bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of dapagliflozin vs vildagliptin on cardiometabolic parameters in diabetic patients with coronary artery disease: a randomised study
Authors: Phrommintikul Arintaya , Wongcharoen Wanwarang , Kumfu Sirinart , Jaiwongkam Thidarat , Gunaparn Siriluck , Chattipakorn Siriporn , Chattipakorn Nipon 
Published: February 2019

AimsSodium glucose co‐transporter‐2 inhibitors have been shown to reduce cardiovascular events and heart failure in type 2 diabetic (T2D) patients with high cardiovascular risk. Dipeptidyl peptidase‐4 inhibitors showed neutral effects and may increase risk of heart failure. We aimed to compare cardiometabolic effects of dapagliflozin and vildagliptin in T2D patients with coronary artery disease (CAD).MethodsForty‐nine T2D patients with CAD were randomly assigned to dapagliflozin (n = 25) or vildagliptin (n = 24) for 6 months in a double‐blind fashion. Cardiometabolic parameters were collected at baseline and at the end of treatments.ResultsMean age was 63.2 ± 7.9 years (female 46.9%). Baseline characteristics did not differ between two groups. At 6 months, HbA1C significantly decreased in both dapaglifozin and vildagliptin groups (0.6 ± 1.0% vs 0.8 ± 1.4%, P = 0.22, respectively). There was no difference between the changes in lipid profiles. Body mass index decreased in patients receiving dapagliflozin, whereas it increased in those receiving vildagliptin (−1.27 [95% confidence interval −2.01, −0.53] vs 1.72 [0.72, 2.72] kg, P < 0.001). The reduction in systolic blood pressure and high‐sensitivity troponin T was observed in the dapagliflozin group (−9.87 [−18.00, −1.15] mmHg and 2.49 [−4.50, −0.47] pg/mL) but not in vildagliptin group (−1.97 [−9.42, 5.48] mmHg and 1.98 [−0.02, 3.97] pg/mL). The mean haemoglobin increased in the dapagliflozin group, whereas the mean platelet volume increased in the vildagliptin group. There was no significant change in the inflammatory markers in both the groups.ConclusionsThe extraglycaemic effects of dapagliflozin and vildagliptin on cardiometabolic parameters in T2D with CAD were different. The more favourable effects of dapagliflozin compared to vildagliptin may have explained the cardiovascular benefits observed only in sodium glucose co‐transporter‐2 inhibitors.
Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10‐year pharmacovigilance analysis
Authors: Socié Gérard , Caby‐Tosi Marie‐Pierre , Marantz Jing L. , Cole Alexander , Bedrosian Camille L. , Gasteyger Christoph , Mujeebuddin Arshad , Hillmen Peter , Vande Walle Johan , Haller Hermann 
Published: February 2019

SummaryEculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based on long‐term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient‐years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy‐six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit‐risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab.
Sex differences in mechanisms of arterial stiffness
Authors: DuPont Jennifer J. , Kenney Rachel M. , Patel Ayan R. , Jaffe Iris Z. 
Published: February 2019

Arterial stiffness progressively increases with aging and is an independent predictor of cardiovascular disease (CVD) risk. Evidence supports that there are sex differences in the time course of aging‐related arterial stiffness and the associated CVD risk, which increases disproportionately in postmenopausal women. The association between arterial stiffness and mortality is almost twofold higher in women versus men. The differential clinical characteristics of the development of arterial stiffness between men and women indicate the involvement of sex‐specific mechanisms. This review summarizes the current literature on sex differences in vascular stiffness induced by aging, obesity, hypertension, and sex‐specific risk factors as well as the impact of hormonal status, diet, and exercise on vascular stiffness in males and females. An understanding of the mechanisms driving sex differences in vascular stiffness has the potential to identify novel sex‐specific therapies to lessen CVD risk, the leading cause of death in males and females.LINKED ARTICLESThis article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc
Modafinil protects hippocampal neurons by suppressing excessive autophagy and apoptosis in mice with sleep deprivation
Authors: Cao Yin , Li Qinglin , Liu Lulu , Wu Hui , Huang Fei , Wang Changhong , Lan Yunyi , Zheng Fang , Xing Faping , Zhou Qiang , Li Qi , Shi Hailian , Zhang Beibei , Wang Zhengtao , Wu Xiaojun 
Published: February 2019

Background and PurposeSleep deprivation compromises learning and memory in both humans and animals, and can be reversed by administration of modafinil, a drug promoting wakefulness. Dysfunctional autophagy increases activation of apoptotic cascades, ultimately leading to increased neuronal death, which can be alleviated by autophagy inhibitors. This study aimed to investigate the alleviative effect and mechanism of modafinil on the excessive autophagy occurring in the hippocampus of mice with deficiency of learning and memory induced by sleep deprivation.Experimental ApproachThe Morris water maze was used to assess the effects of modafinil on male C57BL/6Slac mice after 48‐hr sleep deprivation. The HT‐22 hippocampal neuronal cell line was also used. Nissl staining, transmission electron microscope, immunofluorescence, Western blot, transient transfection, and autophagy inducer were used to study the effect and mechanism of modafinil on hippocampal neurons with excessive autophagy and apoptosis.Key ResultsModafinil improved learning and memory in sleep‐deprived mice, associated with the inhibition of excessive autophage and apoptosis and an enhanced activation of the PI3K/Akt/mTOR/P70S6K signalling pathway in hippocampal neurons. These effects of modafinil were abolished by rapamycin. In addition, modafinil suppressed the aberrant autophagy and apoptosis induced by rapamycin and reactivated PI3K/Akt/mTOR/P70S6K signals in HT‐22 cells.Conclusions and ImplicationsThese results suggested that modafinil alleviated impaired learning and memory of sleep‐deprived mice potentially by suppressing excessive autophagy and apoptosis of hippocampal neurons. This novel mechanism may add to our knowledge of modafinil in the clinical treatment of impaired memory caused by sleep loss.
The role of neutrophil activation in determining the outcome of pregnancy and modulation by hormones and/or cytokines
Authors: Hahn S , Hasler P , Vokalova L , van Breda S V , Lapaire O , Than N G , Hoesli I , Rossi S W 
Published: February 2019

Summary
Neutrophils are often exclusively considered as a first-line innate immune defence, able to rapidly kill or trap pathogens and causing in case of over-activation tissue damage. In the female reproductive tract, however, the presence and activity of neutrophils seems to be tightly regulated. Major players in orchestrating this regulation are cyclical steroid sex hormones present during the menstrual cycle and pregnancy. This review describes the role of sex hormones in regulating directly or indirectly the functionality of neutrophils, the role of neutrophils during fertilization and pregnancy and in controlling viral, fungal and bacterial infection. This review also discusses the consequence of overt neutrophil activation in pregnancy pathologies.
Neuroimmunology – the past, present and future
Authors: Nutma E , Willison H , Martino G , Amor S 
Published: February 2019

SummaryNeuroimmunology as a separate discipline has its roots in the fields of neurology, neuroscience and immunology. Early studies of the brain by Golgi and Cajal, the detailed clinical and neuropathology studies of Charcot and Thompson’s seminal paper on graft acceptance in the central nervous system, kindled a now rapidly expanding research area, with the aim of understanding pathological mechanisms of inflammatory components of neurological disorders. While neuroimmunologists originally focused on classical neuroinflammatory disorders, such as multiple sclerosis and infections, there is strong evidence to suggest that the immune response contributes to genetic white matter disorders, epilepsy, neurodegenerative diseases, neuropsychiatric disorders, peripheral nervous system and neuro-oncological conditions, as well as ageing. Technological advances have greatly aided our knowledge of how the immune system influences the nervous system during development and ageing, and how such responses contribute to disease as well as regeneration and repair. Here, we highlight historical aspects and milestones in the field of neuroimmunology and discuss the paradigm shifts that have helped provide novel insights into disease mechanisms. We propose future perspectives including molecular biological studies and experimental models that may have the potential to push many areas of neuroimmunology. Such an understanding of neuroimmunology will open up new avenues for therapeutic approaches to manipulate neuroinflammation.
Immediately restored single implants in the aesthetic zone of the maxilla using a novel design: 5‐year results from a prospective single‐arm clinical trial
Authors: Ma Sunyoung , Tawse‐Smith Andrew , Brown Simon D.K. , Duncan Warwick 
Published: February 2019

AbstractBackgroundSingle implant crowns have become the preferred rehabilitation treatment option for replacing a missing tooth.PurposeThis study evaluates 5‐year clinical success of using tilted implants placed immediately after extraction followed by rehabilitation with all‐ceramic crowns.Materials and MethodsTwenty‐seven participants requiring 28 single implant crowns in the aesthetic zone of maxilla were recruited to participate in a single‐arm clinical trial. All participants were rehabilitated according to immediate implant placement using CP grade 4 titanium implants with roughened surfaces and a 12°‐angled platform. Provisional implant crowns were connected within 4 hours of implant placement and loaded according to progressive loading protocol. At 8 weeks (baseline), definitive screw‐retained crowns fabricated using densely sintered zirconia abutments with the veneering porcelain were delivered. Participants were followed up to 5 years and 16 participants with 17 single implant crowns attended Year 5 recall. Data collection included changes in marginal bone levels (MBLs), mid‐buccal mucosal levels (MBMLs), implant stability quotient (ISQ) values, and any prosthodontic maintenance issues.ResultsThe mean changes in MBLs at each recall was bone fill of 0.5 ± 1.18 mm (surgery—baseline), increase of 0.1 ± 0.57 mm (baseline—Year 1), and marginal bone loss of 0.1 ± 0.25 mm (Years 1‐5). A minimal change occurred with the MBMLs during the observation period. The mean ISQ value at each time point increased from 65.1 (implant placement), to 67.4 (baseline) and 69.9 (Years 1 and 5). Prosthodontic maintenance issues occurred only during the first year which included fracture of veneering ceramic and zirconia abutment as well as aesthetic concerns.ConclusionsWithin the limitations of this study, the data collected would suggest that replacing a single missing tooth using titanium oral implants with 12° platform tilt and zirconia abutments can be a successful rehabilitation option in the esthetically demanding zone of anterior maxilla.
Inflammatory cells infiltrate and angiogenesis in locally advanced and metastatic cholangiocarcinoma
Authors: Tamma Roberto , Annese Tiziana , Ruggieri Simona , Brunetti Oronzo , Longo Vito , Cascardi Eliano , Mastropasqua Mauro Giuseppe , Maiorano Eugenio , Silvestris Nicola , Ribatti Domenico 
Published: February 2019

AbstractBackgroundCholangiocarcinoma (CCA) is the second most common subtype of primary hepatobiliary cancer and one of the most aggressive characterized by an extremely poor prognosis with limited treatment options. Inflammatory cells in tumour microenvironment support tumour growth in term of progression, angiogenesis and metastatic capacity. A link between inflammation and biliary carcinogenesis has been previously observed but the mechanisms involved remain to be determined.MethodsWe investigated the microvascular density (MVD) and inflammatory cells in tissue samples from 40 patients with CCA with locally advanced CCA and metastatic CCA by means of immunohistochemical analysis of macrophages, mast cells, B and T lymphocytes and we correlated inflammatory infiltrate with MVD.ResultsWe observed significant decrease in the levels of CD31 positive vessels, and CD8, CD4, CD68 and tryptase‐positive cells in metastatic lesions as compared to the localized ones. A negative correlation between CD31 and CD8 and CD31 and CD4 in localized CCA samples was found as assessed by Spearman correlation analysis.ConclusionsIn locally advanced CCA patients, there is a significant increase of immune cell infiltrate constituted by CD8+ and CD4+ lymphocytes, macrophages and mast cells as compared to the metastatic ones. This alteration in the tumour microenvironment infiltrate is related to a significant increased MVD in localized CCA lesions compared with the metastatic ones. Moreover, we observed a negative correlation between MVD and CD8+, CD4+ cells in localized CCA patients.
Serum osteopontin negatively impacts on intima‐media thickness in patients with systemic lupus erythematosus
Authors: Carbone Federico , Dallegri Franco , Montecucco Fabrizio , Poggi Alessandro , Nobili Flavio Mariano , Cacciapaglia Fabio , Afeltra Antonella , Moccetti Tiziano , Colombo Barbara M. 
Published: February 2019

AbstractBackgroundUltrasound evaluation of carotid intima‐media thickness (cIMT) has been extensively used for potentially improving cardiovascular (CV) risk stratification in several patients’ categories. Subjects with systemic lupus erythematosus (SLE) have been investigated by both imaging and molecular biomarker approaches with contrasting results. Here, we focused on the role of osteopontin (OPN) as biomarker of subclinical atherosclerosis associated with SLE.Materials and MethodsEighty females (age 18‐65 years) affected by SLE and eighty age‐matched healthy female controls without a clinical history of CV disease underwent ultrasound evaluation of cIMT and blood sample assay of high‐sensitivity C‐reactive protein (hs‐CRP) and OPN.ResultsHealthy controls and SLE patients significantly differed for CV risk factors (ie, waist circumference, hypertension and dyslipidaemia) and the inflammatory status. Noteworthy, an opposite association between cIMT and OPN was observed in the two study groups. Whereas OPN was positively associated with mean cIMT (r = 0.364; P = 0.001) in SLE patients, a negative correlation was found in healthy controls. Furthermore, in SLE patients increased circulating levels of OPN were associated with the use of hydroxychloroquine and the positivity for the anti‐dsDNA autoantibodies. At linear regression analysis, only OPN remained independently associated with cIMT also after adjustment for age, smoking pack‐year, Heart SCORE, disease length and steroid therapy length.ConclusionsThese results indicate that serum OPN levels were strongly associated with subclinical atherosclerosis in patients with LES and it might be a useful CV biomarker that requires additional validation in larger trials.
Crystal structures of human 17β‐hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP+ reveal the mechanism of substrate inhibition
Authors: Li Tang , Stephen Preyesh , Zhu Dao‐Wei , Shi Rong , Lin Sheng‐Xiang 
Published: February 2019

Human 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1) catalyses the last step in estrogen activation and is thus involved in estrogen‐dependent diseases (EDDs). Unlike other 17β‐HSD members, 17β‐HSD1 undergoes a significant substrate‐induced inhibition that we have previously reported. Here we solved the binary and ternary crystal structures of 17β‐HSD1 in complex with estrone (E1) and cofactor analog NADP+, demonstrating critical enzyme‐substrate‐cofactor interactions. These complexes revealed a reversely bound E1 in 17β‐HSD1 that provides the basis of the substrate inhibition, never demonstrated in estradiol complexes. Structural analysis showed that His221 is the key residue responsible for the reorganization and stabilization of the reversely bound E1, leading to the formation of a dead‐end complex, which exists widely in NADP(H)‐preferred enzymes for the regulation of their enzymatic activity. Further, a new inhibitor is proposed that may inhibit 17β‐HSD1 through the formation of a dead‐end complex. This finding indicates a simple mechanism of enzyme regulation in the physiological background and introduces a pioneer inhibitor of 17β‐HSD1 based on the dead‐end inhibition model for efficiently targeting EDDs.DatabasesCoordinates and structure factors of 17β‐HSD1‐E1 and 17β‐HSD1‐E1‐NADP+ have been deposited in the Protein Data Bank with accession code 6MNC and 6MNE respectively.Enzymes17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1) EC 1.1.1.62.
Concept of stress dead zone in cracked plates: Theoretical, experimental, and computational studies
Authors: Farahani Behzad V. , Eslami Shayan , de Melo Francisco Q. , Tavares Paulo J. , Moreira Pedro M.G.P. 
Published: February 2019

AbstractThis paper presents a study on stress dead zone implications and its characterization with uniaxial tensile testing on MT polycarbonate plate specimens. To obtain the experimental solution, digital image correlation (DIC) is used. Numerically, based on LEFM, the problem is solved using advanced discretization techniques, finite element, and meshless methods. Considering stress dead zone notion, it aims to determine alternative analytical solution of the SIF. Thus, the compliance method is adopted, which is associated with the specimen's dead zone region that does not involve the cracking resistance. Hence, LEFM formulations complying with strain energy release rate criterion are assumed. A proper comparison is made amongst results obtained from all theoretical, experimental, and numerical analyses. Furthermore, this work focuses on the variational fields' evaluation and, in particular, verification on the theoretical assumption of dead zone characteristics. The obtained results support adopted methodologies and are encouragingly robust and cost‐effective.
Pricing strategies for dual‐channel supply chains under a trade credit policy
Authors: Qin Juanjuan , Ren Liguo , Xia Liangjie , Wang Ziping , Chang Haodong 
Published: February 2019

AbstractThis paper discusses the impact of a trade credit policy on alleviating conflicts arising on a dual‐channel supply chain that includes one manufacturer and one value‐added retailer. We use the Stackelberg game to model the problem and characterize optimal pricing strategies for each supply chain partner, examining different circumstances in terms of retail price and trade credit contracts. When a consistent price strategy is applied in the dual channels under conditions of an exogenous credit period, trade credit can help both partners to achieve win‐win situations in the following circumstances: (1) when the retail channel's market share is small and the retailer's interest rate is high; or (2) when the retail channel's market share is large and the retailer's interest rate is lower than the manufacturer's. The study also concludes that when an inconsistent price strategy is applied, a trade credit contract can alleviate channel conflicts when the retailer's interest rate is higher than the manufacturer's. Otherwise, the partners may terminate cooperation. However, when the manufacturer has the power to determine and set the credit period, trade credit cannot alleviate channel conflicts under consistent price and inconsistent price scenarios.
A cash transportation vehicle routing problem with combinations of different cash denominations
Authors: Xu Guoxun , Li Yanfeng , Szeto W. Y. , Li Jun 
Published: February 2019

AbstractThis paper investigates a new cash transportation problem, which is a variant of the capacitated vehicle routing problem. To better satisfy the demands of customers (e.g., banks, large retailers, shopping centers, automated teller machines, etc.), the combination of different cash denominations (i.e., $100, $50, $20, etc.) is considered. The robbery risk, which is measured by both the amount of cash being carried and the distance covered by the vehicle carrying the cash, is limited by a risk threshold. The problem is formulated as mixed‐integer linear programming to minimize the total cost, which consists of the total travel cost and the total penalties due to the unmet expected demand of customers. A combined hybrid tabu search metaheuristic is proposed to solve this problem. Tabu search is adopted for determining routing decisions while three methods, namely the exact method, the greedy method, and the mixed method, are proposed to be embedded within the tabu search to determine the denomination combination strategy. The numerical studies show that the proposed method makes a good tradeoff between the solution quality and the computation time. Experimental results also reveal the effects of the unit penalty and the risk threshold.
Cation deficiency associated with the chemical exfoliation of lithium cobalt oxide
Authors: Pachuta Kevin G. , Pentzer Emily B. , Sehirlioglu Alp 
Published: February 2019

AbstractCompositional changes associated with the chemical exfoliation of lithium cobalt oxide, a layered transition metal oxide, are discussed. Starting from a layered bulk structure, lithium cobalt oxide can undergo chemical exfoliation through a two‐step method: treatment with a protic acid, then treatment with tetramethylammonium hydroxide (this intercalates the layered structure and yields exfoliated nanosheets). This work provides an in‐depth analysis of compositional and structural changes occurring to the powder upon the first step to exfoliation, treatment with acid, revealing variations in vacancies and valence changes depending on the conditions used. Through coupled analysis of X‐ray photoelectron spectroscopy, X‐ray diffraction, UV‐Vis absorption spectroscopy, and inductively coupled plasma‐optical emission spectroscopy data, we illustrate that both lithium and cobalt ions are diffusing out the structure along with the dissolution of full unit cells. As such, nanosheets accessed from the bulk by this exfoliation process should not be considered simply as divisions of the original unit cell. This work provides fundamental insights on the stability of LiCoO2 and the exfoliation of layered transition metal oxides, beyond the access of individual nanosheets, and is vital to determining structure‐property relationships of chemically exfoliated nanosheets (eg, changes in valency which dictate catalytic activity, magnetic susceptibility, etc).