Chronic administration of ORG 2766 for 6 months produces a subtle impairment in strategic learning by rats

Dysfunctions in serotonergic pathways may underlie several psychiatric disorders. The reuptake of serotonin (5-HT) from synaptic terminals is mediated by a specific transporter (5-HTT). Genetic variation in the gene coding for the 5-HTT protein might be involved in the predisposition to psychiatric disorders. A systematic screening of the whole coding sequence of the 5-HTT gene in mood disorder (MD) and obsessive-compulsive disorder (OCD) patients, as well as in healthy controls, using PCR and denaturing gradient gel electrophoresis (DGGE) revealed the presence of two mutations. The first was in intron 4, and the second was a C-->A transversion leading to an amino-acid exchange (Leu-->Met) in position 255 of the deduced protein sequence. No further occurrence of this substitution was found in an extended sample of patients and controls. Therefore, structural modifications of the 5-HTT gene do not seem to play either a major or minor role in the genetic predisposition to MD or OCD.     

Comparison of different oxygen exchange models

A functional distribution of coronary volume can be estimated from the response of arterio-venous O2 content difference (AVO2) to a flow step. However, the results depend on the assumed O2 exchange model. The previously used model consisted of a single mixed compartment with O2 exchange (reference model). The purpose of this study is to provide an estimate of the errors made in the volume estimations by not taking into account factors as flow heterogeneity, different mixing sites or Krogh-like O2 exchange. The approach is indirect: the response of the AVO2 to a flow step has been calculated with alternative O2 exchange models in which factors mentioned are incorporated. These transients are fitted with the reference model. The resulting estimated volumes are different from the volumes assumed in the alternative models. Large differences are obtained with some of the alternative models, e.g. the model with Krogh characteristics. However, these models seem unrealistic because capillary pO2 is higher than venous pO2. Only small differences in volume are obtained with the more realistic models. Therefore, these results indicate that the coronary volumes are approximated well by the estimations obtained with the reference model. These volume estimations were 9.9 and 3.8 ml 100 g-1 for the O2 exchange vessels and the distal venous volume, respectively.     

Effects of abstinence and family history for alcoholism on platelet adenylyl cyclase activity

Platelet adenylyl cyclase (AC) activity was measured in 32 alcohol-dependent subjects and 27 control subjects who were categorized as either family history-positive (FHP) or family history-negative (FHN) for alcoholism. The interview and blood sample collections were performed shortly after cessation of heavy drinking in the alcoholic group, and repeat blood samples were obtained at the end of the first and second weeks of monitored abstinence. Control subjects received the same interview and provided blood samples at the time of the interview. When subjects were not segregated for FHP or FHN status, there were no statistically significant differences in basal, cesium fluoride (CsF)-, or forskolin-stimulated mean AC activities between the controls and the alcoholics, at study entry or with 1 or 2 weeks of abstinence. On the other hand, over the 2-week course of sobriety from heavy drinking, the CsF-stimulated AC activity of FHP alcohol-dependent subjects decreased significantly (p = 0.03). FHP alcohol-dependent subjects after 2 weeks of sobriety had significantly lower mean CsF-stimulated AC activity than FHN controls (p = 0.04), whereas the FHN alcoholic subjects' CsF-stimulated AC activity did not differ significantly from FHN controls at this point in time. When all subjects were pooled and then categorized as either FHP or FHN, there was a significant difference in mean CsF-stimulated AC activity (p = 0.02) between the FHP and FHN subject groups. Genetic factors and abstinence appear to have roles in determining low platelet AC activity in alcoholic and nonalcoholic subjects. CsF-stimulated platelet AC activity, in particular, appears to act as a trait marker for a genetic vulnerability to developing alcoholism, but recent heavy drinking in male alcoholics is a factor that can mask differences between FHP and FHN subjects.     

Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group

BACKGROUND: The congenital long-QT syndrome, caused by mutations in cardiac potassium-channel genes (KVLQT1 at the LQT1 locus and HERG at the LQT2 locus) and the sodium-channel gene (SCN5A at the LQT3 locus), has distinct repolarization patterns on electrocardiography, but it is not known whether the genotype influences the clinical course of the disease. METHODS: We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus. We determined the cumulative probability and lethality of cardiac events (syncope, aborted cardiac arrest, or sudden death) occurring from birth through the age of 40 years according to genotype in the 246 gene carriers and in all 1378 members of the families studied. RESULTS: The frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than among subjects with mutations at the LQT3 locus (18 percent) (P<0.001 for the comparison of all three groups). In a multivariate Cox analysis, the genotype and the QT interval corrected for heart rate were significant independent predictors of a first cardiac event. The cumulative mortality through the age of 40 among members of the three groups of families studied was similar; however, the likelihood of dying during a cardiac event was significantly higher (P<0.001) among families with mutations at the LQT3 locus (20 percent) than among those with mutations at the LQT1 locus (4 percent) or the LQT2 locus (4 percent). CONCLUSIONS: The genotype of the long-QT syndrome influences the clinical course. The risk of cardiac events is significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although cumulative mortality is similar regardless of the genotype, the percentage of cardiac events that are lethal is significantly higher in families with mutations at the LQT3 locus.     

Evaluation on non invasive diagnostic tests for the second look in epithelial ovarian cancer

OBJECTIVE: To determine the usefulness of diagnostic tests performed before a second look laparotomy in patients with epithelial ovarian cancer. STUDY DESIGN: Thirty-three patients with epithelial ovarian cancer attended at Fundación Jiménez Díaz from 1984 to 1995 were studied. All patients initially underwent cyto-reducing surgery, followed by at least six platinum-based chemotherapy cycles. Prior to second look laparotomy all patients were evaluated by computerized tomography (CT) of the pelvis and abdomen, CA-125, pelvic-abdominal echography and gynecologic examination. To evaluate sensitivity, specificity, positive predictive value and negative predictive value for each test contingency tables were used. RESULTS: Eleven out of the 33 second look patients (33%) had histologic or cytologic evidence of disease. Six out of the eleven positive second look had a positive CT prior to second look (sensitivity of 55%). CT showed lack of disease in 21 out of the 22 negative second look cases (specificity 95%). Positive and negative predictive values of the test were 86% and 81%, respectively. Nine cases out of the 28 who had a CA-125 obtained had a positive second look. Four out of these nine patients had an increased CA-125 value (sensitivity 44%, specificity 95%, positive predictive value 80% and negative predictive value 78%). Sensitivity, specificity, positive predictive value and negative predictive value of physical examination and echography were 36%, 100%, 100%, 76% and 27%, 95%, 75%, 72%, respectively. On the other hand, sensitivity, specificity, positive predictive value and negative predictive value of all tests taken together were 64%, 91%, 78% and 83%, with a rate of false-negative results of 17% and a rate of false-positive results of 22%. CONCLUSION: Pelvic-abdominal computerized tomography, CA-125, pelvic-abdominal echography and gynecologic examination can be an alternative to second look laparotomy for the diagnosis of persistence or recurrence of the disease in patients with epithelial ovarian cancer.     

Survey of the diagnosis and management of antisperm antibodies

A questionnaire was sent to all Human Fertilization and Embryology Authority-registered reproductive medicine centres throughout the UK to survey their policy for the diagnosis and management of antisperm antibodies. Forty-eight responses were received from the 74 units that use husbands' spermatozoa for treatments (65%). Most centres use at least one test to detect antibodies, although a minority perform no tests on the basis that their clinical practice would be unaltered if antibodies were present. Positive tests are classed as clinically significant at levels varying from > or = 10% to > or = 50% for direct sperm binding tests (mixed antiglobulin reaction, immunobead test), and ranging from any positive reaction to > or = 1:32 for the microtitre tests (gelatin and tray agglutination tests, microimmobilization test). Strategies for managing affected patients include no intervention, artificial insemination and intrauterine insemination (IUI) using spermatozoa prepared by various techniques, in-vitro fertilization (IVF) with or without increased insemination concentration, and intracytoplasmic sperm injection. Criteria for the latter are diverse, some centres managing all antibody-positive patients this way, while others resort to it only in severe cases or after other treatments have failed. Half of the respondents occasionally or regularly employ steroids, either alone or in conjunction with IUI or IVF. Overall, it appears that much confusion exists as to how best to manage couples presenting with antibody-related infertility.     

Studies of the coronary circulation in Chagas' heart disease

Pathogenesis of chronic Chagas' heart disease may include various disturbances in the coronary circulation, that could be responsible for the myocardial lesions seen in human hearts and in experimental models of the disease. In this paper we critically reviewed the anatomical and functional abnormalities described in chronic chagasic patients, pertaining to the so-called vascular pathogenetic theory of Chagas' disease. The epicardial coronary arteries are usually free of significant obstructive disease in nonselected groups of chagasic patients examined at autopsy or by coronary angiography. However, chagasic patients who were studied after an episode of acute myocardial infarction, show the same patterns of atherosclerotic coronary artery disease seen in the general nonchagasic population. Studies of chagasic patients with angiographically normal coronary arteries, by several scintigraphy methods, revealed myocardial perfusion abnormalities which may be caused by the microcirculatory derangements described in animals experimentally infected with the T. cruzi. Since hypoperfusion has been detected in regions with normal or mildly impaired wall motion, it is likely that the microvascular disturbances precede and may be causative mechanism for the subsequent myocardial damage. We speculate that hibernating ventricular areas may occur in chagasic patients, on the basis of the evidence gathered from these studies. Recent investigations of chronic patients with Chagas' disease and chest pain showed attenuation of the vasomotor responses to physiological and pharmacological stimuli, in the epicardial coronary arteries.     

A second magnesium ion is critical for ATP binding in the kinase domain of the oncoprotein v-Fps

The activity of the kinase domain of the oncoprotein v-Fps was found to be sensitive to the concentration of magnesium ions. Plots of initial velocity versus free magnesium concentration are hyperbolic and do not extrapolate to the origin at stoichiometric ATP-Mg, indicating that there are two sites for metal chelation on the enzyme and the second is nonessential for catalysis. The second metal is strongly activating and increases the reaction rate constant almost 20-fold from 0.5 to 8.3 s-1 using 0.2 mM ATP-Mg and 1 mM peptide, EAEIYEAIE. This increase in rate is due to a large increase in the apparent affinity of ATP-Mg at high magnesium concentrations. At 0.5 and 10 mM free Mg2+, KATP-Mg is 3.6 and 0.22 mM, respectively. Extrapolation of the observed affinity of ATP-Mg to zero and infinite free metal indicates that KATP-Mg is greater than 8 mM in the absence of the second metal and 0.1 mM in the presence of the second metal, a minimum 80-fold enhancement. By comparison, free levels of the divalent ion do not influence maximum turnover (kcat) and have only a 2-fold effect on the Km for the peptide substrate between 0.5 and 20 mM free Mg2+. Viscosometric studies indicate that free Mg2+ does not influence the rates of phosphoryl transfer or net product release above 0.5 mM but does affect directly the dissociation constant for ATP-Mg. The Kd for ATP-Mg in the absence and presence of the second metal ion is >32 and 0.4 mM, respectively. At high magnesium concentrations, ATP-Mg and the peptide substrate bind independently, while at lower concentrations (0.5 mM), there is significant negative binding synergism suggesting that the second metal may help to reduce charge repulsion between ATP-Mg and the peptide. The data indicate that the first metal is sufficient for phosphoryl transfer. While the second metal could have some influence on phosphoryl transfer or product binding, it is a potent activator that functions minimally by controlling ATP-Mg binding.