bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineering glutathione biosynthesis of Saccharomyces cerevisiae increases robustness to inhibitors in pretreated lignocellulosic materials
Authors: Ask Magnus , Mapelli Valeria , Höck Heidi , Olsson Lisbeth , Bettiga Maurizio
Published: October 2013

Background

Production of bioethanol from lignocellulosic biomass requires the development of robust microorganisms that can tolerate the stressful conditions prevailing in lignocellulosic hydrolysates. Several inhibitors are known to affect the redox metabolism of cells. In this study, Saccharomyces cerevisiae was engineered for increased robustness by modulating the redox state through overexpression of GSH1, CYS3 and GLR1, three genes involved in glutathione (GSH) metabolism.

Results

Overexpression constructs were stably integrated into the genome of the host strains yielding five strains overexpressing GSH1, GSH1/CYS3, GLR1, GSH1/GLR1 and GSH1/CYS3/GLR1. Overexpression of GSH1 resulted in a 42% increase in the total intracellular glutathione levels compared to the wild type. Overexpression of GSH1/CYS3, GSH1/GLR1 and GSH1/CYS3/GLR1 all resulted in equal or less intracellular glutathione concentrations than overexpression of only GSH1, although higher than the wild type. GLR1 overexpression resulted in similar total glutathione levels as the wild type. Surprisingly, all recombinant strains had a lower [reduced glutathione]:[oxidized glutathione] ratio (ranging from 32–67) than the wild type strain (88), suggesting a more oxidized intracellular environment in the engineered strains. When considering the glutathione half-cell redox potential (Ehc), the difference between the strains was less pronounced. Ehc for the recombinant strains ranged from -225 to -216 mV, whereas for the wild type it was estimated to -225 mV. To test whether the recombinant strains were more robust in industrially relevant conditions, they were evaluated in simultaneous saccharification and fermentation (SSF) of pretreated spruce. All strains carrying the GSH1 overexpression construct performed better than the wild type in terms of ethanol yield and conversion of furfural and HMF. The strain overexpressing GSH1/GLR1 produced 14.0 g L-1 ethanol in 48 hours corresponding to an ethanol yield on hexoses of 0.17 g g-1; while the wild type produced 8.2 g L-1 ethanol in 48 hours resulting in an ethanol yield on hexoses of 0.10 g g-1.

Conclusions

In this study, we showed that engineering of the redox state by modulating the levels of intracellular glutathione results in increased robustness of S. cerevisiae in SSF of pretreated spruce.
A novel polymorphism (901G > a) of C5L2 gene is associated with coronary artery disease in Chinese Han and Uyghur population
Authors: Zheng Ying-Ying , Xie Xiang , Ma Yi-Tong , Yang Yi-Ning , Fu Zhen-Yan , Li Xiao-Mei , Ma Xiang , Chen Bang-Dang , Liu Fen
Published: September 2013

Background

C5L2, a G protein-coupled receptor (GPCR), has been demonstrated to be a ligand for acylation-stimulating protein (ASP). The aim of the present study is to evaluate the association of a novel variation (901A > G) of C5L2 gene with coronary artery disease (CAD).

Methods

We identified a novel single nucleotide polymorphism (SNP), (901G > A), in exon 2 using a polymerase chain reaction direct-sequencing method. This nucleotide change causes the amino-acid order from Arginine to glutaminate at codon 300. We analyzed the relationship between this SNP and CAD in two independent case–control studies: one was in a Han population (492 CAD patients and 577 control subjects) and the other was in a Uygur population (319 CAD patients and 554 control subjects).

Results

The frequency of AG genotype in CAD subjects was less than that in the control subjects not only in Han (1.8% vs 8.6%, P < 0.001, OR = 0.143, 95% CI: 0.068 ~ 0.302) but also in Uygur population (0.9% vs 5.2%, P = 0.001, OR = 0.246, 95% CI: 0.072 ~ 0.837). After adjustment for known CAD risk factors such as hypertension, diabetes, smoking, age and gender, the difference remained significant.

Conclusion

The 901G > A polymorphism of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China.
Characteristic analysis of α-fetoprotein-producing gastric carcinoma in China
Authors: Li Xiao-Dong , Wu Chang-Ping , Ji Mei , Wu Jun , Lu Binfeng , Shi Hong-Bing , Jiang Jing-Ting
Published: October 2013

α-Fetoprotein-producing gastric cancer (AFPGC) is a rare type of gastric cancer. The largest population of patients with AFPGC is found in China. In the present study, a total of 4,779 GC patients, including 317 AFPGC patients, from 11 clinical studies in China with a general AFPGC/GC ratio of 6.63% were summarized and analyzed. On the basis of analysis of the clinical data, the patients with AFPGC had larger tumor size, weaker cell differentiation, worse histopathological types, deeper serosal infiltration, more lymph node and liver metastases, poorer stages, shorter survival time and more positive expression of vascular endothelial growth factors than the patients without AFPGC. Our observation is consistent with previous results reported in studies of AFPGC. Overall, AFPGC is a subtype of GC with a poor prognosis.
Family history and risk of ductal carcinoma in situ and triple negative breast cancer in a Han Chinese population: a case–control study
Authors: Zhou Wenbin , Pan Hong , Liang Mengdi , Xia Kai , Liang Xiuqing , Xue Jinqiu , Cheng Lin , Xue Jialei , Chen Si , Liu Xiaoan , Ding Qiang , Ling Lijun , Wang Shui
Published: October 2013

Background

The association between family history and risk of triple negative breast cancer and ductal carcinoma in situ (DCIS) has not been well investigated, especially in Asian populations. We investigated the association between family history and risk of DCIS or triple negative breast cancer in a Han Chinese population.

Methods

A case–control study, comprising 926 breast cancer patients and 1,187 benign breast disease controls, was conducted in our hospital. Multivariate logistic regression was used to assess the relationships between family history and risk of DCIS or triple negative breast cancer.

Results

Subjects with a family history of breast cancer had higher breast cancer risk than those without a family history (odds ratio (OR) = 2.11, 95% confidence interval (CI) = 1.26 to 3.52). Family history was not significantly associated with an increased risk of DCIS (OR = 1.27, 95% CI = 0.36 to 4.46), while family history was significantly associated with an increased risk of invasive breast cancer (OR = 2.22, 95% CI = 1.32 to 3.75), irrespective of triple negative breast cancer (OR = 3.35, 95% CI = 1.43 to 7.88) or non-triple negative breast cancer (OR = 2.14, 95% CI = 1.21 to 3.80).

Conclusion

Our results indicate that having a family history of breast cancer is associated with an increased risk of triple negative breast cancer with a magnitude of association similar to that for non-triple negative breast cancer. Furthermore, family history is not significantly associated with an increased risk of DCIS. Future cohort studies with larger sample sizes are still needed to explore these relationships.
Analysis of tuberculosis prevalence surveys: new guidance on best-practice methods
Authors: Floyd Sian , Sismanidis Charalambos , Yamada Norio , Daniel Rhian , Lagahid Jaime , Mecatti Fulvia , Vianzon Rosalind , Bloss Emily , Tiemersma Edine , Onozaki Ikushi , Glaziou Philippe , Floyd Katherine
Published: September 2013

Background

An unprecedented number of nationwide tuberculosis (TB) prevalence surveys will be implemented between 2010 and 2015, to better estimate the burden of disease caused by TB and assess whether global targets for TB control set for 2015 are achieved. It is crucial that results are analysed using best-practice methods.

Objective

To provide new theoretical and practical guidance on best-practice methods for the analysis of TB prevalence surveys, including analyses at the individual as well as cluster level and correction for biases arising from missing data.

Analytic methods

TB prevalence surveys have a cluster sample survey design; typically 50-100 clusters are selected, with 400-1000 eligible individuals in each cluster. The strategy recommended by the World Health Organization (WHO) for diagnosing pulmonary TB in a nationwide survey is symptom and chest X-ray screening, followed by smear microscopy and culture examinations for those with an abnormal X-ray and/or TB symptoms. Three possible methods of analysis are described and explained. Method 1 is restricted to participants, and individuals with missing data on smear and/or culture results are excluded. Method 2 includes all eligible individuals irrespective of participation, through multiple missing value imputation. Method 3 is restricted to participants, with multiple missing value imputation for individuals with missing smear and/or culture results, and inverse probability weighting to represent all eligible individuals. The results for each method are then compared and illustrated using data from the 2007 national TB prevalence survey in the Philippines. Simulation studies are used to investigate the performance of each method.

Key findings

A cluster-level analysis, and Methods 1 and 2, gave similar prevalence estimates (660 per 100,000 aged ≥ 10 years old), with a higher estimate using Method 3 (680 per 100,000). Simulation studies for each of 4 plausible scenarios show that Method 3 performs best, with Method 1 systematically underestimating TB prevalence by around 10%.

Conclusion

Both cluster-level and individual-level analyses should be conducted, and individual-level analyses should be conducted both with and without multiple missing value imputation. Method 3 is the safest approach to correct the bias introduced by missing data and provides the single best estimate of TB prevalence at the population level.
Human Polyomavirus JC monitoring and noncoding control region analysis in dynamic cohorts of individuals affected by immune-mediated diseases under treatment with biologics: an observational study
Authors: Bellizzi Anna , Anzivino Elena , Rodio Donatella Maria , Cioccolo Sara , Scrivo Rossana , Morreale Manuela , Pontecorvo Simona , Ferrari Federica , Di Nardo Giovanni , Nencioni Lucia , Carluccio Silvia , Valesini Guido , Francia Ada , Cucchiara Salvatore , Palamara Anna Teresa , Pietropaolo Valeria
Published: October 2013

Background

Progressive multifocal leukoencephalopathy (PML) onset, caused by Polyomavirus JC (JCPyV) in patients affected by immune-mediated diseases during biological treatment, raised concerns about the safety profile of these agents. Therefore, the aims of this study were the JCPyV reactivation monitoring and the noncoding control region (NCCR) and viral protein 1 (VP1) analysis in patients affected by different immune-mediated diseases and treated with biologics.

Methods

We performed JCPyV-specific quantitative PCR of biological samples collected at moment of recruitment (t0) and every 4 months (t1, t2, t3, t4). Subsequently, rearrangements’ analysis of NCCR and VP1 was carried out. Data were analyzed using χ2 test.

Results

Results showed that at t0 patients with chronic inflammatory rheumatic diseases presented a JCPyV load in the urine significantly higher (p≤0.05) than in patients with multiple sclerosis (MS) and Crohn’s disease (CD). It can also be observed a significant association between JC viruria and JCPyV antibodies after 1 year of natalizumab (p=0.04) in MS patients. Finally, NCCR analysis showed the presence of an archetype-like sequence in all urine samples, whereas a rearranged NCCR Type IR was found in colon-rectal biopsies collected from 2 CD patients after 16 months of infliximab. Furthermore, sequences isolated from peripheral blood mononuclear cells (PBMCs) of 2 MS patients with JCPyV antibody at t0 and t3, showed a NCCR Type IIR with a duplication of a 98 bp unit and a 66 bp insert, resulting in a boxB deletion and 37 T to G transversion into the Spi-B binding site. In all patients, a prevalence of genotypes 1A and 1B, the predominant JCPyV genotypes in Europe, was observed.

Conclusions

It has been important to understand whether the specific inflammatory scenario in different immune-mediated diseases could affect JCPyV reactivation from latency, in particular from kidneys. Moreover, for a more accurate PML risk stratification, testing JC viruria seems to be useful to identify patients who harbor JCPyV but with an undetectable JCPyV-specific humoral immune response. In these patients, it may also be important to study the JCPyV NCCR rearrangement: in particular, Spi-B expression in PBMCs could play a crucial role in JCPyV replication and NCCR rearrangement.
Qualitative investigation of barriers to accessing care by people who inject drugs in Saskatoon, Canada: perspectives of service providers
Authors: Lang Katherine , Neil Jaycie , Wright Judith , Dell Colleen Anne , Berenbaum Shawna , El-Aneed Anas
Published: October 2013

Background

People who inject drugs (PWID) often encounter barriers when attempting to access health care and social services. In our previous study conducted to identify barriers to accessing care from the perspective of PWIDs in Saskatoon, Canada: poverty, lack of personal support, discrimination, and poor knowledge and coordination of service providers among other key barriers were identified. The purpose of the present investigation was to explore what service providers perceive to be the greatest barriers for PWIDs to receive optimal care. This study is an exploratory investigation with a purpose to enrich the literature and to guide community action.

Methods

Data were collected through focus groups with service providers in Saskatoon. Four focus groups were held with a total of 27 service providers. Data were transcribed and qualitative analysis was performed. As a result, concepts were identified and combined into major themes.

Results

Four barriers to care were identified by service providers: inefficient use of resources, stigma and discrimination, inadequate education and the unique and demanding nature of PWIDs. Participants also identified many successful services.

Conclusion

The results from this investigation suggest poor utilization of resources, lack of continuing education of health care providers on addictions and coping skills with such demanding population, and social stigma and disparity. We recommend improvements in resource utilization through, for example, case management. In addition, sensitivity training and more comprehensive service centers designed to meet PWID’s complex needs may improve care. However, community-wide commitment to addressing injection drug issues will also be required for lasting solutions.
Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice
Authors: Kerr Travis M , Muller Christopher L , Miah Mahfuzur , Jetter Christopher S , Pfeiffer Rita , Shah Charisma , Baganz Nicole , Anderson George M , Crawley Jacqueline N , Sutcliffe James S , Blakely Randy D , Veenstra-VanderWeele Jeremy
Published: October 2013

Background

Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes.

Methods

To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity.

Results

One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior.

Conclusions

Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.
Control of mRNA stability contributes to low levels of nuclear poly(A) binding protein 1 (PABPN1) in skeletal muscle
Authors: Apponi Luciano H , Corbett Anita H , Pavlath Grace K
Published: October 2013

Background

The nuclear poly(A) binding protein 1 (PABPN1) is a ubiquitously expressed proteinthat plays critical roles at multiple steps in post-transcriptional regulation ofgene expression. Short expansions of the polyalanine tract in the N-terminus ofPABPN1 lead to oculopharyngeal muscular dystrophy (OPMD), which is an adult onsetdisease characterized by eyelid drooping, difficulty in swallowing, and weaknessin the proximal limb muscles. Why alanine-expanded PABPN1 leads to muscle-specificpathology is unknown. Given the general function of PABPN1 in RNA metabolism,intrinsic characteristics of skeletal muscle may make this tissue susceptible tothe effects of mutant PABPN1.

Methods

To begin to understand the muscle specificity of OPMD, we investigated thesteady-state levels of PABPN1 in different tissues of humans and mice.Additionally, we analyzed the levels of PABPN1 during muscle regeneration afterinjury in mice. Furthermore, we assessed the dynamics of PABPN1 mRNA decay inskeletal muscle compared to kidney.

Results

Here, we show that the steady-state levels of both PABPN1 mRNA and protein aredrastically lower in mouse and human skeletal muscle, particularly those impactedin OPMD, compared to other tissues. In contrast, PABPN1 levels are increasedduring muscle regeneration, suggesting a greater requirement for PABPN1 functionduring tissue repair. Further analysis indicates that modulation of PABPN1expression is likely due to post-transcriptional mechanisms acting at the level ofmRNA stability.

Conclusions

Our results demonstrate that PABPN1 steady-state levels and likely control ofexpression differ significantly in skeletal muscle as compared to other tissues,which could have important implications for understanding the muscle-specificnature of OPMD.
Effects of varying duty cycle and pulse width on high-intensity focused ultrasound (HIFU)-induced transcranial thrombolysis
Authors: Hölscher Thilo , Raman Rema , Fisher David J , Ahadi Golnaz , Zadicario Eyal , Voie Arne
Published: October 2013

The goal was to test the effects of various combinations of pulse widths (PW) and duty cycles (DC) on high-intensity focused ultrasound (HIFU)-induced sonothrombolysis efficacy using an in vitro flow model. An ExAblate™ 4000 HIFU headsystem (InSightec, Inc., Israel) was used. Artificial blood clots were placed into test tubes inside a human calvarium and exposed to pulsatile flow. Four different duty cycles were tested against four different pulse widths. For all study groups, an increase in thrombolysis efficacy could be seen in association with increasing DC and/or PW (p < 0.0001). Using transcranial HIFU, significant thrombolysis can be achieved within seconds and without the use of lytic drugs in vitro. Longer duty cycles in combination with longer pulse widths seem to have the highest potential to optimize clot lysis efficacy.
Pharmacokinetics and biodistribution of the cyclin-dependent kinase inhibitor -CR8- in mice
Authors: Sallam Hatem , El-Serafi Ibrahim , Meijer Laurent , Hassan Moustapha
Published: October 2013

Background

CR8 is a second generation inhibitor of cyclin-dependent kinases derived from roscovitine. CR8 was shown to be 50–100 fold more potent than roscovitine in inducing apoptosis in different tumor cell lines. In the present investigation, we have established an analytical method for the quantification of CR8 in biological samples and evaluated its bioavailability, biodistribution and pharmacokinetics in mice.

Methods

A liquid chromatography method utilizing UV-detection was used for the determination of CR8. CR8 was administered either orally (100 mg/kg) or i.v. (50 mg/kg) and the animals were sacrificed at different time points. Blood samples and organs were collected, after which the pharmacokinetic parameters were calculated for plasma and organs.

Results

CR8 was eluted at 5 minutes in the high performance liquid chromatography system used. The LLOQ detection was 0.10 μg/ml and linearity was observed within the 0.10-10 μg/ml range (r2 > 0.998). The accuracy and precision were >86%, while the recovery from plasma was >95%. CR8 was stable for 2 months at room temperature in both solution and plasma. CR8 pharmacokinetics was fitted to a two-compartment open model after oral administration and to a one compartment model after i.v. injection. The elimination half-life was about 3 hours. Organ exposure to CR8 (expressed as % AUC organ vs. AUC plasma) was highest in liver (205%), adipose tissue (188%) and kidney (150%) and low in bone marrow (30%) and brain (15%) as compared to plasma. The oral bioavailability of CR8 was found to be essentially 100%.

Conclusions

We have developed a rapid and simple method for the analysis of CR8. CR8 pharmacokinetics pattern showed 100% bioavailability, long half-life and limited distribution to brain and bone marrow, which may allow systemic exposure higher than the IC50 reported for cell death in tumor cell lines. CR8 displays favorable pharmacological properties and is therefore a good candidate for future clinical studies.
An oxidoreductase from ‘Alphonso’ mango catalyzing biosynthesis of furaneol and reduction of reactive carbonyls
Authors: Kulkarni Ram , Chidley Hemangi , Deshpande Ashish , Schmidt Axel , Pujari Keshav , Giri Ashok , Gershenzon Jonathan , Gupta Vidya
Published: October 2013

Two furanones, furaneol (4-hydroxy-2,5-dimethyl-3(2H)-furanone) and mesifuran (2,5-dimethyl-4-methoxy-3(2H)-furanone), are important constituents of flavor of the Alphonso cultivar of mango (Mangifera indica). To get insights into the biosynthesis of these furanones, we isolated an enone oxidoreductase gene from the Alphonso mango. It has high sequence similarity to an alkenal/one oxidoreductase from cucumber (79% identity) and enone oxidoreductases from tomato (73% identity) and strawberry (72% identity). The complete open reading frame was expressed in E. coli and the (his)6-tagged recombinant protein was purified by affinity chromatography. The purified protein assayed with NADH as a reducing agent converted D-fructose-1,6-diphosphate into furaneol, the immediate precursor of mesifuran. The enzyme was also able to convert two highly reactive carbonyls, 3-buten-2-one and 1-penten-3-one, produced by lipid peroxidation in plants, into their saturated derivatives. Expression profiling in various ripening stages of Alphonso fruits depicted an expression maxima at 10 days after harvest stage, shortly before the appearance of the maximum amount of furanones (completely ripe stage, 15 days after harvest). Although no furanones were detected at the 0 day after harvest stage, significant expression of this gene was detected in the fruits at this stage. Overall, the results suggest that this oxidoreductase plays important roles in Alphonso mango fruits.
CD56+ monocytes have a dysregulated cytokine response to lipopolysaccharide and accumulate in rheumatoid arthritis and immunosenescence
Authors: Krasselt Marco , Baerwald Christoph , Wagner Ulf , Rossol Manuela
Published: October 2013

Introduction

Peripheral blood monocytes are no longer regarded as a homogeneous cell population, but can be differentiated both phenotypically and functionally into various subpopulations. In rheumatoid arthritis, the subpopulation of CD14bright/CD16+ monocyte is expanded and prone towards generation of Th17 cells. CD56+ monocytes represent a different subpopulation, which is also expanded in conditions associated with autoimmunity like inflammatory bowel diseases. The aim of the study was the quantification and functional characterization of the CD56+ monocyte subset in rheumatoid arthritis (RA).

Methods

Frequencies of peripheral blood monocyte subpopulations were analyzed by flow cytometry in 86 healthy controls and 75 RA patients. In 16 patients, anti-tumor necrosis factor (TNF) therapy was initiated, and the CD56+ monocyte frequency was monitored longitudinally. Lipopolysaccharide (LPS)-induced cytokine production of CD56+ and CD56– monocytes was determined by intracellular staining or cytokine secretion assays.

Results

In healthy individuals, 8.6% ± 0.6 of the monocytes co-expressed CD56, with the majority of CD56+ monocytes being CD14bright (7.9% ± 0.5), while only a minor population was CD14dim (0.7% ± 0.1). We found a strong positive correlation between an individual’s age and the frequency of CD56+ monocytes. Upon stimulation with LPS, CD56+ monocytes became more frequently positive for TNF, IL-10 and IL-23 than CD56– monocytes. In addition, CD56+ monocytes spontaneously produced more reactive oxygen intermediates than CD56- monocytes. In RA patients, the frequency of CD56+ monocytes was significantly higher than in healthy controls (12.2% ± 0.9 vs. 7.9% ± 0.5, p = 0.0002), and this difference most pronounced in RA patients below 40 years of age (11.1% ± 1.6 vs. 4.1% ± 0.4, P < 0.0001). Treatment of the patients with an anti-TNF blocking agent significantly reduced CD56+ monocyte frequencies (baseline 12.4% vs. 24 weeks treatment 8.0%, P = 0.0429), and the magnitude of this decrease was found to correlate with the change in disease activity under the therapy.

Conclusion

The CD14bright/CD56+ monocyte subset is expanded in aging individuals as well as in patients with RA. The pro-inflammatory production of cytokines and reactive oxygen species as well as the elimination of those cells in patients with a good response towards TNF inhibiting agents indicates a possible contribution of those monocytes in the inflammatory response in RA.
ACPA fine-specificity profiles in early rheumatoid arthritis patients do not correlate with clinical features at baseline or with disease progression
Authors: van Beers Joyce JBC , Willemze Annemiek , Jansen Jeroen J , Engbers Gerard HM , Salden Martin , Raats Jos , Drijfhout Jan W , van der Helm-van Mil Annette HM , Toes Rene EM , Pruijn Ger JM
Published: October 2013

Introduction

Autoantibodies against citrullinated peptides/proteins (ACPA) are found in approximately 75% of the sera of patients with rheumatoid arthritis (RA). The RA-specific ACPA are frequently present prior to disease onset and their presence associates with a more erosive disease course. ACPA can therefore be used to aid the diagnosis and prognosis of RA. Recently, it became clear that ACPA are very heterogeneous, both in an individual patient and among different patients. The aim of this study was to investigate whether clinically meaningful ACPA profiles exist in early RA patients.

Methods

Twenty citrullinated peptides and the corresponding non-citrullinated control peptides were immobilized on microarray sensor chips. Sera from 374 early arthritis patients were analyzed by surface plasmon resonance imaging (i SPR) of biomolecular interactions on the sensor chip.

Results

Cluster analysis of the reactivities with the citrullinated peptides, after subtraction of the reactivities with the corresponding control peptides confirmed the heterogeneity of the ACPA response in RA and revealed 12 distinct ACPA profiles. The association of the 5 most frequent profiles with clinical features at diagnosis and during the disease course was examined, showing no statistically significant associations.

Conclusions

Compared to the detection of ACPA in RA sera by CCP-based assays, ACPA profiling in early arthritis patients did not reveal associations with disease activity and progression scores.
Insomnia – Poems by Doctors
Authors: Chiu Helen
Published: October 2013

Once again he has to stand guard and watch,

His heart sinks as the crimson torch

Of a glorious sunset,

Heralds the falling night, and the dreaded hours in bed.
Treatment for mild cognitive impairment: systematic review
Authors: Cooper Claudia , Li Ryan , Lyketsos Constantine , Livingston Gill
Published: October 2013

Background

More people are presenting with mild cognitive impairment (MCI), frequently a precursor to dementia, but we do not know how to reduce deterioration.

Aims

To systematically review randomised controlled trials (RCTs) evaluating the effects of any intervention for MCI on cognitive, neuropsychiatric, functional, global outcomes, life quality or incident dementia.

Method

We reviewed 41 studies fitting predetermined criteria, assessed validity using a checklist, calculated standardised outcomes and prioritised primary outcome findings in placebo-controlled studies.

Results

The strongest evidence was that cholinesterase inhibitors did not reduce incident dementia. Cognition improved in single trials of: a heterogeneous psychological group intervention over 6 months; piribedil, a dopamine agonist over 3 months; and donepezil over 48 weeks. Nicotine improved attention over 6 months. There was equivocal evidence that Huannao Yicong improved cognition and social functioning.

Conclusions

There was no replicated evidence that any intervention was effective. Cholinesterase inhibitors and rofecoxib are ineffective in preventing dementia. Further good-quality RCTs are needed and preliminary evidence suggests these should include trials of psychological group interventions and piribedil.

Declarations of interest

C.L. has received grant support (research or continuing medical education) from NIMH, NIA, Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Lilly, Ortho-McNeil, Bristol-Myers Squibb, Novartis, National Football League (NFL), Elan, Functional Neuromodulation; and has been a consultant/advisor to AstraZeneca, GlaxoSmithKline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, Bristol-Myers Squibb; and received honorarium or travel support from Pfizer, Forest, GlaxoSmithKline, Health Monitor.
Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: Results of a Randomized Phase III Trial
Authors: Cheng Ann-Lii , Kang Yoon-Koo , Lin Deng-Yn , Park Joong-Won , Kudo Masatoshi , Qin Shukui , Chung Hyun-Cheol , Song Xiangqun , Xu Jianming , Poggi Guido , Omata Masao , Pitman Lowenthal Susan , Lanzalone Silvana , Yang Liqiang , Lechuga Maria Jose , Raymond Eric
Published: October 2013

Purpose

Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer.

Patients and Methods

Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS).

Results

Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B–infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C–infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%).

Conclusion

OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B–infected patients. OS was superior in hepatitis C–infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.
A Prognostic DNA Methylation Signature for Stage I Non–Small-Cell Lung Cancer
Authors: Sandoval Juan , Mendez-Gonzalez Jesus , Nadal Ernest , Chen Guoan , Carmona F. Javier , Sayols Sergi , Moran Sebastian , Heyn Holger , Vizoso Miguel , Gomez Antonio , Sanchez-Cespedes Montse , Assenov Yassen , Müller Fabian , Bock Christoph , Taron Miquel , Mora Josefina , Muscarella Lucia A. , Liloglou Triantafillos , Davies Michael , Pollan Marina , Pajares Maria J. , Torre Wenceslao , Montuenga Luis M. , Brambilla Elisabeth , Field John K. , Roz Luca , Lo Iacono Marco , Scagliotti Giorgio V. , Rosell Rafael , Beer David G. , Esteller Manel
Published: October 2013

Purpose

Non–small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.

Patients and Methods

A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.

Results

Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).

Conclusion

The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.
The Presence of Adenosine A2a Receptor in Thyrocytes and Its Involvement in Graves' IgG-Induced VEGF Expression
Authors: Zhang Lin , Xu Jin , Sun Nannan , Cai Hu , Ren Meng , Zhang Jie , Yu Chunxiao , Wang Zhe , Gao Ling , Zhao Jiajun
Published: October 2013

Goitrogenesis in Graves' disease (GD) has been attributed to anti-TSH receptor antibody stimulation. Recently, a role for adenosine A2a receptor (A2aR) in goiter formation was reported in the thyroglobulin-A2aR transgenic mice. However, it is unclear whether A2aR is expressed in the thyroid and whether it is associated with the pathogenesis of goiter in GD. Here, we confirmed the expression of A2aR in FRTL-5 cells, primary normal human thyrocytes (both sexes were used without regard to sex), and thyroid tissue (both sexes were used without regard to sex) by PCR, Western blotting, immunohistochemistry, and immunofluorescence. After treatments with A2aR-specific agonist 2-p-(2-Carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine or GD IgG, the mRNA and protein levels of vascular endothelial growth factor (VEGF), a growth factor related to goitrogenesis, were evaluated along with upstream signaling pathways. A2aR activation and GD IgG promoted the expression of VEGF in thyrocytes, which was accompanied by the activation of cAMP/protein kinase A/phosphorylated-cAMP-response element-binding protein, peroxisome proliferator-activated receptor γ coactivator-1α, and hypoxia-inducible factor-1α. The changes induced by GD IgG were partially abrogated by A2aR small interfering RNA and an A2aR antagonist. These results were supported by data on the goiter samples from the thyrotropin receptor adenovirus-induced GD mouse model (female). These data demonstrate that GD IgG could up-regulate the VEGF expression through A2aR, indicating a potential mechanism for goitrogenesis in GD.
Loss of 5α-Reductase Type 1 Accelerates the Development of Hepatic Steatosis but Protects Against Hepatocellular Carcinoma in Male Mice
Authors: Dowman Joanna K. , Hopkins Laurence J. , Reynolds Gary M. , Armstrong Matthew J. , Nasiri Maryam , Nikolaou Nikolaos , van Houten E. Leonie A. F. , Visser Jenny A. , Morgan Stuart A. , Lavery Gareth G. , Oprescu Andrei , Hübscher Stefan G. , Newsome Philip N. , Tomlinson Jeremy W.
Published: October 2013

Nonalcoholic fatty liver disease (NAFLD) has been associated with glucocorticoid excess and androgen deficiency, yet in the majority of patients with steatohepatitis, circulating cortisol and androgen levels are normal. The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. We hypothesize that 5αR has an important role in the pathogenesis of steatohepatitis through regulation of intracrine/paracrine hormone availability. Human liver samples from patients with NAFLD and normal donor tissue were used for gene expression and immunohistochemical analysis. NAFLD samples were scored using the Kleiner classification. In addition, 5αR1−/−, 5αR2−/−, and wild-type (WT) mice were fed normal chow or American lifestyle-induced obesity syndrome (ALIOS) diet for 6 or 12 months. Liver histology was graded and staged. Hepatic and circulating free fatty acid and triglyceride levels were quantified, and gene and protein expression was measured by real-time PCR and immunohistochemistry. 5αR1 and -2 were highly expressed in human liver, and 5αR1 protein expression increased with severity of NAFLD. 5αR1−/− (but not 5αR2−/−) mice fed an ALIOS diet developed greater hepatic steatosis than WT mice, and hepatic mRNA expression of genes involved in insulin signaling was decreased. Furthermore, 60% of WT mice developed focal hepatocellular lesions consistent with hepatocellular carcinoma after 12 months of the ALIOS diet, compared with 20% of 5αR2−/− and 0% of 5αR1−/− mice (P < .05). 5αR1 deletion accelerates the development of hepatic steatosis but may protect against the development of NAFLD-related hepatocellular neoplasia and therefore has potential as a therapeutic target.
Effect of Increasing Glutathione With Cysteine and Glycine Supplementation on Mitochondrial Fuel Oxidation, Insulin Sensitivity, and Body Composition in Older HIV-Infected Patients
Authors: Nguyen Dan , Hsu Jean W , Jahoor Farook , Sekhar Rajagopal V
Published: October 2013

Background

HIV-infected patients are reported to have impaired oxidation of fatty acids despite increased availability, suggesting a mitochondrial defect. We investigated whether diminished levels of a key mitochondrial antioxidant, glutathione (GSH), was contributing to defective fatty acid oxidation in older HIV-infected patients, and if so, the metabolic mechanisms contributing to GSH deficiency in these patients.

Methods

In an open-label design, 8 older GSH-deficient HIV-infected males were studied before and after 14 days of oral supplementation with the GSH precursors cysteine and glycine. A combination of stable-isotope tracers, calorimetry, hyperinsulinemic-euglycemic clamp, and dynamometry were used to measure GSH synthesis, fasted and insulin-stimulated (fed) mitochondrial fuel oxidation, insulin sensitivity, body composition, anthropometry, forearm-muscle strength, and lipid profiles.

Results

Impaired synthesis contributed to GSH deficiency in the patients and was restored with cysteine plus glycine supplementation. GSH improvement was accompanied by marked improvements in fasted and fed mitochondrial fuel oxidation. Associated benefits included improvements in insulin sensitivity, body composition, anthropometry, muscle strength, and dyslipidemia.

Conclusions

This work identifies 2 novel findings in older HIV-infected patients: 1) diminished synthesis due to decreased availability of cysteine and glycine contributes to GSH deficiency and can be rapidly corrected by dietary supplementation of these precursors and 2) correction of GSH deficiency is associated with improvement of mitochondrial fat and carbohydrate oxidation in both fasted and fed states and with improvements in insulin sensitivity, body composition, and muscle strength. The role of GSH on ameliorating metabolic complications in older HIV-infected patients warrants further investigation. (J Clin Endocrinol Metab 99: 169–177, 2014)
Biochemical and molecular characteristics of Listeria monocytogenes isolates from a prosthetic mitral heart valve-bearing patient´s blood cultures
Authors: Leal Nilma Cintra , Costa Ana Paula Rocha da , Vilela Marinalda Anselmo , Mendes-Marques Carina Lucena , Almeida Alzira Maria Paiva de
Published: October 2013

Background: In Brazil, listeriosis is not a notifiable disease; thus, the incidence of Brazilian cases remains unknown. Listeria monocytogenes is not always included in automated systems, and its detection depends on the high skill level of microbiology laboratory professionals. This paper describes the characteristics of L. monocytogenes isolates fortuitously obtained from an endocarditis case in Recife, PE, Brazil. Methods: Six bacterial isolates obtained from six blood cultures from a 28-year-old male bearing a prosthetic mitral heart valve were analyzed by PCR using primers specific of L. monocytogenes to confirm a presumptive identification, determine the serotype and presence of the virulence genes (inlA, inlB, inlC, inlJ, hly, plcA, actA, prfA) in an attempt to determine the Listeria genotype by PCR-ribotyping. Results: The samples were identified as L. monocytogenes 4b. All investigated virulence genes were amplified by PCR, and the identity of the amplified segments was confirmed by sequencing. A deletion of 105 base pairs was detected in the actA gene. All of the samples generated the same PCR-ribotype pattern, clustered into a single ribotype, and were considered a single strain. Conclusion: L. monocytogenes infection should be considered in endocarditis differential diagnoses, especially among high-risk groups, due to its high pathogenicity and the environmental ubiquity.
Evaluation of hysteroscopy as a complementary exam in the investigation of chronic pelvic pain.
Authors: Meneses Dias Bruno Hállan , Rodrigues de Andrade Ana Carolina , Holanda Pascoal da Silva Angélica Maria , De Vasconcelos Filho Francisco Eugênio , Parente Paiva Jordana , Das Chagas Medeiros Francisco
Published: October 2013

Introduction: Chronic pelvic pain (CPP) is a difficult condition to identify and many disorders are correlated. This study investigates the role of hysteroscopy as a complementary exam in the diagnosis of CPP. Methods: One hundred ninety-one medical records of women with indication to perform a hysteroscopy and presented CPP were reviewed. Results: The analysis showed abnormalities in 99 patients. Of these, more than 70% presented conditions that could cause CPP. Cervical stenosis and findings suggestive of adenomyosis were the most frequent ocurrences. Conclusions: Hysteroscopy is useful to detect pathological conditions of the cervix and uterine cavity that may coexist with chronic pelvic pain.
Atividades de controle de Aedes aegypti em municípios da Região Sul do Estado de São Paulo.
Authors: Domingos Maria de Fátima , Oliveira Cleide Dantas de , Barbosa Gerson Laurindo , Wanderley Dalva Marli Valério
Published: October 2013

Introdução: Neste estudo, são analisadas as atividades de vigilância e controle do Aedes aegypti, vetor da dengue, executadas por municípios selecionados da região do Litoral Sul do Estado de São Paulo. Método: Análise de dados secundários extraídos do programa informatizado referente às atividades de vigilância e controle do Aedes aegypti. Resultados: Índice de Infestação Predial: foram realizadas 31 medidas, com valores médios inferiores a 2,0; Casa-a-casa: as maiores coberturas foram observadas nos segundos quadrimestres de cada ano, devido ao comprometimento das equipes com a transmissão no primeiro semestre; Pontos Estratégicos: houve redução do número de imóveis trabalhados nos últimos quatro anos, positividade média foi de 33,8% com tendência de aumento; Imóveis Especiais: registrou-se diminuição no número de imóveis trabalhados nos últimos dois anos, e a positividade média foi de 24,7%. Conclusão: Verificaram-se baixas coberturas das atividades previstas na norma técnica, o que pode favorecer a manutenção da infestação. Não foi possível constatar a implantação das orientações técnicas a partir dos resultados dos índices de infestação para subsidiar o emprego de medidas de controle entomológico.
The Causal Links Between Foreign Direct Investment And Economic Growth In Pakistan
Authors: Ahmad Najid , Hayat Muhammad Farhat , Luqman Muhammad , Ullah Shafqat
Published: October 2013

This paper investigates the relationship between foreign direct investment and economic growth in Pakistan. The co-integration and error correction model is used to show the relationship between foreign direct investment and gross domestic product in Pakistan. Gross domestic product is taken as dependent variable while foreign direct investment, labor force and domestic capital as independent variables. The results suggest that there is a positive relation between foreign direct investment and gross domestic product in short as well as long run. If we want to make economic progress then there is a need to invite foreign investors because foreign direct investment increases GDP that is economic growth.
Polymeric sorbents for removal of Cr(VI) from environmental samples
Authors: Pakade Vusumzi , Chimuka Luke
Published: October 2013

Chromium (Cr) is an important raw material in some chemical industries including paint, pigments, textiles, leather tanning, steel fabrication, electroplating, cement preservation, and canning industries. Once in the environment, Cr exists in various oxidation states depending on pH and concentration. Trivalent [Cr(III)] and hexavalent [Cr(VI)] forms are the most common with Cr(VI) being the most toxic to biota. The review discusses various types of polymeric sorbents that have been prepared for the extraction of Cr(VI) from environmental samples, mostly aqueous samples. Sorbents are categorized into biosorbents, hybrid sorbents, synthetic polymeric, and modified natural polymeric sorbents. Most of the emphasis will be on the advantages and disadvantages of different synthetic polymeric sorbents. Important parameters that define the performance of the sorbents, that is, binding capacity, equilibration time, optimum sample pH, and selectivity, are compared.