Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice

Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN?) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [¹⁴C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [¹⁴C]-diclofenac was incubated with HRN? mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN? mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN? mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN? mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN? mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN? mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment.     

Variation in the insertion of the palmaris longus tendon

The palmaris longus is harvested as a tendon graft in various surgical procedures. We herein report the variations in the insertion of the palmaris longus tendon. During a routine dissection, a rare variation in the insertion of the palmaris longus tendon was observed. In the left forearm, the palmaris longus tendon bifurcated, while in the right forearm, the palmaris longus tendon trifurcated, giving rise to an accessory muscle, which passed superficial to the ulnar artery and ulnar nerve. The accessory muscle was supplied by a deep branch of the ulnar nerve, and the ulnar artery was observed to be tortuous. During reconstructive surgeries, surgeons should bear in mind the accessory muscle. Also, since the palmaris longus muscle provides a very useful graft in tendon surgery, every surgeon should be aware of the variations in the insertion of the palmaris longus tendon.     

Additive Effects of Sevoflurane and Propofol on γ-Aminobutyric Acid Receptor Function

Background: Previous studies have shown that propofol and sevoflurane enhance the function of [gamma]-aminobutyric acid type A (GABAA) receptors. However, it is not known whether these two drugs modulate the same molecular pathways. In addition, little is known about receptor function in the presence of both propofol and sevoflurane. The aim of this study was to better understand the interactions of propofol and sevoflurane with the GABAA receptor.

Methods: Wild-type [alpha]1, [beta]2, [gamma]2s GABAA receptor subunit complementary DNAs were transfected into human embryonic kidney cells grown on glass coverslips using a calcium phosphate transfection method. After transfection (36-72 h), cells were whole cell patch clamped and exposed to combinations of the following: 0.3-1,000 [mu]m [gamma]-aminobutyric acid (GABA), 0-10 [mu]m propofol, and 0-1,650 [mu]m sevoflurane. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger.

Results: Both propofol and sevoflurane alone enhanced the amplitude of GABAA receptor responses to submaximal concentrations of GABA in a dose-dependent manner. The enhancement was underpinned by an increase in the apparent affinity of the receptor for GABA. Coapplication of both anesthetics further enhanced the apparent affinity of the receptor for GABA.     

Giant mediastinal liposarcoma: a case report.

Liposarcomas are extremely rare in the mediastinum. They may achieve considerable size before causing any symptoms. Mediastinal liposarcomas may invade surrounding structures like the pericardium or the superior vena cava. Complete surgical excision is the optimal treatment in resectable cases. Excision of adjacent structures like the pericardium may be needed if the tumor infiltrates them. We report on a case of a giant liposarcoma of the mediastinum involving both hemithoraces and extending into the neck, which was successfully managed by complete surgical excision.     

Spontaneous gallbladder perforation—An unusual presentation of carcinoma of the pancreas

A 50 year old man with a two month history of upper abdominal pain and a one month history of anorexia and weight loss, presented with icterus and evidence of peritonitis. Laparotomy revealed biliary peritonitis which had been caused by a rupture of the fundus of the gallbladder. The common bile duct was dilated and there was a large growth in the head of the pancreas with multiple hepatic metastases. A cholecysto-jejunostomy and gastrojejunostomy were done and the patient had an uneventful recovery.     

Angiosarcoma of the pleura.

Angiosarcoma is a rare, highly malignant tumor arising from endothelial cells of small blood vessels. They usually occur in the skin, deep soft tissues, breast and liver. Pleural angiosarcomas are extremely rare and are restricted to case reports in medical literature. It is very difficult to distinguish them from malignant mesotheliomas on clinical, radiological and even histopathological features. Immunohistochemistry is valuable in making the diagnosis, showing negative reactivity for mesothelial markers and positivity for vascular markers. Prognosis is generally dismal except in occasional cases where the disease is localized and amenable for surgical resection. We report a 55-year-old man who presented to us with chest pain, cough and hemoptysis and was diagnosed to have a pleural angiosarcoma.     

Is Coronary Graft Doppler More Sensitive for Indiviual Graft Flows Than TEE During CABG Surgery?

Abstract    In this case report we describe a situation where despite a normal TEE exam immediately postcardiopulmonary bypass, there was no flow in the left internal mammary artery graft to the left anterior descending artery. This was picked up by coronary Doppler and subsequently repaired.     

Establishment and characterization of an in vitro model of acquired resistance to cisplatin in a human testicular nonseminomatous germ cell line.

Clinically, human testicular nonseminomatous germ cell tumors exhibit remarkable sensitivity to platinum-based chemotherapy. To define better the mechanistic basis for this unusual sensitivity, the biochemical determinants of platinum-induced cytotoxicity have been investigated in a human testicular tumor cell line (GCT27) established from a previously untreated patient and in an in vitro derived 5.6-fold cisplatin-resistant stable variant (GCT27cisR). Compared to 12 ovarian and 5 cervical human tumor cell lines, the parent GCT27 line was among the most sensitive to the cytotoxic effects of both cisplatin (dosage producing 50% inhibition, 0.2 microM) and carboplatin (dosage producing 50% inhibition, 2.9 microM), thus reflecting clinical data. A 4-day exposure sulforhodamine B-staining assay was used to determine that GCT27cisR was cross-resistant to carboplatin and iproplatin and the classical bifunctional alkylating agents melphalan and chlorambucil. Partial cross-resistance was observed to tetraplatin, methotrexate, and mitomycin C. No cross-resistance was observed to Adriamycin, etoposide, vinblastine, bleomycin, 1-beta-D-arabinofuranosylcytosine, and 5-fluorouracil. Intracellular cisplatin accumulation across the dose range 2.5-100 microM (for 2 h) was 1.6 +/- 0.39-fold (mean +/- SD) greater for the parent line. There was no significant difference in glutathione levels between the two lines. The acquired resistance line was 1.9-fold more resistant than the parent line to the cytotoxic effects of cadmium chloride. There was no significant difference between the two lines, however, in the total amounts of platinum bound to DNA after cisplatin exposure (25, 50, or 100 microM for 2 h). The removal of total platinum adducts from DNA was significantly faster for GCT27cisR compared to the parent line (half-times of removal, 32 and 67 h, respectively). These data suggest that the abnormal sensitivity of the parent testicular tumor cell line to platinum-containing anticancer drugs may be due predominantly to an inherent defect in the ability of these cells to remove platinum from their DNA. This defect is apparently lost in the acquired resistance counterpart. Reduced intracellular accumulation and increased cytoplasmic concentrations of metallothionein may also contribute, in part, to the acquisition of cisplatin resistance in this model.