L-Ala-substituted rat galanin analogs distinguish between hypothalamic and jejunal galanin receptor subtypes

In order to explore which amino acids or which blocks of amino acids in the 29 amino acid neuropeptide galanin are important for recognition of the endogenous ligand by galanin receptor subtypes present in the jejunum and in the hypothalamus, respectively, we have carried out L-Ala substitutions of individual amino acids or of blocks of amino acids in the rat galanin sequence and examined the binding of the obtained analogs to the rat hypothalamic and jejunal galanin receptor subtypes. This study reveals that the galanin sequence YLLGPH^9–14 is essential for recognition of galanin by both the rat hypothalamic and jejunal galanin receptor subtypes. Substitution of the N-terminal amino acids, GWTL^1–4, leads to total loss of affinity of galanin for both hypothalamic and jejunal galanin receptors. The α-helical C-terminal amino acid (25–29) part of galanin has no greater influence on the affinity of galanin to the hypothalamic galanin receptor subtype. L-Ala substitution of the C-terminal amino acids of galanin KHGLT^25–29 shows, however, that this C-terminal motif is essential for the recognition by the jejunal galanin receptor subtype, whereas amino acids in the middle portion of galanin NSAG^5–8 are of importance for binding to the hypothalamic but not to the jejunal receptor. [Ala^5–8] Galanin thus has a more than 100-fold higher affinity to jejunal receptor than to the hypothalamic receptor, while [Ala^25–29] galanin has a more than 100-fold higher affinity for the hypothalamic than for jejunal galanin receptor subtypes. pH dependence of the galanin binding to these receptor subtypes is also different. © Munksgaard 1997.     

Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States

The role of hepatitis B virus (HBV) genotypes in the outcome of acute HBV infection is unclear. In this study, we aimed to evaluate the clinical and virological features of patients with hepatitis B-related acute liver failure (HBV-ALF) in the US. Clinical and laboratory features of consecutive patients with HBV-ALF from the US ALF Study Group were analysed. Prevalence of HBV genotypes, precore stop (G1896A) and core promoter dual (T1762A, A1764T) variants among patients with HBV-ALF were compared with a cohort of 530 patients with chronic HBV infection. Thirty-four HBV-ALF patients were studied: mean age 41 years, 56% men, 25 had detectable HBV-DNA. HBV genotypes A, B, C and D were found in 36, 24, 8 and 32% patients, respectively. Precore stop and core promoter dual variants were detected in 32 and 44% of patients, respectively. Twenty-three (68%) patients survived: 14 after liver transplant, nine without transplant. Older age was the only independent factor associated with poor outcome. Compared with patients with chronic HBV infection, patients with ALF were more likely to be non-Asians (88% vs 44%, P = 0.005) and to have genotype D (32% vs 10%, P < 0.01). A higher prevalence of HBV genotype D persisted even after matching for race and HBeAg status (32% vs 16%, P = 0.007). We concluded that HBV genotype D was more frequently found in patients with HBV-ALF than those with chronic HBV infection in the US. Further studies are needed to determine if HBV genotypes play a role in the outcome of acute HBV infection.     

Toxicology and carcinogenesis study of chloral hydrate (ad libitum and dietary controlled) (CAS no. 302-17-0) in male B6C3F1 mice (gavage study)

[structure: see text] Chloral hydrate is used medically as a sedative or hypnotic and as a rubefacient in topical preparations, and it is often given to children as a sedative during dental and other medical procedures. Chloral hydrate is used as a central nervous system depressant and sedative in veterinary medicine and as a general anesthetic in cattle and horses. It is a byproduct of the chlorination of water and has been detected in plant effluent after the bleaching of softwood pulp. Chloral, the anhydrous form of chloral hydrate, is used as a synthetic intermediate in the production of insecticides and herbicides. Chloral hydrate was nominated for study by the Food and Drug Administration based upon widespread human exposure and its potential hepatotoxicity and the toxicity of related chemicals. A dietary control component was incorporated in response to concerns within the regulatory community relating to increased background neoplasm incidences in rodent strains used for toxicity testing and to the proposed use of dietary restriction to control background neoplasm incidence in rodent cancer studies. Male B6C3F1 mice (ad libitum-fed or dietary-controlled) received chloral hydrate (99% pure) by gavage for 2 years. 2-YEAR STUDY IN MALE MICE: Groups of 120 male mice received chloral hydrate in distilled water by gavage at doses of 0, 25, 50, or 100 mg/kg 5 days per week for 104 to 105 weeks. Each dose group was divided into two dietary groups of 60 mice. The ad libitum-fed mice had free access to feed, and the dietary-controlled mice received feed in measured daily amounts calculated to maintain body weight on a previously computed idealized body weight curve. Twelve mice from each diet and dose group were evaluated at 15 months. SURVIVAL, FEED CONSUMPTION, AND BODY WEIGHTS: Survival of dosed groups of ad libitum-fed and dietary-controlled mice was similar to that of the corresponding vehicle controls. When compared to the ad libitum-fed groups, dietary control significantly increased survival in the vehicle controls and 25 and 50 mg/kg groups. Mean body weights of all dosed groups were similar to those of the vehicle control groups throughout the study. The dietary-controlled mice were successfully maintained at or near their target idealized body weights. There was less individual variation in body weights in the dietary-controlled groups than in the corresponding ad libitum-fed groups. Feed consumption by 25 and 50 mg/kg ad libitum-fed mice was generally similar to that by the vehicle controls throughout the study. Feed consumption by 100 mg/kg ad libitum-fed mice was slightly less than that by the vehicle controls throughout the study. HEPATIC ENZYME ANALYSIS: Chloral hydrate did not significantly induce either lauric acid 4-hydroxylase activity or CYP4A immunoreactive protein in any of the dosed groups of ad libitum-fed mice. However, 100 mg/kg did significantly induce both lauric acid 4-hydroxylase activity and CYP4A immunoreactive protein in the dietary-controlled mice. Moreover, the induction response profile of CYP4A was similar to the increase in the incidence of liver neoplasms at 2 years in the dietary-controlled mice with the major effect occurring in the 100 mg/kg group. The serum enzymes alanine aminotransferase, amylase, aspartate aminotransferase, and lactate dehydrogenase were also assayed at 2 years. In the ad libitum-fed groups there was a significant increase in aspartate aminotransferase activity in the 50 mg/kg group. There were no other significant effects in any dosed group, but in general the dietary-controlled groups exhibited lower values than the corresponding ad libitum-fed groups. ORGAN WEIGHTS AND PATHOLOGY FINDINGS: The heart weight of ad libitum-fed male mice administered 100 mg/kg and the kidney weights of 50 and 100 mg/kg ad libitum-fed mice were significantly less than those of the vehicle controls at 2 years. The liver weights of all dosed groups of ad libitum-fed and dietary-controlled mice were greater than those of the vehicle control groups at 2 years, but the increases were not statistically significant. The incidence of hepatocellular adenoma or carcinoma (combined) in ad libitum-fed mice administered 25 mg/kg was significantly greater than that in the vehicle controls at 2 years. The incidences of hepatocellular carcinoma and of hepatocellular adenoma or carcinoma (combined) occurred with positive trends in dietary-controlled male mice at 2 years, and the incidence of hepatocellular carcinoma in 100 mg/kg dietary-controlled mice was significantly increased. CONCLUSIONS: Under the conditions used in this 2-year gavage study, there was some evidence of carcinogenic activity of chloral hydrate in male B6C3F1 mice based on increased incidences of hepatocellular adenoma or carcinoma (combined) in ad libitum-fed mice and on increased incidences of hepatocellular carcinoma in dietary-controlled mice. In the dietary-controlled mice, induction of enzymes associated with peroxisome proliferation was observed at higher doses.     

Screening and interventions for overweight in children and adolescents: recommendation statement

The U.S. Preventive Services Task Force (USPSTF) is an independent panel of non-federal experts in prevention and primary care that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services. This recommendation addresses the evidence for the accuracy of screening children and adolescents using BMI, the effectiveness of behavioral and pharmacologic interventions in improving health outcomes in these children, and the potential harms of routine screening and intervention. Using USPSTF methodology, an analytic framework with key questions was developed to guide the systematic review, which serves as the basis for this recommendation. The number of children and adolescents who are overweight has more than doubled in the last 25 years. Childhood and adolescent overweight is associated with increased health risks. The USPSTF found insufficient evidence for the effectiveness of behavioral counseling or other preventive interventions with overweight children and adolescents that can be conducted in primary care settings. Currently, available studies are limited by factors such as small sample sizes, poor generalizability, and variable follow-up. Based upon this critical gap in the evidence for effectiveness, the USPSTF concludes that the evidence is insufficient to recommend for or against routine screening for overweight in children and adolescents as a means to prevent adverse health outcomes ("I" recommendation). There are several gaps in the research evidence on screening and interventions for overweight children and adolescents in the primary care setting. Research is needed to provide well-defined and effective approaches to medical and psychological screening in children, as well as effective clinical approaches for the prevention and treatment of overweight in children that can be implemented by primary care clinicians.