bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential Prevention of Pacing‐Induced Heart Failure Using Simple Pacemaker Programming Algorithm
Authors: Chwyczko Tomasz , Dąbrowski Rafał , Maciąg Aleksander , Sterliński Maciej , Smolis‐Bąk Edyta , Borowiec Anna , Kowalik Ilona , Łabęcka Andrada , Jankowska Agnieszka , Kośmicki Marek , Janas Jadwiga , Pytkowski Mariusz , Szwed Hanna
Published: May 2013

Introduction

Right ventricular pacing (RVP) causes ventricular desynchronization and may lead to the development of heart failure (HF). Prolongation of atrioventricular delay (AVD) in DDDR pacemakers reduces unnecessary RV stimulation. The aim of the study was to verify the influence of RVP reduction on HF symptoms.

Methods

The study comprised 31 patients (17 men, mean age: 71.6 ± 8 yrs) with DDDR pacemaker implanted due to sinus node dysfunction (SND). At baseline, 28 patients did not present any symptoms of HF. Three patients were in NYHA class II. Patients were randomized either to 150 ms AVD or to minimizing right ventricular pacing (MRVP). Crossing over to the alternate mode took place after 4 months. Cardiopulmonary exercise test (CPX), echocardiography (ECHO) and BNP measurements were done before pacemaker implantation, after 4 and 8 months.

Results

The percentage of RVP was significantly higher in 150 ms AVD than in MRVP: 81.7 ± 22.6 versus 14.2±20.5%, P < 0.0001. Patients with 150 ms mode had worse CPX parameters than those with MRVP mode: peak oxygen uptake was 14.2±4.3 versus 19.9±6.3 ml/kg per min, P = 0.0001, higher BNP concentrations: 72.3±48.3 versus 49.4±43.9 pg/ml, P = 0.001 and worse left ventricle [LV] function: ejection fraction: 53.2±6.7 versus 57.3±5.5%, P < 0.0001; LV diastolic diameter: 4.86±0.52 versus 4.66±0.5 cm, P < 0.01.

Conclusion

Predominant RVP in patients without symptoms of HF at baseline may be responsible for worse performance in cardiopulmonary exercise test, higher BNP concentrations and impairment of LV function. Specific DDDR pacemaker programming promotes intrinsic AV conduction and may prevent the development of pacing‐induced HF.
Electrocardiographic Abnormalities and Elevated cTNT at Admission for Intracerebral Hemorrhage: Predictors for Survival?
Authors: Hjalmarsson Clara , Bergfeldt Lennart , Bokemark Lena , Manhem Karin , Andersson Björn
Published: May 2013

Background

Cerebrovascular lesions are often associated with electrocardiographic (ECG) abnormalities. The main purpose of this work was to investigate the prognostic value of ECG abnormalities and/or elevated cardiac troponin (cTNT) on admission in patients with nontraumatic intracerebral hemorrhage (ICH).

Methods

Ninety‐seven consecutive patients with ICH were included. The predictive value of ECG abnormalities and increased TNT on survival were evaluated using Cox proportional hazard model.

Results

The most frequently observed ECG abnormalities were the presence of a Q wave (39.6%), followed by prolonged QTc (>0.44 s; 35.4%), which was an independent predictor for long‐term mortality (P = 0.019). No difference in QTc was observed between patients with right versus left ICH. Increased cTNT levels at admission had no prognostic value.

Conclusion

Various ECG changes were common in patients presenting with an ICH, but only prolonged QTc was found to be an independent predictor of poor survival during follow‐up after ICH.
Clinical decision making: how surgeons do it
Authors: Crebbin Wendy , Beasley Spencer W. , Watters David A. K.
Published: May 2013

Clinical decision making is a core competency of surgical practice. It involves two distinct types of mental process best considered as the ends of a continuum, ranging from intuitive and subconscious to analytical and conscious. In practice, individual decisions are usually reached by a combination of each, according to the complexity of the situation and the experience/expertise of the surgeon. An expert moves effortlessly along this continuum, according to need, able to apply learned rules or algorithms to specific presentations, choosing these as a result of either pattern recognition or analytical thinking. The expert recognizes and responds quickly to any mismatch between what is observed and what was expected, coping with gaps in information and making decisions even where critical data may be uncertain or unknown. Even for experts, the cognitive processes involved are difficult to articulate as they tend to be very complex. However, if surgeons are to assist trainees in developing their decision‐making skills, the processes need to be identified and defined, and the competency needs to be measurable. This paper examines the processes of clinical decision making in three contexts: making a decision about how to manage a patient; preparing for an operative procedure; and reviewing progress during an operative procedure. The models represented here are an exploration of the complexity of the processes, designed to assist surgeons understand how expert clinical decision making occurs and to highlight the challenge of teaching these skills to surgical trainees.
Empirical Likelihood for Nonparametric Models Under Linear Process Errors
Authors: Qin Yongsong , Lei Qingzhu , Luo Lijun
Published: May 2013

In this paper, we study the construction of confidence intervals for a nonparametric regression function under linear process errors by using the blockwise technique. It is shown that the blockwise empirical likelihood (EL) ratio statistic is asymptoticallydistributed. The result is used to obtain EL based confidence intervals for the nonparametric regression function. The finite‐sample performance of the method is evaluated through a simulation study.
Exercise Studies in Patients With Rotary Blood Pumps: Cause, Effects, and Implications for Starling‐Like Control of Changes in Pump Flow
Authors: Salamonsen Robert F. , Pellegrino Vincent , Fraser John F. , Hayes Kate , Timms Daniel , Lovell Nigel Hamilton , Hayward Christopher
Published: May 2013

This multicenter study examines in detail the spontaneous increase in pump flow at fixed speed that occurs in exercise. Eight patients implanted with the VentrAssist rotary blood pump were subjected to maximal and submaximal cycle ergometry studies, the latter being completed with patients supine and monitored with right heart catheter and echocardiography. Maximal exercise studies conducted in each patient at three different pump speeds on separate days established initially the magnitude and consistency of increases in pump flow that correlated well with changes in heart rate. However, there was considerable variation, coefficients of variation for mean heart rate and pump flow being 47.9 and 49.3%, respectively. Secondly, these studies indicated that increasing pump flows caused significant improvements in maximal exercise capacity. An increase of 2.1 L/min (35%) in maximum blood flow caused 12 W (16%) further increase in achievable work, 1.26 (9.3%) mL/kg/min in maximal oxygen uptake, and 2.3 (23%) mL/kg/min in anaerobic threshold. Mean increases in lactate were 0.85 mm (24%), but mean B‐type natiuretic peptide fell by 126 mm, (−78%). From submaximal supine exercise studies, multiple linear regression of pump flow on factors thought to underlie the spontaneous increase in pump flow indicated that it was associated with increases in heart rate (P = 0.039), pressure gradient across the left ventricle (P = 0.032), and right atrial pressure (P = 0.003). These changes have implications for the recently reported Starling‐like controller for pump flow based on pump pulsatility values, which emulates the Starling curve relating pump output to left ventricular preload. Unmodified, the controller would not permit the full benefits of this effect to be afforded to patients implanted with rotary blood pumps. A modification to the pump control algorithm is proposed to eliminate this problem
Review article: prescribing medications in patients with cirrhosis – a practical guide
Authors: Lewis J. H. , Stine J. G.
Published: May 2013

Background

Most drugs have not been well studied in cirrhosis; recommendations on safe use are based largely on experience and/or expert opinion, with dosing recommendations often based on pharmacokinetic (PK) changes.

Aim

To provide a practical approach to prescribing medications for cirrhotic patients.

Methods

An indexed MEDLINE search was conducted using keywords cirrhosis, drug‐induced liver injury, pharmacodynamics (PDs), PKs, drug disposition and adverse drug reactions. Unpublished information from the Food and Drug Administration and industry was also reviewed.

Results

Most medications have not been adequately studied in cirrhosis, and specific prescribing information is often lacking. Lower doses are generally recommended based on PK changes, but data are limited in terms of correlating PD effects with the degree of liver impairment. Very few drugs have been documented to have their hepatotoxicity potential enhanced by cirrhosis; most of these involve antituberculosis or antiretroviral agents used for HIV or viral hepatitis. Paracetamol can be used safely when prescribed in relatively small doses (2–3 g or less/day) for short durations, and is recommended as first‐line treatment of pain. In contrast, NSAIDs should be used cautiously (or not at all) in advanced cirrhosis. Proton pump inhibitors have been linked to an increased risk of spontaneous bacterial peritonitis (SBP) in cirrhosis and should be used with care.

Conclusions

Most drugs can be used safely in cirrhosis, including those that are potentially hepatotoxic, but lower doses or reduced dosing frequency is often recommended, due to altered PKs. Drugs that can precipitate renal failure, gastrointestinal bleeding, SBP and encephalopathy should be identified and avoided.
Estimation of variance components for carcass traits in Japanese Black cattle using 50K SNP genotype data
Authors: Watanabe Toshio , Matsuda Hirokazu , Arakawa Aisaku , Yamada Takahisa , Iwaisaki Hiroaki , Nishimura Shota , Sugimoto Yoshikazu
Published: May 2013

Genomic selection using high‐density single nucleotide polymorphism (SNP) genotype data may accelerate genetic improvements in livestock animals. In this study, we attempted to estimate the variance components of six carcass traits in fattened Japanese Black steers using SNP genotype data. Six hundred and seventy‐three steers were genotyped using an Illumina Bovine SNP50 BeadChip and phenotyped for cold carcass weight, ribeye area, rib thickness, subcutaneous fat thickness, estimated yield percent and marbling score. Additive polygenic variance and the variance attributable to a set of SNPs that had statistically significant effects on the trait were estimated via Gibbs sampling with two models: (i) a model with the chosen SNPs and the additive polygenic effects; and (ii) a model with the polygenic effects alone. The proportion of the estimated variance attributable to the SNPs became higher as the number of SNP effects that fit increased. High correlations between breeding values estimated with the model containing the polygenic effect alone and those estimated by chosen SNPs were obtained. No fraction of the total genetic variance was explained by SNPs associated with the trait at P ≥ 0.1. Our results suggest that for the carcass traits of Japanese Black cattle, a maximum of half of the total additive genetic variance may be explained by SNPs between 100 several tens to several 100s.
A survey of fermentation products and bacterial communities in corn silage produced in a bunker silo in China
Authors: Wang Chao , Han Hongyan , Gu Xueying , Yu Zhu , Nishino Naoki
Published: May 2013

To evaluate the current practice of corn silage management in China, samples of bunker‐made silage were collected from 14 farms within a 500‐km radius of Beijing for the analysis of fermentation products and bacterial communities. Mean values for dry matter (DM) content were as low as 250 g/kg in both corn stover (St) and whole crop corn (Wc) silages, and pH values averaged 4.48 and 3.73, respectively. Only three of the 14 silages exhibited a lactic‐to‐acetic acid ratio > 1.0, indicating that the presence of acetic acid was predominant in fermentation. Although 1,2‐propanediol content was marginal in most cases (< 5.0 g/kg dry matter (DM)), two Wc silages had 1,2‐propanediol levels > 25 g/kg DM. In contrast, 3 St silages had large amounts (> 10 g/kg DM) of butyric acid, and two of the three butyrate silages also had high concentrations of 1‐propanol. Denaturing gradient gel electrophoresis analysis demonstrated that the bacterial community appeared similar in 10 out of the 14 silage samples. Bands indicating Lactobacillus buchneri, L. acetotolerans and Acetobacter pasteurianus were found in both the St and Wc silages, accounting for the high acetic acid content found across silage samples.
Intravenous Lipid Emulsion Entraps Amitriptyline into Plasma and Can Lower its Brain Concentration – An Experimental Intoxication Study in Pigs
Authors: Heinonen Juho A. , Litonius Erik , Backman Janne T. , Neuvonen Pertti J. , Rosenberg Per H.
Published: May 2013

Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of amitriptyline and haemodynamic recovery, when lipid was given after amitriptyline distribution into well‐perfused organs. Twenty anaesthetized pigs received amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid® (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma amitriptyline concentrations and haemodynamics were followed till 75 min. after amitriptyline infusion. Then, frontal brain and heart apex samples were taken for amitriptyline measurements. Arterial plasma total amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain amitriptyline concentration by 25% (p = 0.038) and amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial amitriptyline tissue distribution, was able to entrap amitriptyline back into plasma from brain and possibly from other highly perfused, lipid‐rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups.
Histamine H3 receptors, the complex interaction with dopamine and its implications for addiction
Authors: Ellenbroek B A
Published: May 2013

Histamine H3 receptors are best known as presynaptic receptors inhibiting the release of histamine, as well as other neurotransmitters including acetylcholine and dopamine. However, in the dorsal and ventral striatum, the vast majority of H3 receptors are actually located postsynaptically on medium sized spiny output neurons. These cells also contain large numbers of dopamine (D1 and D2) receptors and it has been shown that H3 receptors form heterodimers with both D1 and D2 receptors. Thus, the anatomical localization of H3 receptors suggests a complex interaction that could both enhance and inhibit dopaminergic neurotransmission. Dopamine, especially within the striatal complex, plays a crucial role in the development of addiction, both in the initial reinforcing effects of drugs of abuse, as well as in maintenance, relapse and reinstatement of drug taking behaviour. It is, therefore, conceivable that H3 receptors can moderate the development and maintenance of drug addiction. In the present review, we appraise the current literature on the involvement of H3 receptors in drug addiction and try to explain these data within a theoretical framework, as well as provide suggestions for further research.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/
10.1111/bph.2013.170.issue‐1
O‐GlcNAcylation and p50/p105 binding of c‐Rel are dynamically regulated by LPS and glucosamine in BV2 microglia cells
Authors: Hwang So‐Young , Hwang Ji‐Sun , Kim Song‐Yi , Han Inn‐Oc
Published: May 2013

Background and Purpose

Previously, we demonstrated that glucosamine (GlcN) exerts a suppressive effect on LPS‐induced inducible NOS (iNOS) through the inhibition of NF‐κB activation in BV2 mouse microglial cells. The purpose of the present study was to examine the mechanisms by which GlcN inhibits NF‐κB activation.

Experimental Approach

BV2 cells were stimulated with LPS with or without GlcN. NF‐κB/c‐Rel activities were studied by EMSA, nuclear translocation, reporter assay or chromatin immunoprecipitation. Wheat germ agglutinin precipitation or galactosyltransferase assay were used to measure O‐linked N‐acetylglucosamine (O‐GlcNAc) modification (O‐GlcNAcylation) of c‐Rel. Protein‐protein interactions were examined by co‐immunoprecipitation.

Key Results

LPS stimulated the activation of c‐Rel, increased the O‐GlcNAcylation of c‐Rel and enhanced the binding of c‐Rel to the NF‐κB site in the iNOS promoter; GlcN attenuated these effects of LPS. O‐GlcNAcylation of both nuclear and cytosolic forms of c‐Rel was increased by LPS and reduced by GlcN. LPS increased the interaction of c‐Rel with O‐GlcNAc transferase (OGT) and p50/p105, and GlcN suppressed these interactions. Knockdown of OGT reduced the c‐Rel O‐GlcNAcylation and c‐Rel–p50 interaction in response to LPS, but did not affect either the binding of c‐Rel to the iNOS promoter or the transcriptional activity of c‐Rel.

Conclusions and Implications

In BV2 microglial cells, the anti‐inflammatory effect of GlcN is mediated by prevention of the prolonged activation of transcription factors, c‐Rel and NF‐κB. Further clarification of the mechanism by which GlcN exerts this effect will facilitate the development of pharmacological strategies for preventing excessive NO formation when targeting inflammatory diseases of the periphery or CNS.
Activation of NF‐κB after chronic ethanol intake and haemorrhagic shock/resuscitation in mice
Authors: Maraslioglu M , Weber R , Korff S , Blattner C , Nauck C , Henrich D , Jobin C , Marzi I , Lehnert M
Published: May 2013

Background and Purpose

Chronic ethanol abuse and haemorrhagic shock are major causes of global mortality and, separately, induce profound hepato‐ and immune‐toxic effects via activation of NF‐κB. Here, we assessed the effects of chronic ethanol intake upon the pathophysiological derangements after haemorrhagic shock with subsequent resuscitation (H/R), with particular attention to the contribution of NF‐κB.

Experimental Approach

Transgenic NF‐κBEGFP mice, expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF‐κB cis‐elements were fed a Lieber‐DeCarli diet containing ethanol (EtOH‐diet) or an isocaloric control diet for 4 weeks and were then pairwise subjected to H/R. Liver tissues and peripheral blood were sampled at 2 or 24 h after H/R. Cytokines in blood and tissue and leukocyte activation (as CD11b expression) were measured, along with EGFP as a marker of NF‐κB activation.

Key Results

The EtOH‐diet increased mortality at 24 h after H/R and elevated liver injury, associated with an up‐regulation of NF‐κB‐dependent genes and IL‐6 release; it also increased production of NF‐κB‐driven intercellular adhesion molecule 1 (ICAM‐1) and EGFP in liver tissue. At 2h after the H/R procedure in ethanol‐fed mice we observed the highest proportion of NF‐κB activated non‐parenchymal cells and an NF‐κB‐dependent increase in polymorphonuclear leukocyte CD11b expression.

Conclusions and Implications

The EtOH‐diet exacerbated liver injury after H/R, accompanying an overwhelming hepatic and systemic immune response. Our findings contribute to evidence implicating NF‐κB as a key player in the orchestration of the immune response in haemorrhagic shock patients with a history of chronic ethanol abuse.
Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca2+]i in mesenteric microvessels of pregnant rats
Authors: Mazzuca Marc Q , Dang Yiping , Khalil Raouf A
Published: May 2013

Background and Purpose

Normal pregnancy is associated with decreased vascular resistance and increased release of vasodilators. Endothelin‐1 (ET‐1) causes vasoconstriction via endothelin receptor type A (ETAR), but could activate ETBR in the endothelium and release vasodilator substances. However, the roles of ETBR in the regulation of vascular function during pregnancy and the vascular mediators involved are unclear.

Experimental Approach

Pressurized mesenteric microvessels from pregnant and virgin Sprague–Dawley rats were loaded with fura‐2/AM for simultaneous measurement of diameter and [Ca2+]i.

Key Results

High KCl (51 mM) and phenylephrine (PHE) caused increases in vasoconstriction and [Ca2+]i that were similar in pregnant and virgin rats. ET‐1 caused vasoconstriction that was less in pregnant than virgin rats, with small increases in [Ca2+]i. Pretreatment with the ETBR antagonist BQ‐788 caused greater enhancement of ET‐1‐induced vasoconstriction in pregnant rats. ACh caused endothelium‐dependent relaxation and decreased [Ca2+]i, and was more potent in pregnant than in virgin rats. ET‐1 + ETAR antagonist BQ‐123, and the ETBR agonists sarafotoxin 6c (S6c) and IRL‐1620 caused greater vasodilation in pregnant than in virgin rats with no changes in [Ca2+]i, suggesting up‐regulated ETBR‐mediated relaxation pathways. ACh‐, S6c‐ and IRL‐1620‐induced relaxation was reduced by the NO synthase inhibitor Nω‐nitro‐l‐arginine methyl ester, and abolished by tetraethylammonium or endothelium removal. Western blots revealed greater amount of ETBR in intact microvessels of pregnant than virgin rats, but reduced levels in endothelium‐denuded microvessels, supporting a role of endothelial ETBR.

Conclusions and Implications

The enhanced ETBR‐mediated microvascular relaxation may contribute to the decreased vasoconstriction and vascular resistance during pregnancy.
Quercetin and allopurinol reduce liver thioredoxin‐interacting protein to alleviate inflammation and lipid accumulation in diabetic rats
Authors: Wang Wei , Wang Chuang , Ding Xiao‐Qin , Pan Ying , Gu Ting‐Ting , Wang Ming‐Xing , Liu Yang‐Liu , Wang Fu‐Meng , Wang Shui‐Juan , Kong Ling‐Dong
Published: May 2013

Background and Purpose

Thioredoxin‐interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD‐like receptor 3 (NLRP3) inflammasome, inflammation and lipid metabolism, suggesting it has a role in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD) in diabetes. In this study we investigated whether TXNIP is involved in type 1 diabetes‐associated NAFLD and whether antioxidants, quercetin and allopurinol, alleviate NAFLD by targeting TXNIP.

Experimental Approach

Diabetes was induced in male Sprague‐Dawley rats by a single i.p. injection of 55 mg·kg−1 streptozotocin. Quercetin and allopurinol were given p.o. to diabetic rats for 7 weeks. Hepatic function, oxidative stress, inflammation and lipid levels were determined. Rat BRL‐3A and human HepG2 cells were exposed to high glucose (30 mM) in the presence and absence of antioxidants, TXNIP siRNA transfection or caspase‐1 inhibitor, Ac‐YVAD‐CMK.

Key Results

Quercetin and allopurinol significantly inhibited the TXNIP overexpression, activation of NLRP3 inflammasome, down‐regulation of PPARα and up‐regulation of sterol regulatory element binding protein‐1c (SREBP‐1c), SREBP‐2, fatty acid synthase and liver X receptor α, as well as elevation of ROS and IL‐1β in diabetic rat liver. These effects were confirmed in hepatocytes in vitro and it was further shown that TXNIP down‐regulation contributed to the suppression of NLRP3 inflammasome activation, inflammation and changes in PPARα and SREBPs.

Conclusions and Implications

Inhibition of hepatic TXNIP by quercetin and allopurinol contributes to the reduction in liver inflammation and lipid accumulation under hyperglycaemic conditions. The targeting of hepatic TXNIP by quercetin and allopurinol may have therapeutic implications for prevention of type 1 diabetes‐associated NAFLD.
Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two‐state and operational models
Authors: Roche David , Gil Debora , Giraldo Jesús
Published: May 2013

Two‐state and operational models of both agonism and allosterism are compared to identify and characterize common pharmacological parameters. To account for the receptor‐dependent basal response, constitutive receptor activity is considered in the operational models. By arranging two‐state models as the fraction of active receptors and operational models as the fractional response relative to the maximum effect of the system, a one‐by‐one correspondence between parameters is found. The comparative analysis allows a better understanding of complex allosteric interactions. In particular, the inclusion of constitutive receptor activity in the operational model of allosterism allows the characterization of modulators able to lower the basal response of the system; that is, allosteric modulators with negative intrinsic efficacy. Theoretical simulations and overall goodness of fit of the models to simulated data suggest that it is feasible to apply the models to experimental data and constitute one step forward in receptor theory formalism.

Linked Articles

Another recent review on allosteric modulation can be found at:

Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2. British Journal of Pharmacology 168: 554–575. doi: 10.1111/j.1476‐5381.2012.02223.x

And in this issue of BJP there is an article on a new allosteric modulator:

Newman AS, Batis N, Grafton G, Caputo F, Brady CA, Lambert J, Peters JA, Gordon J, Brain KL, Powell AD and Barnes NM (2013). 5‐Chloroindole: a potent allosteric modulator of the 5‐HT3 receptor. British Journal of Pharmacology 169: 1228–1238. doi: 10.1111/bph.12213
Functional interaction between pre‐synaptic α6β2‐containing nicotinic and adenosine A2A receptors in the control of dopamine release in the rat striatum
Authors: Garção P , Szabó E C , Wopereis S , Castro A A , Tomé Â R , Prediger R D , Cunha R A , Agostinho P , Köfalvi A
Published: May 2013

Background and Purpose

Pre‐synaptic nicotinic ACh receptors (nAChRs) and adenosine A2A receptors (A2ARs) are involved in the control of dopamine release and are putative therapeutic targets in Parkinson's disease and addiction. Since A2ARs have been reported to interact with nAChRs, here we aimed at mapping the possible functional interaction between A2ARs and nAChRs in rat striatal dopaminergic terminals.

Experimental Approach

We pharmacologically characterized the release of dopamine and defined the localization of nAChR subunits in rat striatal nerve terminals in vitro and carried out locomotor behavioural sensitization in rats in vivo.

Key Results

In striatal nerve terminals, the selective A2AR agonist CGS21680 inhibited, while the A2AR antagonist ZM241385 potentiated the nicotine‐stimulated [3H]dopamine ([3H]DA) release. Upon blockade of the α6 subunit‐containing nAChRs, the remaining nicotine‐stimulated [3H]DA release was no longer modulated by A2AR ligands. In the locomotor sensitization experiments, nicotine enhanced the locomotor activity on day 7 of repeated nicotine injection, an effect that no longer persisted after 1 week of drug withdrawal. Notably, ZM241385‐injected rats developed locomotor sensitization to nicotine already on day 2, which remained persistent upon nicotine withdrawal.

Conclusions and Implications

These results provide the first evidence for a functional interaction between nicotinic and adenosine A2AR in striatal dopaminergic terminals, with likely therapeutic consequences for smoking, Parkinson's disease and other dopaminergic disorders.
Profiling of histamine H4 receptor agonists in native human monocytes
Authors: Gschwandtner M , Koether B , Werfel T , Stark H , Gutzmer R
Published: May 2013

Background and Purpose

Since the identification of the histamine H4 receptor, several ligands activating this receptor have been described and more compounds are in development. These ligands are well characterized in pharmacological assays, including radioligand competition binding studies, GTPγS and GTPase assays. In most cases, these experiments are performed in transfected cell lines, expressing unnaturally high levels of target receptors and G‐protein signalling components. In this study we investigated the specific properties of H4 receptor ligands in native cells.

Experimental Approach

Histamine and five different H4 receptor agonists – 4‐methylhistamine, UR‐PI376, clobenpropit, VUF8430 and ST‐1006 – were characterized in freshly isolated human monocytes. The ligands (10 nM–10 μM) were tested as inhibitors of IL‐12p70 secretion from human monocytes and the effects of the H2 receptor antagonist ranitidine and the H4 receptor antagonist JNJ7777120 on their action was investigated.

Key Results

Histamine and all the tested agonists reduced IL‐12p70 secretion into monocyte supernatants by 40–70%. The potencies varied with pEC50 values ranging from 5.7 to 6.9, depending on the agonist used. All potencies were lower than those determined in the original investigations of the compounds. Pretreatment of monocytes with H2 or H4 receptor antagonists showed that some H4 receptor ligands also had low activity at the H2 receptor.

Conclusions and Implications

Our study demonstrates discrepancies between the potencies obtained from assays in transfected cell lines and assays in native human cells, indicating the importance of evaluating H4 receptor ligands in native cells.

Linked Articles

This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/
10.1111/bph.2013.170.issue‐1
Death receptors as targets in cancer
Authors: Micheau O , Shirley S , Dufour F
Published: May 2013

Anti‐tumour therapies based on the use pro‐apoptotic receptor agonists, including TNF‐related apoptosis‐inducing ligand (TRAIL) or monoclonal antibodies targeting TRAIL‐R1 or TRAIL‐R2, have been disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti‐cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future clinical trials.

Linked Articles

This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue‐8
Reading Angles in Maps
Authors: Izard Véronique , O'Donnell Evan , Spelke Elizabeth S.
Published: May 2013

Preschool children can navigate by simple geometric maps of the environment, but the nature of the geometric relations they use in map reading remains unclear. Here, children were tested specifically on their sensitivity to angle. Forty‐eight children (age 47:15–53:30 months) were presented with fragments of geometric maps, in which angle sections appeared without any relevant length or distance information. Children were able to read these map fragments and compare two‐dimensional to three‐dimensional angles. However, this ability appeared both variable and fragile among the youngest children of the sample. These findings suggest that 4‐year‐old children begin to form an abstract concept of angle that applies both to two‐dimsional and three‐dimensional displays and that serves to interpret novel spatial symbols.
Geographic and taxonomic variation inBatrachochytrium dendrobatidisinfection and transmission within a highly endemic amphibian community
Authors: Bielby J. , Bovero S. , Angelini C. , Favelli M. , Gazzaniga E. , Perkins M. , Sotgiu G. , Tessa G. , Garner T. W. J.
Published: May 2013

Aim

In a highly endemic, threatened amphibian assemblage, we measure and describe the geographic and taxonomic distribution of the amphibian chytrid fungus,Batrachochytrium dendrobatidis(Bd), with a view to identifying those sites and species most at risk of infection and its negative consequences. Additionally, we aimed to determine the potential for direct transmission events between two known carriers ofBdinfection.

Location

The island ofSardinia.

Methods

We collected swab and tissue samples of amphibians from a wide range of geographic sites and species. We used epidemiological and statistical techniques to quantify deviations from a random distribution. We used random forests to investigate habitat use and overlap in two species known to be infected byBdto quantify a surrogate measure of the contact rates between these two species.

Results

Both geographic and taxonomic distributions ofBdwere highly non‐random: we identified a cluster of infections in the north of the island and found that two species,Euproctus platycephalusandDiscoglossus sardus, had a relatively high prevalence of infection within this cluster. Our analyses suggest that, on the basis of their fine‐scale habitat use, they have relatively little opportunity for direct transmission and could maintainBdinfection independently.

Main conclusions

Our results illustrate how obtaining detailed information on the geographic and taxonomic distribution of infection is a useful first step in assessing the risk of infection for species within the region. Attempting to quantify possible routes of transmission amongst species further aids us in identifying mechanisms of pathogen persistence within the host community. Within this assemblage, we have identified two hosts that carry infection and may be at risk. Further, our research suggests that these two species may be able to maintain infection independently of one another, which has implications for attempts to mitigate this parasite.
Conservation implications of divergent global patterns of ant and vertebrate diversity
Authors: Jenkins Clinton N. , Guénard Benoit , Diamond Sarah E. , Weiser Michael D. , Dunn Robert R.
Published: May 2013

Aim

Global conservation planning is often oriented around vertebrates and plants, yet most organisms are invertebrates. To explore the potential conservation implications of this bias, we assessed how well patterns of diversity for an influential group of invertebrates, the ants, correspond with those of three vertebrate groups (birds, mammals and amphibians).

Location

Global.

Methods

We compiled data on the number of genera of ants and the three vertebrate groups for 370 political regions across the world. We then compared their correlations both for overall diversity and between subsets of genera likely to be of conservation concern. We also developed generalized additive models (GAM) to identify regions where vertebrates and ants diverged in their diversity patterns.

Results

While ant and vertebrate diversity do positively correlate, the correlations are substantially weaker for the ant lineages of the greatest conservation concern. Vertebrates also notably fail to predict ant diversity in specific geographic areas, including Australia and Southeast Asia, parts of Africa and Madagascar, and south‐western China. These failures may be genuine differences in diversity patterns, or they may indicate important gaps in our knowledge of ant and vertebrate diversity.

Main conclusions

We conclude that it is currently unwise to assume that global conservation priorities based on vertebrates will conserve ants as well. We suspect that this also applies to other invertebrates.
The puzzle(s) of pharmacoresistant epilepsy
Authors: Pohlmann‐Eden Bernd , Weaver Donald F.
Published: May 2013

Despite the availability of >25 antiepileptic drugs, 30% of people with epilepsy do not respond to conventional agents, exhibiting pharmacoresistance (PR)—a high percentage that has not changed significantly in decades. This is not surprising given that all current pharmaceutical agents merely reduce the incidence of seizures (“antiictogenic”); they do not interfere with the natural history of epilepsy and are therefore not antiepileptogenic. The two prevailing hypotheses of pharmacoresistance, the target hypothesis and the transporter hypothesis, can only partially explain the complexity and the diversity of PR. It is a neuropharmacologic priority that we change our approach to understanding PR. Herein we suggest the need to regard PR as a complex puzzle in which the target and transporter hypotheses represent a very small piece of the whole. Indeed, we do not even know if this piece of the whole is epiphenomenal or neurobiologically causal. To grasp the whole, we need to constantly gather information (look around for other pieces) from other perspectives and insights coming from clinical, epidemiologic, neuroradiologic, genetic, and other data. A recent research workshop on PR, the 2nd Halifax International Epilepsy Conference & Retreat, chose this eclectic and all‐encompassing approach. The participants were fully aware that their diverse contributions represent only still‐fragmented pieces of this frustrating but clinically important puzzle.
Road to refractory epilepsy: The Glasgow story
Authors: Brodie Martin J.
Published: May 2013

This short article reviews 30 years of prospective observations on outcomes relevant to an expanding cohort of adolescent and adult patients with newly diagnosed epilepsy, who received their first antiepileptic drug (AED) and subsequent long‐term follow‐up at the Epilepsy Unit at the Western Infirmary in Glasgow, United Kingdom. Despite the fact that the overall prognosis has slowly improved over this time, >30% of the patients remain uncontrolled despite the introduction of a range of new AEDs, some with unique mechanisms of action, over the last 20 years. Most patients followed a constant course (59% controlled, 25% refractory), which could usually be predicted early. The remaining 16% fluctuated between periods of remission and relapse. The likelihood of seizure freedom declined with successive drug regimens, most markedly from the first to the third. A number of factors predicting poorer outcomes have been identified, particularly high pretreatment seizure density and concomitant psychiatric comorbidities. Novel approaches to identifying and treating the processes underpinning the generation and propagation of seizures are required if the current rather disappointing scenario is to be substantially improved.
The enigma of placebo effects in drug‐refractory epilepsies
Authors: Krämer Günter
Published: May 2013

Placebo effects in the therapy of epilepsy were already known before the introduction of effective antiepileptic drugs (AEDs). They have physiologic correlates, and are even stronger in other neurologic disorders such as pain. Placebo effects in epilepsy have many facets. Our understanding of this phenomenon has increased in the last two decades: placebo effects are stronger in children than in adults, and may be culture‐ and setting‐dependent; and impressive placebo effects occur in animals with epilepsy as well. More research is needed to fully elucidate the mechanism of placebo effects in epilepsy care, particularly as we go forth with studies addressing the issue of pharmacoresistance.
The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs
Authors: Rogawski Michael A.
Published: May 2013

Pharmacoresistance to antiepileptic drugs (AEDs) is a barrier to seizure freedom for many persons with epilepsy. For nearly two decades, pharmacoresistance has been framed in terms of factors affecting the access of AEDs to their molecular targets in the brain or the actions of the drugs on these targets. Shortcomings in this prevailing view led to the formulation of the intrinsic severity hypothesis of pharmacoresistance to AEDs, which is based on the recognition that there are neurobiologic factors that confer phenotypic variation among individuals with etiologically similar forms of epilepsy and postulates that more severe epilepsy is more difficult to treat with AEDs. In recent years, progress has been made identifying potential genetic mechanisms of variation in epilepsy severity, including subclinical mutations in ion channels that increase or reduce epilepsy severity in mice. Efforts are underway to identify clinically important genetic modifiers. If it can be demonstrated that such severity factors play a role in pharmacoresistance, treatments could be devised to reverse severity mechanisms. By overcoming pharmacoresistance, this new approach to epilepsy therapy may allow drug refractory patients to achieve seizure freedom without side effects.
The methylation hypothesis of pharmacoresistance in epilepsy
Authors: Kobow Katja , El‐Osta Assam , Blümcke Ingmar
Published: May 2013

Seizures cannot be medically controlled in approximately 40% of people with epilepsy. Although we are beginning to understand how to better treat certain seizure types, we still do not know the regulatory events that determine antiepileptic drug resistance. Proposed pathoetiologic mechanisms include altered expression of drug targets (i.e., receptor or ion channel modifications), endothelial drug transporter activation (i.e., increasing drug clearance), or intrinsic severity factors. The latter hypothesis results from an often confirmed clinical observation, that seizure severity is a reliable predictor for the development of pharmacoresistance (PR) in epilepsy. Herein, we propose, that genome modifications that do not involve changes to the DNA sequence per se (i.e., epigenetic changes) could confer PR in patients with epilepsy. Seizures cause excessive neuronal membrane depolarization, which can influence the cellular nucleus; we thus hypothesize that seizures can mediate epigenetic modifications that result in persistent genomic methylation, histone density, and posttranslational modifications, as well as noncoding RNA‐based changes. Although experimental evidence is lacking in epilepsy, such mechanisms are well characterized in cancer, either as a result of anticancer drugs themselves or cancer‐related intrinsic signals (i.e., noncoding RNAs). We suggest that similar mechanisms also play a role in PR epilepsies. Addressing such epigenetic mechanisms may be a successful strategy to increase the brain's sensitivity to antiepileptic drugs and may even act as disease‐modifying treatment.
Is routine electroencephalography (EEG) a useful biomarker for pharmacoresistant epilepsy?
Authors: Steinhoff Bernhard J. , Scholly Julia , Dentel Christel , Staack Anke Maren
Published: May 2013

People with seizure disorders who have been treated at the Kork Epilepsy Center over a prolonged time period and who thus provide data concerning the chronic course of epilepsy were investigated in order to address the potential role of electroencephalography (EEG) as a biomarker for pharmacoresistant epilepsy. Clinical course and the corresponding findings from their first recorded EEG, their first EEG following appropriate treatment, and their last EEG were compared. Furthermore, we investigated if interictal epileptiform discharges (IEDs) differ in amplitude and morphology if recorded in long‐term seizure‐free patients. The early cessation of IEDs was a relatively good marker for a good prognosis, especially in idiopathic generalized epilepsies. However, persistent IEDs had no major impact on the long‐term prognosis. We found no differences between IEDs in seizure‐free patients or patients with ongoing seizures. Therefore, in our hands, routine EEG was not an appropriate biomarker for the prediction of pharmacoresistant epilepsy. Additional factors such as etiology and pathophysiology also need to be considered.
Can we develop pathology‐specific MRI contrast for “MR‐negative” epilepsy?
Authors: Feindel Kirk W.
Published: May 2013

Recent improvements in magnetic resonance imaging (MRI) hardware, software, and analysis routines are helping to put cases of “MR‐negative” epilepsy on the decline. However, most standard‐of‐care MRI relies on careful manipulation and presentation of T1, T2, and diffusion‐weighted contrast, which characterize the behavior of water in “bulk” tissue rather than providing pathology‐specific contrast. Research efforts in MR physics continue to identify and develop novel theory, and methods such as diffusional kurtosis imaging (DKI) and temporal diffusion spectroscopy that can better characterize tissue substructure, and chemical exchange saturation transfer (CEST) that can target underlying biochemical processes. The potential role of each technique in targeting pathologies implicated in “MR‐negative” epilepsy is outlined herein.
A conceptual framework for the use of neuroimaging to study and predict pharmacoresistance in epilepsy
Authors: Pohlmann‐Eden Bernd , Crocker Candice E. , Schmidt Matthias H.
Published: May 2013

Twenty percent to 49% of newly treated patients with epilepsy will develop pharmacoresistance (PR). The mechanisms leading to PR are unclear. There is currently no unifying theory to explain the variety of presentations of PR and the diversity of potential contributing factors. Etiology of seizures seems to play a critical role in at least a subset of PR. Many magnetic resonance imaging (MRI) studies in the advanced stages of epilepsy suggest a strong association between lesions such as hippocampal sclerosis and focal cortical dysplasia and PR. Unfortunately, almost all of these studies are cross‐sectional and retrospective. There is a need for a new perspective on the role of preexisting lesions in the evolution of epilepsy and PR. We propose in this article to study a unique population of drug‐naive patients with either first seizure or new‐onset epilepsy longitudinally with advanced MRI imaging techniques, including magnetic resonance spectroscopy and diffusion tensor imaging. We hope to be able to monitor imaging findings and the development of PR early in the course of the disease in a subset of these patients with temporal lobe epilepsy (TLE). Our goal is to understand the pathogenesis of PR, to dissect changes associated with the development of PR from changes associated with chronic seizures and medication, and ultimately to predict PR at the onset of disease.
Pharmacoresistant epilepsy: Unmet needs in solving the puzzle(s)
Authors: Weaver Donald F. , Pohlmann‐Eden Bernd
Published: May 2013

Pharmacoresistant epilepsy is a significant medical problem. The 2nd Halifax International Epilepsy Conference & Retreat identified crucial needs, which if successfully addressed, will aid in paving the way to improved lives for people with pharmacoresistant epilepsy. These are needs: (1) for an evidence‐based and dynamic definition of pharmacoresistant epilepsy; (2) for a comprehensive description of the natural history of pharmacoresistant epilepsy; (3) for a comprehensive description of the complications and comorbidities of pharmacoresistant epilepsy; (4) for a rigorous delineation of the epidemiology and socioeconomic impact of pharmacoresistant epilepsy; (5) for clinically meaningful diagnostic and prognostic physiologically based electroencephalography (EEG) biomarkers; (6) for clinically meaningful diagnostic and prognostic anatomically based (MRI Imaging) biomarkers; (7) for biomolecular/biochemical mechanistic understanding of etiopathogenesis for pharmacoresistant epilepsy; (8) for representative animal models of pharmacoresistant epilepsy; (9) for new and effective drugs or other novel treatments for pharmacoresistant epilepsy; and (10) to promote continuing research and research funding targeting pharmacoresistant epilepsy.