bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined Transcranial Direct Current Stimulation and Robot-Assisted Arm Training in Subacute Stroke Patients
Authors: Hesse Stefan , Waldner Andreas , Mehrholz Jan , Tomelleri Christopher , Pohl Michael , Werner Cordula
Published: August 2011

Background. No rehabilitation intervention has effectively improved functional use of the arm and hand in patients with severe upper limb paresis after stroke. Pilot studies suggest the potential for transcranial direct current stimulation and bilateral robotic training to enhance gains. Objective. In a double-blind, randomized trial the combination of these interventions was tested. Methods. This study randomized 96 patients with an ischemic supratentorial lesion of 3 to 8 weeks’ duration with severe impairment of motor control with a Fugl-Meyer score (FMS) for the upper limb <18 into 3 groups. For 6 weeks, group A received anodal stimulation of the lesioned hemisphere, group B received cathodal stimulation of the nonlesioned side for 20 minutes at 2.0 mA, and group C received sham stimulation. The electrodes were placed over the hand area and above the contralateral orbit. Contemporaneously, the subjects practiced 400 repetitions each of 2 different bilateral movements on a robotic assistive device. Results. The groups were matched at onset. The FMS improved in all patients at 6 weeks ( P < .001). No between-group differences were found; initial versus finish FMS scores were 7.8 ± 3.8 versus 19.1 ± 14.4 in group A, 7.9 ± 3.4 versus 18.8 ± 10.5 in group B, and 8.2 ± 4.4 versus 19.2 ± 15.0 in group C. No significant changes between groups were present at 3 months. Conclusions. Neither anodal nor cathodal transcranial direct current stimulation enhanced the effect of bilateral arm training in this exploratory trial of patients with cortical involvement and severe weakness. Unilateral hand training and upregulation of the nonlesioned hemisphere might also be tried in this population.
Factors Associated With Health-Related Quality of Life After Stroke
Authors: Algurén Beatrix , Fridlund Bengt , Cieza Alarcos , Sunnerhagen Katharina Stibrant , Christensson Lennart
Published: August 2011

Background. In line with patient-centered health care, it is necessary to understand patients’ perceptions of health. How stroke survivors perceive their health at different time points after stroke and which factors are associated with these feelings provide important information about relevant rehabilitation targets. Objective. This study aimed to identify the independent factors of health-related quality of life (HRQoL) from a biopsychosocial perspective using the methods of multivariate regression at 3 different time points poststroke. Methods. Included in the study were 99 patients from stroke units with diagnosed first-ever stroke. At admission and at 6 weeks, 3 months, and 1 year poststroke, HRQoL was assessed using the EuroQoL-5D Visual Analogue Scale (EQ-5D VAS). Consequences in Body Functions and Activities and Participation, and Environmental Factors were documented using 155 categories of the International Classification of Functioning, Disability and Health (ICF) Core Set for Stroke. Results. For a period of 1 year, problems with recreation and leisure, personality functions, energy and drive functions, and gait pattern functions were repeatedly associated with worse HRQoL. Whereas Body Functions and Activities and Participation explained more than three-fourths of the variances of HRQoL at 6 weeks and 3 months ( R2 = 0.80-0.93), the variation at 1 year was best explained by either Body Functions or Environmental Factors ( R2 = 0.51). Conclusions. The results indicate the importance of Body Functions and Activities and Participation (mainly personality functions and recreation and leisure) on HRQoL within 3 months poststroke, but increased impact of Environmental Factors on HRQoL at 1 year.
Seeking Help for Intimate Partner Violence
Authors: Meyer Silke
Published: August 2011

The criminal justice system (CJS) frequently encounters victims of intimate partner violence (IPV). Despite these frequent encounters, professionals in the CJS often fail to adequately address victims’ needs. The experiences of female IPV victims ( N = 29) who approached the CJS in Southeast Queensland, Australia for support and protection are examined throughout this article. Findings from the in-depth interviews reveal that women often face stereotypical and victim-blaming attitudes despite an existing policy environment that promotes victim protection and offender accountability. Implications for policy and practice are discussed
On the coupling of axial and shear deformations of single-walled carbon nanotubes and graphene: a numerical study
Authors: Georgantzinos S K , Giannopoulos G I , Anifantis N K
Published: August 2011

This paper presents a numerical investigation for the evaluation of elastic coupling of extension and twist in single-walled carbon nanotubes. The carbon nanotubes are modelled according to their atomistic structure. The harmonic approximation is utilized for describing the interaction potential energies. The force field is simulated via suitable straight and torsional springs that express the interatomic interactions and interconnect nodes placed on the atomic positions. By using appropriate boundary conditions, the nanotubes are loaded axially and the resulted twist is numerically predicted using finite element procedures. The numerical outcomes reveal that the stretching deformation of single-walled carbon nanotubes leads to their torsion only for the chiral case. A complete parametric study with respect to geometric characteristics of nanotubes shows that the coupling is strongly dependent on the diameter, chiral angle, and nanotube length. To explain these observations, the inherent graphene sheet geometries used for the generation of single-walled carbon nanotubes are also studied under extension. The results prove similar coupling phenomena occur between extension and in-plane shear. Comparisons with results provided in the open literature are also performed, where possible.
Using the continual reassessment method to estimate the minimum effective dose in phase II dose-finding studies: a case study
Authors: Zohar Sarah , Resche-Rigon Matthieu , Chevret Sylvie
Published: August 2011

Background

The Continual Reassessment Method typically is presented as the method of choice for the purpose of dose-finding based on a toxicity scale in phase I clinical trials. However, this adaptive statistical approach also can be applied easily to dose-finding experiments in phase II trials.

Purpose

To provide a case study from a real clinical trial to illustrate the use of the Continual Reassessment Method in the context of phase II dose finding.

Methods

The Continual Reassessment Method was used to model the dose-failure relationship in order to estimate the minimal effective dose. This approach was retrospectively used to determine the minimal effective dose of granulocyte colony-stimulating factor for peripheral blood stem cell collection in allografted patients following chemotherapy.

Results

After the inclusion of 25 patients, the minimal effective dose was estimated to be the third dose level tested in the study.

Limitations

The main limitation of the Continual Reassessment Method, which is not specific to the method but to the dose-finding setting, is that the empirical choice of the dose range can be either under or over-estimated. The method requires a calibration study prior to trial onset.

Conclusions

Assuming that a dose-effect relationship is monotonically increasing, the use of the Continual Reassessment Method in phase II dose-finding studies allows the estimation of the minimum effective dose for further studies. Modeling the dose-failure relationship allows the direct use of available software developed for the Continual Reassessment Method in the context of phase I clinical trials.
Boosting enrolment in clinical trials: validation of a regional network model
Authors: Kernan W , Viscoli C , Brass L , Amatangelo M , Birch A , Clark W , Conwit R , Furie K , Gorman M , Pesapane B , Kleindorfer D , Lovejoy A , Osborne J , Silliman S , Zweifler R , Horwitz R
Published: August 2011

Background Clinical trials of stroke therapy have been hampered by slow rates of enrolment.

Purpose Our purpose is to validate a previously developed model for accelerating enrolment in clinical trials by replicating it at new locations. The model employs coordinators who travel from a host institution to enrol participants from a network of participating hospitals. Active surveillance assures identification of all eligible patients.

Methods Among 70 U.S. investigators participating in National Institutes of Health-funded trial of stroke prevention, five investigators were invited to develop local identification and outreach networks (LIONs). Each LION comprised a LION coordinating centre servicing multiple hospitals. Hospitals provided names of patients with stroke or transient ischaemic attack to researchers at the LION coordinating centre who initiated contact; patients were offered home visits for consent and randomization. Outcomes were feasibility, enrolment, data quality, and cost.

Results Five LIONs varied in size from two to eight hospitals. All 24 hospitals we approached agreed to participate. The average monthly rate of enrolment at the research sites increased from 1.4 participants to 3.5 after expanding from a single institution model to the LION format (mean change = 2.1, range 0.9–3.7). Monthly performance improved over time. Data quality was similar for LIONs and non-LION sites, except for drug adherence which was lower at LIONs. The average cost to randomize and follow one participant during the study interval was 2.4 times the cost under the per-patient, cost-reimbursement strategy at non-LION sites. The cost ratio declined from 3.4 in year one to 1.8 in year two.

Limitations The LION strategy requires unprecedented collaboration and trust among institutions. Applicability beyond stroke requires confirmation.

Conclusion LIONs are a practical, reproducible method to increase enrolment in trial research. Twelve months were required for the average site to reach its potential. The per-participant cost at LIONs was higher than conventional sites but declined over time.
Payment by results and social impact bonds in the criminal justice sector: New challenges for the concept of evidence-based policy?
Authors: Fox Chris , Albertson Kevin
Published: August 2011

Payment by results allows the government to pay a provider of services on the basis of the outcomes their service achieves rather than the inputs or outputs the provider delivers. Social impact bonds (SIBs) are a form of payment by results which allow the financing of social outcomes via private investment. It is suggested that payment by results and SIBs will drive greater efficiency, innovation and impact in tackling social problems through focusing reward on outcomes and providing minimal prescription as to how these outcomes should be achieved. It is suggested that this may be achieved while also reducing risk for government. Here we set out the challenges likely to arise in developing payment by results models and SIBs in the criminal justice system of England and Wales. These include the uncertainty arising from defining outcomes, estimating the potential impact of interventions, measuring and attributing change, valuing benefits, demonstrating a fiscal return and getting interventions to scale. We conclude that, to a government trying to deliver ‘more for less’, payment by results may offer an attractive solution in some parts of the public sector. However, the case for this approach in the criminal justice sector, where the evidence base is contested and potential savings difficult to quantify and realize, is not yet proven.
Scaphoid nonunion in the presence of a degenerate carpus: don’t rush to salvage surgery
Authors: Kent M. E. , Rehmatullah N. N. T. , Young L. , Chojnowski A. J.
Published: August 2011

We retrospectively studied 13 patients with degenerative change associated with a scaphoid nonunion treated by internal fixation and bone graft. All patients had radiological signs of radioscaphoid degenerative change (scaphoid nonunion advanced collapse – scaphoid nonunion advanced collapse - grade II or more) and had surgery more than 2 years after injury. Ten of the 13 patients achieved union at 6 months with all but one of these demonstrating improvement on the Disability of Arm, Shoulder and Hand (DASH) score. Surgeons presented with this difficult patient group might consider reconstruction before salvage procedures.
Unusual causes of carpal tunnel syndrome: space occupying lesions
Authors: Chen C.-H. , Wu T. , Sun J.-S. , Lin W.-H. , Chen C.-Y.
Published: August 2011

Space occupying lesions found at surgery caused or contributed to carpal tunnel syndrome in 23 of 779 patients operated for carpal tunnel syndrome from January 1999 to December 2008. The mean age of these 23 patients was 52.9 years, and in patients who had a local swelling or palpable mass, ultrasonography or magnetic resonance imaging (MRI) was done. All had open release of the transverse carpal ligament and lesions were removed. Histopathology showed tophaceous gout in 10 men, tenosynovitis in seven patients and tumors in eight. The tumors included ganglion cysts in two, lipoma in three and fibroma of the tendon sheath in one. The neurological symptoms subsided after surgery in all. In patients with gout, one had an infected wound and another had recurrence of symptoms 1 year after later. Carpal tunnel syndrome caused by a space occupying lesion is rare and more complicated than idiopathic carpal tunnel syndrome.
Management of invasive bladder cancer in patients who are not candidates for or decline cystectomy
Authors: Balar Arjun , Bajorin Dean F. , Milowsky Matthew I.
Published: August 2011

Bladder cancer is a common malignancy seen in older adults with coexisting medical illnesses. The management of patients with muscle invasive disease includes perioperative chemotherapy and radical cystectomy; however, patients may decline surgery and older patients with comorbid conditions may not be candidates for surgery and thus alternative treatment strategies are needed. Trimodality bladder preservation protocols for muscle invasive bladder cancer have generally included only those patients who are candidates for a salvage cystectomy. In this review, we discuss the current status of bladder preservation treatment options for patients with muscle-invasive disease who are not candidates for cystectomy or who decline surgery and highlight the need for clinical trials investigating novel treatment approaches in this older patient population.
A shape memory alloy spring-based actuator with stiffness and position controllability
Authors: Hadi A , Yousefi-Koma A , Elahinia M , Moghaddam M M , Ghazavi A
Published: August 2011

In this paper, a one-degree-of-freedom actuator that is based on shape memory alloy (SMA) springs is developed and tested. The use of SMA springs allows a larger actuation workspace and controllable stiffness than SMA wires. It is shown that the actuator demonstrates a good positioning accuracy in addition to a higher level of stiffness control. A strategy based on the variable structure control method is implemented for simultaneous displacement and stiffness control. It is shown that the actuator’s position is always kept within a boundary layer defined around the desired position while a preferred stiffness is also obtained in the actuator. Such an actuator could be used to develop flexible mechanical systems which need to adapt to environmental changes in the form of external loading variation.
Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A
Authors: Jankowska Anna M. , Makishima Hideki , Tiu Ramon V. , Szpurka Hadrian , Huang Yun , Traina Fabiola , Visconte Valeria , Sugimoto Yuka , Prince Courtney , O'Keefe Christine , Hsi Eric D. , List Alan , Sekeres Mikkael A. , Rao Anjana , McDevitt Michael A. , Maciejewski Jaroslaw P.
Published: August 2011

Chronic myelomonocytic leukemia (CMML), a myelodysplastic/myeloproliferative neoplasm, is characterized by monocytic proliferation, dysplasia, and progression to acute myeloid leukemia. CMML has been associated with somatic mutations in diverse recently identified genes. We analyzed 72 well-characterized patients with CMML (N = 52) and CMML-derived acute myeloid leukemia (N = 20) for recurrent chromosomal abnormalities with the use of routine cytogenetics and single nucleotide polymorphism arrays along with comprehensive mutational screening. Cytogenetic aberrations were present in 46% of cases, whereas single nucleotide polymorphism array increased the diagnostic yield to 60%. At least 1 mutation was found in 86% of all cases; novel UTX, DNMT3A, and EZH2 mutations were found in 8%, 10%, and 5.5% of patients, respectively. TET2 mutations were present in 49%, ASXL1 in 43%, CBL in 14%, IDH1/2 in 4%, KRAS in 7%, NRAS in 4%, and JAK2 V617F in 1% of patients. Various mutant genotype combinations were observed, indicating molecular heterogeneity in CMML. Our results suggest that molecular defects affecting distinct pathways can lead to similar clinical phenotypes.
TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow–derived proangiogenic cell differentiation, function, and neovascularization
Authors: Wara Akm Khyrul , Foo ShiYin , Croce Kevin , Sun Xinghui , Icli Basak , Tesmenitsky Yevgenia , Esen Fehim , Lee Jung-Soo , Subramaniam Malayannan , Spelsberg Thomas C. , Lev Eli I. , Leshem-Lev Dorit , Pande Reena L. , Creager Mark A. , Rosenzweig Anthony , Feinberg Mark W.
Published: August 2011

Emerging evidence demonstrates that proangiogenic cells (PACs) originate from the BM and are capable of being recruited to sites of ischemic injury where they contribute to neovascularization. We previously determined that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitor cells (GMPs) differentiate into PACs and possess robust angiogenic activity under ischemic conditions. Herein, we report that a TGF-β1–responsive Krüppel- like factor, KLF10, is strongly expressed in PACs derived from CMPs and GMPs, ∼ 60-fold higher than in progenitors lacking PAC markers. KLF10−/− mice present with marked defects in PAC differentiation, function, TGF-β responsiveness, and impaired blood flow recovery after hindlimb ischemia, an effect rescued by wild-type PACs, but not KLF10−/− PACs. Overexpression studies revealed that KLF10 could rescue PAC formation from TGF-β1+/− CMPs and GMPs. Mechanistically, KLF10 targets the VEGFR2 promoter in PACs which may underlie the observed effects. These findings may be clinically relevant because KLF10 expression was also found to be significantly reduced in PACs from patients with peripheral artery disease. Collectively, these observations identify TGF-β1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states.
Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells
Authors: Chang You-Kang , Chen Ming-Hsiang , Chiang Yi-Hung , Chen Yu-Fan , Ma Wei-Hsien , Tseng Chian-You , Soong Bing-Wen , Ho Jennifer H , Lee Oscar K
Published: August 2011

Background

Spinocerebellar ataxia (SCA) refers to a disease entity in which polyglutamine aggregates are over-produced in Purkinje cells (PCs) of the cerebellum as well as other neurons in the central nervous system, and the formation of intracellular polyglutamine aggregates result in the loss of neurons as well as deterioration of motor functions. So far there is no effective neuroprotective treatment for this debilitating disease although numerous efforts have been made. Mesenchymal stem cells (MSCs) possess multi-lineage differentiation potentials as well as immuno-modulatory properties, and are theoretically good candidates for SCA treatment. The purpose of this study is to investigate whether transplantation of human MSCs (hMSCs) can rescue cerebellar PCs and ameliorate motor function deterioration in SCA in a pre-clinical animal model.

Method

Transgenic mice bearing poly-glutamine mutation in ataxin-2 gene (C57BL/6J SCA2 transgenic mice) were serially transplanted with hMSCs intravenously or intracranially before and after the onset of motor function loss. Motor function of mice was evaluated by an accelerating protocol of rotarod test every 8 weeks. Immunohistochemical stain of whole brain sections was adopted to demonstrate the neuroprotective effect of hMSC transplantation on cerebellar PCs and engraftment of hMSCs into mice brain.

Results

Intravenous transplantation of hMSCs effectively improved rotarod performance of SCA2 transgenic mice and delayed the onset of motor function deterioration; while intracranial transplantation failed to achieve such neuroprotective effect. Immunohistochemistry revealed that intravenous transplantation was more effective in the preservation of the survival of cerebellar PCs and engraftment of hMSCs than intracranial injection, which was compatible to rotarod performance of transplanted mice.

Conclusion

Intravenous transplantation of hMSCs can indeed delay the onset as well as improve the motor function of SCA2 transgenic mice. The results of this preclinical study strongly support further exploration of the feasibility to transplant hMSCs for SCA patients.
NETGEM: Network Embedded Temporal GEnerative Model for gene expression data
Authors: Jethava Vinay , Bhattacharyya Chiranjib , Dubhashi Devdatt , Vemuri Goutham N
Published: August 2011

Background

Temporal analysis of gene expression data has been limited to identifying genes whose expression varies with time and/or correlation between genes that have similar temporal profiles. Often, the methods do not consider the underlying network constraints that connect the genes. It is becoming increasingly evident that interactions change substantially with time. Thus far, there is no systematic method to relate the temporal changes in gene expression to the dynamics of interactions between them. Information on interaction dynamics would open up possibilities for discovering new mechanisms of regulation by providing valuable insight into identifying time-sensitive interactions as well as permit studies on the effect of a genetic perturbation.

Results

We present NETGEM, a tractable model rooted in Markov dynamics, for analyzing the dynamics of the interactions between proteins based on the dynamics of the expression changes of the genes that encode them. The model treats the interaction strengths as random variables which are modulated by suitable priors. This approach is necessitated by the extremely small sample size of the datasets, relative to the number of interactions. The model is amenable to a linear time algorithm for efficient inference. Using temporal gene expression data, NETGEM was successful in identifying (i) temporal interactions and determining their strength, (ii) functional categories of the actively interacting partners and (iii) dynamics of interactions in perturbed networks.

Conclusions

NETGEM represents an optimal trade-off between model complexity and data requirement. It was able to deduce actively interacting genes and functional categories from temporal gene expression data. It permits inference by incorporating the information available in perturbed networks. Given that the inputs to NETGEM are only the network and the temporal variation of the nodes, this algorithm promises to have widespread applications, beyond biological systems.

The source code for NETGEM is available from https://github.com/vjethava/NETGEM
A formalized description of the standard human variant nomenclature in Extended Backus-Naur Form
Authors: Laros Jeroen FJ , Blavier André , den Dunnen Johan T , Taschner Peter EM
Published: August 2011

Background

The use of a standard human sequence variant nomenclature is advocated by the Human Genome Variation Society in order to unambiguously describe genetic variants in databases and literature. There is a clear need for tools that allow the mining of data about human sequence variants and their functional consequences from databases and literature. Existing text mining focuses on the recognition of protein variants and their effects. The recognition of variants at the DNA and RNA levels is essential for dissemination of variant data for diagnostic purposes. Development of new tools is hampered by the complexity of the current nomenclature, which requires processing at the character level to recognize the specific syntactic constructs used in variant descriptions.

Results

We approached the gene variant nomenclature as a scientific sublanguage and created two formal descriptions of the syntax in Extended Backus-Naur Form: one at the DNA-RNA level and one at the protein level. To ensure compatibility to older versions of the human sequence variant nomenclature, previously recommended variant description formats have been included. The first grammar versions were designed to help build variant description handling in the Alamut mutation interpretation software. The DNA and RNA level descriptions were then updated and used to construct the context-free parser of the Mutalyzer 2 sequence variant nomenclature checker, which has already been used to check more than one million variant descriptions.

Conclusions

The Extended Backus-Naur Form provided an overview of the full complexity of the syntax of the sequence variant nomenclature, which remained hidden in the textual format and the division of the recommendations across the DNA, RNA and protein sections of the Human Genome Variation Society nomenclature website (http://www.hgvs.org/mutnomen/). This insight into the syntax of the nomenclature could be used to design detailed and clear rules for software development. The Mutalyzer 2 parser demonstrated that it facilitated decomposition of complex variant descriptions into their individual parts. The Extended Backus-Naur Form or parts of it can be used or modified by adding rules, allowing the development of specific sequence variant text mining tools and other programs, which can generate or handle sequence variant descriptions.
The BioAssay network and its implications to future therapeutic discovery
Authors: Zhang Jintao , Lushington Gerald H , Huan Jun
Published: August 2011

Background

Despite intense investment growth and technology development, there is an observed bottleneck in drug discovery and development over the past decade. NIH started the Molecular Libraries Initiative (MLI) in 2003 to enlarge the pool for potential drug targets, especially from the “undruggable” part of human genome, and potential drug candidates from much broader types of drug-like small molecules. All results are being made publicly available in a web portal called PubChem.

Results

In this paper we construct a network from bioassay data in PubChem, apply network biology concepts to characterize this bioassay network, integrate information from multiple biological databases (e.g. DrugBank, OMIM, and UniHI), and systematically analyze the potential of bioassay targets being new drug targets in the context of complex biological networks. We propose a model to quantitatively prioritize this druggability of bioassay targets, and literature evidence was found to confirm our prioritization of bioassay targets at a roughly 70% accuracy.

Conclusions

Our analysis provide some measures of the value of the MLI data as a resource for both basic chemical biology research and future therapeutic discovery.
Hypoxia-mimetic agents inhibit proliferation and alter the morphology of human umbilical cord-derived mesenchymal stem cells
Authors: Zeng Hui-Lan , Zhong Qi , Qin Yong-Liang , Bu Qian-Qian , Han Xin-Ai , Jia Hai-Tao , Liu Hong-Wei
Published: August 2011

Background

The therapeutic efficacy of human mesenchymal stem cells (hMSCs) for the treatment of hypoxic-ischemic diseases is closely related to level of hypoxia in the damaged tissues. To elucidate the potential therapeutic applications and limitations of hMSCs derived from human umbilical cords, the effects of hypoxia on the morphology and proliferation of hMSCs were analyzed.

Results

After treatment with DFO and CoCl2, hMSCs were elongated, and adjacent cells were no longer in close contact. In addition, vacuole-like structures were observed within the cytoplasm; the rough endoplasmic reticulum expanded, and expanded ridges were observed in mitochondria. In addition, DFO and CoCl2 treatments for 48 h significantly inhibited hMSCs proliferation in a concentration-dependent manner (P < 0.05). This treatment also increased the number of cells in G0/G1 phase and decreased those in G2/S/M phase.

Conclusions

The hypoxia-mimetic agents, DFO and CoCl2, alter umbilical cord-derived hMSCs morphology and inhibit their proliferation through influencing the cell cycle.
A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests
Authors: Johansson Henrik , Lindstedt Malin , Albrekt Ann-Sofie , Borrebaeck Carl AK
Published: August 2011

Background

Allergic contact dermatitis is an inflammatory skin disease that affects a significant proportion of the population. This disease is caused by an adverse immune response towards chemical haptens, and leads to a substantial economic burden for society. Current test of sensitizing chemicals rely on animal experimentation. New legislations on the registration and use of chemicals within pharmaceutical and cosmetic industries have stimulated significant research efforts to develop alternative, human cell-based assays for the prediction of sensitization. The aim is to replace animal experiments with in vitro tests displaying a higher predictive power.

Results

We have developed a novel cell-based assay for the prediction of sensitizing chemicals. By analyzing the transcriptome of the human cell line MUTZ-3 after 24 h stimulation, using 20 different sensitizing chemicals, 20 non-sensitizing chemicals and vehicle controls, we have identified a biomarker signature of 200 genes with potent discriminatory ability. Using a Support Vector Machine for supervised classification, the prediction performance of the assay revealed an area under the ROC curve of 0.98. In addition, categorizing the chemicals according to the LLNA assay, this gene signature could also predict sensitizing potency. The identified markers are involved in biological pathways with immunological relevant functions, which can shed light on the process of human sensitization.

Conclusions

A gene signature predicting sensitization, using a human cell line in vitro, has been identified. This simple and robust cell-based assay has the potential to completely replace or drastically reduce the utilization of test systems based on experimental animals. Being based on human biology, the assay is proposed to be more accurate for predicting sensitization in humans, than the traditional animal-based tests.
On the quest for selective constraints shaping the expressivity of the genes casting retropseudogenes in human
Authors: Sen Kamalika , Podder Soumita , Ghosh Tapash C
Published: August 2011

Background

Pseudogenes, the nonfunctional homologues of functional genes are now coming to light as important resources regarding the study of human protein evolution. Processed pseudogenes arising by reverse transcription and reinsertion can provide molecular record on the dynamics and evolution of genomes. Researches on the progenitors of human processed pseudogenes delved out their highly expressed and evolutionarily conserved characters. They are reported to be short and GC-poor indicating their high efficiency for retrotransposition. In this article we focused on their high expressivity and explored the factors contributing for that and their relevance in the milieu of protein sequence evolution.

Results

We here, analyzed the high expressivity of these genes configuring processed or retropseudogenes by their immense connectivity in protein-protein interaction network, an inclination towards alternative splicing mechanism, a lower rate of mRNA disintegration and a slower evolutionary rate. While the unusual trend of the upraised disorder in contrast with the high expressivity of the proteins encoded by processed pseudogene ancestors is accredited by a predominance of hub-protein encoding genes, a high propensity of repeat sequence containing genes, elevated protein stability and the functional constraint to perform the transcription regulatory jobs. Linear regression analysis demonstrates mRNA decay rate and protein intrinsic disorder as the influential factors controlling the expressivity of these retropseudogene ancestors while the latter one is found to have the most significant regulatory power.

Conclusions

Our findings imply that, the affluence of disordered regions elevating the network attachment to be involved in important cellular assignments and the stability in transcriptional level are acting as the prevailing forces behind the high expressivity of the human genes configuring processed pseudogenes.
Transcriptional responses to glucose in Saccharomyces cerevisiae strains lacking a functional protein kinase A
Authors: Livas Daniela , Almering Marinka JH , Daran Jean-Marc , Pronk Jack T , Gancedo Juana M
Published: August 2011

Background

The pattern of gene transcripts in the yeastSaccharomyces cerevisiaeis strongly affected by the presence of glucose. An increased activity of protein kinase A (PKA), triggered by a rise in the intracellular concentration of cAMP, can account for many of the effects of glucose on transcription. InS. cerevisiaethree genes,TPK1, TPK2, andTPK3, encode catalytic subunits of PKA. The lack of viability oftpk1 tpk2 tpk3triple mutants may be suppressed by mutations such asyak1ormsn2/msn4. To investigate the requirement for PKA in glucose control of gene expression, we have compared the effects of glucose on global transcription in a wild-type strain and in two strains devoid of PKA activity,tpk1 tpk2 tpk3 yak1andtpk1 tpk2 tpk3 msn2 msn4.

Results

We have identified different classes of genes that can be induced -or repressed- by glucose in the absence of PKA. Representative examples are genes required for glucose utilization and genes involved in the metabolism of other carbon sources, respectively. Among the genes responding to glucose in strains devoid of PKA some are also controlled by a redundant signalling pathway involving PKA activation, while others are not affected when PKA is activated through an increase in cAMP concentration. On the other hand, among genes that do not respond to glucose in the absence of PKA, some give a full response to increased cAMP levels, even in the absence of glucose, while others appear to require the cooperation of different signalling pathways. We show also that, for a number of genes controlled by glucose through a PKA-dependent pathway, the changes in mRNA levels are transient. We found that, in cells grown in gluconeogenic conditions, expression of a small number of genes, mainly connected with the response to stress, is reduced in the strains lacking PKA.

Conclusions

InS. cerevisiae, the transcriptional responses to glucose are triggered by a variety of pathways, alone or in combination, in which PKA is often involved. Redundant signalling pathways confer a greater robustness to the response to glucose, while cooperative pathways provide a greater flexibility.
Genome-wide functional annotation and structural verification of metabolic ORFeome of Chlamydomonas reinhardtii
Authors: Ghamsari Lila , Balaji Santhanam , Shen Yun , Yang Xinping , Balcha Dawit , Fan Changyu , Hao Tong , Yu Haiyuan , Papin Jason A , Salehi-Ashtiani Kourosh
Published: August 2011

Background

Recent advances in the field of metabolic engineering have been expedited by the availability of genome sequences and metabolic modelling approaches. The complete sequencing of the C. reinhardtii genome has made this unicellular alga a good candidate for metabolic engineering studies; however, the annotation of the relevant genes has not been validated and the much-needed metabolic ORFeome is currently unavailable. We describe our efforts on the functional annotation of the ORF models released by the Joint Genome Institute (JGI), prediction of their subcellular localizations, and experimental verification of their structural annotation at the genome scale.

Results

We assigned enzymatic functions to the translated JGI ORF models of C. reinhardtii by reciprocal BLAST searches of the putative proteome against the UniProt and AraCyc enzyme databases. The best match for each translated ORF was identified and the EC numbers were transferred onto the ORF models. Enzymatic functional assignment was extended to the paralogs of the ORFs by clustering ORFs using BLASTCLUST.

In total, we assigned 911 enzymatic functions, including 886 EC numbers, to 1,427 transcripts. We further annotated the enzymatic ORFs by prediction of their subcellular localization. The majority of the ORFs are predicted to be compartmentalized in the cytosol and chloroplast. We verified the structure of the metabolism-related ORF models by reverse transcription-PCR of the functionally annotated ORFs. Following amplification and cloning, we carried out 454FLX and Sanger sequencing of the ORFs. Based on alignment of the 454FLX reads to the ORF predicted sequences, we obtained more than 90% coverage for more than 80% of the ORFs. In total, 1,087 ORF models were verified by 454 and Sanger sequencing methods. We obtained expression evidence for 98% of the metabolic ORFs in the algal cells grown under constant light in the presence of acetate.

Conclusions

We functionally annotated approximately 1,400 JGI predicted metabolic ORFs that can facilitate the reconstruction and refinement of a genome-scale metabolic network. The unveiling of the metabolic potential of this organism, along with structural verification of the relevant ORFs, facilitates the selection of metabolic engineering targets with applications in bioenergy and biopharmaceuticals. The ORF clones are a resource for downstream studies.
Isolates from hospital environments are the most virulent of the Candida parapsilosiscomplex
Authors: Sabino Raquel , Sampaio Paula , Carneiro Catarina , Rosado Laura , Pais Célia
Published: August 2011

Background

Candida parapsilosisis frequently isolated from hospital environments, like air and surfaces, and causes serious nosocomial infections. Molecular studies provided evidence of great genetic diversity within theC. parapsilosisspecies complex but, despite their growing importance as pathogens, little is known about their potential to cause disease, particularly their interactions with phagocytes. In this study, clinical and environmentalC. parapsilosisisolates, and strains of the related speciesC. orthopsilosisandC. metapsilosiswere assayed for their ability to induce macrophage cytotocixity and secretion of the pro-inflammatory cytokine TNF-α, to produce pseudo-hyphae and to secrete hydrolytic enzymes.

Results

EnvironmentalC. parapsilosisisolates caused a statistically significant (p= 0.0002) higher cell damage compared with the clinical strains, whileC. orthopsilosisandC. metapsilosiswere less cytotoxic. On the other hand, clinical isolates induced a higher TNF-α production compared with environmental strains (p< 0.0001). Whereas the amount of TNF-α produced in response toC. orthopsilosisstrains was similar to the obtained withC. parapsilosisenvironmental isolates, it was lower forC. metapsilosisstrains. No correlation between pseudo-hyphae formation or proteolytic enzymes secretion and macrophage death was detected (p> 0.05). However, a positive correlation between pseudo-hyphae formation and TNF-α secretion was observed (p= 0.0119).

Conclusions

We show that environmentalC. parapsilosisstrains are more resistant to phagocytic host defences than bloodstream isolates, being potentially more deleterious in the course of infection than strains from a clinical source. Thus, active environmental surveillance and application of strict cleaning procedures should be implemented in order to prevent cross-infection and hospital outbreaks.
Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1
Authors: Gregor Anne , Albrecht Beate , Bader Ingrid , Bijlsma Emilia K , Ekici Arif B , Engels Hartmut , Hackmann Karl , Horn Denise , Hoyer Juliane , Klapecki Jakub , Kohlhase Jürgen , Maystadt Isabelle , Nagl Sandra , Prott Eva , Tinschert Sigrid , Ullmann Reinhard , Wohlleber Eva , Woods Geoffrey , Reis André , Rauch Anita , Zweier Christiane
Published: August 2011

Background

Heterozygous copy-number and missense variants inCNTNAP2andNRXN1have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability.

Methods

99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations inCNTNAP2andNRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in eitherCNTNAP2orNRXN1, the remaining allele was sequenced.

Results

By molecular karyotyping and mutational screening ofCNTNAP2andNRXN1in a group of severely intellectually disabled patients we identified a heterozygous deletion inNRXN1in one patient and heterozygous splice-site, frameshift and stop mutations inCNTNAP2in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions withinNRXN1orCNTNAP2we could identify a defect on the second allele. One deletion inNRXN1and one deletion inCNTNAP2occurredde novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation.

Conclusions

We report on patients with heterozygous defects inCNTNAP2orNRXN1associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene.
The Chinese version of the Obsessive-Compulsive Inventory-Revised scale: Replication and extension to non-clinical and clinical individuals with OCD symptoms
Authors: Peng Zi-wen , Yang Wen-han , Miao Guo-dong , Jing Jin , Chan Raymond CK
Published: August 2011

Background

The Obsessive-Compulsive Inventory-Revised (OCI-R) was designed to evaluate the severity of obsessive-compulsive symptoms in both clinical and non-clinical samples. The aim of the study was to evaluate the psychometric properties of a Chinese version of this scale.

Methods

The Chinese version of the OCI-R was administered to both a non-clinical sample (209 undergraduate students) and a clinical sample (56 obsessive-compulsive disorder (OCD) patients). Confirmatory factor analysis was conducted to examine the construct validity of the OCI-R in the non-clinical sample. The internal consistency at baseline and test-retest reliabilities at 4-week interval was examined in both the non-clinical and clinical samples.

Results

The confirmatory factor analysis of the non-clinical sample confirmed a 6-factor model suggested by the original authors of the instrument (df = 120, RMSEA = 0.068, CFI = 0.88, NNFI = 0.85, GFI = 0.89). The internal consistency and test-retest reliability were at an acceptable range for both the non-clinical and clinical samples. The OCI-R also showed good clinical discrimination for patients with OCD from healthy controls.

Conclusions

The Chinese version of the OCI-R is a valid and reliable instrument for measuring OCD symptoms in the Chinese context.
Septic arthritis of the knee: Presentation of a novel irrigation-suction system tested in a cadaver study
Authors: Ateschrang Atesch , Albrecht Dirk , Schröter Steffen , Hirt Bernhard , Weise Kuno , Dolderer Jürgen H
Published: August 2011

Background

The established treatment for bacterial arthritis of the knee joint is arthroscopic surgery with irrigation and debridement. The aim of this article is to summarize the relevant data in treating bacterial arthritis of the knee joint, and based on these findings to present a novel irrigation suction system, tested in a cadaver study, as an additional tool in the postoperative treatment phase of arthroscopic surgery for knee joint infections.

Method

The novel automated irrigation-suction system presented here was compared to conventional continuous suction irrigation in a total of six knee joints. All knee joints were filled with 80 ml methylene blue stain and rinsed by two different methods. Fluid specimens were taken after ten and twenty minutes to be compared by photometric extinction measurement at a wave length of 500 nm.

Results

After ten minutes, the average extinction was e1C= 0.8 for the continuous suction irrigation and e1N= 0.4 for the novel irrigation-suction system. After twenty minutes, we recorded an average extinction of e2C= 0.3 for continuous suction irrigation and e2N= 0.001 for the novel irrigation-suction system. The studentst-test revealed superior results after ten and twenty minutes of washing out the knee joints with a p < 0.001 for the novel irrigation-suction system.

Conclusion

A novel irrigation-suction system may be an effective tool for postoperative knee joint irrigation in arthroscopic therapy for bacterial arthritis of the knee. Further animal studies are needed to verify the effects in vivo.
Disparities exist between National food group recommendations and the dietary intakes of women
Authors: Blumfield Michelle L , Hure Alexis J , MacDonald-Wicks Lesley K , Patterson Amanda J , Smith Roger , Collins Clare E
Published: August 2011

Background

Preconception and pregnancy dietary intakes can influence the health of future generations. In this study we compared the food intakes of reproductive-aged women by pregnancy status, to current Australian recommendations.

Methods

Data are from the Australian Longitudinal Study on Women's Health, younger cohort aged 25-30 years in 2003, with self-reported status as pregnant (n = 606), trying to conceive (n = 454), given birth in the last 12 months (n = 829) or other (n = 5597). Diet was assessed using a validated 74-item food frequency questionnaire. Food group servings and nutrient intakes were compared to the Australian Guide to Healthy Eating (AGHE) and Australian Nutrient Reference Values (NRVs).

Results

No women met all AGHE food group recommendations. Highest adherence rates [mean (95% CI) servings/day] were for meat [85%, 1.9(1.8-1.9)], fruit [44%, 2.1(2.1-2.2)] and dairy [35%, 1.8(1.8-1.9)], with < 14% meeting remaining recommendations. Women who achieved NRVs (folate, iron, calcium, zinc, fibre) for pregnancy, breastfeeding and adult life stages were 1.5%, 3.3% and 13.7%, respectively. Compared to AGHE, women consumed more servings of fruit (4.9 vs 4.0;P = 0.034) and dairy (3.4 vs 2.0;P = 0.006) to achieve pregnancy NRVs; more dairy (2.9 vs 2.0;P = 0.001), less fruit (3.9 vs 5.0;P < .001) and vegetables (3.4 vs 7.0;P < .001) to achieve breastfeeding NRVs; more fruit (3.6 vs 3.0;P < .001), dairy (2.5 vs 2.0;P < .001), meat (1.8 vs 1.5;P = 0.015), less vegetables (3.6 vs 5.0;P < .001) to achieve adult NRVs.

Conclusions

The AGHE does not align with contemporary diets of Australian women or enable them to meet all NRVs. Current tools to guide food consumption by women during pregnancy require revision.