Esperanza de vida tras el reemplazo de válvula aórtica en pacientes jóvenes / Life expectancy after aortic valve replacement in young patients

Introducción y objetivos: Se desconoce si los pacientes jóvenes con estenosis aórtica grave tienen una esperanza de vida restaurada tras el reemplazo de la válvula aórtica (RVAo). Métodos: Se incluyó a todos los pacientes entre 50 y 65 años sometidos a RVAo en 27 centros españoles durante 18 años. Se comparó la supervivencia observada y la esperada a los 15 años de seguimiento. Se repitieron todos los análisis con los pacientes sin complicaciones durante el posoperatorio inmediato. Resultados: Se analizó a 5.084 pacientes. En la muestra total, la supervivencia observada a los 10 y los 15 años fue del 85,3% (IC95%, 84,1-86,4%) y el 73,7% (IC95%, 71,6-75,6%). Las supervivencias esperadas fueron del 90,1 y el 82,1%. La supervivencia relativa acumulada a 1, 5, 10 y 15 años de seguimiento fue del 97,4% (IC95%, 96,9-97,9%), el 96,5% (IC95%, 95,7-97,3%), el 94,7% (IC95%, 93,3-95,9%) y el 89,8% (IC95%, 87,3-92,1%). Para los pacientes sin complicaciones, la supervivencia relativa acumulada a 1, 5, 10 y 15 años fue del 100,3% (IC95%, 99,8-100,5%), el 98,9% (IC95% 97,6-99,9%), el 97,3% (IC95%, 94,9-99,4%) y el 91,9% (IC95%, 86,5-96,8%). Conclusiones:La esperanza de vida de los pacientes jóvenes con estenosis aórtica grave intervenidos para RVAo es menor que la de la población general. La esperanza de vida de los pacientes sin complicaciones durante el posoperatorio inmediato también está reducida. Por lo tanto, las características basales probablemente sean los principales factores que explican la reducción de la esperanza de vida (AU)

Introduction and objectives: In young patients with severe aortic stenosis, it is unknown whether their life expectancy restored after aortic valve replacement (AVR) is unknown. Methods: We analyzed all patients aged between 50 and 65 years who underwent isolated AVR in 27 Spanish centers during an 18-year period. We compared observed and expected survival at 15 years of follow-up. We repeated all analyses for patients without complications in the postoperative period. Results: A total of 5084 patients were analyzed. For the overall sample, observed survival at 10 and 15 years was 85.3% (95%CI, 84.1%-86.4%) and 73.7% (95%CI, 71.6%-75.6%), respectively. Expected survival was 90.1% and 82.1%. Cumulative relative survival for 1, 5, 10 and 15 years of follow-up was 97.4% (95%CI, 96.9%-97.9%), 96.5% (95%CI, 95.7%-97.3%), 94.7% (95%CI, 93.3%-95.9%), and 89.8% (95%CI, 87.3%-92.1%). For patients without complications, cumulative relative survival for 1, 5, 10 and 15 years was 100.3% (95%CI, 99.8%-100.5%), 98.9% (95%CI 97.6% -99.9%), 97.3% (95%CI, 94.9%-99.4%), and 91.9% (95%CI, 86.5%-96.8%). Conclusions: Life expectancy in young patients who have severe aortic stenosis and undergo AVR is lower than that of the general population. Life expectancy of individuals without complications during the postoperative period is also reduced. Therefore, baseline characteristics are likely the main factors that explain the reduction in life expectancy (AU)

Association of ATP synthase alpha-chain with neurofibrillary degeneration in Alzheimer's disease.

Amyloid deposits and neurofibrillary tangles (NFT) are the two hallmarks that characterize Alzheimer's disease (AD). In order to find the molecular partners of these degenerating processes, we have developed antibodies against insoluble AD brain lesions. One clone, named AD46, detects only NFT. Biochemical and histochemistry analyses demonstrate that the labeled protein accumulating in the cytosol of Alzheimer degenerating neurons is the alpha-chain of the ATP synthase. The cytosolic accumulation of the alpha-chain of ATP synthase is observed even at early stages of neurofibrillary degenerating process. It is specifically observed in degenerating neurons, either alone or tightly associated with aggregates of tau proteins, suggesting that it is a new molecular event related to neurodegeneration. Overall, our results strongly suggest the implication of the alpha-chain of ATP synthase in neurofibrillary degeneration of AD that is illustrated by the cytosolic accumulation of this mitochondrial protein, which belongs to the mitochondrial respiratory system. This regulatory subunit of the respiratory complex V of mitochondria is thus a potential target for therapeutic and diagnostic strategies.

Platelet activation in thrombotic disorders.

Recent advances have resulted in the elucidation of the principal molecular pathways of platelet function. Parallel studies have led to the identification of glycoprotein antigens whose presence at the platelet surface indicates an activated state. Such markers include GMP-140 and other glycoproteins of intracellular membranes whose translocation requires secretion and fusion of granule membranes with those joined to the surface. Other markers include activation-dependent epitopes on the GP IIb-IIIa complex and adhesive proteins bound to the activated GP IIb-IIIa receptor. Such epitopes can be detected by specific monoclonal antibodies. Quantification of their binding by flow cytometry allows an estimation of epitope expression within the whole platelet population. Our studies are designed to answer the question of whether measuring these epitopes is useful for predicting thrombosis in patients with acute cardiovascular disease. For this, we have examined three states where platelet function may be modified and where the risk of thrombosis and/or bleeding is increased. These include (i) patients with severe burns, (ii) patients who have undergone coronary angioplasty, and (iii) patients receiving fibrinolytic therapy following myocardial infarction. Our results show that activated platelets can be detected in the circulation and that their level reflects the degree of the lesion. Nonetheless, we have as yet failed to show a direct correlation between their presence and a future pathological event.

[Tolerability of tianeptine in 170 patients with depression treated during one year]. / Acceptabilité de la tianeptine chez 170 patients déprimés traités un an.

Tianeptine, a new antidepressant, has a tricyclic molecular structure. Its main biochemical activity consists of an increase in the reuptake of 5 HT both in men and animals, after acute and chronic administration. Tianeptine demonstrated its antidepressive clinical efficacy in several double-blind versus reference drug trials. A multicentre open trial, including depressed patients enabled us to evaluate the safety of tianeptine and to control the maintenance of the therapeutic efficacy in the course of its long-term prescription. Depressed patients included showed a major depressive episode, single (296.22) or recurrent (296.32) without melancholia or psychotic features, or a dysthymic disorder (300.40), according to DSM III criteria. A minimum MADRS score of a least 25, and the informed consent of the patients were required. The dose of tianeptine was 3 tablets per day (12.5 mg/tablet) with the possibility of increasing to 4 or decreasing to 2 tablets per day, depending on the symptomatology. Therapeutic efficacy was evaluated by item 1 and 2 of the Global Clinical Impression (CGI), the Montgomery and Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HARS) and the Hopkins Symptom Check-List (HSCL). Clinical and paraclinical safety were evaluated by CGI item 3, standardized ratings of patients' complaints (CHESS 84), interruption for side effects, evaluation of blood pressure, weight, biological parameters, EKGs. This intermediate evaluation concerns the first 170 depressed patients treated over a one-year period as well as the total group of patients included (n = 447).(ABSTRACT TRUNCATED AT 250 WORDS)

A further insight into the binding of blood clotting factors to membranes.

The active site of factor Xa, labelled with dansylglutamylglycylarginine (DnsEGR) is sensitive to association with Ca2+, factor Va and phospholipids. When bound to factor Va, DnsEGR-factor-Xa does not change the composition of the binding site of factor Va, as shown by fluorescence energy-transfer experiments between the Trp residues of factor Va and pyrene-labelled phospholipids. Prothrombin was cleaved by alpha-chymotrypsin into two parts: N-terminal residues 1-41 (peptide 1-41) containing the gamma-carboxyglutamic acid residues (Gla), and des-(1-41)-prothrombin; their membrane association was investigated. Peptide 1-41 contains the aromatic residues Tyr and Trp in positions 24 and 41, respectively, and is suitable for fluorescence spectroscopy. The absence of fluorescence energy transfer between these residues suggests that they are more than 2.8 nm apart. Binding of Ca2+ and of phospholipids involves essentially the Tyr residue, while the C-terminal characteristics of the Trp residue remain unchanged. The conformational change which takes place on binding does not shorten the distance between Tyr and Trp beyond 2.8 nm. Our conclusion is that peptide 1-41 has an extended conformation. This result is compatible with the disordered character of the Gla region found in the crystalline structure of fragment 1 of prothrombin. Ca2+ induces a greater fluorescence energy transfer between prothrombin and membranes labelled with pyrene but has no influence on the binding of des-(1-41)-prothrombin. Moreover, the binding curves of des(1-41)-prothrombin are similar to those of prothrombin in the absence of Ca2+. It is concluded that the Ca2+-independent association of prothrombin with membranes involves essentially that part of the prothrombin molecule deleted in the Gla region.

[Efficacy and tolerance of alprazolam and bromazepam in flexible doses. Double-blind study in 119 ambulatory anxious patients]. / Efficacité et tolérance de l'alprazolam et du bromazépam à doses ajustables. Etude en double aveugle chez 119 sujets anxieux ambulatoires.

Double-blind study comparing efficacy and safety of alprazolam and bromazepam in 119 ambulatory anxious patients receiving flexible dosage. 119 ambulatory anxious patients (global score on the Hamilton anxiety rating scale between 18 and 35) have been included in this double-blind trial (duration 4 weeks) comparing alprazolam and bromazepam given at flexible dosage. The global score on the Hamilton anxiety rating scale improved by 57.8% and 55.3% for alprazolam and bromazepam respectively. The percentage of therapeutic success according to the psychiatrist and the patient were respectively 82.7% and 79.3% for alprazolam compared to 74.1% and 71.9% for bromazepam. Fewer side-effects were recorded in the alprazolam group (97) than in the bromazepam group (120) and global safety of alprazolam seemed superior (p = 0.07). At trial-end, mean dosage reached 1.70 mg/day for alprazolam and 10.35 mg for bromazepam, but no correlation was found between anxiety intensity and optimal daily dosage used; however, a correlation has been found between the improvement of the overall Hamilton rating scale score and the dosage given (p = 0.02). The overall results suggest that the efficacy/safety ratio is better for alprazolam.

Topology of the binding site of blood-clotting factors in model membranes. A fluorescence study.

Factors II, X and IX are blood-clotting proteins which bind to phospholipid interfaces in the presence of Ca2+ to activate coagulation. The topology of their binding site on the membrane was investigated in two ways. First, the transition temperature changes of equimolar mixtures of dipalmitoylglycerophosphocholine/phosphatidylserine and dimyristoylglycerophosphocholine/dipalmitoylglycerophosphoserin e were examined by the fluorescence polarization of 1,6-diphenylhexatriene. Results show that Ca2+ triggers a shift of about 3-4 degrees C and that blood-clotting factors further increase this shift by about 1.5 degree C. This suggests that in the gel phase, Ca2+ induces some aggregation of the phosphatidylserine molecules which is reinforced by blood proteins. Second, isothermal energy transfer experiments were performed with natural lipids in their fluid phase. The tryptophan residues of the factors were the energy donors, and pyrene covalently bound to a fatty acid chain of either phosphatidylcholine or phosphatidic acid was the energy acceptor. These pyrene-phospholipids probe either the neutral or the acidic component of phospholipid mixtures. It is concluded that the binding sites of the factors are constituted by both types of lipids and that their composition depends on the membrane. Factor II exhibits some specificity for acidic phospholipids and seems to be surrounded by non-interacting zwitterionic lipids. Factor IX appears to be surrounded by statistically the same amount of charged and zwitterionic lipids. We also demonstrate that binding can also occur without Ca2+. This Ca2+-independent binding probably involves electrostatic and hydrophobic forces but its physiological significance remains to be elucidated.

[Clinical and therapeutic approach to anxiety-depression syndromes. Effectiveness of bromazepam (author's transl)]. / Approche clinique et thérapeutique des syndromes anxio-dépressifs. Intérêt du bromazépam.

In anxiety-depression syndromes intricacy of the symptoms is such that the relative importance of the two components must be assessed for adequate treatment with anxiolytic and/or antidepressant drugs. The anxiolytic activity of bromazepam was evaluated in 30 patients with anxiety-depression syndrome. A tricyclic antidepressant was added in cases with marked disorders in mood. Results were assessed by means of the Hamilton and Pull-Guelfi scales and Beaumont's self-evaluation scores. Fourteen patients were treated with bromazepam alone in doses adjusted to the therapeutic response, and 16 patients received both bromazepam showed rapid and consistent anxiolytic activity, except in 4 cases which required adjunction of an antidepressant. The drug was well tolerated, provided individual susceptibilities were taken into consideration.

Snake venom phospholipases A2. A fluorescence study of their binding to phospholipid vesicles correlation with their anticoagulant activities.

The interaction of snake venom phospholipases A2 with phospholipids has been studied by intrinsic fluorescence. This has been performed in order to understand why some enzymes possess anticoagulant properties while others have no action on blood clotting. We show that phospholipases A2 can be distinguished according to their binding properties to phospholipid vesicles. Strong inhibitors of coagulation interact with phospholipids with a significant change of their fluorescence while poor inhibitors have little or no effect. Strong inhibitors have a great affinity toward phosphatidylserine and do not require Ca2+ for interaction. Similar results are obtained with phosphatidylcholine-phosphatidylserine 1:1 mixtures. The diether analogue of phosphatidylcholine shows that formation of the complex is promoted by Ca2+ and can occur whenever the lipids are in crystal or fluid phase. Inactivation of anticoagulant phospholipase A2 decreased the affinity of enzyme for the phospholipids. The change in the intrinsic fluorescence of the phospholipases A2 on binding indicates a modification of the environment of the tryptophan residues. This is discussed in terms of the so-called interface recognition site as seen in the case of pancreatic phospholipase A2. It is concluded that the phospholipases may inhibit coagulation by competing with clotting proteins for the lipid surface. Although not considered in this study, the consequence of the hydrolysis of lipids remains to be estimated.

[Cesium]. / Le cesium.

Cesium is an alkaline metal close to Rubidium, which is studied in psychopharmacology in the prospect of a possible antidepressive effect. It has stimulating properties of the motor activity on the animal, antagonizes some sedative substances but does not modify either self-stimulation behaviour or induced agressivity. Given in large doses, Cesium presents hypertensive effects bound with a stimulation of the adrenal Epinephrine secretion. As for the synapses Cesium increases the neuro-transmitter release. However the Norepinephrine turn-over is not modified in the central nervous system while that of Serotonin is increased as well as the cerebral concentrations of Tryptophan, Serotonin and 5.HIAA. These very fragmentary data about the toxico-pharmacological properties of Cesium, as well as the very prolonged half-life of this ion (from 50 to 100 days), explain that contrary to Rubidium it has not still been used in man.

[A new synthetic antiparkinsonian drug, tropatepine hydrochloride in extrapyramidal syndromes induced by neuroleptics]. / Un nouvel antiparkinsonien de synthèse le chlorhydrate de tropatépine dans les syndromes extrapyramidaux induits par les neuroleptiques

Tropatepine hydrochloride was given per oral route to 184 patients and per injections to 34 patients. Average prescribed doses were about 20 mg (2 tablets). This clinical study has shown that tropatepine hydrochloride has an antiparkinson activity against neuroleptic-induced extra-pyramidal syndrome. In comparison to the activity of the other synthetic antiparkinson drugs, the activity of tropatepine hydrochloride is: -- similar on akineto-hypertonia and on tremor; -- better on akathisia and, though less frequently, on anormal dyskinetic movements due to long term neuroleptic treatment. Tolerance is good ; furthermore clinical and biological performed examinations have shown that the drug seems free of toxic effects In more than 200 treated patients no severe mental aberration and no habituation have been reported.