bluuebunny/crossref_metadata_2025 huggingface dataset:
New role of the dual knife for precut papillotomy in difficult bile duct cannulation
Authors: Liu Feng , Liu Jianqiang , Li Zhaoshen
Published: July 2012

The dual knife is usually used for endoscopic submucosal dissection (ESD). To date, however, there have been no clinical trials of the safety and effectiveness of precut papillotomy using the dual knife for biliary access in patients failing conventional endoscopic retrograde cholangiopancreatography (ERCP) cannulation. We herein report 18 patients who underwent precut papillotomy with the dual knife. All had intact papilla, and had failed deep cannulation of the bile ducts. After successful biliary cannulation and standard endoscopic sphincterotomy, if necessary, stone removal or plastic or metal stent insertion was attempted. Selective bile‐duct cannulation was achieved in all 18 patients (100%), at an average time of 4.2 min (range, 3–6 min). Of these 18 patients, six had malignant bile duct obstruction and 12 had common bile duct stones. One patient developed post‐ERCP pancreatitis, which resolved after conservative management. There were no deaths related to the procedure.
Clinical implications of the transversus abdominis plane block in pediatric anesthesia
Authors: Mai Christine L. , Young Mark J. , Quraishi Sadeq A.
Published: July 2012

Optimal perioperative analgesia for infants and children after major abdominal surgery poses a challenge when central neuraxial techniques are contraindicated. As a regional anesthesia technique, the transversus abdominis plane (TAP) block has been shown to reduce opioid consumption and improve pain scores compared to traditional perioperative pain strategies. Accordingly, TAP blocks may be considered as an alternative to central neuraxial analgesia to optimize perioperative pain control. Advancements in ultrasound technology have further improved the reliability and safety profile of this technique. Despite growing recognition of the diverse clinical scenarios where TAP blocks may be of benefit, its use among pediatric anesthesiologists remains limited. This article describes the history, anatomy, and a review of the current literature on TAP blocks with an emphasis on outcomes in pediatric patients.
The effect of zinc limitation on the transcriptome ofPseudomonas protegens Pf‐5
Authors: Lim Chee Kent , Hassan Karl A. , Penesyan Anahit , Loper Joyce E. , Paulsen Ian T.
Published: July 2012

Zinc is an important nutrient but can be lacking in some soil environments, influencing the physiology of soil‐dwelling bacteria. Hence, we studied the global effect of zinc limitation on the transcriptome of the rhizosphere biocontrol strainPseudomonas protegens Pf‐5 (formerlyPseudomonas fluorescens). We observed that the expression of the putative zinc uptake regulator (Zur) gene was upregulated, and we mapped putativeZur binding sites in thePf‐5 genome using bioinformatic approaches. In line with the need to regulate intracellular zinc concentrations, an array of potential zinc transporter genes was found to be zinc‐regulated. To adapt to low‐zinc conditions, a gene cluster encoding non‐zinc‐requiring paralogues of zinc‐dependent proteins was also significantly upregulated. Similarly, transcription of genes encoding non‐zinc‐requiring paralogues of ribosomal proteinsL31 andL36 was increased by zinc limitation. A strong transcriptional downregulation of the putative copper chaperone gene (copZ) was also observed, suggesting interplay between zinc and copper homeostasis. Importantly, zinc also affected biocontrol attributes inPf‐5, most notably reducing the expression of the gene cluster responsible for biosynthesis of the antibiotic 2,4‐diacetylphloroglucinol (DAPG) under zinc limitation. This study clearly defines changes to the molecular physiology ofPf‐5 that enable it to survive under zinc limitation.
Acanthamoeba feature a unique backpacking strategy to trap and feed on Listeria monocytogenes and other motile bacteria
Authors: Doyscher Dominik , Fieseler Lars , Dons Lone , Loessner Martin J. , Schuppler Markus
Published: July 2012

Despite its prominent role as an intracellular human pathogen, Listeria monocytogenes normally features a saprophytic lifestyle, and shares many environmental habitats with predatory protozoa. Earlier studies claimed that Acanthamoeba may act as environmental reservoirs for L. monocytogenes, whereas others failed to confirm this hypothesis. Our findings support the latter and provide clear evidence that L. monocytogenes is unable to persist in Acanthamoeba castellanii and A. polyphaga. Instead, external Listeria cells are rapidly immobilized on the surface of Acanthamoeba trophozoites, forming large aggregates of densely packed bacteria that we termed backpacks. While the assembly of backpacks is dependent on bacterial motility, flagellation alone is not sufficient. Electron micrographs showed that the aggregates are held together by filaments of likely amoebal origin. Time‐lapse microscopy revealed that shortly after the bacteria are collected, the amoeba can change direction of movement, phagocytose the backpack and continue to repeat the process. The phenomenon was also observed with avirulent L. monocytogenes mutants, non‐pathogenic Listeria, and other motile bacteria, indicating that formation of backpacks is not specific for L. monocytogenes, and independent of bacterial pathogenicity or virulence. Hence, backpacking appears to represent a unique and highly effective strategy of Acanthamoeba to trap and feed on motile bacteria.
FixedbSubsampling and the Block Bootstrap: Improved Confidence Sets based onp-Value Calibration
Authors: Shao Xiaofeng , Politis Dimitris N.
Published: July 2012

Subsampling and block-based bootstrap methods have been used in a wide range of inference problems for time series. To accommodate the dependence, these resampling methods involve a bandwidth parameter, such as the subsampling window width and block size in the block-based bootstrap. In empirical work, using different bandwidth parameters could lead to different inference results, but traditional first-order asymptotic theory does not capture the choice of the bandwidth. We propose to adopt the fixed b approach, as advocated by Kiefer and Vogelsang in the heteroscedasticity–auto-correlation robust testing context, to account for the influence of the bandwidth on inference. Under the fixed b asymptotic framework, we derive the asymptotic null distribution of the p-values for subsampling and the moving block bootstrap, and further propose a calibration of the traditional small-b-based confidence intervals (regions or bands) and tests. Our treatment is fairly general as it includes both finite dimensional parameters and infinite dimensional parameters, such as the marginal distribution function. Simulation results show that the fixed b approach is more accurate than the traditional small b approach in terms of approximating the finite sample distribution, and that the calibrated confidence sets tend to have smaller coverage errors than the uncalibrated counterparts.
Accountability or Representation? How Electoral Systems Promote Public Trust in African Legislatures
Authors: CHO WONBIN
Published: July 2012

Elections serve as instruments of democracy, but they do so differently in various parts of the world. This article focuses on the democratizing role of elections in 16 sub‐Saharan African countries represented in Afrobarometer survey data. It traces confidence in legislative institutions to whether a citizen perceives competitive elections to produce accountability and/or representation. The analysis shows that elections function differently depending on the nature of legislative institutions. Majoritarian electoral systems promote a sense of citizen control over policymakers (i.e., accountability) whereas proportional representation (PR) systems increase the perception of inclusion across a society's factions (i.e., representation). Because sub‐Saharan African citizens typically prioritize representation rather than accountability when evaluating their legislative institutions, controlling for other influences, PR systems are much better at boosting public trust in the region. These findings have important implications for democratic development in Africa.
Comparison between CHADS2 and CHA2DS2‐VASc score in a stroke cohort with atrial fibrillation
Authors: Giralt‐Steinhauer E. , Cuadrado‐Godia E. , Ois Á. , Jiménez‐Conde J. , Rodríguez‐Campello A. , Soriano C. , Roquer J.
Published: July 2012

Background and purpose

In patients with atrial fibrillation (AF), stroke risk stratification schemes have been developed to optimize antithrombotic treatment. The CHADS2 score is frequently used but has limitations. The CHA2DS2‐VASc score improves risk prediction. Our objectives are to describe CHADS2 and CHA2DS2‐VASc score distribution in a cohort of patients with AF and first‐ever ischaemic stroke (FIS) and to identify differences in embolic risk stratification.

Methods

Our cohort included 589 patients with FIS, previous modified Rankin score ≤ 3, and non‐valvular AF. We recorded demographic data, vascular risk factors, and antithrombotic pre‐treatment. The CHADS2 and CHA2DS2‐VASc scores were calculated according to clinical status before stroke onset.

Results

In 186 (31.6%) patients, AF was previously unknown. Of patients with known AF and CHADS2 ≥2 (n = 320), only 103 (32.2%) were taking anticoagulants; more than half of these patients had an INR <2. The CHADS2 score placed 142 (24.1%) patients in the low–intermediate risk (score ≤ 1) category compared with 21 (3.6%) with CHA2DS2‐VASc, P < 0.001. Applying CHA2DS2‐VASc reclassified 121 (85.2%) subjects in the CHADS2 low–intermediate risk category as high risk (≥2), an indication for anticoagulants. Of the 21 patients who suffered a stroke despite their low CHA2DS2‐VASc score (≤1), seven (33.3%) reported alcohol overuse, and six (28.5%) had a concomitant stroke etiology.

Conclusions

About 25% of FIS patients with AF had a CHADS2 score ≤ 1. Despite the high CHADS2 score of our population, few patients received the recommended antithrombotic treatment according to their thromboembolic risk. Using the CHA2DS2‐VASc schema significantly increased the percentage of patients indicated for anticoagulation.
The potential prognostic role of cardiovascular autonomic failure in α‐synucleinopathies
Authors: Fanciulli A. , Strano S. , Colosimo C. , Caltagirone C. , Spalletta G. , Pontieri F. E.
Published: July 2012

Cardiovascular autonomic failure is the second most common dysautonomic feature of α‐synucleinopathies and has significant impact on daily activities and quality of life. Here we provide a systematic review of cardiovascular autonomic failure in α‐synucleinopathies, emphasizing its impact on cognitive functions and disease outcomes. Articles spanning the period between January 1985 and April 2012 were identified from the PubMed database using a keyword‐based search. Epidemiological studies highlight the negative prognostic effect of cardiovascular autonomic failure on cardiovascular and cerebrovascular outcomes and overall mortality in all α‐synucleinopathies. Altered cerebral perfusion, vascular pressure stress, and related disruption of the blood–brain barrier may also contribute to the white matter hyperintensities and cognitive dysfunction frequently found in patients affected by neurocardiovascular instability. These findings support the hypothesis that cardiovascular autonomic failure may play a negative prognostic role in α‐synucleinopathies and suggest that precocious screening and therapeutic management of cardiovascular autonomic failure may positively impact disease course.
PTX3 Genetic Variation and Dizygotic Twinning in The Gambia: Could Pleiotropy with Innate Immunity Explain Common Dizygotic Twinning in Africa?
Authors: Sirugo Giorgio , Edwards Digna R. Velez , Ryckman Kelli K. , Bisseye Cyrille , White Marquitta J. , Kebbeh Bunja , Morris Gerard A. J. , Adegbola Richard A. , Tacconelli Alessandra , Predazzi Irene M. , Novelli Giuseppe , Vannberg Fredrik O. , Odunsi Kunle , Page Grier P. , Williams Scott M.
Published: July 2012

Dizygotic (DZ) twinning has a genetic component and is common among sub‐Saharan Africans; in The Gambia its frequency is up to 3% of live births. Variation in PTX3, encoding Pentraxin 3, a soluble pattern recognition receptor that plays an important role both in innate immunity and in female fertility, has been associated with resistance to Mycobacterium tuberculosis pulmonary disease and to Pseudomonas aeruginosa infection in cystic fibrosis patients. We tested whether PTX3 variants in Gambian women associate with DZ twinning, by genotyping five PTX3 single nucleotide polymorphisms (SNPs) in 130 sister pairs (96 full sibs and 34 half sibs) who had DZ twins. Two, three and five SNP haplotypes differed in frequency between twinning mothers and those without a history of twinning (from P= 0.006 to 3.03e‐06 for two SNP and three SNP haplotypes, respectively). Twinning mothers and West African tuberculosis‐controls from a previous study shared several frequent haplotypes. Most importantly, our data are consistent with an independently reported association of PTX3 and female fertility in a sample from Ghana. Taken together, these results indicate that selective pressure on PTX3 variants that affect the innate immune response to infectious agents, could also produce the observed high incidence of DZ twinning in Gambians.
Do quality improvement systems improve health library services? A systematic review
Authors: Gray Hannah , Sutton Gary , Treadway Victoria
Published: July 2012

Background

A turbulent financial and political climate requires health libraries to be more accountable than ever. Quality improvement systems are widely considered a ‘good thing to do’, but do they produce useful outcomes that can demonstrate value?

Objectives

To undertake a systematic review to identify which aspects of health libraries are being measured for quality, what tools are being used and what outcomes are reported following utilisation of quality improvement systems.

Results

Many health libraries utilise quality improvement systems without translating the data into service improvements. Included studies demonstrate that quality improvement systems produce valuable outcomes including a positive impact on strategic planning, promotion, new and improved services and staff development. No impact of quality improvement systems on library users or patients is reported in the literature.

Conclusions

The literature in this area is sparse and requires updating. We recommend further primary research is conducted in health libraries focusing upon the outcomes of utilising quality improvement systems. An exploration of quality improvement systems in other library sectors may also provide valuable insight for health libraries.
Patient perceptions of epinephrine auto‐injectors: exploring barriers to use
Authors: Money Arthur G. , Barnett Julie , Kuljis Jasna , Lucas Jane
Published: July 2012

Scand J Caring Sci; 2013; 27; 335–344

Patient perceptions of epinephrine auto‐injectors: exploring barriers to use

Background:  In recent years, government initiatives have proposed that patient self‐care should serve as a key resource in response to the anticipated increase in global demand for health care. However, if patients are to be empowered as self‐carers, barriers to engagement must be identified and overcome. Anaphylaxis is an increasingly common life‐threatening allergic reaction. Patients at risk of anaphylaxis are prescribed epinephrine auto‐injectors and play a crucial role in delivering their own care and management of this condition. One key recommendation is that patients routinely carry an epinephrine auto‐injector with them and deploy the device when needed. However, only a small proportion of patients that require epinephrine actually receive it.

Objective:  To explore the reasons why patients who have been prescribed epinephrine auto‐injectors fail to adhere to self‐care and management recommendations.

Methods:  In‐depth interviews with 15 adults who have been prescribed epinephrine auto‐injectors were carried out to explore the barriers that exist in the provision of effective self‐care and management of anaphylaxis.

Results:  Inconsistent health professional advice, perceived stigma of carrying a ‘weapon‐like’ device, poor device design and limited patient training were identified as barriers to carriage or use. Patients were reluctant to carry devices in public because of perceived and observed stigma and suspicion. They were happy to ignore expiry dates, and some participants were confident that the emergency services would provide them with the appropriate care they needed, and therefore, did not carry the device in urban areas.

Conclusions and clinical implications:  Improved training of patients, the public and health professionals around both the carriage and use of auto‐injectors are areas for urgent attention if improved levels of self‐care are to be attained. The design of epinephrine auto‐injectors should also receive attention as patients often fail to carry them owing to size and aesthetics.
Soil organic‐C accumulation and N availability under improved pastures established in Mediterranean oak woodlands
Authors: Gómez‐Rey M. X. , Garcês A. , Madeira M.
Published: July 2012

Long‐term effects of improved pasture establishment (with high proportion of legumes) on soil organic‐C status and N availability in Mediterranean cork oak (Quercus suberL.) woodlands were assessed. Soils were sampled beneath scattered crowns and in open areas, considering two systems: unmanaged and managed woodlands where improved pastures were installed 26 and 32 years ago. Total and labile C and N pools were measured and C and N mineralization were determined over 24 weeks laboratory incubation. Soils under improved pastures showed higher organic‐C, total‐N and net N mineralization than those under unmanaged pasture, mainly when established beneath trees. Potentially mineralizable C, C mineralization rate and microbial C were not statistically different between the unmanaged and improved pasture sites, but were higher closer to the tree than in the open area (1.8, 1.2 and 1.2 times, respectively). TheqCO2was higher in improved pastures (1.7 times). Labile pool of C and N extracted with hot water increased under improved pasture (3.4 and 1.7 times, respectively). Results indicate that soil quality amelioration by improved pastures is stronger in the presence of oak trees. Management systems that favour oak tree maintenance and regeneration should be taken into account to reverse soil degradation.
Low intimacy as a mediator between depression and clinic couple relationship satisfaction
Authors: FINKBEINER NICOLE M. , EPSTEIN NORMAN B. , FALCONIER MARIANA K.
Published: July 2012

This study examined low intimacy as a mediator between partners' depression symptoms and low relationship satisfaction in a sample of 82 heterosexual couples who sought therapy at an outpatient clinic. Both the amount of intimate behavior that partners enact and the level of pleasure they experience from each other's intimate acts were assessed. Using an actor–partner interdependence model approach, path model analysis simultaneously included both partners' scores on measures of depression, intimate behavior, pleasure from partner's intimate behavior, and relationship satisfaction. Overall, female depression symptoms had a greater impact than male depression symptoms on the couple relationship. Male depression had little effect on intimacy, whereas the female partner's depression affected her pleasure from the male's intimate behavior and both partners' enactment of intimate behavior. The results indicate the importance of examining reciprocal influences between partners' functioning to understand and treat intimacy problems.
Central neuropeptide Y and the sigma ligand, JO 1784, reverse corticotropin‐releasing factor‐induced inhibition of gastric acid secretion in rats
Authors: Gué M. , Yoneda M. , Mönnikes H. , Junien J.‐L. , Taché Y.
Published: July 2012

The central interactions between the sigma ligand, JO 1784, [(+)‐N‐cylcopropylmethyl‐N‐methyl‐1,4‐diphenyl‐1‐ethylbut‐3‐en‐1‐ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin‐releasing factor (CRF)‐induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 μg kg−1 h−1, i.v.) stimulated conditions.

Intracisternal injection of CRF (10 μg), bombesin (0.1 μg) and human recombinant interleukin‐1β (hIL‐1β, 0.1 μg) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 μg) or JO 1784 (0.5 μg) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose‐related (0.01–0.5 μg) and peptide‐specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL‐1β.

The putative sigma receptor antagonist, BMY 14802, (1 mg kg−1, s.c.) did not influence pentagastrin‐stimulated acid secretion nor CRF‐induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY.

CRF (3 μg) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin‐stimulated gastric acid secretion by 61% and 51%; NPY (0.03 μg) or JO 1784 (0.03 μg) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action. Microinjection into the LH had no effect.

In conclusion, NPY and JO 1784 (a sigma ligand) interacts with CRF in the PVN to block CRF‐induced inhibition of pentagastrin‐stimulated gastric acid secretion. The central action of JO 1784 and NPY is specific to CRF and may involve sigma binding sites.
Modification by hypoxia, hyperkalaemia and acidosis of the cardiac electrophysiological effects of a range of antiarrhythmic drugs
Authors: Pacini D.J. , Boachie‐Ansah G. , Kane K.A.
Published: July 2012

The electrophysiological effects of a series of drugs with Class I antiarrhythmic activity were examined in sheep Purkinje fibres, superfused in vitro with either a normal or hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS).

In normal sheep Purkinje fibres, lignocaine, disopyramide, nicainoprol and propranolol all significantly reduced action potential height and the maximum rate of depolarization of phase zero (MRD) and abbreviated the action potential, without modifying resting membrane potential (RMP).

Verapamil at the highest concentration studied, 8 μm, significantly reduced MRD with an associated slight membrane depolarization and abbreviated action potential duration measured at 50% repolarization (APD50).

Superfusion of sheep Purkinje fibres with a hypoxic, hyperkalaemic and acidotic PSS resulted in marked reductions in resting membrane potential, upstroke and duration of the action potential.

In the presence of modified PSS, lignocaine, propranolol and verapamil all reduced MRD to a greater extent than in normal PSS. The effects of nicainoprol on MRD were not affected whereas those of disopyramide were significantly attenuated.

Under simulated ischaemic conditions, lignocaine, propranolol and nicainoprol did not produce a concentration‐dependent reduction in action potential duration whereas disopyramide and verapamil, respectively, prolonged and abbreviated both APD50 and APD90.

The Na+ channel blocking actions of the different subtypes of Class I antiarrhythmic agents studied, as well as their effects on action potential duration, were modified differently by simulated ischaemia.
Human α‐calcitonin gene‐related peptide stimulates adenylate cyclase and guanylate cyclase and relaxes rat thoracic aorta by releasing nitric oxide
Authors: Gray David W. , Marshall Ian
Published: July 2012

The signal transduction pathway for vasorelaxation induced by human α‐calcitonin gene‐related peptide (human α‐CGRP) was studied in rat thoracic aortic rings preconstricted with noradrenaline (10−7 m).

Vasorelaxation by human α‐CGRP was inhibited by haemogobin (10−6 m) and methylene blue (10−5 m) but was unaffected by ibuprofen (10−5 m).

Acetylcholine caused a 16 fold increase in levels of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) with levels of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) being unaltered. Human α‐CGRP caused a 12 fold increase in levels of cyclic GMP but, in contrast to acetylcholine, evoked a 2.5 fold rise in levels of cyclic AMP. The rises in cyclic nucleotides evoked by human α‐CGRP and acetylcholine were dependent on the presence of an intact endothelium.

NG‐nitro‐l‐arginine (l‐NOARG: 10−5 m), which inhibits nitric oxide synthase, inhibited the relaxant response to human α‐CGRP and cyclic GMP accumulation without affecting the cyclic AMP accumulation.

The data presented in this paper suggests that human α‐CGRP relaxes the rat thoracic aorta by releasing nitric oxide and stimulating guanylate cyclase. The stimulation of adenylate cyclase by human α‐CGRP probably precedes the activation of nitric oxide synthase but could be unrelated to the relaxant response.
Multiple σ binding sites in guinea‐pig and rat brain membranes: G‐protein interactions
Authors: Connick J.H. , Hanlon G. , Roberts J. , France L. , Fox P.K. , Nicholson C.D.
Published: July 2012

Evidence is accumulating for multiple sigma (σ) sites in the mammalian CNS.

We have addressed this problem and have examined σ site — G‐protein coupling in guinea‐pig and rat brain membranes.

Ditolylorthoguanidine (DTG), (+)‐3‐(3‐hydroxyphenyl)‐N‐1‐(propyl)piperidine (3PPP) and dextromethorphan displaced [3H]‐DTG (3.4 nm) with low Hill slopes of 0.5, 0.6 and 0.6, respectively in guinea‐pig brain membranes.

In the presence of 5′‐guanylylimidodiphosphate (Gpp(NH)p; 100 μm), the specific binding of [3H]‐DTG was reduced by 36.7%, the Hill slope of 3PPP was increased to near unity, the ability of dextromethorphan to displace DTG was virtually abolished and the Hill slope for DTG remained low (0.7), indicating the presence of at least two binding sites. These data indicate that although Gpp(NH)p removes a dextromethorphan high affinity site, two DTG selective sites remain in the presence of Gpp(NH)p.

The present study suggests that DTG binds to at least three sites in guinea‐pig brain membranes, at least one of which is G‐protein linked.

In rat brain membranes, DTG displaced itself (3.4 nm) with a Hill slope near 1. 3PPP displacement of [3H]‐DTG was comparable with the guinea‐pig (Hill slope 0.5) and displaced from more than 1 site. Dextromethorphan did not displace [3H]‐DTG at concentrations below 10 μm.

The heterogeneity of σ sites appears to be less in rat than in guinea‐pig brain membranes.
Protection by Ca2+ channel blockers (nifedipine, diltiazem and verapamil) against the toxicity of oxidized low density lipoprotein to cultured lymphoid cells
Authors: Nègre‐Salvayre Anne , Salvayre Robert
Published: July 2012

Ca2+ channel blockers from 3 different chemical classes (diltiazem, verapamil and nifedipine) were compared in their ability to inhibit low density lipoprotein (LDL) oxidation and to protect cells directly against the cytotoxicity of oxidized LDL.

LDL oxidation promoted either by u.v. radiations or by copper ions was inhibited by nifedipine (IC50 of 10 ± 2 and 4 ± 0.5 μmol 1−1, respectively) whereas diltiazem and verapamil were only poorly active or completely ineffective. As expected, LDL protected from oxidation by nifedipine (nifedipine/oxidized LDL) were much less cytotoxic than (unprotected) oxidized LDL (or than LDL oxidized in the presence of diltiazem or verapamil). The cytotoxic effect correlated well with the lipid peroxidation derivatives measured as the thiobarbituric acid reactive substances (TBARS) content of LDL oxidized in the presence of Ca2+ channel blockers, which suggests that the antioxidant effect of Ca2+ channel blockers protected cells indirectly from the cytotoxic effect of oxidized LDL.

Nifedipine also exhibited a direct cytoprotective effect against the cytotoxicity of oxidized LDL as demonstrated by incubating cells in the presence of unprotected oxidized LDL and nifedipine (IC50 of 1 ± 0.2 μmol 1−1), whereas diltiazem and verapamil did not exhibit any significant protective effect. At the concentrations used, the protective effect of nifedipine was not due to inhibition of LDL uptake by Ca2+ channel blockers.

The direct protective activity of nifedipine is probably unrelated to its antioxidant properties since it did not inhibit the cellular TBARS evoked by oxidized LDL taken up by the cells, in contrast to vitamin E.

Nifedipine (and diltiazem to a lesser extent) inhibited the slow [Ca2+]i rise induced by oxidized LDL and the subsequent cytotoxicity.

It is proposed that relatively high concentrations of nifedipine (unlike diltiazem and verapamil) protect cultured lymphoid cells against the cytotoxicity of oxidized LDL by two different mechanisms: (i) an antioxidant effect inhibiting LDL oxidation (outside the cell); (ii) a direct cytoprotective effect (at lower concentrations), the mechanism of which is unknown. These data could explain in part the mechanism of action of nifedipine in the prevention of cellular damage potentially involved in atherogenesis.
Nitric oxide is involved in 5‐HT‐induced relaxations of the guinea‐pig colon ascendens in vitro
Authors: Briejer Michel R. , Akkermans Louis M.A. , Meulemans Ann L. , Lefebvre Romain A. , Schuurkes Jan A.J.
Published: July 2012

In the guinea‐pig colon ascendens, 5‐hydroxytryptamine (5‐HT) induces contractions, mediated by 5‐HT2, 5‐HT3 and 5‐HT4 receptors, and relaxations, through a 5‐HT1 receptor subtype, that triggers the release of an inhibitory neurotransmitter. Nitric oxide (NO) is one of the main candidates of NANC inhibitory neurotransmission in the gut. The aim of this study was to establish whether NO is involved in 5‐HT‐induced relaxations of the guinea‐pig colon ascendens.

Antagonists to block the contractile responses to 5‐HT via 5‐HT2, 5‐HT3 and 5‐HT4 receptors were present throughout the experiments and methacholine was administered to precontract the strips. Under these conditions, 5‐HT concentration‐dependently induced relaxations from 10 nm onwards (EC50 = 258 (172–387) nm). The relaxations were inhibited by metergoline (10 nm) and methiothepine (100 nm) and abolished by tetrodotoxin (TTX, 320 nm). Guanethidine (3.2 μm) did not affect them.

NG‐nitro‐l‐arginine (l‐NNA) inhibited the responses to 5‐HT (IC50 = 18.7 (13.3–26.3) μm); at the highest 5‐HT concentration a maximum inhibition of about 75% was observed with 320 μm l‐NNA. This inhibition was reversed with l‐arginine. Relaxations to glyceryl trinitrate (GTN) were not inhibited by l‐NNA.

Haemoglobin (32 μm) inhibited the relaxations to 5‐HT and GTN, but not those to isoprenaline (Iso). Methylene blue (10 μm) inhibited the relaxations to 5‐HT but did not affect those caused by GTN or Iso.

It is concluded that 5‐HT induces relaxations that involve NO. We also confirmed that 5‐HT induces these relaxations via (a) 5‐HT1 receptor subtype(s), located on neurones.
Electrophysiological effects of diprafenone, a dimethyl congener of propafenone on guinea‐pig ventricular cells
Authors: Kodama Itsuo , Suzuki Ryoko , Honjo Haruo , Toyama Junji
Published: July 2012

The effects of diprafenone and propafenone on transmembrane action potential were examined and compared in papillary muscles and single ventricular myocytes isolated from guinea‐pig hearts.

In papillary muscles, both diprafenone and propafenone ≥ 10−6 m caused a significant and dose‐dependent decrease in the maximum upstroke velocity () of the action potential.

In the presence of either drug, trains of stimuli at rates ≥ 0.1 Hz led to an exponential decline in . A time constant (τR) for recovery from the use‐dependent block was 15.5 s for diprafenone and 8.8 s for propafenone.

The use‐dependent block of with diprafenone was enhanced when the resting potential was depolarized by high (8, 10 mm) [K+]o, whereas that with propafenone was virtually unchanged. τR with diprafenone was shortened by the depolarization, while that with propafenone was rather prolonged.

In single myocytes perfused with diprafenone or propafenone, 10 ms conditioning clamp to 0 mV caused a significant decrease in of subsequent action potential. A prolongation of the clamp pulse duration resulted in a modest enhancement of the inhibition with diprafenone, while a large enhancement of the inhibition occurred with propafenone.

These findings suggest that diprafenone, like propafenone, may block the sodium channel during both the activated and inactivated states. The relative contribution of inactivation block is less important for diprafenone than for propafenone. The different voltage‐dependence of use‐dependent block with diprafenone from propafenone would contribute to its high antiarrhythmic potency.
Changes in purinergic responses of the rabbit isolated central ear artery after chronic electrical stimulation in vivo
Authors: Maynard K.I. , Loesch A. , Burnstock G.
Published: July 2012

The effect of chronic (4–16 days) electrical stimulation (5 Hz, 0.3 ms, 4–10 V) of the great auricular nerve in vivo on sympathetic cotransmission in the rabbit isolated central ear artery was examined.

Chronic stimulation had no significant effect on frequency‐dependent (4–60 Hz) neurogenic contractions or contractile responses induced by exogenous noradrenaline (0.1–300 μm).

In contrast, contractions induced by exogenous α,β‐methylene ATP (10.0 μm) were significantly decreased in preparations from 16‐day stimulated animals in comparison with sham‐operated, 4‐day and 8‐day chronically stimulated animal groups.

It is concluded that chronic electrical stimulation of nerves supplying the ear artery may lead to the selective alteration of postjunctional P2x‐purinoceptor mechanisms, while the effects mediated by postjunctional α1‐adrenoceptors remain unchanged.
A possible role of the L‐arginine‐nitric oxide pathway in the modulation of cholinergic transmission in the guinea‐pig taenia coli
Authors: Knudsen M.A. , Tøttrup A.
Published: July 2012

The role of the l‐arginine‐nitric oxide (NO) pathway for non‐adrenergic, non‐cholinergic (NANC) relaxation of the guinea‐pig taenia coli was studied by recording isometric tension in response to transmural field stimulation (TMS).

In preparations precontracted with prostaglandin F2α (PGF2α, 10−6 m), TMS induced frequency‐dependent responses of the muscle strips which could be abolished by tetrodotoxin (10−6 m). NG‐nitro‐l‐arginine (l‐NNA, 10−4 m), an l‐arginine analogue, and potent inhibitor of NO synthesis, stereospecifically inhibited maximum relaxations, but did not shift the frequency‐response curve. Preincubation with NG‐nitro‐d‐arginine (d‐NNA, 10−4 m), atropine (10−6 m) plus l‐NNA (10−4 m), or atropine (10−6 m) alone, had no influence on the frequency‐response characteristics.

l‐NNA (10−7−10−4 m) concentration‐dependently inhibited relaxations in PGF2α (10−6 m) precontracted strips in response to TMS, but did not abolish relaxations. Preincubation with l‐arginine (10−4 m) inhibited these effects of l‐NNA. l‐NNA (10−4 m) had no effect on the inhibitory response during TMS in strips preincubated with atropine (10−6 m).

The relaxation induced by sodium nitroprusside and forskolin (10−9−10−4 m) was not influenced by l‐NNA (10−4 m) preincubation as expressed by identical pD2 and Emax values.

Contractions induced by PGF2α (10−9−10−4 m) and carbachol (10−9−10−4 m) were not affected by pretreatment with l‐NNA (10−4 m), as expressed by identical pD2 and Emax values.

In conclusion, the l‐arginine‐NO pathway seems to play a role in the NANC innervation of the guinea‐pig taenia coli. The inhibitory effect of NO or a NO‐like compound depends on the integrity of the cholinergic pathways and it is proposed that this compound exerts its effects prejunctionally on cholinergic nerves, by inhibiting the release of acetylcholine.
Iron‐sulphur cluster nitrosyls, a novel class of nitric oxide generator: mechanism of vasodilator action on rat isolated tail artery
Authors: Flitney F.W. , Megson I.L. , Flitney D.E. , Butler A.R.
Published: July 2012

Two iron‐sulphur cluster nitrosyls have been investigated as potential nitric oxide (NO·) donor drugs (A: tetranitrosyltetra‐μ3‐sulphidotetrahedro‐tetrairon; and B: heptanitrosyltri‐μ3‐thioxotetraferrate(1‐)). Both compounds are shown to dilate precontracted, internally‐perfused rat tail arteries.

Bolus injections (10 μl) of compound A or B generate two kinds of vasodilator response. Doses below a critical threshold concentration (DT) evoke transient (or T‐type) responses, which resemble those seen with conventional nitrovasodilators. Doses > DT produce sustained (or S‐type) responses, comprising an initial, rapid drop of pressure, followed by incomplete recovery, resulting in a plateau of reduced tone which can persist for several hours.

T‐ and S‐type responses are attenuated by ferrohaemoglobin (Hb) and by methylene blue (MB), but not by inhibitors of endothelial NO· synthase. Addition of either Hb or MB to the internal perfusate can restore agonist‐induced tone when administered during the plateau phase of an S‐type response. Moreover, subsequent removal of Hb causes the artery to re‐dilate fully.

We conclude that T‐ and S‐type responses are both mediated by NO·. It is postulated that S‐type responses represent the sum of two vasodilator components: a reversible component, superimposed upon a non‐recoverable component. The former is attributed to free NO·, preformed in solution at the time of injection; and the latter to NO· generated by gradual decomposition of a ‘store’ of iron‐sulphur‐nitrosyl complexes within the tissue. This hypothesis is supported by histochemical studies which show that both clusters accumulate in endothelial cells.
Blockade of 5‐HT3 receptor‐mediated currents in dissociated frog sensory neurones by benzoxazine derivative, Y‐25130
Authors: Yakushiji Takashi , Akaike Norio
Published: July 2012

The effect of Y‐25130, ((±)‐N‐(1‐azabicyclo[2.2.2]oct‐3‐yl)‐6‐chloro‐4‐methyl‐3‐oxo‐3,4‐dihydro‐2H‐1,4‐benzoxazine‐8‐carboxamide hydrochloride), a high affinity 5‐hydroxytryptamine3 (5‐HT3) receptor ligand, was examined on the 5‐HT‐induced response in dissociated frog dorsal root ganglion (DRG) neurones by use of the extremely rapid concentration‐jump (“concentration‐clamp’) and the conventional whole‐cell patch‐clamp techniques.

5‐HT induced a rapid transient inward current associated with an increase in membrane conductance at a holding potential of — 70 mV. The current amplitude increased sigmoidally as 5‐HT concentration increased. The half‐maximum value (Ka) and the Hill coefficient estimated from the concentration‐response curve were 1.7 × 10−5 m and 1.7, respectively.

The current‐voltage (I—V) relationship of 5‐HT‐induced current (I5‐HT) showed inward rectification at potentials more positive than — 40 mV. The reversal potential (E5‐HT) was — 11 mV. The E5‐HT value was unaffected by total replacement of intracellular K+ by Cs+, indicating that the 5‐HT‐gated channels might be large cation channels.

Both the activation and inactivation phases of I5‐HT were single exponentials. The time constants of activation and inactivation (τa and τi) decreased with increasing 5‐HT concentration.

The 5‐HT response was mimicked by a selective 5‐HT3 receptor agonist, 2‐methyl‐5‐HT, but the maximum response induced was approximately 25% that of 5‐HT. The 5‐HT response was reversibly antagonized by the 5‐HT3 receptor antagonists, ICS 205–930, metoclopramide and Y‐25130, but not by a 5‐HT1A receptor antagonist, spiperone, and a 5‐HT2 receptor antagonist, ketanserin. The half‐inhibition concentrations (IC50) were 4.9 × 10−10 m for Y‐25130, 4.8 × 10−10 m for ICS 205–930 and 8.6 × 10−9 m for metoclopramide.

Y‐25130 (5 × 10−10 m) caused a rightward shift of the concentration‐response curve for 5‐HT while decreasing the maximum response.

The results suggest that Y‐25130 is a potent antagonist of the 5‐HT3 receptor‐channel complex.
Role of nitric oxide and guanosine 3′,5′‐cyclic monophosphate in mediating nonadrenergic, noncholinergic relaxation in guinea‐pig pulmonary arteries
Authors: Liu S.F. , Crawley D.E. , Rohde J.A.L. , Evans T.W. , Barnes P.J.
Published: July 2012

Nonadrenergic, noncholinergic (NANC) nerves mediate vasodilatation in guinea‐pig pulmonary artery (PA) by both endothelium‐dependent and endothelium‐independent mechanisms. The transmitter(s) involved in the endothelium‐independent pathway have not yet been identified. We have therefore investigated the possibility that nitric oxide (NO) and guanosine 3′,5′‐cyclic monophosphate (cyclic GMP) may mediate this neural vasodilator response in guinea‐pig branch PA rings denuded of endothelium.

Electric field stimulation (EFS, 50 V, 0.2 ms) induced a frequency‐dependent (1–24 Hz), tetrodotoxin‐sensitive relaxation of the U44069‐precontracted PA rings in the presence of adrenergic and cholinergic blockade.

The NO synthase inhibitors NG‐monomethyl l‐arginine (l‐NMMA, 100 μm) and NG‐nitro l‐arginine methyl ester (l‐NAME, 30 μm), and the guanylyl cyclase inhibitor methylene blue (5 μm) inhibited the EFS (16 Hz)‐induced relaxation by 53 ± 5, 74 ± 9 and 82 ± 9% respectively (n = 5–7, P < 0.01, compared with control rings).

Excess concentrations of l‐, but not d‐arginine (300 μm) completely reversed the inhibitory effect of l‐NMMA.

The EFS‐elicited relaxation (4 Hz) was potentiated by 1 μm zaprinast, a type V phosphodiesterase inhibitor which inhibits guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) degradation, but was unaffected by 0.1 μm zardaverine, a type III/IV phosphodiesterase inhibitor which inhibits cyclic AMP degradation.

EFS (50 V, 0.2 ms, 16 Hz) induced a 3 fold increase in tissue cyclic GMP content, an action which was inhibited by l‐NMMA (100 μm).

Pyrogallol (100 μm), a superoxide anion generator, also inhibited the EFS‐induced relaxation by 53 ± 9%, and this effect was prevented by superoxide dismutase.

Chemical sympathetic denervation with 6‐hydroxydopamine had no effect on the relaxant response to EFS in the endothelium‐denuded PA rings.

In endothelium‐denuded branch PA rings at resting tone, l‐NMMA (100 μm) significantly augmented the adrenergic contractile response, an effect which was completely reversed by l‐arginine, but not by d‐arginine. In the same groups of vessel rings, l‐NMMA had no significant effect on the matched contractile response to exogenous noradrenaline.

These results suggest that NO may be released from intramural nerve endings other than adrenergic nerves (probably NANC nerves), and this leads to vasodilatation via activation of guanylyl cyclase.
The effect of aliphatic alcohols on the transient potassium current in hippocampal neurones
Authors: Saint David A.
Published: July 2012

The transient potassium current was recorded in single hippocampal CA1 neurones from the rat by use of the whole‐cell patch clamp technique. The effects on this current of a homologous series of aliphatic alcohols, ranging from butanol to octanol, were investigated.

The predominant effect of octanol (and the other alcohols) was to cause an increase in the initial rate of decay of the transient potassium current together with a slight decrease in the rate of decay of later phases of the current, such that the current decay became markedly non‐monotonic. The alcohols also caused a decrease in peak current amplitude which could not be accounted for soley by the change in current decay kinetics.

The effect of the alcohols was concentration‐dependent and readily reversible. Increasing chain length increased the potency of each alcohol by about 3 fold for each methylene group added. Other than a difference in potency, there appeared to be little difference in the action of aliphatic alcohols of different chain length on the transient current.

The alcohols did not appreciably change the voltage‐dependence of steady state inactivation or activation of the transient potassium current.

The rate of inactivation of the transient current in these cells was only weakly voltage‐dependent. This weak voltage‐dependence was not changed by the presence of aliphatic alcohols, neither was the effect of the alcohols themselves voltage‐dependent.

The potencies of each of the aliphatic alcohols were well correlated with their respective membrane/buffer partition coefficients, a finding which implies a hydrophobic locus of action.
The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening
Authors: Khan Jaffar M , Lyon Alexander R , Harding Sian E
Published: July 2012

The current drug screening models are deficient, particularly in detecting cardiac side effects. Human stem cell‐derived cardiomyocytes could aid both early cardiotoxicity detection and novel drug discovery. Work over the last decade has generated human embryonic stem cells as potentially accurate sources of human cardiomyocytes, but ethical constraints and poor efficacy in establishing cell lines limit their use. Induced pluripotent stem cells do not require the use of human embryos and have the added advantage of producing patient‐specific cardiomyocytes, allowing both generic and disease‐ and patient‐specific pharmacological screening, as well as drug development through disease modelling. A critical question is whether sufficient standards have been achieved in the reliable and reproducible generation of ‘adult‐like’ cardiomyocytes from human fibroblast tissue to progress from validation to safe use in practice and drug discovery. This review will highlight the need for a new experimental system, assess the validity of human induced pluripotent stem cell‐derived cardiomyocytes and explore what the future may hold for their use in pharmacology.

LINKED ARTICLES This article is part of a themed section on Regenerative Medicine and Pharmacology: A Look to the Future. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue‐2
Estimation of Body‐Size Traits by Photogrammetry in Large Mammals to Inform Conservation
Authors: BERGER JOEL
Published: July 2012

Abstract:  Photography, including remote imagery and camera traps, has contributed substantially to conservation. However, the potential to use photography to understand demography and inform policy is limited. To have practical value, remote assessments must be reasonably accurate and widely deployable. Prior efforts to develop noninvasive methods of estimating trait size have been motivated by a desire to answer evolutionary questions, measure physiological growth, or, in the case of illegal trade, assess economics of horn sizes; but rarely have such methods been directed at conservation. Here I demonstrate a simple, noninvasive photographic technique and address how knowledge of values of individual‐specific metrics bears on conservation policy. I used 10 years of data on juvenile moose (Alces alces) to examine whether body size and probability of survival are positively correlated in cold climates. I investigated whether the presence of mothers improved juvenile survival. The posited latter relation is relevant to policy because harvest of adult females has been permitted in some Canadian and American jurisdictions under the assumption that probability of survival of young is independent of maternal presence. The accuracy of estimates of head sizes made from photographs exceeded 98%. The estimates revealed that overwinter juvenile survival had no relation to the juvenile's estimated mass (p < 0.64) and was more strongly associated with maternal presence (p < 0.02) than winter snow depth (p < 0.18). These findings highlight the effects on survival of a social dynamic (the mother‐young association) rather than body size and suggest a change in harvest policy will increase survival. Furthermore, photographic imaging of growth of individual juvenile muskoxen (Ovibos moschatus) over 3 Arctic winters revealed annual variability in size, which supports the idea that noninvasive monitoring may allow one to detect how some environmental conditions ultimately affect body growth.