David Tarasi

Atrial Natriuretic Peptide Gene Polymorphisms and Risk of Ischemic Stroke in Humans

Background and Purpose— A precise definition of genetic factors responsible for common forms of stroke is still lacking. The purpose of the present study was to investigate the contributory role of the genes encoding atrial natriuretic peptide (ANP) and type A natriuretic peptide receptor (NPRA) in humans’ susceptibility to develop ischemic stroke. Methods— Allele and genotype frequencies of ANP and NPRA were characterized in an Italian case-control study with patients affected by vascular disease or risk factors. Subjects were recruited from the island of Sardinia (206 cases, 236 controls). Results— A significant association between the ANP/TC2238 polymorphic site and stroke occurrence was found when a recessive model of inheritance was assumed. The risk conferred by this mutant genotype, when estimated by multivariate logistic regression analysis, was 3.8 (95% confidence interval, 1.4 to 10.9). A significantly increased risk of stroke recurrence was observed among cases carrying the ANP/CC2238 genotype compared with cases carrying the ANP/TT2238 genotype (P =0.04). No direct association of NPRA with stroke occurrence was detected. However, a significant epistatic interaction between the ANP/CC2238 genotype and an allelic variant of NPRA led to a 5.5-fold increased risk of stroke (95% confidence interval, 1.5 to 19.4). Conclusions— Our findings support a direct contributory role of ANP to stroke in humans. A significant interaction between ANP and NPRA on stroke occurrence was found.

The renin-angiotensin system as a risk factor and therapeutic target for cardiovascular and renal disease

The renin-angiotensin system (RAS) plays an important homeostatic role in BP regulation, water and salt balance, and tissue growth control under physiologic conditions. On the other hand, a pivotal involvement of the RAS in the pathophysiology of cardiovascular and renal disease is extensively supported by both basic and clinical evidence. In particular, it is today recognized that angiotensin II (AngII), the biologic effector of the RAS, may prompt a number of relevant structural and functional abnormalities through the activation of a complex of cellular effects mostly mediated via its binding with the AT(1) subtype receptors. The key role of these AngII-linked mechanisms of disease is strongly corroborated by large interventional studies. In fact, pharmacologic interference with RAS activity, by both preventing AngII formation with angiotensin-converting enzyme inhibitors or antagonizing its binding to cell membrane receptors by selective antagonists, is associated with highly beneficial outcomes in major disease conditions (hypertension, diabetes, renal failure, heart failure, myocardial infarction, stroke, and others). This article briefly reviews the current views on the biologic organization of RAS evidence supporting a pathogenic role of the RAS activity in promoting cardiac, vascular, and renal disease, and finally provides the basis for considering inhibition of RAS activity a major target for therapeutic interventions in these conditions.

Activity of moxifloxacin in combination with vancomycin or teicoplanin against Staphylococcus aureus isolated from device-associated infections unresponsive to glycopeptide therapy

Abstract We tested the in vitro bactericidal activity of moxifloxacin, a new 8-methoxyquinolone, alone and in combination with vancomycin or teicoplanin at different multiples of minimum inhibitory concentration (MIC) against 8 methicillin-ciprofloxacin-resistant Staphylococcus aureus (M-C-RSA) and 1 methicillin-ciprofloxacin susceptible S. aureus (M-C-SSA) recently isolated from device-associated infections unresponsive to or relapsing after glycopeptide therapy, despite device removal. MICs of vancomycin ranged from 1 to 4 μg/ml, MICs of teicoplanin ranged from 2 to 8 μg/ml; MICs of moxifloxacin were always 2 μg/ml against M-CRSA isolates and 0.125 μg/ml against the M-C-SSA isolate. The 9 strains resulted tolerant when tested for vancomycin, teicoplanin, and moxifloxacin used alone at 2xMIC. In all cases the combination of moxifloxacin and teicoplanin or vancomycin appeared to be bactericidal already at MIC concentration for glycopeptides plus 0.5xMIC concentration for moxifloxacin. If these results are confirmed in vivo in animal experiments, the combination of moxifloxacin with glycopeptides might be useful for treating device-associated infections, and in preventing the frightening phenomenon of increasing MICs for glycopeptides.

Genetic Factors Underlying Impaired Endothelium-Dependent Vasorelaxation in the Stroke-Prone Spontaneously Hypertensive Rat

AbstractBackground: Impaired endothelial-dependent vasorelaxation (IEDV) precedes the development of cerebrovascular lesions in an experimental animal model of inherited stroke, the stroke-prone spontaneously hypertensive rat (SHRSP). We have previously shown that in this experimental model IEDV segregates in the SHRSP/stroke-resistant spontaneously hypertensive rat (SHR) F2 generation independently of blood pressure levels, thus suggesting the existence of a specific genetic basis for this trait. Aim: The aim of this study was to identify the genetic determinants of the occurrence of IEDV in the SHRSP by random marker genome screening. Method: One-hundred and thirty-seven SHR/SHRSP F2 rats (64 males, 73 females) were studied (age 10 weeks). The quantitative phenotypes used for the study were: fractional vasorelaxation to acetylcholine on thoracic aorta rings pre-constricted with norepinephrine, and the integer of the total area under the vasoconstriction and vasodilatation curves. Result: None of the markers tested showed a significant linkage to the phenotype under investigation. A trend toward significance was found for only five of the genetic markers. Conclusion: These results do not allow us to identify specific genetic determinants of IEDV in our experimental model. On a more general perspective, the analysis of genetic factors involved in the pathogenesis of intermediate phenotypes may represent an interesting strategy to gain further insight in to the prevention of cardiovascular diseases.

Cerebral abscesses due to methicillin-resistant Staphylococcus aureus complicating stroke

Abstract A 76-year-old man suffered a stroke with global aphasia and right hemiplegia. The ischemic infarction was demonstrated by computed tomography. After 2 months, multiple brain abscesses developed at the site of the original infarction. Blood and abscess aspiration cultures yielded a methicillin-resistant Staphylococcus aureus (MRSA). Infection was probably caused by hematogenous dissemination from aspiration pneumonia. Secondary localization in a previous hemorrhage or infarction area, as a consequence of a bloodstream infection, is rarely documented, with only a few cases reported in the medical literature. To our knowledge, this is the first case with this antibiotic-resistant organism.