patients tolerant to CPAP. In addition, the lowest nocturnal oxygen saturation significantly increased from 68.3 +/- 12.1% to 75.3 +/- 7.1% after surgery. Subjectively, Epworth sleepiness scale (ESS) significantly decreased from 11.7 +/- 4.1 to 3.3 +/- 1.3 after surgery, but the number of apnea and hypopnea episodes per hour did not change significantly. In five patients, for whom it was possible to perform a CPAP titration before nasal surgery, the value decreased significantly from 16.8 +/- 1.1 to 12.0 +/- 1.9 cmH2O. The bilateral nasal resistance of the 410SAS patients with CPAP therapy (control group) was 0.24 +/- 0.11 Pa/cm3/sec. The cut off value for differentiation between CPAP failure patients and control group was determined as 0.38 Pa/cm3 /sec. CONCLUSION: Increased nasal resistance is a determinant of CPAP failure, and the surgical correction of severe nasal obstruction should thus be considered to facilitate treatment of OSAS patients with CPAP.     

Hearing loss in patients with enlarged vestibular aqueduct: air-bone gap and audiological Bing test

The Bing test is based on the principle that occlusion of the external auditory meatus improves the perception of bone-conducted sounds unless there is a conductive hearing impairment. An air-bone gap has been reported in patients with large vestibular aqueduct (LVA) syndrome without apparent middle ear dysfunction. We therefore performed the Bing test on nine patients with this syndrome to evaluate whether it is associated with an air-bone gap or middle ear dysfunction. Bone conduction thresholds did not change significantly during the Bing test in any patient. Because an air-bone gap is observed in patients with abnormal communication between the inner ear and cerebrospinal fluid through the LVA, dehiscent superior canal, or dilated inner ear meatus; we propose that a 'three windows' model (in which the abnormal communication provided by the enlarged endolymphatic duct and sac in LVA acts as the 'third window' for sound conductance) might explain the air-bone gap in such patients.     

Origins of the edge shadowing artefact in medical ultrasound imaging

Ultrasound (US) B-mode images distal to smooth, rounded cavities, such as cysts, containing a fluid with a speed of sound mismatch to the surrounding tissue, often exhibit a "refractile" edge shadowing artefact. This usually appears as narrow, hypoechoic, shadow lines extending a significant distance distal to the lateral edges of the fluid cavity and parallel to the US beam. The true reasons for this artefact are likely to be complex and to vary from case to case, with many different explanations found in the literature. However, we present a simplified theoretical model for the phenomenon based on a pulsed, finite-beam solution of US scattering from circular fluid-filled cylinders that suggests that "edge" shadows can occur distal not only to edges but also to points where the incident beam intersects the cavity near to the critical angle. Both mechanisms support the view that edge shadows can arise from the combination of unusually high wavefront spreading and the speckle-generating nature of the surrounding tissue. In vitro data from a tissue-mimicking phantom confirms that the edge shadow structure depends on the sign of the speed of sound contrast between the cylinder fluid and the surrounding medium.     

Clinical Doppler ultrasound for the assessment of plaque ulceration in the stenosed carotid bifurcation by detection of distal turbulence intensity: a matched model study

The assessment of flow disturbances due to carotid plaque ulceration may provide added diagnostic information to Doppler ultrasound (DUS) of the carotid stenosis, and indicate whether the associated hemodynamics are a potential thromboembolic source. We evaluated the effect of ulceration in a moderately stenosed carotid bifurcation on distal turbulence intensity (TI) measured using clinical DUS in matched anthropomorphic models. Several physiologically relevant ulcer geometries (hemispherical, mushroom-shaped, and ellipsoidal pointing distally and proximally) and sizes (2-mm, 3-mm and 4-mm diameter hemispheres) were investigated. An offline analysis was performed to determine several velocity-based parameters from ensemble-averaged spectral data, including TI. Significant elevations in TI were observed in the post-stenotic flow field of the stenosed carotid bifurcation by the inclusion of ulceration (P < 0.001) in a region two common carotid artery diameters distal to the site of ulceration during the systolic peak and the diastolic phase of the cardiac cycle. Both the size and shape of ulceration had a significant effect on TI in the distal region (P < 0.001). Due to the use of a clinical system, this method provides the means to evaluate for plaque ulcerations in patients with carotid atherosclerosis using DUS.