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.     

GABAergic Interneurons at Supraspinal and Spinal Levels Differentially Modulate the Antinociceptive Effect of Nitrous Oxide in Fischer Rats

Background: The study hypothesizes that nitrous oxide (N2O) releases opioid peptide in the brain stem, which results in inhibition of [gamma]-aminobutyric acid-mediated (GABAergic) neurons that tonically inhibit the descending noradrenergic inhibitory neurons (DNIN), resulting in activation of DNIN. In the spinal cord, activation of DNIN leads to the release of norepinephrine, which inhibits nociceptive processing through direct activation of [alpha]2 adrenoceptor and indirect activation of GABAergic neurons through [alpha]1 adrenoceptor. Arising from this hypothesis, it follows that GABAergic neurons will modulate the antinociceptive effect of N2O in diametrically opposite directions at supraspinal and spinal levels. The authors have tested this tenet and further examined the effect of midazolam, a GABA-mimetic agent, on N2O-induced antinociceptive effect.

Methods: Adult male Fischer rats were administered muscimol (GABAA receptor agonist) intracerebroventricularly (icv), gabazine (GABAA receptor antagonist) intrathecally (intrathecal), or midazolam intraperitoneally (intraperitoneal). Fifteen minutes later, they were exposed to air or 75% N2O and were subjected to the plantar test after 30 min of gas exposure. In some animals administered with midazolam, gas exposure was continued for 90 min, and the brain and spinal cord were examined immunohistochemically.

Results: The N2O-induced antinociceptive effect, which was attenuated by icv muscimol, intrathecal gabazine, and intraperitoneal midazolam. Midazolam inhibited N2O-induced c-Fos expression (a marker of neuronal activation) in the pontine A7 and spinal cord.     

Thyroid stimulating hormone response to thyrotropin in prepubertal depression

In an effort to evaluate whether differences exist in the hypothalamic-pituitary-thyroid axis of depressed children, a thyrotropin releasing hormone (TRH) stimulation test was administered to 55 prepubertal subjects who were divided into three groups matched for age and sex: a depressed group (endogenous N = 15, nonendogenous N = 15), a psychiatric nondepressed control group (N = 16), and a normal control group (N = 9). Each subject was tested at two dosages of TRH, 2 micrograms/kg and 7 micrograms/kg. Increasing age and female sex were positively correlated with a greater thyroid stimulating hormone (TSH) response. TSH response to TRH was examined with subjects reclassified by severe suicidal ideation, severe aggression, and parental history of alcoholism. Results of this study are contrasted with the adult psychiatric literature.     

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.     

Trace elements in human clinical specimens: evaluation of literature data to identify reference values

Reference values are proposed for the concentrations of As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Mo, Pb, Se, and Zn in whole blood, blood serum, urine, milk, liver, and hair from adult human subjects. For F, I, and Ni, it was not possible to evaluate reference intervals for all the specimens mentioned above. For several elements, including Al, B, Br, Cs, Li, Rb, U, and V, the present status of the literature does not provide an adequate basis for formulating baseline concentrations; therefore, results from selected investigations are listed for information only. For elements such as Cu, Fe, and Zn, which are known to be homeostatically controlled, the concentrations in whole blood and blood serum follow a gaussian-like frequency distribution, and we could consider both median and mean values for evaluation. On the other hand, elements whose concentrations in tissues and body fluids are influenced by dietary availability (e.g., As and Se) or environmental factors (e.g., Cd, Hg, and Pb) show wide scatter. In these cases, the median appeared to be a better indicator of the central tendency than the mean, when different populations are involved. These points are illustrated.