Suppressive activity of macrolide antibiotics on nitric oxide production by lipopolysaccharide stimulation in mice.

BACKGROUND: Low-dose and long-term administration of macrolide antibiotics into patients with chronic airway inflammatory diseases could favorably modify their clinical conditions. However, the therapeutic mode of action of macrolides is not well understood. Free oxygen radicals, including nitric oxide (NO), are well recognized as the important final effector molecules in the development and the maintenance of inflammatory diseases. PURPOSE: The influence of macrolide antibiotics on NO generation was examined in vivo. METHODS: Male ICR mice, 5 weeks of age, were orally administered with either roxithromycin, clarithromycin, azithromycin or josamycin once a day for 2-4 weeks. The mice were then injected intraperitoneally with 5.0 mg/kg lipopolysaccharide (LPS) and the plasma NO level was examined 6 h later. RESULTS: Although pre-treatment of mice with macrolide antibiotics for 2 weeks scarcely affected NO generation by LPS injection, the administration of macrolide antibiotics, except for josamycin, for 4 weeks significantly inhibited LPS-induced NO generation. The data in the present study also showed that pre-treatment of mice with macrolide antibiotics for 4 weeks significantly suppresses not only production of pro-inflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, but also inducible nitric oxide synthase mRNA expressions, which are enhanced by LPS injection. CONCLUSION: These results strongly suggest that suppressive activity of macrolide antibiotics on NO generation in response to LPS stimulation in vivo may, in part, account for the clinical efficacy of macrolides on chronic inflammatory diseases

Dehydration reduces stroke volume and cardiac output during exercise because of impaired cardiac filling and venous return, not left ventricular function

Dehydration accrued during intense prolonged whole-body exercise in the heat compromises peripheral blood flow and cardiac output ((Q) over dot). A markedly reduced stroke volume (SV) is a key feature of the dehydration-induced cardiovascular strain, but whether the lower output of the heart is mediated by peripheral or cardiac factors remains unknown. Therefore, we repeatedly quantified left ventricular (LV) volumes, LV mechanics (LV twist, a marker of systolic muscle function, and LV untwisting rate, an independent marker of LV muscle relaxation), left intra-ventricular pressure gradients, blood volume and peripheral blood flow during 2 hr of cycling in the heat with and without dehydration (DEH: 4.0 +/- 0.2% body mass loss and EUH: euhydration control, respectively) in eight participants (three females and five males). While brachial and carotid blood flow, blood volume, SV, LV end-diastolic volume (LVEDV), cardiac filling time, systemic vascular conductance and (Q) over dot were reduced in DEH compared to EUH after 2 hr, LV twist and untwisting rate tended to be higher (p = .09 and .06, respectively) and intra-ventricular pressure gradients were not different between the two conditions (p = .22). Furthermore, LVEDV in DEH correlated strongly with blood volume (r = .995, p < .01), head and forearms beat volume (r = .98, p < .05), and diastolic LV filling time (r = .98, p < .05). These findings suggest that the decline in SV underpinning the blunted (Q) over dot with exercise-induced dehydration is caused by compromised LV filling and venous return, but not intrinsic systolic or diastolic LV function

Role of the DELSEED Loop in Torque Transmission of F1-ATPase

AbstractF1-ATPase is an ATP-driven rotary motor that generates torque at the interface between the catalytic β-subunits and the rotor γ-subunit. The β-subunit inwardly rotates the C-terminal domain upon nucleotide binding/dissociation; hence, the region of the C-terminal domain that is in direct contact with γ—termed the DELSEED loop—is thought to play a critical role in torque transmission. We substituted all the DELSEED loop residues with alanine to diminish specific DELSEED loop-γ interactions and with glycine to disrupt the loop structure. All the mutants rotated unidirectionally with kinetic parameters comparable to those of the wild-type F1, suggesting that the specific interactions between DELSEED loop and γ is not involved in cooperative interplays between the catalytic β-subunits. Glycine substitution mutants generated half the torque of the wild-type F1, whereas the alanine mutant generated comparable torque. Fluctuation analyses of the glycine/alanine mutants revealed that the γ-subunit was less tightly held in the α3β3-stator ring of the glycine mutant than in the wild-type F1 and the alanine mutant. Molecular dynamics simulation showed that the DELSEED loop was disordered by the glycine substitution, whereas it formed an α-helix in the alanine mutant. Our results emphasize the importance of loop rigidity for efficient torque transmissions

Introducing Nonuniform Strain to Graphene Using Dielectric Nanopillars

A method for inducing nonuniform strain in graphene films is developed. Pillars made of a dielectric material (electron beam resist) are placed between graphene and the substrate, and graphene sections between pillars are attached to the substrate. The strength and spatial pattern of the strain can be controlled by the size and separation of the pillars. Application of strain is confirmed by Raman spectroscopy as well as from scanning electron microscopy (SEM) images. From SEM images, the maximum stretch of the graphene film reaches about 20%. This technique can be applied to the formation of band gaps in graphene.Comment: Appl. Phys. Express, in pres

Relationship between postprandial glucose level and carotid artery stiffness in patients without diabetes or cardiovascular disease

BACKGROUND: The aim of this study was to evaluate the relationship between postprandial glucose level and atherosclerosis in patients without diabetes and cardiovascular disease by determining carotid ultrasonographic variables and serum levels of 1,5-anhydroglucitol (1,5-AG). METHODS: The subjects were 72 patients without diabetes and cardiovascular disease being treated for hypertension or dyslipidemia. The clinical characteristics of all subjects, including the serum level of 1,5-AG, which appears to be well suited for monitoring postprandial hyperglycemia, were evaluated after an overnight fast. The average intima-media thickness (IMT) and the average pulsatility index (PI) of the right and left common carotid arteries were determined with high-resolution ultrasonography and used as ultrasonographic variables. The subjects were divided into a Lower 1,5-AG group (n = 36) and a Higher 1,5-AG group (n = 36). We evaluated the relationship between clinical characteristics and ultrasonographic variables of the carotid artery in both groups. RESULTS: The average PI in the Lower 1,5-AG group was significantly higher than that in the Higher 1,5-AG group, but the average IMT did not differ between the groups. Linear regression analysis, with the ultrasonographic variables as the dependent variables, with 1,5-AG as the independent variable, and adjusted for other clinical characteristics, showed significant correlation between 1,5-AG and the PI but not between 1,5-AG and IMT. CONCLUSION: Our results suggest that postprandial hyperglycemia increases carotid artery stiffness, but not morphological change, in patients without diabetes or cardiovascular disease

Application of ventriculoperitoneal shunt as a treatment for hydrocephalus in a dog with syringomyelia and Chiari I malformation

A twenty-month-old Chihuahua male dog was presented to us suffering with ataxia. Based on the physical examination, X-ray and magnetic resonance imaging (MRI) examinations, we diagnosed the dog with hydrocephalus, Chiari I malformation and syringomyelia. Treatment consisted of internal medical treatment and the placement of a ventriculoperitoneal (VP) shunt. The ventricular dilatation was relieved and the dog improved neurologically; however, the Chiari I malformation and syringomyelia remained after surgically positioning the VP shunt