bluuebunny/crossref_metadata_2025 huggingface dataset:
Competitive Adsorption Behaviour of Binary Mixtures on Titanium Dioxide
Authors: Zhong Lexuan , Haghighat Fariborz
Published: June 2015

Exploration of the adsorption mechanism for mixtures at photocatalyst surfaces is a prerequisite for a full understanding of photocatalytic oxidation (PCO) technology for treatment of gaseous contaminants in indoor air applications. However, there has been very little work on the competitive adsorption of photocatalysts. In this article, an experimental and analytical study on the co‐adsorption of nine binary mixtures on a commercial PCO filter was investigated using a bench‐scale single‐pass continuous flow system. Adsorption tests were performed with a concentration of 500 ppb for the selected mixtures at various molar ratios. The experiments were performed at 40 % RH, 21 °C, and a gas flow rate of 10 L/min. Quantitative methods were developed to describe inhibitory and facilitatory effects on the adsorption of one component by the other. It was found that for the non‐polar mixture of p‐xylene and toluene, the polar mixture of MEK and acetone, and the polar/non‐polar mixture of MEK and p‐xylene, adsorption selectivity varied from 0.83–1.81, 1.80–1.21, and 2.60–1.78, respectively, when mixing ratio of each mixture changed from 1:2.33 to 2.33:1. In addition, a time‐dependent co‐adsorption model was developed and validated with the experimental results. It was concluded that competitive adsorption performance is dependent upon the composition of the gas mixture, the natures of the adsorbate and substrate, and the initial molar ratio of VOCs.
A Study of the Hydrocyclone for the Separation of Light and Heavy Particles in Aqueous Slurry
Authors: Ghadirian Morteza , Afacan Artin , Hayes Robert E. , Mmbaga Joseph P. , Mahmood Talat , Xu Zhenghe , Masliyah Jacob
Published: June 2015

This paper describes an experimental and modelling investigation of a hydrocyclone for the separation of light and heavy particles in an aqueous slurry. The effects of overflow pressure, feed flow rate, particle size, vortex finder length, and particle concentration are investigated. A model based on the governing conservation equations for mass and momentum is solved using a commercial software package, Ansys 12 Fluid Dynamics. Turbulence is modelled using the large eddy simulation, and the discrete particle model is used to predict the particle separation. It is shown by experimentation and modelling that increasing the vortex finder length results in an increase in the recovery of light particles in the overflow. The recovery of light particles increases as their size increases. Increasing the feed flow rate and decreasing the solid concentration in the feed also improves light particle recovery. A computational model based on LES gave close agreement with experimental results for low overall particle concentration.
Length‐Scale‐Dependent Phase Transformation of LiFePO4: An In situ and Operando Study Using Micro‐Raman Spectroscopy and XRD
Authors: Siddique N. A. , Salehi Amir , Wei Zi , Liu Dong , Sajjad Syed D. , Liu Fuqiang
Published: June 2015

The charge and discharge of lithium ion batteries are often accompanied by electrochemically driven phase‐transformation processes. In this work, two in situ and operando methods, that is, micro‐Raman spectroscopy and X‐ray diffraction (XRD), have been combined to study the phase‐transformation process in LiFePO4 at two distinct length scales, namely, particle‐level scale (∼1 μm) and macroscopic scale (∼several cm). In situ Raman studies revealed a discrete mode of phase transformation at the particle level. Besides, the preferred electrochemical transport network, particularly the carbon content, was found to govern the sequence of phase transformation among particles. In contrast, at the macroscopic level, studies conducted at four different discharge rates showed a continuous but delayed phase transformation. These findings uncovered the intricate phase transformation in LiFePO4 and potentially offer valuable insights into optimizing the length‐scale‐dependent properties of battery materials.
A New Process for Maleic Anhydride Synthesis from a Renewable Building Block: The Gas‐Phase Oxidehydration of Bio‐1‐butanol
Authors: Pavarelli Giulia , Velasquez Ochoa Juliana , Caldarelli Aurora , Puzzo Francesco , Cavani Fabrizio , Dubois Jean‐Luc
Published: June 2015

We investigated the synthesis of maleic anhydride by oxidehydration of a bio‐alcohol, 1‐butanol, as a possible alternative to the classical process of n‐butane oxidation. A vanadyl pyrophosphate catalyst was used to explore the one‐pot reaction, which involved two sequential steps: 1) 1‐butanol dehydration to 1‐butene, catalysed by acid sites, and 2) the oxidation of butenes to maleic anhydride, catalysed by redox sites. A non‐negligible amount of phthalic anhydride was also formed. The effect of different experimental parameters was investigated with chemically sourced 1‐butanol, and the results were then confirmed by using genuinely bio‐sourced 1‐butanol. In the case of bio‐1‐butanol, however, the purity of the product remarkably affected the yield of maleic anhydride. It was found that the reaction mechanism includes the oxidation of butenes to crotonaldehyde and the oxidation of the latter to either furan or maleic acid, both of which are transformed to produce maleic anhydride.
Rapid phenotypic fingerprinting of cell products by robust measurement of ubiquitous surface markers
Authors: Baradez Marc‐Olivier , Lekishvili Tamara , Marshall Damian
Published: June 2015

Flow cytometry is one of the most versatile and powerful approach for the quantitative analysis of cell suspensions. With widespread applications in basic and clinical research, its commonest use is in the detection of cell populations labelled against markers specific for a particular phenotype. In this study, we aimed to expand the potential of flow cytometry by describing a method based on robust automated quantification of ubiquitous cell surface markers. We demonstrate that automatic fluorescence standardization combined with whole cell population analysis yields highly reproducible results and can alleviate many of the difficulties associated with conventional analyses. This new generic approach is very flexible for quantifying the uniqueness of entire cell populations regardless of their composition. It provides quantitative phenotypic fingerprints rapidly, does not incorporate subjective factors, is more amenable to standardization, and is easily transferable across a wide diversity of applications, such as quality control for cell manufacture and authentication of cell products. © 2015 International Society for Advancement of Cytometry
An Optimized Bioassay for Mucin1 Detection in Serum Samples
Authors: Florea Anca , Ravalli Andrea , Cristea Cecilia , Săndulescu Robert , Marrazza Giovanna
Published: June 2015

Two simple and sensitive electrochemical approaches for Mucin1 (MUC1) tumor marker using magnetic beads coupling screen‐printed arrays were developed. The single‐use bioassays are based on a sandwich format in which aptamers or antibodies were coupled respectively to Streptavidin or Protein G‐modified magnetic beads. The bioreceptor‐modified beads are used to capture the MUC1 protein from the sample and sandwich assay is performed by the addition of a labeled secondary aptamer or antibody. The enzyme alkaline phosphatase and its substrate (1‐naphthyl phosphate) are then used for the electrochemical detection by differential pulse voltammetry (DPV). The analytical performances of the designed bioassays were compared in terms of sensitivity, selectivity and reproducibility. Using the optimized conditions, a linear range from 0 to 0.28 nM was obtained, with 0.19 nM LOD using antibody‐based and 0.07 nM LOD using aptamer‐based sandwich assay in MUC1 buffered solutions. The results also showed that the aptamer‐based approach exhibited higher selectivity for MUC1, allowing the detection of the protein in complex matrices. The developed aptasensor for MUC1 detection was applied on serum samples obtained from cancer patients, providing promising perspectives for clinical applications.
Fabrication of Silver Nanoparticles Decorated on Activated Screen Printed Carbon Electrode and Its Application for Ultrasensitive Detection of Dopamine
Authors: Palanisamy Selvakumar , Thirumalraj Balamurugan , Chen Shen‐Ming , Ajmal Ali M. , Muthupandi K. , Emmanuel R. , Prakash P. , Al‐Hemaid Fahad M. A.
Published: June 2015

In the present study, we report the fabrication of silver nanoparticles (AgNPs) decorated on activated screen printed carbon electrode (ASPCE). The AgNPs were prepared by using Justicia glauca leaf extract as a reducing and stabilizing agent and the ASPCE was prepared by a simple electrochemical activation of screen printed carbon electrode (SPCE). The ASPCE/AgNPs shows a reversible electrochemical behaviour with enhanced response for DA than that of other modified SPCEs. Under optimum conditions, the electrochemical oxidation current response of DA is linear over the concentration range from 0.05 to 45.35 µM. The limit of detection is found as 0.017 µM with a high sensitivity of 7.85 µA µM−1 cm−2.
Electrocatalytic Oxidation of Acyclovir on Poly(p‐Aminobenzene Sulfonic Acid) Film Modified Glassy Carbon Electrode
Authors: Can Saide , Yilmaz Selehattin , Saglikoglu Gulsen , Sadikoglu Murat , Menek Necati
Published: June 2015

Acyclovir is an antiviral effective drug active compound. A glassy carbon electrode (GCE) was modified with an electropolymerized film of p‐aminobenzene sulfonic acid (p‐ABSA) in phosphate buffer solution (PBS). The polymer film‐modified electrode was used to electrochemically detect acyclovir. Polymer film showed excellent electrocatalytic activity for the oxidation of acyclovir. The anodic peak potential value of the acyclovir at the poly(p‐ABSA) modified glassy carbon electrode was 950 mV obtained by DPV. A linear calibration curve for DPV analysis was constructed in the acyclovir concentration range 2×10−7–9×10−6 mol L−1. Limit of detection (LOD) and limit of quantification (LOQ) were obtained as 5.57×10−8 and 1.85×10−7 mol L−1 respectively. The proposed method exhibits good recovery and reproducibility.
Nitric oxide regulates cell behavior on an interactive cell‐derived extracellular matrix scaffold
Authors: Xing Qi , Zhang Lijun , Redman Travis , Qi Shaohai , Zhao Feng
Published: June 2015

During tissue injury and wound healing process, there are dynamic reciprocal interactions among cells, extracellular matrix (ECM), and mediating molecules which are crucial for functional tissue repair. Nitric oxide (NO) is one of the key mediating molecules that can positively regulate various biological activities involved in wound healing. Various ECM components serve as binding sites for cells and mediating molecules, and the interactions further stimulate cellular activities. Human mesenchymal stem cells (hMSCs) can migrate to the wound site and contribute to tissue regeneration through differentiation and paracrine signaling. The objective of this work was to investigate the regulatory effect of NO on hMSCs in an interactive ECM‐rich microenvironment. In order to mimic the in vivo stromal environment in wound site, a cell‐derived ECM scaffold that was able to release NO within the range of in vivo wound fluid NO level was fabricated. Results showed that the micro‐molar level of NO released from the ECM scaffold had an inhibitory effect on cellular activities of hMSCs. The NO impaired cell growth, altered cell morphology, disrupted the F‐actin organization, also decreased the expression of focal adhesion related molecules integrin α5 and paxillin. These results may contribute to the elucidation of how NO acts on hMSCs in wound healing process. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 3807–3814, 2015.
Simple and Sensitive Voltammetric Determination of Esculetin Using Electrochemically Reduced Graphene Oxide Modified Electrode
Authors: Li Yinfeng , Li Ying , Li Kunjing , Ye Baoxian
Published: June 2015

A simple and sensitive voltammetric sensor for esculetin, based on electrochemically reduced graphene oxide film modified glassy carbon electrode, was reported for the quantitative determination of esculetin in the Chinese traditional herbal drug Viola yedoensis Makino. Electrochemical impedance spectroscopy and scanning electron microscopy were employed to study the characteristic of the graphene oxide film. The electrochemical behavior of esculetin on this sensor was investigated in pH 3.0 phosphate buffer solution by cyclic voltammetry. Significant advantages were achieved by the excellent conductivity and the high surface‐to‐volume ratio of electrochemically reduced graphene oxide. A calibration plot of oxidation peak currents versus esculetin concentrations was linear in the range of 4.0 ξ 10‐8 mol L‐1 to 5.0 ξ 10‐6 mol L‐1 with a detection limit of 2.0 ξ 10‐8 mol L‐1. The practical application of the present sensor was demonstrated by determining the concentration of esculetin in real sample with no interference.
Quinine Derivative Bonded the Hybrid Mesoporous Silicas Chiral Stationary Phase: Preparation and Application in Liquid Chromatography
Authors: Zhou Jie , Du Qiuzheng , Sun Fang , Zheng Xuxia , Chen Shanshan , Luo Pei
Published: June 2015

A novel chiral stationary phase (QN‐APEPMOs) was synthesized by immobilizing quinine derivative (QN) onto spherical ammoniapropyl‐functionalized ethane‐bridged periodic mesoporous organosilicas (APEPMOs). The mesoporous material was prepared by a one‐step co‐condensation of 1,2‐bis (triethoxysilyl) ethane (BTSE) and 3‐ammoniapropyl triethoxysilane (KH‐550) using cetyltrimethyl‐ammoniumchlorine (C18TACl) as a template with the aid of ethanol (co‐solvent) in basic medium. And O‐9‐(tert‐butyl carbamoyl) quinine derivative was immobilized on APEPMOs particles through the vinylic double bond. All of the products were characterized. The results showed that APEPMOs were perfect substrates for chiral stationary phase (CSP) and quinine moieties have been successfully immobilized onto the silica gel. To evaluate the chiral discrimination ability of the synthesized CSP, some analytes have been investigated on QN‐APEPMOs in high performance liquid chromatography (RP‐HPLC) in reversed phase. Three acidic compounds were baseline separated. The results demonstrated that QN‐APEPMOs had high selectivity for acidic compounds such as: carboxylic and sulfonic acids. And the reproducibility of the chiral column was good, while the stability was not very good.
Pharmacokinetics and pharmacodynamics of a human monoclonal anti‐FGF23 antibody (KRN23) in the first multiple ascending‐dose trial treating adults with X‐linked hypophosphatemia
Authors: Zhang Xiaoping , Imel Erik A. , Ruppe Mary D. , Weber Thomas J. , Klausner Mark A. , Ito Takahiro , Vergeire Maria , Humphrey Jeffrey , Glorieux Francis H. , Portale Anthony A. , Insogna Karl , Carpenter Thomas O. , Peacock Munro
Published: June 2015

In X‐linked hypophosphatemia (XLH), serum fibroblast growth factor 23 (FGF23) is increased and results in reduced renal maximum threshold for phosphate reabsorption (TmP), reduced serum inorganic phosphorus (Pi), and inappropriately low normal serum 1,25 dihydroxyvitamin D (1,25[OH]2D) concentration, with subsequent development of rickets or osteomalacia. KRN23 is a recombinant human IgG1 monoclonal antibody that binds to FGF23 and blocks its activity. Up to 4 doses of KRN23 were administered subcutaneously every 28 days to 28 adults with XLH. Mean ± standard deviation KRN23 doses administered were 0.05, 0.10 ± 0.01, 0.28 ± 0.06, and 0.48 ± 0.16 mg/kg. The mean time to reach maximum serum KRN23 levels was 7.0 to 8.5 days. The mean KRN23 half‐life was 16.4 days. The mean area under the concentration–time curve (AUCn) for each dosing interval increased proportionally with increases in KRN23 dose. The mean intersubject variability in AUCn ranged from 30% to 37%. The area under the effect concentration–time curve (AUECn) for change from baseline in TmP per glomerular filtration rate, serum Pi, 1,25(OH)2D, and bone markers for each dosing interval increased linearly with increases in KRN23 AUCn. Linear correlation between serum KRN23 concentrations and increase in serum Pi support KRN23 dose adjustments based on predose serum Pi concentration. © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology
Don't rush to crush: audit of modification to oral medicines for patients with swallowing difficulties
Authors: Downey Catherine E. , Thakerar Arti , Kirsa Sue
Published: June 2015

Background

Oral medicines are frequently modified prior to administration for patients with swallowing difficulties or enteral tubes. The current Australian guideline, the Don't Rush to Crush (
DRTC
) Handbook has been available since 2011, and this study compares practice with its recommendations.

Aim

To assess compliance with Australian guidelines for the preparation of medications in patients who are unable to swallow solid oral medicines, and to provide nursing education as necessary to improve practice.

Method

An observational audit was undertaken during morning medication rounds in an 18‐bed medical oncology ward over 4 weeks. For each occasion that an oral medicine was modified, the preparation method was assessed against recommendations in the
DRTC
Handbook for appropriateness. A number of education strategies were implemented with support and input from senior nursing staff focusing on medication modification for patients with fine‐bore nasogastric tubes. A re‐audit was undertaken to assess practice improvement.

Results

Education improved the proportion of medications prepared safely from 45% (37/82) to 91% (68/75) and those prepared according to the optimal method of preparation from 33% (27/82) to 60% (45/75). In the initial audit, 52% (43/82) of medications modified were strained prior to patient administration. Practical and collaborative education eliminated the straining of medications, and guidelines for difficult medications for patients with nasogastric tubes were developed.

Conclusion

Collaborative education that is practical and targeted can improve how oral medicines are modified for patients with swallowing difficulties and enteral tubes.
Methaemoglobinaemia associated with trimethoprim/sulfamethoxazole treatment on a background of leflunomide‐induced pneumonitis
Authors: Klusak Anna , Truloff Natasha
Published: June 2015

Background

Immunomodulating drugs such as leflunomide are known to be associated with immunosuppression and infection. Off‐label use of such agents may place patients at increased risk of potentially unforeseen adverse effects not commonly observed in clinical trials.

Aim

To describe a case of leflunomide‐induced pneumonitis, which may have contributed to the development of Pneumocystis jirovecii pneumonia (PJP). Treatment of the infection with trimethoprim/sulfamethoxazole (TMP‐SMX) in this case was associated with the development of methaemoglobinaemia, a relatively rare adverse effect associated with this agent.

Clinical details

A 72‐year‐old female presented with a 2‐week history of progressive dyspnoea and orthopnoea with a background of newly diagnosed, biopsy proven, membranous glomerulonephropathy. She had recently started leflunomide and prednisolone for resistant proteinuria. Soon after admission, her respiratory status deteriorated with tachypnoea (30–40/min) and hypoxia requiring large amounts of supplemental oxygen (oxygen saturation (SaO2) 95%, partial pressure of oxygen (PO2) 68 mmHg with 10 L/min of oxygen). A chest X‐ray and computed tomography revealed diffuse bilateral ground glass opacities with multimodal consolidation. Sputum polymerase chain reaction testing was positive for P. jirovecii, and a diagnosis of PJP was made. Subsequent treatment with primaquine and TMP‐SMX was linked to the development of drug‐induced methaemoglobinaemia (MeHb).

Outcome

The antimicrobial regime was changed to intravenous (IV) pentamidine as an alternative treatment for P. jirovecii pneumonia. Despite this, there was further deterioration associated with a suspected secondary bacterial pneumonia. Additional IV antibiotics were added, including piperacillin/tazobactam and vancomycin. Following failure to respond to this treatment, active interventions were withdrawn after family discussions. Palliative care measures were implemented and she died 4 days later.

Conclusion

Pharmacists should be aware of the potential for serious, rare adverse effects associated with immunomodulating drugs. Patients must be informed of the risks associated with treatment and the evidence for benefit when these drugs are prescribed for off‐label use. PJP pneumonia prophylaxis should be considered for patients commencing high dose, chronic corticosteroid therapy. Methaemoglobin should be measured for patients who become significantly hypoxic after treatment with trimethoprim/sulfamethoxazole.
Concomitant roxithromycin use among elderly patients taking warfarin resulting in significant over‐anti‐coagulation
Authors: Rotella Joe‐Anthony , Taylor David M.
Published: June 2015

Background

There is a paucity of literature regarding the potential association between roxithromycin and excessive anti‐coagulation in patients taking warfarin. An interaction may have important health implications for these patients, particularly the elderly, who are at greater risk of bleeding events due to falls and consequent injuries, as well as major gastrointestinal haemorrhage.

Aim

To report five cases of a possible roxithromycin–warfarin drug interaction, all resulting in extreme elevations of the international normalised ratio (INR) and requiring admission and intervention with vitamin K.

Clinical details

A retrospective medical record review of patients presenting to the emergency department of a tertiary‐level, university‐affiliated hospital was undertaken. Patients treated with warfarin and who had an excessively elevated international normalised ratio at presentation were identified. Of 102 525 cases screened, 72 cases were selected for further analysis. In five cases, elderly patients were taking roxithromycin for treatment of a lower respiratory tract infection and had a recorded international normalised ratio in the range of 10.1–14.5. Three of these five patients had impaired renal function.

Outcomes

No patient had bleeding complications but all required admission and treatment with vitamin K. One patient died during admission but the cause of death was not related to bleeding. In each case, a potential roxithromycin–warfarin interaction was rated as probable using a commonly employed scale.

Conclusion

The elevation of the international normalised ratio observed with these patients was most likely to have been caused by a drug interaction. Each patient required admission and considerable clinical intervention in order to correct the over‐anti‐coagulation. Hence, the clinician needs to be aware of the potential consequences of this drug interaction.
Impact of altered administrative processes for clozapine supply in a large‐scale Australian mental health shared‐care program
Authors: Bjorksten Cecilia E. , Berry Sherman
Published: June 2015

Clozapine is an effective antipsychotic agent that is associated with a range of serious adverse effects. Changes in the administrative processes for claiming reimbursement for the costs associated with clozapine through the Australian Pharmaceutical Benefits Scheme have been associated with significant clinical, financial and logistic challenges. This practice report illustrates the impact of the administrative changes upon consumers, doctors, pharmacists and other staff associated with a large Australian mental health service. It is noteworthy that the implementation of the changes had cross‐jurisdictional impact, with the introduction of changes in a federally funded programme creating major impacts upon a service funded and run by a state‐based management. Implementing change of this type can have a major negative impact upon consumers and staff: it is essential that such changes should be achieved in the context of genuine consultation and cooperative efforts.
Comprehensive analysis of sequences of a protein switch
Authors: Chen Szu‐Hua , Meller Jaroslaw , Elber Ron
Published: June 2015

Switches form a special class of proteins that dramatically change their three‐dimensional structures upon a small perturbation. One possible perturbation that we explore is that of a single point mutation. Building on the pioneering experimental work of Alexander et al. (Alexander et al. PNAS, 2007; 104,11963–11968) that determines switch sequences between α and α+β folds we conduct a comprehensive sequence sampling by a Markov Chain with multiple fitness criteria to identify new switches given the experimental folds. We screen for switch sequences using a combination of contact potential, secondary structure prediction, and finally molecular dynamics simulations. Statistical properties of switch sequences are discussed and illustrated to be most sensitive to mutation at the N‐ and C‐ termini of the switch protein. Based on this analysis, a particularly stable putative switch pair is identified and proposed for further experimental analysis.
Comparison of topological clustering within protein networks using edge metrics that evaluate full sequence, full structure, and active site microenvironment similarity
Authors: Leuthaeuser Janelle B. , Knutson Stacy T. , Kumar Kiran , Babbitt Patricia C. , Fetrow Jacquelyn S.
Published: June 2015

The development of accurate protein function annotation methods has emerged as a major unsolved biological problem. Protein similarity networks, one approach to function annotation via annotation transfer, group proteins into similarity‐based clusters. An underlying assumption is that the edge metric used to identify such clusters correlates with functional information. In this contribution, this assumption is evaluated by observing topologies in similarity networks using three different edge metrics: sequence (BLAST), structure (TM‐Align), and active site similarity (active site profiling, implemented in DASP). Network topologies for four well‐studied protein superfamilies (enolase, peroxiredoxin (Prx), glutathione transferase (GST), and crotonase) were compared with curated functional hierarchies and structure. As expected, network topology differs, depending on edge metric; comparison of topologies provides valuable information on structure/function relationships. Subnetworks based on active site similarity correlate with known functional hierarchies at a single edge threshold more often than sequence‐ or structure‐based networks. Sequence‐ and structure‐based networks are useful for identifying sequence and domain similarities and differences; therefore, it is important to consider the clustering goal before deciding appropriate edge metric. Further, conserved active site residues identified in enolase and GST active site subnetworks correspond with published functionally important residues. Extension of this analysis yields predictions of functionally determinant residues for GST subgroups. These results support the hypothesis that active site similarity‐based networks reveal clusters that share functional details and lay the foundation for capturing functionally relevant hierarchies using an approach that is both automatable and can deliver greater precision in function annotation than current similarity‐based methods.
Pharmacokinetic study of metopimazine by oral route in children
Authors: Mallet Eric , Bounoure Frederic , Skiba Mohamed , Saussereau Elodie , Goullé Jean‐Pierre , Castanet Mireille
Published: June 2015

Metopimazine (MPZ) is an antiemetic considered as a currently used drug. In France, it has become the leading antiemetic mediator due to its good tolerance, however, its pharmacokinetics has never previously been studied in children. MPZ was administered by oral route to 8 children with a single dose of 0.33 mg/kg during an endocrine exploration using stimuli well known for its adverse emetic effects. We used biological remnants from sera following an hGH test in order to obtain the MPZ pharmacokinetics. Plasmatic concentrations of MPZ and the active acid metabolite AMPZ, were quantified by HPLC‐MS/MS during a 270 min test period. MPZ is quickly absorbed with a median Cmax of 17.2 ng/mL at one hour and its half‐life is 2.18 h. The plasmatic concentrations of AMPZ were higher than MPZ with a median Cmax of 76.3 ng/mL, a Tmax to 150 min and its concentration was approximately maintained at 50 ng/mL from 1 to 4 h. The plasmatic concentrations in children are similar to those observed in adults. No adverse effects, nausea or vomiting occurred during the trial. Therefore, these results confirm the MPZ dosage that should be used in children under 15 kg administered as 0.33 mg/kg up to 3 times a day.
The discovery of a selective and potent A2a agonist with extended lung retention
Authors: Åstrand Annika B. M. , Lamm Bergström Eva , Zhang Hui , Börjesson Lena , Söderdahl Therese , Wingren Cecilia , Jansson Anne‐Helene , Smailagic Amir , Johansson Camilla , Bladh Håkan , Shamovsky Igor , Tunek Anders , Drmota Tomas
Published: June 2015

Although the anti‐inflammatory role of the A2a receptor is well established, controversy remains with regard to the therapeutic value for A2a agonists in treatment of inflammatory lung diseases, also as a result of unwanted A2a‐mediated cardiovascular effects. In this paper, we describe the discovery and characterization of a new, potent and selective A2a agonist (compound 2) with prolonged lung retention and limited systemic exposure following local administration. To support the lead optimization chemistry program with compound selection and profiling, multiple in vitro and in vivo assays were used, characterizing compound properties, pharmacodynamics (PD), and drug concentrations. Particularly, pharmacokinetic‐PD modeling was applied to quantify the effects on the cardiovascular system, and an investigative toxicology study in rats was performed to explore potential myocardial toxicities. Compound 2, in comparison to a reference A2a agonist, UK‐432,097, demonstrated higher solubility, lower lipophilicity, lower plasma protein binding, high rat lung retention (28% remaining after 24 h), and was efficacious in a lung inflammatory rat model following intratracheal dosing. Despite these properties, compound 2 did not provide a sufficient therapeutic index, that is, separation of local anti‐inflammatory efficacy in the lung from systemic side effects in the cardiovascular system. The plasma concentration that resulted in induction of hypotension (half maximal effective concentration; EC50 0.5 nmol/L) correlated to the in vitro A2a potency (rIC50 0.6 nmol/L). Histopathological lesions in the heart were observed at a dose level which is threefold above the efficacious dose level in the inflammatory rat lung model. In conclusion, compound 2 is a highly potent and selective A2a agonist with significant lung retention after intratracheal administration. Despite its local anti‐inflammatory efficacy in rat lung, small margins to the cardiovascular effects suggested limited therapeutic value of this compound for treatment of inflammatory lung disease by the inhaled route.
Sulfonamide inhibitors of α2β1 integrin reveal the essential role of collagen receptors in in vivo models of inflammation
Authors: Nissinen Liisa , Ojala Marika , Langen Barbara , Dost Rita , Pihlavisto Marjo , Käpylä Jarmo , Marjamäki Anne , Heino Jyrki
Published: June 2015

Small molecule inhibitors of α2β1 integrin, a major cellular collagen receptor, have been reported to inhibit platelet function, kidney injury, and angiogenesis. Since α2β1 integrin is abundantly expressed on various inflammation‐associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti‐inflammatory properties. Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid‐induced ear edema, PAF stimulated air pouch, ovalbumin‐induced skin hypersensitivity, adjuvant arthritis, and collagen‐induced arthritis. Thus, these sulfonamides are potential drugs for acute and allergic inflammation, hypersensitivity, and arthritis. One sulfonamide with potent anti‐inflammatory activity has previously been reported to be selective for activated integrins, but not to inhibit platelet function. Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.
Analysis of drug combinations: current methodological landscape
Authors: Foucquier Julie , Guedj Mickael
Published: June 2015

Combination therapies exploit the chances for better efficacy, decreased toxicity, and reduced development of drug resistance and owing to these advantages, have become a standard for the treatment of several diseases and continue to represent a promising approach in indications of unmet medical need. In this context, studying the effects of a combination of drugs in order to provide evidence of a significant superiority compared to the single agents is of particular interest. Research in this field has resulted in a large number of papers and revealed several issues. Here, we propose an overview of the current methodological landscape concerning the study of combination effects. First, we aim to provide the minimal set of mathematical and pharmacological concepts necessary to understand the most commonly used approaches, divided into effect‐based approaches and dose–effect‐based approaches, and introduced in light of their respective practical advantages and limitations. Then, we discuss six main common methodological issues that scientists have to face at each step of the development of new combination therapies. In particular, in the absence of a reference methodology suitable for all biomedical situations, the analysis of drug combinations should benefit from a collective, appropriate, and rigorous application of the concepts and methods reviewed here.
Reduced activity of SKCa and Na‐K ATPase underlies the accelerated impairment of EDH‐type relaxations in mesenteric arteries of aging spontaneously hypertensive rats
Authors: Kong Billy W. C. , Man Ricky Y. K. , Gao Yuansheng , Vanhoutte Paul M. , Leung Susan W. S.
Published: June 2015

Aging is accompanied by endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) and/or reduced endothelium‐dependent hyperpolarizations (EDH). This study examines the hypothesis that hypertension aggravates the impairment of EDH‐type relaxation due to aging. EDH‐type relaxations were studied in superior mesenteric arteries isolated from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats of 12, 36, 60, and 72 weeks of age. EDH‐type relaxations in WKY were reduced with aging, and this was associated with an impairment of the function of small‐conductance calcium‐activated potassium channels (SKCa) and sodium‐potassium ATPase (Na‐K ATPase). EDH‐type relaxation in SHR was smaller than that in WKY arteries, and further reduction occurred with aging. Pharmacological experiments suggested a reduced involvement of SKCa and Na‐K ATPase and activation of adenosine monophosphate‐activated protein kinase and silent information regulator T1 (sirtuin‐1; SIRT1) in mesenteric arteries of 12‐week‐old SHR. These pharmacological findings suggest that in superior mesenteric arteries of the rat, the reduction in EDH‐type relaxation occurs with aging and that such a reduction is exacerbated in hypertension. The latter exacerbation appears to involve proteins associated with the process of cellular senescence and is related to impaired function of SKCa and Na‐K ATPase, a phenomenon that is also observed in mesenteric arteries of older normotensive rats.
Effects of Early U.S. Compulsory Schooling Laws on Educational Assortative Mating: The Importance of Context
Authors: Rauscher Emily
Published: June 2015

Modernization theory predicts that rising education should increase assortative mating by education and decrease sorting by race. Recent research suggests that effects of educational expansion depend on contextual factors, such as economic development. Using log-linear and log-multiplicative models of male household heads ages 36 to 75 in the 1940 U.S. census data—the first U.S. census with educational attainment information—I investigate how educational assortative mating changed with one instance of educational expansion: early U.S. compulsory school attendance laws. To improve on existing research and distinguish effects of expansion from changes due to particular years or cohorts, I capitalize on state variation in the timing of these compulsory laws (ranging from 1852 to 1918). Aggregate results suggest that compulsory laws had minimal impact on assortative mating. However, separate analyses by region (and supplemental analyses by race) reveal that assortative mating by education decreased with the laws in the South but increased in the North. Whether due to economic, legal, political, or other differences, results suggest that the implications of educational expansion for marital sorting depend on context. Contemporary implications are discussed in light of President Obama’s 2012 suggested extension of compulsory schooling to age 18.
Structural disorder within paramyxoviral nucleoproteins
Authors: Longhi Sonia
Published: June 2015

In this review I summarize available data pointing to the abundance of structural disorder within the nucleoprotein (N) from three paramyxoviruses, namely the measles (MeV), Nipah (NiV) and Hendra (HeV) viruses. I provide a detailed description of the molecular mechanisms that govern the disorder‐to‐order transition that the intrinsically disordered C‐terminal domain (NTAIL) of their N proteins undergoes upon binding to the C‐terminal X domain (XD) of the homologous phosphoproteins. I also show that a significant flexibility persists within NTAIL–XD complexes, which makes them illustrative examples of “fuzziness”. Finally, I discuss the functional implications of structural disorder for viral transcription and replication in light of the promiscuity of disordered regions and of the considerable reach they confer to the components of the replicative machinery.
Asymmetries of the central sulcus in young adults: Effects of gender, age and sulcal pattern
Authors: Sun Bo , Ge Haitao , Tang Yuchun , Hou Zhongyu , Xu Junhai , Lin Xiangtao , Liu Shuwei
Published: June 2015

In this study, we clarified the gender and age‐related asymmetries of the central sulcus (CS) in early adulthood using a parametric ribbon method. The CS was reconstructed and parameterized automatically from 3D MR images of 112 healthy right‐handed subjects. The 3D anatomic morphology of the CS was presented using 5 sulcal parameters, including sulcal depth position‐based profile (DPP), average depth (AD), average width (AW), top length (TL) and bottom length (BL). Asymmetry differences in DPPs were found in the medial and lateral part of the CS. In addition, significant gender differences were observed in the medial and middle parts of the right CS DPPs but scattered in the left side. We found leftward asymmetries of TL in males, but rightward asymmetries of AW in females. Males had a greater AW than females in the right hemisphere. Moreover, the females had bilateral longer TL and a longer left BL than did males. We also found significant age‐related reductions in bilateral TL and increases in bilateral AW, with males presenting more obvious age‐related change than females. There were sexual differences of the CS patterns, in which Type b was the most dominant sulcal pattern in males, whereas Type a was dominant in females. Three‐way ANOVA revealed sexual and asymmetry changes of TL and BL among different CS patterns. Our findings indicate that the lateralization performances of the CS manifest as sexually and regionally different. In addition, it is suggested that males may undergo a faster progress of aging compared to females.
Couple years protection lost, a new tool for family planning programs to prioritize stockout interventions
Authors: Schwandt Hilary M. , Saad Abudulmumin
Published: June 2015

Objective

To develop and evaluate a new measure—couple years protection lost (CYPL)—to identify facilities with the most damaging contraceptive stockouts and therefore direct program response.

Methods

As part of a prospective descriptive study, data were gathered on stocks of contraceptives (oral contraceptive pill, intrauterine device, and two types of implant) at 10 family planning facilities in Abuja, Nigeria, between January and August 2012. CYPL values—a summation of average client volume across contraceptive methods multiplied by the number of stockouts and the USAID couple years of protection value for each method—were calculated for each facility.

Results

Over the 8‐month study period, the 10 facilities had CYPL values ranging from 15.7 to 588.7. Two facilities had a similarly high number of stockouts (9 vs 8), but completely different CYPL values (462.1 vs 15.7).

Conclusion

By utilizing the CYPL measure, health programs can target family planning facilities with the most damaging stockouts first and thus strategically reduce the negative impact of contraceptive stockouts.
Misoprostol versus prostaglandin E2 gel for labor induction in premature rupture of membranes after 34 weeks of pregnancy
Authors: Zhang Yan , Wang Jun , Yu Yan , Xie Cui , Xiao Meiqun , Ren Lirong
Published: June 2015

Background

Both misoprostol and prostaglandin E2 (PGE2) gel are used for labor induction in women with premature rupture of membranes (PROM).

Objectives

To evaluate studies comparing the effects of misoprostol and PGE2 gel in labor induction.

Search strategy

Databases including Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant papers.

Selection criteria

Randomized controlled trials comparing the use of misoprostol and PGE2 gel for labor induction in women with PROM were included.

Data collection and analysis

For meta‐analyses, the Mantel–Haenszel method was used for dichotomous data, and the inverse variance method was used for continuous data.

Main results

Four randomized controlled studies (n = 615) were included. There were no significant differences between the two groups in the induction‐to‐delivery interval (mean difference – 4.44 hours; 95% confidence interval [CI] −9.35 to 0.48), rate of cesarean delivery (odds ratio [OR] 0.90; 95% CI 0.44–1.85), and rate of neonatal intensive care unit admission (OR 0.89; 95% CI 0.57–1.38). Women receiving misoprostol had a significantly higher rate of tachysystole than did those receiving PGE2 gel (OR 4.84; 95% CI 2.46–9.54).

Conclusions

Misoprostol is as efficacious and safe as PGE2 gel for labor induction in women with PROM.
Early cost‐utility analysis of general and cerebrospinal fluid‐specific Alzheimer's disease biomarkers for hypothetical disease‐modifying treatment decision in mild cognitive impairment
Authors: Handels Ron L.H. , Joore Manuela A. , Tran‐Duy An , Wimo Anders , Wolfs Claire A.G. , Verhey Frans R.J. , Severens Johan L.
Published: June 2015

Introduction

The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease‐modifying Alzheimer's disease (AD) treatment.

Methods

A decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add‐on test when current practice concluded the presence or absence of AD.

Results

The simulated MCI population was aged on average 68.3 and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, €33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3‐year delay in dementia conversion.

Discussion

The results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses explored different CSF positions.
Effects of enteral nutrition with parenteral glutamine supplementation on the immunological function in septic rats
Authors: Fan Jun , Wu Lidong , Li Guoping , Tao Shaoyu , Sheng Zhiyong , Meng Qingyan , Li Fengxin , Yu Lijuan , Li Li
Published: June 2015

The aim of the present study was to investigate the effects of enteral nutrition (EN) with parenteral glutamine (GLN) supplementation on inflammatory response, lymphatic organ apoptosis, immunological function and survival in septic rats by caecal ligation and puncture (CLP). Male rats were randomly assigned into two experimental groups and two sham CLP control groups (n 10 per group). After CLP or sham CLP model and nutrition programme were completed, the GLN concentrations of plasma and tissues and several indices of immunological function including serum Ig content, circulating lymphocyte number, the CD4:CD8 ratio, the neutrophil phagocytosis index (NPI), the organ index and apoptosis of thymus and spleen, and plasma cytokine levels were determined. Moreover, the survival in septic rats was observed. The results revealed that EN with parenteral GLN supplementation remarkably increased the GLN concentrations of plasma and tissues, serum Ig content, the circulating lymphocyte number, the CD4:CD8 ratio, the indexes of thymus and spleen, NPI and survival compared with the control group (P< 0·05). In contrast, the apoptosis of thymus and spleen and the levels of TNF-α, IL-1β and IL-6 in plasma were obviously decreased compared with the control group (P< 0·05). These results show that EN with parenteral GLN supplementation diminished the release of inflammatory cytokines, attenuated lymphatic organ apoptosis, enhanced the immunological function and improved survival in septic rats.
THE SOUTHERN PROBLEM: REPRESENTING SUDAN'S SOUTHERN PROVINCES TOc. 1970
Authors: WILLIS JUSTIN
Published: June 2015

Southern Sudanese politicians of the 1950s and 1960s have been criticized for a rivalrous, divisive politics, which left the south disunited and vulnerable. While acknowledging that these men were a tiny, squabbling group, remote from those they sought to represent, this article suggests that they faced an impossible task. The demand to represent ‘the south’ did not come solely, or even largely, from the people who lived in the southern provinces: southern politics was heavily extraverted, pulled by the interests and prejudices of northern Sudanese, Egyptians, Britons, and others. Like other African nationalists of the time, southern Sudanese politicians struggled to weave together different levels of moral community, from the very local to the imagined nation. Yet they did so in uniquely unfavourable circumstances: subject to constant harassment and occasionally lethal violence, unable to secure political compromise, and without patronage resources. Representing the south gave these men space to talk about the increasingly desperate circumstances of those who lived in Sudan's southern provinces; but it gave them almost no space at all to negotiate a civic culture of southern politics.