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.     

Combined aortic and mitral valve repair in active infective endocarditis

We describe a case of successful combined repair of the aortic and mitral valves for an indication of active infective endocarditis involving both valves. Mitral valve repair was achieved by vegetation debridement, fixation of the anterior mitral commissure, resection and suturing of the posterior mitral leaflet, and posterior annuloplasty with autologous pericardium. Aortic valve repair was achieved by vegetectomy and commissural plication. Postoperative clinical course was without signs of recurrent infection, and echocardiogram demonstrated mitral valve competence with trivial aortic regurgitation. We concluded that simultaneous valve repair is a viable option in the context of active endocarditis.     

Clinical experience of biliary tract carcinoma associated with anomalous union of the pancreaticobiliary ductal system

Between 1978 and 1988, 15 patients with gallbladder cancer and 2 patients with bile duct cancer were seen among 49 patients with anomalous union of the pancreaticobiliary ductal system. Radiographic findings revealed two types of this anomalous condition: one in which the pancreatic duct entered the common bile duct (type 1) and one in which the common bile duct entered the pancreatic duct (type 2). In gallbladder cancer, the common bile duct presented no dilatation, or in some patients, mild dilatation, and type-1 anomalous union was frequently found among these patients. In contrast, the two patients with bile duct cancer had cystic dilatation of the common bile duct and type-2 anomalous union. The bile amylase level, which was determined in seven patients, was extremely high in all the patients. Histopathologically, the tumors in most patients showed papillary to papillo-tubular proliferation in the mucosal layer while atypical epithelial hyperplasia was noted in the vicinity of the tumor area. These findings suggest that this congenital anomaly in both ducts results in a loss of the normal sphincteric mechanism of the duodenal papilla, and that chronic relapsing cholecystitis or cholangitis, caused by the reflux of pancreatic juice into the biliary tract, can induced progressive changes to atypical epithelial hyperplasia which may develop into carcinoma.     

The use and cost of HIV service provision in England in 1996. National Prospective Monitoring System (NPMS) Steering Group and NPMS Working Party on Costs.

OBJECTIVE: The aim of the study was to measure the use and estimate the cost of HIV service provision in England. DESIGN AND SETTING: Standardised activity and case-severity data were collected prospectively in 10 English HIV clinics (5 London and 5 non-London sites) for the periods 1 January 1996 to 30 June 1996 and 1 July 1996 to 31 December 1996 and linked to unit cost data. In total, 5440 patients with HIV infection attended during the first 6 months and 5708 during the second 6 months in 1996. MAIN OUTCOME MEASURES AND RESULTS: The mean number of inpatient days per patient-year for patients with AIDS was 19.7 [95% confidence interval (CI): 13.7 to 25.7] for January to June and 20.8 (95% CI: 15.3 to 26.4) for July to December 1996. The mean number of outpatient visits for asymptomatic patients with HIV infection was 14.8 (95% CI: 11.9 to 17.6) and 13.3 (95% CI: 10.8 to 15.7) for the respective periods and 16.1 (95% CI: 13.21 to 18.97) and 15.7 (95% CI: 11.2 to 20.2), respectively, for patients with symptomatic non-AIDS (i.e. symptomatic patients with HIV infection but without AIDS-defining conditions). Substantial centre-to-centre variation was observed, suggesting that many clinics can continue the shift from an inpatient- to an outpatient-based service. Cost estimates per patient-year for HIV service provision for 1996 varied from 4695 Pounds (95% CI: 3769 Pounds to 5648 Pounds) for asymptomatic patients, to 7605 Pounds (95% CI: 6273 Pounds to 8909 Pounds) for symptomatic non-AIDS patients to 20,358 Pounds (95% CI: 17,681 Pounds to 23,206 Pounds) for patients with AIDS. CONCLUSIONS: Different combinations of antiretroviral therapy affect the cost estimates of HIV service provision differently. Anticipated reduction in inpatient-related activity through the increased use of combination antiretroviral therapy will further shift service provision from an inpatient- to outpatient-based service and reduce costs per patient-year. The extent and duration of such effects are currently unknown. The long term effects of combination treatment on the morbidity and mortality patterns of individuals infected with HIV are also currently unknown, as are their implications on the use and cost of HIV service provision. Multicentre databases like the National Prospective Monitoring System (NPMS) will provide healthcare professionals with information to improve existing services and anticipate the impact of new developments.     

Progressive cerebellar ataxia with diencephalic symptoms (Toyokura)--a case report]

We reported a 16-year-old boy suffering from dwarfism, diabetes insipidus and progressive cerebellar ataxia. The disease entity here reported was originally reported by Toyokura et al. in 1967, under the title of "progressive cerebellar ataxia with diencephalic symptoms". Ten similar cases have been reported in literature so far, all of which were Japanese except for two sibling cases reported by Robinson et al. The topographic distribution of the lesion in this disorder, however, had been conjectured to be at spinocerebellar tract and diencephalon only on a clinical ground. By applying the modern techniques of neuroimaging, electrophysiological and endocrinological test in our patient, the authors were able to demonstrate the lesion of the disorder more precisely. CT and MRI of the head revealed degenerative changes in deeper structures of the bilateral cerebellar hemispheres. ABR abnormality suggested the presence of a wide lesion in the brain stem. Pituitary hormones (GH and ACTH) sufficiently responded to the loading of hypothalamic hormones such as growth hormone releasing factor and corticotropin releasing factor, in spite of poor responses of GH under the insulin stimulation or sleep. These clinical and laboratory findings suggested that the patient has a systemic degenerative disease which preferentially involves hypothalamus, brain stem and cerebellum.     

Renal tissue gas tensions during hemorrhagic shock

To evaluate the development of renal hypoxia during hemorrhagic shock, fourteen dogs were induced in this study. The animals were divided equally into a group in which mean arterial pressure (MAP) was kept at 50mmHg (group 1), and into another where MAP was kept at 40mmHg for 180mim (group 2). Renal tissue gas tensions were determined by a mass spectrometer. In the 50-mmHg group, renal tissue oxygen tension (Pr_{O 2}) dropped for 15min following hemorrhage, remained constant for 90min, then fell further for 150min before a plateau was established. In the 40-mmHg group, the Pr_{O 2} dropped for 90min before reaching a plateau. The second Pr_{O 2} decline occurred at the same level in both the 50-mmHg group and the 40-mmHg group. The point at which the same Pr_{O 2} level occurred for each group suggests the cessation of oxygen consumption and the conditions of renal hypoxia. It is assumed that renal hypoxia occurs in 120min at a MAP of 50-mmHg and in 60min at a MAP of 40mmHg.(Murakawa K, Izumi R, Kobayashi A: Renal tissue gas tentions during hemorrhagic shock. J Anesth 3: 10–15, 1989)     

Differential diagnosis of adrenal masses by chemical shift and dynamic gadolinium enhanced MR imaging

Chemical shift MRI is widely used for identifying adenomas, but it is not a perfect method. We determined whether combined dynamic MRI methods can lead to improved diagnostic accuracy. Fifty-seven adrenal masses were examined by chemical shift and dynamic MR imaging using 2 MR systems. The masses included 38 adenomas and 19 non-adenomas. In chemical shift MRI studies, the signal intensity index (SI) was calculated, and the lesions classified into 5 types in the dynamic MRI studies. Of the 38 adenomas studied, 37 had an SI greater than 0. In the dynamic MRI, 34 of 38 adenomas showed a benign pattern (type 1). If the SI for the adenomas in the chemical shift MRI was considered to be greater than 0, the positive predictive value was 0.9, and the negative predictive value was 0.94 and kappa = 0.79. If type 1 was considered to indicate adenomas in the dynamic MRI, the corresponding values were 0.94, 0.81 and kappa = 0.77 respectively. The results obtained when the 2 methods were combined were 1, 0.95 and kappa = 0.96 respectively. The chemical shift MRI was found to be useful for identifying adenomas in most cases. If the adrenal mass had a low SI (0 < SI < 5), dynamic MRI was also found to be helpful for making a differential diagnosis.     

Ensemble noise and current relaxation analysis of K+ current in single isolated salivary acinar cells from rat

The K⁺ channel in rat parotid gland acinar cells were investigated by ensemble current noise analysis in single isolated cells employing the giga-seal whole cell current recording mode. Sets of 20–40 identical de- and hyperpolarization voltage steps were applied and the resultant current records were processed by computer to obtain the mean and the variance of the current. The time-course of the mean current could be fitted by the sum of two exponentials, suggesting a 3-state model. The simplest plausible hypothesis is a model with one open and two closed states. Assuming this model, the relationship between the variance (₂) and the mean current (I) could be fitted by the function ₂/I=i–I/N. The estimated single channeli/V-relations were similar to those taken from single channel current recordings, and the size of the population of channels per cell (N) was 76±26 (n=12). The validity of the model was tested by a successful simulation of the time-course of the variance.