bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of a lifestyle intervention among persons with a psychiatric disability: a cluster randomised controlled trail on symptoms, quality of life and sense of coherence
Authors: Forsberg Karl A , Björkman Tommy , Sandman Per O , Sandlund Mikael
Published: April 2010

Aims and objectives. The aim of this study was to investigate how a lifestyle intervention programme influences psychiatric and psychosocial factors among persons with psychiatric disabilities.

Background. Persons with psychiatric disabilities often suffer from a simultaneous physical health problem, where circulatory disorder, hyperlipideamia, digestive disease, diabetes mellitus and obesity are prevalent. Studies have also shown a relationship between physical activity and mental health. But few randomised controlled trails have been aimed specifically at lifestyle interventions and their effect on psychiatric health and quality of life among persons with psychiatric disabilities.

Design. A cluster randomised controlled trail.

Methods. Forty‐one persons with a DSM‐IV diagnosis in eight supported housing facilities and two housing support programmes and their carers were on cluster level randomly assigned to a 12‐month health intervention programme in the form of study circles with diet sessions and physical activities or a control programme. The changes in the mean of quality of life, level of functioning, psychiatric symptoms and sense of coherence was investigated and its relationship to physical health and attendance.

Results. A significant increase in the sense of coherence was seen in both programmes but also significant improvements in the intervention group compared to controls at the follow‐up.

Conclusions. Structured activities in the form of lifestyle intervention programmes with a sufficient level of challenge that encourage persons with psychiatric disabilities to participate in activities in a social context may contribute to a significant increase in the sense of coherence.

Relevance to clinical practice. Improving physical health with lifestyle programmes in the form of study circles and when involving their cares will in addition to increased physical health end in improved sense of coherence.
Infection probability score, APACHE II and KARNOFSKY scoring systems as predictors of infection onset in haematology–oncology patients
Authors: Apostolopolou Eleni , Raftopoulos Vasilios , Terzis Konstantinos , Pissaki Kiriaki , Pagoni Maria , Delibasi Sossana
Published: April 2010

Aim.  To assess the predictive power of three systems: Infection Probability Score, APACHE II and KARNOFSKY score to the onset of healthcare‐associated infections in haematology–oncology patients.

Background.  The high incidence of healthcare‐associated infections is a frequent problem in haematology–oncology patients that affects morbidity and mortality of these patients.

Design.  A retrospective surveillance survey.

Method.  The survey was conducted for seven months in the haematology unit of a general hospital in Greece to assess the predictive power of Infection Probability Score, APACHE II and KARNOFSKY score to the onset of healthcare‐associated infections. The sample consisted of 102 hospitalised patients. The diagnosis of healthcare‐associated infections was based on the definitions proposed by CDC.

Results.  Among the participants, 53 (52%) were males and 49 (48%) were females with a mean age of 53·30 (SD 18·59) years old (range, 17–85 years). The incidence density of healthcare‐associated infections (the number of new cases of healthcare‐associated infections per 1000 patient‐days) was 21·8 infections per 1000 patient‐days. Among the 102 patients, healthcare‐associated infections occurred in 32 (31·4%) patients who had a total of 48 healthcare‐associated infections (47·5%). Among the 38 patients with neutropenia, 26 (68·4%) had more than one healthcare‐associated infection. Of the 48 detected healthcare‐associated infections, the most frequent type was blood‐stream infection (n = 17, 35·4%), followed by Clostridium difficile infection (n = 11, 22·9%) and respiratory tract infection (n = 8, 3·4%). The best cut‐off value of Infection Probability Score (IPS) for the prediction of a healthcare‐associated infection was 10 with sensitivity of 59·4% and specificity of 74·3%.

Conclusions.  Between the three different prognostic scoring systems, IPS had the best sensitivity in predicting healthcare‐associated infections.

Relevance to clinical practice.  IPS is an effective tool and should be used from nurses for the early detection of haematology–oncology patients who are susceptible to the onset of a healthcare‐associated infection.
Protective immunization of calves against Ostertagia ostertagi using fourth stage larval extracts
Authors: HALLIDAY A. M. , SMITH W. D.
Published: April 2010

ConA lectin was used to isolate glycoproteins from detergent extracts of fourth stage Ostertagia ostertagi larvae. This preparation contained proteins additional to those observed in a similar fraction prepared from adult O. ostertagi. Two vaccine trials were conducted with this preparation, and sub‐fractions thereof, in groups of 6–8 worm‐free calves. All groups were challenged with 50 000 O. ostertagi larvae 1 week after the final immunization, and protection was assessed by comparing the egg and worm counts of the immunized groups with their respective controls. Immunization with the ConA‐binding antigen or its sub‐fractions induced high titre serum antibody responses. In the first trial, the cumulative egg count of the group immunized with unfractionated antigen was 60% lower than the corresponding control value, and worm counts were 47% lower. In the second trial, the cumulative egg counts of the vaccinated groups ranged from 70% to 85% lower than the corresponding controls, with worm counts up to 64% lower. It was concluded that detergent‐soluble, ConA‐binding extracts prepared from O. ostertagi fourth stage larvae contained protective immunogens that were as effective as the best antigens published for O. ostertagi to date.
Improving animal and human health through understanding liver fluke immunology
Authors: PIEDRAFITA D. , SPITHILL T. W. , SMITH R. E. , RAADSMA H. W.
Published: April 2010

Sheep, goats and cattle represent the most numerous and economically important agricultural species worldwide used as sources for milk, fibre and red meat. In addition, in the developing world, these species often represent the sole asset base for small‐holder livestock farmers and cattle/buffaloes often provide the majority of draught power for crop production. Production losses caused by helminth diseases of these animals are a major factor in extending the cycle of poverty in developing countries and a major food security issue for developed economies.Fasciolaspp. are one of the most important zoonotic diseases with a global economic impact in livestock production systems and a poorly defined but direct effect on human health. Improvements in human and animal health will require a concerted research effort into the development of new accurate and simple diagnostic tests and increased vaccine and drug development againstFasciolainfections. Here, the use of definitive natural host breeds with contrasting resistance toFasciolainfections is discussed as a resource to contrast parasite–host interactions and identify parasite immune evasion strategies. Such studies are likely to boost the discovery of new vaccine, drug and diagnostic candidates and provide the foundation for future genetic selection of resistant animals.
The immunology of human hookworm infections
Authors: McSORLEY H. J. , LOUKAS A.
Published: April 2010

Hookworms are one of the most prevalent parasites of humans in developing countries, but we know relatively little about the immune response generated to hookworm infection. This can be attributed to a lack of permissive animal models and a relatively small research community compared with those of the more high‐profile parasitic diseases. However, recently, research has emerged on the development of vaccines to control hookworm infection and the use of hookworm to treat autoimmune and allergic disorders, contributing to a greater understanding of the strategies used by hookworms to modulate the host’s immune response. A substantial body of research on the immunobiology of hookworms originates from Australia, so this review will summarize the current status of the field with a particular emphasis on research carried out ‘down under’.
Ontogenetic Changes in Web Design in Two Orb‐Web Spiders
Authors: Hesselberg Thomas
Published: April 2010

The first orb web built by newly hatched spiders resembles the adult web in its overall form and structure. However, many details show ontogenetic changes. One possible explanation for these changes is that the tiny early‐instar spiders with their minute brains will make more mistakes and build less ‘perfect’ orb webs than older and larger juveniles and adults. To test this hypothesis, known as the size limitation hypothesis, I analysed orb webs from three developmental stages, spiderlings, juveniles and adult females, in two neotropical orb‐web spiders, the araneid Eustala illicita and the nephilid Nephila clavipes. Neither species showed clear signs of being behaviourally limited or more prone to committing errors as spiderlings than were older juveniles or adults. These findings therefore do not support the size limitation hypothesis in either species. Finally, I looked for evidence of the ‘biogenetic law’, which predicts that juveniles should build less derived orb webs than the adults. Evidence for this was found in E. illicita, but not in N. clavipes.
Transcriptional control of the pvdS iron starvation sigma factor gene by the master regulator of sulfur metabolism CysB in Pseudomonas aeruginosa
Authors: Imperi Francesco , Tiburzi Federica , Fimia Gian Maria , Visca Paolo
Published: April 2010

In the Gram‐negative pathogen Pseudomonas aeruginosa, the alternative sigma factor PvdS acts as a key regulator of the response to iron starvation. PvdS also controls P. aeruginosa virulence, as it drives the expression of a large set of genes primarily implicated in biogenesis and transport of the pyoverdine siderophore and synthesis of extracellular factors, such as protease PrpL and exotoxin A. Besides the ferric uptake regulatory protein Fur, which shuts off pvdS transcription under iron‐replete conditions, no additional regulatory factor(s) controlling the pvdS promoter activity have been characterized so far. Here, we used the promoter region of pvdS as bait to tentatively capture, by DNA‐protein affinity purification, P. aeruginosa proteins that are able to bind specifically to the pvdS promoter. This led to the identification and functional characterization of the LysR‐like transcription factor CysB as a novel regulator of pvdS transcription. The CysB protein directly binds to the pvdS promoter in vitro and acts as a positive regulator of PvdS expression in vivo. The absence of a functional CysB protein results in about 50% reduction of expression of PvdS‐dependent virulence phenotypes. Given the role of CysB as master regulator of sulfur metabolism, our findings establish a novel molecular link between the iron and sulfur regulons in P. aeruginosa.
Learning from games: Does collaboration help?
Authors: van der Meij Hans , Albers Eefje , Leemkuil Henny
Published: April 2010

This paper examines whether people benefit more from playing a commercial off‐the‐shelf game in pairs rather than in solitary mode. The basic idea behind this didactic method is that there is a serious risk that solitary game play yields insufficient articulation and explanation for learning to take place. Participants in the experimental condition played a strategy game in collaborative mode (pairs). Solitary play formed the control condition. During game play data were gathered about engagement (ie, flow). Also, the dialogues of the pairs were recorded. After game completion participants individually completed a knowledge test. For solitary players this ended the session. Collaborating pairs could discuss test answers (without receiving experimenter feedback) and give a final group answer. Collaboration was found not to affect game engagement and also did not affect individual knowledge test scores. The collaboration presumably did not advance the players' individual knowledge because the game dialogues mainly dealt with superficial game features such as move proposals. The collaborating players benefitted significantly from the opportunity to discuss test scores. The discussion revolves around game selection and game didactics (including scripted collaboration and debriefing) as routes for future studies to follow in ways of improving game utilisation in school.
Game‐based feedback for educational multi‐user virtual environments
Authors: Charles Darryl , Charles Therese , McNeill Michael , Bustard David , Black Michaela
Published: April 2010

It is generally accepted that informative and timely feedback is important to a student's learning experience within higher education. In the study of commercial digital games it has also become increasingly understood that games are particularly good at providing effective feedback of this form to gameplayers. We discuss recent game based learning research that attempts to harness the motivating qualities of digital games to inform the design of educational technology. Results from this research demonstrate student participation and performance can be improved by providing Game‐Based Feedback (GBF) to students. The GBF approach awards points to students for the successful completion of tasks throughout a course of study. Points and achievements accumulated over time builds a profile that provides a student with a potentially powerful representation of their educational identity. In this paper, we argue that virtual worlds are particularly suitable for this form of GBF and can further enhance a student's understanding of their educational standing. We outline a Virtual Learning Landscape (VLL) design that is embedded within a multi‐user virtual environment, where educational feedback is supplied to students via their avatar and a virtual world's landscape. The core structural principles of the proposed VLL are explained and several examples of the use of the VLL are provided to illustrate the system.
Does the New Digital Generation of Learners Exist? A Qualitative Study
Authors: Sánchez Jaime , Salinas Alvaro , Contreras David , Meyer Eduardo
Published: April 2010

This paper seeks to contribute to the discussion on the current generation of students and their relationship to technology, providing qualitative, empirical information obtained in the Chilean context. The study analyses and discusses the ideas regarding the emergence of a new generation of learners, or digital natives, as characterised by wide‐ranging access to digital media and by having new skills and abilities. In‐depth interviews held with students and teachers from four different cities in the country are analysed. The data shows evidence of a generation of learners without shared traits, with segments of learners presenting practices that do not characterise the entire generation. In addition, the data shows that the skills and abilities described in the literature do not represent a precise description of those that the students exploit when using technology. Beyond the ability to work simultaneously on several tasks, some learners have the ability to manage the attention that they pay to their work on the computer in sophisticated ways, and although some prefer images to words on paper, among others, there is still a taste for reading actual printed books. All in all, students and teachers describe a certain distance and conflict between the practices with the use of ICTs and their everyday school experiences.
Benford’s Law and Fraud Detection: Facts and Legends
Authors: Diekmann Andreas , Jann Ben
Published: April 2010

Is Benford’s law a good instrument to detect fraud in reports of statistical and scientific data? For a valid test, the probability of ‘false positives’ and ‘false negatives’ has to be low. However, it is very doubtful whether the Benford distribution is an appropriate tool to discriminate between manipulated and non-manipulated estimates. Further research should focus more on the validity of the test and test results should be interpreted more carefully.
Localized convexity subarachnoid haemorrhage – a sign of early cerebral venous sinus thrombosis
Authors: Panda S. , Prashantha D. K. , Ravi Shankar S. , Nagaraja D.
Published: April 2010

Background:  The diagnosis of cerebral venous sinus thrombosis (CVST) requires a high index of suspicion owing to the wide spectrum of clinical manifestations. Amongst the different presentations, radiological evidence of subarachnoid haemorrhage (SAH) often leads to diagnostic errors.

Methods:  Between March 2005 and December 2007, 233 patients with CVST were reviewed at our centre, and this report summarizes 10 cases that presented with SAH. The early clinico‐radiological pointers towards a diagnosis of CVST are highlighted and previously published reports are reviewed.

Results:  The mean age at presentation was 33 years (range 25–50), and the median duration from onset of symptoms to admission was 5 days (range 2–15). In all cases, there was radiological evidence of SAH with or without associated parenchymal bleeding or other signs of CVST. SAH was usually localized, involving the sulci of the cerebral convexity and sparing the basal cisterns. Aetiologically, there were two cases with both hyperhomocysteinaemia and polycythaemia and one case each of antiphospholipid antibody (APLA) syndrome, post‐partum state, oral contraceptive use and dehydration because of diarrhoea. Eight patients improved with anticoagulant therapy despite the presence of SAH.

Conclusions:  Localized SAH (whether focal, unilateral or bilateral), especially when confined to the parasagittal or dorsolateral convexity of the brain and without involvement of the basal cisterns, may provide an early pointer towards an underlying CVST. The presence of predisposing factors for CVST accords a further diagnostic hint.
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.

Alternative 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.

Cerebral 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.

The 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.

Proteinase‐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.

The 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

Two 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

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

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

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

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

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.
Pharmacokinetics of Sulfobutylether-Beta-Cyclodextrin and Voriconazole in Patients with End-Stage Renal Failure during Treatment with Two Hemodialysis Systems and Hemodiafiltration
Authors: Hafner Verena , Czock David , Burhenne Jürgen , Riedel Klaus-Dieter , Bommer Jürgen , Mikus Gerd , Machleidt Christoph , Weinreich Thomas , Haefeli Walter E.
Published: April 2010

Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. At the start of renal replacement therapy, the patients received a single 2-h infusion of voriconazole (4 mg per kg of body weight) solubilized with SBECD. SBECD, voriconazole, and voriconazole-
N
-oxide concentrations were quantified in plasma and dialysate samples by high-performance liquid chromatography (HPLC) and by HPLC coupled to tandem mass spectrometry (LC-MS-MS) and analyzed by noncompartmental methods. Nonparametric repeated-measures analysis of variance (ANOVA) was used to analyze differences between treatment phases. SBECD and voriconazole recoveries in dialysate samples were 67% and 10% of the administered doses. SBECD concentrations declined with a half-life ranging from 2.6 ± 0.6 h (Genius dialysis) to 2.4 ± 0.9 h (hemodialysis) and 2.0 ± 0.6 h (hemodiafiltration) (
P
< 0.01 for Genius dialysis versus hemodiafiltration). Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased.
In Vitro
Activities of DC-159a, a Novel Fluoroquinolone, against
Mycobacterium
Species
Authors: Disratthakit Areeya , Doi Norio
Published: April 2010

The
in vitro
activities of DC-159a against seven species of
Mycobacterium
were compared with moxifloxacin, gatifloxacin, levofloxacin, and rifampin. DC-159a was the most active compound against quinolone-resistant multidrug-resistant
M. tuberculosis
(MIC
90
, 0.5 μg/ml) as well as drug-susceptible isolates (MIC
90
, 0.06 μg/ml). The anti-tubercle bacilli activity of DC-159a was 4- to 32-fold more potent than those of currently available quinolones. DC-159a also demonstrated the highest activities against clinically important nontuberculous mycobacteria.
Molecular Characterization of β-Lactamase Genes and Their Genetic Structures inAcinetobacterGenospecies 3 Isolates in Taiwan
Authors: Huang Li-Yueh , Lu Po-Liang , Chen Te-Li , Chang Fang-Yee , Fung Chang-Phone , Siu L. K.
Published: April 2010

The genetic structure of β-lactamases inAcinetobactergenospecies 3 (AG3) isolates in Taiwan was studied to analyze their high rates of resistance to β-lactams, including carbapenems (57.9%).blaIMP-1andblaIMP-8were located in a class 1 integron.blaOXA-58was bracketed by ISAba3. A novel TnpF-like integrase gene was identified upstream ofblaVEB-3. Adjacent to the 5′ sequence of theblaADCgene,folEwas identified. Four newAcinetobacter-derived cephalosporinase (ADC) enzymes were found, which clustered phylogenetically with published AG3 ADC proteins.
Low Prevalence of
fks1
Hot Spot 1 Mutations in a Worldwide Collection of
Candida
Strains
Authors: Castanheira Mariana , Woosley Leah N. , Diekema Daniel J. , Messer Shawn A. , Jones Ronald N. , Pfaller Michael A.
Published: April 2010

We evaluated the prevalence of
fks1
hot spot (HS) 1 mutations among 133
Candida
strains from six species displaying various caspofungin MIC values (from ≤0.008 to >8 μg/ml). Only 4 (2.9%) strains displayed FKS1 HS1 amino acid substitutions: 1
C. albicans
(F641Y) among 32 isolates tested (3.1%), 1
C. glabrata
(S645P) among 34 isolates tested (2.9%), and 2
C. tropicalis
(F641S) among 12 isolates tested (16.7%). The 4 isolates displaying FKS1 HS1 alterations showed elevated caspofungin MIC results (1 to >8 μg/ml) but lower anidulafungin and micafungin MIC values (0.12 to 4 μg/ml and 0.25 to 4 μg/ml, respectively) in some instances within the wild-type MIC population, as determined using the epidemiologic cutoff values (ECV).
Candida krusei
,
C. parapsilosis
, and
C. guilliermondii
isolates tested showed no FKS1 HS1 alterations regardless of echinocandin MIC result. We additionally analyzed 8
C. albicans
and 7
C. glabrata
strains for mutations on other HS regions of
fks1
and
fks2
. Three
C. glabrata
strains showed alterations on FKS2 HS1 (two S645P and one L644W). In general, strains displaying S645P alteration showed higher echinocandin MIC values than strains harboring other mutations. Overall,
Candida
spp. strains showing caspofungin MIC values within the ECV did not display
fks
HS mutations. In contrast, strains showing alterations in this region displayed anidulafungin and/or micafungin MIC values within the wild-type population, suggesting that caspofungin could be the most sensitive agent for detection of these resistance mutations. Furthermore, results from this large, geographically diverse
Candida
spp. collection demonstrated that
fks1
HS1 mutations remain uncommon among isolates with various echinocandin MIC levels.
Discovery of a Gene Conferring Multiple-Aminoglycoside Resistance in
Escherichia coli
Authors: Davis Margaret A. , Baker Katherine N. K. , Orfe Lisa H. , Shah Devendra H. , Besser Thomas E. , Call Douglas R.
Published: April 2010

Bovine-origin
Escherichia coli
isolates were tested for resistance phenotypes using a disk diffusion assay and for resistance genotypes using a DNA microarray. An isolate with gentamicin and amikacin resistance but with no corresponding genes detected yielded a 1,056-bp DNA sequence with the closest homologues for its inferred protein sequence among a family of 16S rRNA methyltransferase enzymes. These enzymes confer high-level aminoglycoside resistance and have only recently been described in Gram-negative bacteria.