Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia

Hypercholesterolemia impairs arteriolar dilatation, but whether the vascular abnormalities accompanying this condition include large artery function is unknown. We addressed this issue in 13 normotensive subjects with familial hypercholesterolemia (serum cholesterol 401.6 \ub1 16.9 mg/dl, mean \ub1 S.E., FHC) and no evidence of atherosclerotic lesions, in whom radial artery (RA) diameter and blood pressure (BP) were measured beat to beat by an echotracking and a Finapres device, respectively. RA compliance (RAG) was derived from the diameter/BP relationship and expressed over the systo-diastolic BP range, both at baseline and after a 12-min brachial artery occlusion. RAC was expressed also as the area under the RAC/BP curve divided for pulse BP. Measurements included maximal forearm blood flow (plethysmography) and minimal forearm vascular resistance (FVR) which were obtained from the values following the 12-min brachial arterial occlusion. Data were collected before and after 6- and 24-month lipid lowering treatment (simvastatin 40 mg/day). Ten age-matched normotensive normocholesterolemic healthy subjects (N) served as controls. Compared to N, baseline RAC was strikingly reduced in FHC (-53.5%, P < 0.01). After ischemia RAC increased significantly and markedly in N (+38.7, P < 0.01), while only a modest and non-significant increase was observed in FHC. Minimal FVR was markedly higher in FHC than in N (3.5 \ub1 0.9 vs 1.6 \ub1 0.1 units, P < 0.01). In FHC (7 subjects) RAC remained unchanged after 6 months of lipid lowering treatment, but increased markedly (+55.2%, P < 0.05) when treatment was prolonged to 24 months. Lipid lowering treatment also reduced minimal FVR, the effect being significant bath after 6 and after 24 months. No changes in RAC and minimal FVR were seen after 6 months in controls. Thus, in subjects with a marked increase in serum cholesterol due to FHC, not only arteriolar dilatation, but also RAC and distensibility are markedly impaired. This impairment can be favourably affected by an effective lipid lowering treatment of long duration

Anti-Pseudomonal activity of the amphibian antimicrobial peptide Esculentin(1-21) and plausible mode of action

The formation of Pseudomonas biofilms is very common in the lungs of cystic fibrosis patients with chronic infections. The colonization of the respiratory tract by this pathogen usually starts with the tissue adhesion of non-mucoid and motile strains. Subsequently they evolve a mucoid phenotype forming sessile communities, with a protective layer around the cells that confers more resistance to antibiotic therapy. Conventional antibiotics are frequently ineffective mainly because of their undesiderable side effects, emergence of resistant strains or because their lacking activity against pathogenic forms. Due to these reasons, novel anti-infective agents are of great interest to the medical community. Here we report on the potent activity and membrane-perturbing effects of the amphibian antimicrobial peptide esculentin(1-21), on both the free-living and sessile forms of P. aeruginosa, as a possible mechanism for biofilm disruption. Moreover Esc(1-21) does not induce resistant strains in vitro after multiple exposure to the peptide. Overall, this peptide is a promising template for the generation of new antibiotic formulations to advance care of infections caused by P. aeruginos

BOMBININS

The bombinin family of antimicrobial peptides is constituted by a number of molecules isolated from skin secretions of frogs belonging to the genus Bombina. These peptides can be grouped into two distinct subfamilies: the bombinin and the bombinin H. The former comprises 27-amino-acid residue peptides with antimicrobial activity against Gram-negative and Gram-positive bacteria and fungi; the latter includes 20- or 17-residue hemolytic peptides, some of which containing a D-amino acid in the second position of the sequence. The presence of this posttranslational modification confers the two isoforms distinctive biological properties, the D-amino acid–containing peptide being always more active than the corresponding L-isomer

Effects of isolated systolic hypertension and essential hypertension on large and middle-sized artery compliance

Background: Systolic hypertension of the elderly is characterized by a reduction in arterial compliance. Whether and to what extent this involves arteries of various structure and size is not well known Objective: To study carotid and radial artery compliance in systolic hypertension of the elderly, compared to essential hypertension and normotension. Methods: We investigated 28 elderly patients with systolic hypertension (age 68.6 \ub1 1.4 years, mean \ub1 SE; systolic blood pressure > 160 mmHg and diastolic blood pressure < 90 mmHg) plus 17 age-matched patients with essential hypertension and 15 age- matched healthy normotensive subjects. Radial and carotid artery compliance were evaluated using echotracking techniques. In both arteries compliance was assessed statistically and dynamically, i.e. as compliance values throughout the diasto-systolic pressure range. Measurements included intima-media wall thickness of the radial artery. Results: Compared to normotensive subjects, carotid artery compliance was reduced in essential hypertension and more so in systolic hypertension. However, although in both groups radial artery wall thickness was markedly greater than in the normotensive group, radial artery compliance was markedly reduced in systolic hypertension, but unchanged in essential hypertension. Conclusions: In systolic hypertension of the elderly the reduction of arterial compliance is marked in both muscular and large elastic arteries, while in elderly essential hypertensives changes in arterial compliance are moro heterogeneous, i.e. only carotid artery compliance is reduced. The different effects of these two types of hypertension on arterial mechanics are visible throughout the physiological range of blood pressure and probably accounted for by different alterations in vessel wall structure

Environmental responses and productivity of the CAM plant, Agave tequilana

Mastitis, or inflammation of the mammary gland, is the most common and expensive illness of dairy cows throughout the world. Although stress and physical injuries may give rise to inflammation of the udders, infections by bacteria or other microorganisms remain the major cause, and infusion of antibiotics is the main treatment approach. However, the increased emergence of multidrug-resistant pathogens and the production of milk contaminated with antibiotics has become a serious threat in the livestock. Hence, there is an urgent need for the discovery of new therapeutic agents with a new mode of action. Gene-encoded AMPs, which represent the first line of defence in all living organisms, are considered as promising candidates for the development of new anti-infective agents. This paper reports on the antibacterial activities in vitro and in an animal model, of the frog skin AMP esculentin 1-21 [Esc(1-21)], along with a plausible mode of action. Our data revealed that this peptide (i) is highly potent against the most common mastitis-causingmicrobes (e.g. Streptococcus agalactiae); and (ii) is active in vivo, causing a visible regression of the clinical stage of mastitis in dairy cows, after 1 week of peptide treatment. Biophysical characterisation revealed that the peptide adopts an a-helical structure in microbial mimicking membranes and is able to permeate the membrane of S. agalactiae in a dose-dependent manner. Overall, these data suggest Esc(1-21) as an attractive AMP for the future design of new antibiotics to cure mastitis in cattle. Copyright " 2009 European Peptide Society and John Wiley & Sons, Ltd.",,,,,,"10.1002/psc.1148",,,"http://hdl.handle.net/20.500.12104/41291","http://www.scopus.com/inward/record.url?eid=2-s2.0-70349647481&partnerID=40&md5=6f06e86a5ca18aa8ae47f15fcac2b6c

Frog skin antimicrobial peptides promote survival of Caenorhabditis elegans infected by a multi-drug resistant strain of Pseudomonas aeruginosa

In the past two decades, numerous families of genetically encoded antimicrobial peptides (AMPs), from all living organisms, have been described [1,2]. They are conserved components of the innate immune response, and represent the first host defence line against microbial infections. Alghough AMPs show a marked variation in size, sequence and structure, most of them are polycationic and fold into an amphipathic helical or beta-sheet structure, a feature which aids their interaction and insertion into microbial membranes that are believed to be the principal target for their killing mechanism. Before reaching the negatively-charged bacterial membrane, AMPs need to bind, via electrostatic interactions, the anionic components of the microbial cell surface and diffuse through the cell wall. The growing emergence of multidrug-resistant (MDR) microorganisms makes it increasingly difficult to treat infections. These infections include those associated with Pseudomonas aeruginosa, which is hard to eradicate, especially in patients with a compromised immune system[3]. Amphibian skin is one of the richest sources for such AMPs, but only a few studies on their in vivo activity and mode of action have been reported. Here we investigated: (i) the activity and mechanism underlying the killing of short AMPs from frog skin (e.g., temporins and esculentin fragments[4] ) on a MDR clinical isolate of P. aeruginosa; (ii) their in vivo antimicrobial activity and mode of action, using the mini-host model of Caenorhabditis elegans[5]. Our data revealed that in vivo, both temporin-1Tb and esculentin(1-18) were highly active in promoting the survival of pseudomonas-infected nematodes, although temporin-1Tb did not show significant activity in vitro, under the experimental conditions used. Importantly, esculentin(1-18) permeated the membrane of Pseudomonas cells within the gut of the infected nematode. To the best of our knowledge, this is the first report showing the ability of a CAMP to permeate the microbial membrane within a living organism. Besides shedding light on a plausible mode of action in vivo of frog skin AMPs, our data suggest these peptides as templates for the design and development of new anti-infective agents. References 1 Zasloff, M. (2002) Nature. 415, 389-395 2 Brown, K. L., and Hancock, R. E. (2006) Curr Opin Immunol. 18, 24-30 3. R.E. Hancock And D.P. Speert. Drug Resist. Updat (2000), 3, 247-25 4. M.L. Mangoni et al. Antimicrob. Agents and Chemother. (2008), 52, 85-91 5 T. I. Moy et al. Proc. Natl. Acad. Sci. USA(2006), 103,10414-10419