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Background: Age-related macular degeneration is the primary cause of blindness in developed countries. Current treatments of this degenerative disease mainly include laser, photodynamic therapy with verteporfin and administration of anti-vascular endothelial growth factors. The LUEUR (LUcentis® En Utilisation Réelle) study is composed of a cross-sectional part (LUEUR1), which examined the current management of wet AMD in France, and a follow-up part (LUEUR2), which will assess the development of patients treated for wet AMD over 4 years. Here we describe the results of LUEUR1., Methods: Patients with wet AMD were enrolled during a routine medical examination in LUEUR1, a cross-sectional, observational, prospective, multicentre study. Investigators recorded patient demographics, visual acuity, characteristics of wet AMD lesions, date of AMD diagnosis, comorbidities, previous treatments, treatments prescribed at inclusion, and low vision rehabilitation., Results: A total of 72 investigators recruited 1,019 patients with wet AMD, corresponding to 1,405 eyes affected by the disease. The mean age of patients was 78.7 ± 7.3 years. Most were female (62.3%) and non-smokers (66.9%). The mean visual acuity was 49.12 ± 24.18 Early Treatment Diabetic Retinopathy Study letters. Most eyes showed occult (52.8%) and subfoveal (84.6%) choroidal neovascularisation. Bilateral wet AMD affected 37.9% of patients. The median time since diagnosis was 12 months. Ranibizumab-based therapy (67.3%) and photodynamic therapy (29.8%) were the most frequent previous treatments. Prior to inclusion, 5.6% of patients had low vision rehabilitation. When a treatment was prescribed on the day of inclusion, it was most often ranibizumab (89.0% of all treatments at inclusion)., Conclusions: The results of this study illustrate the impact of anti-vascular endothelial growth factor therapies on the treatment of wet AMD in a real-life context. Specifically, ranibizumab-based therapy appears to have largely replaced laser photocoagulation and verteporfin-based photodynamic therapy.

Objective: We tested whether determination of the ACE insertion/deletion polymorphism is useful for renal and cardiovascular prognoses of type 2 diabetic subjects., Research Design and Methods: The French participants (3,126 of 4,912) in the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) trial were studied for their prognosis over 4 years according to their ACE insertion/deletion polymorphism. We used two cohorts of French type 2 diabetic patients for replication: a 3-year follow-up study (n = 917; Survie, Diabete de type 2 et Genetique [SURDIAGENE] study) and a case-control study on diabetic nephropathy (n = 1,277; Diabete de type 2, Nephropathie et Genetique [DIAB2NEPHROGENE] study). We investigated the effect of the insertion/deletion polymorphism on the primary outcome in the DIABHYCAR trial (defined as the first of the following events to occur: cardiovascular death, nonfatal myocardial infarction, stroke, heart failure leading to hospital admission, or end-stage renal failure) and its components., Results: In DIABHYCAR, the primary outcome and most of its components were not affected by the ACE insertion/deletion genotype. Only renal outcome was favored by the I allele (P = 0.03). The risk of myocardial infarction was not affected by ACE genotype, but the probability of fatal outcome increased with the number of D alleles (P < 0.03). In SURDIAGENE, the association between the ACE I allele and renal outcome was not replicated. In DIAB2NEPHROGENE, no association was found with nephropathy., Conclusions: We were not able to demonstrate the manifest usefulness of the ACE insertion/deletion polymorphism for the prognosis of type 2 diabetic subjects.

What is the place of fish oils in the care of coronary heart disease (CHD) patients? As several clinical trials have already addressed this question without giving definitive answers, we did a meta-analysis of trials regarding the efficacy of omega-3 fatty acids in preventing cardiovascular mortality and morbidity. We searched the MEDLINE (1966-2003), EMBASE databases, proceedings abstracts and references of reviewed articles. Randomized controlled trials (RCTs) of the efficacy of omega-3 fatty acids among adults with recent or acute myocardial infarction (MI), or angina were selected. Two reviewers abstracted data independently. Five relevant outcomes, mortality from all causes, fatal and non-fatal MI, non-fatal stroke and angina, were measured. Data were synthesized using a fixed effect model. Ten RCTs with 14,727 patients were included. No significant heterogeneity was detected. Daily intake of omega-3 fatty acids for a mean duration of 37 months decreased all causes of mortality by 16% (relative risk 0.84, 95% confidence interval [0.76; 0.94]) and the incidence of death due to MI by 24% (0.76, [0.66; 0.88]). No significant effect was found for the other outcomes. Because of the suboptimal quality of the studies included into the meta-analysis and the absence of data in patients receiving statins, these results do not justify adding fish oils systematically to the heavy pharmaceutical assortment already recommended in CHD patients.

A survey network for congenital toxoplasmosis (TOXO-NET) was set up in December 1996 in Piedmont (Italy). Participants were asked to classify the infections in pregnant mothers and newborns by the criteria of the European Network on Congenital Toxoplasmosis published by Lebech in 1996. Because the IgG Avidity test is largely employed as a 2nd level test in toxoplasmosis diagnosis and it could be helpful to date infection, the co-ordinators of TOXO-NET suggested including it in the "case definition" of "probable" infection and "unlikely" infection. 117 cases of toxoplasmosis in pregnancy divided into the risk categories under Lebech's criteria were re-examined using the "new" case definitions. 77 out of 117 (65.8%) Toxoplasma gondii infections during pregnancy could be defined with only one serum sample using the IgG Avidity test. The IgG Avidity test proved a useful method to classify the Toxoplasma gondii infections in pregnancy, especially when we had only one serum sample.

In Italy, the management of Toxoplasma infection screening in pregnant women is often unproductive and inefficient and generates a wide variability of costs. This study evaluated performance parameters in the screening management of a population of pregnant women, estimated its costs and compared them with the costs of a full application of Ministerial Documents of 1995 and 1998. We controlled until delivery 830 pregnant women who had done the first blood test between September 1st and December 31st 1997. The costs of direct and indirect testing were analysed using the Excel database and statistical software package. Of the 573 pregnant women defined 'susceptible' at the first test, only 240 (42%) did further blood tests during the II and III trimesters, 30% did no more tests and the remaining women adopted a heterogeneous behaviour. The mean cost of each screening was found to be euro 54.47/pregnancy and euro 60.05/pregnancy with a full application of the Ministerial Document of 1995. A full application of Ministerial Document of 1998, instead, would have involved a cost of euro 94.28/pregnancy for 5 tests, euro 111.40/pregnancy for 6 tests and euro 128.51 for 7 tests. The study shows that the management of toxoplasmosis screening during pregnancy needs greater attention to the prescription of tests, so that useless testing can be reduced and the efficacy of the screening improved, two important goals the Ministerial Documents were designed to achieve.

Aims: Family-based studies suggest a genetic basis for nephropathy in Type 2 diabetes. The angiotensin-I-converting enzyme (ACE) gene is a candidate gene for Type 1 diabetes nephropathy. We assessed the association between high urinary albumin concentration and ACE insertion/deletion (I/D) polymorphism, in French Type 2 diabetes patients., Methods: We studied 3139 micro/macroalbuminuric French patients recruited in the DIABHYCAR Study, an ACE inhibition trial in Type 2 diabetes patients with renal and cardiovascular outcomes. The main inclusion criteria were age >/= 50 years, urinary albumin concentration >/= 20 mg/l assessed centrally during two consecutive screening visits, and plasma creatinine concentration

Objective: The DIABHYCAR (type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril) study allowed investigators to analyze factors leading to the development of congestive heart failure (CHF) in type 2 diabetic patients with abnormal urinary albumin concentration., Research Design and Methods: Type 2 diabetic subjects of both sexes aged >or=50 years who had a urinary albumin concentration >or=20 mg/l were randomly allocated to 1.25 mg/day ramipril or placebo in addition to their usual treatment and treated for 3-6 years in a double-blind fashion. Major outcomes including hospitalization for CHF were recorded during the follow-up., Results: Of the 4912 included patients, 187 developed CHF during the study. There was no significant difference in the incidence of CHF between the two treatment groups. Using a multivariate analysis, independent risk factors for the occurrence of CHF were age, history of cardiovascular disease, baseline urinary albumin concentration, baseline HbA(1c), and smoking habits. A total of 68 of the 187 patients (36.4%) died during the 12 +/- 11-month period after the first hospitalization for CHF, whereas the annual mortality rate of the population who did not develop CHF was 3.2%., Conclusions: Presence of atherosclerotic disease, baseline urinary albumin concentration, and HbA(1c) level were indicators for further development of CHF. Occurrence of CHF is a major prognostic turn in a diabetic patient's life.

Arterial stiffness is a strong determinant of cardiovascular risk. Pulse wave velocity (PWV) is an index of arterial stiffness, and its prognostic value has been repeatedly emphasized. The purpose of the present study was to assess the effect of heart rate (HR) on PWV. Twenty-two subjects with a mean age of 77.8+/-8.4 (SD) years and permanent cardiac pacing were studied. In each subject, PWV was measured at 5 different pacing frequencies in the same session (60, 70, 80, 90, 100 bpm), the order of the various frequencies being randomly determined. Furthermore, to test the reproducibility, a repeat measurement of PWV was obtained in one randomly selected frequency. Blood pressure (BP) was measured by conventional means at each pacing frequency. PWV appeared fairly reproducible because no significant difference was disclosed between the 2 measurements obtained at the same HR level (P=0.5) and both measurements were strongly correlated (r=0.87, P<0.001). No significant BP variation was observed during pacing. There was a highly significant effect of HR on PWV estimated by a one-way, within-subjects analysis of variance (P=0.01). This study demonstrates that HR is an important factor in the intraindividual variation of PWV in elderly subjects. This raises methodological concern about the measurement of this parameter. Standardizing PWV for HR level seems mandatory if one wants to interpret PWV changes in clinical trials or in the follow-up of patients.

Purpose: The aim was to investigate in patients receiving doxorubicin whether any alteration in myocardial oxidative metabolism or blood flow as assessed by positron emission tomography (PET) could be observed either after the first dose of the drug, or during its chronic administration., Methods: Six female non-heart-failure cancer patients treated with doxorubicin were included in a longitudinal study. Resting radionuclide cineangiography and PET scanning with carbon-11 acetate were performed the day before the initiation of doxorubicin treatment at a dosage of 50 mg/m2 every 3 weeks, and 3 weeks after the cumulative administration of 300 mg/m2 (chronic toxicity). In addition, PET was performed 24 h after the first administration of doxorubicin (evaluation of acute toxicity). Myocardial oxidative metabolism and blood flow were assessed by PET (acute and chronic toxicity), and left ventricular ejection fraction was measured by radionuclide angiography (chronic toxicity)., Results: Using PET for both acute and chronic toxicity evaluations, no significant effect of doxorubicin was observed either on the flux through the tricarboxylic acid (TCA) cycle or on myocardial blood flow. However, systolic left ventricular function showed a small but significant impairment after the administration of 300 mg/m2 of doxorubicin., Conclusions: Other hypotheses should be explored to better explain the predominant mechanisms of the cardiotoxicity of anthracyclines in humans.

We compared the efficacy and safety of three doses of beraprost sodium, an epoprostenol analogue, with placebo in the treatment of intermittent claudication (Fontaine's stage II). One hundred sixty-four patients were randomized to receive either placebo, 20 micrograms beraprost sodium (BPS60 group), 40 micrograms beraprost sodium (BPS120 group), or 60 micrograms beraprost sodium (BPS180 group) three times daily administered orally in a double-blind manner for 12 weeks. Treadmill exercise tests were performed twice during an initial selection phase (D-28 and D0) at week 10 (at trough beraprost concentration) and week 12 (at peak beraprost concentration) of the treatment phase. At week 10, all groups showed an increase in pain-free walking distance, and this distance was greatest in the BPS60 and BPS120 groups (p = 0.055). At week 12, a similar pattern was observed, and the difference was significant between the groups (p = 0.023). The most frequent adverse events reported were gastrointestinal disorders, headaches, skin disorders, and flushes. Patients who received either 60 or 120 micrograms of beraprost sodium daily had an increased pain-free walking distance. Further studies are required to investigate why the highest dose used (180 micrograms daily) showed lower efficacy. Having both vasodilating and antiplatelet properties and being able to increase pain-free walking distance in the short term, beraprost sodium is a promising drug for the treatment of intermittent claudication.

An effect model is a function that defines the relationship between the clinical efficacy of a treatment and specific covariates. The simplest effect model defines the probability of failure in treated patients as a linear function of the probability for these patients if they received no treatment. We used this approach to explore the effects of Class I antiarrhythmic agents in patients after myocardial infarction. Evidence from one large trial, the Cardiac Arrhythmic Suppression Trial (CAST), and the pooling of data from several smaller trials suggests that these agents have harmful effects in postmyocardial infarction patients. The relevance of results from pooled data is dependent on the homogeneity of the trials and is assessed by a heterogeneity test that is dependent on the analytical method used, i.e., odds ratio or rate difference methods, which correspond to two different effect models. We have developed an effect model that considers both iatrogenic effects of these drugs, i.e., depression of ventricular function and arrhythmogenic effects. When applied to the data from 13 published trials (including CAST), we found that these drugs may be beneficial in high-risk patients (with a 1-year mortality rate of > or = 15%) and that the background lethal iatrogenic effect is likely to affect low- and very low-risk patients (1-year mortality rate of < or = 5%). The accuracy of the proposed model was confirmed with use of the results from the recent CAST II study.

The effects of diltiazem, a new slow channel inhibitor, on the cardiac conduction and refractoriness have been studied using His bundle recordings and the extrastimulus method. In order to determine the role played by possible changes in vagal tone, diltiazem (0.15 mg.kg-1, followed immediately by a 30 min infusion of 0.01 mg.kg-1.min-1) has been administered intravenously to six atropinized dogs, anesthetized with chloralose (100 mg.kg-1) ("atropine group") and to six others which were given chloralose (80 mg.kg-1) and dextromoramide (0.1 mg.kg-1) to ensure the persistence of vagal tone ("vagal tone group"). In the "atropine group", atrioventricular (AV) nodal conduction time increased by 137% and AV node effective refractory period by 55%. Heart rate was slowed down by 15% and arterial pressure fell slightly. In the "vagal tone group", the only significant changes were a 26% increase in AV nodal conduction time and a slight fall in arterial pressure. Inhibition of the slow channel accounts for the effects of diltiazem within the "atropine group". A reflex decrease in vagal tone is probably responsible for the somewhat different results observed in the "vagal tone group". Diltiazem resembles verapamil and should share its antiarrhythmic properties.

Effects of mild hyperkalemia on conduction velocity, effective refractory periods (ERPs) and sinus rate were studied on 16 anesthetized dogs, using endocavitary His bundle recordings, the extrastimulus method and standard electrocardiogram. Six dogs were placed under acetylcholine infusion (300 micrograms/kg/min) (ACh group), 10 received atropine sulfate 0.2 mg/kg intravenously (atropine group). Intraventricular conduction time, ventricular ERP and QRS duration of the EKG were studied on 7 other open-chested dogs (ventricular group). During a 60 min potassium chloride infusion (0.025 mmol/kg/min, 30 min, then 0.05 mmol/kg/min, 30 min), following observations were made: - In the ACh group, AV node conduction time (A-H interval) decreased by 20% and AV node ERP by 17%, whereas, in the atropine group, the former parameter was not affected and atrial ERP increased by 29%. - At the same time, sinus rate increased in the ACh group and was unaffected in the atropine group. - Conduction times in atrial contractile tissue (S-A interval), His-Purkinje system (H-V interval) and ventricular contractile tissue, like ventricular ERP, exhibited no variation or very slight, occasionally biphasic variations under both conditions. These results can be accounted for by an "anticholinergic" effect of mild hyperkalemia which is discussed.

The cerebral vasodilatory effect of 10-methoxy-1,6-dimethyl-ergoline-8 beta-methanol-(5-bromonicotinate) (nicergoline, Sermion) was examined by recording the cardiac output of the vertebral artery in the dog. As from a dosage of 25 micrograms/kg nicergoline increases permanently the cardiac output to a normal or nearly normal level which had been decreased by phenylephrine reducing the increased local vascular resistance. The alpha-sympatholytical properties of nicergoline were more precisely proved by reducing the reactive increase in blood pressure after epinephrine and norepinephrine (3 micrograms/kg) by administration of nicergoline in 3 doses (25, 50 and 100 micrograms/kg). The same method was used with phentalamine in dosages of 125, 250 and 500 micrograms/kg. The statistical comparison of the results obtained with both substances shows that the ratio of equiactive doses is about 3:1 in favour of nicergoline.

Theophylline-induced variations of cardiac metabolism have been investigated by determining concentrations of various energetic substrates and of high-energy phosphates in myocardial tissue, the repeated sampling of myocardium being made possible by an extracorporal circulation system. When administered in therapeutic, or even slightly higher doses, theophylline does not modify triglyceride, glycerol and free fatty acid content or phosphocreatine and ATP content in subepicardial and subendocardial layers, but it does lower glycogen and raise lactate concentration. Consequently, the changes in anaerobic glycolysis due to myocardial ischemia may be enhanced if, as is probably the case, theophylline fails to restore the supply of oxygen.

The effect of levomepromazine on sinusal automaticity, myocardial excitability and auriculoventricular conduction have been studied in dogs by measuring the spontaneous heart rate, the effective refractory period of the conduction system, the time of auriculonodal and infrahisian conduction. Chloralose-anaesthetized dogs were administered 5 mg/kg levomepromazine via IV route and 10 mg/kg one hour later. While sinusal automaticity is never altered, the other parameters studied were modified only when high doses were used. Therefore these quinidine-like effects are very unlikely to come up even following suicidal massive ingestion of levomepromazine.