bluuebunny/crossref_metadata_2025_split huggingface dataset:
Turning up the heat on the provenance debate: Testing the ‘local is best’ paradigm under heatwave conditions
Authors: Hancock Nola , Hughes Lesley 
Published: February 2014

AbstractA key aspect of successful restoration projects is the sourcing of propagation material suited to the environmental and biotic conditions of the proposed planting site. Traditionally, the use of propagules collected locally has been advocated for revegetation on the assumption that this material is better adapted to local conditions. A rapidly changing climate, however, is challenging the assumption that the use of local genetic stock will provide the best restoration outcome in the long term. We tested the ‘local is best’ paradigm using open top chambers to simulate the predicted summer temperatures for 2050 in western Sydney, Australia. We compared the establishment success of Eucalyptus tereticornis and Themeda australis, dominant species in Cumberland Plain Woodland, grown from local versus non‐local seed. All plants survived an exceptional summer heatwave and few differences between temperature treatments were found. No evidence of local superiority was found for survival or growth of non‐reproductive tissues of either species. However, local provenance plants of E. tereticornis suffered significantly greater herbivory in the ambient temperature treatment than one non‐local provenance, and local provenance plants of T. australis demonstrated significant superiority to most non‐local provenances in all categories of reproductive growth. For both species, the provenances from warmer climates demonstrated comparable, and often better, growth performance than the local provenance plants.
Institutional review of patients presenting with suspected appendicitis
Authors: Teo Andrew Teck Kwee , Lefter Liviu Paul , Zarrouk Ali Jafar Mohamad , Merrett Neil Donald 
Published: February 2014

AbstractBackgroundAppendicitis is a common gastrointestinal surgical emergency. Treatment balances the risks of negative appendicectomy (NA) against potential complicated appendicitis in determining clinical priority. This study reviewed the population characteristics, results of the diagnostic modalities and Alvarado score (AlvS) of patients with suspected appendicitis.MethodsA clinical audit of emergency appendicectomies was performed. Generalized linear models with a binomial distribution were used to evaluate the association between the age groups, gender, white cell count (WCC), neutrophil count (NC) and C‐reactive protein (CRP) levels versus NAs and the different types of appendicitis. The utilization and accuracy of preoperative ultrasound and computed tomography (CT) and a preliminary analysis of AlvS were also evaluated.ResultsPatients 17 to 24 years old had significantly higher odds of NA but lower odds of complicated appendicitis compared with patients above 40 years. Adult women and men had significantly higher odds of NA and suppurative appendicitis (SA), respectively. Only adults with SA and acute appendicitis had significantly higher odds of raised WCC, NC and CRP. The sensitivity of CT for adult females was high (100%). Patients who had CT and an AlvS of more than 7 did not have NAs.ConclusionElevated WCC, NC and CRP were all associated with acute appendicitis and SA in adults only. CT is useful for refining the diagnosis in adult females. A combination of inflammatory markers, ultrasound and AlvS may be used selectively to complement or maximize the advantages of CT.
Extracellular calcium regulates keratinocyte proliferation and HPV 16 E6 RNA expression in vitro
Authors: Turunen Aaro , Syrjänen Stina 
Published: February 2014

Human papillomaviruses (HPV) are known to immortalize oral keratinocytes in vitro, but the underlying mechanisms causing the following resistance to differentiation remain unclear. We investigated the effect of extracellular calcium on the proliferation of HPV16‐positive keratinocytes and on the mRNA expression of the viral E6‐oncogene. HPV16‐positive hypopharyngeal carcinoma cells (UD‐SCC‐2), spontaneously immortalized‐ (HMK) and HPV16 E6/E7‐immortalized human gingival keratinocytes (IHGK) were grown for 3, 6 and 9 days in Keratinocyte Serum‐free Medium with calcium concentrations ranging from 0 mM to 6 mM. Calcium concentrations up to 0.09 mM increased cellular proliferation, which decreased at higher concentrations. A shift of calcium concentration from 0 to 4 mM increased E6 expression in UD‐SCC‐2 cells 2.4‐fold by day 9. Simultaneously, E2 expression increased. The most significant upregulation of E6 and E2 expressions was observed at day 9, grown in high‐calcium media and the increase in E6 expression coincided with an increase in involucrin expression, likely indicating cell differentiation. Despite this, HPV‐positive cells continued to proliferate even at high‐calcium media in contrast to HPV‐negative cells. Overexpression of E6 mRNA may be an important feature of HPV16‐positive cells to resist the natural calcium gradient in differentiating keratinocytes allowing cell proliferation.
Dilated intercellular space diameter as marker of reflux‐related mucosal injury in children with chronic cough and gastro‐oesophageal reflux disease
Authors: Borrelli O. , Mancini V. , Thapar N. , Ribolsi M. , Emerenziani S. , de'Angelis G. , Bizzarri B. , Lindley K. J. , Cicala M. 
Published: February 2014

SummaryBackgroundThe diagnostic corroboration of the relationship between gastro‐oesophageal reflux disease (GERD) and chronic cough remains challenging.AimsTo compare oesophageal mucosal intercellular space diameter (ISD) in children with GERD, children with gastro‐oesophageal reflux (GER)‐related cough (GrC) and a control group, and to explore the relationship between baseline impedance levels and dilated ISD in children with GER‐related cough.MethodsForty children with GERD, 15 children with GrC and 12 controls prospectively underwent oesophagogastroduodenoscopy (EGD) with oesophageal biopsies taken 2–3 cm above squamocolumnar junction. ISD were quantified using transmission electron microscopy. Impedance‐pH monitoring with evaluation of baseline impedance in the most distal impedance channel was performed in both patient groups.ResultsA significant difference in mean ISD values was found between GrC patients (0.9 ± 0.2 μm) and controls (0.5 ± 0.2 μm, P < 0.001), whereas there was no difference between GrC and GERD group (1 ± 0.3 μm, NS). No difference was found in the mean ISD between GrC children with or without pathological oesophageal acid exposure time (1 ± 0.3 vs. 0.9 ± 0.2 μm), and there was no correlation between ISD and any reflux parameter. Finally, there was no correlation between ISD and distal baseline impedance values (r:−0.35; NS).ConclusionsIn children with reflux‐related cough, dilated intercellular space diameter appears to be an objective and useful marker of oesophageal mucosal injury regardless of acid exposure, and its evaluation should be considered for those patients where the diagnosis is uncertain. In children with reflux‐related cough, baseline impedance levels have no role in identifying reflux‐induced oesophageal mucosal ultrastructural changes.
Nine scoring models for short‐term mortality in alcoholic hepatitis: cross‐validation in a biopsy‐proven cohort
Authors: Papastergiou V. , Tsochatzis E. A. , Pieri G. , Thalassinos E. , Dhar A. , Bruno S. , Karatapanis S. , Luong T. V. , O'Beirne J. , Patch D. , Thorburn D. , Burroughs A. K. 
Published: February 2014

SummaryBackgroundSeveral prognostic models have emerged in alcoholic hepatitis (AH), but lack of external validation precludes their universal use.AimTo validate the Maddrey Discriminant Function (DF); Glasgow Alcoholic Hepatitis Score (GAHS); Mayo End‐stage Liver Disease (MELD); Age, Bilirubin, INR, Creatinine (ABIC); MELD‐Na, UK End‐stage Liver Disease (UKELD), and three scores of corticosteroid response at 1 week: an Early Change in Bilirubin Levels (ECBL), a 25% fall in bilirubin, and the Lille score.MethodsSeventy‐one consecutive patients with biopsy‐proven AH, admitted between November 2007‐September 2011, were evaluated. The clinical and biochemical parameters were analysed to assess prognostic models with respect to 30‐ and 90‐day mortality.ResultsThere were no significant differences in the areas under the receiver operating characteristics curve (AUROCs) relative to 30‐day/90‐day mortality: MELD 0.79/0.84, DF 0.71/0.74, GAHS 0.75/0.78, ABIC 0.71/0.78, MELD‐Na 0.68/0.76, UKELD 0.56/0.68. One‐week rescoring yielded a trend towards improved predictive accuracies (30‐day/90‐day AUROCs: 0.69–0.84/0.77–0.86). In patients with admission DF ≥32 (n = 31), response to corticosteroids according to ECBL, 25% fall in bilirubin and the Lille model yielded AUROCs of 0.73/0.73, 0.78/0.72 and 0.81/0.82 for a 30‐day/90‐day outcome respectively. All models showed excellent negative predictive values (NPVs; range: 86–100%), while the positive ones were low (range: 17–50%).ConclusionsMELD, DF, GAHS, ABIC and scores of corticosteroid response proved to be valid in an independent cohort of biopsy‐proven alcoholic hepatitis. MELD modifications incorporating sodium did not confer any prognostic advantage over classical MELD. Based on excellent NPVs, the models are best to identify patients at low risk of death.
Antithyroid drug‐related hepatotoxicity in hyperthyroidism patients: a population‐based cohort study
Authors: Wang Meng‐Ting , Lee Wan‐Ju , Huang Tien‐Yu , Chu Che‐Li , Hsieh Chang‐Hsun 
Published: February 2014

AimsThe evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population‐based manner.MethodsWe conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non‐infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively.ResultsThe study cohort comprised 71 379 ATD initiators, with a median follow‐up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person‐years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person‐years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89‐fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08‐fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22).ConclusionsMMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose‐dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis.
Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review
Authors: De Vera Mary A. , Bhole Vidula , Burns Lindsay C. , Lacaille Diane 
Published: February 2014

AimsWhile suboptimal adherence to statin medication has been quantified in real‐world patient settings, a better understanding of its impact is needed, particularly with respect to distinct problems of medication taking. Our aim was to synthesize current evidence on the impacts of statin adherence, discontinuation and persistence on cardiovascular disease and mortality outcomes.MethodsWe conducted a systematic review of peer‐reviewed studies using a mapped search of Medline, Embase and International Pharmaceutical Abstracts databases. Observational studies that met the following criteria were included: defined patient population; statin adherence exposure; defined study outcome [i.e. cardiovascular disease (CVD), mortality]; and reporting of statin‐specific results.ResultsOverall, 28 studies were included, with 19 studies evaluating outcomes associated with statin adherence, six with statin discontinuation and three with statin persistence. Among adherence studies, the proportion of days covered was the most widely used measure, with the majority of studies reporting increased risk of CVD (statistically significant risk estimates ranging from 1.22 to 5.26) and mortality (statistically significant risk estimates ranging from 1.25 to 2.54) among non‐adherent individuals. There was greater methodological variability in discontinuation and persistence studies. However, findings of increased CVD (statistically significant risk estimates ranging from 1.22 to 1.67) and mortality (statistically significant risk estimates ranging from 1.79 to 5.00) among nonpersistent individuals were also consistently reported.ConclusionsObservational studies consistently report an increased risk of adverse outcomes associated with poor statin adherence. These findings have important implications for patients and physicians and emphasize the importance of monitoring and encouraging adherence to statin therapy.
Investigating the molecular mechanisms through which FTY720‐P causes persistent S1P1 receptor internalization
Authors: Sykes David A , Riddy Darren M , Stamp Craig , Bradley Michelle E , McGuiness Neil , Sattikar Afrah , Guerini Danilo , Rodrigues Ines , Glaenzel Albrecht , Dowling Mark R , Mullershausen Florian , Charlton Steven J 
Published: February 2014

Background and PurposeThe molecular mechanism underlying the clinical efficacy of FTY720‐P is thought to involve persistent internalization and enhanced degradation of the S1P1 receptor subtype (S1P1R). We have investigated whether receptor binding kinetics and β‐arrestin recruitment could play a role in the persistent internalization of the S1P1R by FTY720‐P.Experimental Approach[3H]‐FTY720‐P and [33P]‐S1P were used to label CHO‐S1P1/3Rs for binding studies. Ligand efficacy was assessed through [35S]‐GTPγS binding and β‐arrestin recruitment. Metabolic stability was evaluated using a bioassay measuring intracellular Ca2+ release. CHO‐S1P1/3R numbers were determined, following FTY720‐P treatment using flow cytometry.Key ResultsThe kinetic off‐rate of [3H]‐FTY720‐P from the S1P1R was sixfold slower than from the S1P3R, and comparable to [33P]‐S1P dissociation from S1P1/3Rs. S1P and FTY720‐P stimulated [35S]‐GTPγS incorporation to similar degrees, but FTY720‐P was over 30‐fold less potent at S1P3Rs. FTY720‐P stimulated a higher level of β‐arrestin recruitment at S1P1Rs, 132% of the total recruited by S1P. In contrast, FTY720‐P was a weak partial agonist at S1P3R, stimulating just 29% of the total β‐arrestin recruited by S1P. Internalization experiments confirmed that cell surface expression of the S1P1R but not the S1P3R was reduced following a pulse exposure to FTY720‐P, which is metabolically stable unlike S1P.Conclusions and ImplicationsFTY720‐P and S1P activation of the S1P1R results in receptor internalization as a consequence of an efficient recruitment of β‐arrestin. The combination of slow off‐rate, efficacious β‐arrestin recruitment and metabolic stability all contribute to FTY720‐P's ability to promote prolonged S1P1R internalization and may be critical factors in its efficacy in the clinic.
Signalling profiles of H3 relaxin, H2 relaxin and R3(BΔ23–27)R/I5 acting at the relaxin family peptide receptor 3 (RXFP3)
Authors: Kocan M , Sarwar M , Hossain M A , Wade J D , Summers R J 
Published: February 2014

Background and PurposeRelaxin family peptide receptor 3 (RXFP3) is expressed in brain areas important for processing sensory information and feeding, suggesting that it may be a target for anti‐anxiety and anti‐obesity drugs. We examined the effects of H3 relaxin, the biased agonist H2 relaxin and the antagonist, R3(BΔ23–27)R/I5, on RXFP3 signalling to establish their suitability as tools to assess the physiological roles of RXFP3.Experimental ApproachThe signalling profile of the RXFP3 ligands was determined using reporter gene assays, multiplexed signalling assays and direct examination of receptor–G protein and receptor–β‐arrestin interactions using BRET.Key ResultsH2 relaxin activated p38MAPK and ERK1/2 with lower efficacy than H3 relaxin, but had similar efficacy for JNK1/2 phosphorylation. H2 or H3 relaxin activation of p38MAPK, JNK1/2 or ERK1/2 involved Pertussis toxin‐sensitive G‐proteins. R3(BΔ23–27)R/I5 blocked H3 relaxin AP‐1 reporter gene activation, but not H2 relaxin AP‐1 activation or H3 relaxin NF‐κB activation. R3(BΔ23–27)R/I5 activated the SRE reporter, but did not inhibit either H2 or H3 relaxin SRE activation. R3(BΔ23–27)R/I5 blocked H3 relaxin‐stimulated p38MAPK and ERK1/2 phosphorylation, but was a weak partial agonist for p38MAPK and ERK1/2 signalling. p38MAPK activation by R3(BΔ23–27)R/I5 was G protein‐independent. H3 relaxin‐activated RXFP3 interacts with Gαi2, Gαi3, GαoA and GαoB whereas H2 relaxin or R3(BΔ23–27)R/I5 induce interactions only with Gαi2 or GαoB. Only H3 relaxin promoted RXFP3/β‐arrestin interactions that were blocked by R3(BΔ23–27)R/I5.Conclusion and ImplicationsUnderstanding signalling profile of drugs acting at RXFP3 is essential for development of therapies targeting this receptor.
GSK‐3β inhibition promotes early engraftment of ex vivo‐expanded haematopoietic stem cells
Authors: Dolnikov A. , Xu N. , Shen S. , Song E. , Holmes T. , Klamer G. , O'Brien T. A. 
Published: February 2014

AbstractObjectivesUmbilical cord blood (UCB) is a source of stem cells used for allogeneic transplantation, in addition to bone marrow and peripheral blood. Limited numbers of stem cells in a single UCB unit is associated with slow haematopoietic recovery and high risk of graft failure, particularly in adult patients. UCB stem cells can be expanded ex vivo; however, rapid differentiation reduces their regenerative potential. We have recently shown that Wnt/β‐catenin signalling is down‐regulated in ex vivo‐expanded stem cells; therefore, we propose that re‐activation of Wnt signalling using GSK‐3β inhibition may act to improve regenerative potential of these ex vivo‐expanded stem cells.Materials and methodsImmunocompromised mice were employed in transplantation studies to determine stem‐cell engraftment. Flow cytometry was used to phenotype the engrafted human cells. Retroviral gene transfer was used to examine the role of Myc gene up‐regulated by GSK‐3β inhibition, in ex vivo‐expanded stem cells.ResultsTreatment with GSK‐3β inhibitor, 6‐bromoindirubin 3′‐oxime (BIO) improved early human cell engraftment in the mice and elevated the numbers of myeloid progenitor cells in cytokine‐stimulated culture. BIO up‐regulated β‐catenin and c‐myc in ex vivo‐expanded stem cells. Ectopic expression of Myc acted to increase clonogenic potential and to delay differentiation of haematopoietic progenitor cells, suggesting the potential mechanism to improve regenerative potential of ex vivo‐expanded grafts.ConclusionsPharmacological inhibition of GSK‐3β provided a novel approach to improve early engraftment of ex vivo‐expanded haematopoietic progenitor cells.
Cutaneous lymphatic malformation characterized by swelling of digits: a report of six cases
Authors: Wang Lei , Gao Tianwen , Wang Gang 
Published: February 2014

BackgroundCutaneous lymphatic malformations represent a group of heterogeneous diseases. In clinical practice, some cases of cutaneous lymphatic malformation have been found to differ from the well‐characterized entities, and are difficult to classify.ObjectiveTo report the clinical, histopathological and immunohistochemical characteristics of six cases of lymphatic malformation characterized by swelling of the digits.MethodsSix patients with swelling of the digits were included in this study. Histopathological examination and immunohistochemical staining of CD31, D2‐40, Prox1, Wilms tumor 1 (WT‐1) and human herpesvirus‐8 (HHV‐8) were performed for all cases.ResultsAll cases were congenital lesions and presented as swelling of single or multiple digits. Histopathologically, the lesions showed proliferation of small‐to‐medium‐sized vessels in the dermis and subcutaneous tissue. These abnormal vessels were positive for CD31, D2‐40 and Prox1, and negative for WT‐1 and HHV‐8.ConclusionThe six cases reported herein represent a specific cutaneous lymphatic malformation different from previously reported entities.
Role of selective peroxisome proliferator‐activated receptor modulators in managing cardiometabolic disease: tale of a roller‐coaster
Authors: Sahebkar A. , Watts G. F. 
Published: February 2014

AbstractAtherogenic dyslipidaemia is a hypertriglyceridaemic phenotype, associated with increased plasma concentrations of small, dense low‐density lipoprotein (sdLDL) particles, triglyceride‐rich lipoproteins (TRLs) and non‐high‐density lipoprotein cholesterol (non‐HDL‐C), and low HDL particles. Atherogenic dyslipidaemia commonly accompanies several metabolic disorders including type 2 diabetes, metabolic syndrome, non‐alcoholic fatty liver disease (NAFLD) and obesity, and increases the risk of cardiovascular disease (CVD). Statins significantly lower plasma LDL‐cholesterol and CVD risk, but their efficacy in correcting hypertriglyceridaemia is limited. Untreated hypertriglyceridaemia may partly account for residual risk of CVD in patients on statin treatment. Activators of peroxisome proliferator‐activated receptor (PPAR) α are more effective in correcting TRL and HDL metabolism than statins. A dual PPARα/δ agonist (GFT‐505) may have additional benefits on hepatic insulin sensitivity, steatosis and fibrosis. Selective PPAR modulators (SPPARMs) have the potential of increasing therapeutic specificity, while reducing unwanted off‐target effects. This review provides a summary of findings from randomized controlled trials of the efficacy of fenofibrate (as the most widely used PPARα agonist) and novel selective PPARα (ABT‐335 and k‐877), PPARα/δ (GFT‐505), PPARδ (MBX‐8025 and GW501516) and PPARγ (INT131) agonists in the treatment of atherogenic dyslipidaemia and NAFLD.