bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression of PU.1‐linked TLR4 expression by cilostazol with decrease of cytokine production in macrophages from patients with rheumatoid arthritis
Authors: Park SY , Lee SW , Baek SH , Lee CW , Lee WS , Rhim BY , Hong KW , Kim CD 
Published: October 2012

Background and PurposeThe present study assessed the effects of cilostazol on LPS‐stimulated TLR4 signal pathways in synovial macrophages from patients with rheumatoid arthritis (RA). These effects were confirmed in collagen‐induced arthritis (CIA) in mice.Experimental ApproachExpression of TLR4, PU.1, NF‐κB p65 and IκBα on synovial fluid macrophages from RA patients was determined by Western blotting, and cytokines were measured by elisa. Anti‐arthritic effects were evaluated in CIA mice.Key ResultsIntracellular cAMP was concentration‐dependently raised by cilostazol (1–100 μM). Cilostazol significantly suppressed LPS‐stimulated increase of TLR4 expression by blocking PU.1 transcriptional activity in RA macrophages. In addition, cilostazol decreased LPS‐induced myeloid differentiation factor 88 (MyD88) expression, but not that of TNF receptor‐associated factor 6 (TRAF6). Cilostazol also suppressed IkBα degradation and NF‐κB p65 nuclear translocation. Moreover, LPS‐induced increase of cytokine production (TNF‐α, IL‐1β) was inhibited by cilostazol, an effect which was accompanied by suppression of IκBα degradation, and NF‐κB p65 nuclear translocation. However, expression of anti‐inflammatory IL‐10 was elevated by cilostazol and forskolin/IBMX. In mice with CIA, post‐treatment with cilostazol (30 mg kg−1 day−1) decreased expression of TLR4 in knee joints in association with decreased recruitment of macrophages. Consequently, synovial inflammation, proteoglycan depletion and bone erosion were significantly inhibited by cilostazol treatment.Conclusions and ImplicationsCilostazol down‐regulated LPS‐stimulated PU.1‐linked TLR4 expression and TLR4/MyD88/NF‐κB signal pathways, and then suppressed inflammatory cytokine production in synovial macrophages from RA patients. Also cilostazol markedly inhibited the severity of CIA in mice.
To B or not to B cells-mediate a healthy start to life
Authors: Nguyen T G , Ward C M , Morris J M 
Published: October 2012

SummaryMaternal immune responses during pregnancy are critical in programming the future health of a newborn. The maternal immune system is required to accommodate fetal immune tolerance as well as to provide a protective defence against infections for the immunocompromised mother and her baby during gestation and lactation. Natural immunity and antibody production by maternal B cells play a significant role in providing such immunoprotection. However, aberrations in the B cell compartment as a consequence of maternal autoimmunity can pose serious risks to both the mother and her baby. Despite their potential implication in shaping pregnancy outcomes, the role of B cells in human pregnancy has been poorly studied. This review focuses on the role of B cells and the implications of B cell depletion therapy in pregnancy. It highlights the evidence of an association between aberrant B cell compartment and obstetric conditions. It also alludes to the potential mechanisms that amplify these B cell aberrances and thereby contribute to exacerbation of some maternal autoimmune conditions and poor neonatal outcomes. Clinical and experimental evidence suggests strongly that maternal autoantibodies contribute directly to the pathologies of obstetric and neonatal conditions that have significant implications for the lifelong health of a newborn. The evidence for clinical benefit and safety of B cell depletion therapies in pregnancy is reviewed, and an argument is mounted for further clinical evaluation of B cell-targeted therapies in high-risk pregnancy, with an emphasis on improving neonatal outcomes and prevention of neonatal conditions such as congenital heart block and fetal/neonatal alloimmune thrombocytopenia.
Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor
Authors: Gouilleux-Gruart V , Chapel H , Chevret S , Lucas M , Malphettes M , Fieschi C , Patel S , Boutboul D , Marson M-N , Gérard L , Lee M , Watier H , Oksenhendler E ,   DEFI study group
Published: October 2012

Summary
Treatment of common variable immunodeficiency disorders (CVID) is based on replacement therapy using intravenous (i.v.) or subcutaneous (s.c.) immunoglobulin (Ig)G. Interindividual variation of IgG dose is common. A total of 380 CVID patients on stable IgG replacement from two prospective cohorts were analysed. An ‘efficiency’ index was defined as the ratio of serum IgG trough level minus IgG residual to the average weekly dose of IgG infusion. A reduced efficiency of IgG was associated independently with the i.v. route (P &lt; 0·001) and with the presence of at least one CVID disease-related phenotype (lymphoproliferation, autoimmune cytopenia or enteropathy) (P &lt; 0·001). High IgG efficiency was noted in patients homozygotes for the variable number tandem repeat (VNTR) 3/3 polymorphism of the neonatal Fc receptor gene [IgG Fc fragment receptor transporter alpha chain (FCGRT)] promoter, and this was particularly significant in patients treated with IVIG (P &lt; 0.01). In a multivariate analysis, FCGRT VNTR 3/3 genotype (P = 0·008) and high serum albumin (P &lt; 0·001) were associated independently with increased efficiency of i.v. Ig.
Evaluating the utility of ambulatory blood pressure monitoring in kidney transplant recipients
Authors: Wen Kevin C. , Gourishankar Sita 
Published: October 2012

AbstractHypertension is a major risk factor for graft dysfunction and cardiovascular disease in kidney transplant recipients (KTX). Accurate monitoring is therefore essential to provide optimal therapy. We evaluated whether 24‐h ambulatory blood pressure monitoring (ABPM) is superior to clinic blood pressure (CBP) measurement in prevalent KTX. Twenty‐four‐hour ABPM was performed in 244 prevalent KTX. The average clinic systolic blood pressure (SBP) was 137.1 ± 19.4 mm Hg, and diastolic blood pressure (DBP) was 79.9 ± 10.5 mm Hg. The ABPM average SBP was 131.3 ± 15.4 mm Hg and DBP was 75.37 ± 8.8 mm Hg; daytime ABPM average SBP was 133.5 ± 15.0 mm Hg and DBP 77.4 ± 9.1 mm Hg. The correlations between CBP, 24‐h ABPM, and daytime ABPM were approximately 0.5. CBP measurements overestimate both 24‐h and daytime ABPM by linear regression (p < 0.001). In this largest study to date evaluating blood pressure monitoring in KTX, we found that CBP overestimates ABPM, highlighting the prevalence of white coat hypertension. The improved accuracy of ABPM will decrease overprescribing of BP medications to avoid hypotension, drug interactions, and non‐adherence. In contrast, identifying the nocturnal “non‐dippers”, not evident by CBP, facilitates appropriate management, as under‐treatment of hypertension could lead to accelerated graft dysfunction, cardiovascular disease, and mortality. These data suggest the improved accuracy of 24‐h ABPM is beneficial for BP monitoring in KTX recipients.
The long‐term efficacy of nucleos(t)ide analog plus a year of low‐dose HBIG to prevent HBV recurrence post‐liver transplantation
Authors: Tanaka Tomohiro , Benmousa Ali , Marquez Max , Therapondos George , Renner Eberhard L. , Lilly Leslie B. 
Published: October 2012

AbstractHepatitis B immunoglobulin (HBIG), given in combination with nucleos(t)ide therapy, has reduced the rate of recurrent hepatitis B virus (HBV) following liver transplantation (LT), although the most effective protocol is unknown. We have retrospectively evaluated the use of long‐term nucleos(t)ide analog in combination with one yr of low‐dose HBIG. One hundred and fifty‐two adults with HBV‐related liver disease underwent LT in our center from January 1999 to August 2009; of these, 132 patients who received one yr of HBIG combined with long‐term nucleos(t)ide analogs (largely on lamivudine [LAM] alone, n = 97) afterward were included for the purposes of this study. Median follow‐up post‐transplantation was 1752 d. Patient survival was 93.9%, 86.9% and 84.1% at 1, 5, and 10 yr, respectively; none of the 17 deceased patients had recurrent HBV. HBV recurrence was observed in nine patients (all received LAM+HBIG), yielding recurrence rates of 2.3%, 5.1%, and 8.6% at 1, 3, and 5/10 yr, respectively. All recurrences were successfully managed, usually with additional antiviral treatment. In conclusion, this study, with its long‐term follow‐up, demonstrates that short course of low‐dose HBIG (without anti‐HBs monitoring) combined with the use of long‐term nucleos(t)ide analog is effective and less cumbersome than many protocols in current use.
Acute kidney injury following living donor liver transplantation
Authors: Inoue Yusuke , Soyama Akihiko , Takatsuki Mitsuhisa , Hidaka Masaaki , Muraoka Izumi , Kanematsu Takashi , Eguchi Susumu 
Published: October 2012

AbstractBackgroundAlthough acute kidney injury (AKI) is regarded as a frequent complication following deceased donor liver transplantation, the incidence of AKI following living donor partial liver transplantation (LDLT) has not yet been sufficiently investigated.Patients and Methodswe used two definitions and investigated the influence of AKI on patient and graft survival. The definitions for the degree of AKI were as follows: AKI 1 was characterized by an increase in serum creatinine of 0.5 mg/dL, while AKI 2 was 1.0 mg/dL above the baseline within one wk during the post‐operative course. The incidence and its impact were investigated.ResultsThe incidence of AKI 1 was 63.1%. The development of AKI 1 was correlated with intra‐operative blood loss (p = 0.013), the length of post‐operative ICU stay, and hospitalization (p = 0.020 and 0.038). The incidence of AKI 2 was 27.7%, and AKI 2 was correlated with the length of both the post‐operative ICU and hospital stays. The development of AKI 2 was significantly correlated with graft survival (p = 0.015).ConclusionRecognizing the peri‐operative risk and development of AKI is important, because AKI post‐LDLT is associated with a poorer graft survival and a possible worse long‐term prognosis.
Distinctive Frequencies of +874T/A IFN‐γ Gene Polymorphism in a Healthy Serbian Population
Authors: Popadic Dusan , Savic Emina , Spuran Zorica , Markovic Milos , Stojkovic Marija Mostarica , Ramic Zorica , Pravica Vera 
Published: October 2012

AbstractPurpose: Single nucleotide polymorphism (SNP) in IFN‐γ gene (+874T/A) that determines high (TT), low (AA), and intermediate (TA) responder phenotypes has shown associations with susceptibility to infectious and chronic inflammatory diseases, as well as disease outcome. Therefore, the susceptibility to and outcome of certain diseases can vary in different ethnic populations partially due to the notable differences in frequencies of genotypes and alleles between them. The aim of this study was to determine the distribution of +874T/A genotype and allele frequencies in a healthy Serbian population as a reference for further disease association studies.Materials and Methods: Genomic DNA samples from 166 healthy volunteers were evaluated for IFN‐γ SNP at position +874 using TaqMan SNP genotyping assay.Results: The frequencies of AA, AT, and TT genotypes were 28.9%, 49.4%, and 21.7%, respectively. The A and T allele frequencies were 53.6% and 46.4%.Conclusions: Analysis of genotype and allele frequencies for IFN‐γ+874T/A SNP in healthy subjects revealed, for the first time, the genetic profile for this polymorphism in a Serbian population resembling most European populations, but differing from some Asian and African ethnic groups. Clin Trans Sci 2012; Volume 5: 461–463
The CTSA as an Exemplar Framework for Developing Multidisciplinary Translational Teams
Authors: Calhoun William J. , Wooten Kevin , Bhavnani Suresh , Anderson Karl E. , Freeman Jean , Brasier Allan R. 
Published: October 2012

AbstractTranslational science requires that scientists from multiple disciplines work together to improve the prevention, diagnosis, and treatment of human disease. Although a literature exists on the design and management of multidisciplinary teams, little has been written on multidisciplinary translational teams (MTTs). MTTs are distinct hybrid entities, with goals taken from both industry and academic models. We identified 30 design factors in 10 domains from a literature survey relevant to our MTT model: specific goals, structures, and processes. These dimensions were adapted to our own institutional environment in the selection and management of 11 MTTs that exploited resources of University of Texas Medical Branch (UTMB) Clinical and Translational Sciences Awards (CTSA). Case illustrations of two specific MTTs illustrate some of the challenges encountered and opportunities realized in terms of education and scientific advances. Network depiction of disciplinarity indicated that CTSA KRs and CTSA leadership contributed to discipline diversity especially in small (or nascent) MTTs. A separate depiction of MTT‐KR utilization indicated that data analysis, translational technologies, and novel methods were heavily utilized by MTTs, whereas other KRs contributed significant effort to infrastructure development. We conclude that the CTSA can provide a rich  infrastructural framework and scientific environment for the development of successful MTTs. Clin Trans Sci 2013; Volume 6: 60–71
Penetration and biological effects of topically applied cyclosporin A nanoparticles in a human skin organ culture inflammatory model
Authors: Frušić‐Zlotkin Marina , Soroka Yoram , Tivony Ran , Larush Liraz , Verkhovsky Lilian , Brégégère François Menahem , Neuman Rami , Magdassi Shlomo , Milner Yoram 
Published: October 2012

AbstractSystemic antipsoriatic therapies have potentially life‐threatening, long‐term side effects. The efficacy of topical drugs is poor, but may be improved by the use of delivery systems based on drug nanoparticles. To produce nanoparticles (NP) composed of cyclosporin A, a classical antipsoriatic drug, and to investigate their penetration and biological effects in human skin affected by psoriatic symptoms, poly‐ε‐caprolactone (PCL) and cyclosporin A (CsA) NP were prepared by the solvent evaporation method. Skin penetration was followed using fluorescently labeled NP in human skin organ cultures (hSOC). Psoriatic symptoms were mimicked in hSOC by the treatment with epidermal growth factor (EGF) and bacterial lipopolysaccharide (LPS). Cell viability in hSOC was evaluated by the resazurin test, and cytokine secretion into the growth medium was measured by immunodetection. We showed that topically applied NP diffused throughout the epidermis within two hours and through the dermis within the following day. They significantly reduced the secretion of inflammatory cytokines IL–1β, IL–6, IL–8, IL–20 and IL–23. At active doses, no cytotoxicity was detected. This type of NP display relevant properties for the use as topical anti‐inflammatory agents and may help to resorb psoriatic lesions.
Crystal structure of greglin, a novel non‐classical Kazal inhibitor, in complex with subtilisin
Authors: Derache Chrystelle , Epinette Christophe , Roussel Alain , Gabant Guillaume , Cadene Martine , Korkmaz Brice , Gauthier Francis , Kellenberger Christine 
Published: October 2012

Greglin is an 83‐residue serine protease inhibitor purified from the ovaries of the locust Schistocerca gregaria. Greglin is a strong inhibitor of subtilisin and human neutrophil elastase, acting at sub‐nanomolar and nanomolar concentrations, respectively; it also inhibits neutrophil cathepsin G, α‐chymotrypsin and porcine pancreatic elastase, but to a lesser extent. In the present study, we show that greglin resists denaturation at high temperature (95 °C) and after exposure to acetonitrile and acidic or basic pH. Greglin is composed of two domains consisting of residues 1–20 and 21–83. Mass spectrometry indicates that the N‐terminal domain (1–20) is post‐translationally modified by phosphorylations at three sites and probably contains a glycosylation site. The crystal structure of the region of greglin comprising residues 21–78 in complex with subtilisin was determined at 1.75 Å resolution. Greglin represents a novel member of the non‐classical Kazal inhibitors, as it has a unique additional C‐terminal region (70–83) connected to the core of the molecule via a supplementary disulfide bond. The stability of greglin was compared with that of an ovomucoid inhibitor. The thermostability and inhibitory specificity of greglin are discussed in light of its structure. In particular, we propose that the C‐terminal region is responsible for non‐favourable interactions with the autolysis loop (140‐loop) of serine proteases of the chymotrypsin family, and thus governs specificity.DatabaseThe atomic coordinates and structure factors for the greglin–subtilisin complex have been deposited with the RCSB Protein Data Bank under accession number 4GI3.Structured digital abstract

Greglin and Subtilisin Carlsberg bind by X-ray crystallography (View interaction)
Climate warming over the past three decades has shortened rice growth duration in China and cultivar shifts have further accelerated the process for late rice
Authors: Zhang Tianyi , Huang Yao , Yang Xiaoguang 
Published: October 2012

AbstractAn extensive dataset on rice phenology in China, including 202 series broadly covering the past three decades (1980s–2000s), was compiled. From these data, we estimated the responses of growth duration length to temperature using a regression model based on the data with and without detrending. Regression coefficients derived from the detrended data reflect only the temperature effect, whereas those derived from data without detrending represent a combined effect of temperature and confounding cultivar shifts. Results indicate that the regression coefficients calculated from the data with and without detrending show an average shortening of the growth duration of 4.1–4.4 days for each additional increase in temperature over the full growth cycle. Using the detrended data, 95.0% of the data series exhibited a negative correlation between the growth duration length and temperature; this correlation was significant in 61.9% of all of the data series. We then compared the difference between the two regression coefficients calculated from data with and without detrending and found a significantly greater temperature sensitivity using the data without detrending (−2.9 days °C−1) than that derived from the detrended data (−2.0 days °C−1) in the period of emergence to heading for the late rice, producing a negative difference in temperature sensitivity (−0.9 days °C−1). This implies that short‐duration cultivars were planted with increase in temperature and exacerbated the undesired phenological change. In contrast, positive differences were detected for the single (0.6 days °C−1) and early rice (0.5 days °C−1) over the full growth cycle, which might indicate that long‐duration cultivars were favoured with climate warming, but these differences were insignificant. In summary, our results suggest that a major, temperature induced change in the rice growth duration is underway in China and that using a short‐duration cultivar has been accelerating the process for late rice.
Soybean extract showed modulation of retinoic acid‐related gene expression of skin and photo‐protective effects in keratinocytes
Authors: Park N.‐H. , Park J.‐S. , Kang Y.‐G. , Bae J.‐H. , Lee H.‐K. , Yeom M.‐H. , Cho J.‐C. , Na Y. J. 
Published: October 2012

SynopsisSoy extracts are well known as medicinal and nutritional ingredients, and exhibit benefits towards human skin including depigmenting or anti‐ageing effects. Despite the wrinkle decreasing effects of retinoids on skin as an anti‐ageing ingredient, retinoid application can causes photo‐sensitive responses such as skin irritation. Thus, their daytime usage is not recommended. The aim of this study is the investigation into the activities of soybean extract as an anti‐ageing ingredient and their comparison to retinoids in this respect. Soybean extract decreased the relative ratio of MMP‐1/TIMP‐1 mRNA to the same degree as retinoic acid in normal human fibroblasts. It also affected mRNA levels of HAS2 and CRABP2 in normal human keratinocytes. Furthermore, we investigated its effect on mRNA expression of histidase, an enzyme that converts histidine into urocanic acid, the main UV light absorption factor of the stratum corneum. Unlike the complete inhibition of histidase exhibited by the mRNA expression of retinoic acid, the effect of soybean extract on histidase gene expression was weaker in normal human keratinocytes. Also, soybean extract pretreatment inhibited UVB‐induced cyclobutane pyrimidine dimer formation dose‐dependently in normal human keratinocytes. In this study, we found that soybean extract modulated retinoic acid‐related genes and showed photo‐protective effects. Our findings suggest that soybean extract could be an anti‐ageing ingredient that can be safely used under the sunlight.
Morphological characterization of solar lentigines by in vivo reflectance confocal microscopy: a longitudinal approach
Authors: Pollefliet C. , Corstjens H. , González S. , Hellemans L. , Declercq L. , Yarosh D. 
Published: October 2012

SynopsisSolar lentigines are benign hyperpigmented skin lesions. Despite their widespread distribution, knowledge on the mechanisms of development is largely unknown. A clinical study was designed in which solar lentigines were characterized using various non‐invasive clinical techniques. A subset of solar lentigines was followed over a 5‐year time period. One hundred and twenty‐eight solar lentigines were evaluated using in vivo reflectance confocal microscopy (RCM) for the evaluation of the length and density of their dermal papillae as well as the deformation of the alignment pattern of hyperrefractive basal cells. Skin colour, colour contrast, the size of the solar lentigo, epidermal proliferation rate, melanin and haemoglobin content were quantified. RCM imaging of solar lentigines revealed a profound structural deformation of the dermal papillae, as the alignment pattern of hyperrefractive basal cells shifted from a circle in non‐lesional skin to an irregular non‐circular shape in solar lentigines. There was a rise in the number of dermal papillae, and these dermal papillae were significantly longer. Solar lentigines had increased melanin and haemoglobin levels and a higher rate of epidermal proliferation. For a subset of nineteen solar lentigines, a longitudinal study was set‐up in which these measurements were repeated 5 years after the first evaluation. The deformation and the number of the hyperrefractive dermal papillary rings increased significantly over the 5‐year time span. The size of the lesion increased, and the skin colour became darker. RCM is a useful non‐invasive clinical tool for the characterization of solar lentigines, in particular the compressive deformation of the dermal papillae. This deformation became more severe over a time period of 5 years. To our knowledge, this is the first time that the in vivo time‐dependent progression of solar lentigines was supported by RCM images, contributing to an improved understanding of the formation and progression of solar lentigines.