bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrin-mediated internalization of Staphylococcus aureus does not require vinculin
Authors: Borisova Marina , Shi Yong , Buntru Alexander , Wörner Susanne , Ziegler Wolfgang H , Hauck Christof R
Published: January 2013

Background

Disease manifestations of Staphylococcus aureus are connected to the fibronectin (Fn)-binding capacity of these Gram-positive pathogens. Fn deposition on the surface of S. aureus allows engagement of α5β1 integrins and triggers uptake by host cells. For several integrin- and actin-associated cytoplasmic proteins, including FAK, Src, N-WASP, tensin and cortactin, a functional role during bacterial invasion has been demonstrated. As reorganization of the actin cytoskeleton is critical for bacterial entry, we investigated whether vinculin, an essential protein linking integrins with the actin cytoskeleton, may contribute to the integrin-mediated internalization of S. aureus.

Results

Complementation of vinculin in vinculin -/- cells, vinculin overexpression, as well as shRNA-mediated vinculin knock-down in different eukaryotic cell types demonstrate, that vinculin does not have a functional role during the integrin-mediated uptake of S. aureus.

Conclusions

Our results suggest that vinculin is insignificant for the integrin-mediated uptake of S. aureus despite the critical role of vinculin as a linker between integrins and F-actin.
Thrombocytopenia is not mandatory to diagnose haemolytic and uremic syndrome
Authors: Sallée Marion , Ismail Khalil , Fakhouri Fadi , Vacher-Coponat Henri , Moussi-Francés Julie , Frémaux-Bacchi Véronique , Burtey Stéphane
Published: January 2013

Background

Hemolytic and uremic syndrome (HUS) diagnosis involves association of non immune hemolytic anemia, thrombocytopenia, and renal failure. HUS without thrombocytopenia has been observed, we call it partial HUS. Its real frequency and outcome are unknown. The aim of this study was to determine the prevalence of patients with normal platelets count in two HUS cohorts and to compare their outcome to patients with thrombocytopenia.

Methods

We retrospectively identified HUS diagnosis in two different cohorts. The first cohort was from a single center and consisted of all cases of HUS whatever the aetiology, the second was multicentric and consisted of atypical HUS patients. These cohorts were divided into two groups depending on the presence or absence of thrombocytopenia. Clinical and biological data were compared between thrombopenic and non thrombopenic group.

Results

We identified 13% (20/150) of patients with normal platelets count: 10 episodes (18%) of HUS in six patients (14%) in the monocentric cohort and 14 patients (13%) with 17 episodes (12%) in the multicentric cohort of atypical HUS. Groups differed in platelets count and LDH level. In both cohorts, renal outcome was similar to patient presenting with thrombocytopenia.

Conclusion

HUS with normal platelets count is not infrequent. Relative to classical clinical presentation of HUS, partial HUS has similar characteristics and identical poor renal outcome and so must be treated in the same way.
Predictors of the number of under-five malnourished children in Bangladesh: application of the generalized poisson regression model
Authors: Islam Mohammad Mafijul , Alam Morshed , Tariquzaman Md , Kabir Mohammad Alamgir , Pervin Rokhsona , Begum Munni , Khan Md Mobarak Hossain
Published: January 2013

Background

Malnutrition is one of the principal causes of child mortality in developing countries including Bangladesh. According to our knowledge, most of the available studies, that addressed the issue of malnutrition among under-five children, considered the categorical (dichotomous/polychotomous) outcome variables and applied logistic regression (binary/multinomial) to find their predictors. In this study malnutrition variable (i.e. outcome) is defined as the number of under-five malnourished children in a family, which is a non-negative count variable. The purposes of the study are (i) to demonstrate the applicability of the generalized Poisson regression (GPR) model as an alternative of other statistical methods and (ii) to find some predictors of this outcome variable.

Methods

The data is extracted from the Bangladesh Demographic and Health Survey (BDHS) 2007. Briefly, this survey employs a nationally representative sample which is based on a two-stage stratified sample of households. A total of 4,460 under-five children is analysed using various statistical techniques namely Chi-square test and GPR model.

Results

The GPR model (as compared to the standard Poisson regression and negative Binomial regression) is found to be justified to study the above-mentioned outcome variable because of its under-dispersion (variance < mean) property. Our study also identify several significant predictors of the outcome variable namely mother’s education, father’s education, wealth index, sanitation status, source of drinking water, and total number of children ever born to a woman.

Conclusions

Consistencies of our findings in light of many other studies suggest that the GPR model is an ideal alternative of other statistical models to analyse the number of under-five malnourished children in a family. Strategies based on significant predictors may improve the nutritional status of children in Bangladesh.
Evidence for cervical cancer mortality with screening program in Taiwan, 1981–2010: age-period-cohort model
Authors: Su Shih-Yung , Huang Jing-Yang , Ho Chien-Chang , Liaw Yung-Po
Published: January 2013

Background

Cervical cancer is the most common cancer experienced by women worldwide; however, screening techniques are very effective for reducing the risk of death. The national cervical cancer screening program was implemented in Taiwan in 1995. The objective of this study was to examine and provide evidence of the cervical cancer mortality trends for the periods before and after the screening program was implemented.

Methods

Data from 1981 to 2010 of the causes of death registered were obtained from the Department of Health, Taiwan. Age-standardized mortality rates, age-specific rates, and age-period-cohort models that employed the sequential method were used to assess temporal changes that occurred between 1981 and 2010, with 1995 used as the separating year.

Results

The results showed that for both time periods of 1981 to 1995 and 1996 to 2010, age and period had significant effects, whereas the birth cohort effects were insignificant. For patients between 80 and 84 years of age, the mortality rate for 1981 to 1995 and 1996 to 2010 was 48.34 and 68.08. The cervical cancer mortality rate for 1996 to 2010 was 1.0 for patients between 75 and 79 years of age and 1.4 for patients between 80 and 84 years of age compared to that for 1981 to 1995. Regarding the period effect, the mortality trend decreased 2-fold from 1996 to 2010.

Conclusions

The results of this study indicate a decline in cervical cancer mortality trends after the screening program involving Papanicolaou tests was implemented in 1995. However, the positive effects of the screening program were not observed in elderly women because of treatment delays during the initial implementation of the screening program.
Improved health outcomes with Etanercept versus usual DMARD therapy in an Asian population with established rheumatoid arthritis
Authors: Bae Sang-Cheol , Gun Suk Chyn , Mok Chi Chiu , Khandker Rezaul , Nab Henk W , Koenig Andrew S , Vlahos Bonnie , Pedersen Ron , Singh Amitabh
Published: January 2013

Background

Patient reported outcomes (PROs) are especially useful in assessing treatments for rheumatoid arthritis (RA) since they measure dimensions of health-related quality of life that cannot be captured using strictly objective physiological measures. The aim of this study was to compare the effects of combination etanercept and methotrexate (ETN + MTX) versus combination synthetic disease modifying antirheumatic drugs (DMARDs) and methotrexate (DMARD + MTX) on PRO measures among RA patients from the Asia-Pacific region, a population not widely studied to date. Patients with established moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were studied.

Methods

Patients were randomized to either ETN + MTX (N = 197) or DMARD + MTX (N = 103) in an open-label, active-comparator, multicenter study, with PRO measures designed as prospective secondary endpoints. The Health Assessment Questionnaire (HAQ), Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), Medical Outcomes Short Form-36 Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS) and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) were used.

Results

Significantly greater improvements were noted for the ETN + MTX group at week16 for HAQ mean scores and for proportion of patients achieving HAQ score ≤ 0.5, compared to patients in the DMARD + MTX group. SF-36 Summary Scores for physical and mental components and for 6 of 8 health domains showed significantly greater improvements at week16 for the ETN + MTX group; only scores for physical functioning and role-emotional domains did not differ significantly between the two treatment arms. Greater improvements at week16 were noted for the ETN + MTX group for FACIT-Fatigue, HADS, and WPAI:GH mean scores.

Conclusion

Combination therapy using ETN + MTX demonstrated superior improvements using a comprehensive set of PRO measures, compared to combination therapy with usual standard of care DMARDs plus MTX in patients with established rheumatoid arthritis from the Asia-Pacific region.

Trial registration

clintrials.gov # NCT00422227
The hexane fraction of Ardisia crispa Thunb. A. DC. roots inhibits inflammation-induced angiogenesis
Authors: Hamsin Dayang Erna Zulaikha Awang , Hamid Roslida Abdul , Yazan Latifah Saiful , Taib Che Norma Mat , Ting Yeong Looi
Published: January 2013

Background

Ardisia crispa (Myrsinaceae) is used in traditional Malay medicine to treat various ailments associated with inflammation, including rheumatism. The plant’s hexane fraction was previously shown to inhibit several diseases associated with inflammation. As there is a strong correlation between inflammation and angiogenesis, we conducted the present study to investigate the anti-angiogenic effects of the plant’s roots in animal models of inflammation-induced angiogenesis.

Methods

We first performed phytochemical screening and high-performance liquid chromatography (HPLC) fingerprinting of the hexane fraction of Ardisia crispa roots ethanolic extract (ACRH) and its quinone-rich fraction (QRF). The anti-inflammatory properties of ACRH and QRF were tested using the Miles vascular permeability assay and the murine air pouch granuloma model following oral administration at various doses.

Results

Preliminary phytochemical screening of ACRH revealed the presence of flavonoids, triterpenes, and tannins. The QRF was separated from ACRH (38.38% w/w) by column chromatography, and was isolated to yield a benzoquinonoid compound. The ACRH and QRF were quantified by HPLC. The LD50 value of ACRH was 617.02 mg/kg. In the Miles vascular permeability assay, the lowest dose of ACRH (10 mg/kg) and all doses of QRF significantly reduced vascular endothelial growth factor (VEGF)-induced hyperpermeability, when compared with the vehicle control. In the murine air pouch granuloma model, ACRH and QRF both displayed significant and dose-dependent anti-inflammatory effects, without granuloma weight. ACRH and QRF significantly reduced the vascular index, but not granuloma tissue weight.

Conclusions

In conclusion, both ACRH and QRF showed potential anti-inflammatory properties in a model of inflammation-induced angiogenesis model, demonstrating their potential anti-angiogenic properties.
Maternal undernutrition does not alter Sertoli cell numbers or the expression of key developmental markers in the mid-gestation ovine fetal testis
Authors: Andrade Luis P , Rhind Stewart M , Rae Michael T , Kyle Carol E , Jowett Jamie , Lea Richard G
Published: January 2013

Background

The aim of this study was to determine the effects of maternal undernutrition on ovine fetal testis morphology and expression of relevant histological indicators. Maternal undernutrition, in sheep, has been reported, previously, to alter fetal ovary development, as indicated by delayed folliculogenesis and the altered expression of ovarian apoptosis-regulating gene products, at day 110 of gestation. It is not known whether or not maternal undernutrition alters the same gene products in the day 110 fetal testis.

Design and methods

Mature Scottish Blackface ewes were fed either 100% (Control; C) or 50% (low; L) of estimated metabolisable energy requirements of a pregnant ewe, from mating to day 110 of gestation. All pregnant ewes were euthanized at day 110 and a sub-set of male fetuses was randomly selected (6 C and 9 L) for histology studies designed to address the effect of nutritional state on several indices of testis development. Sertoli cell numbers were measured using a stereological method and Ki67 (cell proliferation index), Bax (pro-apoptosis), Mcl-1 (anti-apoptosis), SCF and c-kit ligand (development and apoptosis) gene expression was measured in Bouins-fixed fetal testis using immunohistochemistry.

Results

No significant differences were observed in numbers of Sertoli cells or testicular Ki67 positive cells. The latter were localised to the testicular cords and interstitium. Bax and Mcl-1 were localised specifically to the germ cells whereas c-kit was localised to both the cords and interstitium. SCF staining was very sparse. No treatment effects were observed for any of the markers examined.

Conclusions

These data suggest that, unlike in the fetal ovary, maternal undernutrition for the first 110 days of gestation affects neither the morphology of the fetal testis nor the expression of gene products which regulate apoptosis. It is postulated that the effects of fetal undernutrition on testis function may be expressed through hypothalamic-pituitary changes.
A global resource to translational medicine: the International Park of Translational Medicine and BioMedicine (IPTBM)
Authors: Wu Xiaodan , Marincola Francesco M , Liebman Michael N , Wang Xiangdong
Published: January 2013

Translational science consists of research and development that integrates multiple resources to expedite the successful treatment of disease. The International Park of Translational BioMedicine (IPTBM) is currently being developed within the interface between Zhejiang Province and Shanghai Municipality. IPTBM has been designed to pioneer comprehensive biomedical research that spans the continuum from the education of young scientists to providing the infrastructure necessary for clinical testing and direct observation to better understand human biology while promoting viable commercial results within a vibrant biotechnology community. IPTBM’s goal is to attract global partners organized around five fundamental pillars: 1) Institutional Development, 2) Project Implementation, 3) Development and Production, 4) Investment and 5) Regulatory Clusters to address the needs of an international platform of scientists, institutes, universities, commercial enterprises, investors, politicians, and other stakeholders. The IPTBM differs from existing models including CTSA’s (US, NIH) technology because of its comprehensive approach to merge education, research, innovation, and development to translate clinical and public health needs into target-oriented and cost-efficient projects.
Structural and electrical characteristics of high-κ Er2O3 and Er2TiO5 gate dielectrics for a-IGZO thin-film transistors
Authors: Chen Fa-Hsyang , Her Jim-Long , Shao Yu-Hsuan , Matsuda Yasuhiro H , Pan Tung-Ming
Published: January 2013

In this letter, we investigated the structural and electrical characteristics of high-κ Er2O3 and Er2TiO5 gate dielectrics on the amorphous indium-gallium-zinc-oxide (a-IGZO) thin-film transistor (TFT) devices. Compared with the Er2O3 dielectric, the a-IGZO TFT device incorporating an Er2TiO5 gate dielectric exhibited a low threshold voltage of 0.39 V, a high field-effect mobility of 8.8 cm2/Vs, a small subthreshold swing of 143 mV/decade, and a high I
on/I
off current ratio of 4.23 × 107, presumably because of the reduction in the oxygen vacancies and the formation of the smooth surface roughness as a result of the incorporation of Ti into the Er2TiO5 film. Furthermore, the reliability of voltage stress can be improved using an Er2TiO5 gate dielectric.
Novel coarse-to-fine dual scale technique for tuberculosis cavity detection in chest radiographs
Authors: Xu Tao , Cheng Irene , Long Richard , Mandal Mrinal
Published: January 2013

Although many lung disease diagnostic procedures can benefit from computer-aided detection (CAD), current CAD systems are mainly designed for lung nodule detection. In this article, we focus on tuberculosis (TB) cavity detection because of its highly infectious nature. Infectious TB, such as adult-type pulmonary TB (APTB) and HIV-related TB, continues to be a public health problem of global proportion, especially in the developing countries. Cavities in the upper lung zone provide a useful cue to radiologists for potential infectious TB. However, the superimposed anatomical structures in the lung field hinder effective identification of these cavities. In order to address the deficiency of existing computer-aided TB cavity detection methods, we propose an efficient coarse-to-fine dual scale technique for cavity detection in chest radiographs. Gaussian-based matching, local binary pattern, and gradient orientation features are applied at the coarse scale, while circularity, gradient inverse coefficient of variation and Kullback–Leibler divergence measures are applied at the fine scale. Experimental results demonstrate that the proposed technique outperforms other existing techniques with respect to true cavity detection rate and segmentation accuracy.
A possible coincidence of cytomegalovirus retinitis and intraocular lymphoma in a patient with systemic non-Hodgkin’s lymphoma
Authors: Svozílková Petra , Heissigerová Jarmila , Brichová Michaela , Kalvodová Bohdana , Dvořák Jan , Říhová Eva
Published: January 2013

Purpose

To present a possible coincidence of cytomegalovirus retinitis and intraocular lymphoma in a patient with systemic non-Hodgkin’s lymphoma.

Case presentation

A 47-year-old woman presented with decreased visual acuity associated with white retinal lesions in both eyes. A history of pneumonia of unknown aetiology closely preceded the deterioration of vision. Five years previously the patient was diagnosed with follicular non-Hodgkin’s lymphoma. She was treated with a chemotherapy regimen comprised of cyclophosphamide, adriamycin, vincristin, and prednisone with later addition of the anti-CD20 antibody rituximab. She experienced a relapse 19 months later with involvement of the retroperitoneal lymph nodes, and commenced treatment with rituximab and 90Y-ibritumomab tiuxetan. A second relapse occurred 22 months after radioimmunotherapy and was treated with a combination of fludarabine, cyclophosphamide, and mitoxantrone followed by rituximab. The patient experienced no further relapses until the current presentation (April, 2010).

Pars plana vitrectomy with vitreous fluid analysis was performed in the right eye. PCR testing confirmed the presence of cytomegalovirus in the vitreous. Atypical lymphoid elements, highly suspicious of malignancy were also found on cytologic examination. Intravenous foscarnet was administered continually for three weeks, followed by oral valganciclovir given in a dose of 900 mg twice per day. In addition, the rituximab therapy continued at three monthly intervals. Nevertheless, cessation of foscarnet therapy was followed by a recurrence of retinitis on three separate occasions during a 3-month period instigating its reinduction to the treatment regime after each recurrence.

Conclusions

Cytomegalovirus retinitis is an opportunistic infection found in AIDS patients as well as in bone marrow and solid organ transplant recipients being treated with systemic immunosuppressive drugs. This case presents a less common incidence of cytomegalovirus retinitis occurring in a patient with non-Hodgkin’s lymphoma. We demonstrated a possible coexistence of cytomegalovirus retinitis and intraocular lymphoma in this particular patient. The final diagnosis was based on clinical manifestations together with the course of uveitis and its response to treatment alongside the results of vitreous fluid analysis. This report highlights the importance of intraocular fluid examination in cases with nonspecific clinical manifestations. Such an examination allows for the detection of simultaneously ongoing ocular diseases of differing aetiologies and enables the prompt initiation of effective treatment.
Birds and people in semiarid northeastern Brazil: symbolic and medicinal relationships
Authors: Bezerra Dandara Monalisa Mariz , de Araujo Helder Farias Pereira , Alves Ângelo Giuseppe Chaves , Alves Rômulo Romeu Nóbrega
Published: January 2013

Background

At least 511 species of birds occur in the semiarid region of northeastern Brazil and many of them interact with human populations in a number of different ways, including their use in zootherapeutics and their links with local beliefs.

Objective

The present work examined these types of birds/human interactions (use in zootherapeutics and their links with local beliefs) in the semiarid region of Rio Grande do Norte State in northeastern Brazil.

Methods

Information was obtained through semi-structured interviews with 120 local residents.

Results

A total of 16 wild bird species distributed among 11 families were found to interact directly with humans, with Columbidae being the best represented family. Seven species were identified in the medicinal category, five were related to symbolic aspects, while four species were identified as being related to both categories (medicinal and symbolic).

Conclusion

The accumulated folk knowledge, beliefs, and practices involving the avifauna in the semiarid region of Brazil, whether symbolic or medicinal, demonstrated the cultural importance of this vertebrate group to local human populations and revealed a belief system intrinsically related to cynegetic practices in the region.

Portuguese abstract

Introdução

No semiárido do Brasil ocorrem 511 espécies de aves, algumas das quais interagem frequentemente com as populações humanas locais de diferentes formas, incluindo o uso como zooterápico e a inserção em crenças.

Objetivo

Esta pesquisa registrou as aves diretamente associadas a essas formas de interação (o uso como zooterápico e a inserção em crenças) na região semiárida do Estado do Rio Grande do Norte, Nordeste do Brasil.

Métodos

As informações foram obtidas através de entrevistas semiestruturadas aplicadas a 120 moradores locais.

Resultados

Foram registradas 16 espécies de aves silvestres distribuídas em 11 famílias, sendo Columbidae a que apresentou o maior número de representantes. Sete espécies foram indicadas apenas na categoria medicinal, cinco espécies apenas relacionadas a aspectos simbólicos e quatro foram indicadas como relacionadas a ambas as categorias (medicinal e simbólica).

Conclusão

Os conhecimentos, crenças e práticas relacionadas à avifauna no semiárido brasileiro, seja no aspecto simbólico ou medicinal, demonstra a importância cultural que esse grupo de vertebrados representa para as populações locais, revelando um sistema de crenças que está intrinsicamente relacionado às práticas cinegéticas na região.
Animal model of Mycoplasma fermentans respiratory infection
Authors: Yáñez Antonio , Martínez-Ramos Azucena , Calixto Teresa , González-Matus Francisco Javier , Rivera-Tapia José Antonio , Giono Silvia , Gil Constantino , Cedillo Lilia
Published: January 2013

Background

Mycoplasma fermentans has been associated with respiratory, genitourinary tract infections and rheumatoid diseases but its role as pathogen is controversial. The purpose of this study was to probe that Mycoplasma fermentans is able to produce respiratory tract infection and migrate to several organs on an experimental infection model in hamsters. One hundred and twenty six hamsters were divided in six groups (A-F) of 21 hamsters each. Animals of groups A, B, C were intratracheally injected with one of the mycoplasma strains: Mycoplasma fermentans P 140 (wild strain), Mycoplasma fermentans PG 18 (type strain) or Mycoplasma pneumoniae Eaton strain. Groups D, E, F were the negative, media, and sham controls. Fragments of trachea, lungs, kidney, heart, brain and spleen were cultured and used for the histopathological study. U frequency test was used to compare recovery of mycoplasmas from organs.

Results

Mycoplasmas were detected by culture and PCR. The three mycoplasma strains induced an interstitial pneumonia; they also migrated to several organs and persisted there for at least 50 days. Mycoplasma fermentans P 140 induced a more severe damage in lungs than Mycoplasma fermentans PG 18. Mycoplasma pneumoniae produced severe damage in lungs and renal damage.

Conclusions

Mycoplasma fermentans induced a respiratory tract infection and persisted in different organs for several weeks in hamsters. This finding may help to explain the ability of Mycoplasma fermentans to induce pneumonia and chronic infectious diseases in humans.
External validation of anti-Müllerian hormone based prediction of live birth in assisted conception
Authors: Khader Amani , Lloyd Suzanne M , McConnachie Alex , Fleming Richard , Grisendi Valentina , La Marca Antonio , Nelson Scott M
Published: January 2013

Background

Chronological age and oocyte yield are independent determinants of live birth in assisted conception. Anti-Müllerian hormone (AMH) is strongly associated with oocyte yield after controlled ovarian stimulation. We have previously assessed the ability of AMH and age to independently predict live birth in an Italian assisted conception cohort. Herein we report the external validation of the nomogram in 822 UK first in vitro fertilization (IVF) cycles.

Methods

Retrospective cohort consisting of 822 patients undergoing their first IVF treatment cycle at Glasgow Centre for Reproductive Medicine. Analyses were restricted to women aged between 25 and 42 years of age. All women had an AMH measured prior to commencing their first IVF cycle. The performance of the model was assessed; discrimination by the area under the receiver operator curve (ROCAUC) and model calibration by the predicted probability versus observed probability.

Results

Live births occurred in 29.4% of the cohort. The observed and predicted outcomes showed no evidence of miscalibration (p = 0.188). The ROCAUC was 0.64 (95% CI: 0.60, 0.68), suggesting moderate and similar discrimination to the original model. The ROCAUC for a continuous model of age and AMH was 0.65 (95% CI 0.61, 0.69), suggesting that the original categories of AMH were appropriate.

Conclusions

We confirm by external validation that AMH and age are independent predictors of live birth. Although the confidence intervals for each category are wide, our results support the assessment of AMH in larger cohorts with detailed baseline phenotyping for live birth prediction.
Apoptosis rate and transcriptional response of pancreatic islets exposed to the PPAR gamma agonist Pioglitazone
Authors: Lamounier Rodrigo N , Coimbra Cassio N , White Peter , Costal Flavia L , Oliveira Leonardo S , Giannella-Neto Daniel , Kaestner Klaus H , Corrêa-Giannella Maria Lúcia
Published: January 2013

To explore the molecular pathways underlying thiazolidinediones effects on pancreatic islets in conditions mimicking normo- and hyperglycemia, apoptosis rate and transcriptional response to Pioglitazone at both physiological and supraphysiological glucose concentrations were evaluated. Adult rat islets were cultured at physiological (5.6 mM) and supraphysiological (23 mM) glucose concentrations in presence of 10 μM Pioglitazone or vehicle. RNA expression profiling was evaluated with the PancChip 13k cDNA microarray after 24-h, and expression results for some selected genes were validated by qRT-PCR. The effects of Pioglitazone were investigated regarding apoptosis rate after 24-, 48- and 72-h. At 5.6 mM glucose, 101 genes were modulated by Pioglitazone, while 1,235 genes were affected at 23 mM glucose. Gene networks related to lipid metabolism were identified as altered by Pioglitazone at both glucose concentrations. At 23 mM glucose, cell cycle and cell death pathways were significantly regulated as well. At 5.6 mM glucose, Pioglitazone elicited a transient reduction in islets apoptosis rate while at 23 mM, Bcl2 expression was reduced and apoptosis rate was increased by Pioglitazone. Our data demonstrate that the effect of Pioglitazone on gene expression profile and apoptosis rate depends on the glucose concentration. The modulation of genes related to cell death and the increased apoptosis rate observed at supraphysiological glucose concentration raise concerns about Pioglitazone’s direct effects in conditions of hyperglycemia and reinforce the necessity of additional studies designed to evaluate TZDs effects on the preservation of β-cell function in situations where glucotoxicity might be more relevant than lipotoxicity.
High targeted migration of human mesenchymal stem cells grown in hypoxia is associated with enhanced activation of RhoA
Authors: Vertelov Grigory , Kharazi Ludmila , Muralidhar M G , Sanati Givon , Tankovich Timothy , Kharazi Alex
Published: January 2013

Introduction

A feature which makes stem cells promising candidates for cell therapy is their ability to migrate effectively into damaged or diseased tissues. Recent reports demonstrated the increased motility of human mesenchymal stem cells (hMSC) grown under hypoxic conditions compared to normoxic cells. However, the directional migration of hMSC cultured in hypoxia has not been investigated. In this study we examined the in vitro transmembrane migration of hMSC permanently cultured in hypoxia in response to various cytokines. We also studied the involvement of RhoA, a molecule believed to play an essential role in the migration of MSC via reorganization of the cytoskeleton.

Methods

We compared the directional migration of human hMSCs grown permanently under normal (21%, normoxic) and low O2 (5%, hypoxic) conditions until passage 4 using an in vitro transmembrane migration assay. A series of 17 cytokines was used to induce chemotaxis. We also compared the level of GTP-bound RhoA in the cell extracts of calpeptin-activated hypoxic and normoxic hMSC.

Results

We found that hMSC cultured in hypoxia demonstrate markedly higher targeted migration activity compared to normoxic cells, particularly towards wound healing cytokines, including those found in ischemic and myocardial infarction. We also demonstrated for the first time that hMSC are dramatically more sensitive to activation of RhoA.

Conclusions

The results of this study indicate that high directional migration of hMSCs permanently grown in hypoxia is associated with the enhanced activation of RhoA. The enhanced migratory capacity of hypoxic hMSC would further suggest their potential advantages for clinical applications.
Addition of Rituximab to Chlorambucil Produces Superior Event-Free Survival in the Treatment of Patients With Extranodal Marginal-Zone B-Cell Lymphoma: 5-Year Analysis of the IELSG-19 Randomized Study
Authors: Zucca Emanuele , Conconi Annarita , Laszlo Daniele , López-Guillermo Armando , Bouabdallah Reda , Coiffier Bertrand , Sebban Catherine , Jardin Fabrice , Vitolo Umberto , Morschhauser Franck , Pileri Stefano A. , Copie-Bergman Christiane , Campo Elias , Jack Andrew , Floriani Irene , Johnson Peter , Martelli Maurizio , Cavalli Franco , Martinelli Giovanni , Thieblemont Catherine
Published: January 2013

Purpose

Apart from localized gastric disease, there is no consensus on standard initial treatment of mucosa-associated lymphoid tissue lymphoma. The IELSG-19 study (Randomized Trial of Chlorambucil Versus Chlorambucil Plus Rituximab Versus Rituximab in MALT Lymphoma) was launched to compare chlorambucil alone versus chlorambucil plus rituximab in patients not previously given systemic anticancer therapy.

Patients and Methods

Patients not responding to or not suitable for local therapy were eligible. In arm A, chlorambucil was given daily 6 mg/m2orally (PO) for 6 weeks. Responding patients and those with stable disease continued to be given daily chlorambucil 6 mg/m2PO for 14 consecutive days every 28 days for four cycles. In arm B, intravenous rituximab 375 mg/m2per day was added on days 1, 8, 15, 22, 56, 84, 112, and 140. After completion of the planned accrual, the protocol was amended to introduce a third arm with rituximab alone. We report the planned final analysis of the first two arms (113 patients in arm A and 114 in arm B).

Results

At a median follow-up of 62 months, the 5-year event-free survival (EFS) was significantly better for the patients treated in arm B (68% v 50%; P = .002) who, despite similar overall response rates (90% v 87%), achieved a higher complete remission rate (78% v 65%; P = .025). Progression-free survival was also improved but it did not reach statistical significance (P = .057). Five-year overall survival (OS) was 89% in both arms. Both treatments were well tolerated without unexpected toxicities.

Conclusion

Both treatments were active; the better response rate and EFS obtained with the addition of rituximab did not translate into improved OS.
Deintensification Candidate Subgroups in Human Papillomavirus–Related Oropharyngeal Cancer According to Minimal Risk of Distant Metastasis
Authors: O'Sullivan Brian , Huang Shao Hui , Siu Lillian L. , Waldron John , Zhao Helen , Perez-Ordonez Bayardo , Weinreb Ilan , Kim John , Ringash Jolie , Bayley Andrew , Dawson Laura A. , Hope Andrew , Cho John , Irish Jonathan , Gilbert Ralph , Gullane Patrick , Hui Angela , Liu Fei-Fei , Chen Eric , Xu Wei
Published: January 2013

Purpose

To define human papillomavirus (HPV) –positive oropharyngeal cancers (OPC) suitable for treatment deintensification according to low risk of distant metastasis (DM).

Patients and Methods

OPC treated with radiotherapy (RT) or chemoradiotherapy (CRT) from 2001 to 2009 were included. Outcomes were compared for HPV-positive versus HPV-negative patients. Univariate and multivariate analyses identified outcome predictors. Recursive partitioning analysis (RPA) stratified the DM risk.

Results

HPV status was ascertained in 505 (56%) of 899 consecutive OPCs. Median follow-up was 3.9 years. HPV-positive patients (n = 382), compared with HPV-negative patients (n = 123), had higher local (94% v 80%, respectively, at 3 years; P < .01) and regional control (95% v 82%, respectively; P < .01) but similar distant control (DC; 90% v 86%, respectively; P = .53). Multivariate analysis identified that HPV negativity (hazard ratio [HR], 2.9; 95% CI, 2.0 to 5.0), N2b-N3 (HR, 2.9; 95% CI, 1.8 to 4.9), T4 (HR, 1.8; 95% CI, 1.2 to 2.9), and RT alone (HR, 1.8; 95% CI, 1.1 to 2.5) predicted a lower recurrence-free survival (RFS; all P < .01). Smoking pack-years > 10 reduced overall survival (HR, 1.72; 95% CI, 1.1 to 2.7; P = .03) but did not impact RFS (HR, 1.1; 95% CI, 0.7 to 1.9; P = .65). RPA segregated HPV-positive patients into low (T1-3N0-2c; DC, 93%) and high DM risk (N3 or T4; DC, 76%) groups and HPV-negative patients into different low (T1-2N0-2c; DC, 93%) and high DM risk (T3-4N3; DC, 72%) groups. The DC rates for HPV-positive, low-risk N0-2a or less than 10 pack-year N2b patients were similar for RT alone and CRT, but the rate was lower in the N2c subset managed by RT alone (73% v 92% for CRT; P = .02).

Conclusion

HPV-positive T1-3N0-2c patients have a low DM risk, but N2c patients from this group have a reduced DC when treated with RT alone and seem less suited for deintensification strategies that omit chemotherapy.
Risk of Therapy-Related Secondary Leukemia in Hodgkin Lymphoma: The Stanford University Experience Over Three Generations of Clinical Trials
Authors: Koontz Michael Zach , Horning Sandra J. , Balise Raymond , Greenberg Peter L. , Rosenberg Saul A. , Hoppe Richard T. , Advani Ranjana H.
Published: January 2013

Purpose

To assess therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) risk in patients treated for Hodgkin lymphoma (HL) on successive generations of Stanford clinical trials.

Patients and Methods

Patients with HL treated at Stanford with at least 5 years of follow-up after completing therapy were identified from our database. Records were reviewed for outcome and development of t-AML/MDS.

Results

Seven hundred fifty-four patients treated from 1974 to 2003 were identified. Therapy varied across studies. Radiotherapy evolved from extended fields (S and C studies) to involved fields (G studies). Primary chemotherapy was mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or procarbazine, mechlorethamine, and vinblastine (PAVe) in S studies; MOPP, PAVe, vinblastine, bleomycin, and methotrexate (VBM), or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in C studies; and VbM (reduced dose of bleomycin compared with VBM) or mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) in G studies. Cumulative exposure to alkylating agent (AA) was notably lower in the G studies compared with the S and C studies, with a 75% to 83% lower dose of nitrogen mustard in addition to omission of procarbazine and melphalan. Twenty-four (3.2%) of 754 patients developed t-AML/MDS, 15 after primary chemotherapy and nine after salvage chemotherapy for relapsed HL. The incidence of t-AML/MDS was significantly lower in the G studies (0.3%) compared with the S (5.7%) or C (5.2%) studies (P < .001). Additionally, in the G studies, no t-AML/MDS was noted after primary therapy, and the only patient who developed t-AML/MDS did so after second-line therapy.

Conclusion

Our data demonstrate the relationship between the cumulative AA dose and t-AML/MDS. Limiting the dose of AA and decreased need for secondary treatments have significantly reduced the incidence of t-AML/MDS, which was extremely rare in the G studies (Stanford V era).
Patient Income Level and Cancer Clinical Trial Participation
Authors: Unger Joseph M. , Hershman Dawn L. , Albain Kathy S. , Moinpour Carol M. , Petersen Judith A. , Burg Kenda , Crowley John J.
Published: January 2013

Purpose

Studies have shown an association between socioeconomic status (SES) and quality of oncology care, but less is known about the impact of patient SES on clinical trial participation.

Patients and Methods

We assessed clinical trial participation patterns according to important SES (income, education) and demographic factors in a large sample of patients surveyed via an Internet-based treatment decision tool. Logistic regression, conditioning on type of cancer, was used. Attitudes toward clinical trials were assessed using prespecified items about treatment, treatment tolerability, convenience, and cost.

Results

From 2007 to 2011, 5,499 patients were successfully surveyed. Forty percent discussed clinical trials with their physician, 45% of discussions led to physician offers of clinical trial participation, and 51% of offers led to clinical trial participation. The overall clinical trial participation rate was 9%. In univariate models, older patients (P = .002) and patients with lower income (P = .001) and education (P = .02) were less likely to participate in clinical trials. In a multivariable model, income remained a statistically significant predictor of clinical trial participation (odds ratio, 0.73; 95% CI, 0.57 to 0.94; P = .01). Even in patients age ≥ 65 years, who have universal access to Medicare, lower income predicted lower trial participation. Cost concerns were much more evident among lower-income patients (P < .001).

Conclusion

Lower-income patients were less likely to participate in clinical trials, even when considering age group. A better understanding of why income is a barrier may help identify ways to make clinical trials better available to all patients and would increase the generalizability of clinical trial results across all income levels.
Ethical Issues for Control-Arm Patients After Revelation of Benefits of Experimental Therapy: A Framework Modeled in Neuroblastoma
Authors: Unguru Yoram , Joffe Steven , Fernandez Conrad V. , Yu Alice L.
Published: January 2013

In 2009, the Children's Oncology Group (COG) phase III randomized controlled trial, ANBL0032, found that adding immunotherapy (Ch14.18) to standard therapy significantly improved outcomes in patients with high-risk neuroblastoma when administered within 110 days after autologous stem-cell transplantation (SCT). After careful deliberation and consultation, the COG Neuroblastoma Committee decided to offer Ch14.18 to prior trial participants who had been randomly assigned to the control arm (no immunotherapy), regardless of the time that had elapsed since SCT. This decision occurred in the context of a limited supply of Ch14.18 and no data regarding its role when administered beyond 110 days. In this article, we analyze the numerous ethical challenges highlighted by the ANBL0032 trial, including the limits of researchers' reciprocity-based obligations to study participants, post-trial access to beneficial therapies, and the balance between scientific knowledge and parental hope. These deliberations may be useful to other researchers when considering their ethical obligations to control-arm participants in the wake of a positive randomized trial.
Improving Diagnosis of Tumor-Induced Osteomalacia With Gallium-68 DOTATATE PET/CT
Authors: Clifton-Bligh Roderick J. , Hofman Michael S. , Duncan Emma , Sim Ie-Wen , Darnell David , Clarkson Adele , Wong Tricia , Walsh John P. , Gill Anthony J. , Ebeling Peter R. , Hicks Rodney J.
Published: January 2013

Context:

Tumor-induced osteomalacia (TIO) is a rarely diagnosed disorder presenting with bone pain, fractures, muscle weakness, and moderate-to-severe hypophosphatemia resulting from fibroblast growth factor 23-mediated renal phosphate wasting. Tumors secreting fibroblast growth factor 23 are often small and difficult to find with conventional imaging.

Objective:

We studied the utility of 68Ga-DOTA-octreotate (DOTATATE) somatostatin receptor positron emission tomography (PET)/computed tomography (CT) imaging in the diagnosis of TIO.

Design and Setting:

A multicenter case series was conducted at tertiary referral hospitals.

Patients and Methods:

Six patients with TIO diagnosed between 2003 and 2012 in Australia were referred for DOTATATE PET imaging. We reviewed the clinical history, biochemistry, imaging characteristics, histopathology, and clinical outcome of each patient.

Results:

Each case demonstrated delayed diagnosis despite severe symptoms. DOTATATE PET/CT imaging demonstrated high uptake and localized the tumor with confidence in each case. After surgical excision, there was resolution of clinical symptoms and serum phosphate, except in one patient who demonstrated residual disease on PET/CT. All tumors demonstrated high somatostatin receptor subtype 2 cell surface receptor expression using immunohistochemistry.

Conclusions:

In patients with TIO, DOTATATE PET/CT can successfully localize phosphaturic mesenchymal tumors and may be a practical first step in functional imaging for this disorder. Serum phosphate should be measured routinely in patients with unexplained muscle weakness, bone pain, or stress fractures to allow earlier diagnosis of TIO.
Dynamics of Epistemic Modality
Authors: Willer Malte
Published: January 2013

A dynamic semantics for epistemically modalized sentences is an attractive alternative to the orthodox view that our best theory of meaning ascribes to such sentences truth-conditions relative to what is known. This essay demonstrates that a dynamic theory about might and must offers elegant explanations of a range of puzzling observations about epistemic modals. The first part of the story offers a unifying treatment of disputes about epistemic modality and disputes about matters of fact while at the same time avoiding the complexities of alternative theories. The second part of the story extends the basic framework to cover some complicated data about retraction and the interaction between epistemic modality and tense. A comparison between the suggestion made in this essay and current versions of the orthodoxy is provided.
Methicillin-resistantStaphylococcus aureus(MRSA)
Authors: Goyal N. , Miller A. , Tripathi M. , Parvizi J.
Published: January 2013

Staphylococcus aureus is one of the leading causes of surgical site infection (SSI). Over the past decade there has been an increase in methicillin-resistant S. aureus (MRSA). This is a subpopulation of the bacterium with unique resistance and virulence characteristics. Nasal colonisation with either S. aureus or MRSA has been demonstrated to be an important independent risk factor associated with the increasing incidence and severity of SSI after orthopaedic surgery. Furthermore, there is an economic burden related to SSI following orthopaedic surgery, with MRSA-associated SSI leading to longer hospital stays and increased hospital costs. Although there is some controversy about the effectiveness of screening and eradication programmes, the literature suggests that patients should be screened and MRSA-positive patients treated before surgical admission in order to reduce the risk of SSI.

Cite this article: Bone Joint J 2013;95-B:4–9.
Long-term trends in the Oxford knee score following total knee replacement
Authors: Williams D. P. , Blakey C. M. , Hadfield S. G. , Murray D. W. , Price A. J. , Field R. E.
Published: January 2013

The Oxford knee score (OKS) is a validated and widely accepted disease-specific patient-reported outcome measure, but there is limited evidence regarding any long-term trends in the score. We reviewed 5600 individual OKS questionnaires (1547 patients) from a prospectively-collected knee replacement database, to determine the trends in OKS over a ten-year period following total knee replacement. The mean OKS pre-operatively was 19.5 (95% confidence interval (CI) 18.8 to 20.2). The maximum post-operative OKS was observed at two years (mean score 34.4 (95% CI 33.7 to 35.2)), following which a gradual but significant decline was observed through to the ten-year assessment (mean score 30.1 (95% CI 29.1 to 31.1)) (p < 0.001). A similar trend was observed for most of the individual OKS components (p < 0.001). Kneeling ability initially improved in the first year but was then followed by rapid deterioration (p < 0.001). Pain severity exhibited the greatest improvement, although residual pain was reported in over two-thirds of patients post-operatively, and peak improvement in the night pain component did not occur until year four. Post-operative OKS was lower for women (p < 0.001), those aged < 60 years (p < 0.003) and those with a body mass index > 35 kg/m2 (p < 0.014), although similar changes in scores were observed. This information may assist surgeons in advising patients of their expected outcomes, as well as providing a comparative benchmark for evaluating longer-term outcomes following knee replacement.

Cite this article: Bone Joint J 2013;95-B:45–51.