bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase I/II trial of HQK‐1001, an oral fetal globin gene inducer, in β‐thalassaemia intermedia and HbE/β‐thalassaemia
Authors: Fucharoen Suthat , Inati Adlette , Siritanaratku Noppadol , Thein Swee L. , Wargin William C. , Koussa Suzanne , Taher Ali , Chaneim Nattawara , Boosalis Michael , Berenson Ronald , Perrine Susan P. 
Published: March 2013

Summaryβ‐thalassaemia intermedia (BTI) syndromes cause haemolytic anaemia, ineffective erythropoiesis, and widespread complications. Higher fetal globin expression within genotypes reduces globin imbalance and ameliorates anaemia. Sodium 2,2 dimethylbutyrate (HQK‐1001), an orally bioavailable short‐chain fatty acid derivative, induces γ‐globin expression experimentally and is well‐tolerated in normal subjects. Accordingly, a randomized, blinded, placebo‐controlled, Phase I/II trial was performed in 21 adult BTI patients (14 with HbE/β0 thalassaemia and seven with β+/β0 thalassaemia intermedia, to determine effective doses for fetal globin induction, safety, and tolerability. HQK‐1001 or placebo were administered once daily for 8 weeks at four dose levels (10, 20, 30, or 40 mg/kg per day), and subjects were monitored for laboratory and clinical events. Pharmacokinetic profiles demonstrated a t1/2 of 10–12 h. Adverse events with HQK‐1001 treatment were not significantly different from placebo treatment. The 20 mg/kg treatment doses increased median HbF above baseline levels by 6·6% and 4·4 g/l (P < 0·01) in 8/9 subjects; total haemoglobin (Hb) increased by a mean of 11 g/l in 4/9 subjects. These findings identified a safe oral therapeutic which induces fetal globin in BTI. Further investigation of HQK‐1001 with longer dosing to definitively evaluate its haematological potential appears warranted.
Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline‐induced pulmonary hypertension in rats
Authors: Alencar Allan K N , Pereira Sharlene L , Montagnoli Tadeu L , Maia Rodolfo C , Kümmerle Arthur E , Landgraf Sharon S , Caruso‐Neves Celso , Ferraz Emanuelle B , Tesch Roberta , Nascimento José H M , de Sant'Anna Carlos M R , Fraga Carlos A M , Barreiro Eliezer J , Sudo Roberto T , Zapata‐Sudo Gisele 
Published: March 2013

Background and PurposePulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N‐acylhydrazone derivative, 3,4‐dimethoxyphenyl‐N‐methyl‐benzoylhydrazide (LASSBio‐1359), on monocrotaline (MCT)‐induced pulmonary hypertension in rats.Experimental ApproachPAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg−1) and 2 weeks later, oral LASSBio‐1359 (50 mg·kg−1) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed.Key ResultsMCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio‐1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre‐contracted arterial rings, and this dysfunction was reversed by LASSBio‐1359. In pulmonary artery rings from normal Wistar rats, LASSBio‐1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio‐1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio‐1359 and the A2A receptor agonist, CGS21680, were very similar.Conclusion and ImplicationsIn rats with MCT‐induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio‐1359, most probably through the activation of adenosine A2A receptors.
Activation of mitochondrial function and Hb expression in non‐haematopoietic cells by an EPO inducer ameliorates ischaemic diseases in mice
Authors: Hsu Pei‐Lun , Horng Lin‐Yea , Peng Kang‐Yung , Wu Chia‐Ling , Sung Hui‐Ching , Wu Rong‐Tsun 
Published: March 2013

Background and PurposeMany organs suffer from ischaemic injuries that reduce their ability to generate sufficient energy, which is required for functional maintenance and repair. Erythropoietin (EPO) ameliorates ischaemic injuries by pleiotropic effects. The aim of this study was to investigate the effect and mechanism of a small molecule EH‐201, and found it as a potent EPO inducer and its effect in non‐haematopoietic cells for therapeutic potential in ischemic disorders.Experimental ApproachMice kidney slices, primary hepatocytes, primary cardiomyocytes and C2C12 myoblasts were treated with EH‐201. The effects of this treatment on EPO, Hb expression and mitochondrial biogenesis were analysed. In vivo, doxorubicin‐induced cardiomyopathic mice were treated with EH‐201. The mice were subjected to an endurance test, electrocardiography and echocardiography, and a histological examination of the isolated hearts was performed. EH‐201 was also administered to cisplatin‐induced nephropathic mice.Key ResultsIn non‐haematopoietic cells, EH‐201 was potent at inducing EPO. EH‐201 also stimulated mitochondrial biogenesis and enhanced the expression of Hb by a mechanism dependent on EPO‐mediated signalling. In mechanistic studies, using EPO and EPO receptor‐neutralizing antibodies, we confirmed that EH‐201 enhances EPO‐EPOR autocrine activity. EH‐201 robustly increased the endurance performance activity of healthy and cardiomyopathic mice during hypoxic stress, enhanced myocardial mitochondrial biogenesis and Hb expression, and also improved cardiac function. EH‐201 ameliorated anaemia and renal dysfunction in nephropathic mice.Conclusions and ImplicationsThe enhancement and recovery of cellular functions through the stimulation of mitochondrial activity and Hb production in non‐haematopoietic cells by an inducer of endogenous EPO has potential as a therapeutic strategy for ischaemic diseases.
Taking Shape: Supporting Preschoolers' Acquisition of Geometric Knowledge Through Guided Play
Authors: Fisher Kelly R. , Hirsh‐Pasek Kathy , Newcombe Nora , Golinkoff Roberta M. 
Published: March 2013

Shape knowledge, a key aspect of school readiness, is part of early mathematical learning. Variations in how children are exposed to shapes may affect the pace of their learning and the nature of their shape knowledge. Building on evidence suggesting that child‐centered, playful learning programs facilitate learning more than other methods, 4‐ to 5‐year‐old children (N = 70) were taught the properties of four geometric shapes using guided play, free play, or didactic instruction. Results revealed that children taught shapes in the guided play condition showed improved shape knowledge compared to the other groups, an effect that was still evident after 1 week. Findings suggest that scaffolding techniques that heighten engagement, direct exploration, and facilitate “sense‐making,” such as guided play, undergird shape learning.
Early Childhood Housing Instability and School Readiness
Authors: Ziol‐Guest Kathleen M. , McKenna Claire C. 
Published: March 2013

This study assesses the consequences of housing instability during the first 5 years of a child's life for a host of school readiness outcomes. Using data from the Fragile Families and Child Wellbeing Study (n = 2,810), this study examines the relation between multiple moves and children's language and literacy and behavior problems at age 5. The moderating role of poverty is further tested in this relation. The findings show that moving three or more times in a child's first 5 years is significantly associated with increases in attention problems, and internalizing and externalizing behavior, but only among poor children.
Involvement of high mobility group box 1 and the therapeutic effect of recombinant thrombomodulin in a mouse model of severe acute respiratory distress syndrome
Authors: Kudo D , Toyama M , Aoyagi T , Akahori Y , Yamamoto H , Ishii K , Kanno E , Maruyama R , Kaku M , Kushimoto S , Kawakami K 
Published: March 2013

SummaryAcute respiratory distress syndrome (ARDS) is accompanied by severe lung inflammation induced by various diseases. Despite the severity of the symptoms, therapeutic strategies have been ineffective. High mobility group box 1 (HMGB1), which was identified originally as a DNA binding protein, has been proposed as a mediator of acute lung injury. In addition to its anti-coagulant activity, recombinant thrombomodulin (rTM) possesses an ability to suppress the inflammatory response through neutralizing HMGB1. T regulatory (Treg) cells in the lungs are reported to modify innate immune responses during resolution of acute lung injury. In the present study, we investigated the therapeutic effect of rTM, and the contribution of Treg cells to this effect, in a mouse model of severe ARDS. C57BL/6 mice received sequential intratracheal administration of α-galactosylceramide (α-GalCer) and lipopolysaccharide (LPS), which resulted in the development of severe ARDS. HMGB1 levels in the lungs increased to a higher level in ARDS mice compared to those in mice treated with LPS alone. HMGB1 was expressed in the infiltrating neutrophils and macrophages in lungs. Treg cells were reduced significantly in the lungs of ARDS mice compared to those in mice treated with LPS alone. rTM administration prolonged the survival time and ameliorated the development of ARDS, which was associated with increased Treg cells and synthesis of interleukin (IL)-10 and transforming growth factor (TGF)-β in the lungs. These results suggest that HMGB1 is involved in the development of severe ARDS and rTM shows therapeutic effects through promoting the accumulation of Treg cells at the inflammatory sites.
Lack of activity of 15-epi-lipoxin A4 on FPR2/ALX and CysLT1 receptors in interleukin-8-driven human neutrophil function
Authors: Planagumà A , Domenech T , Jover I , Ramos I , Sentellas S , Malhotra R , Miralpeix M 
Published: March 2013

Summary
Neutrophil recruitment and survival are important control points in the development and resolution of inflammatory processes. 15-epi-lipoxin (LX)A4 interaction with formyl peptide receptor 2 (FPR2)/ALX receptor is suggested to enhance anti-inflammatory neutrophil functions and mediate resolution of airway inflammation. However, it has been reported that 15-epi-LXA4 analogues can also bind to cysteinyl leukotriene receptor 1 (CysLT1) and that the CysLT1 antagonist MK-571 binds to FPR2/ALX, so cross-reactivity between FPR2/ALX and CysLT1 ligands cannot be discarded. It is not well established whether the resolution properties reported for 15-epi-LXA4 are mediated through FPR2/ALX, or if other receptors such as CysLT1 may also be involved. Evaluation of specific FPR2/ALX ligands and CysLT1 antagonists in functional biochemical and cellular assays were performed to establish a role for both receptors in 15-epi-LXA4-mediated signalling and function. In our study, a FPR2/ALX synthetic peptide (WKYMVm) and a small molecule FPR2/ALX agonist (compound 43) induced FPR2/ALX-mediated signalling, enhancing guanosine triphosphate-gamma (GTPγ) binding and decreasing cyclic adenosine monophosphate (cAMP) levels, whereas 15-epi-LXA4 was inactive. Furthermore, 15-epi-LXA4 showed neither binding affinity nor signalling towards CysLT1. In neutrophils, 15-epi-LXA4 showed a moderate reduction of interleukin (IL)-8-mediated neutrophil chemotaxis but no effect on neutrophil survival was observed. In addition, CysLT1 antagonists were inactive in FPR2/ALX signalling or neutrophil assays. In conclusion, 15-epi-LXA4 is not a functional agonist or an antagonist of FPR2/ALX or CysLT1, shows no effect on IL-8-induced neutrophil survival and produces only moderate inhibition in IL-8-mediated neutrophil migration. Our data do not support an anti-inflammatory role of 15-epi-LXA4- FPR2/ALX interaction in IL-8-induced neutrophil inflammation.
Short‐ and long‐term impact of body mass index on laparoscopic rectal cancer surgery
Authors: Denost Q. , Quintane L. , Buscail E. , Martenot M. , Laurent C. , Rullier E. 
Published: March 2013

AbstractAim  Obesity is associated with increased technical difficulty in laparoscopic surgery. However, its impact has been measured mainly for colectomy but not specifically for rectal excision. The aim of the study was to assess the impact of body mass index (BMI) on technical feasibility and oncological outcome of laparoscopic rectal excision for cancer.Method  A total of 490 patients treated by laparoscopic rectal excision for rectal cancer from January 1999 to June 2010 were included. Seventy per cent had had preoperative radiochemotherapy. Patients were separated into four groups according to BMI (kg/m2): < 20, 20–25, 25–30 and ≥ 30. The impact of BMI on conversion, surgical morbidity, quality of excision (Quirke mesorectal grade and circumferential resection margin) and long‐term oncological outcome was determined.Results  Among the 490 patients BMI was < 20 in 43, 20–25 in 223, 25–30 in 177 and ≥ 30 in 47. Mortality (overall 1%) and morbidity (overall 19%) were similar between the groups. Conversion in the four groups was 5%, 14%, 23% and 32% (P = 0.001). The quality of mesorectal excision and circumferential margins did not differ between the groups. The 5‐year local recurrence rates (0%, 4.6%, 5.3% and 5.9% respectively; P = 0.823) and the overall and disease‐free survival were not significantly influenced by BMI.Conclusion  In laparoscopic surgery for rectal cancer, BMI influenced the risk of conversion but not surgical morbidity, quality of surgery and survival. This suggests that all patients, including obese patients, are suitable for laparoscopic surgery.
Medical students' child oral‐health‐related knowledge, practices and attitudes
Authors: AlYousef Y. , Damiano P. , Weber‐Gasparoni K. , Qian F. , Murph J. , Nothwehr F. 
Published: March 2013

AbstractObjectiveThis study evaluated medical interns' oral health knowledge, and other factors influencing their ability and willingness to perform oral‐health‐related practices for high‐caries‐risk children.MethodsA 15‐item survey was emailed to all eligible graduating fifth‐year medical students at King Khalid University Hospital to address these areas of interest. Chi‐square statistics and logistic regression models were used to analyse data.ResultsOne‐hundred and twenty‐one (49%) usable surveys were returned from two mailings. On questions regarding comfort levels when performing oral‐health‐related practices on children under age 3, physicians noted high levels of comfort with all specified oral health practices. Regarding satisfaction of students with medical training, the majority of respondents (87.5%) rated their medical training as fair or poor in preparing them for oral health assessments compared to only 35%, 29% and 7% of respondents giving fair or poor ratings to child abuse identification, caring for special needs patients and primary care paediatric practice, respectively. Additionally, although 90% of respondents noted that the role of primary physicians in counselling/referring children with oral health was important, 60% did not agree with the AAPD and AAP guidelines that state that all children should be referred to a dentist by 12 months of age. Multivariate logistic regression analyses revealed several statistically significant variables that predict the likelihood of performing various oral‐health‐related practices. The choice of public‐health‐oriented future clinical goals, the level of oral health knowledge, how interns rated their oral health training in medical school and the average number of children seen per week, all – to varying degrees – proved important predicator variables for the likelihood of performing them once in practice.ConclusionsMore oral‐health‐related training of medical students seems warranted and could improve their interest in providing oral‐health‐related screening and referrals in practice. Increasing student exposure to child patients and increasing exposures to oral health knowledge and problems could be targeted towards students interested in primary care and public health to use resources most efficiently in the effort to combat the growing caries levels amongst young children in Saudi Arabia.
Long‐term follow‐up study on patients with Miyoshi phenotype of distal muscular dystrophy
Authors: Linssen W. H. J. P. , de Voogt W. G. , Krahn M. , Bernard R. , Levy N. , Wokke J. H. J. , Ginjaar H. B. , de Visser M. 
Published: March 2013

Background and purposeTo describe the long‐term follow‐up of a cohort of 22 patients with the Miyoshi phenotype of distal muscular dystrophy (MMD).MethodsA long‐term clinical follow‐up study was conducted. Patients were genotyped for dysferlin (MMD1) or anoctamin 5 (MMD3) mutations. Patients also underwent cardiological evaluation.ResultsThere were 10 patients with MMD1, eight patients with MMD3 and four patients with linkage to chromosome 10 (MMD2). All patients deteriorated over 5.7 (range: 4.2–6.6) years of follow‐up. Weakness increased significantly (P < 0.035) in all but the neck extensor, serratus anterior, and wrist flexor and extensor muscles. The decrease of strength was most pronounced in the iliopsoas (15%), toe extensors (15%), anterior tibial and peroneal muscles (10%). Patients with MMD1 showed early onset of the disease (mean 22 years) with typically symmetrical distribution of weakness starting in the calf muscles. Patients with MMD1 had a worse clinical course compared with patients with MMD3. Ninety percent of the former had to make use of a wheelchair within 15 years after onset of the disease, whereas patients with MMD3, who have a significantly later onset (mean 35 years) of asymmetrical calf muscle weakness and atrophy, remained ambulant during the first 15 years of their disease. None of the patients with MMD2 became fully confined to the wheelchair. None of the 22 MMD phenotype patients had heart disease.ConclusionsPatients with MMD1 have a worse clinical course compared with patients with MMD3. There are no cardiological abnormalities in all MMD categories.
Prognosis and prognostic factors in non‐traumatic acute‐onset compressive mononeuropathies – radial and peroneal mononeuropathies
Authors: Bsteh G. , Wanschitz J. V. , Gruber H. , Seppi K. , Löscher W. N. 
Published: March 2013

Background and purposeLittle is known about the natural history of non‐traumatic compressive mononeuropathies. To improve patient management, prognostic factors and outcome in patients with non‐traumatic peroneal and radial mononeuropathies were studied.MethodsRetrospective clinical, electrophysiological and sonographic data of patients with non‐traumatic peroneal and radial mononeuropathies were evaluated. Clinical, electrophysiological and sonographic evaluations had to take place 2–12 weeks after symptom onset and follow‐up had to be for >6 months.ResultsTwenty‐five patients with peroneal mononeuropathy and 58 with radial mononeuropathy were included. Mean follow‐up was 8.9 ± 2.4 months. Approximately 90% of patients recovered to a muscle strength of British Medical Research Council grade 4 or 5. Multiple logistic regression analysis revealed conduction block on nerve conduction studies, younger age and less severe initial weakness as indicators for a good prognosis. Peripheral nerve ultrasound was not prognostic in the 40 patients where it was available.ConclusionsThe present study shows a good prognosis for spontaneous recovery after non‐traumatic acute‐onset compressive peroneal and radial mononeuropathies. Patients with denervation on needle electromyography, older age and severe initial weakness have a poorer prognosis and should be closely monitored to facilitate timely surgery whenever weakness persists. Peripheral nerve ultrasound seems to be of limited prognostic value in these mononeuropathies.
Intramodality and intermodality agreement in radiography and computed tomography of equine distal limb fractures
Authors: Crijns C. P. , Martens A. , Bergman H.‐J. , van der Veen H. , Duchateau L. , van Bree H. J. J. , Gielen I. M. V. L. 
Published: March 2013

SummaryReasons for performing studyComputed tomography (CT) is increasingly accessible in equine referral hospitals.ObjectivesTo document the level of agreement within and between radiography and CT in characterising equine distal limb fractures.Study designRetrospective descriptive study.MethodsImages from horses that underwent radiographic and CT evaluation for suspected distal limb fractures were reviewed, including 27 horses and 3 negative controls. Using Cohen's kappa and weighted kappa analysis, the level of agreement among 4 observers for a predefined set of diagnostic characteristics for radiography and CT separately and for the level of agreement between the 2 imaging modalities were documented.Results and conclusionsBoth CT and radiography had very good intramodality agreement in identifying fractures, but intermodality agreement was lower. There was good intermodality and intramodality agreement for anatomical localisation and the identification of fracture displacement. Agreement for articular involvement, fracture comminution and fracture fragment number was towards the lower limit of good agreement. There was poor to fair intermodality agreement regarding fracture orientation, fracture width and coalescing cracks; intramodality agreement was higher for CT than for radiography for these features.Potential relevanceFurther studies, including comparisons with surgical and/or post mortem findings, are required to determine the sensitivity and specificity of CT and radiography in the diagnosis and characterisation of equine distal limb fractures.
Evaluating the performance of banking under risk regulations: a slacks‐based Data Envelopment Analysis assessment framework
Authors: Yang Chih‐Ching 
Published: March 2013

AbstractDespite increasing deregulation and globalization in financial markets worldwide, banking is still one of the most regulated industries in many countries. The contribution of the present article is to introduce a slacks‐based Data Envelopment Analysis assessment framework for assessing bank efficiency and soundness in a risk regulation setting, which is missing from the banking performance literature. Two main sub‐processes within the service flow of a typical bank are considered – the primary banking business for making profit and dealing with the compliance requirements of risk regulations. A Data Envelopment Analysis model is applied to measure the performance of the two sub‐processes, that is, profit‐making efficiency and risk‐controlling efficiency. The research framework and models are applied to an empirical study of the banking sector in Taiwan covering the period 2007 – 2010. We demonstrate how to use the empirical results to monitor the efficiency status for individual banks from 1 year to another, providing an early warning for those with low efficiency. Our empirical results show that there is considerable potential for efficiency improvement in Taiwan's banking industry, and the room for risk‐controlling efficiency improvement is even larger. The two efficiency estimates are positively correlated with each other, and both have been improved year by year. However, an economic recession can lower efficiency estimates.