Aminotriazole effects on lung and heart H2O2 detoxifying enzymes and TBA-RS at two pO2

In order to clarify the physiological role in vivo of H2O2-detoxifying enzymes at low and high levels of O2 tension we studied catalase (CAT), glutathione peroxidases (GP), and in vivo peroxidation (TBA-RS) in the lung and heart of Rana perezi frogs chronically treated with hyperoxia, aminotriazole (AT) -a CAT inhibitor-, or both. Hyperoxia did not change CAT, GP or TBA-RS. Aminotriazole caused an almost complete depletion of CAT, a 30% decrease of GP and a 132% (lung) to 200% (heart) increase of TBA-RS. Changes similar to these were found in the group treated with AT in hyperoxia. No mortality or changes in total or organ weight occurred in the experimental groups. Main conclusions are: (1) The maximal hyperoxia tolerance showed by frogs among vertebrates does not need antioxidant enzyme induction from lung or heart and is probably related to the presence of high constitutive levels of GP in relation to metabolic rate. (2) Even in normoxia the tissues present significant amounts of H2O2, and CAT is needed to avoid oxidative damage. GP does not compensate its absence. The implications of these results in relation to oxygen toxicity in man is discussed.     

Cloacal exstrophy: individualized management through a staged surgical approach

Cloacal exstrophy, centered on the maldevelopment of the primitive streak mesoderm and cloacal membrane, results in bladder and intestinal exstrophy, omphalocele, gender confusion, and hindgut deformity. The surgical management and outcome of 10 of 14 survivors (1965 to 1988) are described. Genotypic males (6) were assigned male (2) or female (4) phenotype. Genotypic females (4) were unchanged. All had omphalocele closure in the newborn period. Two had loop stomas. Eight had end stomas (ileostomy [6], ileocolostomy [2]). Toddler and adolescent reconstruction differed in each. Early in the study, abdominoperineal pull-through failed in four patients, necessitating permanent stoma. Four patients had a stoma from the outset. Augmentation using colon remnant improved water loss and nutrition in two infants. Exstrophy turn-in for urinary reservoir was considered in all, but was impossible in three who required urinary diversion. Six patients had exstrophy turn-in and now void by clean intermittent catheterization (4), continent vesicostomy (1), and incontinent (1). Hindgut augmentation improved urinary capacity in two. Two genotypic-phenotypic males had penile lengthening. Four genotypic male-phenotypic females had early orchiectomy with subsequent clitoroplasty or vaginoplasty. Four genotypic-phenotypic females had clitoroplasty or vaginoplasty. Cloacal exstrophy is compatible with a useful life and sound psychologic development, but requires staged reconstruction with long-term support and follow-up.     

Pattern of postprandial carbohydrate metabolism and effects of portal and peripheral insulin delivery

The importance of portal insulin delivery in the regulation of postprandial carbohydrate metabolism is uncertain. To address this question, three groups of dogs were studied: one group in which pancreatic venous drainage was transected and reanastomosed (portal insulin delivery), one in which the pancreatic drainage was transected and anastomosed to the inferior vena cava (peripheral insulin delivery), and one that received only a sham operation. Plasma insulin was greater (P less than 0.05) during peripheral insulin delivery than in either the portal or sham groups, respectively, before and after meal ingestion. On the other hand, C-peptide concentrations did not differ between groups, resulting in a higher (P less than 0.001) insulin to C-peptide ratio in the peripheral group. This indicated that the hyperinsulinemia in the peripheral group was due to decreased insulin clearance rather than increased insulin secretion. Isotopically determined splanchnic uptake of ingested glucose, postprandial suppression of hepatic glucose release, incorporation of CO2 into glucose (a qualitative measure of gluconeogenesis), and total-body glucose uptake were virtually identical in all groups. Similarly, plasma lipid, beta-hydroxybutyrate, and lactate concentrations did not differ between groups. Our data indicate that, despite differences in systemic insulin concentration, portal and peripheral insulin delivery comparably regulate hepatic and extrahepatic carbohydrate metabolism after meal ingestion.     

Corneal epithelial barrier function after oxybuprocaine provocation in diabetics

Corneal epithelial permeability for fluorescein was determined after provocation by a local anesthetic in 18 non-insulin-dependent diabetes mellitus (NIDDM) patients, 23 insulin-dependent diabetes mellitus (IDDM) patients, and 22 healthy controls to evaluate the corneal epithelial barrier function in diabetes. All volunteers had Oxybuprocaine instilled into one eye and saline into the other eye. The epithelial permeability values were determined by fluorophotometry, and the ratio between both eyes was calculated for each individual. The mean permeability values of the saline-instilled eyes in the diabetic patients did not differ significantly from those in the healthy controls (P greater than 0.2). The individual ratios between Oxybuprocaine- and saline-instilled eyes in the NIDDM and IDDM patients differed significantly from those in the healthy controls (mean ratios: 2.6, 1.9, and 1.0, respectively; P less than 0.002). The permeability ratios and the percentage glycosylated hemoglobin (HbAlc) were linearly correlated in the NIDDM patients but not in the IDDM patients (r = 0.73, P less than 0.001, and r = 0.09, P greater than 0.68, respectively). The results showed that the corneal epithelial barrier function in the diabetic patients was not impaired compared with that in the healthy controls. After provocation by a local anesthetic, the barrier function was impaired in the diabetic patients only.     

Changes in asthmatic patients' symptoms and lifestyles on institution of inhaled budesonide therapy

An open, multi-centre, general practice study was carried out in 1661 asthmatic patients to assess the efficacy, in terms of symptom relief and changes in lifestyle, of budesonide and to record objective lung function changes and any adverse events. After a 1-week run-in period on any pre-trial anti-asthma medication, patients received either 200 micrograms or 400 micrograms budesonide twice daily by metered dose inhaler for 4 weeks. Peak expiratory flow rate (PEFR) was measured by the doctor on entry, after the run-in, and at the end of the study and patients were asked to complete diary cards on a daily basis to record compliance, bronchodilator usage and the severity of cough, wheeze and sleep disturbance, and weekly to record 5 lifestyle assessments, e.g. physical activity. Analysis of data from the clinic visits and 1375 completed diary cards showed that PEFR increased significantly from 321 +/- 3 l/min at the end of the run-in to 368 +/- 3 l/min at the end of the trial; 77% of patients had an improved PEFR. Bronchodilator use decreased significantly from 4.2 +/- 0.1 times/day during the run-in period to 3.0 +/- 0.1 times/day at the end of the study; 65% of patients used less bronchodilator. Significant improvements were recorded in all the symptoms and lifestyle indices monitored; 76% of patients improved in at least 5 of the 11 assessments. Treatment-emergent adverse events occurred in 103 (6%) of patients: none was classified as serious or unexpected. No sub-group of patients was identified in which the results were at variance from the full sample. It is concluded that budesonide improves patients' lifestyle and ability to carry out normal activities, as well as improving PEFR and reducing bronchodilator use, in mild to moderately severe asthmatics treated in general practice.     

Development of an intravenous desferrioxamine mesylate treatment protocol for swine: monitoring of desferrioxamine and metabolites by high-performance liquid chromatography

Desferrioxamine (DFO) metabolism and its pharmacokinetics were studied in a swine model using high-performance liquid chromatography. DFO and three iron-binding metabolites occurred in plasma. Interindividual differences in pharmacokinetics and metabolism were observed. Urine analysis in 4 pigs showed three iron-binding metabolites. The mean percent dose excreted in urine in the form of the parent drug was 45 +/- 10% and 10 +/- 2% (means +/- SD) in the form of metabolites. Of the total amount of the parent drug infused, 3 h after initiation, 87% was in the form of DFO, whereas 13% was present as the DFO-iron III complex which represented 45 mg of urinary iron elimination. The described DFO infusion protocol provides for sufficient DFO to chelate significant amounts of ferric iron in excess of normal levels, thus allowing experimental studies of iron chelation in a variety of disease states.     

Antihepatotoxic Effects of chlorogenic acid from Anthocephalus cadamba

In the present study, chlorogenic acid (CGA) isolated from Anthocephalus cadamba was screened for hepatoprotective activity by in vitro and in vivo assay methods using carbon tetrachloride (CCl₄) as a model of liver injury. Intraperitoneal administration of CGA to mice at a dose of 100 mg/kg body weight for 8 days caused significant reversal in lipid peroxidation, enzymatic leakage, cytochrome P450 (Cyt P450) inactivation and produced enhancement of cellular antioxidant defence in CCl₄-intoxicated mice, revealing that the antioxidative action of CGA is responsible for its liver protective activity. CGA exhibited a better therapeutic protective action than silymarin (SM), in CCl₄-administered mice.     

3β-Hydroxysteroid Dehydrogenase/Isomerase and Aromatase Activity in Primary Cultures of Developing Zebra Finch Telencephalon: Dehydroepiandrosterone as Substrate for Synthesis of Androstenedione and Estrogens

3β-hydroxysteroid dehydrogenase/Δ⁵−Δ⁴isomerase (3β-HSD) activity was measured in primary dissociated cell cultures prepared from telencephalons of developing zebra finches. 3β-HSD activity was confirmed after cultures were incubated with [7-³H]pregneno- lone (Preg) or (1,2,6,7-³H-) dehydroepiandrosterone (DHEA) and³H-progesterone (Prog) and³H-androstenedione (AE) were detected in the medium. Product identity was confirmed by recrystallizations and by HPLC analysis. When DHEA was used as substrate,³H-estradiol and³H-estrone were also detected in the culture medium, presumably derived from the aromatization of³H-AE or³H-T produced from³H-DHEA. To test this idea, cultures were incubated with³H-DHEA together with radioinert AE or with fadrozole HCl, a potent and specific aromatase inhibitor. In the presence of radioinert AE,³H-AE increased but metabolites of³H-AE decreased in the media; in the presence of fadrozole,³H-estrogens decreased but³H-AE and its androgenic metabolite³H-5β-androstanedione increased. These data demonstrate 3β-HSD activity in the songbird brain. The presence of Prog and estradiol in these cultures suggest that Preg and DHEA can potentially serve as substrates for the ultimate formation of active sex steroids in the songbird telencephalon.     

Late, Painful, Subungual Hyperkeratosis in Incontinentia Pigmenti

Abstract: The postpubertal appearance of subungual, painful keratotic tumors is a rare feature of incontinentia pigmenti. A patient affected by incontinentia pigmenti developed subungual, painful, nontumoral, hyperkeratotic lesions of the hands at 10 years of age. The mildness of the subungual lesions may be explained by the early stage of the disorder, but it is difficult to correlate the severity of the fingertip pain with the absence of true tumoral swelling. To our knowledge this is the youngest patient reported so far and the only one with a prepubertal expression of this puzzling disorder.