Effects of haloperidol or SCH-23390 on ethanol-induced conditioned taste aversion.

Dopaminergic systems are thought to play an important role in the motivational effects of ethanol. The present experiments examined the effects of haloperidol (a D2 antagonist) and SCH-23390 (a D1 antagonist) on the acquisition of ethanol-induced conditioned taste aversion. In four separate experiments, adult male Swiss-Webster mice were acclimated to a 2-h/day water restriction regimen. Subsequently they received four conditioning trials consisting of 1-h access to either 0.2 M NaCl (experiments 1-3) or 0.15 % w/v saccharin (experiment 4). After flavor access on trials 1-3, subjects received either haloperidol (0.1, 0.15, or 0.3 mg/kg), SCH-23390 (0.05 mg/kg), or saline followed 30 min later by 0, 2, or 4 g/kg ethanol. Ethanol-flavor pairings reduced subsequent flavor intakes, indicating the development of conditioned taste aversion. Neither haloperidol of SCH-23390 reduced flavor intakes in the absence of ethanol. However, both haloperidol and SCH-23390 reduced ethanol-conditioned aversion depending on ethanol dose and conditioned flavor. These results are consistent with the notion that dopaminergic processes are important for the development of ethanol-induced conditioned taste aversion, and the notion that dopaminergic receptor systems influence both positive and negative motivational effects of ethanol.     

Synthesis and Biological Evaluations of Electrophilic Steroids Inspired by the Taccalonolides

Natural products have served as inspirational scaffolds for the design and synthesis of novel antineoplastic agents. Here we present our preliminary efforts on the synthesis and biological evaluation of a new class of electrophilic steroids inspired by the naturally occurring taccalonolides. We demonstrate that these simplified analogs exhibit highly persistent antiproliferative properties similar to the taccalonolides and retain activity against resistant cancer cell lines that warrants further preclinical development.     

Radiologic abnormalities and autonomic neuropathology in the digestive tract of the ketonuric diabetic Chinese hamster

Summary Barium x-ray patterns of ketonuric diabetic Chinese hamsters displayed marked dilatation of the stomach, small and large intestine. Hypomotility was manifested by flocculation of barium in the small and large bowel. Impaired transit time was further characterized by prolonged emptying of the stomach (mean 570 min diabetics; 200 min controls) and delayed stool formation (mean 230 min diabetics; and 100 min controls) and passage (mean 457 min diabetics; 210 min controls). Ultrastructural analysis of Auerbach's myenteric plexuses of the small intestine indicated acute degeneration in certain distal, unmyelinated axons. Swelling, deposition of glycogen, aggregation of neurofilaments and dense accumulation of lamellar bodies were observed. The severity and frequency of barium flocculation, glycogen deposition, aggregation of neurofilaments and lamellar inclusion bodies in axons were directly related to duration of ketonuria. The data strongly suggest that autonomic neuropathology in the plexuses of Auerbach may be a critical factor underlying gastrointestinal dysfunction in the ketonuric diabetic Chinese hamster.     

Homocysteine and nitrite levels are modulated by MTHFR 677C>T polymorphism in obese women treated with simvastatin

Higher homocysteine (Hcy) levels are associated with cardiovascular risk. The aim of the present study was to evaluate the effect of simvastatin treatment on circulating Hcy levels in obese women without hypertension, diabetes or dyslipidaemia; and to determine whether the 677C>T polymorphism located in methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) gene modulates the effects of this treatment on Hcy and nitrite (as a biomarker of nitric oxide (NO) bioavailability). Twenty‐five obese women (body mass index ≥ 30 kg/m²) who had received 20 mg/day simvastatin for 6 weeks were enrolled in the study. Venous blood samples were collected to measure plasma biomarkers and gene polymorphisms. Simvastatin treatment significantly reduced total cholesterol, low‐density lipoprotein–cholesterol, thiobarbituric acid‐reactive substances, high‐sensitivity C‐reactive protein and Hcy, whereas nitrite levels were increased. The reduction in Hcy levels in carriers of the T allele was ?20.3% compared with –9.4% in patients with the CC genotype. Importantly, before treatment, nitrite levels were significantly higher in patients with the CC genotype compared with T allele carriers, whereas after treatment these levels were similar between groups. Our findings demonstrate that obese women without comorbidities and carrying the T variant of the 677C>T polymorphism of MTHFR exhibit benefits with simvastatin treatment, mainly in terms of increased NO levels.     

The ictal EEG as a predictive factor for outcome following corpus callosum section in adults

Published reports have indicated that after callosotomy half or more of all patients will experience a 50% or greater reduction in seizure frequency. Those callosotomy patients whose seizures produce falls appear to have the best results. We studied the value of ictal EEG in 41 patients 18 years or older who had undergone either a total or partial callosotomy at our program. Ictal EEG's were separated into two categories: Type I: generalized slow spike wave, electrodecrement, non-evolving low amplitude fast activity; Type II: all other patterns. Types I and II were then compared to a defined one-year outcome for the targeted seizure type using Chi-square or Fishers Exact Test. Previously identified predictors of good or worthwhile outcome as defined by the literature were also evaluated. RESULTS: A significant association was noted for presence of specifically defined EEG patterns and a 90% reduction in seizure frequency but not for other factors analyzed. CONCLUSION: The ictal EEG but not other factors is able to identify a group of patients who have a better than 90% chance for total or nearly total resolution of seizures causing sudden falls.     

Splice variants but not mutations of DNA polymerase beta are common in bladder cancer

DNA polymerase beta (POLbeta) is a highly conserved protein that functions in base excision repair. Loss of the POLbeta locus on chromosome 8p is a frequent event in bladder cancer, and loss of POLbeta function could hinder DNA repair leading to a mutator phenotype. Both point mutations and large intragenic deletions of POLbeta have been reported from analysis of various tumor cDNAs but not from genomic DNA. We noticed that the breakpoints of the presumed rearrangements were delineated by exon-exon junctions, which could instead be consistent with alternative splicing of POLbeta mRNA. We tested the hypothesis that the reported intragenic deletion were splice variants by screening genomic DNA of human bladder tumors, bladder cancer cell lines, and normal bladder tissues for mutations or deletions in exons 1-14, exon alpha, and the promoter region of POLbeta. We found no evidence of somatic mutations or deletions in our sample set, although two polymorphisms were identified. Examination of cDNA from a subset of the original sample set revealed that truncated forms of POLbeta were surprisingly common. Forty-eight of 89 (54%) sequenced cDNA clones had large deletions, each beginning and/or ending exactly at exon-exon junctions. Because these deletions occur at exon-exon junctions and are seen in cDNA but not genomic DNA, they are consistent with alternative mRNA splicing. We describe 12 different splicing events occurring in 18 different combinations. Loss of exon 2 was the most frequent, being found in 42 of 49 (86%) of the variant sequenced clones. The splice variants appear to be somewhat more common and variable in bladder cancer cell lines and tumor tissues but occur at a high frequency in normal bladder tissues as well. We examine alternative splicing in terms of the information content of splice donor and acceptor site sequences, and discuss possible explanations for the predominant splicing event, the loss of exon 2.