bluuebunny/crossref_metadata_2025_split huggingface dataset:
EFNS guidelines on the diagnostic approach to pauci‐ or asymptomatic hyperCKemia
Authors: Kyriakides T. , Angelini C. , Schaefer J. , Sacconi S. , Siciliano G. , Vilchez J. J. , Hilton‐Jones D. 
Published: April 2010

Objective:  To provide evidence‐based guidelines to general neurologists for the assessment of patients with pauci‐ or asymptomatic hyperCKemia.Background:  Recent epidemiologic studies show that up to 20% of ‘normal’ individuals have an elevated creatine kinase activity in the serum (sCK). The possibility of a subclinical myopathy is often raised, and patients may be unnecessarily denied treatment with statins.Search strategy:  Electronic databases including Medline, the Cochrane Library and the American Academy of Neurology were searched for existing guidelines. Articles dealing with series of patients investigated for asymptomatic/pauci‐symptomatic hyperCKemia and articles dealing with myopathies that can present with asymptomatic hyperCKemia were identified and reviewed.Results:  The only guidelines found were those approved by the Italian Association of Myology Committee, and the only relevant articles identified describe class IV studies.Recommendations:  HyperCKemia needs to be redefined as values beyond 1.5 times the upper limit of normal (which itself needs to be appropriately defined). Pauci‐ or asymptomatic hyperCKemia with no apparent medical explanation may be investigated with a muscle biopsy if one or more of the following are present; the sCK is ≥3× normal, the electromyogram is myopathic or the patient is <25 years of age. In addition, women with sCK<3 times normal may be offered DNA testing because of the possibility of carrying a dystrophin mutation.
Antiepileptic drugs modify power of high EEG frequencies and their neural generators
Authors: Arzy S. , Allali G. , Brunet D. , Michel C. M. , Kaplan P. W. , Seeck M. 
Published: April 2010

Background:  The clinical and molecular effects of antiepileptic drugs (AEDs) have been extensively investigated. Much less is known about their effects on human electrophysiology.Methods:  Topographic analysis in the frequency domain has been used to analyze 104 electroencephalogram (EEG) epochs of 52 patients presenting with first‐ever generalized seizure, with normal MRI and EEG. Patients were treated with valproate, carbamazepine, or lamotrigine in monotherapy (each group n = 13). Thirteen patients without medication served as a control group.Results:  Carbamazepine and lamotrigine, both sodium‐channel modulators, altered brain topography in the gamma range in the same frequency bands (50–60 Hz). Valproate, which has multiple actions on sodium and calcium channels as well as GABA turnover, modified brain topography in the low gamma range (30–40 Hz). No such changes were found in the control group. For all AEDs, the neural generators were shifted more anteriorly in medial temporal through to inferior frontal regions.Conclusion:  Decreased gamma‐power and anterior shift of neural generators after AED introduction reflect AED influence on human electrophysiology.
Hypoxic ischemia and proteasome dysfunction alter tau isoform ratio by inhibiting exon 10 splicing
Authors: Suh Jaehong , Im Doo Soon , Moon Gyeong Joon , Ryu Keun Sil , De Silva Rohan , Choi In Sun , Lees Andrew J. , Guénette Suzanne Y. , Tanzi Rudolph E. , Gwag Byoung Joo 
Published: April 2010

J. Neurochem. (2010) 114, 160–170.AbstractAlternative splicing of tau exon 10 influences microtubule assembly and stability during development and in pathological processes of the central nervous system. However, the cellular events that underlie this pre‐mRNA splicing remain to be delineated. In this study, we examined the possibility that ischemic injury, known to change the cellular distribution and expression of several RNA splicing factors, alters the splicing of tau exon 10. Transient occlusion of the middle cerebral artery reduced tau exon 10 inclusion in the ischemic cortical area within 12 h, resulting in the induction of three‐repeat (3R) tau in cortical neurons. Ubiquitinated protein aggregates and reduced proteasome activity were also observed. Administration of proteasome inhibitors such as MG132, proteasome inhibitor I and lactacystin reduced tau exon 10 splicing in cortical cell cultures. Decreased levels of Tra2β, an RNA splicing factor responsible for tau exon 10 inclusion, were detected both in cortical cell cultures exposed to MG132 and in cerebral cortex after ischemic injury. Taken together, these findings suggest that transient focal cerebral ischemia reduces tau exon 10 splicing through a mechanism involving proteasome‐ubiquitin dysfunction and down‐regulation of Tra2β.
Ischemic pre‐conditioning alters cerebral microRNAs that are upstream to neuroprotective signaling pathways
Authors: Dharap Ashutosh , Vemuganti Raghu 
Published: April 2010

J. Neurochem. (2010) 113, 1685–1691.AbstractCerebral gene expression is known to be significantly influenced by a sublethal ischemic event (pre‐conditioning; PC) that induces tolerance to future damaging ischemic events. Small non‐coding RNAs known as microRNAs (miRNAs) were recently shown to control the mRNA translation. We currently profiled cerebral miRNAs in the cerebral cortex of rats subjected to PC. The miRNAome reacted quickly and by 6 h following PC, levels of 51 miRNAs were altered (26 up‐ and 25 down‐regulated; > 1.5‐fold change). Twenty of these stayed at the altered level even at 3 days after PC. At least nine miRNAs showed > 5‐fold change at one or more time points between 6 h to 3 days after PC compared with sham. Bioinformatics analysis showed 2007 common targets of the miRNAs that were up‐regulated and 459 common targets of the miRNAs that were down‐regulated after PC. Pathways analysis showed that MAP‐kinase and Mammalian target of rapamycin (mTOR) signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the up‐regulated miRNAs, and Wnt and GnRH signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the down‐regulated miRNAs after PC. We hypothesize that alterations in miRNAs and their down‐stream mRNAs of signaling pathways might play a role in the induction of ischemic tolerance.
Toll‐like receptor 4 in CNS pathologies
Authors: Buchanan Madison M. , Hutchinson Mark , Watkins Linda R. , Yin Hang 
Published: April 2010

J. Neurochem. (2010) 114, 13–27.AbstractThe responses of the brain to infection, ischemia and trauma share remarkable similarities. These and other conditions of the CNS coordinate an innate immune response marked by activation of microglia, the macrophage‐like cells of the nervous system. An important contributor to microglial activation is toll‐like receptor 4, a pathogen‐associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli. The present review traces new efforts to characterize and control toll‐like receptor 4 in inflammatory etiologies of the nervous system.
Astrocytic activation and an inhibition of MAP kinases are required for proteinase‐activated receptor‐2‐mediated protection from neurotoxicity
Authors: Greenwood Sam M. , Bushell Trevor J. 
Published: April 2010

J. Neurochem.(2010)113, 1471–1480.AbstractProteinase‐activated receptor‐2 (PAR‐2) expression levels are altered in several CNS disorders with these changes being proposed to either exacerbate or diminish the disease state depending on the cell type in which this occurs. Here we present data investigating the consequence of PAR‐2 activation on kainate (KA)‐induced neurotoxicity in organotypic hippocampal slices cultures (OHSC). Exposure of OHSC to the PAR‐2 activators trypsin or Ser‐Leu‐Ile‐Gly‐Arg‐Leu (SLIGRL) induced no neurotoxicity when applied alone but was neuroprotective against KA‐induced neurotoxicity. SLIGRL‐mediated neuroprotection involved astrocytic activation as the neuroprotective effect was abolished following OHSC pre‐treatment with fluoroacetate. Moreover, co‐application of either reparixin or LY341495, antagonists of the CXCR2 chemokine receptor and metabotropic glutamate receptors respectively, inhibited the SLIGRL‐mediated neuroprotection. SLIGRL application inhibited both p38 MAPK and ERK activity in OHSC, but not the JNK 1/2 signalling pathway. Accordingly, the co‐application of the p38 MAPK and ERK inhibitors SB203580 and UO126 reduced KA‐induced cell death, mimicking PAR‐2‐mediated neuroprotection. These data indicate that PAR‐2 activation is neuroprotective and involves astrocytic activation, gliotransmitter release, and the subsequent inhibition of MAPK signalling cascades, providing further evidence for PAR‐2 as an interesting therapeutic target in certain CNS disorders.
Interaction of organic cation transporter 3 (SLC22A3) and amphetamine
Authors: Zhu Hao‐Jie , Appel David I. , Gründemann Dirk , Markowitz John S. 
Published: April 2010

J. Neurochem. (2010) 114, 142–149.AbstractThe organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. Relative to wild‐type (WT) animals, Oct3 knockout (KO) mice have displayed altered behavioral and neurochemical responses to psychostimulants such as amphetamine (AMPH) and methamphetamine. In the present study, both in vitro and in vivo approaches were utilized to explore potential mechanisms underlying the disparate neuropharmacological effects observed following AMPH exposure in Oct3 KO mice. In vitro uptake studies conducted in OCT3 transfected cells indicated that dextroamphetamine (d‐AMPH) is not a substrate of OCT3. However, OCT3 was determined to be a high‐capacity and low‐affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5‐HT). Inhibition studies demonstrated that d‐AMPH exerts relatively weak inhibitory effects on the OCT3‐mediated uptake of DA, NE, 5‐HT, and the model OCT3 substrate 4‐(4‐(dimethylamino)styryl)‐N‐methylpyridinium iodide. The IC50 values were determined to be 41.5 ± 7.5 and 24.1 ± 7.0 μM for inhibiting DA and 5‐HT uptake, respectively, while 50% inhibition of NE and 4‐(4‐(dimethylamino)styryl)‐N‐methylpyridinium iodide uptake was not achieved by even the highest concentration of d‐AMPH applied (100 μM). Furthermore, the disposition of d‐AMPH in various tissues including the brain, liver, heart, kidney, muscle, intestine, spleen, testis, uterus, and plasma were determined in both male and female Oct3 KO and WT mice. No significant difference was observed between either genotypes or sex in all tested organs and tissues. Our findings suggest that OCT3 is not a prominent factor influencing the disposition of d‐AMPH. Additionally, based upon the inhibitory potency observed in vitro, d‐AMPH is unlikely to inhibit the uptake of monoamines mediated by OCT3 in the brain. Differentiated neuropharmacological effects of AMPHs noted between Oct3 KO and WT mice appear to be due to the absence of Oct3 mediated uptake of neurotransmitters in the KO mice.
Performance evaluation of the Abbott CELL‐DYN Ruby and the Sysmex XT‐2000i haematology analysers
Authors: LEERS M. P. G. , GOERTZ H. , FELLER A. , HOFFMANN J. J. M. L. 
Published: April 2010

SummaryTwo mid‐range haematology analysers (Abbott CELL‐DYN Ruby and Sysmex XT‐2000i) were evaluated to determine their analytical performance and workflow efficiency in the haematology laboratory. In total 418 samples were processed for determining equivalence of complete blood count (CBC) measurements, and 100 for reticulocyte comparison. Blood smears served for assessing the agreement of the differential counts. Inter‐instrument agreement for most parameters was good although small numbers of discrepancies were observed. Systematic biases were found for mean cell volume, reticulocytes, platelets and mean platelet volume. CELL‐DYN Ruby WBC differentials were obtained with all samples while the XT‐2000i suppressed differentials partially or completely in 13 samples (3.1%). WBC subpopulation counts were otherwise in good agreement with no major outliers. Following first‐pass CBC/differential analysis, 88 (21%) of XT‐2000i samples required further analyser processing compared to 18 (4.3%) for the CELL‐DYN Ruby. Smear referrals for suspected WBC/nucleated red blood cells and platelet abnormalities were indicated for 106 (25.4%) and 95 (22.7%) of the XT‐2000i and CELL‐DYN Ruby samples respectively. Flagging efficiencies for both analysers were found to be similar. The Sysmex XT‐2000i and Abbott CELL‐DYN Ruby analysers have broadly comparable analytical performance, but the CELL‐DYN Ruby showed superior first‐pass efficiency.
The Combination of Meropenem and Levofloxacin Is Synergistic with Respect to both
Pseudomonas aeruginosa
Kill Rate and Resistance Suppression
Authors: Louie Arnold , Grasso Caroline , Bahniuk Nadzeya , Van Scoy Brian , Brown David L. , Kulawy Robert , Drusano G. L. 
Published: April 2010

ABSTRACT

New approaches are needed for the treatment of
Pseudomonas aeruginosa
infections. All available single agents are suboptimal, especially for resistance suppression. Classical β-lactam/aminoglycoside combinations are not used often enough at least in part because of concern for nephrotoxicity. We evaluated the combination of meropenem and levofloxacin against the
P. aeruginosa
PAO1 wild type and its isogenic MexAB pump-overexpressed mutant. The drugs were studied using an
in vitro
hollow-fiber pharmacodynamic infection model. There were 16 different regimens evaluated for both isolates. Both total population and resistant subpopulations were quantified. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The impact of monotherapy versus that of combination therapy for attainment of a 3-log cell kill and for resistance suppression was examined using Kaplan-Meier analysis. Drug exposures were calculated by fitting the concentration-time data using the ADAPT II package of programs. For both isolates, monotherapy allowed resistance emergence with all but the largest exposure or with all exposures. In contrast, there was no resistance emergence with any combination regimen. Kaplan-Meier analysis showed significant differences in time to attainment of a 3-log cell kill as well as time to resistance emergence for monotherapy and combination therapy for both isolates, in favor of the combination regimens. Determination of the pharmacodynamic indices associated with resistance suppression demonstrated a 2- to 3-fold reduction with the use of combinations. Combination therapy with meropenem and levofloxacin provides a significantly faster time to attain a 3-log cell kill and significantly better resistance suppression than does either monotherapy. This combination should be evaluated in a clinical trial.
Predicting Tipranavir and Darunavir Resistance Using Genotypic, Phenotypic, and Virtual Phenotypic Resistance Patterns: an Independent Cohort Analysis of Clinical Isolates Highly Resistant to All Other Protease Inhibitors
Authors: Talbot Annie , Grant Philip , Taylor Jonathan , Baril Jean-Guy , Liu Tommy Fulisma , Charest Hugues , Brenner Bluma , Roger Michel , Shafer Robert , Cantin Régis , Zolopa Andrew 
Published: April 2010

ABSTRACT

Genotypic interpretation systems (GISs) for darunavir and tipranavir susceptibility are rarely tested by the use of independent data sets. The virtual phenotype (the phenotype determined by Virco [the “Vircotype”]) was used to interpret all genotypes in Québec, Canada, and phenotypes were determined for isolates predicted to be resistant to all protease inhibitors other than darunavir and tipranavir. We used multivariate analyses to predict relative phenotypic susceptibility to darunavir and tipranavir. We compared the performance characteristics of the Agence Nationale de Recherche sur le Sida scoring algorithm, the Stanford HIV database scoring algorithm (with separate analyses of the discrete and numerical scores), the Vircotype, and the darunavir and tipranavir manufacturers' scores for prediction of the phenotype. Of the 100 isolates whose phenotypes were determined, 89 and 72 were susceptible to darunavir and tipranavir, respectively. In multivariate analyses, the presence of I84V and V82T and the lack of L10F predicted that the isolates would be more susceptible to darunavir than tipranavir. The presence of I54L, V32I, and I47V predicted that the isolates would be more susceptible to tipranavir. All GISs except the system that provided the Stanford HIV database discrete score performed well in predicting the darunavir resistance phenotype (
R
2
= 0.61 to 0.69); the
R
2
value for the Stanford HIV database discrete scoring system was 0.38. Other than the system that provided the Vircotype (
R
2
= 0.80), all GISs performed poorly in predicting the tipranavir resistance phenotype (
R
2
= 0.00 to 0.31). In this independent cohort harboring highly protease inhibitor-resistant HIV isolates, reduced phenotypic susceptibility to darunavir and tipranavir was rare. Generally, GISs predict susceptibility to darunavir substantially better than they predict susceptibility to tipranavir.
Novel Arylimidamides for Treatment of Visceral Leishmaniasis
Authors: Wang Michael Zhuo , Zhu Xiaohua , Srivastava Anuradha , Liu Qiang , Sweat J. Mark , Pandharkar Trupti , Stephens Chad E. , Riccio Ed , Parman Toufan , Munde Manoj , Mandal Swati , Madhubala Rentala , Tidwell Richard R. , Wilson W. David , Boykin David W. , Hall James Edwin , Kyle Dennis E. , Werbovetz Karl A. 
Published: April 2010

ABSTRACT

Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC
50
], <1 μM) against both
Leishmania donovani
axenic amastigotes and intracellular
Leishmania
, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize
in vitro
and
in vivo
antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC
50
≤ 0.12 μM) against intracellular
L. donovani
,
Leishmania amazonensis
, and
Leishmania major
and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models,
L. donovani
-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.
Semimechanistic Pharmacokinetic-Pharmacodynamic Model with Adaptation Development for Time-Kill Experiments of Ciprofloxacin against
Pseudomonas
aeruginosa
Authors: Grégoire Nicolas , Raherison Sophie , Grignon Claire , Comets Emmanuelle , Marliat Manuella , Ploy Marie-Cécile , Couet William 
Published: April 2010

ABSTRACT

The objective of this study was to implement a semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to describe the effects of ciprofloxacin against
Pseudomonas
aeruginosa
in vitro. Time-kill curves were generated with an initial inoculum close to 5 × 10
6
CFU/ml of
P. aeruginosa
PAO1 and constant ciprofloxacin concentrations between 0.12 and 4.0 μg/ml (corresponding to 0.5× and 16× MIC). To support the model, phenotypic experiments were conducted with the PAO7H mutant strain, which overexpresses the MexEF OprN efflux pump and phenyl arginine β-naphthylamide (PAβN), a known efflux inhibitor of main Mex multidrug efflux systems. A population approach was used for parameter estimation. At subinhibitory ciprofloxacin concentrations (0.12 and 0.25 μg/ml), an initial CFU decay followed by regrowth was observed, attesting to rapid emergence of bacteria with increased but moderate resistance (8-fold increase of MIC). This phenomenon was mainly due to an overexpression of the Mex protein efflux pumps, as shown by a 16-fold diminution of the MIC in the presence of PAβN in these strains with low-level resistance. A PK-PD model with adaptation development was successfully used to describe these data. However, additional experiments are required to validate the robustness of this model after longer exposure periods and multiple dosing regimens, as well as in vivo.
Population Pharmacokinetics and Pharmacodynamic Considerations of Amodiaquine and Desethylamodiaquine in Kenyan Adults with Uncomplicated Malaria Receiving Artesunate-Amodiaquine Combination Therapy
Authors: Jullien Vincent , Ogutu Bernhards , Juma Elizabeth , Carn Gwenaelle , Obonyo Charles , Kiechel Jean-René 
Published: April 2010

ABSTRACT

Amodiaquine (AQ) is an antimalarial drug that was frequently combined with artesunate (AS) for the treatment of uncomplicated malaria due to
Plasmodium falciparum
and is now available as a fixed-dose combination. Despite its widespread use, the simultaneous pharmacokinetics in patients of AQ and its active metabolite, desethylamodiaquine (DAQ), were not characterized to date. The pharmacokinetics of AQ and DAQ in 54 adult patients receiving the AS/AQ combination were therefore investigated by the use of a population approach. AQ followed a 1-compartment model with first-order absorption and elimination, as well as a first-order and irreversible transformation into DAQ, which in turn followed a 2-compartment model with first-order elimination from its central compartment. The mean AQ apparent clearance and distribution volume were 3,410 liters/h and 39,200 liters, respectively. The mean terminal elimination half-life of DAQ was 211 h. Body weight was found to explain the interindividual variability of the apparent volume of distribution of AQ and the elimination rate constant of DAQ. A new dosage form consisting of a fixed-dose combination of AS and AQ was found to have no effect on the pharmacokinetic parameters of AQ and DAQ. All patients achieved parasite clearance within 4 days following the initiation of the treatment, which prevented investigation of the possible relationship between DAQ exposure and treatment outcome. This study provided the first simultaneous pharmacokinetic model for AQ and DAQ.