Addressing reliability and degradation of chemitransistor sensors by electrical tuning of the sensitivity.

Here we show that electrical tuning of the sensitivity of chemitransistor sensors, namely field-effect-transistors (FETs) exploiting nano/mesostructured sensing materials, can be used to effectively address two chief problems of state-of-the-art gas sensors, specifically fabrication reliability and degradation by aging. Both experimental evidences and theoretical calculations are provided to support such a result, using as a case-of-study junction field-effect-transistors (JFETs) exploiting mesostructured porous silicon (PS) as sensing material (PSJFETs) for the detection of nitrogen dioxide (NO(2)) at hundreds ppb. Proof of concept is given by fully compensating the effect of fabrication errors on the sensitivity of two PSJFETs integrated on the same chip, which, though identical in principle, feature sensitivities to NO(2) differing from about 30% before compensation. Although here-demonstrated for the specific case of PSJFETs, the concept of sensor reliability/aging problem compensation by sensitivity electrical-tuning can be applied to other chemitransistor sensors that exploit sensing materials different than PS.

Photoinduced work function changes by isomerization of a densely packed azobenzene-based SAM on Au: a joint experimental and theoretical study.

Responsive monolayers are key building blocks for future applications in organic and molecular electronics in particular because they hold potential for tuning the physico-chemical properties of interfaces, including their energetics. Here we study a photochromic SAM based on a conjugated azobenzene derivative and its influence on the gold work function (Φ(Au)) when chemisorbed on its surface. In particular we show that the Φ(Au) can be modulated with external stimuli by controlling the azobenzene trans/cis isomerization process. This phenomenon is characterized experimentally by four different techniques, kelvin probe, kelvin probe force microscopy, electroabsorption spectroscopy and ultraviolet photoelectron spectroscopy. The use of different techniques implies exposing the SAM to different measurement conditions and different preparation methods, which, remarkably, do not alter the observed work function change (Φ(trans)-Φ(cis)). Theoretical calculations provided a complementary insight crucial to attain a deeper knowledge on the origin of the work function photo-modulation.

NA+/H+ exchanger 1- and aquaporin-1-dependent hyperosmolarity changes decrease nitric oxide production and induce VCAM-1 expression in endothelial cells exposed to high glucose.

Since diabetic hyperglycaemia causes hyperosmolarity, we investigated the contribution of hyperosmolarity in the proinflammatory endothelial effects of hyperglycemia, and investigated the mechanisms involved. Human aortic endothelial cells (HAEC) were incubated for short-term (1-3 days) or long-term (1-2 weeks) exposures to 5.5 mmol/L glucose (normoglycemia, basal), high glucose (25 and 45 mmol/L, HG), or a hyperosmolar control (mannitol 25 and 45 mmol/L, HM), in the presence or absence of the aquaporin-1 (AQP1) inhibitor dimethylsulfoxide (DMSO), the Na+/H+ exchanger 1 (NHE-1) inhibitor cariporide (CA), the protein kinase C (PKC) inhibitor calphostin C or the PKCbeta isoform inhibitor LY379196 (LY). Both short- and long-term exposures to HG and HM decreased the expression of the active, phosphorylated form of endothelial nitric oxide synthase (Ser1146-eNOS) and, in parallel, increased vascular cell adhesion molecule(VCAM)-1 protein at immunoblotting. After 24 h incubation with HG/HM, we observed a significant similar and concentration-dependent enhancement of AQP1 expression. DMSO and CA inhibited hyperosmolarity-induced VCAM-1 expressions, while increasing nitrite levels and Ser1146-eNOS expression. Gene silencing by small interfering RNA reduced the expression of AQP1, and suppressed HG and HM-stimulated VCAM-1 expression. Calphostin C and LY blunted hyperosmolarity-induced VCAM-1 expression, while increasing the expression of Ser1146-eNOS and nitrite production. HG decreases eNOS activation and induces total VCAM-1 expression in HAEC through a hyperosmolar mechanism. These effects are mediated by activation of the water channels AQP1 and NHE-1, and a PKCbeta-mediated intracellular signaling pathway. Targeting osmosignaling pathways may represent a novel strategy to reduce vascular effects of hyperglycemia.

Sulfido-peptide leukotrienes in coronary heart disease - relationship with disease instability and myocardial ischaemia.

BACKGROUND: Urinary excretion of leukotriene (LT) E(4) is an index of LTC(4) biosynthesis and platelet-neutrophil interactions, which may occur in coronary heart disease and contribute to myocardial ischaemia. Enhanced LTC(4) biosynthesis may be a consequence of myocardial ischaemia or be linked to its pathogenetic substrate. METHODS AND RESULTS: Overnight urine collections were obtained from 17 patients with chronic stable angina, three patients with Prinzmetal's angina, 16 patients with non ST-elevation acute coronary syndromes (NSTE-ACS) and six patients with acute ST-elevation myocardial infarction (STEMI). LTE(4) excretion was measured by enzyme immunoassay after HPLC separation. Compared with healthy controls (51.1 +/- 21.3 pg mg(-1) creatinine, mean +/- SD, n = 11) and with non-coronary cardiac controls (36.6 +/- 9.8 pg mg(-1) creatinine, n = 9), LTE(4) excretion was unchanged in stable angina (40.5 +/- 25.8 pg mg(-1) creatinine), but significantly (P < 0.01) increased in NSTE-ACS (122.7 +/- 137.2 pg mg(-1) creatinine) and STEMI (213.4 +/- 172.4 pg mg(-1) creatinine). In these patients, LTE(4) excretion rapidly dropped after day 1, consistent with effective coronary reperfusion. In patients with NSTE-ACS, the increase in LTE(4) excretion was entirely restricted to patients with recent (< 48 h) spontaneous anginal episodes. Myocardial ischaemia elicited by a positive exercise stress test was not accompanied by any detectable increase in LTE(4) excretion, while a significant (P < 0.01) increase was detected after a single-vessel percutaneous coronary interventions (PCI) procedure (n = 10), as compared with diagnostic angiography (n = 9). CONCLUSIONS: In coronary heart disease, increased LTC(4) biosynthesis is restricted to ACS and not linked to myocardial ischaemia per se, but likely to the occurrence of plaque disruption.

Soluble E-selectin in essential hypertension: a correlate of vascular structural changes.

BACKGROUND: Increased expression of the endothelial leukocyte adhesion molecule E-selectin is implicated in vascular disease and may accompany the development of hypertension. We evaluated plasma soluble (s) E-selectin to assess its relationship with endothelium-dependent and endothelium-independent vasodilation in patients with hypertension. METHODS: Thirty-one previously untreated and uncomplicated essential hypertensive patients were compared with 16 normotensive controls for changes in forearm blood flow (by strain-gauge plethysmography) in response to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine, and of the endothelium-independent vasodilator sodium nitroprusside. As an index of structural changes, minimal forearm vascular resistances were calculated as the ratio between maximal vasodilation after 13 min of ischemia and mean blood pressure. RESULTS: Responses to acetylcholine were significantly lower and minimal forearm vascular resistances higher in hypertensives versus controls, whereas responses to nitroprusside were comparable. Baseline sE-selectin concentrations were (mean +/- SEM) 37.4 +/- 1.8 ng/mL in hypertensives and 27.8 +/- 0.7 ng/mL in normotensives (P < .001). In essential hypertensive patients, a significant (P < .01) correlation with the response to nitroprusside (r = -0.47) was found, but not with the response to acetylcholine or minimal forearm vascular resistances. sE-selectin was also positively correlated with age and LDL cholesterol. At multivariate analysis, sE-selectin remained significantly correlated with nitroprusside responses and LDL cholesterol. CONCLUSIONS: In patients with essential hypertension, plasma levels of sE-selectin are higher than in normotensive controls and mostly related to structural vascular changes.

Induction of endothelial-leukocyte interaction by interferon-gamma requires coactivation of nuclear factor-kappaB.

To determine whether nuclear factor (NF)-kappaB is necessary to confer endothelial cell responsiveness to interferon (INF)-gamma in terms of vascular cell adhesion molecule (VCAM)-1 expression and leukocyte adhesion, human endothelial cells were treated with IFN-gamma in the presence of low concentrations (LCs) of interleukin (IL)-1alpha (

Inhibition of endothelial cell activation by nitric oxide donors.

Because nitric oxide (NO) inhibits the expression of endothelial leukocyte adhesion molecules, NO-generating compounds have major therapeutic potential for use outside their classical indications. We report on the in vitro potential antiatherogenicity of two novel cysteine-containing NO donors, SP/W 3672, a fast spontaneous NO releaser, and its prodrug SP/W 5186, which liberates NO after bioactivation. The ability of these two compounds to inhibit monocyte adhesion and surface expression of endothelial adhesion molecules was evaluated and compared with that of other NO donors. SP/W 5186 and SP/W 3672 inhibited the adhesion of U937 monocytes to cultured human endothelial cells more potently than S-nitrosoglutathione (GSNO) or spermine NONOate, whereas nitroglycerin and isosorbide dinitrate were ineffective at comparable concentrations. A similar rank order of potency was found for the inhibition of expression of the adhesion molecules vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin as well as for major histocompatibility complex class II antigen expression. Estimated IC(50) values for vascular cell adhesion molecule-1 were >400 microM for SP/W 4744 (control for SP/W 3672 lacking the cysteine moiety), 200 microM for GSNO and spermine NONOate, 80 microM for SP/W 3672, and 50 microM for SP/W 5186. Moreover, SP/W 5186 inhibited VCAM-1 mRNA levels more potently than GSNO. This effect was likely to be transcriptional because mRNA degradation was not affected. In conclusion, SP/W 3672 and SP/W 5186 are novel potent inhibitors of endothelial activation, and this effect appears to relate to their ability to liberate NO for prolonged periods of time, either spontaneously or after conversion to active hydrolytic products.

Early increase in urinary leukotriene E4 (LTE4) is dependent on allergen dose inhaled during bronchial challenge in asthmatic subjects.

BACKGROUND: Urinary leukotriene E4 (LTE4) excretion is a good marker of the rate of total body production of sulfidopeptide leukotrienes released during allergen challenge. METHODS: Twenty-three subjects with allergic asthma were challenged with inhaled allergen, and the urinary excretion of LTE4 was determined by immunoenzymatic assay (associated with HPLC separation) at various intervals after challenge. RESULTS: Allergen challenge caused an early airway response (EAR) with a drop in FEV1 of 40.3+/-9.9%. This was associated with an increase in urine LTE4 excretion for 0-3 h after allergen inhalation (296+/-225.25 pg/mg creatinine) in comparison with baseline values obtained during the night before challenge (101.02+/-61.97 pg/mg creatinine). Urinary LTE4 excretion was significantly higher in subjects who inhaled a higher dose of allergen during challenge (LTE4 during EAR: 211+/-192 pg/mg creatinine in subjects with inhaled total dose of allergen <0.1 biologic units; 408+/-223 pg/mg creatinine in subjects with inhaled total dose >0.1 biologic units). All subjects showed a late airway response (LAR) to allergen of different severity, from mild (FEV1 fall: 15-20%) to severe (>30%); no correlation was found between the increase in urine LTE4 excreted during LAR (3-7 h after challenge) and the severity of LAR, but only subjects with severe LAR showed a significant increase in LTE4 during LAR in comparison with baseline value. CONCLUSIONS: A release of sulfidopeptide leukotrienes, as evaluated by urinary LTE4 excretion, can be documented during EAR and LAR to allergen in relation to the dose of inhaled allergen, and it can represent a useful index of the events underlying the airway inflammatory responses during allergen challenge.

Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of atherosclerosis.

Vascular cell adhesion molecule-1 (VCAM-1) is a protein expressed on the surface of activated endothelial cells and expressed in early atherosclerosis. Because part of the protein is shed in the circulation and can be detected in peripheral plasma [soluble (s) VCAM-1], we hypothesized that sVCAM-1 may be a circulating marker of the presence and severity of atherosclerosis in humans. We selected 11 patients with essential hypertension plus peripheral vascular disease (PVD) and matched them for age, gender, body mass index, and smoking habits with 11 patients with uncomplicated essential hypertension (UH) and 11 healthy controls. We evaluated plasma concentrations of sVCAM-1 along with those of the soluble form of two other endothelial leukocyte adhesion molecules [sE-selectin and s-intercellular adhesion molecule-1 (sICAM-1)] and other markers of endothelial dysfunction/ damage [s-thrombomodulin, plasminogen activator inhibitor type I, and von Willebrand factor (vWF)]. We also measured insulin, glucose, fibrinogen, total and HDL cholesterol, and the urinary albumin excretion (UAE), which may also be related to atherosclerosis. Results of these assays were related to the echographic assessment of the maximum intima-media thickness (IMTmax) at the carotid bifurcation, as an index of atherosclerosis in the carotids. PVD patients had a clearly elevated IMTmax [2.7 (1.1-3.1) mm, median (range)] compared with both UH patients [1.2 (0.8-2.4) mm] and controls [1 (0.6-2) mm]. sVCAM-1 was clearly higher in PVD patients [990 (273-1808) ng/mL, median (range)] versus 340 (236-975) ng/mL in UH and 386 (204-835) ng/mL in controls, and it separated clinical categories better than sICAM-1, vWF, glucose, insulin, UAE, triglycerides, or total, LDL or HDL cholesterol, sVCAM-1 was also the best biohumoral correlate of IMTmax (R = .59; P < .001) in univariate analysis. Because many of the biohumoral variables assessed were mutually intercorrelated, they were entered in a multivariate analysis to assess their contribution in explaining IMTmax variability. sVCAM-1 remained the only independent predictor of IMTmax and totally abolished the contribution of other variables to IMTmax variability. Thus, sVCAM-1 is a good biohumoral correlate of overt atherosclerosis, independent of underlying hypertension, and may be an in vivo marker of endothelial activation. Its potential value as a surrogate for global risk assessment and its behavior in intervention studies remain to be determined.