bluuebunny/crossref_metadata_2025 huggingface dataset:
The United Kingdom National External Quality Assessment Service for parasitology: toxoplasma serology scheme
Authors: Manser Monika M , Chatterton Jean , Francis Janet , Guy Edward , Holliman Rick , Ho-Yen Darrel , Johnson Julie , Chiodini Peter L
Published: October 2010

Aim

To examine performance in the UK National External Quality Assessment Scheme (UKNEQAS) for toxoplasma serology for evidence of discrepant results as compared with the predistribution and postdistribution results supplied by the toxoplasma reference laboratories.

Methods

Analysis of performance in the toxoplasma IgG and IgM schemes was made for the period 1994–2008 to look for trends in performance.

Results

For the IgG scheme, a mean of 98% of participants obtained the correct result for detection of toxoplasma-specific antibody. The most common problem was failure to detect low levels of antibody. In some cases this was the result of participants deviating from the manufacturer's instructions and using higher cut-off levels. For the IgM scheme, an average of 95% of participants obtained the correct result for toxoplasma antibody detection. The most common problem was the failure of some enzyme immunoassay kits to detect specific toxoplasma IgM antibody, which was detected by the more sensitive immunosorbent agglutination assay.

Conclusions

Performance standards in the UKNEQAS toxoplasma serology schemes were high. The problems encountered have highlighted the importance of detecting low levels of antibody, adhering to the kit manufacturer's instructions and selecting an appropriate assay for the clinical situation.
Muslim patients and cross-gender interactions in medicine: an Islamic bioethical perspective
Authors: Padela Aasim I , del Pozo Pablo Rodriguez
Published: November 2010

As physicians encounter an increasingly diverse patient population, socioeconomic circumstances, religious values and cultural practices may present barriers to the delivery of quality care. Increasing cultural competence is often cited as a way to reduce healthcare disparities arising from value and cultural differences between patients and providers. Cultural competence entails not only a knowledge base of cultural practices of disparate patient populations, but also an attitude of adapting one's practice style to meet patient needs and values. Gender roles, relationship dynamics and boundaries are culture specific, and are frequently shaped by religious teachings. Consequently, religion may be conceptualised as a cultural repertoire, or dynamic tool-kit, by which members of a faith adapt and negotiate their identity in multicultural societies. The manner in which Islamic beliefs and values inform Muslim healthcare behaviours is relatively under-investigated. In an effort to explore the impact of Islam on the relationship between patients and providers, we present an Islamic bioethical perspective on cross-gender relations in the patient-doctor relationship. We will begin with a clinical scenario highlighting three areas of gender interaction that bear clinical relevance: dress code, seclusion of members of the opposite sex and physical contact. Next, we provide a brief overview of the foundations of Islamic law and ethical deliberation and then proceed to develop ethicolegal guidelines pertaining to gender relations within the medical context. At the end of this reflection, we offer some practice recommendations that are attuned to the cultural sensitivities of Muslim patient populations.
Complete devascularization of a juvenile angiofibroma by direct percutaneous embolization with only ethylene vinyl alcohol copolymer (Onyx) through a single needle placement: Figure 1
Authors: Gemmete Joseph J , Chaudhary Neeraj , Pandey Aditya S , McHugh Jonathan B , Marentette Lawrence J
Published: October 2010

Embolization of a juvenile angiofibroma (JNA) is commonly performed prior to surgical resection. Traditionally, it has been performed from an intra-arterial approach with particulate material. A novel technique is described in which a JNA was completely devascularized prior to surgical removal by direct percutaneous embolization with only ethylene vinyl alcohol. A midfacial degloving and medial maxillectomy/maxillotomy was then performed and the tumor extirpated with blunt finger dissection and the assistance of an endoscope, with 200 ml of blood loss.
Cardiovascular mortality during heat and cold events: determinants of regional vulnerability in Taiwan
Authors: Wu Pei-Chih , Lin Chuan-Yao , Lung Shih-Chun , Guo How-Ran , Chou Chang-Hung , Su Huey-Jen
Published: October 2010

Objectives

To identify the vulnerable regions with underlying susceptibility and poor adaptive capability in response to cold and heat events in Taiwan, and to characterise the determinants associated with such an increasing risk to design better adaptive strategies in view of predicted weather changes in the future.

Methods

The authors used spatial regression models to measure the relationships between the spatial characteristics of temperature, extracted factors from demographic and socio-economic parameters, and the mean cardiovascular mortality 2 weeks before and after cold or heat events from 1994 to 2003.

Results

Metropolitan regions were found to have a substantially lower mortality than rural areas after cold and heat events. Events of cold, compared with heat, had greater impacts on the mortality ratio in most townships. A negative association was identified, using a spatial lag model, between the mortality after cold and heat events and urbanisation, and the availability of medical resources. A higher percentage of older people, vulnerable and aborigines might have contributed to the increasing vulnerability of townships during cold and heat events.

Conclusions

These data, using an island-wide spatial analysis, suggest that urban areas have a greater adaptive capability than rural areas, plausibly because people in urban areas have a higher socio-economic status and more medical resources. Social inequality across urban and rural townships is apparent and developing customised adaptation programmes for vulnerable regions to cope with heat and cold event should be prioritised.
Republished paper: Bad stars or guiding lights? Learning from disasters to improve patient safety
Authors: Hughes C , Travaglia J F , Braithwaite J
Published: October 2010

Background

Cross-fertilisation of ideas across industries, settings and contexts potentially improves learning by providing fresh insights into error pathways.

Objectives and hypotheses

To investigate six cases of human error drawn from disasters in the space, shipping, aviation, mining, rail and nuclear industries, and to apprehend similarities and differences in the antecedents to errors, the way they manifest, the course of events and the way they are tackled. The extent to which human intervention can exacerbate the problems by introducing new errors, how the cases are resolved and the lessons learnt were examined.

Design, setting and participants

Exemplar disaster events drawn from a very large sample of human errors.

Results

It is possible to identify and model a generic disaster pathway that applies across several industries, including healthcare.

Conclusions

Despite differences between industries, it is clear that learning from disasters in other industries may provide important insights on how to prevent or ameliorate them in healthcare.
Primary care research and clinical practice: cardiovascular disease
Authors: Mavaddat N , Mant J
Published: November 2010

Improvement in survival of patients with cardiovascular diseases and an ageing population mean that management of cardiovascular conditions remains an important challenge for primary care. Traditionally cardiovascular research has been based largely in secondary or tertiary care settings. The majority of care for people with cardiovascular diseases, however, takes place in the community and within primary care. In recent years, progress has been made in conducting cardiovascular research within primary care itself. A number of different methodologies including large prospective cohort studies, randomised controlled trials, and qualitative designs have been used to inform optimal cardiovascular disease management for those in the community. Some of the recent research evidence in primary care in three areas of cardiovascular medicine—atrial fibrillation, heart failure, and cardiovascular risk prediction and management—are discussed in this review. These seek to demonstrate the contribution made by primary care research to the management of cardiovascular diseases.
Comparison of cutaneous manifestations in chronic kidney disease with or without dialysis
Authors: Khanna Deepshikha , Singal Archana , Kalra Om Prakash
Published: October 2010

Purpose

To study and compare dermatological manifestations in patients with various stages of chronic kidney disease (CKD) and end stage renal disease (ESRD), undialysed and dialysed, in a developing country.

Study design

200 patients were recruited, 50 each in stages 3, 4 and 5 CKD (undialysed) and 50 in stage 5 undergoing maintenance haemodialysis (MHD) for at least 1 month. Patients in stages 3 and 4 constituted pre-ESRD while stage 5 (both dialysed and undialysed) formed the ESRD group. Detailed cutaneous examination was done for all patients and dermatological manifestations were compared among various study groups.

Results

96% of patients had at least one dermatological manifestation. Xerosis was most common and was observed in 72% of patients, followed by pigmentation (50%), pruritus (36%), infections (29%), markers of skin ageing (13%), half-and-half nail (28%), and absent lunula (22%). Perforating disorders (3%), bullous disorders (2%), and nephrogenic systemic fibrosis (1%) were encountered less often. Local complications of dialysis occurred in 64% patients on MHD. Diffuse pigmentation and skin pallor were seen more commonly as compared to findings reported in the west. The frequency of most cutaneous manifestations was similar between dialysed and undialysed patients with ESRD. Xerosis, pigmentation, and pruritus were more frequent in patients with severe disease, and mean duration of disease was significantly higher for patients with pigmentation, pruritus, and half-and-half nail. Longer duration on MHD was associated with greater pigmentation and pruritus.

Conclusion

Dermatological manifestations increase with increasing duration and severity of renal disease. Dialysis may in turn often perpetuate many of these cutaneous complaints. Recognition and management of some of these dermatological manifestations may vastly reduce the morbidity and improve the cutaneous outcome in these patients.
OPTIMAL COMPONENT SELECTION OF COTS BASED SOFTWARE SYSTEM UNDER CONSENSUS RECOVERY BLOCK SCHEME INCORPORATING EXECUTION TIME
Authors: JHA P. C. , KAPUR P. K. , BALI SHIVANI , KUMAR U. DINESH
Published: November 2010

Computer based systems have increased dramatically in scope, complexity, pervasiveness. Most industries are highly dependent on computers for their basic day to day functioning. Safe & reliable software operations are an essential requirement for many systems across different industries. The number of functions to be included in a software system is decided during the software development. Any software system must be constructed in such a way that execution can resume even after the occurrence of failure with minimal loss of data and time. Such software systems which can continue execution even in presence of faults are called fault tolerant software. When failure occurs one of the redundant software modules get executed and prevent system failure. The fault tolerant software systems are usually developed by integrating COTS (commercial off-the-shelf) software components. The motivation for using COTS components is that they will reduce overall system development costs and reduce development time. In this paper, reliability models for fault tolerant consensus recovery blocks are analyzed. In first optimization model, we formulate joint optimization problem in which reliability maximization of software system and execution time minimization for each function of software system are considered under budgetary constraint. In the second model the issue of compatibility among alternatives available for different modules, is discussed. Numerical illustrations are provided to demonstrate the developed models.
ON ADDITIVE CONSISTENT PROPERTIES OF THE INTUITIONISTIC FUZZY PREFERENCE RELATION
Authors: GONG ZAIWU , LI LIANSHUI , CAO JIE , ZHOU FEIXUE
Published: November 2010

We investigate the properties of additive consistent intuitionistic fuzzy preference relations (IFPR). Usually, consistency in fuzzy preference relations (FPR) is associated with transitivity such as general transitivity, weak transitivity, and restricted max–max transitivity. This paper extends the consistency properties of the FPR to those of the IFPR. Since weak transitivity is the minimal logical requirement and a fundamental principle of human judgment, this paper develops three determination theorems and the corresponding algorithms to judge the weak transitivity of an IFPR from different angles. Two numerical examples show that the three methods proposed are feasible and effective.
AN EFFICIENT WAVELET-BASED PALMPRINT VERIFICATION APPROACH
Authors: PRASAD S. M. , GOVINDAN V. K. , SATHIDEVI P. S.
Published: November 2010

This paper proposes a wavelet-based palmprint verification approach which is efficient in terms of accuracy and speed. The prominent wavelet domain features such as subband energy distribution, histogram, and co-occurrence features fail to characterize the palmprints sufficiently due to coefficient perturbations caused by translational and/or rotational variations in palmprints. In this work, firstly, a novel approach, termed as adaptive tessellation of subbands, is proposed to effectively capture the spatially localized energy distribution based on the spread of principal lines. Secondly, a set of discriminating features, termed as high scale codes (HSCODEs), and a translation and rotation invariant matching technique are proposed. HSCODEs effectively characterize the palmprints by capturing the spatial patterns corresponding to the low frequency components. Energy features and selected HSCODEs are fused at score and decision levels. Particularly, score level fusion enhances the verification accuracy significantly. Effectiveness of the proposed approach is examined on PolyU-ONLINE-Palmprint-II (PolyU) database. The experimental results show an overall equal error rate (EER) of 0.22%, which is better than the existing wavelet-based palmprint recognition systems and comparable to the computationally complex state-of-the-art approaches. The speed of the approach is high as all the features are extracted from the same wavelet decomposition of palmprint.

Further, it is shown that the proposed feature extraction technique can be extended for speech signals as well and such features can be fused with palmprint features for accuracy enhancement.
SMOOTHED FINITE ELEMENTS LARGE DEFORMATION ANALYSIS
Authors: LIU S. J. , WANG H. , ZHANG H.
Published: November 2010

The smoothed finite element method (SFEM) was developed in order to eliminate certain shortcomings of the finite element method (FEM). SFEM enjoys some of the flexibilities of meshfree methods. One advantage of SFEM is its applicability to modeling large deformations. Due to the absence of volume integration and parametric mapping, issues such as negative volumes and singular Jacobi matrix do not occur. However, despite these advantages, SFEM has never been applied to problems with extreme large deformation. For the first time, we apply SFEM to extreme large deformations. For two numerical problems, we demonstrate the advantages of SFEM over FEM. We also show that SFEM can compete with the flexibility of meshfree methods.
ON A HIGH-RESOLUTION GODUNOV METHOD FOR A CFD-PBM COUPLED MODEL OF TWO-PHASE FLOW IN LIQUID-LIQUID EXTRACTION COLUMNS
Authors: ZEIDAN D. , ATTARAKIH M. , KUHNERT J. , TIWARI S. , SHARMA V. , DRUMM C. , BART H.-J.
Published: November 2010

This paper is about the numerical solutions for a computational fluid dynamics-population balance model (CFD-PBM) coupled model of two-phase flow in a liquid-liquid extraction column. The model accounts for a complete description between both the dispersed and continuous phases, and constitutes a hyperbolic system of equations having a linearly degenerate nature. A numerical algorithm based on operator splitting approach for the numerical solution of the model is used. The homogeneous part is solved using the TVD MUSCL-Hancock scheme. Numerical results are presented, demonstrating the accuracy of the proposed methods and in particular, the accurate numerical description of the flow in the vicinity of the contact discontinuities.
ROBUST MULTIMODAL PERSON RECOGNITION USING LOW-COMPLEXITY AUDIO-VISUAL FEATURE FUSION APPROACHES
Authors: SHAH DHAVAL , HAN KYU J. , NARAYANAN SHRIKANTH S.
Published: November 2010

In this paper, we first show the importance of face-voice correlation for audio-visual person recognition. We propose a simple multimodal fusion technique which preserves the correlation between audio-visual features during speech and evaluate the performance of such a system against audio-only, video-only, and audio-visual systems which use audio and visual features neglecting the interdependency of a person's spoken utterance and the associated facial movements. Experiments performed on the VidTIMIT dataset show that the proposed multimodal fusion scheme has a lower error rate than all other comparison conditions and is more robust against replay attacks. The simplicity of the fusion technique allows for low-complexity designs for a simple low-cost real-time DSP implementation. We then discuss some problems associated with the previously proposed design and, as a solution to those problems, propose two novel classifier designs which provide more flexibility and a convenient way to represent multimodal data where each modality has different characteristics. We also show that these novel classifier designs offer superior performance in terms of both accuracy and robustness.
Biotic Homogenization of Inland Seas of the Ponto-Caspian
Authors: Shiganova Tamara
Published: November 2010

Comparative analysis of patterns of species invasion, dispersal, and impact on ecosystems in the Ponto-Caspian seas has been ongoing since 1900. The Black Sea is an important international shipping destination. High shipping intensity has facilitated species invasions into the Black Sea. Many species have successfully established because of Black Sea disturbances. The Black Sea serves as a hub for species that then spread further to the Sea of Azov, the Caspian Sea, the Sea of Marmara, and in some cases the eastern Mediterranean Sea. The Black Sea has thus become the main recipient for non-native species and acts as a donor to the seas of Eurasia. Native biodiversity has declined and invaders now dominate the Ponto-Caspian seas. This process has caused biotic homogenization of the Ponto-Caspian, as the same invaders determine community structure and in some cases ecosystem functioning in the different seas. Among these invaders, gelatinous species have become the main drivers of ecosystem functioning. The invasion rate of new species is accelerating.
Activation of AMPK stimulates heme oxygenase-1 gene expression and human endothelial cell survival
Authors: Liu Xiao-ming , Peyton Kelly J. , Shebib Ahmad R. , Wang Hong , Korthuis Ronald J. , Durante William
Published: October 2010

The present study determined whether AMP-activated protein kinase (AMPK) regulates heme oxygenase (HO)-1 gene expression in endothelial cells (ECs) and if HO-1 contributes to the biological actions of this kinase. Treatment of human ECs with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) stimulated a concentration- and time-dependent increase in HO-1 protein and mRNA expression that was associated with a prominent increase in nuclear factor-erythroid 2-related factor 2 (Nrf2) protein. Induction of HO-1 was also observed in rat carotid arteries after the in vivo application of AICAR. Induction of HO-1 by AICAR was blocked by the AMPK inhibitor compound C, the adenosine kinase inhibitor 5′-iodotubercidin, and by silencing AMPK-α1/2 and was mimicked by the AMPK activator A-769662 and by infecting ECs with an adenovirus expressing constitutively active AMPK-α1. AICAR also induced a significant rise in HO-1 promoter activity that was abolished by mutating the antioxidant responsive elements of the HO-1 promoter or by the overexpression of dominant negative Nrf2. Finally, activation of AMPK inhibited cytokine-mediated EC death, and this was prevented by the HO inhibitor tin protoporphyrin-IX or by silencing HO-1 expression. In conclusion, AMPK stimulates HO-1 gene expression in human ECs via the Nrf2/antioxidant responsive element signaling pathway. The induction of HO-1 mediates the antiapoptotic effect of AMPK, and this may provide an important adaptive response to preserve EC viability during periods of metabolic stress.
Latent infection by γherpesvirus stimulates profibrotic mediator release from multiple cell types
Authors: Stoolman Joshua S. , Vannella Kevin M. , Coomes Stephanie M. , Wilke Carol A. , Sisson Thomas H. , Toews Galen B. , Moore Bethany B.
Published: October 2010

Although γherpesvirus infections are associated with enhanced lung fibrosis in both clinical and animal studies, there is limited understanding about fibrotic effects of γherpesviruses on cell types present in the lung, particularly during latent infection. Wild-type mice were intranasally infected with a murine γherpesvirus (γHV-68) or mock-infected with saline. Twenty-eight days postinfection (dpi), ∼14 days following clearance of the lytic infection, alveolar macrophages (AMs), mesenchymal cells, and CD19-enriched cell populations from the lung and spleen express M3and/or glycoprotein B (gB) viral mRNA and harbor viral genome. AMs from infected mice express more transforming growth factor (TGF)-β1, CCL2, CCL12, TNF-α, and IFN-γ than AMs from mock-infected mice. Mesenchymal cells express more total TGF-β1, CCL12, and TNF-α than mesenchymal cells from mock-infected mice. Lung and spleen CD19-enriched cells express more total TGF-β128 dpi compared with controls. The CD19-negative fraction of the spleen overexpresses TGF-β1and harbors viral genome, but this likely represents infection of monocytes. Purified T cells from the lung harbor almost no viral genome. Purified T cells overexpress IL-10 but not TGF-β1. Intracellular cytokine staining demonstrated that lung T cells at 28 dpi produce IFN-γ but not IL-4. Thus infection with a murine γherpesvirus is sufficient to upregulate profibrotic and proinflammatory factors in a variety of lung resident and circulating cell types 28 dpi. Our results provide new information about possible contributions of these cells to fibrogenesis in the lungs of individuals harboring a γherpesvirus infection and may help explain why γHV-68 infection can augment or exacerbate fibrotic responses in mice.
Erythropoietin-driven proliferation of cells with mutations in the tumor suppressor geneTSC2
Authors: Ikeda Yoshihiko , Taveira-DaSilva Angelo M. , Pacheco-Rodriguez Gustavo , Steagall Wendy K. , El-Chemaly Souheil , Gochuico Bernadette R. , May Rose M. , Hathaway Olanda M. , Li Shaowei , Wang Ji-an , Darling Thomas N. , Stylianou Mario , Moss Joel
Published: October 2010

Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction, resulting from proliferation of smooth-muscle-like cells, which have mutations in the tumor suppressor genes TSC1 or TSC2. Among 277 LAM patients, severe disease was associated with hypoxia and elevated red blood cell indexes that accompanied reduced pulmonary function. Because high red cell indexes could result from hypoxemia-induced erythropoietin (EPO) production, and EPO is a smooth muscle cell mitogen, we investigated effects of EPO in human cells with genetic loss of tuberin function, and we found that EPO increased proliferation of human TSC2−/−, but not of TSC2+/−, cells. A discrete population of cells grown from explanted lungs was characterized by the presence of EPO receptor and loss of heterozygosity for TSC2, consistent with EPO involvement. In LAM cells from lung nodules, EPO was localized to the extracellular matrix, supporting evidence for activation of an EPO-driven signaling pathway. Although the high red cell mass of LAM patients could be related to advanced disease, we propose that EPO, synthesized in response to episodic hypoxia, may increase disease progression by enhancing the proliferation of LAM cells.
Polarized migration of lymphatic endothelial cells is critically dependent on podoplanin regulation of Cdc42
Authors: Navarro Angels , Perez Ricardo E. , Rezaiekhaligh Mohammad H. , Mabry Sherry M. , Ekekezie Ikechukwu I.
Published: October 2010

We have shown previously that T1α/podoplanin is required for capillary tube formation by human lung microvascular lymphatic endothelial cells (HMVEC-LLy) and that cells with decreased podoplanin expression fail to properly activate the small GTPase RhoA shortly after the beginning of the lymphangiogenic process. The objective of this study was to determine whether podoplanin regulates HMVEC-LLy migration and whether this regulation is via modulation of small GTPase activation. In analysis of scratch wound assays, we found that small interfering RNA (siRNA) depletion of podoplanin expression in HMVEC-LLy inhibits VEGF-induced microtubule-organizing center (MTOC) and Golgi polarization and causes a dramatic reduction in directional migration compared with control siRNA-transfected cells. In addition, a striking redistribution of cortical actin to fiber networks across the cell body is observed in these cells, and, remarkably, it returns to control levels if the cells are cotransfected with a dominant-negative mutant of Cdc42. Moreover, cotransfection of a dominant-negative construct of Cdc42 into podoplanin knockdown HMVEC-LLy completely abrogated the effect of podoplanin deficiency, rescuing MTOC and Golgi polarization and cell migration to control level. Importantly, expression of constitutively active Cdc42 construct, like podoplanin knockdown, decreased RhoA-GTP level in HMVEC-LLy, demonstrating cross talk between both GTPases. Taken together, the results indicate that polarized migration of lymphatic endothelial cells in response to VEGF is mediated via a pathway of podoplanin regulation of small GTPase activities, in particular Cdc42.
Effects of prenatal ethanol exposure on the lungs of postnatal lambs
Authors: Sozo Foula , Vela Melissa , Stokes Victoria , Kenna Kelly , Meikle Peter J. , De Matteo Robert , Walker David , Brien James , Bocking Alan , Harding Richard
Published: October 2010

Prenatal ethanol exposure increases collagen deposition and alters surfactant protein (SP) expression and immune status in lungs of near-term fetal sheep. Our objectives were to determine 1) whether these prenatal effects of repeated gestational ethanol exposure persist after birth and 2) whether surfactant phospholipid composition is altered following prenatal ethanol exposure. Pregnant ewes were chronically catheterized at 90 days of gestational age (DGA) and given a 1-h daily infusion of ethanol (0.75 g/kg, n = 9) or saline ( n = 7) from 95 to 135 DGA; ethanol administration ceased after 135 DGA. Lambs were born naturally at full term (146 ± 0.5 DGA). Lung tissue was examined at 9 wk postnatal age for alterations in structure, SP expression, and inflammation; bronchoalveolar lavage fluid was examined for alterations in surfactant phospholipid composition. At 134 DGA, surfactant phospholipid concentration in amniotic fluid was significantly reduced ( P < 0.05) by ethanol exposure, and the composition was altered. In postnatal lambs, there were no significant differences between treatment groups in birth weight, postnatal growth, blood gas parameters, and lung weight, volume, tissue fraction, mean linear intercept, collagen content, proinflammatory cytokine gene expression, and bronchoalveolar lavage fluid surfactant phospholipid composition. Although SP-A, SP-B, and SP-C mRNA levels were not significantly different between treatment groups, SP-D mRNA levels were significantly greater ( P < 0.05) in ethanol-treated animals; as SP-D has immunomodulatory roles, innate immunity may be altered. The adverse effects of daily ethanol exposure during late gestation on the fetal lung do not persist to 2 mo after birth, indicating that the developing lung is capable of repair.
Effects of tobacco smoke on IL-16 in CD8+cells from human airways and blood: a key role for oxygen free radicals?
Authors: Andersson Anders , Bossios Apostolos , Malmhäll Carina , Sjöstrand Margareta , Eldh Maria , Eldh Britt-Marie , Glader Pernilla , Andersson Bengt , Qvarfordt Ingemar , Riise Gerdt C. , Lindén Anders
Published: October 2010

Chronic exposure to tobacco smoke leads to an increase in the frequency of infections and in the number of CD8+and CD4+cells as well as the CD4+chemoattractant cytokine IL-16 in the airways. Here, we investigated whether tobacco smoke depletes intracellular IL-16 protein and inhibits de novo production of IL-16 in CD8+cells from human airways and blood while increasing extracellular IL-16 and whether oxygen free radicals (OFR) are involved. Intracellular IL-16 protein in CD8+cells and mRNA in all cells was decreased in bronchoalveolar lavage (BAL) samples from chronic smokers. This was also the case in human blood CD8+cells exposed to water-soluble tobacco smoke components in vitro, in which oxidized proteins were markedly increased. Extracellular IL-16 protein was increased in cell-free BAL fluid from chronic smokers and in human blood CD8+cells exposed to water-soluble tobacco smoke components in vitro. This was not observed in occasional smokers after short-term exposure to tobacco smoke. A marker of activation (CD69) was slightly increased, whereas other markers of key cellular functions (membrane integrity, apoptosis, and proliferation) in human blood CD8+cells in vitro were negatively affected by water-soluble tobacco smoke components. An OFR scavenger prevented these effects, whereas a protein synthesis inhibitor, a β-adrenoceptor, a glucocorticoid receptor agonist, a phosphodiesterase, a calcineurin phosphatase, and a caspase-3 inhibitor did not. In conclusion, tobacco smoke depletes preformed intracellular IL-16 protein, inhibits its de novo synthesis, and distorts key cellular functions in human CD8+cells. OFR may play a key role in this context.
Non‐Weakly Supercyclic Weighted Composition Operators
Authors: Kamali Z. , Hedayatian K. , Khani Robati B.
Published: November 2010

We give sufficient conditions under which a weighted composition operator on a Hilbert space of analytic functions is not weakly supercyclic. Also, we give some necessary and sufficient conditions for hypercyclicity and supercyclicity of weighted composition operators on the space of analytic functions on the open unit disc.
Clinical Evaluation of Efficacy of99mTC -Ethambutol in Tubercular Lesion Imaging
Authors: Singh Namrata , Bhatnagar A.
Published: November 2010

Purpose. The aim of this work was to develop specific radiopharmaceutical and to evaluate its efficacy in human to detect and locate the tubercular lesion.Materials and Methods.99mTc-Ethambutol (EMB) was produced by direct labeling method.In vitro and in vivobiological studies and animal experiments were done. Phase I Clinical trial was performed. As per plan, 2 normal human subjects for biodistribution studies and fourteen patients (8 males and 6 females; age range of 25–50, with one patient aged 12 years as an exception) were chosen for clinical trial. Whole body scan and spots were acquired at 1 hour and 4 hour. Angiography, blood pool, and 24-hours spot images of the infected areas were also acquired.Result. Radiolabeling yielded>85%of labeled complex.In vitro and in vivobiological studies and animal experiments indicated99mTc-EMB as a specific tuberculosis imaging agent. The biodistribution study in normal human subjects suggested stability of99mTc-EMB, with main excretory pathways being renal and hepatobiliary, which appeared to be similar to the known behavior of unlabeled EMB. No adverse reactions were observed.99mTc-EMB got localized in pulmonary and bone tubercular lesions. Scintigrams of99mTc-EMB and99mTc-Ciprofloxacin were compared at different time intervals.Conclusion. The present study states that developed99mTc-EMB has high potential to qualify as a specific tuberculosis imaging radiopharmaceutical and is safe for human use.
Abnormal Gastroscopy Findings Were Related to Lower Meridian Energy
Authors: Huang Sheng-Miauh , Chien Li-Yin , Chang Chun-Chao , Chen Ping-Ho , Tai Chen-Jei
Published: November 2010

According to the theories of Traditional Chinese Medicine (TCM), energy runs through 12 meridians longitudinally up and down the body. The study objectives were to compare the meridian energy between subjects with and without abnormal gastroscopy findings. We applied a cross‐sectional and correlational research design. The study included 1,223 participants who had their health examinations at a university hospital in Taipei from 1st August 2005 through 31st August 2007. Meridian energy was examined using a meridian energy analysis device. The gastroscopy was operated by certified gastroenterologists. Participants with abnormal stomach and esophageal findings using gastroscopy had significantly lower mean meridian energy. There were no significant differences in meridian energy between participants with and without abnormal duodenum findings. When all of the meridians were examined individually, participants with abnormal findings in esophagus and stomach had significantly lower meridian energy in each of the meridians. The results of this study demonstrated that structural abnormality in the gastric area was related to lower meridian energy. Whether enhancing meridian energy could improve gastric and esophageal health merits further studies.
Phase I Clinical Trial of the Chimeric Anti-Mesothelin Monoclonal Antibody MORAb-009 in Patients with Mesothelin-Expressing Cancers
Authors: Hassan Raffit , Cohen Steven J. , Phillips Martin , Pastan Ira , Sharon Elad , Kelly Ronan J. , Schweizer Charles , Weil Susan , Laheru Daniel
Published: October 2010

Purpose: MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a tumor differentiation antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD).

Methods: Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m2. Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009.

Results: A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1–24 infusions). At the 400 mg/m2 dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m2 was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration.

Conclusion: MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m2. In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.
Microenvironmental Regulation of Glioblastoma Radioresponse
Authors: Jamal Muhammad , Rath Barbara H. , Williams Eli S. , Camphausen Kevin , Tofilon Philip J.
Published: October 2010

Purpose: Brain tumor xenografts initiated from human glioblastoma (GBM) stem-like cells (TSC) simulate the biological characteristics of GBMs in situ. Therefore, to determine whether the brain microenvironment affects the intrinsic radiosensitivity of GBM cells, we compared the radioresponse of GBM TSCs grown in vitro and as brain tumor xenografts.

Experimental Design: As indicators of DNA double-strand breaks (DSB), γH2AX, and 53BP1 foci were defined after irradiation of 2 GBM TSC lines grown in vitro and as orthotopic xenografts in nude mice. Microarray analysis was conducted to compare gene expression patterns under each growth condition.

Results: Dispersal of radiation-induced γH2AX and 53BP1 foci was faster in the tumor cells grown as orthotopic xenografts compared with cells irradiated in vitro. In addition, cells irradiated in vivo were approximately 3-fold less susceptible to foci induction as compared with cells grown in vitro. Microarray analysis revealed a significant number of genes whose expression was commonly affected in the 2 GBM models by orthotopic growth conditions. Consistent with the decrease in sensitivity to foci induction, genes related to reactive oxygen species (ROS) metabolism were expressed at higher levels in the brain tumor xenografts.

Conclusion: γH2AX and 53BP1 foci analyses indicate that GBM cells irradiated within orthotopic xenografts have a greater capacity to repair DSBs and are less susceptible to their induction than tumor cells irradiated under in vitro growth conditions. Because DSB induction and repair are critical determinants of radiosensitivity, these results imply that the brain microenvironment contributes to GBM radioresistance.Clin Cancer Res; 16(24); 6049–59. ©2010 AACR.
Braking Bad: Blockade of Inhibitory Pathways Improves Interleukin-15 Therapy
Authors: Carson William E.
Published: October 2010

Blockade of the CTLA-4 and PD-1 inhibitory pathways in T cells via the administration of neutralizing antibodies at the time of interleukin (IL)-15 therapy markedly enhanced the survival of tumor-bearing mice as compared with those receiving IL-15 alone or IL-15 in combination with just one of the antibodies. Clin Cancer Res; 16(24); 5917–9. ©2010 AACR.
Pediatric Graves’ Disease: Controversies in Management
Authors: Rivkees Scott A.
Published: November 2010

Background/Aims: Graves’ disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. Caused by immunologic stimulation of the thyroid-stimulating hormone receptor, lasting remission occurs in only a minority of pediatric patients with GD, including children treated with antithyroid drugs (ATDs) for many years. Thus the majority of pediatric patients with GD will need thyroidectomy or treatment with radioactive iodine (RAI; 131I). Results: When ATDs are used in children, only methimazole should be used. Propylthiouracil is associated with an unacceptable risk of severe liver injury in children and should never be used as first-line therapy. If remission (defined as normal thyroid function off ATDs) is not achieved after 1 or 2 years of ATD therapy, 131I or surgery may be considered, with the choice influenced by the age of the individual. When 131I is used, administered doses should be >150 µCi/g of thyroid tissue. When surgery is performed, near total or total thyroidectomy is recommended. Conclusion: Choosing a treatment approach for childhood GD is often a difficult and highly personal decision. Discussion of the advantages and risks of each therapeutic option is essential to help the patient and family select a treatment option.
Emergence of the Phosphoinositide 3-Kinase-Akt- Mammalian Target of Rapamycin Axis in Transforming Growth Factor-β-Induced Epithelial-Mesenchymal Transition
Authors: Lamouille Samy , Derynck Rik
Published: November 2010

During development and in pathological contexts such as fibrosis and cancer progression, epithelial cells can initiate a complex transcriptional reprogramming, accompanied by dramatic morphological changes, in a process named ‘epithelial-mesenchymal transition’ (EMT). In this transition, epithelial cells lose their epithelial characteristics to acquire mesenchymal properties and increased motile and invasive behavior. Transforming growth factor-β (TGF-β) has emerged as a major inducer of EMT through activation of downstream signaling pathways, including Smad and non-Smad signaling pathways. Among the non-Smad pathways, increasing evidence is emerging that the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis plays a major role in TGF-β-induced EMT, notably through the regulation of translation and cell invasion. Pharmacological inhibitors of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin pathway may therefore represent an opportunity to selectively target essential aspects of TGF-β-induced EMT and provide an approach to prevent cancer cell dissemination toward metastasis, without the need to fully inactivate TGF-β signaling.
Cooperative Signaling between Oncostatin M, Hepatocyte Growth Factor and Transforming Growth Factor-β Enhances Epithelial to Mesenchymal Transition in Lung and Pancreatic Tumor Models
Authors: Argast Gretchen M. , Mercado Peter , Mulford Iain J. , O’Connor Matthew , Keane David M. , Shaaban Salam , Epstein David M. , Pachter Jonathan A. , Kan Julie L.C.
Published: November 2010

Epithelial to mesenchymal transition (EMT) plays a dual role in tumor progression. It enhances metastasis of tumor cells by increasing invasive capacity and promoting survival, and it decreases tumor cell sensitivity to epithelial cell-targeting agents such as epithelial growth factor receptor kinase inhibitors. In order to study EMT in tumor cells, we have characterized 3 new models of ligand-driven EMT: the CFPAC1 pancreatic tumor model and the H358 and H1650 lung tumor models. We identified a diverse set of ligands that drives EMT in these models. Hepatocyte growth factor and oncostatin M induced EMT in all models, while transforming growth factor-β induced EMT in both lung models. We observed morphologic, marker and phenotypic changes in response to chronic ligand treatment. Interestingly, stimulation with 2 ligands resulted in more pronounced EMT compared with single-ligand treatment, demonstrating a spectrum of EMT states induced by parallel signaling, such as the JAK and PI3K pathways. The EMT changes observed in response to the ligand were reversed upon ligand withdrawal, demonstrating the ‘metastable’ nature of these models. To study the impact of EMT on cell morphology and invasion in a 3D setting, we cultured cells in a semisolid basement membrane extract. Upon stimulation with EMT ligands, the colonies exhibited changes to EMT markers and showed phenotypes ranging from modest differences in colony architecture (CFPAC1) to complex branching structures (H358, H1650). Collectively, these 3 models offer robust cell systems with which to study the roles that EMT plays in cancer progression.
Pharmacologically Distinctive Behaviors other than Burying Marbles during the Marble Burying Test in Mice
Authors: Hayashi Etsuko , Kuratani Kazuyoshi , Kinoshita Mine , Hara Hideaki
Published: November 2010

In the marble burying test, we focused on the 5 distinctive behavioral parameters of mice other than burying marbles, i.e. digging, latency to the first digging, exploration around marbles, rearing and locomotor activity. Typical anxiolytics or antidepressants with different mechanisms, fluvoxamine (30 mg/kg, selective serotonin reuptake inhibitor), bupropion (60 mg/kg, noradrenaline and dopamine reuptake inhibitor), imipramine (60 mg/kg, tricyclic antidepressant) and diazepam (10 mg/kg, benzodiazepine) were used to examine whether these behavioral parameters are sensitive to pharmacological treatments. Each of the drugs demonstrated an individual action pattern on the 4 behavioral parameters (latency to the first digging, exploration around marbles, rearing and locomotor activity). On the other hand, all 4 drugs reduced burying marbles and digging, which were correlated with each other. These results suggest that the former 4 behavioral parameters are sensitive to pharmacological treatment and that pharmacological regulation mechanisms of them may be different from burying marbles and digging. They could be useful to identify the type of action of a test drug like selective serotonin reuptake inhibitor, noradrenaline and dopamine reuptake inhibitor, tricyclic antidepressant or benzodiazepine.
Salt-Induced Renal Injury in Spontaneously Hypertensive Rats: Effects of Nebivolol
Authors: Varagic Jasmina , Ahmad Sarfaraz , Brosnihan K. Bridget , Habibi Javad , Tilmon Roger D. , Sowers James R. , Ferrario Carlos M.
Published: November 2010

Background: We investigated renal effects of nebivolol, a selective β1-receptor blocker with additional antioxidative ability, in spontaneously hypertensive rats (SHR) where increased salt intake induces oxidative stress and worsens renal function as a result of further activation of the renin-angiotensin and sympathetic nervous systems. Methods: Male SHR were given an 8% salt diet (HS; n = 22) for 5 weeks; their age-matched controls (n = 9) received standard chow. Nebivolol was given at a dose of 10 mg/kg/day for 5 weeks in 11 HS rats. Results: HS increased blood pressure, plasma renin concentration, urinary protein excretion, and renal nitroxidative stress while decreasing renal blood flow and angiotensin 1–7 receptor (mas) protein expression. There was no change in angiotensin II type 1 receptor expression among the experimental groups. Nebivolol did not alter the salt-induced increase in blood pressure but reduced urinary protein excretion, plasma renin concentration, and nitroxidative stress. Nebivolol also increased neuronal NOS expression while preventing the salt-induced decrease in renal blood flow and mas protein expression. Conclusion: Nebivolol prevented salt-induced kidney injury and associated proteinuria in SHR through a blood pressure-independent mechanism. Its protective effects may be related to reduction in oxidative stress, increases in neuronal NOS and restoration of angiotensin II type 1/mas receptor balance.