Observations of the early diuretic response after intravenous administration of bumetanide and furosemide in dogs.

A transient natriuretic peak was observed in dogs the third minute after the i.v. administration of the highly active diuretics bumetanide and furosemide. The peak is dependent on the sodium balance such that it is potentiated during positive sodium balance and is not observed in sodium depleted dogs. A relationship exists between the simultaneous occurrence of the peak and abolition of the cortico-medullary electrolyte gradient.     

Clonidine-induced increase of renal prostaglandin activity and water diuresis in conscious dogs.

I.v. administration of clonidine to conscious dogs induces a water diuresis with hyposmotic urine and minor effect on electrolyte excretion. The diuresis is preceded by an increased urinary PGE excretion, but no change of urinary ADH output is observed. Plasma renin activity decreases. Both ADH infusion and indomethacin pretreatment inhibit the diuretic effect of clonidine. The results support the hypothesis that clonidine-induced water diuresis is mediated via an anti ADH effect due to increased renal prostaglandin activity. Moreover the results suggest that there is no direct stimulation of renin release by PGE.     

The Effect of Arvin on Experimental Pulmonary Embolism in the Rabbit

S ummary . Arvin therapy produced alterations in the histological structure of experimental pulmonary emboli in rabbits. Early and extensive necrosis was observed in the emboli which were not organized by fibroblasts. The emboli disappeared more rapidly from the pulmonary vessels than in non-treated animals.     

Hypothermia and electromagnetic rewarming in the rhesus monkey

Five male rhesus monkeys (Macaca mulatta) were subjected, under ketamine anesthesia, to repeated hypothermia treatments that produced an average rectal temperature of 28.3 degrees C. Following hypothermia induction, the subjects were rewarmed using either a ventrally applied surgical heating pad supplied with 35 degrees C water or a radio-frequency (RF) induction coil operating at 13.56 MHz with an average specific absorption rate (SAR) calculated to be approximately 5.5 W X kg-1. A special temperature probe, nonperturbing to RF, was used in the RF rewarming experiments. Control experiments were also conducted in which only ketamine was administered over a 3-h period. RF rewarming to 35 degrees C typically required only 50 min; whereas, an average of 137 min was required for heating-pad rewarming. Analyses of blood serum collected during and up to 48 h after hypothermia treatments showed elevations at 24 h in creatine phosphokinase (CPK), lactic dehydrogenase (LDH), and glutamic oxaloacetic transaminase (GOT), and these elevations were highest for the ketamine controls and lowest for the RF rewarming experiments. The subjects have been periodically examined since these experiments, and all appear to be in good health. It is concluded that the careful application of RF energy to the central core of the body can successfully be used for rewarming purposes, is more effective than externally applied rewarming techniques, and is potentially useful in remote locations.     

Hyperlipidemia, hypercoagulability, and accelerated thrombosis: studies in congenitally hyperlipidemic rats and in rats and monkeys with induced hyperlipidemia

Inbred Carworth Farms Nelson (CFN) congenitally hyperlipidemic rats had significantly shorter coagulation and prothrombin times and higher levels of coagulation factors, II, V, VII, VIII, and X than did controls. Conversely, congenitally hypolipidemic rats of the same strain had significantly longer coagulation and prothrombin times and lower levels of factors II, V, VII, X and XII and of blood platelets than did controls. A loop-shaped polyethylene cannula was inserted into the aorta to assess the potential for thrombosis. The hyperlipidemic group obstructed this significantly faster and the hypolipidemic group slower than did the controls. Normal CFN rats made hypertensive by unilateral renal artery clip developed hypertension together with significantly elevated serum cholesterol and factor VII and X levels. Rhesus monkeys with diet-induced hyperlipidemia showed shorter prothrombin times and higher factor X levels than did controls on normal diet. By selective breeding, two groups of squirrel monkeys were obtained. Both groups had similar serum cholesterol levels on a normal diet but one group (hyperresponders) showed higher serum cholesterol levels on a cholesterol-containing diet than did the other (hyporesponder) group. Both groups showed significantly elevated levels of factors II, V, VII, IX and X on a cholesterol-containing diet. There was good correlation between the levels of many coagulation factors and serum cholesterol in both rats and monkeys. If thrombosis is important in the genesis of atherosclerosis, these findings could indicate that elevation of plasma lipids may play a role, via the coagulation pathway, in the production of human vascular disease.     

Ventilatory response to carbon dioxide of infants following chronic prenatal methadone exposure

Nine infants chronically exposed to methadone in utero were studied from birth to 7 weeks of age (66 studies). The maternal dose of methadone/HCl during the third trimester ranged from 14 to 70 mg orally once a day. The mean (range) of serum methadone t 1/2 in the neonates was 53 hours (22 to 113). In the first four days of life the methadone-exposed infants had a significantly (P less than 0.005) decreased sensitivity to carbon dioxide compared to control infants as measured by the slope of the ventilatory response curve. The mean slope +/- SD for the methadone-exposed infants, 10.4 +/- 7.7 ml/minute/kg mm Hg, was one third that of the control group (30.0 +/- 9.9 ml/minute/kg/mm Hg). Total ventilation, respiratory frequency, oxygen consumption, and end-tidal PCO2 were not significantly different in the two groups. The depressed ventilatory response to carbon dioxide persisted for an average of 15 days and lasted as long as 31 days in one infant. The time required to achieve a normal slope was not related to the size of the maternal methadone dose, to neonatal serum methadone t 1/2, or to the severity of and therapy for methadone withdrawal. If this abnormality in sensitivity to carbon dioxide persists beyond the neonatal period in some infants, it may contribute to the increased incidence of the sudden infant death syndrome among infants exposed to methadone in utero. Measurement of the ventilatory response to carbon dioxide may be clinically useful to determine which of these infants are at risk for SIDS.     

Cancer incidence in first-degree relatives of a population-based set of cases of early-onset breast cancer

Reliable determination of familial risks for cancer is important for clinical counselling, cancer prevention and understanding cancer aetiology. Family-based gene identification efforts may be targeted if the risks are well characterised and the mode of inheritance is identified. Early-onset breast cancer in a family member is a risk indicator for cancer among first-degree relatives; however, the familial risk pattern has not been assessed fully in population-based incidence studies. We estimated the risks for cancers of the breast, ovary and other sites among the first-degree relatives of 8868 patients in whom breast cancer was diagnosed before they reached the age of 50 years (diagnosed during the period 1943-1999). Population registers and parish records were used to identify 31,235 first-degree relatives, who were followed up to 31 December 2002 for occurrence of cancer by linkage to the Danish Cancer Registry. The observed incidence rates were compared with national rates adjusted for age, sex and calendar period. Overall, 39% of the 674 cases of breast cancer and 43% of the 143 cases of ovarian cancer among relatives were associated with a diagnosis of early-onset breast cancer in a family member. Among relatives under 50 years of age, the proportions were 56% and 58%, respectively, and among relatives 50 years or above the proportions were approximately 30% and 10%. In addition, a slightly but significantly increased risk for cancer of the cervix uteri was observed among relatives, and among those under 50 years of age, we found significantly increased risks for cancers of the colon and gall-bladder. In conclusion, the excess risk for breast cancer in first-degree relatives is large and remains sizable in the subgroup of female relatives aged 50 years or older, and that mutations in BRCA1/2 seem to explain only half of breast cancer cases attributable to family history.     

New ligands with affinity for the alpha4beta2 subtype of nicotinic acetylcholine receptors. Synthesis, receptor binding, and 3D-QSAR modeling

A new series of piperazines, diazepanes, diazocanes, diazabicyclononanes, and diazabicyclodecanes with affinity for the alpha4beta2 subtype of nicotinic acetylcholine receptors were synthesized on the basis of results from a previous computational study. A predictive 3D-QSAR model was developed using the GRID/GOLPE approach (R2 = 0.94, Q2 = 0.83, SDEP = 0.34). The SAR was interpreted in terms of contour maps of the PLS coefficients and in terms of a homology model of the alpha4beta2 subtype of the nicotinic acetylcholine receptors. The results reveal that hydrogen bonding from both hydrogens on the protonated amine and from the pyridine nitrogen to a water molecule as well as van der Waals interactions between the substituent bearing the protonated amine and the receptor is of importance for ligand affinity. The combination of 3D-QSAR and homology modeling proved successful for the interpretation of structure-affinity relationships as well as the validation of the individual modeling approaches.