bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects
Authors: Wright D. Hamish , Stone Julie A. , Crumley Tami M. , Wenning Larissa , Zheng Wei , Yan Kerri , Yang Amy Yifan , Sun Li , Cilissen Caroline , Ramael Steven , Hermanowski‐Vosatka Anne , Langdon Ronald B. , Gottesdiener Keith M. , Wagner John A. , Lai Eseng 
Published: April 2013

AimsTo characterize pharmacokinetic parameters of MK‐0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable‐isotope labelling) the in vivo inhibition of cortisone‐to‐cortisol conversion following oral MK‐0916.MethodsData are presented from two randomized, controlled, double‐blind, rising‐dose phase I studies. In the first study, subjects received single oral doses of 0.4–100 mg MK‐0916 (n = 16). In the second study, subjects received 0.2–225 mg MK‐0916 followed by daily doses of 0.2–100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [13C4]cortisol were measured by high‐pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [13C4]cortisone.ResultsDoses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1–1.8 h). Exposure (measured as the area under the concentration–time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK‐0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone‐to‐cortisol conversion was inhibited by 84%. The relationship between plasma MK‐0916 and hepatic 11β‐hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nm. Exposure to MK‐0916 was generally well tolerated.ConclusionsThese findings indicate that 11β‐hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK‐0916 that are well tolerated.
Methylphenidate use in pregnancy and lactation: a systematic review of evidence
Authors: Bolea‐Alamanac Blanca M. , Green Amy , Verma Gauri , Maxwell Penelope , Davies Simon J. C. 
Published: April 2013

AimsThe aims of this review were to summarize the scientific evidence about the risks of using methylphenidate for ADHD in pregnancy and lactation, to present a case in which interruption of treatment after delivery and during breastfeeding was harmful and to discuss the implications of treating or not treating ADHD in pregnancy and lactation.MethodsFor the systematic review, databases searched included Pubmed, Psychinfo, Web of Science, Embase, Biosis and Medline.ResultsThree articles were found with a total sample of 41 children exposed to methylphenidate in pregnancy. Malformations reported included congenital heart defects (n = 2), finger abnormalities (syndactyly, adactyly and polydactyly n = 2) and limb malformations (n = 1). Other problems included premature birth, asphyxia and growth retardation. One case report (n = 1) and one case series (n = 3) were identified regarding exposure to methylphenidate through breast feeding. In all cases, children developed normally and no adverse effects were reported. In our case report we describe an infant exposed to methylphenidate during pregnancy and breast feeding, who developed normally having no detectable congenital abnormalities.ConclusionsThe number and size of the studies found were small. Identified cases were not representative of the general adult ADHD population having methylphenidate as monotherapy during pregnancy as all the articles reported combinations of methylphenidate with either known teratogenic drugs or drugs of abuse. There is a paucity of data regarding the use of methylphenidate in pregnancy and further studies are required. Although the default medical position is to interrupt any non‐essential pharmacological treatment during pregnancy and lactation, in ADHD this may present a significant risk. Doctors need to evaluate each case carefully before interrupting treatment.
Peripheral T‐cell lymphoma in HIV‐infected patients: a study of 17 cases in the combination antiretroviral therapy era
Authors: Gilardin Laurent , Copie‐Bergman Christiane , Galicier Lionel , Meignin Véronique , Brière Josette , Timsit Julie F. , Bouchaud Olivier , Gaulard Philippe , Oksenhendler Eric , Gérard Laurence 
Published: April 2013

SummaryMost cases of human immunodeficiency virus (HIV)‐associated non‐Hodgkin Lymphoma (NHL) are of B‐cell origin; T‐cell NHLs are rarely reported. Within a single centre prospective cohort of 370 HIV‐NHL, 17 (5%) were of T‐cell origin (82% male; median age, 39 years). Median CD4+ cell count was 0·194 × 109/l and 41% had undetectable plasma HIV‐RNA at lymphoma diagnosis. All patients received combination antiretroviral therapy during chemotherapy. All histological samples were centrally reviewed. The distribution of the histological subtypes differed from the general population with absence of angioimmunoblastic subtype. Lymphoma was disseminated in 14 patients, and seven patients had performance status >2. All patients received full‐dose chemotherapy: eight standard and nine intensive regimens. Two patients who received intensive chemotherapy died during therapy. The complete remission rate was 53%; 62·5% with standard therapy and 44% with intensive therapy. After a median follow‐up of 7·2 years, the median overall survival was 9·4 months. Most deaths (85%) occurred within the first year following diagnosis, as a consequence of lymphoma progression in 10/13 cases. In this rare but severe complication of HIV infection the use of intensive chemotherapy does not appear to be beneficial for response, with increased toxicity.
Responsibility and Privacy — Ethical Aspects of UsingGPSto Track Children
Authors: Fahlquist Jessica Nihlén 
Published: April 2013

WithGPStechnology, children can be monitored 24 h a day throughout their childhood and teens. In spite of the advantages in terms of safety and security, there are ethical problems with this. In this article, some of these are discussed. First, the concept of parental responsibility is explored and discussed in the context ofGPSand children. Second, against the background of psychological research, it is argued that it is not conducive for children's sense of responsibility to be constantly monitored. Third, the question whether children have a right to privacy is discussed. It is concluded that due to the considerable uncertainty concerning the effects of constant monitoring as well as the ethical problems discussed, we ought to adopt a cautious attitude to usingGPSto track children.
Enhancing Quality Interventions Promoting Healthy Sexuality (EQUIPS): A Novel Application of Translational Research Methods
Authors: Chinman Matthew , Acosta Joie , Ebener Patricia , Driver Jennifer , Keith Jamie , Peebles Dana 
Published: April 2013

AbstractTranslational research is expanding, in part, because Evidence‐Based Programs or Practices (EBPs) are not adopted in many medical domains. However, little translational research exists on EBPs that are prevention programs delivered in nonclinical, community‐based settings. These organizations often have low capacity, which undermines implementation quality and outcomes. Rigorous translational research is needed in these settings so within a single study, capacity, implementation quality, and outcomes are measured and links between them tested. This paper overviews the study Enhancing Quality Interventions Promoting Healthy Sexuality (EQUIPS), which tests how well a community‐based setting (Boys & Girls Clubs) conducts an EBP called Making Proud Choices that aims to prevent teen pregnancy and sexually transmitted infections, with and without an implementation support intervention called Getting To Outcomes. The study design is novel as it assesses: Getting To Outcomes’ impact on capacity, implementation quality, and outcomes simultaneously and in both study conditions; will assess sustainability by measuring capacity and fidelity a year after the Getting To Outcomes support ends; and will operate on a large scale similar to many national initiatives. Many studies have not incorporated all these elements and thus EQUIPS could serve as a model for translational research in many domains.
Prevalence and treatment profile of patients with grass pollen and house dust mite allergy
Authors: Worm Margitta , Lee Hae‐Hyuk , Kostev Karel 
Published: April 2013

SummaryBackgroundIn Europe, grass pollen and house dust mites are the most common allergens responsible for IgE‐mediated allergies. The aim of our study was to examine the data provided by various medical practices specialized in allergic diseases in Germany regarding patients with rhinoconjunctivitis in terms of demographic data and the prescribed treatment by different medical specialists.Patients and methodsData from patients who were diagnosed with allergic rhinoconjunctivitis were taken from the “disease‐analyzer” database (IMS Health GmbH) and analyzed. The data assessment was anonymous in accordance with the guidelines for data protection. The information collected included specific data about diagnosis and treatment in private practices in Germany.ResultsThe majority of patients with grass pollen allergy were treated by their general practitioners, while those with house dust mite allergy were treated by a specialist with a background in allergic diseases (pulmonologists, otorhinolaryngologists, and dermatologists). Treatment was primarily symptomatic, usually consisting of antihistamines. Allergen‐specific immunotherapy, the only causal treatment for IgE‐mediated allergies at present, was performed rarely.ConclusionsThe data suggest the need for an interaction and knowledge transfer between various specialists in order to improve patient‐centered care in regard to allergic diseases.
Promoting Research Integrity in Africa: An African Voice of Concern on Research Misconduct and the Way Forward
Authors: Kombe Francis , Anunobi Eucharia Nkechinyere , Tshifugula Nyanyukweni Pandeni , Wassenaar Douglas , Njadingwe Dimpho , Mwalukore Salim , Chinyama Jonathan , Randrianasolo Bodo , Akindeh Perpetua , Dlamini Priscilla S. , Ramiandrisoa Felasoa Noroseheno , Ranaivo Naina 
Published: April 2013

AbstractAfrican researchers and their collaborators have been making significant contributions to useful research findings and discoveries in Africa. Despite evidence of scientific misconduct even in heavily regulated research environments, there is little documented information that supports prevalence of research misconduct in Africa. Available literature on research misconduct has focused on the developed world, where credible research integrity systems are already in place.Public attention to research misconduct has lately increased, calling for attention to weaknesses in current research policies and regulatory frameworks. Africa needs policies, structural and governance systems that promote responsible conduct of research.To begin to offset this relative lack of documented evidence of research misconduct, contributors working in various research institutions from nine African countries agreed to share their experiences to highlight problems and explore the need to identify strategies to promote research integrity in the African continent. The experiences shared include anecdotal but reliable accounts of previously undocumented research misconduct, including some ‘normal misbehavior’ of frontline staff in those countries.Two broad approaches to foster greater research integrity are proposed including promotion of institutional and individual capacity building to instil a culture of responsible research conduct in existing and upcoming research scientist and developing deterrent and corrective policies to minimize research misconduct and other questionable research practices. By sharing these experiences and through the strategies proposed, the authors hope to limit the level of research misconduct and promote research integrity in Africa.
Q&A
Authors: Meeker Shane , Allison Kevin , Schrage Michael 
Published: April 2013

Procter & Gamble's company historian and corporate storyteller sifts through 175 years of P&G history to run the firm's Heritage & Archives Center.This comedian has made a living getting people to tell their stories—and teaching them how to do it with maximum effect.The author of Serious Play offers some thoughts about the state of the art.
Right Ventricular Abnormalities in Takotsubo Cardiomyopathy
Authors: Rodrigues Ana Clara , Guimaraes Laise , Lira Edgar , Oliveira Wercules , Monaco Claudia , Cordovil Adriana , Fischer Claudio H. , Vieira Marcelo , Morhy Samira 
Published: April 2013

BackgroundTakotsubo cardiomyopathy, described as transient regional contractile abnormalities limited to the apical and mid‐segments of the left ventricle (LV), has also been reported to involve basal and/or mid LV segments (inverted Takotsubo); fewer reports, however, have addressed right ventricular (RV) dysfunction.AimTo assess the distribution of regional abnormalities and RV involvement in Takotsubo cardiomyopathy and compare it to the literature.Methods and ResultsWe evaluated 23 patients with both classical and inverted presentations (19 female, aged 64 ± 19 years), including 2 recurrences, totaling 25 episodes. Classical Takotsubo was observed in 15 patients, while 10 had the inverted form. LV ejection fraction (EF) was lower for classical compared to inverted presentation (30 ± 7 vs. 45 ± 4%, P < 0.001) with higher troponin values (1.3 ± 1.4 vs. 0.5 ± 0.6, P = 0.034). RV abnormalities were found in 7 patients (28%), mainly with classical presentation (6 patients), presenting with mid and apical RV impairment. One patient with inverted Takotsubo had mid‐RV involvement. Patients with RV involvement had lower left ventricular ejection fraction (LVEF) (28 ± 10% vs. 40 ± 10%, P = 0.02), but not when adjusted for presentation type. Overall rate of complications was higher for classical compared to inverted presentation, and not influenced by RV involvement.ConclusionRV contractile abnormalities may follow the same LV regional distribution in Takotsubo cardiomyopathy; the type of presentation rather than the presence of RV dysfunction seems to be responsible for an increased risk of complications and severity of functional impairment.
Is Atrial Electromechanical Coupling Delayed in Patients with Secundum Atrial Septal Defect?
Authors: Oflaz Mehmet Burhan , Karapinar Hekim , Kucukdurmaz Zekeriya , Guven Ahmet Sami , Gumrukcuoglu Hasan Ali , Sarikaya Savas , Yilmaz Ahmet 
Published: April 2013

BackgroundThere is no available published information about the atrial electromechanical coupling time (AEMCT) in patients with atrial septal defect (ASD). The aim of this study was to investigate the relationship between ASD and AEMCT obtained by tissue Doppler imaging (TDI).MethodsA total of 35 patients with ASD and 22 healthy controls were included in the study. The time intervals from the onset of the P‐wave on the surface electrocardiogram to the beginning of the late diastolic A‐wave (PA) representing AEMCT were obtained from the lateral mitral annulus, septal mitral annulus, and right ventricular (RV) tricuspid annulus, and named PA‐lateral, PA‐septal, and PA‐tricuspid, respectively. The difference between PA‐septal and PA‐tricuspid, PA‐lateral and PA‐septal, and PA‐lateral and PA‐tricuspid were defined as intra‐right AEMCT, intra‐left AEMCT, and inter‐ AEMCT, respectively.ResultsPA‐tricuspid, PA‐septal, and PA‐lateral values were longer in patients with ASD when compared with the controls, but did not reach statistical significance (39.9 ± 19.1 vs. 37.2 ± 15.5, P = 0.952; 49.6 ± 14.0 vs. 45.4 ± 11.1, P = 0.826 and 60.3 ± 16.3 vs. 59.7 ± 12.5, P = 0.437, respectively). There were no significant differences between the ASD and control groups in terms of inter‐atrial, intra‐right atrial, and intra‐left AEMCT (21.3 ± 2.3 vs. 20.8 ± 4.6, P = 0.957; 9.7 ± 3.3 vs. 6.9 ± 1.3, P = 0.723 and 13.6 ± 4.7 vs. 10.9 ± 4.5, P = 0.518, respectively). Furthermore, ASD diameter and total septum length did not correlate with AEMCT.ConclusionBoth intra‐ and inter‐AEMCT were not increased in patients with ASD than control subjects. In addition, we found no association between the ASD diameter and indices of AEMCT in patients with ASD.
PPARα is involved in the multitargeted effects of a pretreatment with atorvastatin in experimental stroke
Authors: Ouk Thavarak , Potey Camille , Laprais Maud , Gautier Sophie , Hanf Rémi , Darteil Raphaël , Staels Bart , Duriez Patrick , Bordet Régis 
Published: April 2013

AbstractThere is now substantial data in the literature showing that statins can protect against cerebral ischemia. This neuroprotective potency is related to their pleiotropic effects that modulate various pathways implicated in the pathophysiology of stroke. It has been demonstrated that statins exert anti‐inflammatory and vasculoprotective effects, thus contributing to a reduction in infarct size. The underlying mechanisms are still incompletely known. As a cross‐talk between statins and the nuclear receptor PPARα has been described, we hypothesized that this cross‐talk is necessary to neuroprotection in stroke. We studied the effects of a 14‐day preventive atorvastatin treatment (10 mg/kg/day) on C57Bl6 wild‐type and PPARα‐KO mice submitted to experimental stroke. PPARα was involved in the atorvastatin‐induced neuroprotective effect, as confirmed by the measurement of infarct volumes. We also evidenced that the anti‐inflammatory action of atorvastatin is mediated, at least partly, by PPARα. The decrease in IL‐6 plasmatic levels was PPARα dependent. The cerebral expression of the adhesion molecules ICAM‐1 and vascular cell adhesion molecule was reduced by the atorvastatin treatment, and this effect was PPARα dependent in the cortex but not in the striatum of treated animals. Atorvastatin also diminished the cerebral expression of iNOS in the cortex, but had no effect in the striatum of treated mice, whatever the PPARα status. At the vascular level, we found that the atorvastatin‐related endothelial nitric oxide synthase upregulation was regulated by PPARα in the aorta, while there was no effect in the brain. We demonstrate here that PPARα is a key mediator of the multitargeted neuroprotective effects of statins in stroke.
Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis‐associated cationic trypsinogen mutants
Authors: Geisz Andrea , Hegyi Péter , Sahin‐Tóth Miklós 
Published: April 2013

Mutations in human cationic trypsinogen cause hereditary pancreatitis by altering its proteolytic regulation of activation and degradation by chymotrypsin C (CTRC). CTRC stimulates trypsinogen autoactivation by processing the activation peptide to a shorter form, but also promotes degradation by cleaving the calcium‐binding loop in trypsinogen. Mutations render trypsinogen resistant to CTRC‐mediated degradation and/or increase processing of the activation peptide by CTRC. Here we demonstrate that the activation peptide mutations D19A, D22G, K23R and K23_I24insIDK robustly increased the rate of trypsinogen autoactivation, both in the presence and absence of CTRC. Degradation of the mutants by CTRC was unchanged, and processing of the activation peptide was increased fourfold in the D19A mutant only. Surprisingly, however, this increased processing had only a minimal effect on autoactivation. The tetra‐aspartate motif in the trypsinogen activation peptide binds calcium (KD of ~ 1.6 mm), which stimulates autoactivation. Unexpectedly, calcium binding was not compromised by any of the activation peptide mutations. Despite normal binding, autoactivation of mutants D22G and K23_I24insIDK was not stimulated by calcium. Finally, the activation peptide mutants exhibited reduced secretion from transfected cells, and secreted trypsinogen levels were inversely proportional with autoactivation rates. We conclude that D19A, D22G, K23R and K23_I24insIDK form a mechanistically distinct subset of hereditary pancreatitis‐associated mutations that exert their effect primarily through direct stimulation of autoactivation, independently of CTRC. The potentially severe clinical impact of the markedly increased autoactivation is offset by diminished secretion, resulting in a clinical phenotype that is indistinguishable from typical hereditary pancreatitis.
Breakthrough of contaminant plumes in saturated volcanic rock: implications from the Yucca Mountain site
Authors: Kelkar S. , Srinivasan G. , Robinson B. A. , Roback R. , Viswanathan H. , Rehfeldt K. , Tucci P. 
Published: April 2013

AbstractThis manuscript addresses the topic of transverse dispersion and its impact on the behavior of the saturated zone below Yucca Mountain, a site that had been proposed for a US nuclear waste repository. Guided by a review of relevant observations of dispersion in similar formations, this study evaluates the importance of uncertainty in dispersion, particularly dispersion transverse to the mean transport direction, on metrics of interest to the Yucca Mountain risk assessment. Although as expected, larger values of transverse dispersivity lead to greater spreading of the plume in directions orthogonal to the mean flow direction, a corresponding sensitivity is not observed to the travel time statistics of the breakthrough curve at the compliance boundary. Thus, when a risk assessment is based on contaminant mass flux at compliance well or ‘fence line’ downstream from the source, as in the Yucca Mountain case, transverse dispersion may be of secondary importance to other parameters that more directly impact travel times. This result is in contrast to systems in which reactive transport processes are important to the attenuation of the plume, in which case transverse dispersion and mixing may be expected to play a dominant role in controlling the reaction rates and contaminant concentrations in the plume.
Inhibition of connective tissue growth factor (CTGF/CCN2) in gallbladder cancer cells leads to decreased growth in vitro
Authors: Garcia Patricia , Leal Pamela , Ili Carmen , Brebi Priscilla , Alvarez Hector , Roa Juan C. 
Published: April 2013

SummaryGallbladder cancer (GBC) is an aggressive neoplasm associated with late diagnosis, unsatisfactory treatment and poor prognosis. Previous work showed that connective tissue growth factor (CTGF) expression is increased in this malignancy. This matricellular protein plays an important role in various cellular processes and its involvement in the tumorigenesis of several human cancers has been demonstrated. However, the precise function of CTGF expression in cancer cells is yet to be determined. The aim of this study was to evaluate the CTGF expression in gallbladder cancer cell lines, and its effect on cell viability, colony formation and in vitro cell migration. CTGF expression was evaluated in seven GBC cell lines by Western blot assay. Endogenous CTGF expression was downregulated by lentiviral shRNA directed against CTGF mRNA in G‐415 cells, and the effects on cell viability, anchorage‐independent growth and migration was assessed by comparing them to scrambled vector‐transfected cells. Knockdown of CTGF resulted in significant reduction in cell viability, colony formation and anchorage‐independent growth (P < 0.05). An increased p27 expression was observed in G‐415 cells with loss of CTGF function. Our results suggest that high expression of this protein in gallbladder cancer may confer a growth advantage for neoplastic cells.