Datasets:

kjappelbaum

/

chemnlp-chemdner

like 0

Agonism of human pregnane X receptor by rilpivirine and etravirine: Comparison with first generation non-nucleoside reverse transcriptase inhibitors.

test

Rilpivirine and etravirine are second generation non-nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus-1 infection. Pregnane X receptor (PXR) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions. The present study investigated the effects of rilpivirine and etravirine on the activity of human PXR (hPXR), including the mode of activation, and compared them to those of efavirenz, nevirapine, and delavirdine, which are first generation non-nucleoside reverse transcriptase inhibitors. In transiently transfected HepG2 cells, rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, activated human, mouse, and rat PXR. Results from mechanistic studies indicated that rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, bound to the ligand-binding domain of hPXR, as assessed by a transactivation assay and by a competitive ligand-binding assay using time-resolved fluorescence resonance energy transfer; triggered nuclear translocation of a green fluorescence protein-tagged hPXR, as visualized by confocal imaging; and recruited steroid receptor coactivator-1 (SRC-1), SRC-2, and SRC-3 to hPXR, as demonstrated by mammalian two-hybrid assays. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, increased hPXR target gene (CYP3A4) expression in primary cultures of human hepatocytes. In summary, select non-nucleoside reverse transcriptase inhibitors activated human and rodent PXR. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, were identified as agonists of hPXR, as assessed in mechanistic experiments, and inducers of CYP3A4, as determined in primary cultures of human hepatocytes.

test

Inhibitory effects of gypenosides on seven human cytochrome P450 enzymes in vitro.

test

Among the various possible causes for drug interactions, pharmacokinetic factors such as inhibition of drug-metabolizing enzymes, especially cytochrome P450 (CYP) enzymes, are regarded as the most frequent and clinically important. Gypenosides is widely used as functional food and over-the-counter drug in East Asia. In this study, the in vitro inhibitory effects of gypenosides on the major human CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) activities in human liver microsomes were examined using liquid chromatography-tandem mass spectrometry. Gypenosides showed the strongest inhibition of CYP2D6, followed by CYP2C8, CYP3A4 and CYP2C9. The IC50 values were 1.61μg/mL, 20.06μg/mL, 34.76μg/mL (CYP3A4/midazolam), 46.73μg/mL (CYP3A4/testosterone), and 54.52μg/mL, respectively. Gypenosides exhibited competitive inhibition of CYP2D6 (Ki=1.18). In conclusion, Gypenosides might cause herb-drug interactions via inhibition of CYP2D6. An in vivo study is needed to examine this further.

test

Novel racemic tetrahydrocurcuminoid dihydropyrimidinone analogues as potent acetylcholinesterase inhibitors.

test

The synthesis of racemic tetrahydrocurcumin- (THC-), tetrahydrodemethoxycurcumin- (THDC-) and tetrahydrobisdemethoxycurcumin- (THBDC-) dihydropyrimidinone (DHPM) analogues was achieved by utilizing the multi-component Biginelli reaction in the presence of copper sulphate as a catalyst. The evaluation of acetylcholinesterase inhibitors for Alzheimer's disease of these compounds showed that they exhibited higher inhibitory activity than their parent analogues. THBDC-DHPM demonstrated the most potent inhibitory activity with an IC50 value of 1.34±0.03μM which was more active than the approved drug galanthamine (IC50=1.45±0.04μM).

test

Design considerations for PAMAM dendrimer therapeutics.

test

We have previously shown that methotrexate (MTX) conjugated to a cancer-specific poly amido amine (PAMAM) dendrimer has a higher therapeutic index than MTX alone. Unfortunately, these therapeutics have been difficult to advance because of the complicated syntheses and an incomplete understanding of the dendrimer properties. We wished to address these obstacles by using copper-free click chemistry to functionalize the dendrimer scaffolds and to exploring the effects of two dendrimer properties (the targeting ligand and drug linkage) on cytotoxicity. We conjugated either ester or amide-linker modified MTX to dendrimer scaffolds with or without folic acid (FA). Because of multivalency, the FA and MTX functionalized dendrimers had similar capacities to target the folate receptor on cancer cells. Additionally, we found that the ester- and amide-linker modified MTX compounds had similar cytotoxicity but the dendrimer-ester MTX conjugates were much more cytotoxic than the dendrimer-amide MTX conjugates. These results clarify the impact of these properties on therapeutic efficacy and will allow us to design more effective polymer therapeutics.

test

A urinary metabonomics study on biochemical changes in yeast-induced pyrexia rats: a new approach to elucidating the biochemical basis of the febrile response.

test

Fever is a prominent feature of many diseases, such as infection, inflammation and trauma. In the clinic, fever can be easily judged by measuring the body temperature; however, the pathogenesis of fever is still not fully understood. A febrile response is a systemic pathological process that can cause metabolic disorders. Metabonomics can provide powerful tools to reveal the pathological mechanisms for such a systemic disease. Thus, to reveal subtle metabolic changes under the condition of fever and to explore its mechanism, an ultra performance liquid chromatography coupled with a quadrupole time-of-flight mass spectrometry metabonomics approach was employed to investigate the urine biochemical characteristics of yeast-induced pyrexia rats. The acquired data were subjected to principal component analysis for differentiating the pyrexia rats from the control rats. Potential biomarkers were screened by using orthogonal partial least-squares-discriminant analysis and were identified by accurate mass, database, and MS/MS fragment information obtained from the MS(E) technique. Sixteen metabolites in rat urine were identified as potential biomarkers. The relative intensities of the 15 potential biomarkers were calculated. The thermoregulatory circuitry of "endogenous pyrogen (EP) ↑-hypothalamus Na(+)/Ca(2+)-cAMP↑" was partially confirmed in this study. The results suggested that UPLC/MS-based metabolic profiling of rat urine identifies impaired tryptophan metabolism as the mechanism of yeast-induced fever. This research provided informative data that the impaired tryptophan metabolism might be one of the important reasons in elucidating the biochemical basis of the febrile response.

test

Xiaoxuming decoction for acute ischemic stroke: A systematic review and meta-analysis.

test

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoxuming decoction (XXMD) is a well-known traditional Chinese herbal prescription in treatment of patients with stroke. The objective of this study is to assess the efficacy and safety of XXMD for acute ischemic stroke. MATERIALS AND METHODS: A systematic literature search was conducted in 6 databases until June 2012 to identify randomized controlled trials (RCTs) of XXMD for acute ischemic stroke compared with western conventional medicine (WCM). The primary outcome measures were National Institutes of Health Stroke Scale (NIHSS) scores and modified Rankin Scale (mRS) scores. The secondary outcome measures were the clinical effective rate and adverse events at the end of treatment course. The methodological quality of RCTs was assessed independently using 12-item criteria according to the Cochrane Back Review Group. All data were analyzed using Review Manager 5.0 software. RESULTS: Eight RCTs with 601 individuals published from 1992 to 2012 were identified. The studies were deemed to have a high risk of bias. Compared with WCM, 1 RCT showed significant effects of XXMD for improving mRS after stroke (p<0.05); 3 RCTs for improving NIHSS scores [n=186, weighted mean difference (WMD): -1.86, 95% CI: -3.25 to -0.48, z=2.63, p<0.01]; 7 RCTs for improving the clinical effective rate [n=531, risk ratio (RR)=1.17, 95% CI, 1.09 to 1.26, z=4.38, p<0.01]. Five trials contained safety assessments and stated that no adverse event was found, whereas the other 3 trials did not provide the information about adverse events. CONCLUSIONS: This systematic review showed positive but weak evidence of XXMD for acute ischemic stroke because of the poor methodological quality and the small quantity of the included trials. The difficulties of fitting Chinese herbal medicine (CHM) into the double blinded RCTs have raised as follows: (A) traditional Chinese medicine (TCM) as whole systems of healthcare offers unique methodological and theoretical challenges for RCTs; (B) suspicions against the placebo and unwillingness to stop taking other CHMs make recruitment more difficulty, time-consumption, and cost; (C) the shortcomings of the TCM diagnostic process includes the lack of standardization in terminology, disagreement of pattern differentiation (Bianzheng), and neglect of formula corresponding to syndrome (TCM Zheng); (D) It is difficult to design credible herbal placebos with similar appearance, smells and tastes to the experimental CHM and at the same time is absent of any pharmacological activity; (E) the achieving efficacy of CHM complex interventions is often nonspecific and the outcome measures is subjective using Chinese quantitative instrument.

test

Insights into mast cell functions in asthma using mouse models.

test

Therapeutics targeting specific mechanisms of asthma have shown promising results in mouse models of asthma. However, these successes have not transferred well to the clinic or to the treatment of asthma sufferers. We suggest a reason for this incongruity is that mast cell-dependent responses, which may play an important role in the pathogenesis of both atopic and non-atopic asthma, are not a key component in most of the current asthma mouse models. Two reasons for this are that wild type mice have, in contrast to humans, a negligible number of mast cells localized in the smaller airways and in the parenchyma, and that only specific protocols show mast cell-dependent reactions. The development of mast cell-deficient mice and the reconstitution of mast cells within these mice have opened up the possibility to generate mouse models of asthma with a marked role of mast cells. In addition, mast cell-deficient mice engrafted with mast cells have a distribution of mast cells more similar to humans. In this article we review and highlight the mast cell-dependent and -independent responses with respect to airway hyperresponsiveness and inflammation in asthma models using mast cell-deficient and mast cell-engrafted mice.

test

Melanoidins isolated from heated potato fiber (Potex) affect human colon cancer cells growth via modulation of cell cycle and proliferation regulatory proteins.

test

Melanoidins are brown, nitrogen containing, high molecular weight end products of Maillard reaction with poorly established activity towards tumor cells. The goal of present study was to verify whether both heated potato fiber Potex extract (180°C for 2h) and melanoidins isolated from the extract exerts growth-inhibiting activity in human colon cancer cells in vitro. The cells of LS180 colon cancer cell line were tested upon treatment with roasted potato fiber extract (AM4) as well as with high (HMW) and low (LMW) molecular weight fractions isolated from the extract, since both may be regarded as/or contain melanoidins. The tested compounds at concentration of 1000μg/ml reduced cell growth down to 45%, 69% and 54%, respectively. Furthermore, deregulated ERK1/2 signaling was revealed upon treatment. Moreover, multiple alternations in cell cycle regulators activity were found (i.e. cyclinD1, cyclin-dependent kinase 4 and 6, p21, p27, p53, pRb) leading to cell cycle cessation in G0 phase. Importantly, LMW compounds revealed markedly stronger potential to alter specific molecular targets comparing to HMW compounds. Summarizing, the results emphasize that both high and low molecular weight melanoidins contribute to antiproliferative activity of heated potato fiber in LS180 colon cancer cells in vitro.

test

Short-term heating reduces the anti-inflammatory effects of fresh raw garlic extracts on the LPS-induced production of NO and pro-inflammatory cytokines by downregulating allicin activity in RAW 264.7 macrophages.

test

Garlic has a variety of biologic activities, including anti-inflammatory properties. Although garlic has several biologic activities, some people dislike eating fresh raw garlic because of its strong taste and smell. Therefore, garlic formulations involving heating procedures have been developed. In this study, we investigated whether short-term heating affects the anti-inflammatory properties of garlic. Fresh and heated raw garlic extracts (FRGE and HRGE) were prepared with incubation at 25°C and 95°C, respectively, for 2h. Treatment with FRGE and HRGE significantly reduced the LPS-induced increase in the pro-inflammatory cytokine concentration (TNF-α, IL-1β, and IL-6) and NO through HO-1 upregulation in RAW 264.7 macrophages. The anti-inflammatory effect was greater in FRGE than in HRGE. The allicin concentration was higher in FRGE than in HRGE. Allicin treatment showed reduced production of pro-inflammatory cytokines and NO and increased HO-1 activity. The results show that the decrease in LPS-induced NO and pro-inflammatory cytokines in RAW 264.7 macrophages through HO-1 induction was greater for FRGE compared with HRGE. Additionally, the results indicate that allicin is responsible for the anti-inflammatory effect of FRGE. Our results suggest a potential therapeutic use of allicin in the treatment of chronic inflammatory disease.

test

Motor neuron dysfunction in a mouse model of ALS: Gender-dependent effect of P2X7 antagonism.

test

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative progressive currently untreatable disease, characterized by selective motor neuron degeneration; the incidence and prevalence of ALS are greater in men than in women. Although some important mechanisms that might contribute to the death of motor neurons have been identified, the mechanisms underlying disease pathophysiology are still uncertain. In particular, the mechanisms underlying the role of gender in ALS and whether treatments should take into account sexual dimorphism remain only partially understood. Recently, the P2X7 receptor for ATP was reported to display neurotoxic potential in motor neuron disorders, and antagonism of the receptor has been suggested to be helpful in these disorders. Studying transgenic mice with superoxide dismutase 1 gene mutations, widely used as model for ALS, may provide a better understanding of pathogenic mechanisms and of toxicity towards motor neurons, also possibly helping to understand whether treatments for ALS should take into account sexual dimorphism. The aim of the work was (1) investigating on gender-dependence of disease progression in the standard model for ALS - the transgenic mouse bearing superoxide dismutase 1 gene mutations - and (2) assessing if a P2X7 receptor antagonist treatment should take into account sexual dimorphism. We evaluated if gender affect the disease course, the motor performance, the weight loss and the lifespan in mice overexpressing mutant superoxide dismutase 1. We measured motor impairment, motor strength and coordination by rotarod and grip strength testing. Further, we assessed if a treatment with the P2X7 receptor antagonist Brilliant Blue G - a dye that can cross the blood-brain barrier, has low toxicity, and has exhibited therapeutic effects in animal models of neurodegenerative diseases - impact on the disease progression, in male and female ALS mice. We found that (1) the onset and the disease progression, and the survival were dependent on gender: male performed worst than female, lost body weight and died before; (2) treatment with the P2X7 receptor antagonist Brilliant Blue G ameliorated the disease progression. The treatment effect was gender-dependent: amelioration was greater in male than in female. In conclusions, we suggest that not only pathogenetic mechanism of motor neuron toxicity but also the drug treatment effectiveness may depend on gender; sexual dimorphism should be considered when investigating on ALS treatment efficacy in the ALS animal model. Our findings also point on the potential relevance of P2X7 receptor antagonism for ALS treatment, and highlight the importance of adopting a sex-specific approach to searching for treatment of ALS.

test

2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced inflammatory activation is mediated by intracellular free calcium in microglial cells.

test

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been known to induce inflammatory signaling in a number of cell types and tissues. However, the adverse effects of TCDD on the central nervous system (CNS) have not been entirely elucidated. In this study, using reverse transcriptase PCR (RT-PCR) and ELISA, we showed that TCDD up-regulated the expression and secretion of tumor necrosis factor-alpha (TNF-α) in a time-dependent manner in cultured HAPI microglial cells. TCDD also caused a fast (within 30min as judged by the increase in its mRNA level) activation of cytosolic phospholipase A2 (cPLA2). This initial action was accompanied by up-regulation of cyclooxygenase-2 (COX-2), an important inflammation marker within 1h after TCDD treatment. These pro-inflammatory responses were inhibited by two types of Ca(2+) blockers, bis-(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester (BAPTA-AM) and nifedipine, thus, indicating that the effects are triggered by initial increase in the intracellular concentration of free Ca(2+) ([Ca(2+)]i). Further, TCDD exposure could induce phosphorylation- and ubiquitination-dependent degradation of IкBα, and the translocation of NF-κB p65 from the cytosol to the nucleus in this microglial cell line. Thus, the NF-κB signaling pathway can be activated after TCDD treatment. However, Ca(2+) blockers also obviously attenuated NF-κB activation and transnuclear transport induced by TCDD. In concert with these results, we highlighted that the secretion of pro-inflammatory cytokine and NF-κB activation induced by TCDD can be mediated by elevation of [Ca(2+)]i in HAPI microglial cells.

test

Extract from Mimosa pigra attenuates chronic experimental pulmonary hypertension.

test

ETHNOPHARMACOLOGICAL RELEVANCE: Different parts of Mimosa pigra (MPG) are used in traditional medicine in Madagascar, tropical Africa, South America and Indonesia for various troubles including cardiovascular disorders. AIM OF THE STUDY: To investigate the mechanisms underlying the vascular effects of MPG by assessing in vitro its antioxidant and anti-inflammatory properties, and its vascular relaxing effects, and in vivo, its action on hypoxic pulmonary hypertension (PAH) in rats. MATERIAL AND METHODS: The antioxidant activity of MPG leaf hydromethanolic extract was determined by using both the 1,1-diphenyl-2-picrylhydrazyl radical scavenging and the oxygen radical absorbance capacity in vitro assays. Anti-inflammatory properties were assayed on TNFα-induced VCAM-1 expression in endothelial cells. The vasorelaxant effect of MPG extract was studied on rat arterial rings pre-contracted with phenylephrine (1μM) in the presence or absence of the endothelium. In vivo MPG extract effects were analyzed in chronic hypoxic PAH, obtained by housing male Wistar rats, orally treated or not with MPG extract (400mg/kg/d), in a hypobaric chamber for 21 days. RESULTS: MPG leaf extract had antioxidant and anti-inflammatory properties. It induced endothelium-dependent, NO-mediated relaxation of rat aorta and pulmonary artery. In vivo, chronic MPG treatment reduced hypoxic PAH in rat by decreasing by 22.3% the pulmonary arterial pressure and by 20.0% and 23.9% the pulmonary artery and cardiac remodelling, respectively. This effect was associated with a restoration of endothelium function and a 2.3-fold increase in endothelial NO synthase phosphorylation. MPG leaf hydromethanolic extract contained tryptophan and flavonoids, including quercetin glycosides. Both compounds also efficiently limit hypoxia-induced PAH. CONCLUSIONS: Our results show endothelial protective action of MPG leaf hydromethanolic extract which is likely to be due to its antioxidant action. MPG successfully attenuated the development of PAH, thus demonstrating the protective effect of MPG on cardiovascular diseases.

test

The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels.

test

During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'.

test

Genetic deletion of the adenosine A2A receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain.

test

Considerable evidence indicates that adenosine A2A receptors (A2ARs) modulate cholinergic neurotransmission, nicotinic acetylcholine receptor (nAChR) function, and nicotine-induced behavioural effects. To explore the interaction between A2A and nAChRs, we examined if the complete genetic deletion of adenosine A2ARs in mice induces compensatory alterations in the binding of different nAChR subtypes, and whether the long-term effects of nicotine on nAChR regulation are altered in the absence of the A2AR gene. Quantitative autoradiography was used to measure cytisine-sensitive [(125)I]epibatidine and [(125)I]α-bungarotoxin binding to α4β2* and α7 nAChRs, respectively, in brain sections of drug-naïve (n = 6) or nicotine treated (n = 5-7), wild-type and adenosine A2AR knockout mice. Saline or nicotine (7.8 mg/kg/day; free-base weight) were administered to male CD1 mice via subcutaneous osmotic minipumps for a period of 14 days. Blood plasma levels of nicotine and cotinine were measured at the end of treatment. There were no compensatory developmental alterations in nAChR subtype distribution or density in drug-naïve A2AR knockout mice. In nicotine treated wild-type mice, both α4β2* and α7 nAChR binding sites were increased compared with saline treated controls. The genetic ablation of adenosine A2ARs prevented nicotine-induced upregulation of α7 nAChRs, without affecting α4β2* receptor upregulation. This selective effect was observed at plasma levels of nicotine that were within the range reported for smokers (10-50 ng ml(-1)). Our data highlight the involvement of adenosine A2ARs in the mechanisms of nicotine-induced α7 nAChR upregulation, and identify A2ARs as novel pharmacological targets for modulating the long-term effects of nicotine on α7 receptors.

test

Profiling the venom gland transcriptome of Tetramorium bicarinatum (Hymenoptera: Formicidae): The first transcriptome analysis of an ant species.

test

Animal venoms are complex mixtures containing a range of bioactive elements with potential pharmacological and therapeutic use. Even though ants account among the most diverse zoological group, little information is available regarding their venom composition. To initiate the characterization of the transcriptomic venom gland expression of the ant species Tetramorium bicarinatum, 400 randomly selected clones from cDNA library were sequenced and a total of 364 high quality expressed sequence tags (ESTs) were generated. Based on the results of BLAST searches, these sequences were clustered and assembled into 83 contigs (22 multiple sequences) and 61 singletons. About 74% (267) of the contigs matched BLASTx hits with an interesting diversity together with an unusual abundance of cellular transcripts related to gene expression regulation (29% of the total library) reflecting the specialization of this tissue. About eighteen per cent of the ESTs were categorized as Hymenoptera venom compounds, the major part represented by allergens (62% of the total venom compounds). In addition, a high number of sequences (26%) had no similarity to any known sequences. This study provides a first insight of the gene expression scenario of the venom gland of T. bicarinatum which might contribute to acquiring a more comprehensive view on the origin and functional diversity of venom proteins among ants and more broadly among Hymenopteran insects.

test

Simultaneous determination of methanol, acetaldehyde, acetone, and ethanol in human blood by gas chromatography with flame ionization detection.

test

Background: Methanol, acetaldehyde, acetone, and ethanol, which are commonly used as biomarkers of several diseases, in acute intoxications, and forensic settings, can be detected and quantified in biological fluids. Gas chromatography (GC)-mass spectrometry techniques are complex, require highly trained personnel and expensive materials. Gas chromatographic determinations of ethanol, methanol, and acetone have been reported in one study with suboptimal accuracy. Our objective was to improve the assessment of these compounds in human blood using GC with flame ionization detection.Methods: An amount of 50 µl of blood was diluted with 300 µl of sterile water, 40 µl of 10% sodium tungstate, and 20 µl of 1% sulphuric acid. After centrifugation, 1 µl of the supernatant was inje-cted into the gas chromatograph. We used a dimethylpolysiloxane capillary column of 30 m 0.25 mm 0.25 µm.Results: We observed linear correlations from 7.5 to 240 mg/l for methanol, acetaldehyde, and acetone and from 75 to 2400 mg/l for ethanol. Precision at concentrations 15, 60, and 120 mg/l for methanol, acetaldehyde, and acetone and 150, 600, and 1200 mg/ml for ethanol were 0.8-6.9%. Ranges of accuracy were 94.7-98.9% for methanol, 91.2-97.4% for acetaldehyde, 96.1-98.7% for acetone, and 105.5-111.6% for ethanol. Limits of detection were 0.80 mg/l for methanol, 0.61 mg/l for acetaldehyde, 0.58 mg/l for acetone, and 0.53 mg/l for ethanol.Conclusion: This method is suitable for routine clinical and forensic practices.

test

Progression rates from HbA1c 6.0-6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis.

test

AIMS/HYPOTHESIS: Precise estimates of progression rates from 'prediabetes' to type 2 diabetes are needed to optimise prevention strategies for high-risk individuals. There is acceptance of prediabetes defined by impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), but there is some controversy surrounding HbA1c-defined prediabetes ranges, with some favouring 6.0-6.4% (42-46 mmol/mol). Comparing progression rates between groups might aid this issue, thus we aimed to accurately estimate progression rates to diabetes from different prediabetes categories. METHODS: Meta-analysis of prospective observational studies in which participants had prediabetes at baseline (ADA-defined IFG [5.6-6.9 mmol/l], WHO-defined IFG [6.1-6.9 mmol/l], IGT (7.8-11.0 mmol/l) or raised HbA1c [6.0-6.4%/42-46 mmol/mol]) and were followed up for incident diabetes. Incidence rates were combined using Bayesian random effects models. RESULTS: Overall, 70 studies met the inclusion criteria. In the six studies that used raised HbA1c, the pooled incidence rate (95% credible interval) of diabetes was 35.6 (15.1, 83.0) per 1,000 person-years. This rate was most similar to that for ADA-defined IFG (11 studies; 35.5 [26.6, 48.0]) and was non-significantly lower than WHO-defined IFG (34 studies; 47.4 [37.4, 59.8]), IGT (46 studies, 45.5 [37.8, 54.5]) and IFG plus IGT (15 studies, 70.4 [53.8, 89.7]). Similar results were seen when the data were analysed by the criteria used to diagnose diabetes. CONCLUSIONS/INTERPRETATION: This study provides evidence that progression rates differ by prediabetes definition, which has implications for the planning and implementation of diabetes prevention programmes. HbA1c 6.0-6.4% might identify people at a lower diabetes risk than other prediabetes definitions, but further research is needed.

test

Proteasomal cleavage site prediction of protein antigen using BP neural network based on a new set of amino acid descriptor.

test

Effects of Dietary Factors on the Pharmacokinetics of (58)Fe-labeled Hemin After Oral Administration in Normal Rats and the Iron-deficient Rats.

test

Hemin, iron (III) protoporphyrin chloride (IX), as a stable form of heme iron, has been used in iron absorption studies. The aim of the present study was to elucidate the influences of body iron status and three dietary factors (green tea extract, ascorbic acid, and calcium) on the pharmacokinetics of hemin using stable isotope labeling methods followed by ICP-MS measurement. In this study, a rapid, sensitive, and specific ICP-MS method for the determination of (58)Fe originating from hemin in rat plasma was developed and a rat model of iron deficiency anemia was established. It was found that hemin iron absorption increased significantly under iron deficiency anemia status, with AUC0-t and AUC0-∞ showing significant increase in anemic rats compared to normal ones. Green tea extract strongly inhibited hemin iron absorption in both normal rats and iron-deficient rats. In normal rats administered with green tea extract, C max resulted significantly reduced, whereas in anemic rats administered with green tea extract both AUC0-t and AUC0-∞ were reduced. On the other hand, ascorbic acid significantly affected hemin iron absorption only in iron-deficient rats, in which C max showed a significant increase. Interestingly, calcium slowed down the hemin iron absorption rate in normal rats, MRT0-t being significantly different in calcium-treated animals compared to untreated ones. This trend also appeared in the iron-deficient group but it did not reach statistical significance. Our data suggest that the mechanism of hemin iron absorption is regulated by body iron status and dietary factors can influence hemin iron absorption to varying degrees. Moreover, these results may also have general implication in the iron deficiency treatment with iron supplements and fortification of foods.

test

Biocatalytic and structural properties of a highly engineered halohydrin dehalogenase.

test

Two highly engineered halohydrin dehalogenase variants were characterized in terms of their performance in dehalogenation and epoxide cyanolysis reactions. Both enzyme variants outperformed the wild-type enzyme in the cyanolysis of ethyl (S)-3,4-epoxybutyrate, a conversion yielding ethyl (R)-4-cyano-3-hydroxybutyrate, an important chiral building block for statin synthesis. One of the enzyme variants, HheC2360, displayed catalytic rates for this cyanolysis reaction enhanced up to tenfold. Furthermore, the enantioselectivity of this variant was the opposite of that of the wild-type enzyme, both for dehalogenation and for cyanolysis reactions. The 37-fold mutant HheC2360 showed an increase in thermal stability of 8 °C relative to the wild-type enzyme. Crystal structures of this enzyme were elucidated with chloride and ethyl (S)-3,4-epoxybutyrate or with ethyl (R)-4-cyano-3-hydroxybutyrate bound in the active site. The observed increase in temperature stability was explained in terms of a substantial increase in buried surface area relative to the wild-type HheC, together with enhanced interfacial interactions between the subunits that form the tetramer. The structures also revealed that the substrate binding pocket was modified both by substitutions and by backbone movements in loops surrounding the active site. The observed changes in the mutant structures are partly governed by coupled mutations, some of which are necessary to remove steric clashes or to allow backbone movements to occur. The importance of interactions between substitutions suggests that efficient directed evolution strategies should allow for compensating and synergistic mutations during library design.

test

RNA global alignment in the joint sequence-structure space using elastic shape analysis.

test

The functions of RNAs, like proteins, are determined by their structures, which, in turn, are determined by their sequences. Comparison/alignment of RNA molecules provides an effective means to predict their functions and understand their evolutionary relationships. For RNA sequence alignment, most methods developed for protein and DNA sequence alignment can be directly applied. RNA 3-dimensional structure alignment, on the other hand, tends to be more difficult than protein structure alignment due to the lack of regular secondary structures as observed in proteins. Most of the existing RNA 3D structure alignment methods use only the backbone geometry and ignore the sequence information. Using both the sequence and backbone geometry information in RNA alignment may not only produce more accurate classification, but also deepen our understanding of the sequence-structure-function relationship of RNA molecules. In this study, we developed a new RNA alignment method based on elastic shape analysis (ESA). ESA treats RNA structures as three dimensional curves with sequence information encoded on additional dimensions so that the alignment can be performed in the joint sequence-structure space. The similarity between two RNA molecules is quantified by a formal distance, geodesic distance. Based on ESA, a rigorous mathematical framework can be built for RNA structure comparison. Means and covariances of full structures can be defined and computed, and probability distributions on spaces of such structures can be constructed for a group of RNAs. Our method was further applied to predict functions of RNA molecules and showed superior performance compared with previous methods when tested on benchmark datasets. The programs are available at http://stat.fsu.edu/ ∼jinfeng/ESA.html.

test

Fine Tuning of the Structure of Pt-Cu Alloy Nanocrystals by Glycine-Mediated Sequential Reduction Kinetics.

test

Uniform Pt-Cu alloy nanocrystals in the shape of dendrite,, yolk-cage, and box structures are prepared via a facile wet-chemical reduction route in which glycine is demonstrated to alter the reduction kinetics of metal cations, critical to the morphology of the obtained product. These alloy nanocrystals exhibit superior specific activity and stability in the electro-oxidation of methanol.

test

Relationship between serum thyrotropin levels and intrarenal hemodynamic parameters in euthyroid subjects.

test

OBJECTIVE: Low thyroid function may be associated with a reduced glomerular filtration rate (GFR) calculated on the basis of creatinine metabolism. Thyroid hormone directly affects serum creatinine in muscle and low thyroid function might exert a similar direct effect in the kidney. The goal of the study was to evaluate this possibility by assessment of the inulin-based GFR and to examine the mechanism underlying the reduction of GFR. PATIENTS AND METHODS: Renal and glomerular hemodynamics were assessed by simultaneous measurements of plasma clearance of para-aminohippurate (CPAH) and inulin (Cin) in 26 patients with serum creatinine <1.00 mg/dl and without thyroid disease. All subjects were normotensive with or without antihypertensive treatment and were kept in a sodium-replete state. Renal and glomerular hemodynamics were calculated using Gomez`s formulae. RESULTS: Serum thyroid stimulating hormone (TSH), including within the normal range (0.69-4.30 μIU/ml), was positively correlated with vascular resistance at the afferent arteriole (Ra) (r = 0.609, p = 0.0010), but not at the efferent arteriole (Re). Serum TSH was significantly and negatively correlated with renal plasma flow (RPF), renal blood flow (RBF), and glomerular filtration rate (GFR) (r = -0.456, p = 0.0192; r = -0.438, p = 0.0252; r = -0.505, p = 0.0086, respectively). In multiple regression analysis, serum TSH was significantly positively associated with Ra after adjustment for age and mean blood pressure. CONCLUSIONS: These findings suggest that low thyroid function, even within the normal range, is associated with reduced RPF, RBF and GFR, which might be caused by a preferential increase of Ra.

test

Deformation of an elastic capsule in a rectangular microfluidic channel.

test

In the present study we investigate computationally the deformation of an elastic capsule in a rectangular microfluidic channel and compare it with that of a droplet. In contrast to the bullet or parachute shape in a square or cylindrical channel where the capsule extends along the flow direction, in a rectangular channel the capsule extends mainly along the less-confined lateral direction of the channel cross-section (i.e. the channel width), obtaining a pebble-like shape. The different shape evolution in these two types of solid channels results from the different tension development on the capsule membrane required for interfacial stability. Furthermore, in asymmetric channel flows, capsules show a different deformation compared to droplets with constant surface tension (which extend mainly along the flow direction) and to vesicles which extend along the more-confined channel height. Therefore, our study highlights the different stability dynamics associated with these three types of interfaces. Our findings suggest that the erythrocyte deformation in asymmetric vessels (which is similar to that of capsules) results from the erythrocyte's inner spectrin skeleton rather than from its outer lipid bilayer.

test

Molecular-Beam Optical Stark and Zeeman Study of the [17.8]0(+)-X(1)Σ(+) (0,0) Band System of AuF.

test

The [17.8]0(+)-X(1)Σ(+) (0,0) band of gold monofluoride, AuF, has been recorded at a resolution of 40 MHz both field free and in the presence of a static electric and magnetic field. The observed Stark shifts were analyzed to determine the permanent electric dipole moment, μel, of 2.03 ± 0.05 D and 4.13 ± 0.02 D, for the [17.8]0(+)(v = 0) and X(1)Σ(+)(v = 0) states, respectively. The small magnetic tuning observed for the [17.8]0(+)(v = 0) state is attributed to rotational and magnetic field mixing with the [17.7]1 state and has been successfully modeled using an effective Hamiltonian for the (3)Π state. A comparison with the numerous published theoretical predictions is made.

test

Dynamic and Electronic Transport Properties of DNA Translocation through Graphene Nanopores.

test

Graphene layers have been targeted in the last years as excellent host materials for sensing a remarkable variety of gases and molecules. Such sensing abilities can also benefit other important scientific fields such as medicine and biology. This has automatically led scientists to probe graphene as a potential platform for sequencing DNA strands. In this work, we use robust numerical tools to model the dynamic and electronic properties of molecular sensor devices composed of a graphene nanopore through which DNA molecules are driven by external electric fields. We performed molecular dynamic simulations to determine the relation between the intensity of the electric field and the translocation time spent by the DNA to pass through the pore. Our results reveal that one can have extra control on the DNA passage when four additional graphene layers are deposited on the top of the main graphene platform containing the pore in a 2 × 2 grid arrangement. In addition to the dynamic analysis, we carried electronic transport calculations on realistic pore structures with diameters reaching nanometer scales. The transmission obtained along the graphene sensor at the Fermi level is affected by the presence of the DNA. However, it is rather hard to distinguish the respective nucleobases. This scenario can be significantly altered when the transport is conducted away from the Fermi level of the graphene platform. Under an energy shift, we observed that the graphene pore manifests selectiveness toward DNA nucleobases.

test

The tail wagging the dog - regulation of lipid metabolism by protein kinase C.

test

Upon their discovery almost 40 years ago, isoforms of the lipid-activated protein kinase C (PKC) family were initially regarded only as downstream effectors of the second messengers calcium and diacylglycerol, undergoing activation upon phospholipid hydrolysis in response to acute stimuli. Subsequently, several isoforms were found to be associated with the inhibitory effects of lipid over-supply on glucose homeostasis, especially the negative cross-talk with insulin signal transduction, observed upon accumulation of diacylglycerol in insulin target tissues. The PKC family has therefore attracted much attention in diabetes and obesity research, because intracellular lipid accumulation is strongly correlated with defective insulin action and the development of type 2 diabetes. Causal roles for various isoforms in the generation of insulin resistance have more recently been confirmed using PKC-deficient mice. However, during characterization of these animals, it became increasingly evident that the enzymes play key roles in the modulation of lipid metabolism itself, and may control the supply of lipids between tissues such as adipose and liver. Molecular studies have also demonstrated roles for PKC isoforms in several aspects of lipid metabolism, such as adipocyte differentiation and hepatic lipogenesis. While the precise mechanisms involved, especially the identities of protein substrates, are still unclear, the emerging picture suggests that the currently held view of the contribution of PKC isoforms to metabolism is an over-simplification. Although PKCs may inhibit insulin signal transduction, these enzymes are not merely downstream effectors of lipid accumulation, but in fact control the fate of fatty acids, thus the tail wags the dog.

test

Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands.

test

Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen and is a selective κ-opioid receptor agonist. To better understand the ligand-receptor interactions, a series of dicarboxylic ester-type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at κ-, δ- and μ-opioid receptors. Most of the analogues show high affinity to the κ-opioid receptor. Methyl malonyl derivative 4 shows the highest binding affinity (Ki=2nM), analogues 5, 7, and 14 exhibit significant affinity for the κ-receptor (Ki=21, 36 and 39nM).

test

Acute and chronic interference with BDNF/TrkB-signaling impair LTP selectively at mossy fiber synapses in the CA3 region of mouse hippocampus.

test

Brain-derived neurotrophic factor (BDNF) signaling via TrkB crucially regulates synaptic plasticity in the brain. Although BDNF is abundant at hippocampal mossy fiber (MF) synapses, which critically contribute to hippocampus dependent memory, its role in MF synaptic plasticity (long-term potentiation, LTP) remained largely unclear. Using field potential recordings in CA3 of adult heterozygous BDNF knockout (ko, BDNF+/-) mice we observed impaired (∼50%) NMDAR-independent MF-LTP. In contrast to MF synapses, LTP at neighboring associative/commissural (A/C) fiber synapses remained unaffected. To exclude that impaired MF-LTP in BDNF+/- mice was due to developmental changes in response to chronically reduced BDNF levels, and to prove the importance of acute availability of BDNF in MF-LTP, we also tested effects of acute interference with BDNF/TrkB signaling. Inhibition of TrkB tyrosine kinase signaling with k252a, or with the selective BDNF scavenger TrkB-Fc, both inhibited MF-LTP to the same extent as observed in BDNF+/- mice. Basal synaptic transmission, short-term plasticity, and synaptic fatigue during LTP induction were not significantly altered by treatment with k252a or TrkB-Fc, or by chronic BDNF reduction in BDNF+/- mice. Since the acute interference with BDNF-signaling did not completely block MF-LTP, our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP. Our results prove for the first time a mechanistic action of acute BDNF/TrkB signaling in presynaptic expression of MF-LTP in adult hippocampus.

test

Genetics of diabetes - Are we missing the genes or the disease?

test

Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the beta-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action (American Diabetes Association, 2011). The vast majority of cases of diabetes fall into two broad categories. In type 1 diabetes (T1D), the cause is an absolute deficiency of insulin secretion, whereas in type 2 diabetes (T2D), the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. However, the subdivision into two main categories represents a simplification of the real situation, and research during the recent years has shown that the disease is much more heterogeneous than a simple subdivision into two major subtypes assumes. Worldwide prevalence figures estimate that there are 280 million diabetic patients in 2011 and more than 500 million in 2030 (http://www.diabetesatlas.org/). In Europe, about 6-8% of the population suffer from diabetes, of them about 90% has T2D and 10% T1D, thereby making T2D to the fastest increasing disease in Europe and worldwide. This epidemic has been ascribed to a collision between the genes and the environment. While our knowledge about the genes is clearly better for T1D than for T2D given the strong contribution of variation in the HLA region to the risk of T1D, the opposite is the case for T2D, where our knowledge about the environmental triggers (obesity, lack of exercise) is much better than the understanding of the underlying genetic causes. This lack of knowledge about the underlying genetic causes of diabetes is often referred to as missing heritability (Manolio et al., 2009) which exceeds 80% for T2D but less than 25% for T1D. In the following review, we will discuss potential sources of this missing heritability which also includes the possibility that our definition of diabetes and its subgroups is imprecise and thereby making the identification of genetic causes difficult.

test

Structure-activity relationships of hybrid annonaceous acetogenins: Powerful growth inhibitory effects of their connecting groups between heterocycle and hydrophobic carbon chain bearing THF ring on human cancer cell lines.

test

Five novel hybrid molecules of annonaceous acetogenins and insecticides targeting mitochondrial complex I were synthesized and their growth inhibitory activities against 39 human cancer cell lines were investigated. It was revealed that the connecting group between the N-methylpyrazole part and the hydrophobic alkyl chain bearing the THF ring influenced their biological activities significantly. Amide-connected analog 2, in particular, showed selective and very potent activity (<10 nM) against some cancer cell lines.

test

Prevalence and natural history of Graves' orbitopathy in the XXI century.

test

Graves' orbitopathy (GO) is an autoimmune disorder and the main extrathyroidal expression of Graves' disease. There is a spectrum of ocular involvement in Graves' disease, from complete absence of symptoms and signs to sight-threatening conditions. The prevalence of GO varies in different published series of Graves' patients, due to confounding factors (new diagnosis vs. long-lasting disease, way of defining and assessing ocular involvement, treatment of hyperthyroidism with potentially GO-modifying treatments, such as radioiodine). Recent studies, however, suggest that most Graves' patients have mild or no GO at presentation, while moderate-to-severe GO is rare, and sight-threatening GO (mostly due to dysthyroid optic neuropathy) is exceptional in non-tertiary referral centers. The natural course of GO is incompletely defined, particularly in patients with moderate-to12 severe GO, because these patients require prompt and disease-modifying therapies for orbital disease. In patients with mild GO at presentation, progression to severe forms is rare, while partial or complete remission is frequent. Progression of preexisting GO or de novo occurrence of GO is more likely in smokers. There seems to be a trend towards a decline in progression of GO, possibly due to a better control of risk factors (cigarette smoking, thyroid dysfunction, etc.) and a closer interaction between endocrinologists and ophthalmologists allowing an improved integrated management of thyroid and orbital disease.

test

Antiulcer and gastric antisecretory effects of dichloromethane fraction and piplartine obtained from fruits of Piper tuberculatum Jacq. in rats.

test

ETHNOPHARMACOLOGICAL RELEVANCE: Piper tuberculatum Jacq. (Piperaceae) is medicinally used as an analgesic and as a treatment for gastric complaints. Thus, the current study aimed to investigate the gastroprotective and antisecretory properties of the dichloromethane fraction of the fruit of Piper tuberculatum (DFPT) and piplartine, a compound isolated from the DFPT, in rats. MATERIALS AND METHODS: Gastric ulcers were induced in fasted rats by oral administration of absolute ethanol and then mucus content and glutathione (GSH) levels were measured. Mechanisms underlying the antisecretory action were studied through gastric H(+),K(+)-ATPase activity of highly purified rabbit gastric microsomes and pylorus ligature method in rats. RESULTS: In the acute toxicity test the values of estimated LD50 for oral and intraperitoneal administration of DFPT were 1.6266 and 0.2684g/kg, respectively. The DFPT (ED50=29mg/kg, p.o.) and piplartine (4.5mg/kg, p.o.) promoted gastroprotection against acute lesions induced by ethanol, effect that could be related with the maintenance of GSH levels in the gastric mucosa. However, only DFPT stimulated gastric mucus secretion. In vitro, the DFPT and piplartine inhibited the H(+),K(+)-ATPase activity and, in vivo DFPT and piplartine also reduced basal gastric acid secretion, as well as that stimulated by pentagastrin. CONCLUSIONS: These results demonstrate that DFPT and piplatine cause marked gastroprotective effects accompanied by the increase and maintenance of gastric mucus and GSH levels, as well as a reduction in gastric acid secretion through the gastrinergic pathway.

test

Emerging Transporters of Clinical Importance: An Update from the International Transporter Consortium.

test

The International Transporter Consortium (ITC) has described recently seven transporters of particular relevance for drug development (Giacomini et al., Nat. Rev. Drug Discov. 9: 215-236, 2010). Based on the second ITC transporter workshop in 2012, we have identified additional transporters of emerging importance in pharmacokinetics, interference of drugs with transport of endogenous compounds and drug-drug interactions in humans. The multidrug and toxin extrusion proteins (MATEs, gene symbol SLC47A) mediate excretion of organic cations into bile and urine. MATEs are important in renal drug-drug interactions. Multidrug resistance proteins (MRPs or ABCCs) are drug and conjugate efflux pumps, and impaired activity of MRP2 results in conjugated hyperbilirubinemia. The bile salt export pump (BSEP or ABCB11) prevents accumulation of toxic bile salt concentrations in hepatocytes, and BSEP inhibition or deficiency may cause cholestasis and liver injury. Additionally, examples are presented on the roles of nucleoside and peptide transporters in drug targeting and disposition.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 8 April 2013 doi:10.1038/clpt.2013.74.

test

Biomarkers for Smoking Cessation.

test

One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.Clinical Pharmacology & Therapeutics (2013); advance online publication 8 May 2013. doi:10.1038/clpt.2013.57.

test

The effects of water molecules on the electronic and structural properties of peptide nanotubes.

test

The self-assembly of short amino acid chains appears to be one of the most promising strategies for the fabrication of nanostructures. Their solubility in water and the possibility of chemical modification by targeting the amino or carboxyl terminus give peptide-based nanostructures several advantages over carbon nanotube nanostructures. However, because these systems are synthesized in aqueous solution, a deeper understanding is needed on the effects of water especially with respect to the electronic, structural and transport properties. In this work, the electronic properties of l-diphenylalanine nanotubes (FF-NTs) have been studied using the Self-Consistent Charge Density-Functional-based Tight-Binding method augmented with dispersion interaction. The presence of water molecules in the central hydrophilic channel and their interaction with the nanostructures are addressed. We demonstrate that the presence of water leads to significant changes in the electronic properties of these systems decreasing the band gap which can lead to an increase in the hopping probability and the conductivity.

test

Low allopurinol doses are sufficient to optimize azathioprine therapy in inflammatory bowel disease patients with inadequate thiopurine metabolite concentrations.

test

PURPOSE: Recent studies in patients with inflammatory bowel diseases (IBD) on thiopurine therapy suggest that too low 6-thioguanine nucleotide concentrations (6-TGN) and too high methylmercaptopurine nucleotide concentrations (MMPN) can be reversed by a combination therapy of allopurinol and low-dose thiopurines. To date, however, optimal dosing has not been established. The aim of this study was to evaluate the minimal allopurinol doses necessary to achieve adequate 6-TGN concentrations in combination with low-dose azathioprine. METHODS: A stepwise dose-escalation of allopurinol was performed in 11 azathioprine-pretreated IBD patients with inadequately low 6-TGN concentrations (<235 pmol/8 × 10(8) erythrocytes) and/or elevated MMPN concentrations (>5,000 pmol/8 × 10(8) erythrocytes) and/or elevated liver enzymes (alanine aminotransferase and/or aspartate aminotransferase levels one- to threefold the upper limit of normal). Six patients were recruited into an open study, and five were treated in the context of an individualized therapeutic approach. Adverse effects, azathioprine metabolites, liver enzymes and whole blood counts were monitored two to three times per month. RESULTS: Adequate 6-TGN concentrations were achieved with a combination of 25 mg allopurinol and 50 mg azathioprine in one patient and with 50 mg allopurinol and 50 mg azathioprine in nine patients. Median 6-TGN concentrations (range) were 336 (290-488) pmol/8 × 10(8) erythrocytes after an 8-week-long intake of the final dose combination. One patient dropped out due to nausea after the first intake. MMPN concentrations and liver enzymes normalized immediately in all affected patients. All patients finishing the dose-escalation regimen tolerated the treatment without toxicity. CONCLUSIONS: Combination therapy with only 50 mg allopurinol and 50 mg azathioprine daily is sufficient, efficacious and safe in most IBD patients with inadequate thiopurine metabolite concentrations to optimize azathioprine-based IBD therapy.

test

Population pharmacokinetics analysis of cyclophosphamide with genetic effects in patients undergoing hematopoietic stem cell transplantation.

test

PURPOSE: To build a population pharmacokinetic (PK) model of cyclophosphamide (CY) and its metabolite, 4-hydroxycyclophosphamide (HCY), in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) and to identify covariates, including genetic polymorphisms, which affect CY and HCY PK parameters. METHOD: The study cohort comprised 21 patients undergoing HSCT who received CY intravenously between 2009 and 2011. Clinical characteristics and CY and HCY concentration data were collected for all patients, and ABCB1, ABCC2, GSTA1, GSTM1, GSTP1, GSTT1, CYP2B6, CYP2C19, and CYP3A5 genotyping was performed. A hypothetical enzyme compartment was conducted using the NONMEM program. RESULTS: A population PK analysis showed that the ABCC2 1249 genotype and aspartate aminotransferase levels significantly affected non-induced clearance (CL UI) and induced clearance (CL I) of CY, respectively. The final estimate of the mean CL UI and CL I of CY was 15.5 and 0.683 L/h, respectively, and the mean volume of distribution (V 1) of CY was 88.0 L. The inter-individual variability for CL UI, CL I, and V 1 of CY was 52.8, 200, and 18.0 %, respectively. Additionally, the CL UI of CY was significantly decreased to approximately 51 % in patients with the 1249 GA heterozygous genotype compared to those with the 1249 GG wild-type genotype (p < 0.05). There were only three heterozygous GA variants of ABCC2 1249 in the study patients. CONCLUSIONS: The population PK model developed in this study implies an influence of genetic factors on the clearance of CY. Clearance was moderately reduced in patients with the ABCC2 1249GA heterozygous genotype.

test

Synthesis, characterization and organic field effect transistor performance of a diketopyrrolopyrrole-fluorenone copolymer.

test

A diketopyrrolopyrrole (DPP) with fluorenone (FN) based low band gap alternating copolymer (PDPPT-alt-FN) has been synthesized via Suzuki coupling. PDPPT-alt-FN exhibits a deep HOMO level with a lower band gap. Fabricated organic thin film transistors using PDPPT-alt-FN as a channel semiconductor show p-channel behaviour with the highest hole mobility of 0.083 cm(2) V(-1) s(-1) measured in air.

test

Dermatoprotective effects of some plant extracts (genus Ficus) against experimentally induced toxicological insults in rabbits.

test

Aim: Present study was conducted to evaluate the dermatoprotective effects of plant extracts (Ficus religiosa, Ficus benghalensis, and Ficus racemosa) against known irritants such as sodium dodecyl sulfate (SDS), atrazine, and petrol. METHODS: The study was conducted in adult male rabbits. Ethanol extracts of plants were obtained through Soxhlet. All irritants and Ficus extracts were topically applied to the backs of rabbits daily for 4 days, while pure ethanol served as control. Skin was examined after 24, 48, and 96 h for erythema. Skin biopsies were taken on 5th day for microscopic examination. RESULTS: Erythema produced by irritants reduced significantly with the simultaneous application of Ficus extracts. The mean ± SEM epidermal thickness (micrometer) with SDS was 45.40 ± 1.89, F. religiosa + SDS was 18.60 ± 0.51, F. benghalensis + SDS was 18.40 ± 0.25, F. racemosa + SDS was 18.80 ± 0.37, and mixture of three Ficus species + SDS was 16.80 ± 0.37. Similar findings were revealed after using plant extracts with atrazine and petrol. The mean ± SEM epidermal layer count for SDS was 3.60 ± 0.25, atrazine was 3.40 ± 0.25, petrol was 3.40 ± 0.25, and ethanol (control) was 1.00 ± 0.20. This count reduced to 1.20 ± 0.20 for three Ficus species + SDS, 1.40 ± 0.25 for Ficus species + atrazine, and 1.40 ± 0.25 for Ficus species + petrol. CONCLUSION: Ficus species demonstrated the potential to block the dermatotoxic effects of topical irritants and could be used successfully to prevent skin toxicity.

test

Protective effects of caffeic acid phenethyl ester on dose-dependent intoxication of rats with paraquat.

test

PURPOSE: Paraquat (PQ; 1,1'dimethyl-bipyridilium 4,4'-dichloride), which is used extensively throughout the world, is highly toxic to humans. We aimed to investigate the protective effects of different doses of caffeic acid phenethyl ester (CAPE) on PQ-intoxicated rats.Materials and methods:A total of 80 rats were divided into the following eight groups, comprising 10 rats in each group: group 1: control; group 2: administered with CAPE (10 µmol/kg); group 3: administered with 15 mg/kg PQ (PQ15 group); group 4: administered with 30 mg/kg PQ (PQ30 group); group 5: administered with 45 mg/kg PQ (PQ45 group); group 6: administered with 15 mg/kg PQ + CAPE; group 7: administered with 30 mg/kg PQ + CAPE and group 8: administered with 45 mg/kg PQ + CAPE. Both PQ and CAPE were injected intraperitoneally. Pancreatic tissue was examined with both haematoxylin and eosin and immunochemical staining. RESULTS: The ratio of the immunohistochemical staining area to the total pancreatic area of the β cells revealed that statistically significant differences were observed only between the PQ and PQ + CAPE groups (p < 0.05). Discussion:The evaluation of the data suggests that CAPE can be used to prevent acute effects of PQ intoxication.

test

Modulation of carbon tetrachloride-induced nephrotoxicity in rats by n-hexane extract of Sonchus asper.

test

Ecosystem services and the protection, restoration, and management of ecosystems exposed to chemical stressors.

test

Ecosystem services-the benefits people obtain from ecosystem structures and processes-are essential for human survival and well-being. Chemicals are also an essential component of modern life; however, they may cause adverse ecological effects and reduce ecosystem service provision. Environmental policy makers are increasingly adopting the ecosystem services concept, but applying this approach to the protection, restoration, and management of ecosystems requires the development of new understanding, tools, and frameworks. There is an urgent need to understand and predict the effect of single and multiple stressors on ecosystem service delivery across different spatial scales (local to global), to develop indicators that can be used to quantify and map services and identify synergies and trade-offs between them, to establish protection goals and restoration targets defined in terms of the types and levels of service delivery required, and to develop approaches for the assessment and management of chemical risk to ecosystem services that consider the whole life cycle of products and processes. These are major research challenges for the environmental science community in general and for ecotoxicologists and risk assessors in particular. Environ. Toxicol. Chem. 2013;32:974-983. © 2013 SETAC.

test

Hypoglycemia and diabetes: a report of a workgroup of the american diabetes association and the endocrine society.

test

OBJECTIVE To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. PARTICIPANTS Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. EVIDENCE The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. CONSENSUS PROCESS Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012. CONCLUSIONS The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

test

Free-Standing Polyelectrolyte Membranes Made of Chitosan and Alginate.

test

Free-standing films have increasing applications in the biomedical field as drug delivery systems for wound healing and tissue engineering. Here, we prepared free-standing membranes by the layer-by-layer assembly of chitosan and alginate, two widely used biomaterials. Our aim was to produce a thick membrane and to study the permeation of model drugs and the adhesion of muscle cells. We first defined the optimal growth conditions in terms of pH and alginate concentration. The membranes could be easily detached from polystyrene or polypropylene substrate without any postprocessing step. The dry thickness was varied over a large range from 4 to 35 μm. A 2-fold swelling was observed by confocal microscopy when they were immersed in PBS. In addition, we quantified the permeation of model drugs (fluorescent dextrans) through the free-standing membrane, which depended on the dextran molecular weight. Finally, we showed that myoblast cells exhibited a preferential adhesion on the alginate-ending membrane as compared to the chitosan-ending membrane or to the substrate side.

test

Concentration-Dependent Supramolecular Engineering of Hydrogen-Bonded Nanostructures at Surfaces: Predicting Self-Assembly in 2D.

test

Emergence of whole-cell MALDI-MS biotyping for high-throughput bioanalysis of mammalian cells?

test

Since their inception in the 1970s, methods for classification of microorganisms based on mass spectral fingerprints obtained by MALDI-TOF MS have become a mainstay in environmental as well as in clinical microbiology. Recently, related whole-cell MALDI-TOF fingerprinting workflows have been adopted for the classification of mammalian cells. In this report we summarize this work and discuss the challenges of adapting whole-cell MS fingerprinting methods for the successful classification of mammalian cells. We highlight current limitations as well as opportunities and emerging applications of this technology in industrial and clinical settings, such as cell-line authentication, clinical diagnostics, and quality and productivity control in bioprocesses.

test

Theoretical and Kinetic Study of the Reaction of Ethyl Methyl Ketone with HO2 for T = 600 - 1, 600 K. Part II: Addition Reaction Channels.

test

Phase-selective sorbent xerogels as reclamation agents for oil spills.

test

12-Hydroxystearic acid (12-HSA) xerogels derived from 12-HSA-acetronitrile organogels are highly effective sorbent materials capable of adsorbing apolar, spilled materials in aqueous environments. 12-HSA xerogels made from 12-HSA-acetronitrile organogels are more effective than 12-HSA xerogels made from 12-HSA-pentane organogels because of the highly branched fibrillar networks established in acetonitrile molecular gels. This difference arises because of dissimilarities in the network structure between 12-HSA in various solvents. These xerogels, being thermoreversible, allow for both the spilled oil to be reclaimed but also the gelator may be reused to engineer new xerogels for oil spill containment and cleanup.

test

Pregnancy outcome in women exposed to antiepileptic drugs: teratogenic role of maternal epilepsy and its pharmacologic treatment.

test

Infants born to epileptic women treated with Antiepileptic Drugs (AEDs) have an increased risk of major congenital malformations (MCMs). In order to determine the role of maternal epilepsy we conducted a prospective cohort study on three cohorts of pregnant women: i) 385 epileptic women treated with AEDs, ii) 310 non-epileptic women treated with AEDs, iii) 867 healthy women not exposed to AEDs (control group). The rate of MCMs in the epileptic group (7.7%) was not statistically higher than in the non-epileptic one (3.9%) (p=0.068). The rate in the first group was higher compared to the control group (p=0.001), while the rate in the second one was not (p=0.534). Our data confirm that AEDs therapy is the main cause of the increased risk of malformations in the offspring of epileptic women; however a teratogenic role of the maternal epilepsy itself cannot be excluded.

test

Electrophysiological evidence for 4-isobutyl-3-isopropylbicyclophosphorothionate as a selective blocker of insect GABA-gated chloride channels.

test

Invertebrate γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and glutamate-gated chloride channels (GluCls), which function as inhibitory neurotransmitter receptors, are important targets of insecticides and antiparasitic agents. The antagonism of GABACls and GluCls by 4-isobutyl-3-isopropylbicyclophosphorothionate (PS-14) was examined in cultured cockroach and rat neurons using a whole-cell patch-clamp method. The results indicated that PS-14 selectively blocks cockroach GABACls relative to cockroach GluCls and rat GABACls. PS-14 represents a useful probe for the study of insect GABA receptors.

test

Synthesis and antibacterial evaluation of a novel series of 10-hydroxyl ketolide derivatives.

test

A novel series of 10-hydroxyl ketolide derivatives were synthesized, during which a distinctive intermediate, 3-O-descladinosyl-3-oxo-11-deoxy-10,11-epoxy-6-O-methylerythromycin A, was obtained from 6-O-methylerythromycin A. The structure and stereochemistry of this novel structure were confirmed via NMR and X-ray crystallography. Moreover, antibacterial evaluations were established in order to assess our modifications and acquire a deep understanding of the ketolides' structure-activity relationship (SAR).

test