bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reciprocal regulation of inhibitory synaptic transmission by nicotinic and muscarinic receptors in rat nucleus accumbens shell
Authors: Yamamoto Kiyofumi , Ebihara Katsuko , Koshikawa Noriaki , Kobayashi Masayuki 
Published: September 2013

Key points
While cholinergic interneurones are few in number, their axons densely innervate and provide abundant acetylcholine‐containing terminals in the nucleus accumbens (NAc).
Although cholinergic effects on inhibitory postsynaptic currents (IPSCs) via nicotinic and muscarinic receptors have been reported, the relationship between cholinergic modulation of IPSCs and presynaptic cell subtypes in the NAc has remained elusive.
Here we show that muscarinic receptor activation suppresses IPSCs in medium spiny neurone (MSN)→MSN connections, whereas nicotinic receptor activation enhances IPSCs in fast‐spiking neurone→MSN connections.
These reciprocal regulatory mechanisms for IPSCs help us to understand the role of cholinergic processes in physiological and pathophysiological functions of the NAc.
Abstract  Medium spiny neurones (MSNs) in the nucleus accumbens (NAc) are the principal neurones whose activities are regulated by GABAergic inputs from MSNs and fast‐spiking interneurones (FSNs). Cholinergic interneurones play important roles in the regulation of activity in MSNs; however, how acetylcholine modulates inhibitory synaptic transmission from MSNs/FSNs to MSNs remains unknown. We performed paired whole‐cell patch‐clamp recordings from MSNs and FSNs in rat NAc shell slice preparations and examined cholinergic effects on unitary inhibitory postsynaptic currents (uIPSCs). Carbachol (1 μm) suppressed uIPSC amplitude by 58.3 ± 8.0% in MSN→MSN connections, accompanied by increases in paired‐pulse ratio and failure rate, suggesting that acetylcholine reduces the probability of GABA release from the synaptic terminals of MSNs. Carbachol‐induced uIPSC suppression was antagonised by 100 μm atropine, and was mimicked by pilocarpine (1 μm) and acetylcholine (1 μm) but not nicotine (1 μm). Application of AM251 slightly reduced carbachol‐induced uIPSC suppression (30.8 ± 8.9%), suggesting an involvement of endocannabinoid signalling in muscarinic suppression of uIPSCs. In contrast, FSN→MSN connections showed that pilocarpine had little effect on the uIPSC amplitude, whereas both nicotine and acetylcholine facilitated uIPSC amplitude, with decreases in failure rate and paired‐pulse ratio, suggesting that nicotine‐induced uIPSC facilitation is mediated by presynaptic mechanisms. Miniature IPSC recordings support these hypotheses of presynaptic cholinergic mechanisms. These results suggest a differential role for muscarinic and nicotinic receptors in GABA release, which depends on presynaptic neuronal subtypes in the NAc shell.
Differential patterns of replacement and reactive fibrosis in pressure and volume overload are related to the propensity for ischaemia and involve resistin
Authors: Chemaly Elie R. , Kang Soojeong , Zhang Shihong , McCollum LaTronya , Chen Jiqiu , Bénard Ludovic , Purushothaman K‐Raman , Hajjar Roger J. , Lebeche Djamel 
Published: September 2013

Key points
Pressure overload hypertrophy is profibrotic while volume overload hypertrophy is not profibrotic.
Fibrosis occurs in the form of replacement or reactive fibrosis.
Replacement fibrosis in pressure overload is considered ischaemic in origin.
There is less propensity for ischaemia in volume overload, explaining the relative lack of fibrosis.
Reactive fibrosis pathways are more active in pressure than in volume overload.
Local resistin expression reflects replacement fibrosis in chronic ischaemia.
Abstract  Pathological left ventricle (LV) hypertrophy (LVH) results in reactive and replacement fibrosis. Volume overload LVH (VOH) is less profibrotic than pressure overload LVH (POH). Studies attribute subendocardial fibrosis in POH to ischaemia, and reduced fibrosis in VOH to collagen degradation favouring dilatation. However, the mechanical origin of the relative lack of fibrosis in VOH is incompletely understood. We hypothesized that reduced ischaemia propensity in VOH compared to POH accounted for the reduced replacement fibrosis, along with reduced reactive fibrosis. Rats with POH (ascending aortic banding) evolved into either compensated‐concentric POH (POH‐CLVH) or dilated cardiomyopathy (POH‐DCM); they were compared to VOH (aorta–caval fistula). We quantified LV fibrosis, structural and haemodynamic factors of ischaemia propensity, and the activation of profibrotic pathways. Fibrosis in POH‐DCM was severe, subendocardial and subepicardial, in contrast with subendocardial fibrosis in POH‐CLVH and nearly no fibrosis in VOH. The propensity for ischaemia was more important in POH versus VOH, explaining different patterns of replacement fibrosis. LV collagen synthesis and maturation, and matrix metalloproteinase‐2 expression, were more important in POH. The angiotensin II‐transforming growth‐factor β axis was enhanced in POH, and connective tissue growth factor (CTGF) was overexpressed in all types of LVH. LV resistin expression was markedly elevated in POH, mildly elevated in VOH and independently reflected chronic ischaemic injury after myocardial infarction. In vitro, resistin is induced by angiotensin II and induces CTGF in cardiomyocytes. Based on these findings, we conclude that a reduced ischaemia propensity and attenuated upstream reactive fibrotic pathways account for the attenuated fibrosis in VOH versus POH.
Blood pressure and the contractility of a human leg muscle
Authors: Luu Billy L. , Fitzpatrick Richard C. 
Published: September 2013

Key points
At identical activation, muscle force production in a small, non‐postural hand muscle that normally operates near heart level is sensitive to physiological changes in perfusion pressure.
Here we investigate how perfusion pressure affects muscle contractility in a large leg muscle that is subject to high hydrostatic pressures in its normal role.
We show that this large postural muscle and the small hand muscle have similar perfusion–contractility relationships, and that changes in local perfusion and systemic blood pressure produce proportionately the same effects on muscle contractility.
The rapid and reversible modulation of contractility by perfusion pressure may be explained by interstitial [K+] that depends on the balance between energy‐dependent processes in the myocyte and passive vascular removal.
These results help explain how blood pressure is controlled through the pressor response during exercise and how muscle force production and fatigue varies in different postures.
Abstract  These studies investigate the relationships between perfusion pressure, force output and pressor responses for the contracting human tibialis anterior muscle. Eight healthy adults were studied. Changing the height of tibialis anterior relative to the heart was used to control local perfusion pressure. Electrically stimulated tetanic force output was highly sensitive to physiological variations in perfusion pressure showing a proportionate change in force output of 6.5% per 10 mmHg. This perfusion‐dependent change in contractility begins within seconds and is reversible with a 53 s time constant, demonstrating a steady‐state equilibrium between contractility and perfusion pressure. These stimulated contractions did not produce significant cardiovascular responses, indicating that the muscle pressor response does not play a major role in cardiovascular regulation at these workloads. Voluntary contractions at forces that would require constant motor drive if perfusion pressure had remained constant generated a central pressor response when perfusion pressure was lowered. This is consistent with a larger cortical drive being required to compensate for the lost contractility with lower perfusion pressure. The relationship between contractility and perfusion for this large postural muscle was not different from that of a small hand muscle (adductor pollicis) and it responded similarly to passive peripheral and active central changes in arterial pressure, but extended over a wider operating range of pressures. If we consider that, in a goal‐oriented motor task, muscle contractility determines central motor output and the central pressor response, these results indicate that muscle would fatigue twice as fast without a pressor response. From its extent, timing and reversibility we propose a testable hypothesis that this change in contractility arises through contraction‐ and perfusion‐dependent changes in interstitial K+ concentration.
Pharmacodynamic Target Attainment for Various Ceftazidime Dosing Schemes in High-Flux Hemodialysis
Authors: Loo Angela S. , Neely Michael , Anderson Evan J. , Ghossein Cybele , McLaughlin Milena M. , Scheetz Marc H. 
Published: September 2013

ABSTRACT

Ceftazidime is a broad-spectrum cephalosporin with high-level activity against a variety of Gram-negative pathogens, including
Pseudomonas aeruginosa
. Improved outcomes are associated with cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%
T
MIC
) of >45 to 70% of the dosing interval. Optimal dosing to achieve a 90% probability of target attainment (PTA) in patients receiving high-flux hemodialysis (HFHD) is unknown. We used existing data from six anephric adults receiving hemodialysis to construct a population model with the Pmetrics package for R. From the final model's joint probability density, we simulated the PTA for various ceftazidime dosing regimens, HFHD schedules, and organism MICs. For HFHD every 48 h and 1 g of ceftazidime given posthemodialysis, the PTA exceeds 90% for all isolates with MICs of ≤8 μg/ml, assuming a goal of 70%
T
MIC
. For 72-h dialysis intervals, postdialysis dosing of 1 g is adequate for achievement of the 70%
T
MIC
goal only for organisms with MICs of ≤4 μg/ml, while 2 g is adequate for organisms with MICs of ≤8 μg/ml. A dose of 500 mg once daily, regardless of HFHD schedule, has a 90% PTA for organisms with MICs of ≤16 μg/ml, while 1 g once daily may achieve 100% PTA even for resistant organisms with a MIC of 32 μg/ml. Therefore, to ensure maximal ceftazidime activity, once-daily dosing of 500 mg to 1 g ceftazidime in patients receiving HFHD may be preferable for critically ill patients when MIC data are unavailable and for more resistant organisms with ceftazidime MICs of 16 to 32 μg/ml.
Rapid Viral Expansion and Short Drug Half-Life Explain the Incomplete Effectiveness of Current Herpes Simplex Virus 2-Directed Antiviral Agents
Authors: Schiffer Joshua T. , Swan David A. , Corey Lawrence , Wald Anna 
Published: September 2013

ABSTRACT

The nucleoside analogues acyclovir (ACV) and famciclovir (FCV) reduce the frequency and severity of herpes simplex virus 2 (HSV-2) genital shedding, yet despite their high potency
in vitro
and a lack of induced drug resistance, frequent episodes of breakthrough mucosal shedding occur. We tested a published stochastic, spatial mathematical model of HSV-2 replication and spread, in concert with pharmacokinetic and pharmacodynamic equations, against virologic data from clinical trials of twice-daily acyclovir and famciclovir suppression. The model reproduced the key features of clinical trial data, including genital shedding episode rate, expansion and decay dynamics, and heterogeneous peak viral production and duration. In simulations, these agents shortened episode duration by limiting the extent of viral production by 1 to 2 log units and limiting the formation of secondary ulcers by ∼50%. However, drug concentrations were noninhibitory during 42% of the dosing cycle. Even if drug concentrations were high at episode initiation, prolonged episodes often ensued due to drug decay over ensuing hours and subsequent rebound of rapidly replicating HSV-2. The local CD8
+
T-cell density was more predictive of episode viral production (
R
2
= 0.42) and duration (
R
2
= 0.21) than the drug concentration at episode onset (
R
2
= 0.14 and 0.05, respectively), though the model projected that an agent with an equivalent potency but a two times longer half-life would decrease shedding by 80% compared to that of standard twice-daily regimens. Therefore, long half-life is a key characteristic of any agent that might fully suppress HSV-2 reactivations.
Ciprofloxacin Treatment Failure in a Murine Model of Pyelonephritis Due to an AAC(6′)-Ib-cr-Producing Escherichia coli Strain Susceptible to Ciprofloxacin
In Vitro
Authors: Guillard T. , Cambau E. , Chau F. , Massias L. , de Champs C. , Fantin B. 
Published: September 2013

ABSTRACT

AAC(6′)-Ib-cr is a plasmid-mediated quinolone resistance mechanism described worldwide for
Escherichia coli
. Since it confers
in vitro
only a low level of resistance to ciprofloxacin, we evaluated its impact on the
in vivo
activity of ciprofloxacin. Isogenic strains were obtained by transferring plasmid p449, harboring
aac(6
′
)-Ib-cr
, into the quinolone-susceptible strain
E. coli
CFT073-RR and its D87G
gyrA
mutant. MICs were 0.015, 0.06, 0.25, and 0.5 μg/ml against
E. coli
strains CFT073-RR, CFT073-RR/p449, CFT073-RR GyrA
r
, and CFT073-RR GyrA
r
/p449, respectively. Bactericidal activity was reduced at 1× the MIC for the three resistant derivatives, while at a fixed concentration of 0.5 μg/ml, 99.9% killing was observed for all strains except
E. coli
CFT073-RR GyrA
r
/p449. In the murine model of pyelonephritis, an optimal regimen of ciprofloxacin (10 mg/kg of body weight twice a day [b.i.d.]) significantly decreased the bacterial count in the kidneys of mice infected with
E. coli
CFT073 (1.6 versus 4.3 log
10
CFU/g of kidney compared to untreated controls;
P
= 0.0001), while no significant decrease was observed for
E. coli
CFT073-RR/p449 (2.7 versus 3.1 log
10
CFU/g;
P
= 0.84),
E. coli
CFT073-RR GyrA
r
(4.2 versus 4.1 log
10
CFU/g;
P
= 0.35), or
E. coli
CFT073-RR GyrA
r
/p449 (2.9 versus 3.6 log
10
CFU/g;
P
= 0.47). While pharmacokinetic and pharmacodynamic (PK/PD) parameters accounted for ciprofloxacin failure against
gyrA
-containing mutants, this was not the case for the
aac(6
′
)-Ib-cr
-containing strains, suggesting an
in situ
hydrolysis of ciprofloxacin in the latter case.
Interlaboratory Variability of Caspofungin MICs for Candida spp. Using CLSI and EUCAST Methods: Should the Clinical Laboratory Be Testing This Agent?
Authors: Espinel-Ingroff A. , Arendrup M. C. , Pfaller M. A. , Bonfietti L. X. , Bustamante B. , Canton E. , Chryssanthou E. , Cuenca-Estrella M. , Dannaoui E. , Fothergill A. , Fuller J. , Gaustad P. , Gonzalez G. M. , Guarro J. , Lass-Flörl C. , Lockhart S. R. , Meis J. F. , Moore C. B. , Ostrosky-Zeichner L. , Pelaez T. , Pukinskas S. R. B. S. , St-Germain G. , Szeszs M. W. , Turnidge J. 
Published: September 2013

ABSTRACTAlthough Clinical and Laboratory Standards Institute (CLSI) clinical breakpoints (CBPs) are available for interpreting echinocandin MICs forCandidaspp., epidemiologic cutoff values (ECVs) based on collective MIC data from multiple laboratories have not been defined. While collating CLSI caspofungin MICs for 145 to 11,550Candidaisolates from 17 laboratories (Brazil, Canada, Europe, Mexico, Peru, and the United States), we observed an extraordinary amount of modal variability (wide ranges) among laboratories as well as truncated and bimodal MIC distributions. The species-specific modes across different laboratories ranged from 0.016 to 0.5 μg/ml forC. albicansandC. tropicalis, 0.031 to 0.5 μg/ml forC. glabrata, and 0.063 to 1 μg/ml forC. krusei. Variability was also similar among MIC distributions forC. dubliniensisandC. lusitaniae. The exceptions wereC. parapsilosisandC. guilliermondiiMIC distributions, where most modes were within one 2-fold dilution of each other. These findings were consistent with available data from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (403 to 2,556 MICs) forC. albicans,C. glabrata,C. krusei, andC. tropicalis. Although many factors (caspofungin powder source, stock solution solvent, powder storage time length and temperature, and MIC determination testing parameters) were examined as a potential cause of such unprecedented variability, a single specific cause was not identified. Therefore, it seems highly likely that the use of the CLSI species-specific caspofungin CBPs could lead to reporting an excessive number of wild-type (WT) isolates (e.g.,C. glabrataandC. krusei) as either non-WT or resistant isolates. Until this problem is resolved, routine testing or reporting of CLSI caspofungin MICs forCandidais not recommended; micafungin or anidulafungin data could be used instead.
Characterization and Identification of a Novel Candidate Vaccine Protein through Systematic Analysis of Extracellular Proteins of Erysipelothrix rhusiopathiae
Authors: Shi Fang , Ogawa Yohsuke , Sano Akiyuki , Harada Tomoyuki , Hirota Jiro , Eguchi Masahiro , Oishi Eiji , Shimoji Yoshihiro 
Published: September 2013

ABSTRACT

Erysipelothrix rhusiopathiae
, the causative agent of swine erysipelas, is a facultative intracellular Gram-positive bacterium. It has been shown that animals immunized with a filtrate from
E. rhusiopathiae
cultures are protected against lethal challenge. In this study, we identified and characterized the extracellular proteins of
E. rhusiopathiae
to search for novel vaccine antigens. A concentrated culture supernatant from the
E. rhusiopathiae
Fujisawa strain, which has been found to induce protection in mice, was analyzed using two-dimensional electrophoresis. From more than 40 confirmed protein spots, 16 major protein spots were selected and subjected to N-terminal amino acid sequence determination, and 14 protein spots were successfully identified. The identified proteins included housekeeping proteins and other metabolic enzymes. We searched for surface-localized proteins by analyzing the genomes of two
E. rhusiopathiae
strains: Fujisawa and ATCC 19414. Genome analysis revealed that the ATCC 19414 strain has three putative surface-exposed
c
holine-
b
inding
p
roteins (CBPs): CbpA, CbpB, and CbpC. Each CBP contains a putative choline-binding domain. The CbpC gene is mutated in Fujisawa, becoming a nonfunctional pseudogene. Immunogold electron microscopy confirmed that CbpA and CbpB, as well as the majority of the metabolic enzymes examined, are associated with the cell surface of
E. rhusiopathiae
Fujisawa. Immunization with recombinant CbpB, but not with other recombinant CBPs or metabolic enzymes, protected mice against lethal challenge. A phagocytosis assay revealed that antiserum against CbpB promoted opsonin-mediated phagocytosis by murine macrophages
in vitro
. The protective capabilities of CbpB were confirmed in pigs, suggesting that CbpB could be used as a vaccine antigen.
Culture and behaviour in the English National Health Service: overview of lessons from a large multimethod study
Authors: Dixon-Woods Mary , Baker Richard , Charles Kathryn , Dawson Jeremy , Jerzembek Gabi , Martin Graham , McCarthy Imelda , McKee Lorna , Minion Joel , Ozieranski Piotr , Willars Janet , Wilkie Patricia , West Michael 
Published: September 2013

BackgroundProblems of quality and safety persist in health systems worldwide. We conducted a large research programme to examine culture and behaviour in the English National Health Service (NHS).MethodsMixed-methods study involving collection and triangulation of data from multiple sources, including interviews, surveys, ethnographic case studies, board minutes and publicly available datasets. We narratively synthesised data across the studies to produce a holistic picture and in this paper present a high-level summary.ResultsWe found an almost universal desire to provide the best quality of care. We identified many ‘bright spots’ of excellent caring and practice and high-quality innovation across the NHS, but also considerable inconsistency. Consistent achievement of high-quality care was challenged by unclear goals, overlapping priorities that distracted attention, and compliance-oriented bureaucratised management. The institutional and regulatory environment was populated by multiple external bodies serving different but overlapping functions. Some organisations found it difficult to obtain valid insights into the quality of the care they provided. Poor organisational and information systems sometimes left staff struggling to deliver care effectively and disempowered them from initiating improvement. Good staff support and management were also highly variable, though they were fundamental to culture and were directly related to patient experience, safety and quality of care.ConclusionsOur results highlight the importance of clear, challenging goals for high-quality care. Organisations need to put the patient at the centre of all they do, get smart intelligence, focus on improving organisational systems, and nurture caring cultures by ensuring that staff feel valued, respected, engaged and supported.
Carotid artery stenting without post-stenting balloon dilatation
Authors: Ogata Atsushi , Sonobe Makoto , Kato Noriyuki , Yamazaki Tomosato , Kasuya Hiromichi , Ikeda Go , Miki Shunichiro , Matsushima Toshio 
Published: September 2013

PurposeTo evaluate the clinical outcome and MRI findings after carotid artery stenting (CAS) without post-dilatation.MethodsBetween May 2005 and April 2012, a total of 169 consecutive patients (61.4% symptomatic) underwent 176 CAS procedures performed with an embolic protection device (GuardWire, n=116; FilterWire EZ, n=60). All stents were deployed without post-dilatation. Periprocedural complications and mid-term outcomes were analyzed.ResultsThe stroke rate was 2.3% within 30 days post-CAS (asymptomatic patients 1.5%; symptomatic patients 2.8%). Cerebral infarction occurred in one asymptomatic patient (1.5%) and one symptomatic patient (0.9%). Intracranial hemorrhage occurred in two symptomatic patients (1.9%). Post-CAS diffusion-weighted imaging (DWI) revealed a high-intensity area in 26 of 176 procedures (14.8%). Ipsilateral stroke after 31 days occurred in two patients (1.1%) and restenosis occurred in six (3.4%). A post-CAS comparison of the embolic protection devices revealed no difference in stroke incidence within 30 days and in DWI high-intensity area.ConclusionsOur CAS procedure without post-dilatation is feasible, safe and associated with a low incidence of stroke and restenosis.