Effect of 6-hydroxydopamine lesions of the amygdala on intravenous cocaine self-administration under a progressive ratio schedule of reinforcement

Bilateral six-hydroxydopamine (6-OHDA) lesions were placed in the amygdala of rats self-administering cocaine (1.5 mg/kg per injection i.v.) under a progressive ratio schedule of reinforcement. Post-lesion access to three doses of cocaine (1.5, 0.75 and 0.37 mg/kg per injection i.v.) revealed a lesion effect only at the highest dose. At this dose, the lesion caused a significant increase in breaking point. No change in the breaking point was produced at the lower two doses. The biochemical results show a significant reduction in dopamine and DOPAC levels within the amygdala and an increase in dopamine within the NACC. In contrast, noradrenaline and serotonin (5-HT) levels were unaffected by the lesion in any of the dissected areas. These results demonstrate that no specific effect on cocaine reinforcement was produced by 6-OHDA lesions of the amygdala. The possibility that the lesion may have attenuated the anxiogenic qualities of the high dose of cocaine is discussed.     

C-terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties.

We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.     

Age related rejoining of broken chromosomes in human leukocytes following X-irradiation.

One theory of aging is that the ability to repair DNA or chromosome damage decreases with age. This study made use of a method which allows the measurement of chromatid repair in interphase nuclei, the technique of premature chromosome condensation. The number of excess chromosome fragments per cell remaining after 24 h of incubation at 37 degrees C was determined and used as a measure of the ability of leukocytes to repair. The leukocytes from male donors of several ages were used and the cells from older donors showed greater residual damage and, therefore, less repair.     

Impact of Induction Chemotherapy and Preoperative Chemoradiotherapy on Operative Morbidity and Mortality in Patients with Locoregional Adenocarcinoma of the Stomach or Gastroesophageal Junction

Background Significant tumor downstaging has been achieved in patients with localized gastric or gastroesophageal adenocarcinoma by induction chemotherapy and preoperative chemoradiotherapy (CTX–CTXRT). However, the influence of CTX–CTXRT on operative morbidity and mortality has not yet been clarified. The aim of the present study was to document the frequency and nature of morbidity and mortality after surgery combined with CTX–CTXRT, and identify factors predictive of postoperative complications in patients with localized gastric or gastroesophageal adenocarcinoma. Methods A prospectively collected database on 71 consecutive patients who underwent CTX–CTXRT at M.D. Anderson Cancer Center between January 1997 and August 2004 was reviewed. Postoperative morbidity and mortality were investigated, and risk factors for overall complications were identified by multivariate logistic regression analysis. Results Overall morbidity and mortality rates were 38.0% (27 patients) and 2.8% (2 patients), respectively. Age greater than 60 years [relative risk 11.3 (95% confidence interval 2.50–50.6)] and body mass index (BMI) of 26 kg/m² or above [relative risk 4.08 (95% confidence interval 1.08–15.4)] were significant risk factors for overall complications. Conclusions CTX–CTXRT can be performed safely with an acceptable operative morbidity and a low operative mortality rate in patients with gastric or gastroesophageal cancer, with careful consideration of added risk associated with age and obesity.     

A diagnostic algorithm for male genital oedema

Male genital oedema can be defined as swelling or the appearance of swelling of the scrotum and/or the penile shaft and prepuce. Despite the various causes of genital oedema reported in the published work, a concise approach to the evaluation and management has not been sufficiently addressed.