bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of cell‐surface prion protein relative to its recombinant analogue: insights from molecular dynamics simulations of diglycosylated, membrane‐bound human prion protein
Authors: DeMarco Mari L. , Daggett Valerie 
Published: February 2009

AbstractThe prion protein (PrP) is responsible for several fatal neurodegenerative diseases via conversion from its normal to disease‐related isoform. The recombinant form of the protein is typically studied to investigate the conversion process. This constructs lacks the co‐ and post‐translational modifications present in vivo, there the protein has two N‐linked glycans and is bound to the outer leaflet of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. The inherent flexibility and heterogeneity of the glycans, the plasticity of the GPI anchor, and the localization of the protein in a membrane make experimental structural characterization of biological constructs of cellular prion protein (PrPC) challenging. Yet this characterization is central in determining not only the suitability of recombinant (rec)‐PrPC as a model for biological forms of the protein but also the potential role of co‐ and post‐translational modifications on the disease process. Here, we present molecular dynamics simulations of three human prion protein constructs: (i) a protein‐only construct modeling the recombinant form, (ii) a diglycosylated and soluble construct, and (iii) a diglycosylated and GPI‐anchored construct bound to a lipid bilayer. We found that glycosylation and membrane anchoring do not significantly alter the structure or dynamics of PrPC, but they do appreciably modify the accessibility of the polypeptide surface PrPC. In addition, the simulations of membrane‐bound PrPC revealed likely recognition domains for the disease‐initiating PrPC:PrPSc (infectious and/or misfolded form of the prion protein) binding event and a potential mechanism for the observed inefficiency of conversion associated with differentially glycosylated PrP species.
On the relationship between the two branches of the kynurenine pathway in the rat brainin vivo
Authors: Amori Laura , Guidetti Paolo , Pellicciari Roberto , Kajii Yasushi , Schwarcz Robert 
Published: February 2009

AbstractIn the mammalian brain, kynurenine aminotransferase II (KAT II) and kynurenine 3‐monooxygenase (KMO), key enzymes of the kynurenine pathway (KP) of tryptophan degradation, form the neuroactive metabolites kynurenic acid (KYNA) and 3‐hydroxykynurenine (3‐HK), respectively. Although physically segregated, both enzymes use the pivotal KP metabolitel‐kynurenine as a substrate. We studied the functional consequences of this cellular compartmentalizationin vivousing two specific tools, the KAT II inhibitor BFF 122 and the KMO inhibitor UPF 648. The acute effects of selective KAT II or KMO inhibition were studied using a radiotracing method in which thede novosynthesis of KYNA, and of 3‐HK and its downstream metabolite quinolinic acid (QUIN), is monitored following an intrastriatal injection of3H‐kynurenine. In naïve rats, intrastriatal BFF 122 decreased newly formed KYNA by 66%, without influencing 3‐HK or QUIN production. Conversely, UPF 648 reduced 3‐HK synthesis (by 64%) without affecting KYNA formation. Similar, selective effects of KAT II and KMO inhibition were observed when the inhibitors were applied acutely together with the excitotoxin QUIN, which impairs local KP metabolism. Somewhat different effects of KMO (but not KAT II) inhibition were obtained in rats that had received an intrastriatal QUIN injection 7 days earlier. In these neuron‐depleted striata, UPF 648 not only decreased both 3‐HK and QUIN production (by 77% and 66%, respectively) but also moderately raised KYNA synthesis (by 27%). These results indicate a remarkable functional segregation of the two pathway branches in the brain, boding well for the development of selective KAT II or KMO inhibitors for cognitive enhancement and neuroprotection, respectively.
Factors that influence collaboration between psychiatric care and CSSs: experiences of working together in the interest of persons with long‐term mental illness living in the community
Authors: Magnusson Annabella , Lützén Kim 
Published: February 2009

Background:  Since de‐institutionalization of psychiatric care (PC) took place in Sweden during the second half of the 20th century, the intended collaboration between the two organizations, PC and community social service (CSS) has been evaluated as inadequate in providing care for persons with long‐term mental illness living in the community.Aim:  The aim of this explorative study was to examine factors that influence interdisciplinary teamwork between PC and CSSs based on the experience of nursing staff within two separate organizations.Method:  Five focus groups were selected as an appropriate method to collect data. Two of these groups were recruited from the PC and three from the CSSs. The focus groups consisted of psychiatric nurses and mental healthcare workers. A qualitative content analysis was used to identify major themes in the data.Findings:  Two main themes were found, external organizational factors and interpersonal factors that deter or enhance collaboration between PC and CSS. Separate care plans, unclear times for meetings were found to be a plausible reason for communication failure. The focus groups representing each of the two organizations viewed themselves as ‘us and them’. Different ideologies and goals for caring and service and how to use each other’s competence seemed to be explanations as well as consequences of not finding ways to work together.Conclusion:  The results of this study points to the need for the two organizations to find ways to work more effectively together to realize a joint responsibility for the patient/client.
Investigating idebenone and idebenone linoleate metabolism: in vitro pig ear and mouse melanocyte studies
Authors: Wempe Michael F , Lightner Janet W , Zoeller Elizabeth L , Rice Peter J 
Published: February 2009

SummaryObjective  The aim of this study was to investigate inherent in vitro permeability, metabolism, and cytotoxicity of idebenone – an active used to protect skin as an anti‐aging agent – and compare it to idebenone linoleate.Methods  Idebenone and idebenone linoleate were investigated in pig ear skin and melanoma (B16: F10 mouse) cells. Diffusion experiments were conducted at 37 °C (bath temperature) using Franz diffusion cells. Authentic metabolite samples were synthetically prepared. Samples were analyzed using liquid chromatography‐mass spectrometry/mass spectrometry. Cell viability was determined via the 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide (MTT) assay.Results  Idebenone was shown to permeate across viable porcine ear tissue; there was no evidence that idebenone linoleate permeated across porcine ear tissue after 4 h. Idebenone was metabolized to idebenone acid in both pig ear and mouse melanocytes; only minor idebenone linoleate metabolism was observed. Idebenone displayed delayed in vitro toxicity (via MTT assay) in melanocytes, while idebenone linoleate displayed no such in vitro toxicity.Conclusions  The in vitro metabolism and cytotoxicity results suggest that metabolic activation of idebenone is the likely culprit that activates the skin irritation mechanism via idebenone in vivo usage. An idebenone ester (e.g. idebenone linoleate) appears to provide a superior in vitro safety profile over idebenone.
Bounds on the largest singular value of a matrix and the convergence of simultaneous and block‐iterative algorithms for sparse linear systems
Authors: Byrne Charles 
Published: February 2009

AbstractWe obtain the following upper bounds for the eigenvalues of the matrix A†A. For any a in the interval [0, 2] let
image

image

and ca and ra the maxima of the caj and rai, respectively. Then no eigenvalue of the matrix A†A exceeds the maximum of
image

over all i, nor the maximum of
image

over all j. Therefore, no eigenvalue of A†A exceeds cara.Using these bounds, it follows that, for the matrix G with entries
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no eigenvalue of G†G exceeds one, provided that, for some a in the interval [0, 2], we have
image

and
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Using this result, we obtain convergence theorems for several iterative algorithms for solving the problem Ax=b, including the CAV, BICAV, CARP1, SART, SIRT, and the block‐iterative DROP and SART methods.
Inhibition of human recombinant T‐type calcium channels by the endocannabinoid N‐arachidonoyl dopamine
Authors: Ross Hamish R , Gilmore Andrew J , Connor Mark 
Published: February 2009

Background and purpose:  N‐arachidonoyl dopamine (NADA) has complex effects on nociception mediated via cannabinoid CB1 receptors and the transient receptor potential vanilloid receptor 1 (TRPV1). Anandamide, the prototypic CB1/TRPV1 agonist, also inhibits T‐type voltage‐gated calcium channel currents (ICa). These channels are expressed by many excitable cells, including neurons involved in pain detection and processing. We sought to determine whether NADA and the prototypic arachidonoyl amino acid, N‐arachidonoyl glycine (NAGly) modulate T‐type ICaExperimental approach:  Human recombinant T‐type ICa (CaV3 channels) expressed in HEK 293 cells and native mouse T‐type ICa were examined using standard whole‐cell voltage clamp electrophysiology techniques.Key results:  N‐arachidonoyl dopamine completely inhibited CaV3 channels with a rank order of potency (pEC50) of CaV3.3 (6.45) ≥ CaV3.1 (6.29) > CaV3.2 (5.95). NAGly (10 µmol·L−1) inhibited CaV3 ICa by approximately 50% or less. The effects of NADA and NAGly were voltage‐ but not use‐dependent, and both compounds produced significant hyperpolarizing shifts in CaV3 channel steady‐state inactivation relationships. By contrast with anandamide, NADA and NAGly had modest effects on CaV3 channel kinetics. Both NAGly and NADA inhibited native T‐type ICa in mouse sensory neurons.Conclusions and implications:  N‐arachidonoyl dopamine and NAGly increase the steady‐state inactivation of CaV3 channels, reducing the number of channels available to open during depolarization. These effects occur at NADA concentrations at or below to those affecting CB1 and TRPV1 receptors. Together with anandamide, the arachidonoyl neurotransmitter amides, NADA and NAGly, represent a new family of endogenous T‐type ICa modulators.
Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over‐expressing TASTPM mice
Authors: Medhurst AD , Roberts JC , Lee J , Chen CPL‐H , Brown SH , Roman S , Lai MKP 
Published: February 2009

Background and purpose:  Histamine H3 receptor antagonists are currently being evaluated for their potential use in a number of central nervous system disorders including Alzheimer's Disease (AD). To date, little is known about the state of H3 receptors in AD.Experimental approach:  In the present study we used the radiolabelled H3 receptor antagonist [3H]GSK189254 to investigate H3 receptor binding in the amyloid over‐expressing double mutant APPswe × PSI.MI46V (TASTPM) transgenic mouse model of AD and in post‐mortem human AD brain samples.Key results:  No significant differences in specific H3 receptor binding were observed between wild type and TASTPM mice in the cortex, hippocampus or hypothalamus. Specific [3H]GSK189254 binding was detected in sections of human medial frontal cortex from AD brains of varying disease severity (Braak stages I–VI). With more quantitative analysis in a larger cohort, we observed that H3 receptor densities were not significantly different between AD and age‐matched control brains in both frontal and temporal cortical regions. However, within the AD group, [3H]GSK189254 binding density in frontal cortex was higher in individuals with more severe dementia prior to death.Conclusions and implications:  The maintenance of H3 receptor integrity observed in the various stages of AD in this study is important, given the potential use of H3 antagonists as a novel therapeutic approach for the symptomatic treatment of AD.
Pharmacokinetics of oltipraz in diabetic rats with liver cirrhosis
Authors: Ahn CY , Bae SK , Bae SH , Kim T , Jung YS , Kim YC , Lee MG , Shin WG 
Published: February 2009

Background and purpose:  The incidence of diabetes mellitus is increased in patients with liver cirrhosis. Oltipraz is currently in trials to treat patients with liver fibrosis and cirrhosis induced by chronic hepatitis types B and C and is primarily metabolized via hepatic cytochrome P450 isozymes CYP1A1/2, 2B1/2, 2C11, 2D1 and 3A1/2 in rats. We have studied the influence of diabetes mellitus on pharmacokinetics of oltipraz and on expression of hepatic, CYP1A, 2B1/2, 2C11, 2D and 3A in rats with experimental liver cirrhosis.Experimental approach:  Oltipraz was given intravenously (10 mg·kg−1) or orally (30 mg·kg−1) to rats with liver cirrhosis induced by N‐dimethylnitrosamine (LC rats) or with diabetes, induced by streptozotocin (DM rats) or to rats with both liver cirrhosis and diabetes (LCD rats) and to control rats, and pharmacokinetic variables measured. Protein expression of hepatic CYP1A, 2B1/2, 2C11, 2D and 3A was measured using Western blot analysis.Key results:  After i.v. or p.o. administration of oltipraz to LC and DM rats, the AUC was significantly greater and smaller, respectively, than that in control rats. In LCD rats, the AUC was that of LC and DM rats (partially restored towards control rats). Compared with control rats, the protein expression of hepatic CYP1A increased, that of CYP2C11 and 3A decreased, but that of CYP2B1/2 and 2D was not altered in LCD rats.Conclusions and implications:  In rats with diabetes and liver cirrhosis, the AUC of oltipraz was partially restored towards that of control rats.
Investigation of the effects of the novel anticonvulsant compound carisbamate (RWJ‐333369) on rat piriform cortical neuronesin vitro
Authors: Whalley BJ , Stephens GJ , Constanti A 
Published: February 2009

Background and purpose: Carisbamate is being developed for adjuvant treatment of partial onset epilepsy. Carisbamate produces anticonvulsant effects in primary generalized, complex partial and absence‐type seizure models, and exhibits neuroprotective and antiepileptogenic properties in rodent epilepsy models. Phase IIb clinical trials of carisbamate demonstrated efficacy against partial onset seizures; however, its mechanisms of action remain unknown. Here, we report the effects of carisbamate on membrane properties, evoked and spontaneous synaptic transmission and induced epileptiform discharges in layer II‐III neurones in piriform cortical brain slices.Experimental approach: Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings.Key results: Carisbamate (50–400 µmol·L−1) reversibly decreased amplitude, duration and rise‐time of evoked action potentials and inhibited repetitive firing, consistent with use‐dependent Na+channel block; 150–400 µmol·L−1carisbamate reduced neuronal input resistance, without altering membrane potential. After microelectrode intracellular Cl‐loading, carisbamate depolarized cells, an effect reversed by picrotoxin. Carisbamate (100–400 µmol·L−1) also selectively depressed lateral olfactory tract‐afferent evoked excitatory synaptic transmission (opposed by picrotoxin), consistent with activation of a presynaptic Cl‐conductance. Lidocaine (40–320 µmol·L−1) mimicked carisbamate, implying similar modes of action. Carisbamate (300–600 µmol·L−1) had no effect on spontaneous GABAAminiature inhibitory postsynaptic currents and at lower concentrations (50–200 µmol·L−1) inhibited Mg2+‐free or 4‐aminopyridine‐induced seizure‐like discharges.Conclusions and implications: Carisbamate blocked evoked action potentials use‐dependently, consistent with a primary action on Na+channels and increased Cl‐conductances presynaptically and, under certain conditions, postsynaptically to selectively depress excitatory neurotransmission in piriform cortical layer Ia‐afferent terminals.
Self‐augmentation of the lengthening of repolarization is related to the shape of the cardiac action potential: implications for reverse rate dependency
Authors: Virág László , Acsai Károly , Hála Ottó , Zaza Antonio , Bitay Miklós , Bogáts Gábor , Papp Julius Gy , Varró András 
Published: February 2009

Background and purpose: The aims of the present work were to study the mechanism of the reverse rate dependency of different interventions prolonging cardiac action potential duration (APD).Experimental approach: The reverse rate‐dependent lengthening effect of APD‐prolonging interventions and the possible involvement ofIKr(rapid component of the delayed rectifier potassium current) andIK1(inward rectifier potassium current) were studied by using the standard microelectrode and the whole‐cell patch‐clamp techniques in dog multicellular ventricular preparations and in myocytes isolated from undiseased human and dog hearts.Key results: All applied drugs – dofetilide (1 µmol·L−1), BaCl2(10 µmol·L−1), BAY‐K‐8644 (1 µmol·L−1), veratrine (1 µg·mL−1) – lengthened APD in a reverse rate‐dependent manner regardless of their mode of action, suggesting that reverse rate dependency may not represent a specific mechanism of APD prolongation. The E‐4031‐sensitive current (IKr) and the Ba2+‐sensitive current (IK1) were recorded during repolarizing voltage ramps having various steepness and also during action potential waveforms with progressively prolonged APD. Gradually delaying repolarization results in smaller magnitude ofIKrandIK1currents at an isochronal phase of the pulses. This represents a positive feedback mechanism, which appears to contribute to the reverse rate‐dependent prolongation of action potentials.Conclusions and implications: Action potential configuration may influence the reverse rate‐dependent APD prolongation due to the intrinsic properties ofIKrandIK1currents. Drugs lengthening repolarization by decreasing repolarizing outward, or increasing depolarizing inward, currents are expected to cause reverse rate‐dependent APD lengthening with high probability, regardless of which current they modify.
The Wearable Artificial Kidney, Why and How: From Holy Grail to Reality
Authors: Gura Victor , Ronco Claudio , Davenport Andrew 
Published: February 2009

AbstractOnce hemodialysis had become established as a treatment for chronic kidney disease, the early pioneers realized the limitations of the treatment, particularly in terms of the impact intermittent thrice weekly hemodialysis had on a patient’s quality of life—not only time spent on dialysis and time traveling to and from treatment, but also dietary and fluid restrictions. This led to the search for the holy grail—a wearable hemodialysis device (WAK), that would allow patients to receive continuous treatment, while going on with the normal activities of daily life. Such a device would not only provide adequate solute clearances and control both electrolyte and acid–base status, but also improve blood pressure control—all while allowing a liberal diet. Despite many attempts, to develop such a wearable artificial kidney, it is only recently, with the advent of microtechnologies, that it has been possible to construct a truly wearable device, which can accurately regulate ultrafiltration and achieve adequate solute clearances. One such device has recently completed successful human pilot studies, designed to test device reliability, safety, and efficacy.
Impact of Training in Interventional Nephrology on Hemodialysis Vascular Access Types
Authors: Haq Naveed U. , Sayeed Sabinah , Ali Sayed A. 
Published: February 2009

AbstractVascular access has been a major problem in the management of end stage renal disease (ESRD) patients on chronic hemodialysis (HD). Native arteriovenous fistulas (AVFs) are the preferred vascular access for ESRD patients on HD. Multiple factors have been evaluated as causes for poor AVF rates. The purpose of this retrospective analysis was to assess the impact of training of nephrologist in interventional nephrology (IN) on vascular access outcomes. We studied the rates of different types of vascular access amongst patients on chronic HD under the care of two nephrology groups over 25 months in a community dialysis unit. In group A, all vascular access were managed directly by an interventional nephrologist, while in group B they were managed by general nephrologist with no exposure to IN during their training. A total of 129 patients received dialysis for at least 4 months at the unit during those 25 months. The rate of AVFs in group A was 56.6%, while in group B the rate of AVFs was 40.8% (p = 0.059). The rate of AVGs in group A was 22.9% and in group B it was 27.6% (p = 0.647). The tunneled HD catheter rate in group A was 20.4% and in group B it was 31.6% (p = 0.098). The results of this study demonstrate that training of nephrologists in IN leads to increased use of AVF as HD vascular access. We suggest that training programs in nephrology should consider incorporating IN into their programs to increase the prevalence of AVFs.
Reviews: Clinical Implications of Disordered Magnesium Homeostasis in Chronic Renal Failure and Dialysis
Authors: Navarro‐González Juan F. , Mora‐Fernández Carmen , García‐Pérez Javier 
Published: February 2009

AbstractMagnesium (Mg) is the fourth most abundant cation in the body, mainly located within bone and skeletal muscle. The normal total plasma Mg concentration varies in a narrow range, with approximately 60% present as free Mg ions, the biologically active form. The kidney plays a principal role in Mg balance. Approximately 70–80% of plasma Mg is ultrafilterable, and under normal circumstances, 95% of the filtered load of Mg is reabsorbed. As chronic renal failure (CRF) progresses, urinary Mg excretion may be insufficient to balance intestinal Mg absorption and dietary Mg intake becomes a major determinant of serum and total body Mg levels. Until severe reductions in glomerular filtration rate (<30 ml/min), serum Mg levels are usually normal; with lower rates of renal function, serum Mg is increased. Concerning dialysis patients, dialysate Mg plays a critical role in maintaining Mg homeostasis, with serum Mg being largely dependent on the concentration of the ion in the dialysis solution. Magnesium has been implicated in diverse consequences, both beneficial and deleterious, in patients with CRF and dialysis. Potential harmful effects of elevated Mg include altered nerve conduction velocity, increased pruritus, and alterations to osseous metabolism and parathyroid gland function (mineralization defects, contribution to osteomalacic renal osteodystrophy, and adynamic bone disease). Hypermagnesemia also may retard vascular calcification. Low Mg levels have been associated with impairment of myocardial contractility, intradialytic hemodynamic instability, and hypotension. In addition, low Mg has been also linked to carotid intima‐media thickness, a marker of atherosclerotic vascular disease and a predictor of vascular events.