Efficacy and safety of a T-type calcium channel blocker in patients with neuropathic pain: A proof-of-concept, randomized, double-blind and controlled trial.

BACKGROUND: T-type calcium channels have been shown to play an important role in the initiation and maintenance of neuropathic pain and represent a promising therapeutic target for new analgesic treatments. Ethosuximide (ETX), an anticonvulsant and a T-type channel blocker has shown analgesic effect in several chronic pain models but has not yet been evaluated in patients with neuropathic pain. METHODS: This proof-of-concept, multicentre, double-blind, controlled and randomized trial compared the efficacy and safety of ETX (given as add-on therapy) to an inactive control (IC) in 114 patients with non-diabetic peripheral neuropathic pain. After a 7-day run-in period, eligible patients aged over 18 years were randomly assigned (1:1) to ETX or IC for 6 weeks. The primary outcome was the difference between groups in the pain intensity (% of change from the baseline to end of treatment) assessed in the intention-to-treat population. This study is registered with EudraCT (2013-004801-26) and ClinicalTrials.gov (NCT02100046). RESULTS: The study was stopped during the interim analysis due to the high number of adverse events in the active treatment group. ETX failed to reduce total pain and showed a poor tolerance in comparison to IC. In the per-protocol analysis, ETX significantly reduced pain intensity by 15.6% (95% CI -25.8; -5.4) from baseline compared to IC (-7.8%, 95% CI -14.3; -1.3; p = 0.033), but this result must be interpreted with caution because of a small subgroup of patients. CONCLUSION: Ethosuximide did not reduce the severity of neuropathic pain and induces, at the doses used, many adverse events. SIGNIFICANCE: This article shows that ETX is not effective to treat neuropathic pain. Nevertheless, per-protocol analysis suggests a possible analgesic effect of ETX. Thus, our work adds significant knowledge to preclinical and clinical data on the benefits of T-type calcium channel inhibition for the treatment of neuropathic pain.

Cardiovascular risk and lifestyle habits of consumers of a phytosterol-enriched yogurt in a real-life setting.

BACKGROUND: Data on the characteristics of consumers of phytosterol-enriched products and modalities of consumption are rare. An observational study evaluating the lifestyle characteristics and cardiovascular risk (CVR) profile of phytosterol-enriched yogurt consumers was performed in France. METHODS: Subjects were recruited from general practitioners via electronic medical records. Data were obtained from 358 consumers and 422 nonconsumers with 519 subject questionnaires (243 consumers, 276 nonconsumers; 67% response). RESULTS: Consumers had more cardiovascular risk factors than nonconsumers (2.0 ± 1.5 versus 1.6 ± 1.4; P < 0.001) and a higher 10-year SCORE cardiovascular risk (1.8 ± 2.0% versus 1.6 ± 2.2%; P = 0.008); they were older (P = 0.030) and had a higher incidence of hypercholesterolaemia (P < 0.001) and family or personal history of heart disease (P = 0.023/P = 0.026, respectively). Among consumers not on cholesterol-lowering medication, 99% were eligible for lifestyle interventions and 56% were eligible for lipid-lowering drug according to European guidelines. Consumers had a healthier lifestyle, with a higher (fruit/vegetable - saturated fatty acid) score than nonconsumers (P = 0.035), focused more on low-intensity leisure activity (P = 0.023), spent more time travelling by foot or bicycle (P = 0.012) and were more likely to act to reduce CVR. Phytosterol-enriched yogurt intake conformed to recommendations in two-thirds of consumers and was mainly consumed because of concerns over cholesterol levels and CVR. CONCLUSIONS: The higher cardiovascular disease risk profile of phytosterol-enriched yogurt consumers corresponds to a population for whom European guidelines recommend lifestyle changes to manage cholesterol. The coherence of the data in terms of risk factors, adherence to lifestyle recommendations and the consumption of phytosterol-enriched yogurt conforming to recommendations reflects a health-conscious consumer population.

Photocatalytic degradation of carbamazepine in wastewater by using a new class of whey-stabilized nanocrystalline TiO2 and ZnO.

Nanoscale photocatalysts have attracted much attention due to their high surface area to volume ratios. However, due to extremely high reactivity, TiO2 and ZnO nanoparticles prepared using different methods tend to either react with surrounding media or agglomerate, resulting in the formation of much larger flocs and significant loss in reactivity. This work investigates the photocatalytic degradation of carbamazepine (CBZ), a persistent pharmaceutical compound from wastewater (WW) using TiO2 and ZnO nanoparticles prepared in the presence of a water-soluble whey powder as stabilizer. The TiO2 and ZnO nanoparticles prepared in the presence of whey stabilizer displayed much less agglomeration and greater degradation power than those prepared without a stabilizer. Higher photocatalytic degradation of carbamazepine was observed (100%) by using whey stabilized TiO2 nanoparticles with 55 min irradiation time as compared to ZnO nanoparticles (92%). The higher degradation of CBZ in wastewater by using TiO2 nanoparticles as compared to ZnO nanoparticles was due to formation of higher photo-generated holes with high oxidizing power of TiO2. The photocatalytic capacity of ZnO anticipated as similar to that of TiO2 as it has the same band gap energy (3.2 eV) as TiO2. However, in the case of ZnO, photocorrosion frequently occurs with the illumination of UV light and this phenomenon is considered as one of the main reasons for the decrease of ZnO photocatalytic activity in aqueous solutions. Further, the estrogenic activity of photocatalyzed WW sample with CBZ and its by-products was carried out by yeast estrogen screen (YES) assay method. Based upon the YES test results, none of the samples showed estrogenic activity.

Analysis and advanced oxidation treatment of a persistent pharmaceutical compound in wastewater and wastewater sludge-carbamazepine.

Pharmaceutically active compounds (PhACs) are considered as emerging environmental problem due to their continuous input and persistence to the aquatic ecosystem even at low concentrations. Among them, carbamazepine (CBZ) has been detected at the highest frequency, which ends up in aquatic systems via wastewater treatment plants (WWTPs) among other sources. The identification and quantification of CBZ in wastewater (WW) and wastewater sludge (WWS) is of major interest to assess the toxicity of treated effluent discharged into the environment. Furthermore, WWS has been subjected for re-use either in agricultural application or for the production of value-added products through the route of bioconversion. However, this field application is disputable due to the presence of these organic compounds and in order to protect the ecosystem or end users, data concerning the concentration, fate, behavior as well as the perspective of simultaneous degradation of these compounds is urgently necessary. Many treatment technologies, including advanced oxidation processes (AOPs) have been developed in order to degrade CBZ in WW and WWS. AOPs are technologies based on the intermediacy of hydroxyl and other radicals to oxidize recalcitrant, toxic and non-biodegradable compounds to various by-products and eventually to inert end products. The purpose of this review is to provide information on persistent pharmaceutical compound, carbamazepine, its ecological effects and removal during various AOPs of WW and WWS. This review also reports the different analytical methods available for quantification of CBZ in different contaminated media including WW and WWS.

A comparative study of ultrasonication, Fenton's oxidation and ferro-sonication treatment for degradation of carbamazepine from wastewater and toxicity test by Yeast Estrogen Screen (YES) assay.

A comparative study of ultrasonication (US), Fenton's oxidation (FO) and ferro-sonication (FS) (combination of ultrasonication and Fenton's oxidation) advanced oxidation processes (AOPs) for degradation of carbamazepine (CBZ) from wastewater (WW) is reported for the first time. CBZ is a worldwide used antiepileptic drug, found as a persistent emerging contaminant in many wastewater treatment plants (WWTPs) effluents and other aquatic environments. The oxidation treatments of WW caused an effective removal of the drug. Among the various US, FO and FS pre-treatments carried out, higher soluble chemical oxygen demand (SCOD) and soluble organic carbon (SOC) increment (63 to 86% and 21 to 34%, respectively) was observed during FO pre-treatment process, resulting in higher removal of CBZ (84 to 100%) from WW. Furthermore, analysis of by-products formed during US, FO and FS pre-treatment in WW was carried out by using laser diode thermal desorption-atmospheric pressure chemical ionization (LDTD-APCI) coupled to tandem mass spectrometry (MS/MS). LDTD-APCI-MS/MS analysis indicated formation of two by-products, such as epoxycarbamazepine and hydroxycarbamazepine due to the reaction of hydroxyl radicals (OH) with CBZ during the three types of pre-treatment processes. In addition, the estrogenic activity of US, FO and FS pre-treated sample with CBZ and its by-products was carried out by Yeast Estrogen Screen (YES) assay method. Based upon the YES test results, none of the pre-treated samples showed estrogenic activity.

Carbamazepine in municipal wastewater and wastewater sludge: ultrafast quantification by laser diode thermal desorption-atmospheric pressure chemical ionization coupled with tandem mass spectrometry.

In this study, the distribution of the anti-epileptic drug carbamazepine (CBZ) in wastewater (WW) and aqueous and solid phases of wastewater sludge (WWS) was carried out. A rapid and reliable method enabling high-throughput sample analysis for quicker data generation, detection, and monitoring of CBZ in WW and WWS was developed and validated. The ultrafast method (15s per sample) is based on the laser diode thermal desorption-atmospheric pressure chemical ionization (LDTD-APCI) coupled to tandem mass spectrometry (MS/MS). The optimization of instrumental parameters and method application for environmental analysis are presented. The performance of the novel method was evaluated by estimation of extraction recovery, linearity, precision and detection limit. The method detection limits was 12 ng L(-1) in WW and 3.4 ng g(-1) in WWS. The intra- and inter-day precisions were 8% and 11% in WW and 6% and 9% in WWS, respectively. Furthermore, three extraction methods, ultrasonic extraction (USE), microwave-assisted extraction (MAE) and accelerated solvent extraction (ASE) with three different solvent condition such as methanol, acetone and acetonitrile:ethyle acetate (5:1, v/v) were compared on the basis of procedural blank and method recovery. Overall, ASE showed the best extraction efficiency with methanol as compared to USE and MAE. Furthermore, the quantification of CBZ in WW and WWS samples showed the presence of contaminant in all stages of the treatment plant.

Partial ozonation pre-treatment for sludge solubilization and simultaneous degradation of bisphenol A: quantification studies.

Ozonation pre-treatment was investigated for the enhancement of sludge solids and organic matter solubilization and simultaneous degradation of bisphenol A (BPA), an endocrine disruptor compound from wastewater sludge (WWS). The ultrafast method (15 s per sample) used for the analysis of BPA in WWS is based on Laser Diode Thermal Desorption/Atmospheric Pressure Chemical Ionization coupled to tandem Mass Spectrometry. The statistical methods used for optimization studies comprised the response surface method with fractional factorial designs and central composite designs. The ozonation pre-treatment process was carried out with four independent variables, namely WWS solids concentration (15-35 g l(-1)), pH (5-7), ozone dose (5-25 mg g(-1) SS) and ozonation time (10-30 min). It was observed that among all the variables studied, ozone dose had more significantly (probability (p) < 0.001) affected the efficiency of the ozonation pre-treatment by increasing sludge solids (suspended solids (SS) and volatile solids) solubilization and organic matter (soluble chemical oxygen demand and soluble organic carbon) increment and BPA degradation from WWS. During the optimization process, it was found that higher BPA degradation (100%) could be obtained with 24 g l(-1) SS, 6.23 pH with an ozone dose of 26.14 mg g(-1) SS for 16.47 min ozonation time. The higher ozone dose used in this study was observed to be cost effective on the basis of solids and organic matter solubilization and degradation of BPA.

Guanosine-induced decrease in side population of lung cancer cells: lack of correlation with ABCG2 expression.

Cancers contain a 'side population' (SP), a subset of cells that is greatly enriched in stem cells and which contains malignant progenitors. SP cells are characterised by high efflux capability for Hoechst 33342 dye and for anti-cancer therapeutic agents through transporters; ABCG2 (ATP-binding cassette transporter G2) is currently most closely associated with the SP phenotype. Guanosine is an important intercellular signalling molecule; it stimulates stem cell proliferation in vivo and affects cholesterol efflux in vitro through activation of ABCG transporter (ABCG1), raising the possibility that it might also affect ABCG2 and hence the SP. We examined the effects of guanosine on the SP of A549 lung cancer cells. Fluorescence-activated cell sorting (FACS) revealed that exposure to 10 microM guanosine significantly decreased the proportion of SP cells after 48 hours but not after 6 hours. In contrast, Western blot analysis showed that 10 microM guanosine significantly decreased ABCG2 expression after 6 hours, but not after 48 hours. These data demonstrate that guanosine affects both the proportion of SP cells and ABCG2 transporters, but the lack of correlation between ABCG2 expression and the SP phenotype indicates that transporters other than ABCG2 are involved in maintaining the SP phenotype in A549 lung cancer cells.

Sex hormone-binding globulin predicts the incidence of hyperglycemia in women: interactions with adiponectin levels.

OBJECTIVE: Previous evidence has suggested that a low sex hormone-binding globulin (SHBG) concentration is associated with insulin-resistance and a low adiponectin concentration. We investigated the association between SHBG and the risk of hyperglycemia in each sex and we determined potential interactions between SHBG and adiponectin levels in the development of dysglycemia. DESIGN: We used a nested case-control design in the large prospective study, Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR). We studied 227 men and women who were normoglycemic at baseline but hyperglycemic at 3 years (glycemia > or = 6.1 mmol/l or type 2 diabetes). They were matched for sex, age, and body mass index with 227 subjects who remained normoglycemic at 3 years. RESULTS: At baseline, the concentration of SHBG was significantly lower in women who subsequently developed hyperglycemia than in those who remained normoglycemic, with no difference for men. In multiple regression, SHBG at baseline was as an independent determinant of plasma adiponectin levels, in both women (P<0.0001) and men (P=0.002). In multivariate conditional logistic regression taking into account physical activity and changes in waist circumference over the follow-up, plasma SHBG remained significantly associated with the development of hyperglycemia in women but not in men. These associations persisted after adjustment for fasting insulinemia, high fasting glucose, and adiponectin levels. CONCLUSIONS: These findings suggest that a low SHBG level is a strong risk marker for dysglycemia in women, independently of both adiponectinemia and insulinemia. SHBG may therefore improve the identification of women at risk of diabetes.

Evaluación de la puesta en marcha de la Comisión de Cuidados en el Hospital Universitario Son Dureta / Evaluation of the initiation of the Committee on Care in the University Hospital Son Dureta

Introducción: Con la intención de impulsar la implantación del modelo y metodología de cuidados en el marco teórico conceptual de Virginia Henderson, en el Hospital Son Dureta, se decide constituir la Comisión de Cuidados, como órgano de decisión de todos los aspectos relacionados con la actividad cuidadora. Objetivo: El objetivo de este estudio es analizar el impacto de la puesta en marcha de la Comisión de Cuidados, sobre los indicadores de calidad, registros y metodología de cuidados en el hospital. Material y método: Realizamos un estudio comparativo de los resultados obtenidos durante 14 meses, 7 meses antes de la puesta en marcha de la Comisión de Cuidados en el año 2002, y 7 meses después de su puesta en marcha en el año 2003. Las variables de estudio fueron las siguientes: porcentaje de informes de enfermería realizados al alta, porcentaje de informes de valoración realizados al ingreso, la incidencia de úlceras por presión, la tasa de caídas, el número de procedimientos y protocolos realizados y revisados, y la formación teórica ofrecida. Resultados y conclusión: De los resultados obtenidos en ambos períodos, podemos concluir que la puesta en marcha de la Comisión de Cuidados, ha supuesto una mejora en los cuidados realizados por los profesionales, aumentando el número de registros cumplimentados, tanto los de valoración al ingreso como los informes de enfermería al alta, mejorando los indicadores de calidad; debido, en gran medida, al incremento en la participación e implicación, de los profesionales de enfermería del hospital (AU)

Administration of exogenous endothelin-1 following vascular balloon injury: early and late effects on intimal hyperplasia.

Administration of exogenous endothelin-1 (ET-1) has been shown to stimulate neointimal hyperplasia following arterial balloon angioplasty (BA). However, the specific effects of ET-1 on the cellular and extracellular matrix response of the vessel wall after balloon injury and the persistence of these ET-1 effects have not been studied. The objectives of this study were to determine the acute (1 week) and long term (10 weeks) effects of administering exogenous ET-1 after arterial BA on neointimal hyperplasia, collagen synthesis and content, cellular proliferation, and ET(A) and ET(B) receptor expression. Thirty-one rabbits were randomized to receive subcutaneous ET-1 (500 pmol/kg/day for 1 week) or placebo time-release pellets and sacrificed at either 1 or 10 weeks after BA. At 1 week, there was a significant two-fold increase in intimal cross-sectional area (CSA) in ET-1 treated animals compared with placebo. ET-1 treated animals showed significant increases in collagen synthesis (ten-fold) and collagen content (three-fold) compared to placebo treated animals. ET-1 treated animals also had a significant increase (two-fold) in proliferation rates. In addition, ET(A) and ET(B) receptor expression were significantly upregulated in ET-1 treated animals. By 10 weeks these stimulatory effects on intimal CSA and collagen content were no longer evident with a 'catch up' phenomenon observed in the placebo treated animals. Similarly, ET(A) and ET(B) mRNA levels had declined significantly in both groups. Therefore, exogenous ET-1 acutely stimulates extracellular and cellular processes including increased expression of ET(A) and ET(B) receptors contributing to intimal hyperplasia. However, these effects are transient and not maintained long term after withdrawal of exogenous ET-1 stimulation.

Myocardial contractile responsiveness to endothelin-1 in the post-infarction rat model of heart failure: effects of chronic quinapril.

Cardiac endothelin-1 (ET-1) levels and ET receptor expression are increased in congestive heart failure (CHF). In order to determine whether this results in increased responsiveness of ET-A or ET-B receptors to ET-1, we evaluated the contractile effects of ET-1 in isolated papillary muscles isolated from hearts of control rats and from rats 4 weeks post myocardial infarction (MI) having received no therapy or chronic quinapril therapy. The ET-1 dose-response was biphasic in normal muscles. The use of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 revealed that the initial decrease in tension was the result of ET-B receptor stimulation. Blockade of nitric oxide (NO) production with L-NAME abolished the initial decrease in tension. MI resulted in CHF that was partially reversed by quinapril. In MI, the positive inotropic effects of ET-1 were enhanced due to the loss of the initial ET-B receptor mediated decrease in tension, as well as an increase in the positive inotropic effects of ET-A receptors. This was associated with an increase in ET-A and ET-B receptor mRNA and a decrease in cardiac ecNOS protein. Four weeks of therapy with quinapril attenuated the positive inotropic effects of ET-1 and prevented the increase in ET-A receptor mRNA. Although quinapril did not restore the effects of ET-B receptor stimulation or prevent the increase in ET-B mRNA, it did restore cardiac ecNOS protein expression. Thus, the inotropic response to ET-1 is biphasic due to an overall positive inotropic effect of ET-A receptor stimulation and an ET-B receptor mediated decrease in contractility at low ET-1 concentrations which appears to be mediated by cardiac ecNOS (NO). In post-MI CHF, responsiveness to ET-A receptors increases and the ET-B mediated negative inotropic response is lost despite an increase in both receptor subtypes. Quinapril therapy attenuates these effects and normalises cardiac ecNOS protein.

Influence of thermal motion on 1H chemical shifts in proteins: the case of bovine pancreatic trypsin inhibitor.

The possible influence of thermal motion on 1H chemical shifts is discussed for a small stable protein, the bovine pancreatic Kunitz trypsin inhibitor (BPTI). The thermal effects on the aromatic side chains and on the backbone are treated separately. The thermal motion of the aromatic side chains is accounted for in terms of their rotation around the C(alpha)-C(beta) bond and the motion of each individual proton is interpreted as a ratio between the amount of ordered and quite disordered states. The influence of hydrogen bonds is introduced as an extra contribution to the chemical shifts of the bonded proton. Their contribution to the chemical shifts resulting from the polarization of the peptide bond is investigated, as is their influence on local flexibility. Finally, the relative importance of each contribution to the chemical shift information is compared.

Expression of nitric oxide synthases and nitrotyrosine during blood-brain barrier breakdown and repair after cold injury.

This study was undertaken to determine whether the blood-brain barrier (BBB) breakdown and cerebral edema occurring post-trauma are associated with overexpression of the endothelial (e) and inducible (i) nitric oxide synthases (NOS), enzymes responsible for nitric oxide (NO) biosynthesis. These enzymes were determined quantitatively at the mRNA level and qualitatively at the protein level in the rat cerebral cortical cold injury model, during a period up to 6 days post-injury. In addition, peroxynitrite generation at the lesion site was detected by immunolocalization of nitrotyrosine as a marker of NO-superoxide interactions. These studies were correlated with the permeability status of the BBB by immunohistochemical detection of endogenous fibronectin extravasation in the same brains. BBB breakdown was immediate in lesion vessels, it was present as early as 10 minutes post-lesion and delayed in perilesional vessels that showed maximal BBB breakdown between 2-4 days. The BBB was restored to normal at 6 days post-lesion. An increase in both eNOS and iNOS mRNA was observed at the lesion site as compared with the contralateral hemisphere at 12 hours, 2 days, and 4 days. The mRNA returned to resting levels by 6 days. Increased eNOS protein was observed in the endothelium of permeable perilesional vessels and neovessels and in the endothelium of the hyperplastic pial vessels overlying the lesion site. iNOS protein was observed initially in polymorphonuclear leukocytes at the lesion site and later in macrophages, endothelial cells, and the smooth muscle cells of the overlying pial vessels. Furthermore, nitrotyrosine was demonstrated at the lesion site up to 5 days. Up-regulation of the NO synthases at both the mRNA and protein level accompanied by presence of nitrotyrosine during BBB breakdown and angiogenesis suggests that NO has a role in the pathogenesis of these processes.

Potentiation of the antinociceptive effect of clomipramine by a 5-ht(1A) antagonist in neuropathic pain in rats.

The benefit of antidepressant treatment in human neuropathic pain is now well documented, but the effect is limited and slow to appear. It has been demonstrated that the association of a 5-HT(1A) antagonist and a serotoninergic antidepressant reduced the delay of action and increases the thymoanaleptic effect of the drug. The purpose of this work was to evaluate the combination of an antidepressant and a 5-HT(1A) antagonist in animal models of chronic neuropathic pain. We studied the antinociceptive effect of the co-administration of clomipramine and a 5-HT(1A) antagonist (WAY 100,635) in a pain test applied in normal rats and in two models of neurogenic sustained pain (mononeuropathic and diabetic rats). The results show an increase in the antinociceptive effect of acutely injected clomipramine due to WAY 100,635 in these models, which is majored when the two drugs are repeatedly injected. The 5-HT(1A) antagonist reduced the delay of onset and increased the maximal antinociceptive effect of clomipramine. These new findings argue for using the combination of an antidepressant and a 5-HT(1A) antagonist in human neuropathic pain therapy.

N-Terminal domain of HTLV-I integrase. Complexation and conformational studies of the zinc finger.

The HTLV-I integrase N-terminal domain [50-residue peptide (IN50)], and a 35-residue truncated peptide formed by residues 9-43 (IN35) have been synthesized by solid-phase peptide synthesis. Formation of the 50-residue zinc finger type structure through a HHCC motif has been proved by UV-visible absorption spectroscopy. Its stability was demonstrated by an original method using RP-HPLC. Similar experiments performed on the 35-residue peptide showed that the truncation does not prevent zinc complex formation but rather that it significantly influences its stability. As evidenced by CD spectroscopy, the 50-residue zinc finger is unordered in aqueous solution but adopts a partially helical conformation when trifluoroethanol is added. These results are in agreement with our secondary structure predictions and demonstrate that the HTLV-I integrase N-terminal domain is likely to be composed of an helical region (residues 28-42) and a beta-strand (residues 20-23), associated with a HHCC zinc-binding motif. Size-exclusion chromatography showed that the structured zinc finger dimerizes through the helical region.

Human T-lymphotrophic virus type I nucleocapsid protein NCp15: structural study and stability of the N-terminal zinc-finger.

An 18-residue peptide, corresponding to the minimum sequence of the N-terminal zinc-finger domain in the nucleocapsid of human T-lymphotrophic virus type I, was synthesized by a solid-phase method and fully characterized. Its ability to complex metal ions (Co(2+) and Zn(2+)) was clearly established by UV-visible spectroscopy and MS. The stability of these complexes was investigated by an original method with HPLC chromatography. Our results show that, even in the presence of air, the Zn(2+) complex is highly stable. In contrast, the Co(2+) complex undergoes a relatively fast degradation due to an intramolecular oxidation leading to the formation of a disulphide bridge between two cysteine residues. The (1)H-NMR analysis indicates that Zn(2+) binds to the Ndelta atom of the histidine residue rather than to the Nepsilon atom. Two-dimensional NMR techniques were used to determine the solution structure of the zinc-finger, illustrated by the existence of turns in the overall conformation.

Blockade of endothelin receptors markedly reduces atherosclerosis in LDL receptor deficient mice: role of endothelin in macrophage foam cell formation.

OBJECTIVE: We evaluated the direct effects of long-term blockade of ET(A) and ET(B) receptors using a mixed endothelin (ET) receptor antagonist, LU224332, in the low density lipoprotein receptor (LDL-R) knockout mouse model of atherosclerosis. METHODS: Four groups of LDL-R deficient mice were studied: control mice fed normal chow (group I); mice fed a high cholesterol (HC, 1.25%) diet alone (group II), HC fed animals treated with LU224332 (group III); and mice fed normal chow treated with the LU compound (group IV). All treatments were continued for 8 weeks at which time the animals were sacrificed and the aortae were removed and stained with oil red O. Atherosclerotic area (AA) was determined by quantitative morphometry and normalized relative to total aortic area (TA). RESULTS: Cholesterol feeding resulted in a marked increased in total plasma cholesterol ( approximately 15 fold) and widespread aortic atherosclerosis (AA/TA: group I: 0.013+/-0.007; group II: 0.33+/-0. 11; P<0.001). Atherosclerotic lesions were characterized by immunohistochemistry as consisting mainly of macrophages which also showed high levels of ET-1 expression. Treatment with ET antagonist significantly reduced the development of atherosclerosis (AA/TA: group III: 0.19+/-0.07, P<0.01 vs. group II), without altering plasma cholesterol levels and blood pressure. The direct effect of LU224332 on macrophage activation and foam-cell formation was determined in vitro using a human macrophage cell line, THP-1. Treatment of the THP-1 cells with LU224332 significantly reduced cholesterol ester and triacylglycerol accumulation and foam-cell formation on exposure to oxidized LDL (P<0.01 and P<0.05, respectively). CONCLUSION: We conclude that a nonselective ET receptor antagonist substantially inhibited the development of atherosclerosis in a genetic model of hyperlipidemia, possibly by inhibiting macrophage foam-cell formation, suggesting a role for these agents in the treatment and prevention of atherosclerotic vascular disease.

Quantum impurities and the neutron resonance peak in YBa2Cu3O7: Ni versus Zn.

The influence of magnetic (S=1) and nonmagnetic (S=0) impurities on the spin dynamics of an optimally doped high temperature superconductor is compared in YBa2(Cu0.97Ni0.03)3O7 (Tc=80 K) and YBa2(Cu0.99Zn0.01)3O7 (Tc=78 K). In the Ni-substituted system, the magnetic resonance peak (which is observed at Er approximately 40 meV in the pure system) shifts to lower energy with a preserved Er/Tc ratio while the shift is much smaller upon Zn substitution. By contrast Zn, but not Ni, restores significant spin fluctuations around 40 meV in the normal state. These observations are discussed in the light of models proposed for the magnetic resonance peak.