bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxia enhances tenocyte differentiation of adipose‐derived mesenchymal stem cells by inducing hypoxia‐inducible factor‐1α in a co‐culture system
Authors: Yu Yang , Zhou Yulong , Cheng Tao , Lu Xiaolang , Yu Kehe , Zhou Yifei , Hong Jianjun , Chen Ying 
Published: March 2016

AbstractObjectivesTissue engineering is a promising approach for repair of tendon injuries. Adipose‐derived mesenchymal stem cells (ADMSCs) have gained increasing research interest for their potential in improving healing and regeneration of injured tendons. The present study aimed to investigate effects of O2 tension and potential signalling pathways on AMDSC differentiation into tenocytes, in an indirect co‐culture system.Materials and methodsHuman ADMSCs were co‐cultured under normoxia (20% O2) and also under hypoxia (2% O2). Tenocyte differentiation of AMDSCs and expression of hypoxia‐inducible factor‐1 (HIF‐1α) were analysed by reverse transcription‐PCR, Western blotting and immunohistochemistry. Furthermore, HIF‐1α inhibitor and inducer (FG‐4592) effects on differentiation of AMDSCs were studied using qPCR, immunofluorescence and Western blotting.ResultsIndirect co‐culture with tenocytes increased differentiation of ADMSCs into tenocytes; furthermore, hypoxia further enhanced tenocyte differentiation of AMDSCs, accompanied by increased expression of HIF‐1α. HIF‐1α inhibitor attenuated effects of hypoxia on differentiation of ADMSCs; in contrast, FG‐4592 increased differentiation of ADMSCs under both hypoxia and normoxia.ConclusionsTaken together, we found that growing ADMSCs under hypoxia, or activating expression of HIF‐1α to be important in differentiation of ADMSCs, which provides a foundation for application of ADMSCs in vivo for tendon regeneration.
Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy
Authors: Ikarashi Yuichi , Kogiso Tomomi , Hashimoto Etsuko , Yamamoto Kuniko , Kodama Kazuhisa , Taniai Makiko , Torii Nobuyuki , Takaike Hiroko , Uchigata Yasuko , Tokushige Katsutoshi 
Published: March 2016

Poorly controlled diabetes mellitus (DM) patients sometimes show serum transaminase elevations due to steatohepatitis. However, we experienced four cases with type 1 DM with sharp elevations in serum transaminases that could not be explained by steatohepatitis alone and showed bright liver. They were diagnosed with glycogenic hepatopathy (GH) clinicopathologically. The four patients had a median age of 22.5 years (range, 19–29 years) and 12.5 (4–15)‐year histories of type 1 DM and showed marked increases in serum transaminases (aspartate aminotransferase, 698 U/L [469–2763 U/L]; alanine transaminase, 255 U/L [216–956 U/L]). Diabetes mellitus control was poor and hemoglobin A1c was 12.7% (11–16.5%). Three cases had a past history of diabetic ketoacidosis. Hepatomegaly and hyperdense liver were seen on computed tomography scans. Magnetic resonance imaging showed low intensity in T2‐weighted images. The pathological findings revealed pale and swollen hepatocytes and glycogenated nuclei. The architecture of the liver was preserved, and steatosis and fibrosis were mild. The cytoplasm of hepatocytes stained densely positive with periodic acid–Schiff, and the positive staining disappeared after diastase digestion, suggesting glycogen deposition. No other cause of hepatitis was evident, and the diagnosis was GH. Elevated transaminases improved within 1 month with good glycemic control. Transaminase elevations were observed several times in three cases with poor glycemic control. Glycogenic hepatopathy is rare, but extremely high serum elevations of transaminases are important to identify clinically. Despite showing a good clinical course in general, GH sometimes recurs and requires strict glycemic control. Clinicians should be aware of and recognize GH when dealing with uncontrolled DM patients.
Galectin‐7 in the stratum corneum: a biomarker of the skin barrier function
Authors: Niiyama S. , Yoshino T. , Yasuda C. , Yu X. , Izumi R. , Ishiwatari S. , Matsukuma S. , Mukai H. 
Published: March 2016

AbstractObjectiveSkin barrier disruption often occurs in diseased and damaged skin conditions such as atopic dermatitis (AD). We focused the galectin‐7 protein (Gal‐7) as a biomarker of skin condition and assessed whether the content of Gal‐7 in stratum corneum (scGal‐7) could be used as an indicator of skin barrier disruption and as an index of local skin symptoms in AD patients.MethodsAlteration of Gal‐7 expression levels in keratinocyte and scGal‐7 contents after barrier disruption by sodium dodecyl sulphate were evaluated in vitro and in vivo, respectively. Correlation between scGal‐7 content and transepidermal water loss (TEWL) was examined in 126 healthy subjects. We performed single measurements of scGal‐7 contents in 34 AD patients and serial measurements of 15 inpatients among them. SC samples were collected by the tape‐stripping method, and scGal‐7 content was determined using enzyme‐linked immunosorbent assay.ResultsGal‐7 expression in keratinocytes increased after barrier disruption. The scGal‐7 content reflected the disruption of the skin barrier. The scGal‐7 contents and TEWL values correlated in healthy subjects. The scGal‐7 level was higher in AD patients than in healthy subjects. The scGal‐7 contents in the cheek and neck of AD patients significantly correlated with the total and local skin lesion severity scores. Serial measurements in the inpatients showed that the scGal‐7 contents in the cheek and neck decreased in tandem with local severity scores in response to treatment.ConclusionMeasurement of scGal‐7 content in tape‐stripped samples was useful for the evaluation of the skin barrier function in dry skin conditions such as AD.
Pharmacokinetic and pharmacodynamic evaluation of linagliptin for the treatment of type 2 diabetes mellitus, with consideration of Asian patient populations
Authors: Ceriello Antonio , Inagaki Nobuya 
Published: March 2016

AbstractOur aims were to summarize the clinical pharmacokinetics and pharmacodynamics of the dipeptidyl‐peptidase‐4 inhibitor, linagliptin, and to consider how these characteristics influence its clinical utility. Differences between linagliptin and other dipeptidyl‐peptidase‐4 inhibitors were also considered, in addition to the influence of Asian race on the pharmacology of linagliptin. Linagliptin has a xanthine‐based structure, a difference that might account for some of the pharmacological differences observed with linagliptin versus other dipeptidyl‐peptidase‐4 inhibitors. The long terminal half‐life of linagliptin results from its strong binding to dipeptidyl‐peptidase‐4. Despite this, linagliptin shows a short accumulation half‐life, as a result of saturable, high‐affinity binding to dipeptidyl‐peptidase‐4. The pharmacokinetic characteristics of linagliptin make it suitable for once‐daily dosing in a broad range of patients with type 2 diabetes mellitus. Unlike most other dipeptidyl‐peptidase‐4 inhibitors, linagliptin has a largely non‐renal excretion route, and dose adjustment is not required in patients with renal impairment. Furthermore, linagliptin exposure is not substantially altered in patients with hepatic impairment, and dose adjustment is not necessary for these patients. The 5‐mg dose is also suitable for patients of Asian ethnicity. Linagliptin shows unique pharmacological features within the dipeptidyl‐peptidase‐4 inhibitor class. Although most clinical trials of linagliptin have involved largely Caucasian populations, data on the pharmacokinetic/pharmacodynamic properties of linagliptin show that these features are not substantially altered in Asian populations. The 5‐mg dose of linagliptin is suitable for patients with type 2 diabetes mellitus irrespective of their ethnicity or the presence of renal or hepatic impairment.
Multitargeted combination effects of a triherbal formulation containing ELP against osteoporosis: in vitro evidence
Authors: Ko Chun Hay , Lau Kit Man , Chau Lily , Cheung David Wing Shing , Siu Wing Sum , Wong Hing Lok , Shum Wai Ting , Gao Si , Fung Kwok Pui , Leung Ping Chung , Poon Simon Kar-Sing , Lau Clara Bik San 
Published: March 2016

Abstract

Objectives
An anti-osteoporotic herbal formula ELP containing Epimedii Herba (E), Ligustri Lucidi Fructus (L) and Psoraleae Fructus (P) was studied to investigate the herb–herb interaction (or the possible synergistic effect) among each component and to identify the principal herbs in different modes of action.

Methods
Rat osteoblast-like UMR-106 cells proliferation, rat MSCs-derived osteoblastogenesis and RANKL-induced RAW 264.7 osteoclastogenesis were adopted to investigate the bone-forming activity and bone-degrading activity of the herbal extracts. In the statistical aspect, a modified Tallarida's approach was employed to assess the synergistic effects in herbal combinations.

Key findings
Psoraleae Fructus is the active herb for stimulating osteoblast proliferation, and mild synergy was detected in the pairwise combinations EL, LP and formula ELP. In osteoblastogenesis assay, E and L are the principal herbs for promoting osteoblast differentiation and significant synergy was detected in the pairwise combination EL. For inhibiting osteoclast formation, L is the active herb and significant synergy was detected in the 3-way combination ELP.

Conclusions
The presence of E, L and P is essential for ELP formula as a whole to act against osteoporosis via enhancing bone formation and reducing bone reabsorption. An optimal dosage at 150 μg/ml was proposed for ELP based on our findings.
Development of cyclodextrin hydrogels for vaginal delivery of dehydroepiandrosterone
Authors: Mennini Natascia , Casella Giada , Cirri Marzia , Maestrelli Francesca , Mura Paola 
Published: March 2016

Abstract

Objective
To develop a new vaginal delivery system for a sustained release of dehydroepiandrosterone (DHEA) in the treatment of postmenopausal symptoms, aimed to overcome the problems of poor bioavailability of the drug related to its very low water solubility.

Methods
Cyclodextrin (CD)-containing hydrogels were developed, combining in a single device the hydrogel controlled release and mucoadhesion properties, and the CD solubilizing power towards DHEA. The effect of different CDs, alone or in mixtures, on the hydrogel technological and mucoadhesion characteristics was investigated. The best formulations were loaded with DHEA and characterized for loading efficiency and release properties.

Key findings
Hydrogels based on HPβCD/γCD (15/10%w/w) or HPβCD/HP γCD (30/20%w/w) combinations proved to be the most effective, giving ovules with the desired mechanical and mucoadhesive properties. Both formulations showed high drug loading efficiency, due to the solubilizing effect of CDs, and provided a sustained in-situ release, with a rate suitably tunable by varying the drug loaded amount and/or the CD combination.

Conclusions
The proposed formulative strategy allowed to develop an intravaginal device with right consistency and elasticity, easy to apply, able to be retained in situ over 8 h, and to provide an effective DHEA loading and a tunable release rate.
Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant, a novel therapeutic for the pain and inflammation of osteoarthritis in dogs
Authors: Rausch‐Derra L. C. , Rhodes L. , Freshwater L. , Hawks R. 
Published: March 2016

A new anti‐inflammatory drug for pain (grapiprant) was recently shown to have minimal side effects following chronic (9‐month) daily oral dose of 6 or 50 mg/kg suspension. The current study compares the pharmacokinetics of the formulation used in the chronic safety study to those of the tablet formulation that will be marketed upon FDA approval. Sixteen Beagle dogs were randomized to receive single doses of either 6 or 50 mg/kg grapiprant as both suspension and table formulations within a cross‐over design with a 15‐day washout. Clinical observations were vomiting in one high‐dose suspension dog and loose stools in two dogs, one in each 6 mg/kg formulation group. For both formulations, grapiprant reached a maximum concentration within two hours. The tablet formulation had better bioavailability, with AUClast values 34% higher at 6 mg/kg and 64% higher at 50 mg/kg compared to the suspension. Results on Day 0 were similar to those reported on Day 15, suggesting little to no accumulation. Using conversion factors of 1.34 and 1.64, these findings suggest that the 6 and 50 mg/kg suspension doses are equivalent to 4.5 and 30 mg/kg tableted doses, respectively. Combining these findings with the 9‐month safety study demonstrates that safety was evaluated at doses approximately 15‐fold above the demonstrated therapeutic dose of 2 mg/kg and 10‐fold over the ‘safety dose’, defined as the maximum dose a dog of any body weight could receive when dosed at 2 mg/kg with whole or half‐tablets.
Non‐residents’ Holdings, Market Volatility and Public Debt Sustainability. An Analysis with Data for Italy
Authors: Cafiso Gianluca 
Published: March 2016

AbstractNon‐residents’ holdings (NRH) of debt securities have been large in euro area countries, but during the euro area debt crisis some of those countries experienced a steep contraction of such holdings. The analysis aims to provide a data‐founded explanation of what is behind the decrease observed in 2011 by testing two alternative hypotheses. At the same time, we discuss how that decrease might have endangered the sustainability of public debt and study the empirical relevance of the most important of those processes. The topics presented refer to any advanced economy, but we check the hypotheses discussed by taking Italy as a case study because of data constraints. Italy is an interesting country to consider since it is a very large debt issuer. Our results point towards the importance of market volatility to explain variations of NRH, but those holdings do not seem to influence debt sustainability.
CHARACTERISATION AND MODELLING OF PEDESTRIAN FLOWS IN HOSPITAL AND ACADEMIC ENVIRONMENTS
Authors: Alhassan Hashim Mohammed , Mashros Nordiana 
Published: March 2016

This paper examined pedestrian characteristics in two urban facilities namely a teaching hospital and a university campus. The aim was to determine if pedestrian flow features in these facilities differed from those in downtown areas. The objectives were to measure pedestrian flow rates and model their walking behaviour. Eleven sites located within these facilities were selected for study. The results indicated that the male walked faster than the female in the university campus while the female was faster in the hospital environment. Also the university campus saw more groups of pedestrians in the traffic mix than was the case in the hospital environment where 93% of the pedestrians were in single files. The male walked faster than the female by 7% in the university environment while the female were faster by 4% in the hospital environment. The modelling effort showed that the free walking speed in the university environment was 68.052 m/min with a critical density of 3.15 ped/m2. That of the hospital environment was 75.099 m/min and a critical density of 4.36 ped/m2. Since the speed-density relationships for the two facilities revealed a highly randomized plot, the data was fit to the normal distribution and pdf and cdf were used to assess the quality of the flow. For the university environment the results showed that 15% of the combined pedestrians walked below 56.88 m/min while 50% of the pedestrians walked below 66.67m/min and 85% walked below 72.50 m/min. Similarly, the results of the hospital environment showed that 15th percentile of the combined pedestrians walked below 69.75 m/min. The median speed of pedestrians was 72.50 m/min while 85% of the pedestrians walked below 75.25 m/min. In both cases, the 15 percentile speeds were 14% and 18.5% less than the median speeds in both facilities respectively. Thus flow breakdowns are unexpected in the two facilities.
ANALYSIS OF CAR FOLLOWING HEADWAY ALONG MULTILANE HIGHWAY
Authors: Sanik Mohd Erwan , Prasetijo Joewono , Mat Nor Ahmad Hakimi , Hamid Nor Baizura , Yusof Ismail , Jaya Ramadhansyah Putra 
Published: March 2016

This study describes driver’s car following headway on multilane highways. The aim of this study is to analyse the driver’s car following headway along multilane highway at four selected locations. The objectives of this study were to determine car headway at Jalan Batu Pahat – Ayer Hitam multilane highway and to develop linear regression models to present the relationships between headway and speed. Videotaping method was used in field data collection during peak hours. Data were extracted from recorded video by using the image processing technique software. The distance headways and associated vehicles speeds were classified into vehicle following category by vehicle type: car following car, car following heavy goods vehicle, heavy goods vehicle following heavy goods vehicle and heavy goods vehicle following car categories. Linear regressions models were used to develop the relationships between headway and speed. Based on all headway distribution, it is found that patterns of the vehicle headways at four study locations were similar, which shown a significant number of the vehicles travel at headways less than 5 seconds. Furthermore, it can be concluded that many drivers tend to follow the vehicles ahead closely on multilane highways. The regression models were significantly reliable based on their R-square values which are ranging between 0.80 and 0.95. From the analysis, cars were found to maintain larger headways when following heavy goods vehicles compare to when following other cars.
A general model for stray dose calculation of static and intensity‐modulated photon radiation
Authors: Hauri Pascal , Hälg Roger A. , Besserer Jürgen , Schneider Uwe 
Published: March 2016

Purpose:There is an increasing number of cancer survivors who are at risk of developing late effects caused by ionizing radiation such as induction of second tumors. Hence, the determination of out‐of‐field dose for a particular treatment plan in the patient's anatomy is of great importance. The purpose of this study was to analytically model the stray dose according to its three major components.Methods:For patient scatter, a mechanistic model was developed. For collimator scatter and head leakage, an empirical approach was used. The models utilize a nominal beam energy of 6 MeV to describe two linear accelerator types of a single vendor. The parameters of the models were adjusted using ionization chamber measurements registering total absorbed dose in simple geometries. Whole‐body dose measurements using thermoluminescent dosimeters in an anthropomorphic phantom for static and intensity‐modulated treatment plans were compared to the 3D out‐of‐field dose distributions calculated by a combined model.Results:The absolute mean difference between the whole‐body predicted and the measured out‐of‐field dose of four different plans was 11% with a maximum difference below 44%. Computation time of 36 000 dose points for one field was around 30 s. By combining the model‐calculated stray dose with the treatment planning system dose, the whole‐body dose distribution can be viewed in the treatment planning system.Conclusions:The results suggest that the model is accurate, fast and can be used for a wide range of treatment modalities to calculate the whole‐body dose distribution for clinical analysis. For similar energy spectra, the mechanistic patient scatter model can be used independently of treatment machine or beam orientation.
Clofazimine Biocrystal Accumulation in Macrophages Upregulates Interleukin 1 Receptor Antagonist Production To Induce a Systemic Anti-Inflammatory State
Authors: Yoon Gi S. , Keswani Rahul K. , Sud Sudha , Rzeczycki Phillip M. , Murashov Mikhail D. , Koehn Tony A. , Standiford Theodore J. , Stringer Kathleen A. , Rosania Gus R. 
Published: March 2016

ABSTRACT
Clofazimine (CFZ) is a poorly soluble antibiotic and anti-inflammatory drug indicated for the treatment of leprosy. In spite of its therapeutic value, CFZ therapy is accompanied by the formation of drug biocrystals that accumulate within resident tissue macrophages, without obvious toxicological manifestations. Therefore, to specifically elucidate the off-target consequences of drug bioaccumulation in macrophages, we compared the level of inflammasome activation in CFZ-accumulating organs (spleen, liver and lung) in mice after 2 and 8 weeks of CFZ treatment when the drug exists in soluble and insoluble (biocrystalline) forms, respectively. Surprisingly, the results showed a drastic reduction in caspase 1 and interleukin-1β (IL-1β) cleavage in the livers of mice treated with CFZ for 8 weeks (8-week-CFZ-treated mice) compared to 2-week-CFZ-treated and control mice, which was accompanied by a 3-fold increase in hepatic IL-1 receptor antagonist (IL-1RA) production and a 21-fold increase in serum IL-1RA levels. In the lung and spleen, IL-1β cleavage and tumor necrosis factor alpha expression were unaffected by soluble or biocrystal CFZ forms. Functionally, there was a drastic reduction of carrageenan- and lipopolysaccharide-induced inflammation in the footpads and lungs, respectively, of 8-week-CFZ-treated mice. This immunomodulatory activity of CFZ biocrystal accumulation was attributable to the upregulation of IL-1RA, since CFZ accumulation had minimal effect in IL-1RA knockout mice or 2-week-CFZ-treated mice. In conclusion, CFZ accumulation and biocrystal formation in resident tissue macrophages profoundly altered the host's immune system and prompted an IL-1RA-dependent, systemic anti-inflammatory response.
Efficacy of Artilysin Art-175 against Resistant and Persistent Acinetobacter baumannii
Authors: Defraine Valerie , Schuermans Joris , Grymonprez Barbara , Govers Sander K. , Aertsen Abram , Fauvart Maarten , Michiels Jan , Lavigne Rob , Briers Yves 
Published: March 2016

ABSTRACT

Bacteriophage-encoded endolysins have shown promise as a novel class of antibacterials with a unique mode of action, i.e., peptidoglycan degradation. However, Gram-negative pathogens are generally not susceptible due to their protective outer membrane. Artilysins overcome this barrier. Artilysins are optimized, engineered fusions of selected endolysins with specific outer membrane-destabilizing peptides. Artilysin Art-175 comprises a modified variant of endolysin KZ144 with an N-terminal fusion to SMAP-29. Previously, we have shown the high susceptibility of
Pseudomonas aeruginosa
to Art-175. Here, we report that Art-175 is highly bactericidal against stationary-phase cells of multidrug-resistant
Acinetobacter baumannii
, even resulting in a complete elimination of large inocula (≥10
8
CFU/ml). Besides actively dividing cells, Art-175 also kills persisters. Instantaneous killing of
A. baumannii
upon contact with Art-175 could be visualized after immobilization of the bacteria in a microfluidic flow cell. Effective killing of a cell takes place through osmotic lysis after peptidoglycan degradation. The killing rate is enhanced by the addition of 0.5 mM EDTA. No development of resistance to Art-175 under selection pressure and no cross-resistance with existing resistance mechanisms could be observed. In conclusion, Art-175 represents a highly active Artilysin against both
A. baumannii
and
P. aeruginosa
, two of the most life-threatening pathogens of the order
Pseudomonadales
.