Covalent binding of rofecoxib, but not other cyclooxygenase-2 inhibitors, to allysine aldehyde in elastin of human aorta.

In rats, it has been reported that rofecoxib, a cyclooxygenase-2 (COX-2) inhibitor, reacts with the aldehyde group of allysine in elastin to give a condensation covalent adduct, thereby preventing the formation of cross-linkages in the elastin and causing degradation of the elastic fibers in aortas in vivo. Acid, organic solvent, and proteolytic enzyme treatments of human aortic homogenate after incubation with [(14)C]rofecoxib demonstrated that most of the radioactivity is covalently bound to elastin. The in vitro covalent binding was inhibited in the presence of beta-aminopropionitrile, D-penicillamine, and hydralazine, which suggested that the aldehyde group of allysine in human elastin was relevant to the covalent binding. The in vitro covalent binding of [(14)C]rofecoxib was significantly decreased by the addition of only nonradiolabeled rofecoxib but not the other COX-2 inhibitors, celecoxib, valdecoxib, etoricoxib, and CS-706 [2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-1H-pyrrole], a novel selective COX-2 inhibitor. All the above COX-2 inhibitors except for rofecoxib had no reactivity with the aldehyde group of benzaldehyde used as a model compound of allysine aldehyde under a physiological pH condition. On the other hand, no retention of the radioactivity of [(14)C]rofecoxib was observed in human aortic endothelial cells in vitro, suggesting that rofecoxib is not retained in aortic endothelial cells in vivo. These results suggest that rofecoxib, but not other COX-2 inhibitors, is capable of covalently binding to the aldehyde group of allysine in human elastin. This might be one of the main causes of cardiovascular events by rofecoxib in clinical situations.     

Evidence that neurofibrillary tangles undergo glial modification

Summary Ghost tangles, neurofibrillary tangles (NFTs) emerging into extracellular space, appear to be subjected to some microglial association in addition to an invasion of astrocytic processes. Our findings lead us to speculate that the NFTs undergo structural and immunocytochemical modification. Electron microscopic observation of the NFTs in the vascular region indicated either the discharge of NFTs into the vessel or formation of NFTs in the astrocytic end-foot.     

Extracellular or ghost Pick bodies and their lack of tau immunoreactivity: a histological,immunohistochemical and electron microscopic study

Histological, immunohistochemical, and electron microscopic evidence of an extracellular, or ghost Pick body has been found in the granular cell layer and, rarely, in the pyramidal cell layer of the hippocampus of an autopsy case of Pick's disease. The ghost Pick body appeared as a blurred, weak argyrophilic mass in the neuropil, and it was composed of accumulated fibrillary structures, 13 nm in diameter, intermingled with glial filament bundles. These ghost Pick bodies did not react with anti-tau and antiubiquitin antibodies, but did react weakly with antiglial fibrillary acidic protein antibody, whereas intracytoplasmic Pick bodies were strongly immunolabeled with anti-tau but only weakly with anti-ubiquitin anti-bodies. These results suggest that the Pick body is discharged into the neuropil after destruction of the mother neuron, loses its immunoreactivity to certain tau and ubiquitin antibodies during this process (thereby inducing a glial reaction) and remains in the neuropil as a ghost Pick body.     

Glial localization of four‐repeat tau in atypical progressive supranuclear palsy

In the present case, a patient in whom limb apraxia and asymmetrical parkinsonism developed suggesting corticobasal degeneration, is reported. Neuropathologic examination revealed numerous tufted astrocytes in the precentral cortex in addition to the characteristic pathologic findings of PSP. Therefore, on the basis of clinicopathologic features, atypical progressive supranuclear palsy was diagnosed. In addition, the brain tissue of the present patient was investigated with an antibody specific for four‐repeat tau (4R‐tau). In the precentral cortex, numerous tau‐positive tufted astrocytes, pretangles, and threads were positive for 4R‐tau. Using a confocal microscopy we demonstrated that tufted astrocytes positive for 4R‐tau were adjacent to astrocytes positive for GFAP. The present findings suggest that accumulation of four‐repeat tau in astrocytes is a degenerative process rather than a reactive process.     

Amelioration by topical bunazosin hydrochloride of the impairment in ocular blood flow caused by nitric oxide synthase inhibition in rabbits.

We investigated whether topical instillation of an alpha(1)-adrenergic blocker would improve an insufficient blood supply in the optic nerve head (ONH) and visual function, in rabbits. The effect of systemic NOS inhibition on visual-evoked potentials (VEPs) and hemodynamics in ONH were determined. VEPs were recorded before and every 15 min during a 120-min observation period after an intravenous injection of 50 mg/kg N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor. Capillary blood flow in ONH was evaluated by the laser speckle method throughout the same period. Then, we investigated the effect of topical instillation of a recently developed alpha(1) adrenergic blocker, bunazosin hydrochloride (0.01%), 60 min prior to the intravenous L-NAME (50 mg/kg) on the changes by NOS inhibition. The VEP amplitudes were reduced by L-NAME (10, 20, and 50 mg/kg) in a dose-dependent manner, while the VEP implicit time was unchanged, and no significant changes were detected in the electroretinogram. The reductions in ONH capillary blood flow and VEP amplitudes caused by L-NAME (50 mg/kg) were significantly suppressed by an instillation of bunazosin hydrochloride. These results indicate that blocking alpha(1)-adrenergic receptors may ameliorate the impairments in blood flow and retinal function caused by NOS inhibition. The enhancement of basal vascular tone due to deprivation of continuous NO production may be diminished by this alpha(1)-adrenergic blocker.     

Risk of gallstones following gastrectomy in Japanese men

The risk of gallstones developing after gastrectomy in middle-aged Japanese men was investigated in a study of 2,738 men aged between 48 and 56 years who underwent both gallbladder ultrasonography (US) and a barium study of the upper digestive tract. It was revealed that 61 men had gallstones, 37 had had their gallbladder removed previously, and 55 had a history of gastrectomy. The prevalence of gallstones was 3.5 times higher in the men who had previously undergone gastrectomy (7.7%) than in those who had not (2.2%) (P=0.03). Moreover, gallstones tended to be more prevalent in those who had undergone Billroth II gastrectomy (12.5%) compared with those who had undergone Billroth I gastrectomy (5.6%); however, the difference was not significant. These results indicate that gastrectomy using either Billroth I or Billroth II reconstruction predisposes to gallstone formation. Nevertheless, it was estimated that prior gastrectomy was responsible for no more than 5% of gallstones in the study population.     

Uptake and biotransformation of sevof lurane in humans: A comparative study of sevof lurane with halothane, enflurane, and isoflurane

Study Objective: To compare the volatile anesthetic sevoflurane with halothane, enfurane, and isof urane on the uptake and biotransformation in humans.

Design: Prospective pharmacokinetic study of sevofurane administration in human subjects.

Setting: Inpatient surgery clinic at a university medical center.

Patients: Thirty-two Japanese patients, free of systemic diseases, undergoing minor elective surgery with endotracheal general anesthesia.

Interventions: The patients were assigned randomly to one of four groups: halothane, enflurane, isofurane, or sevofurane. One of the four volatile anesthetics being investigated [equivalent to 1.1 minimum alveolar concentration (MAC): halothane, 0.85%; enfurane, 1.85%; isofurane, 1.27%; and sevofurane, 1.88%; in inspired concentrations throughout the first hour of anesthesia] was administered for 60 minutes.

Measurements and Main Results: In all patients, serum and urinary fluoride concentrations were measured. The concentrations of all gases were measured separately with a mass spectrometer. The cumulative uptake of each anesthetic agent during a certain period was calculated as an integration of the uptake rate per minute. The results for one-hour inhalation of sevofurane (1.1 MAC) showed an uptake (corrected for body surface area and MAC) of 490 ml/m²/MAC and estimated degradation rate of 3.3%. For purposes of comparison, similar studies of halothane (uptake, 653 ml/m²/MAC; degradation rate 15.7%), enfurane (1150 ml/m²/MAC; 1.3%), and isofurane (439 ml/m²/MAC; 0.6%) were also conducted. Sevofurane had a peak serum inorganic fluoride concentration of 19.3 μmol/L, and no abnormality in hepatic or renal functions was observed in any of the subjects during the two weeks postoperatively.

Conclusions: Accurate determinations of uptake and degradation rate for sevoflurane and three other volatile anesthetics in Japanese patients were obtained. These findings have established that, despite its relatively large MAC *1.71%), sevoflurane has a small uptake due to its low solubility. However, the degradation rade was shown to be as high as 3.3%, resulting in a higher serum fluoride concentration than seen after administration of isoflurane, halothane, and (possibly) enflurane.     

Efficacy of Intraoperative Cooling Methods

Background: Patients may require perioperative cooling for a variety of reasons including treatment of a malignant hyperthermia crisis and induction of therapeutic hypothermia for neurosurgery. The authors compared heat transfer and core cooling rates with five cooling methods.

Methods: Six healthy volunteers were anesthetized with desflurane and nitrous oxide. The cooling methods were 1) circulating water (5 [degree sign] Celsius, full-length mattress and cover), 2) forced air (10 [degree sign] Celsius, full-length cover), 3) gastric lavage (500 ml iced water every 10 min), 4) bladder lavage (300 ml iced Ringer's solution every 10 min), and 5) ice-water immersion. Each method was applied for 40 min or until the volunteers' core temperatures approached 34 [degree sign] Celsius. The volunteers were rewarmed to normothermia between treatments. Core cooling rates were evaluated using linear regression.

Results: The first volunteer developed abdominal cramping and diarrhea after gastric lavage. Consequently, the technique was not again attempted. Bladder lavage increased heat loss 10 [nearly =] 10 W and decreased core temperature 0.8 +/- 0.3 [degree sign] Celsius/h (r2 = 0.99 +/- 0.002; means +/- SD). Forced-air and circulating-water cooling comparably increased heat flux, [nearly =] 170 W. Consequently, core cooling rates were similar during the two treatments at 1.7 +/- 0.5 [degree sign] Celsius/h (r2 = 0.99 +/- 0.001) and 1.6 +/- 1.1 [degree sign] Celsius/h (r2 = 0.98 +/- 0.02), respectively. Immersion in an ice water slurry increased heat loss [nearly =] 600-800 W and decreased core temperature 9.7 +/- 4.4 [degree sign] Celsius/h (r sup 2 = 0.98 +/- 0.01). Immersion cooling was associated with an afterdrop of [nearly =] 2 [degree sign] Celsius.     

Two cases of Trichosporon beigelii pneumonia in immunocompromised hosts

Two cases of Trichosporon beigelli pneumonia in severely immunocompromised patients are reported. At autopsy, Trichosporon beigelii was detected in all lobes in one patient who had a small cell lung cancer. Polymycotic infection involving Trichosporon beigelii and Aspergillus was proved in the other patient who had a non-Hodgkin's lymphoma. Miconazole therapy was not effective against Trichosporon beigelii infection in both cases. Although diagnosis and management are difficult, Trichosporon beigelii must be considered as a cause of visceral opportunistic fungal infection.