Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent,selective, melanocortin subtype-4 receptor agonist

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.     

Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women

Weight loss in response to caloric restriction is variable. Because skeletal muscle mitochondrial proton leak may account for a large proportion of resting metabolic rate, we compared proton leak in diet-resistant and diet-responsive overweight women and compared the expression and gene characteristics of uncoupling protein (UCP)2 and UCP3. Of 1,129 overweight women who completed the University of Ottawa Weight Management Clinic program, 353 met compliance criteria and were free of medical conditions that could affect weight loss. Subjects were ranked according to percent body weight loss during the first 6 weeks of a 900-kcal meal replacement protocol. The highest and lowest quintiles of weight loss were defined as diet responsive and diet resistant, respectively. After body weight had been stable for at least 10 weeks, 12 of 70 subjects from each group consented to muscle biopsy and blood sampling for determinations of proton leak, UCP mRNA expression, and genetic studies. Despite similar baseline weight and age, weight loss was 43% greater, mitochondrial proton leak-dependent (state 4) respiration was 51% higher (P = 0.0062), and expression of UCP3 mRNA abundance was 25% greater (P < 0.001) in diet-responsive than in diet-resistant subjects. There were no differences in UCP2 mRNA abundance. None of the known polymorphisms in UCP3 or its 5' flanking sequence were associated with weight loss or UCP3 mRNA abundance. Thus, proton leak and the expression of UCP3 correlate with weight loss success and may be candidates for pharmacological regulation of fat oxidation in obese diet-resistant subjects.     

Portal vein pulsatility and spectral width changes in patients with portal hypertension: relation to the severity of liver disease

Using Doppler ultrasound in patients with chronic liver disease (CLD) and portal hypertension, portal vein pulsatility pattern and spectral width changes were assessed and evaluated in relation to the severity of liver disease as determined according to the Child-Pugh score. The pulsatility index (PI) was significantly lower in CLD patients (mean+/-SD: 0.23+/-0.08) compared with healthy subjects (0.39+/-0.1) (p<0.001) and lower in Child-Pugh class C compared with Child-Pugh class A patients (0.21+/-0.07 vs 0.25+/-0.08, respectively) (p<0.05). The spectral width index was significantly higher in CLD patients vs healthy subjects (0.91+/-0.16 vs 0.60+/-0.12, respectively) (p<0.001). The difference was also noted in the early stage (Child-Pugh A patients) when compared with healthy subjects (0.88+/-0.17). In conclusion, portal vein pulsatility and spectral width indices can reflect the early haemodynamic changes in CLD patients. These changes become more pronounced with the progression of liver disease.     

Diagnosis of giardiasis using an enzyme-linked immunosorbent assay (ELISA) on formalin preserved stools

From a total of 162 children, three stool samples were collected from each child over a period of one week and preserved in formalin. Giardia lamblia was diagnosed by direct microscopy of formol-ether concentrates for each of the three samples. The first sample was also subjected to an ELISA test for detection of Giardia Iambia stool antigen in formalin preserved stool specimens. Microscopic examination revealed that 45 children were infected whereas ELISA detected 41 cases giving a sensitivity of 91.1% and a specificity of 99.1%. Predictive value of a positive test was 97.6% and that of a negative test was 96.7%. A significant correlation was present between mean optical density readings of ELISA and number of cysts present. No crossreactivity was observed ELISA is a simple, sensitive and specific test that can be applied in epidemiological studies for detection of Giardia lamblia coproantigen in formalin preserved stool specimens.     

Intraperitoneal chemotherapy strategies in the treatment of epithelial ovarian carcinoma

The intraperitoneal delivery of chemotherapeutic agents is presently being investigated as a part of salvage treatment for epithelial ovarian cancer. There are several promising new agents that appear to demonstrate a benefit in selected patients.     

Development of cholinergic properties in nerve cell cultures in the presence of brain extract

Cells dissociated from cerebral hemispheres of 6-day-old chick embryos were cultured either in standard nutrient medium or in the presence of a brain extract from 8-day-old chick embryo. Morphological observations showed the development of bipolar and multipolar neurons in both culture conditions and acetylcholinesterase activity was found in all neuronal cells. Brain extract stimulated the morphological maturation of neurons, expressed by the formation of fiber bundles, fine structural maturation and development of synapses rich in clear vesicles. Furthermore, acetylcholinesterase and choline acetyltransferase activities were higher in the cultures treated with brain extract. In these cultures, the values of choline acetyltransferase activity reached a peak at 10 days and then decreased. These observations are discussed with particular reference to proliferation, maturation and degeneration of cholinergic neurons.