[Intrabronchial leiomyoma treated with endoscopic resection; report of a case].

A 63-year-old female presented with an abnormal shadow on a chest X-ray. A serial chest computed tomography (CT) showed ground-glass attenuation, which measured 2 cm on S1+2 of the left lung. When bronchofiberscopy was performed to make a diagnosis, a tumor with a smooth surface was revealed which obstructed the right middle bronchus. Leiomyoma was thus diagnosed. At first, a wide wedge resection of left lung tumor was performed. Secondly, a bronchus tumor was successively removed using a high frequency snare and a laser by a bronchofiberscopy. Her postoperative course was uneventful. Leiomyoma of the bronchus is rare benign tumor. This report describes the performance of a resection using bronchofiberscopy with good results.

Transcortical mixed aphasia due to cerebral infarction in left inferior frontal lobe and temporo-parietal lobe.

We present a case of transcortical mixed aphasia caused by a cerebral embolism. A 77-year-old right-handed man was admitted to our hospital with speech disturbance and a right hemianopia. His spontaneous speech was remarkably reduced, and object naming, word fluency, comprehension, reading and writing were all severely disturbed. However, repetition of phonemes and sentences and reading aloud were fully preserved. Although magnetic resonance imaging (MRI) showed cerebral infarcts in the left frontal and parieto-occipital lobe which included the inferior frontal gyrus and angular gyrus, single photon emission CT revealed a wider area of low perfusion over the entire left hemisphere except for part of the left perisylvian language areas. The amytal (Wada) test, which was performed via the left internal carotid artery, revealed that the left hemisphere was dominant for language. Hence, it appears that transcortical mixed aphasia may be caused by the isolation of perisylvian speech areas, even if there is a lesion in the inferior frontal gyrus, due to disconnection from surrounding areas.

Silent cerebral infarction and cognitive function in middle-aged neurologically healthy subjects.

We sought to clarify whether apparently silent cerebral infarcts and periventricular hyperintensities are associated with depressed cognitive function in middle-aged subjects. Subjects were 84 middle-aged neurologically normal adults who wished to undergo a screening examination of the brain. We performed magnetic resonance imaging (MRI) of the brain and neuropsychologic tests in all subjects. Silent cerebral infarcts and periventricular hyperintensities, respectively, were detected in 21 and 14 of 84 subjects. Mini-mental state (MMS) and Raven's colored progressive matrices (RCPM) scores were significantly lower in subjects with than without silent cerebral infarcts. By two-factor analysis of variance, MMS score was affected by silent cerebral infarcts or periventricular hyperintensities, with interactions between the two lesion types (P < 0.05). Silent cerebral infarcts may be an independent factor in the pathogenesis of intellectual dysfunction, but truly independent analysis is difficult because many subjects with silent cerebral infarcts also have periventricular hyperintensities.

Cytochrome P450 3A conjugation to ubiquitin in a process distinct from classical ubiquitination pathway.

We characterize a novel microsome system that forms high-molecular-mass (HMM) CYP3A, CYP2E1, and ubiquitin conjugates, but does not alter CYP4A or most other microsomal proteins. The formation of the HMM bands was observed in hepatic microsomes isolated from rats treated 1 week or more with high doses (50 mg/kg/day) of nicardipine, clotrimazole, or pregnenolone 16alpha-carbonitrile, but not microsomes from control, dexamethasone-, nifedipine-, or diltiazem-treated rats. Extensive washing of the microsomes to remove loosely attached proteins or cytosolic contaminants did not prevent the conjugation reaction. In contrast to prototypical ubiquitination pathways, this reaction did not require addition of ubiquitin, ATP, Mg(2+), or cytosol. Addition of cytosol did result in the degradation of the HMM CYP3A bands in a process that was not blocked by proteasome inhibitors. Immunoprecipitated CYP3A contained HMM ubiquitin. Even so, mass spectrometric analysis of tryptic peptides indicated that the HMM CYP3A was in molar excess to ubiquitin, suggesting that the formation of the HMM CYP3A may have resulted from conjugation to itself or a diffuse pool of ubiquitinated proteins already present in the microsomes. Addition of CYP3A substrates inhibited the formation of the HMM CYP3A and the cytosol-dependent degradation of HMM CYP3A. These results suggest that after extended periods of elevated CYP3A expression, microsomal factors are induced that catalyze the formation of HMM CYP3A conjugates that contain ubiquitin. This conjugation reaction, however, seems to be distinct from the classical ubiquitination pathway but may be related to the substrate-dependent stabilization of CYP3A observed in vivo.

Transient crossed aphasia and persistent amnesia after right thalamic haemorrhage.

A 45-year-old right-handed woman suffered transient aphasia and persistent amnesia after a right thalamic haemorrhage. This patient appeared to have crossed aphasia, although it disappeared within 8 weeks. It is noteworthy that the patient had a unilateral right thalamic lesion but exhibited both verbal and non-verbal memory impairment. Computed tomography and magnetic resonance imaging revealed cerebral haemorrhage in the right thalamus involving the ventral anterior nucleus, medioventral nucleus, mamillothalamic tract, internal medullary lamina, and mediodorsal nucleus. An amytal test was performed and suggested that the right hemisphere was dominant for language functions and the left hemisphere was dominant for visuospatial functions. Single photon emission CT revealed a low perfusion area only in the right thalamus. These findings suggest that the right hemisphere might be dominant for both verbal and non-verbal memory function in this patient, although visuospatial function was lateralized in the left hemisphere.

Memory impairment and spatial disorientation following a left retrosplenial lesion.

We treated a patient in whom a left retrosplenial lesion resulted in memory impairment and spatial disorientation. A 31 year old, right handed man was admitted to our hospital after the sudden onset of headache. He was alert, attentive and cooperative, and showed no motor or sensory deficits. Although intelligence was preserved, memory was obviously deficient. The patient proceeded in wrong directions after he left his hospital room and subsequently his home. Neuroimaging revealed a subcortical hematoma in the left cingulate isthmus, while single-photon emission computed tomography demonstrated decreased perfusion in the splenium and left parietal lobe.

Cytochrome P450 4A fatty acid omega hydroxylases.

The Cytochrome P450 4A subfamily is one of eighteen subfamilies in the CYP4 family and presently consists of twenty individual forms in nine different mammalian species. The major substrates for CYP4A forms are fatty acids, but recent studies have shown other non-fatty acid substrates may be metabolized by specific CYP4A forms. The physiological and metabolic functions of the CYP4A subfamily have not been elucidated, but the ability of CYP4A forms to metabolize medium and long chain length fatty acids at their omega (omega)-carbon atom has generated significant interest because of the possible role that omega-hydroxylated fatty acids may have in cell signalling processes and as an alternative pathway for fatty acid metabolism. A number of different compounds or physiological conditions have been shown to regulate the expression of CYP4A forms in liver and/or kidney. Several CYP4A forms may serve as a marker for the exposure to compounds that are classified as peroxisome proliferators. There is also considerable interest why multiple CYP4A forms exist in different tissues. Recent studies in the rat and human indicate that other CYP4 forms besides CYP4A forms may be responsible for the metabolism of arachidonic acid to its omega-hydroxy product. The focus of this review will be to summarize recent studies that have characterized the substrate specificity of rat, rabbit and human CYP4A forms and discuss the significance of CYP4A-mediated hydroxylation of fatty acids. In addition, dietary effects or novel compounds that have been reported to regulate CYP4A expression in the rat and mouse will be discussed.

Perinatal changes in choroidal 15-hydroxyprostaglandin dehydrogenase: implications for prostaglandin removal from brain.

We have previously shown in the sheep fetus at 0.7 and 0.9 gestation that the choroid plexus, unlike brain parenchyma, catabolizes prostaglandins (PGs). Peculiarly, in the choroid plexus, PGE(2) catabolism persists throughout the neonatal period to abate in the adult, while PGF(2alpha) catabolism abates shortly after birth. To explain this differential behavior and elucidate the function of catabolic enzymes, we examined the cellular location and activity of the rate-limiting enzyme for PGE(2) and PGF(2alpha) catabolism, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Immunofluorescence histochemistry and immunogold electronmicroscopy revealed abundant 15-PGDH expression in the epithelial cytosol close to the brush-border membrane at 0.7 and 0.9 gestation. In contrast, at 5 and 15 days postnatal, 15-PGDH was found throughout the cytosol of stromal fibroblasts. No staining was observed at either location in pregnant adults. PGF(2alpha) catabolism was minimal in the total homogenate and 100000xg supernatant of the fetal choroid plexus at 0.7 and 0.9 gestation, while PGE(2) catabolism was evident at 0.7 gestation only. In contrast, both PGs were catabolized in minced specimens at either age. In conclusion, our study shows immunoreactive 15-PGDH in the choroid plexus from fetal and neonatal, but not pregnant adult, sheep. Results suggest that PGE(2) catabolism is not as critically dependent as that of PGF(2alpha) on tissue integrity and 15-PGDH location. Given the key role being assigned to the choroid plexus in PG removal from brain, we speculate that persistence of PGE(2) catabolism into the early postnatal period protects against central respiratory depression caused by the compound during this susceptible stage of development.

Transcortical sensory aphasia due to a left frontal subcortical haemorrhage.

A case of transcortical sensory aphasia caused by a cerebral haemorrhage in the left frontal lobe is presented. A 72-year-old right-handed woman was admitted to the hospital, with a history of acute onset of speech disturbance and headache. On initial assessment, her spontaneous speech was fluent. She had no difficulty initiating speech, articulated normally, and did not exhibit logorrhea. Her ability to repeat phonemes and short sentences (5-6 words) was fully preserved, however she had severe difficulty with visual recognition of words, and with aural comprehension at the word level, although she was able to read words aloud. Computed tomography and magnetic resonance imaging showed cerebral haemorrhage in the left frontal lobe, involving the superior and middle frontal gyrus. Single photon emission CT revealed a wider area of low perfusion over the entire left frontal lobe, including the superior, middle and inferior frontal gyrus. The aphasia symptoms, mainly poor comprehension, disappeared quickly several weeks after the event. This may have been due to a reduction in the size of the haematoma and a resolution of the oedema around the haematoma. Clinically, the transcortical sensory aphasia in this case was indistinguishable from that caused by damage to the posterior language areas. Further case reports of transcortical sensory aphasia associated with frontal lobe lesions would help to confirm whether a relatively rapid recovery is characteristic in cases such as this.

[Dural arteriovenous fistula at the cranio-cervical junction presenting transient ischemic attack: a case report].

A 58-year-old male was admitted to our hospital because of repeated transient ischemic attack of right hemiparesis and speech disturbance. A CT scan did not demonstrate any remarkable findings. No significant cerebral arterial stenosis or occlusion was found on angiography. However, dural arteriovenous fistula fed by the radiculo-meningeal artery was found at the cranio-cervical junction on left vertebral angiography. The shunt flow from the arteriovenous fistula drained into the superior petrosal sinus and sigmoid sinus in a retrograde fashion. On the angiographic findings when his transient ischemic attack (TIA) had disappeared, the venous drainage had returned to its normal fashion. Venous hypertension around the brain stem was supposed to have caused the transient ischemic attack in this case. We performed coagulation of the draining vein and fistula surgically. After surgery, the patient's TIA completely disappeared. We report the first case of dural arteriovenous fistula at the cranio-cervical junction presenting transient ischemic attack.

Effect of calcium channel antagonists nifedipine and nicardipine on rat cytochrome P-450 2B and 3A forms.

Calcium channel antagonists are widely prescribed for treatment of hypertension. In this study, we examined whether treatment with the calcium channel antagonists, nicardipine, nifedipine or diltiazem, alters cytochrome P-450 2B or 3A (CYP2B or CYP3A, respectively) expression in rat liver. Western blot analyses were undertaken using antibodies specific for one or several members of these cytochrome P-450 subfamilies. Nicardipine was found to be an effective inducer of CYP3A; in particular, CYP3A23 was increased approximately 36-fold following treatment with 100 mg of nicardipine/kg/day. Nicardipine induced CYP2B forms up to approximately 3.1-fold. Nifedipine did not alter CYP3A expression but did increase CYP2B expression such that total CYP2B, CYP2B1, and CYP2B2v (a splice variant of CYP2B2) were increased approximately 5- to 15-fold after treatment with 100 mg of nifedipine/kg/day, with increases in benzyloxyresorufin O-dealkylase and erythromycin N-demethylase activities, respectively. The distinct differences in cytochrome P-450 induction profile induced by nicardipine and nifedipine suggest that they may enhance cytochrome P-450 expression by different mechanisms unrelated to their effects on calcium channels.

[Construct validity of a new computer-assisted cognitive assessment battery in normal adults].

A computer-assisted battery for neuropsychological tests (CNT) has been designed to screen adults for cognitive impairment. The aim of this study was to gather evidence for the construct validity of CNT and also investigate the relationship between CNT and conventional neuropsychological tests. Subjects were 45 healthy adults (21 men and 24 women), who ranged in age from 20 to 70 years (mean = 33.5, SD = 1.9) with no history of substance abuse, or of psychotic or neurological disorders. The CNT in our study consists of six subtests designed to assess various components of driving, such as digit span, visual scanning, visual and verbal memory, complex reaction time, and vigilance. Mini-mental state test, Kana-hiroi test, word fluency, the auditory-verbal learning test and Raven's colored progressive matrices were also performed as conventional neuropsychological tests. Results showed there were high correlations between each CNT subtests and conventional neuropsychological tests. A factor analysis (with varimax rotation) identified 4 factors with eigen values greater than 1, which accounted for over 70% of the variance. CNT was able to estimate each factor related to cognitive function such as learning and memory, attention, judgment, and visual scanning selectively. CNT may thus be a useful tool for detection of cognitive impairment, although this test has important limitations. Broader applications of these tests will require extensive population-based validation.

Improved separation and immunodetection of rat cytochrome P450 4A forms in liver and kidney.

In the study of tissues that contain several forms of one cytochrome P450 subfamily, it is useful to develop immunoblotting techniques so that the various individual members of the family can be distinguished. This paper describes improvements in the immunoblotting technique to distinguish members of the rat cytochrome P450 4A subfamily, 4A1, 4A2, and 4A3, as they are present in Sprague-Dawley rat liver microsomes. This procedure was used to investigate differences in the cytochrome P450 4A forms observed under various conditions such as: untreated versus peroxisome proliferator treated rats, Sprague-Dawley versus Fischer 344 male versus female rats, and liver versus kidney microsomes. In liver microsomes of male Sprague-Dawley rats, forms 4A1, 4A2, and 4A3 were induced by the peroxisome proliferators, clofibrate, di-(2-ethylhexyl) phthalate, dehydroepiandrosterone, aspirin, and ibuprofen. Expression of the 4A forms shows strain specificity. A comparison of the cytochrome P450 4A forms in male Sprague-Dawley and Fischer 344 rats treated with peroxisome proliferators demonstrated that three distinct protein bands are visible on immunoblots of liver microsomes of Sprague-Dawley rats, whereas only two distinct protein bands are detectable in liver microsomes of Fischer 344 rats. The two protein bands in liver microsomes of male Fischer 344 rats migrate in positions corresponding to the 4A2 and 4A3 bands in male Sprague-Dawley rats. There did not appear to be a protein band corresponding to the 4A1 band of Sprague-Dawley rats. Expression of the 4A forms also shows gender specificity. In liver microsomes of female Sprague-Dawley rats, expression of the P450 4A2 form was not observed after treatment with a peroxisome proliferator. Expression of the 4A forms also shows tissue specificity. In kidney, 4A2 is the major protein band in male Sprague-Dawley rats with minor amounts of the 4A3 protein, whereas two prominent protein bands (4A2 and 4A3) are seen in male Fischer 344 rats.

Prostaglandin-metabolizing enzymes during pregnancy: characterization of NAD(+)-dependent prostaglandin dehydrogenase, carbonyl reductase, and cytochrome P450-dependent prostaglandin omega-hydroxylase.

Prostaglandins E2 and F2 alpha regulate a number of physiological functions in reproductive tissues, and concentrations of these bioactive modulators increase during pregnancy. Corresponding to the increase in circulating levels of prostaglandins during pregnancy is an increase in enzymes that metabolize these agents. Three prostaglandin-metabolizing enzymes induced during pregnancy are NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH), NADPH-dependent carbonyl reductase, and cytochrome P450-dependent prostaglandin omega- or 20-hydroxylase. This review discusses the biochemical properties, regulation, and possible functions of these three enzymes.

Hydroxylation of lauramide diethanolamine by liver microsomes.

Lauramide diethanolamine (LDEA)--a compound used in cosmetics and soap products as an emollient, thickener, and foam stabilizer--was observed to be metabolized by rat liver microsomes to two major products that were identified by GC/MS to be the 11-hydroxy and 12-hydroxy derivatives of LDEA. The specific activities for LDEA 11- and 12-hydroxylation in microsomes prepared from control rats were 2.23 +/- 0.40 and 0.71 +/- 0.17 nmol/min/mg protein, respectively. Treatment of rats with the cytochrome P4504A inducer and peroxisome proliferator, diethylhexyl phthalate, increased the LDEA 12-hydroxylation rate to 3.50 +/- 0.48 nmol/min/mg protein, a 5-fold increase in specific activity, whereas the LDEA 11-hydroxylase activity remained unchanged. Because LDEA contains a 12-carbon side chain, LDEA hydroxylation rates were compared with the hydroxylation rates for lauric acid. The specific activities of lauric acid 11- and 12-hydroxylation reactions in diethylhexyl phthalate-treated rats were 1.7-fold and 3.2-fold greater than the LDEA 11- and 12-hydroxylation rates, respectively. When LDEA hydroxylation reactions were performed in the presence of a polyclonal antibody to the rat P4504A forms, formation of 12-hydroxy-LDEA was inhibited by 80%. Rat kidney microsomes also supported the hydroxylation of LDEA at its 11- and 12-carbon atoms, with specific activities of 0.05 +/- 0.01 and 0.28 +/- 0.02 nmol/min/mg protein, respectively. LDEA was also metabolized to 11- and 12-hydroxy derivatives by human liver microsomes at specific activities of 0.22 +/- 0.06 and 0.84 +/- 0.26 nmol/min/mg protein, respectively.

Human liver lauric acid hydroxylase activities.

Nine male and five female human liver microsomal sample were examined for laurate 11- and 12-hydroxylase activities. The mean specific activities for the 11- and 12-hydroxylation reactions were 0.78 +/- 0.33 and 1.07 +/- 0.12 nmol/min/mg protein, respectively. Antibody inhibition experiments, using a polyclonal antibody to a cytochrome P450 (P450) isolated from diethylhexyl phthalate-treated rats, which recognizes forms P4504A1, P4504A2, and P4504A3 of the rate, inhibited the 12-hydroxylase activity by 65%, but did not affect 11-hydroxylase activity. Western-blot analyses of the 14 human liver microsomal samples identified one major protein band at 52 kDa that comigrated with human form 4A11. A correlation coefficient of only 0.19 was calculated when comparing laurate 12-hydroxylase activities and the densitometric values of the immunochemically reactive protein bands in the human liver microsomal samples, which strongly suggests that additional P450 forms also support the 12-hydroxylation of lauric acid. Laurate 11-hydroxylase activity was inhibited by diethyldithiocarbamate, an inhibitor of P4502E1-mediated reactions, and by chlorzoxazone, a P4502E1 substrate. A comparison of laurate 11-hydroxylase activities with densitometric values of the P4502E1 protein bands indicated a strong correlation existed (0.82). An analysis of microsomal samples containing expressed human forms P4501A2, P4502A6, P4502C8, P4502C9, P4502D6, P4502E1, and P4503A4 showed that only form P4502E1 supported the 11-hydroxylation reaction.