Bypass induced liver disease: an experimental study of the effect of post-operative protein supplementation and metronidazole therapy in an animal model

An animal model of jejuno-ileal bypass (JIB) with post-operative weight loss and liver dysfunction was established in the rat. The role of a protein supplemented diet and post-operative metronidazole was investigated using this model. The use of a protein supplemented diet alone markedly reduced the detrimental effects of JIB. Although a beneficial effect was also noted with post-operative metronidazole, it was less marked and there appeared to be no additive benefit when both were used together. The results of this study would support the routine use of a protein enriched diet post-operatively in patients undergoing JIB.     

Effect of thioacetamide-induced hepatic necrosis on the regioselective metabolism of S-warfarin by rat liver mixed-function oxidase enzymes

The biotransformation of S-warfarin was examined using liver microsomes prepared from rats 6-96 hr after treatment with a necrotizing dose (5.6 mmoles/kg) of thioacetamide. Four catalytically distinct classes of enzyme activity were observed which declined in activity with different half-lives after thioacetamide intoxication. S-Warfarin 7-hydroxylase activity was destroyed with a half-life of 16.6 +/- 3.1 hr. 6-Hydroxylase activity was destroyed with a half-life of 25.3 +/- 3.0 hr. 4'-Hydroxylase activity was destroyed with a half-life of 34.6 +/- 4.8 hr, which paralleled the loss of total hepatic cytochrome P-450 with a half-life of 33.4 +/- 3.6 hr. Production of an unidentified metabolite was not affected by thioacetamide intoxication during the first 48 hr. The ratio of rates of product formation were used as an alternative method to test the homogeneity of distinct enzyme catalytic activities. The ratio of measured responses (e.g. chromatographic peak heights) was used directly to determine the product ratios, provided that the rate of formation of each product was directly proportional to the experimentally measured response for each product. The use of product response ratios to discriminate between catalytic activities was inherently more precise because calibration errors were eliminated. Differences in the rates of destruction of warfarin hydroxylases provided further evidence of the multiplicity of hepatic mixed-function oxidases and suggested topographical differences in their location within the liver lobule.     

Prophylactic vs postoperative antibiotic use in complex septorhinoplasty surgery: a prospective, randomized, single-blind trial comparing efficacy

OBJECTIVE: To compare the efficacy of prophylactic vs postoperative antibiotic use in complex septorhinoplasty and strengthen the evidence base for antibiotic use in nasal surgery. DESIGN: A randomized, prospective, single-blinded trial. One hundred sixty-four patients requiring complex septorhinoplasty surgery were recruited sequentially from the waiting lists of the 2 senior authors. Power was calculated at 80% at the 5% significance level. Patients randomized to the prophylactic arm of the study received three 1200-mg intravenous doses of amoxicillin-clavulanate, given at induction of anesthesia and at 6 and 12 hours postoperatively. Patients in the postoperative antibiotic arm received a 7-day course of 375 mg of amoxicillin-clavulanate 3 times a day. Patients allergic to penicillin were given erythromycin. Clinical and microbiological evidence of infection on the 10th postoperative day was categorized as either minor (vestibulitis) or major (nasal or septal cellulitis, septal abscess, secondary hemorrhage, or donor-site infection) infections. RESULTS: At follow-up, 6 (7%) of 82 patients in the prophylactic arm and 9 (11%) of 82 of patients in the postoperative arm showed evidence of infection. Most (80%) of infections were minor. There was no significant difference in infection rates between the prophylactic and postoperative arms on chi2 analysis (P = .42). All 164 patients completed the study on an intention-to-treat basis. CONCLUSION: We recommend the use of prophylactic antibiotics rather than empirical postoperative antibiotics for patients undergoing complex septorhinoplasty.     

Contemporary management of blunt aortic injury

Blunt aortic injury is second only to head injury as the most common cause of blunt trauma related death. The past several years have seen a tremendous growth in the endovascular treatment of such trauma. Short-term and medium-term follow-up data that are emerging seem to support this trend. In this article, the authors discuss about open and endovascular management of blunt aortic injury and provide the latest information regarding endovascular repair of such injuries.     

Incentives and competition in a worksite smoking cessation intervention.

We evaluated a worksite smoking cessation program that employed multicomponents including support groups, incentives, and competition. The combination of incentives and other components increased participation rates to over 80%. Forty-two percent of smokers were abstinent at six months, compared to 13 percent of a control group (difference 29 percent, 95% CI 9, 49).     

Rat and Rabbit Plasma Distribution of Free and Chylomicron-Associated BIRT 377, a Novel Small Molecule Antagonist of LFA-1-Mediated Cell Adhesion

Purpose. The objectives of this study are to determine the plasma distribution of free and chylomicron-associated BIRT 377 within rats and rabbits. Methods. For the rat studies free and chylomicron-associated BIRT 377 was incubated in plasma from CD 1 non-fasted rats for 60 minutes at 37°C. Following incubation the plasma was separated into its lipoprotein and lipoprotein-deficient plasma (LPDP) fractions by three different methods and analyzed for BIRT 377 content by HPLC. For the rabbit studies New Zealand fasted white rabbits (3 kg; n = 4) were administered an intravenous dose of free BIRT 377 (1 mg/kg). Following administration, serial blood samples were obtained and the plasma was analyzed for BIRT 377. The plasma collected at the 0.083-h time point was separated into each of its lipoprotein fractions and analyzed for BIRT 377. Results. 37.8 ± 1.2% of the original drug amount incubated in rat plasma was recovered within the lipoprotein-rich fraction. 41.5 ± 0.4% of the original chylomicron-associated drug concentration incubated was recovered within the lipoprotein-rich fraction. The percentage of drug recovered within the TRL fraction was significantly greater following the incubation of chylomicron-associated BIRT 377 compared to free BIRT 377. In addition, BIRT 377 apparently follows a two-compartment pharmacokinetic model following single intravenous dose administration to rabbits. Conclusions. These findings suggest that plasma lipoprotein binding of BIRT 377 is evident and may be a factor in evaluating the pharmacological fate of this drug when administered to patients that exhibit changes in their plasma lipoprotein lipid.     

A molecular basis of peptic ulceration due to diet

Fresh rice oil protects against gastric ulceration in rats maintained on an impoverished diet, whereas stored oil is ulcerogenic. Rice oil contains ketoaldehydes which are ulcerogenic but their activity is prevented by the presence of antioxidants such as alpha-tocopherol, which is lost on storage. Protection may also be restored by the addition of cysteine. These results in rats in vivo can be duplicated in a rat liver microsomal system in vitro, in which malondialdehyde production is a measure of toxicity. It is proposed that the ulcerogenic activity of rice oil is the direct consequence of the stimulation of endogenous lipid peroxidation due to the lowering of the GSH content in the endoplasmic reticulum by the ketoaldehydes in stored rice oil. A similar mechanism is suggested for the ulcerogenic activity of an impoverished diet which directly lowers the tissue levels of GSH.     

Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists

In the search for a selective adenosine A1 receptor antagonist with greater aqueous solubility than the compounds currently in clinical trials as diuretics, a series of 1,4-substituted 8-cyclohexyl and 8-bicyclo[2.2.2]octylxanthines were investigated. The binding affinities of a variety of cyclohexyl and bicyclo[2.2.2]octylxanthines for the rat and human adenosine A1, A2A, A2B, and A3 receptors are presented. Bicyclo[2.2.2]octylxanthine 16 exhibited good pharmaceutical properties and in vivo activity in a rat diuresis model (ED50=0.3 mg/kg po). Optimization of the bridgehead substituent led to propionic acid 29 (BG9928), which retained high potency (hA1, Ki=7 nM) and selectivity for the adenosine A1 receptor (915-fold versus adenosine A2A receptor; 12-fold versus adenosine A2B receptor) with improved oral efficacy in the rat diuresis model (ED50=0.01 mg/kg) as well as high oral bioavailability in rat, dog, and cynomolgus monkey.     

Activity and gene expression profile of certain antioxidant enzymes to microcystin-LR induced oxidative stress in mice

Microcystins are cyclic heptapeptide toxins produced by certain strains of Microcystis aeruginosa and microcystin-LR (MC-LR) is the most toxic among the 70 variants isolated so far. These toxins have been implicated in both human and livestock mortality. In the present study we investigated the microcystin-LR induced oxidative stress in mice in terms of its effect on activity and gene expression profile of certain antioxidant enzymes and expression of heat shock protein-70 (HSP-70). Mice were treated with 0.5 LD₅₀ (38.31 μg/kg) and 1 LD₅₀ (76.62 μg/kg) and the biochemical variables were determined at 1, 3, 7 days and 15, 30, 60 and 120 min post-exposure for 0.5 and 1 LD₅₀ dose, respectively. A significant time-dependent increase in HSP-70 expression over control was observed at 1 LD₅₀ dose. The toxin induced significant increase in liver body weight index, hepatic lipid perxoidation and depletion of GSH levels at 1 LD₅₀ compared to control group. There was significant decrease in the activity of antioxidant enzymes glutathione peroxidase (GPX), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione-S-transferase (GST) at 1 LD₅₀. Except catalase, there was no effect on other antioxidant enzymes at 0.5 LD₅₀ dose. In contrast to activity of antioxidant enzymes the gene expression profile did not show any significant difference compared to control at 1 LD₅₀. GR showed significant decrease in expression at 1, 3 and 7 days in animals dosed with 0.5 LD₅₀ MC-LR. The results of our in vivo study clearly show the oxidative stress induced by MC-LR, and a correlation with activity and regulation at gene expression level of antioxidant enzymes.