Chemopreventive effects of 2-(allylthio)pyrazine on hepatic lesion, mutagenesis and tumorigenesis induced by vinyl carbamate or vinyl carbamate epoxide

2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a hepatoprotective agent, has been found to selectively inhibit rat hepatic cytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261- 269, 1997), while it enhances the activities of phase II detoxification enzymes such as glutathione S-transferase and epoxide hydrolase. As part of a program in evaluating the chemopreventive potential of 2-AP, we have determined its effects on hepatotoxicity, mutagenicity and tumorigenicity of vinyl carbamate (VC), a prototypic hepatocarcinogen preferentially activated by P450 2E1 to the ultimate carcinogenic metabolite vinyl carbamate epoxide (VCO), which undergoes detoxification by glutathione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male Sprague-Dawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of these compounds as determined by decreased serum aspartate aminotransferase and alanine aminotransferase activities. Furthermore, 2-AP pre-treatment significantly suppressed the VC-induced hepatocarcinogenesis in infant male B6C3F1 mice. In a separate experiment, the multiplicities of skin tumors formed in female ICR mice treated with 5.8 micromol of VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncogene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inhibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreventive agent.      

Sedation for Endoscopy

Abstract  In order to examine the investigators' clinical suspicion that Vietnamese patients were more sensitive to the sedative effects of midazolam than were Caucasians, the pharmacokinetics of a single, weight-adjusted intravenous dose of midazolam (0.05 mg/kg) were compared in a group of healthy Caucasian and Vietnamese male volunteers. The Vietnamese group ( n =8) had a significantly lower height, lean body mass and mean weight (59.8±5.5 vs 72.1±8.1 kg, respectively) compared with the Caucasian group ( n =8). No significant differences were found between the Vietnamese and Caucasian groups with regard to distribution half-life of midazolam (8.38±13.1 vs 1.49±0.63 min, respectively), elimination half-life (2.49±1.80 vs 1.48±0.66 h, respectively), clearance (4.93±1.31 vs 5.90±2.12 mL/min per kg, respectively), steady state volume of distribution (0.863±0.497 vs 0.530±0.132 L/kg, respectively) or percentage of unbound drug in plasma (4.89±0.74 vs 4.11±1.08, respectively). This suggests that dosage of midazolam in Vietnamese should be based on total body-weight. Two Vietnamese subjects who were brothers had marked elevation of distribution half-life and initial volume of distribution and lesser elevations in elimination half-life and volume of distribution at steady state. This suggests that the known subgroup of subjects who demonstrate dyshomogeneity in midazolam volume of distribution may be genetically determined.     

Complex infantile and congenital hip dislocation: assessment with MR imaging

Twenty-five magnetic resonance hip studies were performed on 19 infants with congenital hip dislocation. These patients had a poor initial treatment response, a teratologic dislocation, or a late presentation. Detailed images of single hips obtained with small surface coils resulted in excellent visualization of all the clinically important soft-tissue and cartilaginous structures of the hip. No other imaging modality demonstrates all of these structures simultaneously.     

Initial evaluation of congenital hypothyroidism: a survey of general paediatricians in East Anglia

The practice of general paediatricians in the initial evaluation of congenital hypothyroidism (CHT) was assessed. This was performed by a questionnaire survey of paediatricians in East Anglia of whom 84% responded. Nineteen of 25 clinicians based in seven district hospitals managed children with CHT. The median number of children in the care of each clinician was 4 (range 1-17) and the median number of children attending each hospital was 12 (range 5-23). All except one clinician arranged to confirm the diagnosis with a serum thyroid stimulating hormone concentration and free or total thyroxine. There was variation of opinion on the value of serum triiodothyronine and free triiodothyronine measurements, antibody screening, knee radiographs, and thyroid isotope scans. One clinician sought advice when notified of new children and two expressed the need for an investigation protocol. These findings indicate that most general paediatricians in East Anglia manage only a few children with CHT; the initial diagnosis is appropriately confirmed but they are uncertain about the value of other investigations.     

Mineral content of skeletal bones in otosclerosis

In 63 patients with otosclerosis confirmed by operation, the bone mineral content was determined by photon absorptiometry. The bone mineral content and bone mineral concentration were found to be normal, which lends support to the assumption that otosclerosis is a localized disease and not a manifestation of a generalized disorder of the skeletal system.     

Anastomotic Pseudoaneurysms: Our Experience with 49 Cases

We investigated the factors implicated in the pathogenesis of anastomotic aneurysm formation and the postoperative course of patients with such a complication. Forty-five patients with 49 anastomotic aneurysms were diagnosed and treated in two vascular surgery departments in Athens, Greece, during an 8–year period. Emergent complications occurred in 15 cases, rupture in 11, and thromboembolic episodes in another four. Preoperative diagnostic workup in the remaining elective cases (n = 34) included color duplex scan, computed tomographic scan, and angiography. All patients underwent operation, and cultures were obtained during the surgical procedures. Histological examination of the host artery wall adjacent to the aneurysm was also performed. Aortobifemoral bypass was the original operation performed in the majority of cases (71%), and the femoral anastomosis was the most frequent site involved (85.7%). Emergent procedures were associated with increased mortality (46.6%), whereas elective operation resulted in high patency rates and no mortality. In an attempt to isolate predisposing factors that contributed to aneurysm formation, we concluded that the etiology was multifactorial in approximately one-third of the cases and degenerative host artery disease was the main cause (40%). Arterial degeneration is the leading cause of anastomotic aneurysm formation, and emergency arterial reconstruction in cases of aneurysm complication is associated with a poor prognosis.