bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining inhibitory neurone function in respiratory circuits: opportunities with optogenetics?
Authors: Abdala Ana Paula , Paton Julian F. R. , Smith Jeffrey C. 
Published: November 2014

AbstractPharmacological and mathematical modelling studies support the view that synaptic inhibition in mammalian brainstem respiratory circuits is essential for generating normal and stable breathing movements. GABAergic and glycinergic neurones are known components of these circuits but their precise functional roles have not been established, especially within key microcircuits of the respiratory pre‐Bötzinger (pre‐BötC) and Bötzinger (BötC) complexes involved in phasic control of respiratory pump and airway muscles. Here, we review briefly current concepts of relevant complexities of inhibitory synapses and the importance of synaptic inhibition in the operation of these microcircuits. We highlight results and limitations of classical pharmacological studies that have suggested critical functions of synaptic inhibition. We then explore the potential opportunities for optogenetic strategies that represent a promising new approach for interrogating function of inhibitory circuits, including a hypothetical wish list for optogenetic approaches to allow expedient application of this technology. We conclude that recent technical advances in optogenetics should provide a means to understand the role of functionally select and regionally confined subsets of inhibitory neurones in key respiratory circuits such as those in the pre‐BötC and BötC.
Testing Tuberculosis Drug Efficacy in a Zebrafish High-Throughput Translational Medicine Screen
Authors: Ordas Anita , Raterink Robert-Jan , Cunningham Fraser , Jansen Hans J. , Wiweger Malgorzata I. , Jong-Raadsen Susanne , Bos Sabine , Bates Robert H. , Barros David , Meijer Annemarie H. , Vreeken Rob J. , Ballell-Pages Lluís , Dirks Ron P. , Hankemeier Thomas , Spaink Herman P. 
Published: November 2014

ABSTRACT

The translational value of zebrafish high-throughput screens can be improved when more knowledge is available on uptake characteristics of potential drugs. We investigated reference antibiotics and 15 preclinical compounds in a translational zebrafish-rodent screening system for tuberculosis. As a major advance, we have developed a new tool for testing drug uptake in the zebrafish model. This is important, because despite the many applications of assessing drug efficacy in zebrafish research, the current methods for measuring uptake using mass spectrometry do not take into account the possible adherence of drugs to the larval surface. Our approach combines nanoliter sampling from the yolk using a microneedle, followed by mass spectrometric analysis. To date, no single physicochemical property has been identified to accurately predict compound uptake; our method offers a great possibility to monitor how any novel compound behaves within the system. We have correlated the uptake data with high-throughput drug-screening data from
Mycobacterium marinum
-infected zebrafish larvae. As a result, we present an improved zebrafish larva drug-screening platform which offers new insights into drug efficacy and identifies potential false negatives and drugs that are effective in zebrafish and rodents. We demonstrate that this improved zebrafish drug-screening platform can complement conventional models of
in vivo
Mycobacterium tuberculosis
-infected rodent assays. The detailed comparison of two vertebrate systems, fish and rodent, may give more predictive value for efficacy of drugs in humans.
Molecular Characterization of Fluoroquinolone Resistance in Nontypeable Haemophilus influenzae Clinical Isolates
Authors: Puig Carmen , Tirado-Vélez José Manuel , Calatayud Laura , Tubau Fe , Garmendia Junkal , Ardanuy Carmen , Marti Sara , de la Campa Adela G. , Liñares Josefina 
Published: November 2014

ABSTRACT

Nontypeable
Haemophilus influenzae
(NTHi) is a common cause of respiratory infections in adults, who are frequently treated with fluoroquinolones. The aims of this study were to characterize the genotypes of fluoroquinolone-resistant NTHi isolates and their mechanisms of resistance. Among 7,267
H. influenzae
isolates collected from adult patients from 2000 to 2013, 28 (0.39%) were ciprofloxacin resistant according to Clinical and Laboratory Standards Institute (CLSI) criteria. In addition, a nalidixic acid screening during 2010 to 2013 detected five (0.23%) isolates that were ciprofloxacin susceptible but nalidixic acid resistant. Sequencing of their quinolone resistance-determining regions and genotyping by pulse-field gel electrophoresis and multilocus sequence typing of the 25 ciprofloxacin-resistant isolates available and all 5 nalidixic acid-resistant isolates were performed. In the NTHi isolates studied, two mutations producing changes in two GyrA residues (Ser84, Asp88) and/or two ParC residues (Ser84, Glu88) were associated with increased fluoroquinolone MICs. Strains with one or two mutations (
n
= 15) had ciprofloxacin and levofloxacin MICs of 0.12 to 2 μg/ml, while those with three or more mutations (
n
= 15) had MICs of 4 to 16 μg/ml. Long persistence of fluoroquinolone-resistant strains was observed in three chronic obstructive pulmonary disease patients. High genetic diversity was observed among fluoroquinolone-resistant NTHi isolates. Although fluoroquinolones are commonly used to treat respiratory infections, the proportion of resistant NTHi isolates remains low. The nalidixic acid disk test is useful for detecting the first changes in GyrA or in GyrA plus ParC among fluoroquinolone-susceptible strains that are at a potential risk for the development of resistance under selective pressure by fluoroquinolone treatment.
Arthritis and Benznidazole: More Closely Related than We Thought
Authors: Aldasoro E. , Pinazo M. J. , Oliveira I. , Munoz J. , Posada E. , Requena-Méndez A. , Serret N. , Gascon J. 
Published: November 2014

ABSTRACT

Chagas disease is a parasitic infection that leads to a significant public health problem in countries where the disease is endemic and where it is nonendemic. Benznidazole is the most commonly used drug for the etiological treatment of Chagas disease. Patients treated with benznidazole suffer frequent adverse drug reactions. Although arthralgia is common, arthritis has been reported as a very rare side effect. The objective of this study was to describe arthritis in a cohort of
Trypanosoma cruzi
-infected patients treated with benznidazole.
Mechanism of β-Lactam Action in Streptococcus pneumoniae: the Piperacillin Paradox
Authors: Philippe Jules , Gallet Benoit , Morlot Cécile , Denapaite Dalia , Hakenbeck Regine , Chen Yuxin , Vernet Thierry , Zapun André 
Published: November 2014

ABSTRACT

The human pathogen
Streptococcus pneumoniae
has been treated for decades with β-lactam antibiotics. Its resistance is now widespread, mediated by the expression of mosaic variants of the target enzymes, the penicillin-binding proteins (PBPs). Understanding the mode of action of β-lactams, not only in molecular detail but also in their physiological consequences, will be crucial to improving these drugs and any counterresistances. In this work, we investigate the piperacillin paradox, by which this β-lactam selects primarily variants of PBP2b, whereas its most reactive target is PBP2x. These PBPs are both essential monofunctional transpeptidases involved in peptidoglycan assembly. PBP2x participates in septal synthesis, while PBP2b functions in peripheral elongation. The formation of the “lemon”-shaped cells induced by piperacillin treatment is consistent with the inhibition of PBP2x. Following the examination of treated and untreated cells by electron microscopy, the localization of the PBPs by epifluorescence microscopy, and the determination of the inhibition time course of the different PBPs, we propose a model of peptidoglycan assembly that accounts for the piperacillin paradox.
Carbapenem-Resistant Klebsiella pneumoniae Urinary Tract Infection following Solid Organ Transplantation
Authors: Brizendine Kyle D. , Richter Sandra S. , Cober Eric D. , van Duin David 
Published: November 2014

ABSTRACT

Carbapenem-resistant
Klebsiella pneumoniae
(CRKP) is an emerging pathogen with a devastating impact on organ transplant recipients (OTRs). Data describing urinary tract infections (UTIs) due to CRKP, compared to extended-spectrum β-lactamase (ESBL)-producing and susceptible
K. pneumoniae
, are lacking. We conducted a retrospective cohort study comparing OTRs with a first episode of UTI due to CRKP, ESBL-producing
K. pneumoniae
, or susceptible
K. pneumoniae
. We identified 108 individuals; 22 (20%) had UTIs due to CRKP, 22 (20%) due to ESBL-producing
K. pneumoniae
, and 64 (60%) due to susceptible
K. pneumoniae
. Compared to susceptible
K. pneumoniae
(27%), patients with UTIs due to CRKP or ESBL-producing
K. pneumoniae
were more likely to have a ≥24-hour stay in the intensive care unit (ICU) before or after development of the UTI (64% and 77%, respectively;
P
< 0.001). Among 105/108 hospitalized patients (97%), the median lengths of stay prior to UTI with CRKP or ESBL-producing
K. pneumoniae
(7 and 8 days, respectively) were significantly longer than that for susceptible
K. pneumoniae
(1 day;
P
< 0.001). Clinical failure was observed for 8 patients (36%) with CRKP, 4 (18%) with ESBL-producing
K. pneumoniae
, and 9 (14%) with susceptible
K. pneumoniae
(
P
= 0.073). Microbiological failure was seen for 10 patients (45%) with CRKP, compared with 2 (9%) with ESBL-producing
K. pneumoniae
and 2 (3%) with susceptible
K. pneumoniae
(
P
< 0.001). In multivariable logistic regression analyses, CRKP was associated with greater odds of microbiological failure (versus ESBL-producing
K. pneumoniae
: odds ratio [OR], 9.36, 95% confidence interval [CI], 1.94 to 72.1; versus susceptible
K. pneumoniae
: OR, 31.4, 95% CI, 5.91 to 264). In conclusion, CRKP is associated with ICU admission, long length of stay, and microbiological failure among OTRs with UTIs. Greater numbers are needed to determine risk factors for infection and differences in meaningful endpoints associated with carbapenem resistance.
Enhanced Efficacy of Cidofovir Combined with Vaccinia Immune Globulin in Treating Progressive Cutaneous Vaccinia Virus Infections in Immunosuppressed Hairless Mice
Authors: Smee Donald F. , Dagley Ashley , Downs Brittney , Hagloch Joseph , Tarbet E. Bart 
Published: November 2014

ABSTRACT
The treatment of progressive vaccinia in individuals has involved antiviral drugs, such as cidofovir (CDV), brincidofovir, and/or tecovirimat, combined with vaccinia immune globulin (VIG). VIG is costly, and its supply is limited, so sparing the use of VIG during treatment is an important objective. VIG sparing was modeled in immunosuppressed mice by maximizing the treatment benefits of CDV combined with VIG to determine the effective treatments that delayed the time to death, reduced cutaneous lesion severity, and/or decreased tissue viral titers. SKH-1 hairless mice immunosuppressed with cyclophosphamide and hairless SCID mice (SHO strain) were infected cutaneously with vaccinia virus. Monotherapy, dual combinations (CDV plus VIG), or triple therapy (topical CDV, parenteral CDV, and VIG) were initiated 2 days postinfection and were given every 3 to 4 days through day 11. The efficacy assessment included survival rate, cutaneous lesion severity, and viral titers. Delays in the time to death and the reduction in lesion severity occurred in the following order of efficacy: triple therapy had greater efficacy than double combinations (CDV plus VIG or topical plus parenteral CDV), which had greater efficacy than VIG alone. Parenteral administration of CDV or VIG was necessary to suppress virus titers in internal organs (liver, lung, and spleen). The skin viral titers were significantly reduced by triple therapy only. The greatest efficacy was achieved by triple therapy. In humans, this regimen should translate to a faster cure rate, thus sparing the amount of VIG used for treatment.
Induction of Candida albicans Drug Resistance Genes by Hybrid Zinc Cluster Transcription Factors
Authors: Schneider Sabrina , Morschhäuser Joachim 
Published: November 2014

ABSTRACT

The pathogenic yeast
Candida albicans
can develop resistance to azole antifungal drugs by overexpressing
ERG11
, which encodes the drug target, or the multidrug efflux pumps
MDR1
and
CDR1
/
CDR2
. The constitutive upregulation of these genes is usually caused by gain-of-function mutations in the zinc cluster transcription factors Upc2, Mrr1, and Tac1, respectively. These transcription factors are also required for the induction of their target genes in drug-susceptible strains in the presence of specific stimuli. By swapping the DNA-binding domains of Mrr1, Tac1, and Upc2 we investigated if the hybrid transcription factors could activate their new target genes in response to the same signals. When Tac1 was targeted to the
MDR1
and
ERG11
promoters, the expression of these genes became inducible by fluphenazine. Similarly,
MDR1
and
CDR2
were strongly upregulated by fluconazole when Upc2 was fused to the DNA-binding domains of Mrr1 and Tac1, respectively. In contrast, Mrr1 was unable to promote gene expression in response to benomyl when it was targeted to the
CDR2
and
ERG11
promoters instead of the
MDR1
promoter. These results suggest that Tac1 and Upc2 themselves are activated by the inducers fluphenazine and fluconazole, respectively, whereas benomyl does not activate Mrr1 itself but a coregulatory factor that is present at the promoters of Mrr1 target genes. Strains in which the expression levels of Mrr1 and Tac1 target genes were controlled by Upc2 exhibited increased fluconazole resistance, demonstrating that the ability to efficiently upregulate the expression of efflux pumps in the presence of the drug results in enhanced intrinsic fluconazole resistance.
Contribution of Veillonella parvula to Pseudomonas aeruginosa-Mediated Pathogenicity in a Murine Tumor Model System
Authors: Pustelny Christian , Komor Uliana , Pawar Vinay , Lorenz Anne , Bielecka Agata , Moter Annette , Gocht Benjamin , Eckweiler Denitsa , Müsken Mathias , Grothe Claudia , Lünsdorf Heinrich , Weiss Siegfried , Häussler Susanne 
Published: November 2014

ABSTRACT

The recent finding that high numbers of strict anaerobes are present in the respiratory tract of cystic fibrosis (CF) patients has drawn attention to the pathogenic contribution of the CF microbiome to airway disease. In this study, we investigated the specific interactions of the most dominant bacterial CF pathogen,
Pseudomonas aeruginosa
, with the anaerobic bacterium
Veillonella parvula
, which has been recovered at comparable cell numbers from the respiratory tract of CF patients. In addition to growth competition experiments, transcriptional profiling, and analyses of biofilm formation by
in vitro
studies, we used our recently established
in vivo
murine tumor model to investigate mutual influences of the two pathogens during a biofilm-associated infection process. We found that
P. aeruginosa
and
V. parvula
colonized distinct niches within the tumor. Interestingly, significantly higher cell numbers of
P. aeruginosa
could be recovered from the tumor tissue when mice were coinfected with both bacterial species than when mice were monoinfected with
P. aeruginosa
. Concordantly, the results of
in vivo
transcriptional profiling implied that the presence of
V. parvula
supports
P. aeruginosa
growth at the site of infection in the host, and the higher
P. aeruginosa
load correlated with clinical deterioration of the host. Although many challenges must be overcome to dissect the specific interactions of coinfecting bacteria during an infection process, our findings exemplarily demonstrate that the complex interrelations between coinfecting microorganisms and the immune responses determine clinical outcome to a much greater extent than previously anticipated.
The efficacy of a supervised and a home-based core strengthening programme in adults with poor core stability: a three-arm randomised controlled trial
Authors: Chuter V H , de Jonge X A K Janse , Thompson B M , Callister R 
Published: November 2014

BackgroundPoor core stability is linked to a range of musculoskeletal pathologies and core-strengthening programmes are widely used as treatment. Treatment outcomes, however, are highly variable, which may be related to the method of delivery of core strengthening programmes. We investigated the effect of identical 8 week core strengthening programmes delivered as either supervised or home-based on measures of core stability.MethodsParticipants with poor core stability were randomised into three groups: supervised (n=26), home-based (n=26) or control (n=26). Primary outcomes were the Sahrmann test and the Star Excursion Balance Test (SEBT) for dynamic core stability and three endurance tests (side-bridge, flexor and Sorensen) for static core stability. The exercise programme was devised and supervised by an exercise physiologist.ResultsAnalysis of covariance on the change from baseline over the 8 weeks showed that the supervised group performed significantly better on all core stability measures than both the home-based and control group. The home-based group produced significant improvements compared to the control group in all static core stability tests, but not in most of the dynamic core stability tests (Sahrmann test and two out of three directions of the SEBT).ConclusionsOur results support the use of a supervised core-strengthening programme over a home-based programme to maximise improvements in core stability, especially in its dynamic aspects. Based on our findings in healthy individuals with low core stability, further research is recommended on potential therapeutic benefits of supervised core-strengthening programmes for pathologies associated with low core stability.Trial registration numberACTRN12613000233729.
Biceps femoris and semitendinosus—teammates or competitors? New insights into hamstring injury mechanisms in male football players: a muscle functional MRI study
Authors: Schuermans Joke , Van Tiggelen Damien , Danneels Lieven , Witvrouw Erik 
Published: November 2014

BackgroundThe hamstring injury mechanism was assessed by investigating the exercise-related metabolic activity characteristics of the hamstring muscles using a muscle functional MRI (mfMRI) protocol.Methods27 healthy male football players and 27 football players with a history of hamstring injuries (recovered and playing fully) underwent standardised mfMR Imaging. The mfMRI protocol consisted of a resting scan, a strenuous bilateral eccentric hamstring exercise and a postexercise scan. The exercise-related T2 increase or the signal intensity shift between both scans was used to detect differences in metabolic activation characteristics (1) between the different hamstring muscle bellies and (2) between the injury group and the control group.ResultsA more symmetrical muscle recruitment pattern corresponding to a less economic hamstring muscle activation was demonstrated in the formerly injured group (p<0.05). The injured group also demonstrated a significantly lower strength endurance capacity during the eccentric hamstring exercise.ConclusionsThese findings suggest that the vulnerability of the hamstring muscles to football-related injury is related to the complexity and close coherence in the synergistic muscle recruitment of the biceps femoris and the semitendinosus. Discrete differences in neuromuscular coordination and activity distribution, with the biceps femoris partly having to compensate for the lack of endurance capacity of the semitendinosus, probably increase the hamstring injury risk.
Population-based cohort study on the risk of pneumonia in patients with non-traumatic intracranial haemorrhage who use proton pump inhibitors
Authors: Ho Sai-Wai , Tsai Ming-Che , Teng Ying-Hock , Yeh Ying-Tung , Wang Yu-Hsun , Yang Shun-Fa , Yeh Chao-Bin 
Published: November 2014

ObjectivesThis nationwide cohort study investigated the association between proton pump inhibitor (PPI) usage and the risk of pneumonia in patients with non-traumatic intracranial haemorrhage (ICH).DesignNationwide population-based cohort study.SettingLongitudinal Health Insurance Database 2010 (LHID2010) sampled from the Taiwan National Health Insurance Research Database.Participants4644 patients with non-traumatic ICH from 2010 to 2011 were identified. Patients aged <18 years and newly diagnosed with non-traumatic ICH complicated with pneumonia during the same admission period were excluded. A total of 2170 participants were eligible for the final analysis.Main outcome measurePatients using PPIs or not during the study period were tracked to identify the occurrence of any type of pneumonia.ResultsThe adjusted HR of the risk of pneumonia for ICH patients who used PPIs was 1.61 (95% CI 1.32 to 1.97, p<0.001). The risk of pneumonia was positively associated with the administration of PPIs. We observed a greater risk of pneumonia in patients who used PPIs than in those who did not. Moreover, we observed that the risk of pneumonia in patients who used PPIs was 2.60 and 2.04 (95% CI 2.01 to 3.38, p<0.001; 95% CI 1.34 to 3.10, p<0.001) greater than that in patients who did not use PPIs when the defined daily dose was <30 and 30−60, respectively.ConclusionsThe results of this study indicate that the use of PPIs in patients with non-traumatic ICH is associated with an increased risk of pneumonia, and the severity of this risk depends on the defined daily dose. Physicians should exercise caution when prescribing PPIs for patients with non-traumatic ICH.
Behavioural and faecal glucocorticoid metabolite responses of single caging in six cats over 30 days
Authors: Ellis J. J. , Protopapadaki V. , Stryhn H. , Spears J. , Cockram M. S. 
Published: November 2014

ObjectivesThe aim was to characterize the behaviour and faecal glucocorticoid metabolite (FGM) responses of six cats (Felis catus) to single caging for 30 days.DesignIn this observational study, changes in outcome measures were monitored with habituation to caging. Continuous focal observations of the activity, location in the cage, and posture were conducted from video recordings for one 24‐hour period/week/cat. Cat‐Stress‐Scores were recorded daily. All faecal samples were collected for analysis of FGM.ResultsThe percentage time spent eating increased, while percentage time spent grooming decreased, from week 1 to week 2. Cat‐Stress‐Score declined significantly from week 1 to week 2. FGM concentrations were significantly greater in week 1 than in week 5. A posthabituation time budget of the behaviour of the cats in the single cages showed that inactivity dominated the time budget and the cats were located on the shelf almost half of the time.ConclusionsResults suggests that a shelf was a resource of value to the cats, and that its inclusion in enclosure design is important. Quantitative and qualitative behavioural data indicated that there was an initial stress response to caging that stabilised after the first week, while FGM concentration took longer to stabilise.
LASP1 Is a HIF1α Target Gene Critical for Metastasis of Pancreatic Cancer
Authors: Zhao Tiansuo , Ren He , Li Jing , Chen Jing , Zhang Huan , Xin Wen , Sun Yan , Sun Lei , Yang Yongwei , Sun Junwei , Wang Xiuchao , Gao Song , Huang Chongbiao , Zhang Huafeng , Yang Shengyu , Hao Jihui 
Published: November 2014

AbstractLASP1 is an actin-binding protein associated with actin assembly dynamics in cancer cells. Here, we report that LASP1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) where it promotes invasion and metastasis. We found that LASP1 overexpression in PDAC cells was mediated by HIF1α through direct binding to a hypoxia response element in the LASP1 promoter. HIF1α stimulated LASP1 expression in PDAC cells in vitro and mouse tumor xenografts in vivo. Clinically, LASP1 overexpression in PDAC patient specimens was associated significantly with lymph node metastasis and overall survival. Overall, our results defined LASP1 as a direct target gene for HIF1α upregulation that is critical for metastatic progression of PDAC. Cancer Res; 75(1); 111–9. ©2014 AACR.