The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-Coenzyme A 1 Desaturase and Mixed Function Oxidase Activities in Rats

The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-CoenzymeA Desaturase and Mixed Function Oxidase Activities in Rats.VANRAFELGHAM, M. J., AND ANDERSON, M. E. (1988). Fundam. Appl.Toxicol. 11, 503-510. Perfluorodecanoic acid (PFDA) causes adioxin-lilce toxic syndrome and alters the hepatic oleate/stearateratio in rats. The acute toxic effects of a single ip dose (50mg/kg) of PFDA on hepatic stearoyl-CoA desaturase and mixedfunction oxidases were studied in male Fischer-344 rats, 14days after dosing. PFDA causes a marked decrease in food intakein rats, resulting in severe body weight loss with delayed lethality(2-3 weeks after dosing). To distinguish the effects of hypophagiafrom those caused by PFDA, pair-fed control rats were used inaddition to ad libitum-fed controls. Stearoyl-CoA desaturaseactivity, responsible for the conversion of stearoyl-CoA tooleoyl-CoA, was absent in both PFDA dosed rats and their pair-fedcontrols at Day 14. Electron transfer through the desaturasesystem was significantly reduced in PFDA-treated rats only,and in these rats there was a significant reduction in microsomalcytochrome an important component of this electron transfersystem. Pentobarbital sleeping times were significantly prolongedin both the PFDA-dosed and pairfed rats, as compared with thead libitumfed controls. This effect was more pronounced in PFDA-dosedrats. Waking plasma pentobarbital concentration was similarin all treatment groups. Hepatic microsomal cytochrome PASOcontent was unaffected. Aminopyrine N-de-methylase activitywas greatly reduced in PFDA-dosed rats. Although pairfed controlsalso had reduced demethylase activity, it was not as pronouncedas in PFDA-dosed rats, and was probably due to the fasted conditionof these animals. Although the mechanism of action of PFDA isnot known, it is possible that PFDA affects microsomal enzymesby altering the structure and/or function of the membranes inwhich they are located, through effects on lipid metabolism.     

Plasma Levels of Peptide YY Correlate with Cisplatin-induced Emesis in Dogs

Abstract— The effect of cisplatin on plasma peptide YY (PYY) and 5-hydroxytryptamine (5-HT) concentrations was determined in conscious dogs (n = 6 per group) pretreated with either saline, or the 5-HT₃-receptor antagonists ondansetron or granisetron. Cisplatin (30 mg kg^?1, i.v.) caused emesis (18·8 ± 2·9 episodes; 75–284 min) and significantly increased the mean area under the curve (AUC) over a 6-h period of plasma PYY concentrations (7·4 ± 1·8 to 11·5 ± 3·7 ng) in all saline-pretreated dogs, whereas the mean AUC of plasma 5-HT concentrations did not significantly increase (34·7 ± 7·4 vs 35·6 ± 12·3 pM h). The concentrations of PYY correlated closely with the incidence of emesis (r = 0·99). In animals pretreated (36 min) with ondansetron (0·316 mg kg^?1, i.v.) or granisetron (0·316 mg kg^?1, i.v.), the number of cisplatin-induced emetic episodes was significantly (P < 0·005) decreased compared with control. In animals receiving cisplatin and pretreated with ondansetron, PYY concentrations were not significantly altered, whereas the mean AUC of plasma concentrations of 5-HT over 6 h increased (35·6 ± 12·3 to 82·3 ± 34·6 Pm h; P < 0·05). In animals receiving cisplatin and pretreated with granisetron, plasma concentrations of 5-HT were not significantly altered, whereas the mean AUC of plasma PYY concentrations were significantly reduced compared with control (6·2 ± 1·7 vs 11·5 ± 3·7 ng h). Furthermore, in animals receiving ondansetron without cisplatin treatment, there was no change in the mean AUC of 5-HT or PYY concentrations, whereas the mean AUC of plasma 5-HT concentrations increased significantly (34·7 ± 7·4 to 68·6 ± 37·2 Pm h; P < 0·05) in animals treated with granisetron alone. These studies indicate that plasma concentrations of PYY, and not 5-HT, correlate with cisplatin-induced emesis in dogs. Peptide YY may be an important mediator in cancer chemotherapy-induced emesis and other types of emesis.     

Synthesis and biological activities of some cholecystokinin analogues substituted in position 29 by a β-alanine

Syntheses of analogues of the C-terminal heptapeptide of cholecystokinin are described. These analogues were obtained by replacing glycine 29 by a β-alanine. The C-terminal phenylalanine amide was in some cases substituted by 2-phenylethyl alcohol and/or residues of the C-terminal tetrapeptide by their d -enantiomers. These compounds were tested for their action on stimulation of amylase release from rat pancreatic acini and for their ability to inhibit binding of labeled CCK to rat pancreatic acini and guinea pig brain membranes. Some of these derivatives behaved as CCK receptor antagonists.     

Prevalence and clinical presentation of constipation in children with severe generalized cerebral palsy

Aim Our aim was to study the prevalence and characteristics of constipation in children with profound multiple disabilities, as data in this area are scarce. Method A cross‐sectional observational study was performed in specialized day‐care centres and schools in the Netherlands. The study included 152 children (81 males, 71 females; mean age 9y 6mo, SD 4y 6mo). Intellectual disability ranged from moderate (7%) to profound (52%) in all participants who also had severe motor disabilities (83% classified at Gross Motor Function Classification System level V). We collected data on defaecation characteristics, food and fluid intake, and laxative consumption using standardized bowel diaries and interviews. Constipation was defined as (1) scybalous, pebble‐like, hard stools in over a quarter of defaecations in combination with a defaecation frequency of less than three times per week during a 2‐week study period; (2) large stools palpable on abdominal examination; or (3) laxative use or manual disimpaction of faeces. Results Of the studied population, 57% were constipated and 55% used laxatives, 27% of whom showed symptoms of constipation. Daily intakes of water and fibre were below the required standards in 87% and 53% of participants respectively, without a proven relation to constipation. Interpretation Constipation is a common problem in children with severe disabilities. Laxative use is high but dosing is frequently inadequate to prevent symptoms.     

Postulated Carbon Tetrachloride Mode of Action: A Review

Under the 2005 U.S. EPA Guidelines for Carcinogen Risk Assessment (1 U.S. EPA. 2005. Guidelines for carcinogen risk assessment, Washington, DC: Risk Assessment Forum. http://www.epa.gov/iris/backgrd.htm EPA/630/P-03/001b. Available from [Google Scholar]), evaluations of carcinogens rely on mode of action data to better inform dose response assessments. A reassessment of carbon tetrachloride, a model hepatotoxicant and carcinogen, provides an opportunity to incorporate into the assessment biologically relevant mode of action data on its carcinogenesis. Mechanistic studies provide evidence that metabolism of carbon tetrachloride via CYP2E1 to highly reactive free radical metabolites plays a critical role in the postulated mode of action. The primary metabolites, trichloromethyl and trichloromethyl peroxy free radicals, are highly reactive and are capable of covalently binding locally to cellular macromolecules, with preference for fatty acids from membrane phospholipids. The free radicals initiate lipid peroxidation by attacking polyunsaturated fatty acids in membranes, setting off a free radical chain reaction sequence. Lipid peroxidation is known to cause membrane disruption, resulting in the loss of membrane integrity and leakage of microsomal enzymes. By-products of lipid peroxidation include reactive aldehydes that can form protein and DNA adducts and may contribute to hepatotoxicity and carcinogenicity, respectively. Natural antioxidants, including glutathione, are capable of quenching the lipid peroxidation reaction. When glutathione and other antioxidants are depleted, however, opportunities for lipid peroxidation are enhanced. Weakened cellular membranes allow sufficient leakage of calcium into the cytosol to disrupt intracellular calcium homeostasis. High calcium levels in the cytosol activate calcium-dependent proteases and phospholipases that further increase the breakdown of the membranes. Similarly, the increase in intracellular calcium can activate endonucleases that can cause chromosomal damage and also contribute to cell death. Sustained cell regeneration and proliferation following cell death may increase the likelihood of unrepaired spontaneous, lipid peroxidation- or endonuclease-derived mutations that can lead to cancer. Based on this body of scientific evidence, doses that do not cause sustained cytotoxicity and regenerative cell proliferation would subsequently be protective of liver tumors if this is the primary mode of action. To fulfill the mode of action framework, additional research may be necessary to determine alternative mode(s) of action for liver tumors formed via carbon tetrachloride exposure.     

Atrioventricular Interval Optimization and Exercise Tolerance

Modern pacemakers offer many programming options regarding the AV interval including the ability to vary AV intervals depending on whether atrial activity is paced or spontaneous and to shorten AV intervals with increasing rates. To determine if optimization of these features improves exercise tolerance, 14 patients with intact sinus node function and AV block treated with dual chamber pacemakers were enrolled in a randomized double-blind crossover trial. Doppler echocardiographic measurements of cardiac index and mitral flow were assessed over a range of programmable AV intervals at rest to determine each patient's optimal AV interval. Eleven patients completed serial graded exercise tests with spiroergometry after randomly programming the AV interval three ways in a crossover manner: fixed AV interval = 150 ms without rate adaptation (150/Fixed), fixed AVinterval = 150 ms with rate adaptation (150/R), or optimized AV interval with rate adaptive AV interval shortening (optimized/R). Exercise capacity was determined by maximum oxygen uptake. Ten men and four women, age 64 +/- 8 years, were enrolled. At rest, optimization of the AVintervalimproved the cardiac index by 21% (P < 0.001) and mitral flow by 13.4% (P < 0.001) when compared to least-favorable AV intervals. During exercise, no differences in maximum heart rates were noted. Maximum oxygen uptake was increased in both groups with rate adaptive AVinterval shortening when compared tofixed AVinterval without rate adaptation: 13.9% (adjusted P < 0.04) and 14.6% (adjusted P < 0.02) in optimized/R and 150/R, respectively. No differences were noted between optimized/R and 150/R. In conclusion, rate adaptive AV interval shortening improved exercise tolerance independent of changes in heart rate. However, optimization of the AV interval with Doppler echocardiography at rest did not further improve exercise capacity.     

Tanning and Cutaneous Malignancy

BACKGROUND Exposure to ultraviolet radiation (UVR) results in a darkening of the skin known as tanning. Recently, it has been shown that tanning is a response to UVR-induced DNA damage and represents the skin's efforts to protect itself against further injury. Despite the link between UVR and cutaneous malignancy, people continue to pursue tanning from natural and artificial sources. This trend is reflected in the exponential rise in skin cancer incidence.
OBJECTIVE The objective of this study was to review our current understanding of the factors controlling the tanning response and the relationship to cutaneous carcinogenesis, as well as the impact that the multibillion dollar tanning industry has had on the practice of dermatology.
MATERIALS AND METHODS Extensive literature review was conducted in subjects related to tanning and the relationship to cutaneous malignancy.
RESULTS Our knowledge of tanning and its effects on the skin has increased tremendously. It is clear that tanning contributes to the development of skin cancer. Despite this information, the incidence of skin cancer continues to increase exponentially.
CONCLUSIONS Skin cancer poses a major public health concern and tanning remains the most modifiable risk factor in its etiology. Social, economic, and legislative issues have become tightly intertwined with the complex nature of human behavior in the continued pursuit of an activity that clearly has detrimental effects on one's health.