The screening of Alzheimer's patients with CSF biomarkers, modulates the distribution of APOE genotype: impact on clinical trials.

Polymorphism of the apolipoprotein E gene (APOE) plays a role in the level of neuropathological lesions and in drug response in Alzheimer's disease (AD). The aim of this study was to investigate whether the selection of AD patients based on cerebrospinal fluid (CSF) biomarkers assessment may be biased by their APOE distribution. We studied the relationships between APOE genotype and CSF biomarkers levels in a total of 432 patients (AD, n = 244; non-AD, n = 188) explored for cognitive disorders.

Cerebrospinal fluid PKR level predicts cognitive decline in Alzheimer's disease.

The cerebrospinal fluid (CSF) levels of the proapoptotic kinase R (PKR) and its phosphorylated PKR (pPKR) are increased in Alzheimer's disease (AD), but whether CSF PKR concentrations are associated with cognitive decline in AD patients remain unknown. In this study, 41 consecutive patients with AD and 11 patients with amnestic mild cognitive impairment (aMCI) from our Memory Clinic were included. A lumbar puncture was performed during the following month of the clinical diagnosis and Mini-Mental State Examination (MMSE) evaluations were repeated every 6 months during a mean follow-up of 2 years.

Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score.

Objectives: Previous studies in HIV-infected populations have yielded conflicting results on the effect of antiretroviral therapy (ART) on cognition. Our objective was to investigate the effect of several years of ART with stable central nervous system penetration effectiveness (CPE) score on neuropsychological performance in HIV-infected individuals.

Methods: We analysed a clinical cohort of HIV-infected patients who initiated ART between June 2003 and December 2006 and maintained stable CPE scores.

Increased cerebrospinal fluid levels of double-stranded RNA-dependant protein kinase in Alzheimer's disease.

Background: The pathological hallmarks of Alzheimer's disease (AD) include accumulation of amyloid-β (Aß) peptide forming extracellular senile plaques, neurofibrillary tangles made of hyperphosphorylated tau protein with neuronal loss. Aβ peptide (1-42), total tau (T-tau), and phosphorylated tau at threonine 181 (p181tau) levels in the cerebrospinal fluid (CSF) are now validated biomarkers. The proapoptotic kinase R (PKR), is activated by Aβ accumulates in degenerating neurons in AD brains and controls protein synthesis and indirectly tau phosphorylation.

Practice of contemporary dance improves cognitive flexibility in aging.

As society ages and frequency of dementia increases exponentially, counteracting cognitive aging decline is a challenging issue for countries of the developed world. Previous studies have suggested that physical fitness based on cardiovascular and strength training helps to improve attentional control in normal aging. However, how motor activity based on motor-skill learning can also benefit attentional control with age has been hitherto a neglected issue.

CSF Aβ₁₋₄₂ levels and glucose metabolism in Alzheimer's disease.

Glucose dysmetabolism has been consistently associated with an increased risk of cognitive disorders, and brain insulin resistance could play a role in Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We have investigated the relationship between CSF concentrations of amyloid-β peptide 1-42 (Aβ₁₋₄₂), total tau, and phosphorylated tau (ptau-181) and plasma and CSF glucose levels in a cohort of 94 newly diagnosed non-diabetics AD patients.

Effects of low density and high density lipoproteins isolated from non-insulin dependent diabetic patients on prostaglandin secretion by mouse macrophage cell line P388D1.

We have previously shown that low-density (LDL) and high-density (HDL) lipoprotein from healthy subjects can promote in vitro prostaglandin (PG) release by murine macrophages. In this pilot study, we have measured PG production induced by lipoproteins of six diabetic patients with poor metabolic control, compared to five healthy controls. Plasma lipoprotein levels were similar in both groups.

Distribution of salicylate in pigmented rabbit ocular tissues after application of a prodrug, sodium monomethyl trisilanol orthohydroxybenzoate: in vivo and ex vivo studies.

SMB (sodium monomethyl trisilanol orthohydroxybenzoate) is an organic complex of silicium and salicylate and the main component of a collyrium used in lens transparency abnormalities. Biotransformation and penetration of salicylate in the whole eyeball have been investigated in vivo after repeated instillations of those 14C-radiolabeled eyedrops. We also studied more accurately the salicylate diffusion within the lens under ex vivo conditions.

Inhibition of preretinal proliferation by free radical scavengers in an experimental model of tractional retinal detachment.

An original model of experimental proliferative vitreoretinopathy consisting of an intravitreal injection of 10(7) human platelets and 1 IU of hyaluronidase was developed in pigmented rabbits. One group of 11 eyes served as non-treated controls. Two other groups of 11 eyes each received Ginkgo Biloba extracts which are known free radical scavengers (EGb761, Ipsen, France), given orally in two doses, 50 mg kg-1 day-1 and 100 mg kg-1 day-1 respectively, from the day after the platelet injection to the end of the first month.

Toxicologic and pharmacokinetic analysis of intravitreal injections of foscarnet, either alone or in combination with ganciclovir.

Purpose: The retinal toxicity of single and repeated intravitreal injections of foscarnet was investigated. In addition, the effects of a combination of foscarnet and ganciclovir were studied, and a pharmacokinetic study to determine the ocular pharmacokinetics of foscarnet after intravitreal injection was carried out.

Methods: Forty rabbits (both albino and pigmented) were used in this study.

Central nervous system control of intraocular pressure.

Normal intraocular pressure (IOP) is the result of an equilibrium between aqueous humor (AH) production, AH outflow and episcleral venous pressure. Most available antiglaucoma agents produce their effects by interacting with autonomic mechanisms (beta-blockers, epinephrine or parasympathomimetics). In contrast, the role of the central nervous system (brain and nerves) in the regulation of IOP remains unclear in view of the complex haemodynamic, metabolic or hormonal changes which occur under experimental conditions.

Drugs designed to maintain the transparence of the ocular lens.

Research into the biological basis of lens transparency has demonstrated the implication of lens sugar stress in the diabetic cataract whereas senile cataract is the result of natural degeneration which is enhanced by various external factors such as cosmic and ionizing rays, or oxidative processes. Drugs have been developed which are aimed at being effective on lens pathological physiology and metabolism, concurrently. Such molecules: aldose reductase inhibitors (ARIs: sorbinil, AD-5467, CT-112 and imirestat), acetyl salicylic acid (ASA), salicylate (SA) and sodium monomethyl trisilanol orthohydroxybenzoate (SMB, a prodrug for salicylate) have undergone pharmacodynamic, pharmacokinetic and/or clinical studies which are presented here.

Effect of human native low-density and high-density lipoproteins on prostaglandin production by mouse macrophage cell line P388D1: possible implications in pathogenesis of atherosclerosis.

Macrophages have been shown to play a key-role in the development of atherosclerotic lesions. Monocyte attraction and activation in the arterial wall lead to foam cell formation, cholesterol accumulation and secretion of inflammation mediators. Among macrophage secretions, prostacyclin and thromboxane are prostaglandins involved in the regulation of coagulation and vascular permeability.

Growth factors in vitreous and subretinal fluid cells from patients with proliferative vitreoretinopathy.

Mechanisms accounting for the development of proliferative vitreoretinopathy (PVR) in patients with rhegmatogenous retinal detachment remain poorly understood. In a previous study, we found the presence of various growth factors in preretinal membranes that were surgically removed from patients with PVR. The present immunohistological study was undertaken in intravitreal and subretinal fluid cells from patients suffering from PVR in various stages of development, in order to seek the presence of 4 growth-promoting factors for retinal pigment epithelial cells: acidic fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin-like growth factor type I (IGF-I) and transforming growth factor-beta (TGF-beta).

Physiological roles of dopamine and neuropeptides in the retina.

The retina is a highly complex nervous tissue that converts light into patterns of electrical action potentials in order to process visual information. To carry out its function as a transducer and processor of visual information, the retina must be structurally and biochemically organized to send a coherent signal to the visual areas of the brain. In recent years, a number of biologically active substances have been demonstrated to be located within neurons in the retina.

Clinical pharmacology of nicardipine in liver transplant patients.

Slow calcium channel antagonists are widely used among transplanted patients suffering from hypertension, although some of them tend to reduce hepatic blood flow. The aim of our study was to determine the pharmacological properties of nicardipine in transplanted patients with hypertension. Ten hours after liver transplantation, six patients (three men, three women) received 5 mg of intravenous nicardipine to prevent high blood pressure during intensive care.

MHC class II antigen expression by ocular cells in proliferative diabetic retinopathy.

An immunohistological study was performed on ciliary biopsies of the pars plana obtained surgically in 10 patients suffering from diabetic retinopathy and on 15 surgical specimens of pre-retinal neovascularized membranes. Using immunofluorescence and immunoperoxidase procedures, linear deposits of IgG, IgA and complement components were found in the 8 pars plana from patients with proliferative diabetic retinopathy, at the basal pole of the pigment epithelial cells and within the stroma. In contrast, these deposits were absent from normal pars plana and from the cases of background retinopathy.

Is verapamil also a non-selective beta blocker?

Verapamil is a calcium channel blocker widely used as an antihypertensive agent, and its pharmacological effects may partly be due to some degree of beta blockade. In order to evaluate the changes occurring in beta-2 adrenoceptor density, 40 patients with mild to moderate hypertension received verapamil 240 mg (once a day) or captopril 20 mg (twice a day) during 30 days, in a double-blind randomized study, after a placebo run-in period. The lymphocytic membrane beta-2 adrenoceptor density (Bmax) was determined before the administration of active drugs and after a 15-day treatment.

[Evaluation of anti-atheromatous properties of calcium channel inhibitors].

Calcium is involved in several biochemical atherogenesis processes and its activity is antagonised in cell and animal experimental models by all classes of slow channel calcium inhibitors. However, the doses required in animals to slow the development of atherosclerotic lesions are above therapeutically acceptable doses in man. The clinical relevance of their anti-atherosclerotic activity in the few clinical studies undertaken is difficult to assess because of the variable criteria of judgment used.

[Gingival hyperplasia secondary to the use of calcium antagonists: analysis].

Calcium antagonists are drugs restricting transmembrane calcium delivery. They possess a wide range of action against vasoconstriction and spastic reactions and were therefore initially recommended for the treatment of angina pectoris. With the increasing number and classes of calcium antagonists new therapeutic indications have emerged.

Retinal dopaminergic receptor affinity and ocular pharmacokinetic profile of piribedil.

Binding studies on retinal dopamine receptors have revealed the existence of both D1 and D2 receptors. Human retina micro-autoradiographs confirm the distribution of dopaminergic receptors in the plexiform layers. Piribedil, a dopaminergic agonist, is able to bind to D2 receptors, while its metabolite (S584) preferentially displaces D1-specific radioligands.

Placebo effect in cardiovascular clinical pharmacology.

A placebo is a pharmacologically inactive substance that can have a therapeutic effect if administered to a patient who believes that he or she is receiving an effective treatment. It is generally admitted that the placebo effect decreases blood pressure in 20% to 30%, when evaluated by casual sphygmomanometer or ambulatory systems. In order to evaluate the occurrence of a placebo effect in cardiovascular pharmacology, we analysed two studies.

Immunohistological study of subretinal membranes in age-related macular degeneration.

An immunohistological study was performed on 6 specimens of subretinal membranes obtained surgically from patients suffering from age-related disciform macular degeneration. using immunoperoxidase procedures, we found in those membranes large amounts of IgG, IgA and IgE as well as C1q, C3c and C3d complement components diffusely distributed in the connective stroma and within the new blood vessel walls. Moreover, subretinal membranes contained numerous isolated HLA-DR- and -DQ-expressing cells, including glial, pigment epithelial and vascular endothelial cells.