bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor necrosis factor–inhibiting therapy preferentially targets bone destruction but not synovial inflammation in a tumor necrosis factor–driven model of rheumatoid arthritis
Authors: Binder Nikolaus B. , Puchner Antonia , Niederreiter Birgit , Hayer Silvia , Leiss Harald , Blüml Stephan , Kreindl Roman , Smolen Josef S. , Redlich Kurt
Published: December 2012

Objective

To investigate how tumor necrosis factor (TNF)–inhibiting therapy affects bone destruction and inflammation in a TNF‐driven mouse model of rheumatoid arthritis.

Methods

In order to evaluate the influence of TNF on osteoclastogenesis in vitro, different concentrations of TNF were added to spleen cell–derived monocytes in the absence or presence of different concentrations of RANKL. In addition, the effects of TNF inhibition on osteoclast precursors as well as local bone destruction in vivo were assessed by treating TNF‐transgenic mice with different doses of adalimumab.

Results

TNF stimulated osteoclastogenesis mainly by increasing the number of osteoclast precursor cells in vitro. This TNF effect was independent of the presence of RANKL. In the hTNF‐transgenic mouse model of destructive arthritis, low‐dose TNF‐inhibiting therapy with adalimumab had no effect on synovial inflammation but significantly inhibited local bone destruction and the generation of osteoclasts. This inhibition was accompanied by a reduction in the number of c‐Fms–positive osteoclast precursor cells in the bone marrow and a reduction of the osteoclast precursor pools in the blood and inflamed synovial membrane of hTNF‐transgenic mice.

Conclusion

Low‐dose TNF‐inhibiting therapy significantly reduces bone erosions by reducing the number of circulating and joint‐invading osteoclast precursors. This effect is uncoupled from its antiinflammatory action.
Inducible expression of kallikrein in renal tubular cells protects mice against spontaneous lupus nephritis
Authors: Shao Xinli , Yang Ru , Yan Mei , Li Yajuan , Du Yong , Raman Indu , Zhang Bo , Wakeland Ward , Igarashi Peter , Mohan Chandra , Li Quan‐Zhen
Published: December 2012

Objective

To ascertain whether engineered expression of kallikreins within the kidneys, using an inducible Cre/loxP system, can ameliorate murine lupus nephritis.

Methods

In mice with a lupus‐prone genetic background, we engineered the expression of tamoxifen‐inducible Cre recombinase under the control of a kidney‐specific promoter whose activation initiates murine kallikrein‐1 expression within the kidneys. These transgenic mice were injected with either tamoxifen or vehicle at age 2 months and then were monitored for 8 months for kallikrein expression and disease.

Results

Elevated expression of kallikrein was detected in the kidney and urine of tamoxifen‐injected mice but not in controls. At age 10 months, all vehicle‐injected mice developed severe lupus nephritis, as evidenced by increased proteinuria (mean ± SD 13.43 ± 5.65 mg/24 hours), increased blood urea nitrogen (BUN) and serum creatinine levels (39.86 ± 13.45 mg/dl and 15.23 ± 6.89 mg/dl, respectively), and severe renal pathology. In contrast, the tamoxifen‐injected mice showed significantly reduced proteinuria (6.6 ± 4.12 mg/24 hours), decreased BUN and serum creatinine levels (15.71 ± 8.17 mg/dl and 6.64 ± 3.39 mg/dl, respectively), and milder renal pathology. Tamoxifen‐induced up‐regulation of renal kallikrein expression increased nitric oxide production and dampened renal superoxide production and inflammatory cell infiltration, alluding to some of the pathways through which kallikreins may be operating within the kidneys.

Conclusion

Local expression of kallikreins within the kidney has the capacity to dampen lupus nephritis, possibly by modulating inflammation and oxidative stress.
Matrix‐assisted laser desorption ionization–imaging mass spectrometry: A new methodology to study human osteoarthritic cartilage
Authors: Cillero‐Pastor Berta , Eijkel Gert B. , Kiss Andras , Blanco Francisco J. , Heeren Ron M. A.
Published: December 2012

Objective

Information about the distribution of proteins and the modulation that they undergo in the different phases of rheumatic pathologies is essential to understanding the development of these diseases. We undertook this study to demonstrate the utility of mass spectrometry (MS)–based molecular imaging for studying the spatial distribution of different components in human articular cartilage sections.

Methods

We compared the distribution of peptides and proteins in human control and osteoarthritic (OA) cartilage. Human control and OA cartilage slices were cut and deposited on conductive slides. After tryptic digestion, we performed matrix‐assisted laser desorption ionization–imaging MS (MALDI‐IMS) experiments in a MALDI–quadrupole time‐of‐flight mass spectrometer. Protein identification was undertaken with a combination of multivariate statistical methods and Mascot protein database queries. Hematoxylin and eosin staining and immunohistochemistry were performed to validate the results.

Results

We created maps of peptide distributions at 150‐μm raster size from control and OA human cartilage. Proteins such as biglycan, prolargin, decorin, and aggrecan core protein were identified and localized. Specific protein markers for cartilage oligomeric matrix protein and fibronectin were found exclusively in OA cartilage samples. Their distribution displayed a stronger intensity in the deep area than in the superficial area. New tentative OA markers were found in the deep area of the OA cartilage.

Conclusion

MALDI‐IMS identifies and localizes disease‐specific peptides and proteins in cartilage. All the OA‐related peptides and proteins detected display a stronger intensity in the deep cartilage. MS‐based molecular imaging is demonstrated to be an innovative method for studying OA pathology.
Neutrophil cannibalism triggers transforming growth factor β1 production and self regulation of neutrophil inflammatory function in monosodium urate monohydrate crystal–induced inflammation in mice
Authors: Steiger Stefanie , Harper Jacquie L.
Published: December 2012

Objective

To identify macrophage‐independent sources of transforming growth factor β1 (TGFβ1) production during monosodium urate monohydrate (MSU) crystal–induced inflammation and to determine how TGFβ1 alters MSU crystal–recruited neutrophil functions.

Methods

C57BL/6J mice were injected intraperitoneally with MSU crystals with or without TGFβ1‐neutralizing antibody. MSU crystal–recruited peritoneal and blood neutrophils were purified and cultured ex vivo. Peritoneal neutrophils were treated with the caspase inhibitor Q‐VD‐OPh, anti‐TGFβ1 antibody, or fluorochrome‐labeled apoptotic neutrophils. Neutrophils were analyzed for expression of annexin V, caspase 3, and TGFβ1 by flow cytometry or fluorescence microscopy, for superoxide production using the redox‐sensitive dye water‐soluble tetrazolium 1, and for TGFβ1 and interleukin‐1β (IL‐1β) production by enzyme‐linked immunosorbent assay.

Results

Eighteen hours after MSU crystal administration in vivo, TGFβ1 levels were elevated in peritoneal lavage fluids, and a significant number of peritoneal neutrophils were TGFβ1+. Purified blood or peritoneal neutrophils cultured ex vivo showed TGFβ1+ neutrophils coexpressing the apoptosis marker caspase 3 and increased TGFβ1 production, both of which dropped following inhibition of apoptosis. Live neutrophils that had phagocytosed apoptotic neutrophils showed greatest TGFβ1 expression. Superoxide production by purified MSU crystal–recruited neutrophils ex vivo was enhanced by anti‐TGFβ1 antibody treatment. Neutrophils purified from the peritoneum of MSU crystal–challenged mice treated with anti‐TGFβ1 antibody produced elevated levels of superoxide, but neutrophil IL‐1β production was unaffected.

Conclusion

Neutrophil cannibalism and TGFβ1 production have the potential to make a significant contribution to the controlled resolution of neutrophil‐driven inflammatory diseases such as gout.
Tumor Necrosis Factor α–Induced MicroRNA‐18a Activates Rheumatoid Arthritis Synovial Fibroblasts Through a Feedback Loop in NF‐κB Signaling
Authors: Trenkmann Michelle , Brock Matthias , Gay Renate E. , Michel Beat A. , Gay Steffen , Huber Lars C.
Published: December 2012

Objective

To elucidate whether the microRNA (miRNA) cluster miR‐17–92 contributes to the activated phenotype of rheumatoid arthritis synovial fibroblasts (RASFs).

Methods

RASFs were stimulated with tumor necrosis factor α (TNFα), and the expression and regulation of the miR‐17–92 cluster were studied using real‐time quantitative PCR (PCR) and promoter activity assays. RASFs were transfected with single precursor molecules of miRNAs from miR‐17–92 and the expression of matrix‐degrading enzymes and cytokines was measured by quantitative PCR and enzyme‐linked immunosorbent assay. Potential miRNA targets were identified by computational prediction and were validated using reporter gene assays and Western blotting. The activity of NF‐κB signaling was determined by reporter gene assays.

Results

We found that TNFα induces the expression of miR‐17–92 in RASFs in an NF‐κB–dependent manner. Transfection of RASFs with precursor molecules of single members of miR‐17–92 revealed significantly increased expression levels of matrix‐degrading enzymes, proinflammatory cytokines, and chemokines in precursor miR‐18a (pre‐miR‐18a)–transfected RASFs. Using reporter gene assays, we identified the NF‐κB pathway inhibitor TNFα‐induced protein 3 as a new target of miR‐18a. In addition, pre‐miR‐18a–transfected RASFs showed stronger activation of NF‐κB signaling, both constitutively and in response to TNFα stimulation.

Conclusion

Our data suggest that the miR‐17–92–derived miR‐18a contributes to cartilage destruction and chronic inflammation in the joint through a positive feedback loop in NF‐κB signaling, with concomitant up‐regulation of matrix‐degrading enzymes and mediators of inflammation in RASFs.
Borderline Mean Pulmonary Artery Pressure in Patients With Systemic Sclerosis: Transpulmonary Gradient Predicts Risk of Developing Pulmonary Hypertension
Authors: Valerio Christopher J. , Schreiber Benjamin E. , Handler Clive E. , Denton Christopher P. , Coghlan John G.
Published: December 2012

Objective

To determine whether patients with systemic sclerosis (SSc) and borderline mean pulmonary artery pressure (PAP) at cardiac catheterization are more likely to develop pulmonary hypertension (PH) than those in whom pulmonary pressure is normal.

Methods

Patients with SSc in whom PH and significant interstitial lung disease had been excluded at baseline were enrolled in our prospective cohort. Analysis of followup data identified patients who met prespecified criteria prompting repeat catheterization to reassess for possible PH. Using Kaplan‐Meier, receiver operating characteristic, and Cox regression methods, we studied the development of PH and death.

Results

Of 228 patients in this study, 86 had borderline mean PAP (21–24 mm Hg) at baseline. Following prespecified criteria, 76 patients underwent repeat catheterization, and 29 of these developed PH. Two cases were related to disease of the left side of the heart. The average mean PAP increased from baseline (20.2 mm Hg) to followup (24.3 mm Hg) (P < 0.05 by Student's t‐test). Patients with borderline mean PAP were more likely to develop PH than patients with mean PAP ≤20 mm Hg (P < 0.001 by log rank test, hazard ratio [HR] 3.7). A transpulmonary gradient (TPG) ≥11 mm Hg at baseline also predicted PH (P < 0.001 by log rank test, HR 7.9). Incident development of pulmonary arterial hypertension (PAH) was not benign, with a mortality of 18% within 3 years.

Conclusion

Our findings indicate that borderline mean PAP and an elevated TPG in patients with SSc predict progression to PH. These patients should be monitored closely for the development of PH. Our findings indicate that catheterization data are useful in patients considered at risk of PAH.
p53 Controls Autoimmune Arthritis via STAT‐Mediated Regulation of the Th17 Cell/Treg Cell Balance in Mice
Authors: Park Jin‐Sil , Lim Mi‐Ae , Cho Mi‐La , Ryu Jun‐Geol , Moon Young‐Mee , Jhun Joo‐Yeon , Byun Jae‐Kyeong , Kim Eun‐Kyung , Hwang Sue‐Yun , Ju Ji Hyeon , Kwok Seung‐Ki , Kim Ho‐Youn
Published: December 2012

Objective

To investigate the connection between p53 and interleukin‐17–producing Th17 cell/Treg cell balance in rheumatoid arthritis (RA).

Methods

Th17 cell and Treg cell frequencies were analyzed by flow cytometry, and cytokine levels in the supernatant were determined using enzyme‐linked immunosorbent assays. The expression of transcription factors was analyzed by immunostaining and Western blotting, and the interactions between p53 and STAT‐3 or STAT‐5 were determined by immunoprecipitation–Western blot analysis. A p53 agonist was administered in the collagen‐induced arthritis (CIA) model, and the effects in vivo were determined.

Results

CD4+ T cells from p53–/– mice decreased the activity of STAT‐5, lowered the level of phosphorylated STAT‐5, and compromised Treg cell differentiation. The protein p53 bound STAT‐5 directly, and this interaction was enhanced with increasing p53 activity. Under inflammatory conditions, p53 suppressed Th17 cell differentiation and skewed T cells toward Treg cell differentiation through the activation of STAT‐5 signaling cascades. In mice with CIA, injection of a p53 overexpression vector or an antagonist of Mdm2 had the effect of controlling arthritis development in vivo. The regulatory effect of p53 was recapitulated in the cells of RA patients, with more pronounced suppression due to the repressed status of p53 in RA.

Conclusion

We demonstrated a link between p53‐mediated and STAT‐mediated regulation of Th17 cells/Treg cells in RA. Our results suggest that factors involved in this pathway might constitute novel therapeutic targets for the treatment of RA.
Large Two‐Photon Absorption of Terpyridine‐Based Quadrupolar Derivatives: Towards their Applications in Optical Limiting and Biological Imaging
Authors: He Tingchao , Lim Zheng Bang , Ma Lin , Li Hairong , Rajwar Deepa , Ying Yongjun , Di Ziyun , Grimsdale Andrew C. , Sun Handong
Published: December 2012

Developing organic chromophores with large two‐photon absorption (TPA) in both organic solvents and aqueous media is crucial owing to their applications in solid‐state photonic devices and biological imaging. Herein, a series of novel terpyridine‐based quadrupolar derivatives have been synthesized. The influences of electron‐donating group, type of conjugated bridge, as well as solvent polarity on the molecular TPA properties have been investigated in detail. In contrast to the case in organic solvents, bis(thienyl)‐benzothiadiazole as a rigid conjugated bridge will completely quench molecular two‐photon emission in aqueous media. However, the combination of alkylcarbazole as the donor and bis(styryl)benzene as a conjugation bridge can enlarge molecular TPA cross‐sections in both organic solvent and aqueous media. The reasonable two‐photon emission brightness for the organic nanoparticles of chromophores 3–5 in the aqueous media, prepared by the reprecipitation method, enables them to be used as probes for in vivo biological imaging.
Simple Robust Tuning of2DoF PIDControllers From A Performance/Robustness Trade‐off Analysis
Authors: Alfaro V.M. , Vilanova R.
Published: December 2012

This paper presents the performance/robustness trade‐off analysis of servo‐control and regulatory‐control systems. In this analysis, first‐order‐plus‐dead‐time (FOPDT) and second‐order‐plus‐dead‐time (SOPDT) controlled processes with one‐degree‐of‐freedom (1DoF) and two‐degree‐of‐freedom (2DoF) proportional integral (PI) and proportional integral derivative (PID) controllers are considered. The analysis shows that for the same process, performance‐optimized1DoF PIcontrollers are more robust to changes in the process characteristics, but the optimal performance of these controllers is inferior to that of the correspondingPIDcontrollers. Regulatory‐control performance‐optimized PI andPIDcontrollers are less robust than the corresponding servo‐control systems, and a greater level of performance degradation is required in the former case to ensure that the robustness level becomes comparable to that in the latter case.

On the basis of this analysis, a simply robust tuning method was developed for2DoF PIDcontrollers; the use of this procedure helps in achieving the desired level of robustness in closed‐loop control systems. The proposed tuning method allows the use of a single set of rules for the robust tuning ofPIDcontrollers forFOPDTandSOPDTcontrolled processes
A New Adaptive Sliding Mode Control of Uncertain Nonlinear Systems
Authors: Liu Zhitao , Su Hongye , Pan Shuwen
Published: December 2012

In this paper, a new adaptive sliding mode control is proposed to control nonlinear systems with parametric uncertainties and matched and unmatched external disturbances. The proposed method first combines immersion and invariance (I&I) adaptive scheme with sliding mode control (SMC), which preserves the advantages of the two methods. The proposed method is different from the approach of combining the backstepping adaptive scheme and sliding mode control in the parameter estimation law, which allows for prescribed dynamics to be assigned to the estimation error and is easier to tune. Finally, the method is applied to control a class of power systems, and simulation results show the advantages of the proposed method.
Violence Risk Assessment in Clinical Settings: Being Sure about Being Sure
Authors: Buchanan Alec
Published: December 2012

Psychiatrists and psychologists have available structured risk assessment instruments to assess the risk of patient violence. These instruments are also used to help make important legal decisions, including which prisoners will be evaluated for continued detention at the end of their sentence. The predictive validity of structured instruments has been demonstrated in operationally defined groups. Their application to individual cases has led to objections that the standard deviations for the risk categories generated by the instruments overlap significantly. This debate has paid insufficient attention to the differences between aleatory (statistical) and epistemic (degree of confirmation) approaches to uncertainty. The approach to uncertainty in psychiatric violence risk assessment is, of necessity, largely epistemic. Providing statistical data can only be part of establishing the precision of an estimate of the probability of someone acting violently. Copyright © 2012 John Wiley & Sons, Ltd.
Exposure of colonic epithelial cells to oxidative and endoplasmic reticulum stress causes rapid potassium efflux and calcium influx
Authors: Shabala Lana , Walker Emma J , Eklund Annelie , Randall‐Demllo Sarron , Shabala Sergey , Guven Nuri , Cook Anthony L , Eri Rajaraman D
Published: December 2012

Endoplasmic reticulum (ER) stress and oxidative stress have recently been linked to the pathogenesis of inflammatory bowel diseases. Under physiological conditions, intestinal epithelial cells are exposed to ER and oxidative stress affecting the cellular ionic homeostasis. However, these altered ion flux ‘signatures’ during these stress conditions are poorly characterized. We investigated the kinetics of K+, Ca2+ and H+ ion fluxes during ER and oxidative stress in a colonic epithelial cell line LS174T using a non‐invasive microelectrode ion flux estimation technique. ER and oxidative stress were induced by cell exposure to tunicamycin (TM) and copper ascorbate (CuAsc), respectively, from 1 to 24 h. Dramatic K+ efflux was observed following acute ER stress with peak K+ efflux being −30·6 and −138·7 nmolm−2 s−1 for 10 and 50 µg ml−1, respectively (p < 0·01). TM‐dependent Ca2+ uptake was more prolonged with peak values of 0·85 and 2·68 nmol m−2 s−1 for 10 and 50 µg ml−1 TM, respectively (p < 0·02). Ion homeostasis was also affected by the duration of ER stress. Increased duration of TM treatment from 0 to 18 h led to increases in both K+ efflux and Ca2+ uptake. While K+ changes were significantly higher at each time point tested, Ca2+ uptake was significantly higher only after prolonged treatment (18 h). CuAsc also led to an increased K+ efflux and Ca2+ uptake. Functional assays to investigate the effect of inhibiting K+ efflux with tetraethylammonium resulted in increased cell viability. We conclude that ER/oxidative stress in colonic epithelial cells cause dramatic K+, Ca2+ and H+ ion flux changes, which may predispose this lineage to poor stress recovery reminiscent of that seen in inflammatory bowel diseases. Copyright © 2012 John Wiley & Sons, Ltd.
Catalytic Mechanism of the Arylsulfatase Promiscuous Enzyme from Pseudomonas Aeruginosa
Authors: Marino Tiziana , Russo Nino , Toscano Marirosa
Published: December 2012

To elucidate the working mechanism of the “broad substrate specificity” by the Pseudomonas aeruginosa aryl sulfatase (PAS) enzyme, we present here a full quantum chemical study performed at the density functional level. This enzyme is able to catalyze the hydrolysis of the original p‐nitrophenyl‐sulfate (PNPS) substrate and the promiscuous p‐nitrophenyl‐phosphate (PNPP) one with comparable reaction kinetics. Based on the obtained results, a multistep mechanism including activation of the nucleophile, the nucleophilic attack, and the cleavage of the SO (PO) bond is proposed. Regarding the phosphate monoester, the results indicate that only some steps of the promiscuous reaction are identical to those in the native process. Differences concern mainly the last step in which the His115 residue acts as a general base to accept the proton by the O atom of the FGly51 in the PNPS, whereas in PNPP, the Asp317 protonated residue works as a general acid to deliver a proton by a water molecule to the oxygen atom of the CO bond. The shapes of the relative potential‐ energy surface (PES) are similar in the two examined cases but the rate‐determining step is different (nucleophile attack vs. nucleophile activation). The influence of the dispersion contributions on the investigated reactions was also taken into account.
Process Performance of a Biotrickling Filter Using a Flow‐Directional‐Switching Method
Authors: Wang Liping , He Shilong , Xu Jiangcen , Li Jie , Mao Zhen
Published: December 2012

Non‐uniform distribution of biomass and the accumulation of excess biomass at the inlet of a unidirectional flow biotrickling filter (UF‐BTF) may lead to severe operating problems including increasing airflow resistance in packed bed, clogging, and low contaminant removal efficiencies, even performance loss. Therefore, a flow‐directional‐switching biotrickling filter (FDS‐BTF) was designed to improve performance such as the maximum elimination capacity and elimination efficiency. Toluene was chosen as the unique carbon source for microorganism. The results indicated that the purification performance of FDS‐BTF was superior to UF‐BTF. The maximum elimination capacity of FDS‐BTF was up to 480 g/(m3 h), which was 17.1% higher than that of UF‐BTF. After a 50‐day continuous operation, FDS‐BTF attained the stable purification performance and the outlet concentrations of toluene could meet the emission standard with inlet concentrations ranging from 720 to 1100 mg/m3 for an empty bed residence time (EBRT) of 23.9 s. The average well color development in FDS‐BTF was higher than that in UF‐BTF. It indicated that FDS‐BTF could improve the metabolic activity, which may improve the uniform distribution of biomass along the length of packed bed. When two systems were shut down, 24 and 48 h, respectively, the time that FDS‐BTF and UF‐BTF needed to restore the former elimination efficiency after a shut down of 48 h were 3–4 and 9–10 h. These data indicated that the purification performance of FDS‐BTF was superior to UF‐BTF.
Effects of Nitrogen Fertilization on Soil Microbial Biomass and Community Functional Diversity in Temperate Grassland in Inner Mongolia, China
Authors: He Yating , Qi Yuchun , Dong Yunshe , Xiao Shengsheng , Peng Qin , Liu Xinchao , Sun Liangjie
Published: December 2012

Nitrogen (N) fertilization may profoundly affect soil microbial communities. In this study, a field fertilization experiment was conducted in temperate grassland in Inner Mongolia, China to examine the effect of N fertilization on soil microbial properties and the main factors related to the characteristics of soil microbial community. Soil microbial biomass carbon (MBC) and microbial functional diversity along an N gradient were measured over three months (June to August). The result showed that N fertilization significantly decreased MBC under high N treatment (N200, 200 kg N ha−1 y−1) compared with the control (N0, 0 kg N ha−1 y−1) in the three months. Microbial functional diversity in July and August were significantly increased by low N treatment (N50, 50 kg N ha−1 y−1). Among the three fertilization treatments, microbial functional diversity under N200 in the three months was significantly lower than that of N50. The decrease of MBC and functional diversity under N200 were mainly due to the significant decline of plant belowground biomass under high N treatment. The increase of functional diversity under N50 treatment was due to the higher plant aboveground biomass as a result of the higher soil moisture availability. This finding highlighted that the higher N fertilization (N200) was not suitable for the growth and improvement of functional diversity of the soil microbial community, and that site and plant community play an important role in regulating the characteristics of soil microbial community.
Carbamazepine Removal from Groundwater: Effectiveness of the TiO2/UV, Nanoparticulate Zero‐Valent Iron, and Fenton (NZVI/H2O2) Processes
Authors: Shirazi Elham , Torabian Ali , Nabi‐Bidhendi Gholamreza
Published: December 2012

Pharmaceutical compounds, widely produced and used all around the world, are partly responsible for the widespread water pollution in the environment. Carbamazepine (CBZ) is an antiepileptic drug that persists in the environment for many years. In the present study, we used the TiO2/UV, nanoparticulate zero‐valent iron (NZVI), and NZVI/H2O2 treatment processes to compare efficiency of CBZ removal from water. Influence of NZVI loading, H2O2 concentration, TiO2 loading, UV lamp power, and the matrix (distilled water and groundwater) on CBZ removal efficiency was evaluated using full factorial design. Results indicated that the NZVI/H2O2 process oxidized CBZ within 5 min. On the other hand, the NZVI process alone did not reduce CBZ concentration after 120 min of process time. The NZVI/H2O2 process was equally effective in CBZ removal from both distilled water and groundwater whereas the TiO2/UV process was less effective due to the presence of ions in groundwater. CBZ removal efficiency of the TiO2/UV process declined 30% when the matrix was changed from distilled water to groundwater. Negative divalent ions, i.e., ${\rm SO}_{{\rm 4}}^{{\rm 2}- } $ and ${\rm CO}_{{\rm 3}}^{{\rm 2}- } $, were the main cause of reduction of CBZ removal efficiency from groundwater. It is likely that these two ions adsorb onto, and consequently prevent the superoxide anion ${\rm O}_{{\rm 2}}^{\bullet - } $ and hydroxyl radical OH• from being generated on, the surface of the TiO2.
Removal of Carbamazepine, Naproxen, and Trimethoprim from Water by Amberlite XAD‐7: A Kinetic Study
Authors: Domínguez‐Vargas Joaquín R. , Gonzalez Teresa , Palo Patricia , Cuerda‐Correa Eduardo M.
Published: December 2012

The adsorption kinetics of carbamazepine, naproxen, and trimethoprim in aqueous solution by Amberlite™ XAD‐7 has been studied. The influence of adsorbent dose (1–3 g/L), stirring rate (80–240 rpm), pH (2–9), temperature (20–60°C), and initial concentration (25–75 ppm) on the adsorption kinetics has been analyzed. The removal efficiency in the first 2 h reaches 85% for carbamazepine, 60% for naproxen, and 70% for trimethoprim. pH appears to be the most important factor conditioning the removal of these latter solutes, whereas carbamazepine adsorption seems to be independent of the pH of the adsorptive solution. Initial concentration and operation temperature moderately influence the adsorption process. Finally, stirring rate scarcely affects the process. The experimental data have been fitted to four kinetic models, namely pseudo‐first and pseudo‐second order, intra‐particle diffusion and Bangham's. The model providing the best fit is the pseudo‐second order one. Again, pH is the factor that affects the adsorption rate in a more remarkable manner although other parameters such as temperature and stirring rate also contribute to accelerate the removal of the solutes. Under the optimal operation conditions, Amberlite™ XAD‐7 exhibits a promising ability for the removal of the pharmaceuticals under study.
Screening for and Identification of an Anti‐clam Vibrio Marine Bacterium from an Aquaculture Pond in the Yellow Sea
Authors: Sun Xing , Zhao Gengmao , Gu Chenhao , Liu Ling , Zhu Ming , Liu Zhaopu
Published: December 2012

The identification and use of probiotic bacterial stains is a practical approach to protect clams grown in aquaculture farms from disease. The inhibition of the pathogenic bacterium Vibrio alginolyticus was used as a trait to select a candidate probiotic bacterial strain in this study. An ideal bacterial strain, SW‐1, was isolated from seawater from a clam farm. The selected isolate SW‐1 was identified based on its physiological, morphological, and biochemical characteristics and its 16S rDNA sequence. The experiments showed that strain SW‐1 had a high similarity to Pseudoalteromonas piscicida and could inhibit the growth of V. alginolyticus (V.‐MP‐1). SW‐1 also improved the survival of clams following challenge with the pathogenic V.‐MP‐1. The mortality of clams was 100% after infection with 108 CFU/mL of V. alginolyticus, whereas mortality was only 11% when clams were infected with 108 CFU/mL of V.‐MP1 while simultaneously exposed to the same concentration of Pseudoalteromonas SW‐1, indicating that Pseudoalteromonas SW‐1 could be used as a probiotic to protect farmed clams, and thus reduce the effects of antibiotics on aquatic environment.
Microwave‐Assisted In Situ Synthesis of Graphene/PEDOT Hybrid and Its Application in Supercapacitors
Authors: Sun Dong , Jin Li , Chen Yun , Zhang Jian‐Rong , Zhu Jun‐Jie
Published: December 2012

A graphene/poly(3,4‐ethylenedioxythiophene) (G/PEDOT) hybrid was prepared by the in situ polymerization of 3,4‐ethylenedioxythiophene using the precursor of graphene, graphene oxide, as an oxidant under microwave heating. The G/PEDOT hybrid was characterized by ultraviolet–visible absorption spectroscopy, Fourier transform infrared spectroscopy, atomic force microscopy, X‐ray photoelectron spectroscopy, field‐emission scanning electron microscopy, energy‐dispersive X‐ray spectroscopy, and electrochemical impedance spectroscopy. The electrochemical properties of G/PEDOT hybrid electrodes were investigated by cyclic voltammetry and galvanostatic charge–discharge measurements. The G/PEDOT hybrid as a supercapacitor electrode material afforded high specific capacitance and good cycling stability (93 % retention after 10 000 cycles at a high current density of 5 A g−1) during the charge–discharge process. A maximum specific capacitance as high as 270 F g−1 at a current density of 1 A g−1 was achieved in 1 M H2SO4 electrolyte solution. In addition, the energy density of the G/PEDOT hybrid reached 34 W h kg−1 at a power density of 25 kW kg−1.
Phase competition of Cu64Zr36 and its effect on glass forming ability of the alloy
Authors: Cui X. , Zu F. Q. , Zhang W. J. , Wang Z. Z. , Li X. Y.
Published: December 2012

In the present paper, crystallization behavior and glass forming ability (GFA) of Cu64Zr36 bulk metallic glass (BMG) were studied based on the crystal phase competition. Electrical resistivity and X‐ray diffraction results indicate that Cu64Zr36 glass underwent a two‐stage crystallization process, during which Cu10Zr7 and Cu51Zr14 crystals precipitate at first and then there are only Cu10Zr7 and Cu8Zr3 phases at the end of the second stage. Intriguingly, it was found that it is the competing phase Cu10Zr7 that weakens GFA of the Cu64Zr36 alloy, because the Cu10Zr7 precipitate is fully restrained in the cast rod when substituting Zr with 7.5at%Ti and thereby its diameter with fully amorphous structure is enlarged from 1 mm to 2 mm.
Synthesis and Evaluation as Antitubercular Agents of 5‐Arylethenyl and 5‐(Hetero)aryl‐3‐Isoxazolecarboxylate
Authors: Vergelli Claudia , Cilibrizzi Agostino , Crocetti Letizia , Graziano Alessia , Dal Piaz Vittorio , Wan Baojie , Wang Yuehong , Franzblau Scott , Giovannoni Maria Paola
Published: December 2012

Preclinical Research

A new series of 5‐aryl and 5‐arylethenylisoxazole carboxylate derivatives was synthesized and evaluated for in vitro activity against Mycobacterium tuberculosis H37Rv. Several compounds exhibited minimum inhibitory concentrations in the low micromolar range (2.3–11.4 μM). A variety of substituents introduced around the isoxazole ring allowed the delineation of preliminary SARs for this new series of compounds.
In Vivo Preclinical Evaluation of a Promising Antiarrhythmic Agent, EGIS‐7229
Authors: Drimba László , Nemeth Jozsef , Sári Réka , Di Yin , Kovács Anikó , Szénási Gábor , Szilvássy Zoltán , Peitl Barna
Published: December 2012

Preclinical Research

The basic hemodynamic, electrophysiological, and pharmacological effects of EGIS‐7229 (E‐7229) were evaluated and compared with those of a pure “Class III“ antiarrhythmic drug (GLG‐V‐13) in conscious rabbits. Both compounds decreased heart rate dose‐dependently. Mean arterial blood pressure was not influenced by E‐7229; however, GLG‐V‐13 produced a significant elevation on this parameter. Left ventricular end‐diastolic pressure was gradually increased by E‐7229, while GLG‐V‐13 induced more considerable elevation on that at intermediate doses. QT and QTcb were lengthened by both compounds; however, higher doses of E‐7229 resulted in shortening of the prolonged QT and QTcb. Ventricular effective refractory period (VERP) was significantly prolonged by either drug studied. Threshold doses to produce QT50%, QTmax, VERP50%, and VERPmax were significantly higher for E‐7229 compared with GLG‐V‐13. Significantly higher doses were required for E‐7229 to induce arrhythmias. The safety ratio was comparable for both of the compounds. E‐7229 can exert multiple actions on cardiac ion channels with minimal influence on hemodynamic parameters and reduced proarrhytmic profile in our preclinical model.
Latent autoimmune diabetes in the adults (LADA) in Asia: from pathogenesis and epidemiology to therapy
Authors: Guglielmi Chiara , Palermo Andrea , Pozzilli Paolo
Published: December 2012

Diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion, insulin action or both. An effect of this process is chronic hyperglycaemia with disorder of carbohydrate, fat and protein metabolism and with long‐term complications of diabetes including retinopathy, nephropathy and neuropathy. Latent autoimmune diabetes in adults (LADA) is a type of autoimmune diabetes that resembles Type 1 diabetes (T1D), however, it shows a later onset and slower progression towards insulin necessity. Epidemiological studies suggest that LADA may account for 2–12% of all cases of diabetes in adult population. The epidemiology and phenotypic characteristics of LADA may vary between Caucasian and Asian diabetic patients as lifestyle, food habits and body mass index differ between these two populations. Data on LADA from population‐based studies in Asia are sparse and only few studies have looked at it.

A number of attractive therapeutic interventions may be envisaged for prevention of beta‐cell loss in LADA, including hypoglycaemic and immunomodulatory agents. Because the autoimmune process in LADA seems to be slower than in childhood T1D, there is a wider window of opportunities for intervention. In deciding the best therapeutic approach, features of LADA should guide therapy including presence of other comorbidities that may influence the therapeutic choice.
Continuous glucose monitoring: current clinical use
Authors: Kim Hun‐Sung , Shin Jeong‐Ah , Chang Jin‐Sun , Cho Jae‐Hyoung , Son Ho‐Young , Yoon Kun‐Ho
Published: December 2012

Four kinds of subcutaneous continuous glucose monitoring (CGM) machines have been currently introduced in clinical practice. These machines exhibit real‐time glucose on the monitor every 5 minutes and have alarms to indicate hypoglycaemia and hyperglycaemia. However, thus far, there is no clear consensus about the clinical indications for CGM in actual clinical practice. CGM should be an ideal and powerful tool for monitoring glucose variability. Glycaemic variability has become a major concern over the years with growing evidence on its detrimental impact with respect to the risk of diabetic complications. Although the HbA1c level is ubiquitously measures in clinical practice, this level does not adequately represent glycaemic variability. Currently available evidence indicates that CGM aids in lowering the HbA1c level without increasing the incidence of severe hypoglycaemic episodes in patients with type 1 diabetes. Thus far, CGM has not been indicated for preventing severe hypoglycaemia or for treating type 2 diabetes because sufficient supporting evidence has not been obtained. Promising results have been obtained for the use of CGM for pregnant women with diabetes and for patients with hospital hyperglycaemia. Predictions regarding the feasibility of the closed‐loop system have proven to be optimistic. CGM‐integrated communication systems using information technology such as smart phone help controlling blood glucose more easily and effectively.
Do we need anti‐obesity drugs?
Authors: Hainer Vojtěch , Hainerová Irena Aldhoon
Published: December 2012

The increasing global prevalence of obesity urgently requires an implementation of efficient preventive and therapeutic measures. Weight loss and its maintenance should be considered one of the most important strategies to reduce the incidence of obesity‐related co‐morbidities such as diabetes and cardiovascular diseases. Lifestyle modification focused on diet and physical activity represents the essential component of any kind of weight management. However, only an intensive lifestyle intervention can be efficient in terms of long‐term weight loss. Anti‐obesity drugs affect different targets in the central nervous system or peripheral tissues and improve regulatory and metabolic disturbances that contribute to the development of obesity. Anti‐obesity medications provide modest additional fat loss to that achieved by lifestyle modification alone, reduce visceral fat stores, improve programme adherence, weight loss maintenance, diminish obesity‐related health risks and improve a quality of life. Anti‐obesity drugs do play a role in weight management. Their replacement with placebo is followed by weight regain. Due to adverse events, several anti‐obesity drugs were withdrawn from the market over the past few years and currently only orlistat remains available for long‐term obesity management. Drug withdrawals, failure of clinical trials with several new anti‐obesity compounds as well as inappropriate demands of drug regulating agencies concerning the study protocol led to scepticism about the perspectives in the pharmacotherapy of obesity. However, recently developed anti‐obesity medications such as gut hormone analogues and drug combinations provided encouraging results in terms of weight loss, safety and improvement of cardio‐metabolic health risks.
Second line therapy: type 2 diabetic subjects failing on metformin GLP‐1/DPP‐IV inhibitors versus sulphonylurea/insulin: For GLP‐1/DPP‐IV inhibitors
Authors: Kumar Ajay
Published: December 2012

Following diagnosis, type 2 diabetic subjects are invariably treated with life style modifications and metformin. However, majority of these subjects require addition of another therapeutic agent singly or in combination; with or without insulin within few months to few years. For several decades, sulphonylureas and insulin have been the second line agent of choice. Clinical practice guidelines also suggest a similar approach. Subsequently thiazolidinediones, alpha glucose inhibitors and other agents were added to therapeutic armamentarium. Unfortunately, none of these treatment options could address the issue of progressive decline in beta cell function. Furthermore, they are responsible for unacceptable incidence of hypoglycaemia, weight gain and other side effects related to individual agents.

Type 2 diabetic subjects have great propensity to develop cardiovascular complications. Sulphonylureas, insulin and thiazolidinediones have all been associated with adverse cardiovascular outcomes in differing magnitude. It has been made mandatory by regulatory agencies to ensure cardiovascular safety of any new anti‐diabetic agent.

Glucagon Like Peptide‐1(GLP‐1)‐based therapies have been able to address several of these issues. Incretin mimetics and Di Peptidyl Dipeptidase IV (DPP‐IV) inhibitors cause glucose‐dependent insulin secretion and glucagon suppression from beta and alpha cells of the pancreas respectively. They owe this property to their binding with G‐Protein‐coupled receptors leading to an increased amount of c‐AMP. They do not cause beta cell exhaustion. On the contrary such agents prevent beta cell apoptosis.

Clinical trials have established the superiority of incretin mimetics particularly liraglutide against comparators including glimepiride, rosiglitazone and insulin Glargine in terms of efficacy. Furthermore, they have shown evidence towards beta cell protection, significant weight loss, minimal hypoglycaemia and favourable impact on surrogate markers of cardiovascular outcomes. DPP‐IV inhibitors have limited ability to achieve glycaemic targets. However, they are weight neutral, cause minimal hypoglycaemia and have some beneficial effect on beta cell function. Finally, they are very well tolerated.
Melanocortin 3 receptor gene and melanocortin 4 receptor gene mutations: the Asian Perspective
Authors: Lee Yung Seng
Published: December 2012

Melanocortin 4 receptor (MC4R) deficiency resulting from disruption of one or both MC4R alleles represents the commonest monogenic form of human obesity to date. Human MC4R deficiency was reported to affect 4 and 5.8% of severely obese French and British populations respectively. However, studies elsewhere reported low incidence of MC4R mutations in their obese populations. The significance of MC4R mutations in Asian obese populations has not been adequately examined, though small studies in Japan, China, and Singapore reported few or no pathogenic mutations, suggesting a low prevalence in this part of the world. There were also few common mutations described across populations, suggesting a relative lack of founder effect. The pathogenic role of melanocortin 3 receptor gene (MC3R) mutations in human obesity is not as well described and accepted as MC4R mutations, though it is gradually gaining ground. Two common single nucleotide polymorphisms Thr6Lys and Val81Ile within the coding region were associated with higher body fat and leptin levels in obese children, supported by impaired signaling activity in vitro. There were also reports of missense mutations enriched in obese populations. While MC3R mutations are unlikely to result in an autosomal dominant form of monogenic obesity given the lack of strong co‐segregation in family studies, the studies so far provided evidence that MC3R can be one of the genes which contributes to increased adiposity, and exert an effect on the human phenotype.
Advanced research on risk factors of type 2 diabetes
Authors: Bi Yufang , Wang Tiange , Xu Min , Xu Yu , Li Mian , Lu Jieli , Zhu Xiaolin , Ning Guang
Published: December 2012

The prevalence of type 2 diabetes is increasing globally and poses a heavy burden on public health and socioeconomic development of all nations. Type 2 diabetes is a multifactorial disease and due to a combination of environmental and genetic risk factors. Many environmental risk factors contribute to the pathogenesis of type 2 diabetes, including lifestyles such as sedentary behaviour, diet, smoking and alcohol consumption, internal environmental factors such as inflammatory factors, adipocytokines and hepatocyte factors, external environmental factors such as environmental endocrine disruptors. This review summarizes current research efforts concentrated on the contributors for accelerated type 2 diabetes epidemic. It also provides a novel prospect for future researches.
Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease?
Authors: Saad Farid
Published: December 2012

Obesity, hypertension, insulin resistance (IR), dyslipidaemia, impaired coagulation profile and chronic inflammation characterize cardiovascular risk factors in men. Adipose tissue is an active endocrine organ producing substances that suppress testosterone (T) production and visceral fat plays a key role in this process. Low T leads to further accumulation of fat mass, thus perpetuating a vicious circle. In this review, we discuss reduced levels of T and increased cardiovascular disease (CVD) risk factors by focusing on evidence derived from three different approaches. (i) epidemiological/ observational studies (without intervention); (ii) androgen deprivation therapy (ADT) studies (standard treatment in advanced prostate cancer); and (iii) T replacement therapy (TRT) in men with T deficiency (TD). In epidemiological studies, low T is associated with obesity, inflammation, atherosclerosis and the progression of atherosclerosis. Longitudinal epidemiological studies showed that low T is associated with an increased cardiovascular mortality. ADT brings about unfavourable changes in body composition, IR and dyslipidaemia. Increases in fibrinogen, plasminogen activator inhibitor 1 and C‐reactive protein have also been observed. TRT in men with TD has consistently shown a decrease in fat mass and simultaneous increase in lean mass. T is a vasodilator and in long‐term studies, it was shown to reduce blood pressure. There is increasing evidence that T treatment improves insulin sensitivity and lipid profiles. T may possess anti‐inflammatory and anti‐coagulatory properties and therefore TRT contributes to reduction of carotid intima media thickness. We suggest that T may have the potential to decrease CVD risk in men with androgen deficiency.
Characteristics of hypertension in Chinese and their relevance for the choice of antihypertensive drugs
Authors: Wang Ji‐Guang , Li Yan
Published: December 2012

According to the 4th National Nutrition and Health Survey in 2002, the prevalence of hypertension in China was 18.8%. Despite that, the treatment rate among hypertensive patients was 82%, the control rate remained low in persons with hypertension (6%), because of the low awareness in general (30%) and the low control rate among treated hypertensive patients (25%). One of the major reasons for the increasing prevalence of hypertension is unbalance of dietary sodium and potassium intakes. In the International Study of Macro/Micro‐nutrients and Blood Pressure (INTERMAP), Chinese, compared with American, British, and Japanese populations, had highest dietary sodium intakes and lowest potassium intakes, leading to a two to three times higher sodium/potassium ratio. High dietary sodium intakes may change the circadian rhythm of 24 h blood pressure, which is characterized by a higher night‐time blood pressure. Indeed, the prevalence of isolated night‐time hypertension, defined as a night‐time blood pressure of at least 120 mmHg systolic or 70 mmHg diastolic and a daytime systolic/diastolic blood pressure less than 135/85 mmHg, was higher in Chinese than in Europeans. The complications of hypertension are also different across ethnicities, being mainly stroke instead of myocardial infarction in Chinese. Blood pressure lowering provides more protection against stroke than myocardial infarction, and calcium channel blockers provide more protection against stroke than other classes of antihypertensive drugs. Current Chinese hypertension guidelines recommend calcium channel blockers as the first of the five classes of antihypertensive drugs for stage 1 and low‐risk hypertension.