bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potassium leakage primes stored erythrocytes for phosphatidylserine exposure and shedding of pro‐coagulant vesicles
Authors: Burger Patrick , Kostova Elena , Bloem Esther , Hilarius‐Stokman Petra , Meijer Alexander B. , van den Berg Timo K. , Verhoeven Arthur J. , de Korte Dirk , van Bruggen Robin 
Published: November 2012

SummaryDuring storage, erythrocytes undergo changes that alter their clearance and function after transfusion and there is increasing evidence that these changes contribute to the complications observed in transfused patients. Stored erythrocytes were incubated overnight at 37°C to mimic the temperature after transfusion. After incubation, several markers for erythrocyte damage were analysed. After overnight incubation, stored erythrocytes showed increased potassium leakage, haemolysis, PS exposure and vesicle formation, and all these effects increased with increasing storage time. Furthermore, we demonstrated that long‐term stored erythrocytes develop decreased flippase activity and increased scrambling activity after overnight incubation, leading to PS exposure and the release of vesicles. Reduced intracellular potassium was identified as the cause of the decreased flippase activity. Lastly, we provide evidence that erythrocytes can return to a PS‐negative state by shedding parts of their membrane as PS‐containing vesicles and that these vesicles can serve as a platform for the coagulation cascade. These findings reveal that potassium leakage, a well‐known phenomenon of prolonged erythrocyte storage, primes erythrocytes for PS exposure. PS exposure will lead to vesicle formation and might have an important impact on the post‐transfusion function and side effects of stored erythrocytes.
Motilin: towards a new understanding of the gastrointestinal neuropharmacology and therapeutic use of motilin receptor agonists
Authors: Sanger G J , Wang Y , Hobson A , Broad J 
Published: November 2012

The gastrointestinal hormone motilin has been known about for >40 years, but after identification of its receptor and subsequent development of new tools and methods, a reappraisal of its actions is required. Firstly, it is important to note that motilin and ghrelin receptors are members of the same family (similar genomic organization, gastrointestinal distribution and abilities to stimulate gastrointestinal motility), yet each fails to recognize the ligand of the other; and whereas ghrelin and ghrelin receptors are widespread outside the gastrointestinal tract, motilin and its receptors are largely restricted to the gastrointestinal tract. Secondly, although some studies suggest motilin has activity in rodents, most do not, and receptor pseudogenes exist in rodents. Thirdly, motilin preferentially operates by facilitating enteric cholinergic activity rather than directly contracting the muscle, despite the relatively high expression of receptor immunoreactivity in muscle. This activity is ligand‐dependent, with short‐lasting actions of motilin contrasting with longer‐lasting actions of the non‐selective and selective motilin receptor agonists erythromycin and GSK962040. Finally, the use of erythromycin (also an antibiotic drug) to treat patients requiring acceleration of gastric emptying has led to concerns over safety and potential exacerbation of antibiotic resistance. Replacement motilin receptor agonists derived from erythromycin (motilides) have been unsuccessful. New, non‐motilide, small molecule receptor agonists, designed to minimize self‐desensitization, are now entering clinical trials for treating patients undergoing enteral feeding or with diabetic gastroparesis. Thus, for the translational pharmacologist, the study of motilin illustrates the need to avoid overreliance on artificial systems, on structural information and on animal studies.Linked ArticlesThis article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue‐7
The antibiotic azithromycin is a motilin receptor agonist in human stomach: comparison with erythromycin
Authors: Broad John , Sanger Gareth J 
Published: November 2012

Background and PurposeThe antibiotic azithromycin is a suggested alternative to erythromycin for treating patients with delayed gastric emptying. However, although hypothesized to activate motilin receptors, supportive evidence is unavailable. This was investigated using recombinant and naturally expressed motilin receptors in human stomach, comparing azithromycin with erythromycin.Experimental Approach[125I]‐motilin binding and calcium flux experiments were conducted using human recombinant motilin receptors in CHO cells. Neuromuscular activities were studied using circular muscle of human gastric antrum, after electrical field stimulation (EFS) of intrinsic nerves.Key ResultsAzithromycin (1–100 μM) and erythromycin (3–30 μM) concentration‐dependently displaced [125I]‐motilin binding to the motilin receptor (52 ± 7 and 58 ± 18% displacement at 100 and 30 μM respectively). Azithromycin, erythromycin and motilin concentration‐dependently caused short‐lived increases in intracellular [Ca2+] in cells expressing the motilin receptor. EC50 values were, respectively, 2.9, 0.92 and 0.036 μM (n = 3 each); and maximal activities were similar. In human stomach, EFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. Azithromycin and erythromycin lactobionate (30–300 μM each) facilitated these contractions (apparent Emax values of 2007 ± 396 and 1924 ± 1375%, n = 3–4 each concentration, respectively). These actions were slow in onset and faded slowly. The higher concentrations also evoked short‐lived muscle contraction. Contractions to a submaximally effective concentration of carbachol were unaffected by either drug.Conclusions and ImplicationsAzithromcyin activates human recombinant motilin receptors in therapeutically relevant concentrations, similar to erythromycin. In humans, gastric antrum azithromycin caused long‐lasting facilitation of cholinergic activity. These actions explain the gastric prokinetic activity of azithromycin.
Dealing With Missing Data in Developmental Research
Authors: Enders Craig K. 
Published: November 2012

AbstractApproaches to handling missing data have improved dramatically in recent years and researchers can now choose from a variety of sophisticated analysis options. The methodological literature favors maximum likelihood and multiple imputation because these approaches offer substantial improvements over older approaches, including a strong theoretical foundation, less restrictive assumptions, and the potential for bias reduction and greater power. These benefits are especially important for developmental research where attrition is a pervasive problem. This article provides a brief introduction to modern methods for handling missing data and their application to developmental research.
Intracellular RNA recognition pathway activates strong anti-viral response in human mast cells
Authors: Lappalainen J , Rintahaka J , Kovanen P T , Matikainen S , Eklund K K 
Published: November 2012

SummaryMast cells have been implicated in the first line of defence against parasites and bacteria, but less is known about their role in anti-viral responses. Allergic diseases often exacerbate during viral infection, suggesting an increased activation of mast cells in the process. In this study we investigated human mast cell response to double-stranded RNA and viral infection. Cultured human mast cells were incubated with poly(I:C), a synthetic RNA analogue and live Sendai virus as a model of RNA parainfluenza virus infection, and analysed for their anti-viral response. Mast cells responded to intracellular poly(I:C) by inducing type 1 and type 3 interferons and TNF-α. In contrast, extracellular Toll-like receptor 3 (TLR)-3-activating poly(I:C) failed to induce such response. Infection of mast cells with live Sendai virus induced an anti-viral response similar to that of intracellular poly(I:C). Type 1, but not type 3 interferons, up-regulated the expression of melanoma differentiation–associated gene 5 (MDA-5) and retinoic acid-inducible gene-1 (RIG-1), and TLR-3, demonstrating that human mast cells do not express functional receptors for type 3 interferons. Furthermore, virus infection induced the anti-viral proteins MxA and IFIT3 in human mast cells. In conclusion, our results support the notion that mast cells can recognize an invading virus through intracellular virus sensors and produce high amounts of type 1 and type 3 interferons and the anti-viral proteins human myxovirus resistance gene A (MxA) and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in response to the virus infection.
Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls
Authors: Bradley A S , Ford B , Bansal A S 
Published: November 2012

Summary
Chronic fatigue syndrome (CFS) is a heterogeneous disorder of unknown aetiology characterized by disabling fatigue, headaches, sleep disturbance and several other symptoms. The onset of CFS may follow a viral infection or period of stress. Patients with CFS do not have hypogammaglobulinaemia, predisposition to recurrent bacterial infections or symptoms of autoimmunity. To date, defects in B cell numbers or function have not been shown in the literature. However, treatment with anti-B cell therapy using Rituximab has recently shown benefit to CFS patients. We therefore postulated that patients with CFS had a subtle humoral immune dysfunction, and performed extended B cell immunophenotyping. We undertook a detailed characterization of the proportions of the different B cell subsets in 33 patients with CFS fulfilling the Canadian and Fukada criteria for CFS and compared these with 24 age- and gender-matched healthy controls (HC). CFS patients had greater numbers of naive B cells as a percentage of lymphocytes: 6·3 versus 3·9% in HC (P = 0·034), greater numbers of naive B cells as a percentage of B cells: 65 versus 47% in controls (P = 0·003), greater numbers of transitional B cells: 1·8 versus 0·8% in controls (P = 0·025) and reduced numbers of plasmablasts: 0·5 versus 0·9% in controls (P = 0·013). While the cause of these changes is unclear, we speculate whether they may suggest a subtle tendency to autoimmunity.
Emerging trends in the diagnosis and treatment of acromegaly in Canada
Authors: Vallette Sophie , Ezzat Shereen , Chik Constance , Ur Ehud , Imran Syed Ali , Van Uum Stan , Rivera Juan , Caspar‐Bell Gudrun , Serri Omar 
Published: November 2012

SummaryObjectiveTo evaluate demographic data and quality of care of patients with acromegaly in Canada and their evolution over time and secondly, to evaluate predictors of co‐morbidities and treatment outcomes.Design and patientsRetrospective analyses of clinical, biochemical and treatment outcome data of 649 patients with acromegaly (males: 50·7%) followed from 1980 to 2010 (mean 10·2 years, SD 13·7) in eight tertiary care centres from six Canadian provinces.ResultsIn comparison to 1980–1994, the number of patients referred with acromegaly in the last 15 years was higher with female preponderance (52·8% vs 41·4%, P = 0·01) and an older age at diagnosis (46·4 ± 14 vs 41·3 ± 12 years, P < 0·0001). Diabetes was present in 28%, hypertension in 37% and sleep apnoea in 33% of cases. Pretreatment IGF‐1 levels, but not GH levels were significant predictors of diabetes (P = 0·0002) and hypertension (P < 0·0001). Eighty‐nine per cent of patients underwent pituitary surgery, 64·5% had medical therapy and 22% received radiotherapy. Radiotherapy was less utilized in the past 15 years (16% vs 45%, P < 0·0001). Multimodal therapy achieved remission or control of acromegaly in 70% of patients. Patients in remission or disease control had lower initial random GH (P = 0·04) and IGF‐1 levels (P < 0·0001). Hypopituitarism was present in 23% of patients and cancer in 8·5%.ConclusionsThere was an increase over time of referral for acromegaly management with female predilection. Initial higher IGF‐1, but not GH levels, were predictive of co‐morbidities and persistent active disease after treatment. Disease remission or control was attained in 70% of patients utilizing multimodal therapy.
Current level of glycaemic control and its associated factors in patients with type 2 diabetes across Europe: data from the PANORAMA study
Authors: de Pablos‐Velasco Pedro , Parhofer Klaus G , Bradley Clare , Eschwège Eveline , Gönder-Frederick Linda , Maheux Pierre , Wood Ian , Simon Dominique 
Published: November 2012

AbstractObjectiveTo provide an update on glycaemic control in European patients with type 2 diabetes based on data from the nine‐country, cross‐sectional PANORAMA study (NCT00916513).DesignPost‐hoc analysis to report the number of patients achieving/not achieving glycaemic goal (HbA1c <7%).PatientsPatients were randomly or consecutively selected from physician practices in nine countries. Eligible patients were aged ≥40 years, diagnosed with type 2 diabetes >1 year prior to study entry, and had an available medical record of >1 year.MeasurementsAll data were collected at a single visit, including HbA1c measurement using a common device (A1CNow®). Bivariate and multivariate analyses were used to investigate factors associated with not reaching glycaemic goal.ResultsOf 5817 patients enrolled (aged 65·9 ± 10·4 years, 53·7% male), 37·4% had an HbA1c ≥7%; (range 25·9% in The Netherlands to 52·0% in Turkey). In adjusted multivariate analyses, higher individual glycaemic target, younger age, poor physician‐reported patient adherence to lifestyle/medication, longer diabetes duration, increasing treatment regimen complexity and physician‐reported patient's unwillingness to intensify treatment were associated with not achieving goal. However, bivariate analyses also found gender, socioeconomic factors, body mass index, rate of complications and hypoglycaemia to be associated with not achieving goal.ConclusionsIn PANORAMA, 37·4% of patients enrolled were not at glycaemic goal. Factors relating to patient characteristics, physician selection of individualized HbA1c target and diabetes itself (longer duration, more complex treatment) were strongly associated with not achieving goal. Further studies are warranted to explore these associations and evaluate strategies for improving glycaemic control.
Transplantation of Human Retinal Pigment Epithelium Cells in the Treatment for Parkinson Disease
Authors: Yin Feng , Tian Zeng‐Min , Liu Shuang , Zhao Quan‐Jun , Wang Rui‐Min , Shen Li , Wieman Jeffery , Yan Ying 
Published: November 2012

SummaryBackground and purposeTo assess the clinical effect of transplantation of human retinal pigment epithelial (hRPE) cells into the unilateral postcommissural putamen for treatment for Parkinson disease (PD).Methods and resultsCells from postmortem human eye tissue (10–20 weeks of gestation) were cultured in vitro. Cells from ‐generation passage were implanted in PD postcommissural putamen with stereotactic operation in 12 patients with PD. All patients tolerated surgery well, and no major adverse events occurred. Eleven patients showed improvement in the primary outcome measure at 3 months post‐treatment, particularly the Unified Parkinson's Disease Rating Scale‐M score in the off state. Response reached a peak at 12 months and declined during the next 24 months. At the 36‐month endpoint, there were eight patients who felt better than at baseline. Positron emission tomography (PET) showed a trend with increased dopamine (DA) release during the first 6 months.ConclusionHuman retinal pigment epithelial cells have the characteristics of neural progenitor cells and can be induced to differentiate into DA neurons. The results of this clinical trial suggest that the treatment of transplanted hRPE cells could improve symptoms of PD. These cells might serve as a useful source of DA neurons for neural graft in the treatment for PD.
The Role of Tissue Doppler Imaging in Predicting Left Ventricular Filling Pressures in Patients Undergoing Cardiac Surgery: An Intraoperative Study
Authors: Kumar Kanwal , Nepomuceno Roman G. , Chelvanathan Anjala , Golian Mehrdad , Bohonis Sheena , Cleverley Kelby , Ravandi Amir , Mackenzie Scott , Jassal Davinder S. 
Published: November 2012

Introduction: The perioperative management of patients undergoing cardiac surgery usually requires the accurate assessment of left ventricular filling pressures (LVFP). The gold standard for determining LVFP involves the use of pulmonary artery catheters (PAC). Using tissue Doppler indices (TDI) obtained by transthoracic echocardiography, the ratio of early transmitral filling velocity to the corresponding early mitral annular velocity (E/E′) has a strong correlation with pulmonary capillary wedge pressure (PCWP). Little is known, however, on whether this relationship between E/E′ and PCWP is valid intraoperatively using transesophageal echocardiography (TEE) during cardiac surgery. Objective: The objective of our study was to determine whether TDI obtained by intraoperative TEE during cardiac surgery can accurately estimate PCWP using PAC as the gold standard. Methods and Results: A total of 34 patients (26 males, mean age 64 ± 9 years) undergoing cardiac surgery were prospectively enrolled between 2010 and 2011 at a single tertiary care center. Conventional diastolic and tissue Doppler parameters were evaluated using intraoperative TEE with concurrent PAC monitoring before and after cardiopulmonary bypass (CPB) surgery. At both pre‐ and post‐CPB, there was no significant correlation between lateral, septal, and mean E/E′ obtained by TEE and PCWP. Conclusion: Intraoperative TEE was unable to accurately predict LVFP in patients undergoing cardiac surgery. PAC may continue to be the gold standard in the assessment of LVFP for this patient population.
BDNF‐mediated regulation of ethanol consumption requires the activation of the MAP kinase pathway and protein synthesis
Authors: Jeanblanc Jerome , Logrip Marian L. , Janak Patricia H. , Ron Dorit 
Published: November 2012

AbstractWe previously found that the brain‐derived neurotrophic factor (BDNF) in the dorsolateral striatum (DLS) is part of a homeostatic pathway that gates ethanol self‐administration [Jeanblanc et al. (2009). J Neurosci, 29, 13494–13502)]. Specifically, we showed that moderate levels (10%) of ethanol consumption increase BDNF expression within the DLS, and that direct infusion of BDNF into the DLS decreases operant self‐administration of a 10% ethanol solution. BDNF binding to its receptor, TrkB, activates the mitogen‐activated protein kinase (MAPK), phospholipase C‐γ (PLC‐γ) and phosphatidylinositol 3‐kinase (PI3K) pathways. Thus, here, we set out to identify which of these intracellular pathway(s) plays a role in the regulation of ethanol consumption by BDNF. We found that inhibition of the MAPK, but not PLC‐γ or PI3K, activity blocks the BDNF‐mediated reduction of ethanol consumption. As activation of the MAPK pathway leads to the initiation of transcription and/or translation events, we tested whether the BDNF‐mediated reduction of ethanol self‐administration requires de novo protein synthesis. We found that the inhibitory effect of BDNF on ethanol intake is blocked by the protein synthesis inhibitor cycloheximide. Together, our results show that BDNF attenuates ethanol drinking via activation of the MAPK pathway in a protein synthesis‐dependent manner within the DLS.
Insights on the neural basis of motor plasticity induced by theta burst stimulation from TMS–EEG
Authors: Vernet Marine , Bashir Shahid , Yoo Woo‐Kyoung , Perez Jennifer M. , Najib Umer , Pascual‐Leone Alvaro 
Published: November 2012

AbstractTranscranial magnetic stimulation (TMS) is a useful tool to induce and measure plasticity in the human brain. However, the cortical effects are generally indirectly evaluated with motor‐evoked potentials (MEPs) reflective of modulation of cortico‐spinal excitability. In this study, we aim to provide direct measures of cortical plasticity by combining TMS with electroencephalography (EEG). Continuous theta‐burst stimulation (cTBS) was applied over the primary motor cortex (M1) of young healthy adults, and we measured modulation of (i) MEPs, (ii) TMS‐induced EEG evoked potentials (TEPs), (iii) TMS‐induced EEG synchronization and (iv) eyes‐closed resting EEG. Our results show the expected cTBS‐induced decrease in MEP size, which we found to be paralleled by a modulation of a combination of TEPs. Furthermore, we found that cTBS increased the power in the theta band of eyes‐closed resting EEG, whereas it decreased single‐pulse TMS‐induced power in the theta and alpha bands. In addition, cTBS decreased the power in the beta band of eyes‐closed resting EEG, whereas it increased single‐pulse TMS‐induced power in the beta band. We suggest that cTBS acts by modulating the phase alignment between already active oscillators; it synchronizes low‐frequency (theta and/or alpha) oscillators and desynchronizes high‐frequency (beta) oscillators. These results provide novel insight into the cortical effects of cTBS and could be useful for exploring cTBS‐induced plasticity outside of the motor cortex.
Dissociable contributions of the ventral hippocampus and orbitofrontal cortex to decision‐making with a delayed or uncertain outcome
Authors: Abela Andrew R. , Chudasama Yogita 
Published: November 2012

AbstractIn this study, we examined how risk and delay influence rats' decision‐making, and the role of the ventral hippocampus (VHC) and orbitofrontal cortex (OFC) in the valuation of these two factors. We used a touchscreen testing method in which rats with VHC lesions, OFC lesions and sham control surgery made choices in two decision‐making tasks. In the delay discounting task, rats chose between two visual stimuli, one of which indicated a small, immediate reward, and the other of which indicated a large, delayed reward. In the probability discounting task, two stimuli indicated, instead, a small, certain reward or a large, uncertain reward. The two lesion groups showed a double dissociation with respect to the two tasks. Rats with VHC lesions were intolerant of delay, and were strongly biased towards the small, immediate reward. However, the same rats were indistinguishable from sham controls in the probability discounting task. The opposite pattern was observed for rats with OFC lesions; they performed normally in the delay discounting task, but showed a reduced tolerance for uncertainty as compared with sham‐operated controls. These data support the conclusion that the VHC and OFC contribute differentially to decision‐making that involves delayed or uncertain outcomes. This provides a means for understanding the neural basis of a range of neurological and psychiatric patients who show impaired decision‐making and executive dysfunction.