Local effect of transdermal isosorbide dinitrate ointment on hand vein diameter

Abstract.: Objective: To assess the effect of topically applied isosorbide dinitrate (ISDN) ointment on superficial hand veins preconstricted with phenylephrine. Methods: Using the hand vein compliance technique, venous diameter changes were measured in a double-blind, randomised, placebo-controlled cross-over trial in 12 healthy volunteers. During preconstriction with phenylephrine, placebo or ISDN ointment was administered to assess the dilator effect of transdermal ISDN. Finally a single i.v. dose of nitroglycerine was administered into the hand vein to assess the maximal venous response to organic nitrovasodilators. Results: ISDN ointment (equivalent to 13.4±3.61mg ISDN) caused a significant dilator effect of 39.1±21.7% (mean±SEM, P=0.02) which reached its maximum after 42.5±16.6min. Maximum ISDN effects were inversely correlated with venous baseline diameter (r2=0.38, P=0.03) and independent of the amount of ointment applied or the extent of preconstriction (P>0.3). Conclusion: Similar to nitroglycerine, topical ISDN may relax superficial hand veins within 60min after application, suggesting that it might ease venepuncture particularly of small vessels. The large variability of the effect and the time to reach the effect, however, restrict its practical usefulnes

Indirect evidence for stimulation of nitric oxide release by tumour necrosis factor-α in human veins in vivo

Objectives: The detrimental haemodynamic changes observed in septicaemia are generalised vasodilation, arterial hypotension, and hyporesponsiveness to vasopressor compounds, all of which could be explained by the release of an endogenous vasodilator. Experimental and clinical evidence suggests that tumour necrosis factor-α (TNF) induces the expression of vascular nitric oxide (NO) synthase within hours and that NO released from smooth muscle cells could be involved in the pathogenesis of septic shock. The aim of this study was to investigate the role of NO in the vascular effects of TNF. Methods: Using the dorsal hand vein compliance technique, the effect of the NO synthase inhibitor L-NG-monomethyl-arginine (L-NMMA) on α1-adrenergic responsiveness (phenylephrine 1.25-8000 ng/min) was studied after prolonged local venous infusion of TNF (8.7 μg in 5 h) in 9 volunteers and in 6 volunteers without previous cytokine exposure. Results: Mean (±s.e.) maximum phenylephrine constriction (Emax) was 73 ± 6% and log dose-rates exerting 50% of Emax (log ED50) were 3.2 ± 0.09 (geometric mean: 1535 ng/min). Local co-administration of L-NMMA at a dose sufficiently high to block NO formation (3.4 μmol/min) increased venous sensitivity to phenylephrine threefold (log ED50 2.8 ± 0.1, P < 0.015; geometric mean: 574 ng/min) whereas Emax was similar (73 ± 5%). In the controls the phenylephrine dose-response relationship remained unaffected by simultaneous administration of L-NMMA. Conclusions: As no basal release of NO occurs in hand veins without previous exposure to TNF these results provide direct evidence for induction of NO formation in the human vasculature and consecutive resistance to α-adrenergic venoconstriction. NO might, therefore, be a key mediator of haemodynamic impairment in humans under conditions with known elevations of circulating TNF, such as a septic shoc

Inverse correlation between endothelin-1-induced peripheral microvascular vasoconstriction and blood pressure in glaucoma patients

• Background: The potent vasoconstrictor peptide endothelin-I has been shown to participate in the control of peripheral vascular tone and in the regulation of ocular perfusion. In glaucoma patients vasospasms and arterial hypotension have been identified as risk factors for the progression of glaucomatous damage, and the regulation of endothelin-1 release is disturbed in some of these patients. The aim of this study was to assess the relationship between resting blood pressure and cutaneous vascular responsiveness to endothelin-1 and phenylephrine in patients with glaucoma and in matched controls. • Methods: In 9 patients with primary open-angle glaucoma (POAG), 7 patient with normal tension glaucoma (NTG), and 16 age- and sex-matched controls, endothelin-1 and phenylephrine responses were assessed in the human forearm microcirculation using laser Doppler flowmetry during intra-arterial drug administration. Blood pressure was measured intra-arterially. • Results: In contrast to α1-adrenergic effects, endothelin-1 responses were inversely correlated to both systolic (r 2 = 0.27,P = 0.05) and diastolic (r 2 = 0.54,P = 0.001) blood pressure in glaucoma patients, whereas there was no such correlation in controls. Patients with lower blood pressure values were more sensitive to the vasoconstrictor effects of endothelin-1. Cutaneous responsiveness to endothelin-1 and phenylephrine was similar in glaucoma patients and in controls. • Conclusion: These results reveal that glaucoma patients appear to have peripheral microvascular abnormalities which are exhibited as altered responsiveness to endothelin-1. Thus, this study supports the hypothesis that endothelin-l-related microvascular dysfunction may be involved in the pathogenesis of glaucomatous damag

Constraining the expansion rate of the Universe using low-redshift ellipticals as cosmic chronometers

We present a new methodology to determine the expansion history of the Universe analyzing the spectral properties of early type galaxies (ETG). We found that for these galaxies the 4000\AA break is a spectral feature that correlates with the relative ages of ETGs. In this paper we describe the method, explore its robustness using theoretical synthetic stellar population models, and apply it using a SDSS sample of $\sim$14 000 ETGs. Our motivation to look for a new technique has been to minimise the dependence of the cosmic chronometer method on systematic errors. In particular, as a test of our method, we derive the value of the Hubble constant $H_0 = 72.6 \pm 2.8$ (stat) $\pm2.3$ (syst) (68% confidence), which is not only fully compatible with the value derived from the Hubble key project, but also with a comparable error budget. Using the SDSS, we also derive, assuming w=constant, a value for the dark energy equation of state parameter $w = -1 \pm 0.2$ (stat) $\pm0.3$ (syst). Given the fact that the SDSS ETG sample only reaches $z \sim 0.3$, this result shows the potential of the method. In future papers we will present results using the high-redshift universe, to yield a determination of H(z) up to $z \sim 1$.Comment: 25 pages, 17 figures, JCAP accepte

Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation

A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfunctional lysosomes, as potent modifiers; here, we report 37 additional genes identified from ∼1900 genes screened, including the kinases shaggy/GSK-3beta, par-1/MARK, CamKI and Mekk1. Tau acts synergistically with Mekk1 and p38 to down-regulate extracellular regulated kinase activity, with a corresponding decrease in AT8 immunoreactivity (pS202/T205), suggesting that tau can participate in signaling pathways to regulate its own kinases. Modifiers showed poor correlation with tau phosphorylation (using the AT8, 12E8 and AT270 epitopes); moreover, tested suppressors of wild-type tau were equally effective in suppressing toxicity of a phosphorylation-resistant S11A tau construct, demonstrating that changes in tau phosphorylation state are not required to suppress or enhance its toxicity. Genes related to autophagy, the cell cycle, RNA-associated proteins and chromatin-binding proteins constitute a large percentage of identified modifiers. Other functional categories identified include mitochondrial proteins, lipid trafficking, Golgi proteins, kinesins and dynein and the Hsp70/Hsp90-organizing protein (Hop). Network analysis uncovered several other genes highly associated with the functional modifiers, including genes related to the PI3K, Notch, BMP/TGF-β and Hedgehog pathways, and nuclear trafficking. Activity of GSK-3β is strongly upregulated due to TDP-43 expression, and reduced GSK-3β dosage is also a common suppressor of Aβ42 and TDP-43 toxicity. These findings suggest therapeutic targets other than mitigation of tau phosphorylation

Cognitive and psychomotor function in hypoglycemia: response error patterns and retest reliability

Hypoglycemia has been shown to impair cognitive and psychomotor function, but it has been unclear which measures are most reliable and sensitive for detecting these effects. In a single-blind repeated measures design, healthy young adults (N=17, 8 male, mean age 27 years) performed three PC-based cognitive and psychomotor function tests: a paced auditory serial addition task (PASAT), an adaptive five-choice reaction time test (CRTT), and a manual tracking test on two occasions 4 weeks apart. In each session, a hyperinsulinemic clamp method was used during a normoglycemic (plasma glucose: 4.7 mmol/l) baseline testing period, followed in one session by a normoglycemic target testing period, and in the other session by a hypoglycemic (2.7 mmol/l) target testing period. All cognitive and psychomotor function measures showed high test-retest reliability (r ranging from.69 to.95) and sensitivity to hypoglycemia (Ptextless.01). A new finding is that on the PASAT, hypoglycemia appears to differentially increase the rate of omission errors more than it increases false responses. Data on PASAT reaction time (RT) are also presented

Effect of water deprivation on cognitive-motor performance in healthy men and women

Whether mental performance is affected by slowly progressive moderate dehydration induced by water deprivation has not been examined previously. Therefore, objective and subjective cognitive-motor function was examined in 16 volunteers (8 females, 8 males, mean age: 26 yr) twice, once after 24 h of water deprivation and once during normal water intake (randomized cross-over design; 7-day interval). Water deprivation resulted in a 2.6% decrease in body weight. Neither cognitive-motor function estimated by a paced auditory serial addition task, an adaptive 5-choice reaction time test, a manual tracking test, and a Stroop word-color conflict test nor neurophysiological function assessed by auditory event-related potentials P300 (oddball paradigm) differed (P textgreater 0.1) between the water deprivation and the control study. However, subjective ratings of mental performance changed significantly toward increased tiredness (+1.0 points) and reduced alertness (-0.9 points on a 5-point scale; both: P textless 0.05), and higher levels of perceived effort (+27 mm) and concentration (+28 mm on a 100-mm scale; both: P textless 0.05) necessary for test accomplishment during dehydration. Several reaction time-based responses revealed significant interactions between gender and dehydration, with prolonged reaction time in women but shortened in men after water deprivation (Stroop word-color conflict test, reaction time in women: +26 ms, in men: -36 ms, P textless 0.01; paced auditory serial addition task, reaction time in women +58 ms, in men -31 ms, P = 0.05). In conclusion, cognitive-motor function is preserved during water deprivation in young humans up to a moderate dehydration level of 2.6% of body weight. Sexual dimorphism for reaction time-based performance is present. Increased subjective task-related effort suggests that healthy volunteers exhibit cognitive compensating mechanisms for increased tiredness and reduced alertness during slowly progressive moderate dehydration

Increased high-frequency heart rate variability during insulin-induced hypoglycaemia in healthy humans

Despite causing sympathetic activation, prolonged hypoglycaemia produces little change in HR (heart rate) in healthy young adults. One explanation could be concurrent parasympathetic activation, resulting in unchanged net effects of autonomic influences. In the present study, hypoglycaemic (2.7 mmol/l) and normoglycaemic (4.7 mmol/l) hyperinsulinaemic clamp studies were performed after normoglycaemic baseline clamp periods with 15 healthy volunteers (seven male; mean age, 27 years) on two occasions in a randomized single-blind cross-over design. Non-invasive indices of cardiac autonomic activity and hormones were measured at baseline and 1 h after the beginning of hypoglycaemia or control normoglycaemia. Plasma insulin levels and mean HR were similar during both conditions. During hypoglycaemia, there was a 485% increase in plasma adrenaline (epinephrine). A shortening of the pre-ejection period by 45% suggested strong sympathetic cardiac activation. High-frequency (0.15-0.45 Hz) HRV (HR variability) increased, indicating a concomitant increase in parasympathetic tone. Thus, during hypoglycaemia-induced sympathetic cardiac activation in healthy adults, parasympathetic mechanisms are involved in stabilizing mean HR