bluuebunny/crossref_metadata_2025 huggingface dataset:
A Multiplicity Result for Quasilinear Problems with Nonlinear Boundary Conditions in Bounded Domains
Authors: Khademloo S.
Published: December 2011

We study the following quasilinear problem with nonlinear boundary condition −Δpu − λa(x)u | u|p−2 = b(x)u | u|γ−2, in Ω and (1 − α)|∇u|p−2(∂u/∂n) + αu | u|p−2 = 0,
on ∂Ω, where Ω⊆RN is a connected bounded domain with smooth boundary ∂Ω, the outward unit normal to which is denoted by n. Δp is the p‐Laplcian operator defined by Δpu = div (|∇u|p−2∇u), the functions a and b are sign changing continuous functions in Ω, 1 < p < γ < p*, where p* = Np/(N − p) if N > p and ∞ otherwise. The properties of the first eigenvalue and the associated eigenvector of the related eigenvalue problem have been studied in (Khademloo, In press). In this paper, it is shown that if , the original problem admits at least one positive solution, while if , for a positive constant λ*, it admits at least two distinct positive solutions. Our approach is variational in character and our results extend those of Afrouzi and Khademloo (2007) in two aspects: the main part of our differential equation is the p‐Laplacian, and the boundary condition in this paper also is nonlinear.
Robust Stability of a Class of Unstable Systems under Mixed Uncertainty
Authors: Maher Rami A. , Samir Raghad
Published: December 2011

For unstable plants, the priority of control goes to the stability of synthesis, which means to find a stabilizer controller. In the case where the plant is subjected to structured and unstructured uncertainties, the stability problem becomes more crucial. The problem was solved by a conservative method based on generalized Kharitonov′s theorem and Nevanlinna‐Pick′s interpolation (NPI) technique. This paper introduces a proposed straightforward numerical approach for loop shaping the unstructured additive or multiplicative maximum uncertainty magnitudes. The approach finds controllers, which are capable of stabilizing the interval system while the uncertainty box is enlarged to its maximum dimensions. To illustrate, we introduce some numerical examples.
Use of Biologic Agents in Ocular Manifestations of Rheumatic Disease
Authors: Kraus Courtney L. , Culican Susan M.
Published: December 2011

Biologic agents have dramatically shifted the treatment paradigm for rheumatic disease. Use of these agents can decrease disease burden, allow the patient to be weaned from corticosteroids, and reduce the likelihood of relapse. Eye disease associated with rheumatic conditions may present with a wide range of signs and symptoms. This coexisting pathology should not be overlooked and should be considered a reason for initiation or continuation of biologic therapy. Additionally, many of the ocular manifestations of rheumatic disease respond preferentially to specific targeting molecules. This paper summarizes the available studies on the use, efficacy, and safety of biologic agents in the treatment of ocular manifestations of rheumatic disease.
Strong Convergence of a Modified Extragradient Method to the Minimum‐Norm Solution of Variational Inequalities
Authors: Yao Yonghong , Noor Muhammad Aslam , Liou Yeong-Cheng
Published: December 2011

We suggest and analyze a modified extragradient method for solving variational inequalities, which is convergent strongly to the minimum‐norm solution of some variational inequality in an infinite‐dimensional Hilbert space.
A Human Fab-Based Immunoconjugate Specific for the LMP1 Extracellular Domain Inhibits Nasopharyngeal Carcinoma Growth In Vitro and In Vivo
Authors: Chen Renjie , Zhang Dawei , Mao Yuan , Zhu Jin , Ming Hao , Wen Juan , Ma Jun , Cao Qing , Lin Hong , Tang Qi , Liang Jie , Feng Zhenqing
Published: December 2011

Nasopharyngeal carcinoma (NPC) is a major cause of cancer-related death in Southeast Asia and China. Metastasis and relapse are the primary cause of morbidity and mortality in NPC. Recent evidence suggests that the Epstein–Barr virus latent membrane protein 1 (LMP1) is exclusively expressed in most NPC and is a potential target for biotherapy. In this study, we successfully prepared a novel human antibody Fab (HLEAFab) against LMP1 extracellular domain, which was subsequently conjugated with mitomycin C (MMC), thus forming an immunoconjugate (HLEAFab-MMC). The effects of HLEAFab-MMC on proliferation and apoptosis in NPC cell lines HNE2/LMP1 and the inhibition rate of growth of NPC xenografts in nude mice were examined. The inhibition rate of HNE2/LMP1 cell proliferation was the highest for HLEAFab-MMC (76%) compared with MMC (31%) and HLEAFab (22%) at a concentration of 200 nmol/L and showed dose-dependent fashion. The apoptosis rate of HNE2/LMP1 cell lines was 13.88% in HLEAFab-MMC group, 3.04% in MMC group, 2.78% in HLEAFab group, and 2.10% in negative control group at the same concentration, respectively. In vivo, the inhibition rate of growth of NPC xenografts in nude mice was 55.1% in HLEAFab-MMC group, 26.5% in MMC group, and 5.64% in HLEAFab group. In summary, our findings show that HLEAFab-MMC is a unique immunoconjugate with the potential as a novel therapeutic agent in the treatment of LMP1-expressing NPC. Mol Cancer Ther; 11(3); 594–603. ©2011 AACR.
Application of Mesenchymal Stromal Cells in Bone Marrow Transplantation for Sensitized Recipients
Authors: Xu Lu-Hong , Fang Jian-Pei , Hong Dong-Ling , Wu Yan-Feng
Published: December 2011

Sensitized patients are at high risk for graft rejection during transplantation. It is of interest to investigate the effect of mesenchymal stromal cells (MSCs) in sensitized hematopoietic stem cell transplantation. MSCs were generated from bone marrow cells of BALB/c mice. The molecular markers of MSCs were detected by flow cytometry. MSCs labeled with green fluorescent dye were transplanted into nonsensitized and sensitized recipients, respectively. Homing of MSCs in vivo was monitored at different time points post-transplantation. Additionally, sensitized BALB/c mice under irradiation were transplanted with syngeneic MSCs and allogeneic bone marrow cells, and the rate of survival was monitored daily. The fourth passage of MSCs presented a typical spindle-shaped morphology and met the identification criteria of MSCs. Forty-eight hours post-transplantation, the homing of MSCs was found mainly in the bone morrow of nonsensitized recipients and the spleen of sensitized recipients, respectively. Moreover, all of the sensitized recipients died 12–16 days after receiving syngeneic MSCs and allogeneic bone marrow cells, with a median of 14 days. Our results suggest that the MSCs mainly homed to the spleen of sensitized recipients post-transplantation. MSCs could not enhance the engraftment of allogeneic bone marrow cells in sensitized recipients.
Bronchorrhea following Stroke
Authors: Sung Chung-Yang , Lee Tsong-Hai , Chu Nai-Shin
Published: December 2011

Background: Stroke-induced excessive bronchial secretion is not rare, but seldom discussed. This study emphasizes its recognition, pathophysiology and treatment. Methods: We prospectively collected data from 19 consecutive stroke patients with bronchorrhea who were admitted within 2 days of stroke onset. Results: Sixteen of them (84%) suffered from ischemic stroke, and 3 patients (16%) had hemorrhage. All of them had brainstem involvement, and 11 of them (58%) had localized lesions in the dorsal lateral medulla. In 15 patients (79%), copious secretion developed within 3 days after stroke onset. The frequency of expectoration was variable with fluctuation, and half of the patients (47%) had to spit every 2–5 min during its climax. The duration of increased secretion ranged from 4 days to over 2 months. Half of the patients (53%) received anticholinergic treatment, and the response was fair to good. Conclusions: Our data provide clinical evidence that stroke patients with dorsal medulla involvement might present with bronchorrhea which seemed to be mediated via a parasympathetic mechanism. This is a treatable disease, and early diagnosis and treatment may greatly reduce patients’ suffering, avoid antibiotics abuse, reduce the incidence of aspiration pneumonia, and shorten the length of hospitalization.
Late Onset Glycogen Storage Disease Type II: Pitfalls in the Diagnosis
Authors: Papadimas G.K. , Spengos K. , Papadopoulos C. , Manta P.
Published: December 2011

Background/Aims: Glycogen storage disease type II (GSD-II) is a lysosomal disorder caused by acid α glucosidase (GAA) deficiency. The infantile form is easier to recognize compared with the milder adult form that may manifest as myopathy without specific clinical characteristics. The aim of this study is to highlight frequent diagnostic errors in adult GSD-II patients. Case Reports: We report four patients with confirmed GSD-II who were at first diagnosed with hypothyroid myopathy, connective tissue disorder, an underlying liver disease and muscular dystrophy, respectively. Conclusion: Internists but even neurologists with low suspicion may misdiagnose GSD-II. The early respiratory involvement and the characteristic laboratory abnormalities in a myopathic patient should include GAA deficiency in the differential diagnosis especially in the era of enzyme replacement therapy.
Pattern of Hypertensive Kidney Disease in a Black Kenyan Population
Authors: Ogeng’o Julius A. , Gatonga Patrick , Olabu Beda O. , Ongera Dennis
Published: December 2011

Background: Hypertensive kidney disease is a major cause of morbidity and mortality. Its pattern displays geographical and ethnic variations. Data on these patterns are important for informing management and prevention strategies, but on Kenyans such data are scarce. Objective: By means of a retrospective study at Kenyatta National Hospital, Nairobi, we aimed to describe the pattern of hypertensive kidney disease in a black Kenyan population. Methods: Records of hypertensive patients who had impaired kidney function between January 2000 and December 2010 were examined for mode of diagnosis, age, gender, comorbid factors, treatment and outcome. Data were analyzed using the Statistical Package for Social Sciences, version 16.0 for Windows, and are presented using tables and bar charts. Results: A total of 114 cases (72 males, 42 females) were analyzed. The mean age was 42.7 years (range 12–83), peaking at 51–70 years. The male to female ratio was 1.7:1. Comorbid factors included left ventricular hypertrophy (21.1%), congestive heart failure (15.8%), alcohol (11.4%), cerebrovascular accidents, smoking and retinopathy (10.5% each). Multiple comorbid factors were present in 8.8% of the cases. The majority (52.6%) of the patients survived on hemodialysis, 8.8% underwent successful renal transplant and 22.8% died. Conclusion: Hypertensive kidney disease affects all age groups, males more than females. It is commonly associated with other cardiovascular conditions and carries a high morbidity. Vigilant control of blood pressure is recommended.
Analytical Expressions for Doppler Spectra of Scatter from Hydrometeors Observed with a Vertically Directed Radar Beam
Authors: Fang Ming , Doviak Richard J. , Albrecht Bruce A.
Published: December 2011

A generalized expression is derived for the correlation function of signals backscattered from hydrometeors observed with a vertically pointed radar beam in which particle size distribution, turbulence, and mean wind are not homogeneous. This study extends the previous work of Fang and Doviak by including the effects of particle size distribution on the measured Doppler spectrum. It shows the measured Doppler spectrum to be the volumetric mean of the weighted convolution of the normalized Doppler spectra associated with turbulence, mean wind, particle oscillation/wobble, and terminal velocity. Without particle oscillation/wobble, mean wind, and turbulence, the Doppler spectrum is the mirror image of the terminal velocity spectrum under the condition that the second-order effect of finite beamwidth can be ignored. This generalized Doppler spectrum reduces further to a previously derived expression if the particle size distribution, or equivalently reflectivity, is uniform. Provided there is a unique relationship between the particle’s terminal velocity and its effective diameter, the derived equations can be applied to scatterers consisting of ice particles as well as water droplets. This study derives the analytical expression for the Doppler spectrum of mean wind and also shows that if stationary homogeneous turbulence is the only contributor to spectral broadening, then the average of a large number of radar-measured Doppler spectra will be equal to the velocity probability density function of turbulence independent of the angular, range, reflectivity, and weighting functions.
Thailand’s Sufficiency Economy: Origins and Comparisons with Other Systems of Religious Economics
Authors: Noy Darren
Published: December 2011

The contemporary world is witnessing the growing re-assertion of public religion, including attempts to reorient economic organization and action according to religious teachings. One such attempt is the Thai concept of “sufficiency economy,” an economic model based on the collected sayings and development projects of Thailand’s king. The author examines the sufficiency economy model from three perspectives. First, he analyzes the origins and principles of sufficiency economy as a model for Buddhist economics. Second, he critically analyzes some possible political uses and misuses of the sufficiency economy discourse. Finally, he comparatively examines sufficiency economy in relation to Islamic finance and Gandhian economics.
Green's function and forced vibration response of damped axially moving wire
Authors: Chung Chunhui , Kao Imin
Published: December 2011

In this paper, we present a converted closed-form analytical solution for both free and forced vibration responses of a damped axially moving wire, as well as the boundary value problems, based on the Green's function. The Green's function of a damped axially moving wire is derived through an inverse Laplace transform. The corresponding frequency responses when subject to harmonic point excitation are also presented with simulation results. The results show agreement with the results of previous research on free vibration response and corresponding eigensolutions.
Rejection of nonharmonic disturbances in nonlinear systems via the internal model approach
Authors: Jiang Yuan
Published: December 2011

This paper proposes an asymptotic rejection algorithm for rejecting exotic disturbances in nonlinear systems. Disturbances produced by nonlinear exosystems are nonharmonic and periodic. The proposed algorithm extends the rejection of nonlinear disturbances for nonlinear dynamic systems from systems in the strict feedback form and output feedback form to general nonlinear systems. A new nonlinear internal model is proposed to deal with these disturbances. Furthermore, a state feedback controller is designed to ensure that the system’s state variables asymptotically converge to zero, and disturbances can be completely rejected. The proposed algorithm has various applications, such as active vibration control. The proposed algorithm is demonstrated to completely reject the nonharmonic periodic disturbances produced by a van der Pol oscillator.
Reflections on the history of marketing thought and theory development
Authors: Tamilia Robert D.
Published: December 2011

What happens when accumulated knowledge from the past as regards both practice and theory is absent in marketing education? Simply put, scholarly knowledge gets lost with dire consequences not only for the nature and scope of marketing as an academic discipline but also for the type of research undertaken. The quest to be current, especially in marketing management, has resulted in the fragmentation of marketing into ever more specialized areas resulting in the creation of silos with little room for scholarly work in marketing thought and marketing theory building.
Perseverative negative cognitive processes are associated with depression in people with long-term conditions
Authors: Dickens Chris , Coventry Peter , Khara Angee , Bower Peter , Mansell Warren , Bakerly Nawar Diar
Published: December 2011

Background: Perseverative negative cognitive processes, such as worry, suppression and avoidance of undesirable thoughts, have been linked to persistence and relapse of depression. Such processes could account for poor treatment response though they have received little research attention in people with long-term conditions (LTCs).

Method: We conducted a cross-sectional study to investigate the associations of perseverative negative cognitive processes with depression among medical outpatients with LTCs. In 190 patients, we recorded levels of depression (Hospital Anxiety and Depression Scale), worry (Penn State Worry Questionnaire), suppression (White Bear Suppression Inventory) and avoidance of undesirable thoughts (Acceptance and Action Questionnaire). Associations between these constructs were assessed using linear correlation and logistic regression.

Results: Both depression (32%) and anxiety (40%) were common in patients recruited. After controlling for demographic and medical confounders, subjects in the top tertile of worry, suppression and avoidance of undesirable thoughts were 20 (95% CIs, 6.6–58.3), 10 (95% CIs, 3.5–25.9) and 22 (95% CIs, 6.0–80.0) times more likely to have possible depression compared to those in the lowest tertile.

Conclusions: Prospective research is required to investigate causal relationships between these constructs, and to assess the potential of psychological interventions that target these processes to improve outcomes in patients with LTCs.
Looking Right: The Art of Visual Literacy in British Copyright Litigation
Authors: Bellido Jose
Published: December 2011

The essay explores the interactive role of experts in the construction of the intangible object in copyright law. It pays special attention to the interventions and eventual connections of a British design consultant and fashion designer, Victor Herbert, in different copyright cases such as the well-known Designers Guild Ltd v. Russell Williams (Textiles) Ltd [2001]. The article traces the background of his early court appearances as an expert witness and the range of visual techniques and experiments he developed to “materialize” the incorporeal in copyright law.
In search of a health education model: teachers’ conceptions in four Mediterranean countries
Authors: Caussidier Claude , Hage Fadi El , Munoz François , Remki Latifa , Larribi Rym , Khzami Salah-Eddine , Berger Dominique , de Carvalho Graça S. , Favre Daniel
Published: December 2011

School programs are defined to promote the health of the pupils and to develop their competencies so that they can adopt behaviors favorable to their health. With the European project FP6 Biohead-Citizen (2004–2007), we analyzed the conceptions of teachers as regards health education, in France, Lebanon, Morocco and Tunisia, in reference to the biomedical model and the social health model. These four countries were selected because their school curricula represented different models of health education. Lebanon and Tunisia addressed health education with the biomedical model. In Morocco, the curriculum was also primarily based on the biomedical model and enclosed a few instructions issued from the social health model. In France, the health education curriculum declared an approach based on the health promotion model. Our study was based on multivariate statistical analyses of questionnaires filled out by 2537 in-service and pre-service teachers. Our analysis showed that the conceptions of the teachers concerning health education were not structured and related to a specific model. We also found that the dominating factors of influence on the choices expressed with regards to health education were, among different sociocultural variables, the religion, the home country, and, to a lesser extent, the level of training. Thus, the conceptions of the teachers were not integrated into comprehensive approaches but related to individual characteristics. Consequently health education implementation would require thorough training for pre-service and in-service teachers and should also explicitly take into account their conceptions and values.
Réduction de la mortalité maternelle : quel rôle pour les matrones ?
Authors: Fournier Pierre
Published: December 2011

Résumé

La mortalité maternelle demeure un problème de santé mondiale majeur pour lequel on enregistre peu ou pas de progrès dans de nombreux pays. La communauté internationale est mobilisée autour de cette question et de nombreuses initiatives sont en cours. Actuellement un débat porte sur le rôle des matrones dans la lutte pour la réduction de la mortalité maternelle. Ces accoucheuses traditionnelles ont précédé toutes les formes d’accouchements assistés par du personnel professionnel de santé. On ne peut pas recommander leur utilisation à large échelle car il n’y a pas suffisamment d’évidence sur leur impact, même après avoir été formées ou recyclées. Leur rôle est établi en ce qui concerne la santé périnatale. Pour les mères, elles peuvent contribuer à améliorer des pratiques de santé durant la grossesse, pendant et après l’accouchement. Alors que certains prônent le recours aux matrones qui ont une légitimité culturelle indéniable, d’autres les considèrent comme un frein à la réduction de la mortalité maternelle. Ce commentaire soutient que la tendance à recourir à leurs services diminue de façon inexorable sous le double effet de l’urbanisation et de l’amélioration de l’accès aux services de santé. Le rôle des matrones là où l’accessibilité aux services de santé est faible ne se discute pas car il n’y a pas d’autres alternatives. La mortalité maternelle persiste dans les pays ou les régions dans lesquelles il y a des inégalités d’accès aux services de santé. Le principe d’équité commande que l’on réduise ces inégalités le plus rapidement possible et cela constitue le seul moyen de faire diminuer la mortalité maternelle à l’échelle mondiale.
Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2
Authors: Ting Stephen B. , Deneault Eric , Hope Kristin , Cellot Sonia , Chagraoui Jalila , Mayotte Nadine , Dorn Jonas F. , Laverdure Jean-Philippe , Harvey Michael , Hawkins Edwin D. , Russell Sarah M. , Maddox Paul S. , Iscove Norman N. , Sauvageau Guy
Published: December 2011

The stem cell–intrinsic model of self-renewal via asymmetric cell division (ACD) posits that fate determinants be partitioned unequally between daughter cells to either activate or suppress the stemness state. ACD is a purported mechanism by which hematopoietic stem cells (HSCs) self-renew, but definitive evidence for this cellular process remains open to conjecture. To address this issue, we chose 73 candidate genes that function within the cell polarity network to identify potential determinants that may concomitantly alter HSC fate while also exhibiting asymmetric segregation at cell division. Initial gene-expression profiles of polarity candidates showed high and differential expression in both HSCs and leukemia stem cells. Altered HSC fate was assessed by our established in vitro to in vivo screen on a subcohort of candidate polarity genes, which revealed 6 novel positive regulators of HSC function: Ap2a2, Gpsm2, Tmod1, Kif3a, Racgap1, and Ccnb1. Interestingly, live-cell videomicroscopy of the endocytic protein AP2A2 shows instances of asymmetric segregation during HSC/progenitor cell cytokinesis. These results contribute further evidence that ACD is functional in HSC self-renewal, suggest a role for Ap2a2 in HSC activity, and provide a unique opportunity to prospectively analyze progeny from HSC asymmetric divisions.
Next generation DNA sequencing technology delivers valuable genetic markers for the genomic orphan legume species, Bituminaria bituminosa
Authors: Pazos-Navarro María , Dabauza Mercedes , Correal Enrique , Hanson Kelly , Teakle Natasha , Real Daniel , Nelson Matthew N
Published: December 2011

Background

Bituminaria bituminosa is a perennial legume species from the Canary Islands and Mediterranean region that has potential as a drought-tolerant pasture species and as a source of pharmaceutical compounds. Three botanical varieties have previously been identified in this species: albomarginata, bituminosa and crassiuscula. B. bituminosa can be considered a genomic 'orphan' species with very few genomic resources available. New DNA sequencing technologies provide an opportunity to develop high quality molecular markers for such orphan species.

Results

432,306 mRNA molecules were sampled from a leaf transcriptome of a single B. bituminosa plant using Roche 454 pyrosequencing, resulting in an average read length of 345 bp (149.1 Mbp in total). Sequences were assembled into 3,838 isotigs/contigs representing putatively unique gene transcripts. Gene ontology descriptors were identified for 3,419 sequences. Raw sequence reads containing simple sequence repeat (SSR) motifs were identified, and 240 primer pairs flanking these motifs were designed. Of 87 primer pairs developed this way, 75 (86.2%) successfully amplified primarily single fragments by PCR. Fragment analysis using 20 primer pairs in 79 accessions of B. bituminosa detected 130 alleles at 21 SSR loci. Genetic diversity analyses confirmed that variation at these SSR loci accurately reflected known taxonomic relationships in original collections of B. bituminosa and provided additional evidence that a division of the botanical variety bituminosa into two according to geographical origin (Mediterranean region and Canary Islands) may be appropriate. Evidence of cross-pollination was also found between botanical varieties within a B. bituminosa breeding programme.

Conclusions

B. bituminosa can no longer be considered a genomic orphan species, having now a large (albeit incomplete) repertoire of expressed gene sequences that can serve as a resource for future genetic studies. This experimental approach was effective in developing codominant and polymorphic SSR markers for application in diverse genetic studies. These markers have already given new insight into genetic variation in B. bituminosa, providing evidence that a division of the botanical variety bituminosa may be appropriate. This approach is commended to those seeking to develop useful markers for genomic orphan species.
Protective effect of probiotics on Salmonella infectivity assessed with combined in vitro gut fermentation-cellular models
Authors: Zihler Annina , Gagnon Mélanie , Chassard Christophe , Lacroix Christophe
Published: December 2011

Background

Accurate assessment of probiotics with targeted anti-Salmonella activity requires suitable models accounting for both, microbe-microbe and host-microbe interactions in gut environments. Here we report the combination of two original in vitro intestinal models closely mimicking the complex in vivo conditions of the large intestine. Effluents from continuous in vitro three-stage fermentation colonic models of Salmonella Typhimurium infection inoculated with immobilized child microbiota and Salmonella were directly applied to confluent mucus-secreting HT29-MTX cell layers. The effects of Salmonella, addition of two bacteriocinogenic strains, Bifidobacterium thermophilum RBL67 (thermophilicin B67) and Escherichia coli L1000 (microcin B17), and inulin were tested on Salmonella growth and interactions with epithelial cell layers. Salmonella adhesion and invasion were investigated and epithelial integrity assessed by transepithelial electrical resistance (TER) measurements and confocal microscopy observation. Data from complex effluents were compared with pure Salmonella cultures.

Results

Salmonella in effluents of all reactors of the colonic fermentation model stabilized at mean values of 5.3 ± 0.8 log10 cfu/ml effluent. Invasion of cell-associated Salmonella was up to 50-fold lower in complex reactor samples compared to pure Salmonella cultures. It further depended on environmental factors, with 0.2 ± 0.1% being measured with proximal, 0.6 ± 0.2% with transverse and 1.3 ± 0.7% with distal reactor effluents, accompanied by a similar high decrease of TER across cell monolayers (minus 45%) and disruption of tight junctions. Subsequent addition of E. coli L1000 stimulated Salmonella growth (6.4 ± 0.6 log10 cfu/ml effluent of all 3 reactors) and further decreased TER, but led to 10-fold decreased invasion efficiency when tested with distal reactor samples. In contrast, presence of B. thermophilum RBL67 revealed a protective effect on epithelial integrity compared to previous E. coli L1000 periods, as reflected by a significant mean increase of TER by 58% in all reactors. Inulin addition enhanced Salmonella growth and invasion when tested with distal and proximal reactor samples, respectively, but induced a limited decrease of TER (minus 18%) in all reactors.

Conclusions

Our results highlight the benefits of combining suitable cellular and colonic fermentation models to assess strain-specific first-level host protection properties of probiotics during Salmonella infection, providing an efficient system biology tool for preclinical development of new antimicrobials.
Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation
Authors: Bohonowych Jessica ES , Peng Shuping , Gopal Udhayakumar , Hance Michael W , Wing Shane B , Argraves Kelley M , Lundgren Karen , Isaacs Jennifer S
Published: December 2011

Background

Perturbing Hsp90 chaperone function targets hypoxia inducible factor (HIF) function in a von Hippel-Lindau (VHL) independent manner, and represents an approach to combat the contribution of HIF to cell renal carcinoma (CCRCC) progression. However, clinical trials with the prototypic Hsp90 inhibitor 17-AAG have been unsuccessful in halting the progression of advanced CCRCC.

Methods

Here we evaluated a novel next generation small molecule Hsp90 inhibitor, EC154, against HIF isoforms and HIF-driven molecular and functional endpoints. The effects of EC154 were compared to those of the prototypic Hsp90 inhibitor 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589.

Results

The findings indicate that EC154 is a potent inhibitor of HIF, effective at doses 10-fold lower than 17-AAG. While EC154, 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589 impaired HIF transcriptional activity, CCRCC cell motility, and angiogenesis; these effects did not correlate with their ability to diminish HIF protein expression. Further, our results illustrate the complexity of HIF targeting, in that although these agents suppressed HIF transcripts with differential dynamics, these effects were not predictive of drug efficacy in other relevant assays.

Conclusions

We provide evidence for EC154 targeting of HIF in CCRCC and for LBH589 acting as a suppressor of both HIF-1 and HIF-2 activity. We also demonstrate that 17-AAG and EC154, but not LBH589, can restore endothelial barrier function, highlighting a potentially new clinical application for Hsp90 inhibitors. Finally, given the discordance between HIF activity and protein expression, we conclude that HIF expression is not a reliable surrogate for HIF activity. Taken together, our findings emphasize the need to incorporate an integrated approach in evaluating Hsp90 inhibitors within the context of HIF suppression.
Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in ApcMin/+ mice
Authors: Brudvik Kristoffer W , Paulsen Jan E , Aandahl Einar M , Roald Borghild , Taskén Kjetil
Published: December 2011

Background

The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of β-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E2 (PGE2) - PI-3 kinase pathways. Recent reports show that PGE2-induced phosphorylation of β-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE2 on β-catenin homeostasis.

Findings

Treatment of Apc
Min/+ mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of β-catenin, β-catenin nuclear translocation and expression of the β-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE2-induced β-catenin phosphorylation and c-Myc upregulation.

Conclusion

Based on our findings we suggest that PGE2 act through PKA to promote β-catenin nuclear translocation and tumor development in Apc
Min/+ mice in vivo, indicating that the direct regulatory effect of PKA on β-catenin nuclear translocation is operative in intestinal cancer.
Low-energy structures of clusters supported on metal fcc(110) surfaces
Authors: Zhang Peng , Ma Liuxue , Shao Hezhu , Zhang Jinhu , Zhang Wenxian , Ning Xijing , Zhuang Jun
Published: December 2011

The low-energy structures (LESs) of adatom clusters on a series of metal face-centered cubic (fcc) (110) surfaces are systematically studied by the genetic algorithm, and a simplified model based on the atomic interactions is developed to explain the LESs. Two different kinds of LES group mainly caused by the different next nearest-neighbor (NNN) adatom-adatom interaction are distinguished, although the NNN atomic interaction is much weaker than the nearest-neighbor interaction. For a repulsive NNN atomic interaction, only the linear chain is included in the LES group. However, for an attractive one, type of structure in the LES group is various and replace gradually one by one with cluster size increasing. Based on our model, we also predict the shape feature of the large cluster which is found to be related closely to the ratio of NN and NNN bond energies, and discuss the surface reconstruction in the view of atomic interaction. The results are in accordance with the experimental observations.

PACS: 68.43.Hn; 68.43.Fg.
HIV-1 Group P is unable to antagonize human tetherin by Vpu, Env or Nef
Authors: Sauter Daniel , Hué Stéphane , Petit Sarah J , Plantier Jean-Christophe , Towers Greg J , Kirchhoff Frank , Gupta Ravindra K
Published: December 2011

Background

A new subgroup of HIV-1, designated Group P, was recently detected in two unrelated patients of Cameroonian origin. HIV-1 Group P phylogenetically clusters with SIVgor suggesting that it is the result of a cross-species transmission from gorillas. Until today, HIV-1 Group P has only been detected in two patients, and its degree of adaptation to the human host is largely unknown. Previous data have shown that pandemic HIV-1 Group M, but not non-pandemic Group O or rare Group N viruses, efficiently antagonize the human orthologue of the restriction factor tetherin (BST-2, HM1.24, CD317) suggesting that primate lentiviruses may have to gain anti-tetherin activity for efficient spread in the human population. Thus far, three SIV/HIV gene products (vpu, nef and env) are known to have the potential to counteract primate tetherin proteins, often in a species-specific manner. Here, we examined how long Group P may have been circulating in humans and determined its capability to antagonize human tetherin as an indicator of adaptation to humans.

Results

Our data suggest that HIV-1 Group P entered the human population between 1845 and 1989. Vpu, Env and Nef proteins from both Group P viruses failed to counteract human or gorilla tetherin to promote efficient release of HIV-1 virions, although both Group P Nef proteins moderately downmodulated gorilla tetherin from the cell surface. Notably, Vpu, Env and Nef alleles from the two HIV-1 P strains were all able to reduce CD4 cell surface expression.

Conclusions

Our analyses of the two reported HIV-1 Group P viruses suggest that zoonosis occurred in the last 170 years and further support that pandemic HIV-1 Group M strains are better adapted to humans than non-pandemic or rare Group O, N and P viruses. The inability to antagonize human tetherin may potentially explain the limited spread of HIV-1 Group P in the human population.
Exon duplications in the ATP7A gene: Frequency and Transcriptional Behaviour
Authors: Mogensen Mie , Skjørringe Tina , Kodama Hiroko , Silver Kenneth , Horn Nina , Møller Lisbeth B
Published: December 2011

Background

Menkes disease (MD) is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene. Thirty-three Menkes patients in whom no mutation had been detected with standard diagnostic tools were screened for exon duplications in the ATP7A gene.

Methods

The ATP7A gene was screened for exon duplications using multiplex ligation-dependent probe amplification (MLPA). The expression level of ATP7A was investigated by real-time PCR and detailed analysis of the ATP7A mRNA was performed by RT-PCR followed by sequencing. In order to investigate whether the identified duplicated fragments originated from a single or from two different X-chromosomes, polymorphic markers located in the duplicated fragments were analyzed.

Results

Partial ATP7A gene duplication was identified in 20 unrelated patients including one patient with Occipital Horn Syndrome (OHS). Duplications in the ATP7A gene are estimated from our material to be the disease causing mutation in 4% of the Menkes disease patients. The duplicated regions consist of between 2 and 15 exons. In at least one of the cases, the duplication was due to an intra-chromosomal event. Characterization of the ATP7A mRNA transcripts in 11 patients revealed that the duplications were organized in tandem, in a head to tail direction. The reading frame was disrupted in all 11 cases. Small amounts of wild-type transcript were found in all patients as a result of exon-skipping events occurring in the duplicated regions. In the OHS patient with a duplication of exon 3 and 4, the duplicated out-of-frame transcript coexists with an almost equally represented wild-type transcript, presumably leading to the milder phenotype.

Conclusions

In general, patients with duplication of only 2 exons exhibit a milder phenotype as compared to patients with duplication of more than 2 exons. This study provides insight into exon duplications in the ATP7A gene.
The soluble biomarker calprotectin (a S100 protein) is associated to ultrasonographic synovitis scores and is sensitive to change in patients with rheumatoid arthritis treated with adalimumab
Authors: Hammer Hilde Berner , Fagerhol Magne K , Wien Tale Norbye , Kvien Tore K
Published: December 2011

Introduction

Calprotectin (MRP8/MRP14, S100A8/A9) is associated with disease activity in patients with rheumatoid arthritis (RA). Ultrasonography (US) is a reliable method for evaluation of synovitis (B-mode (BM) and power Doppler (PD)). The present objectives were to explore in RA patients the associations between calprotectin and a comprehensive US examination, as well as the responsiveness of calprotectin compared to other inflammatory markers during anti-TNF treatment.

Methods

A total of 20 RA patients starting treatment with adalimumab were examined longitudinally by US (BM and PD (semi-quantitative scores 0 to 3) of 78 joints, 36 tendons/tendon groups and 2 bursae) and clinically at baseline and after 1, 3, 6 and 12 months. Associations between the US sum scores and the inflammatory markers calprotectin, serum amyloid A (SAA), CRP and ESR were explored by correlation and linear regression analyses, and the response to treatment was assessed by Standardized Response Mean (SRM).

Results

The inflammatory markers, clinical examinations and US sum scores improved during treatment (P < 0.001). Of the inflammatory markers, calprotectin had the highest correlation coefficients with the total BM and PD sum scores (median (range) 0.59 (0.37 to 0.76) for BM and 0.56 (0.38 to 0.72) for PD). Even higher correlations were found between calprotectin and sum US scores of reduced number of joint counts. Calprotectin made a considerable contribution to total US sum scores in the linear regression analyses (P = 0.001 to 0.031) and among the inflammatory markers, calprotectin had the highest SRM (0.84 at one month).

Conclusions

Calprotectin was associated with the sum scores from a comprehensive US assessment and was responsive to change during anti-TNF treatment. Thus, examination of this leukocyte protein could be of additional value in the assessment of RA patients on biologic treatment.
Regenerative potential of human muscle stem cells in chronic inflammation
Authors: Duijnisveld Bouke J , Bigot Anne , Beenakker Karel GM , Portilho Débora M , Raz Vered , van der Heide Huub JL , Visser Cornelis PJ , Chaouch Soraya , Mamchaoui Kamel , Westendorp Rudi GJ , Mouly Vincent , Butler-Browne Gillian S , Nelissen Rob GHH , Maier Andrea B
Published: December 2011

Introduction

Chronic inflammation is a profound systemic modification of the cellular microenvironment which could affect survival, repair and maintenance of muscle stem cells. The aim of this study was to define the role of chronic inflammation on the regenerative potential of satellite cells in human muscle.

Methods

As a model for chronic inflammation, 11 patients suffering from rheumatoid arthritis (RA) were included together with 16 patients with osteoarthritis (OA) as controls. The mean age of both groups was 64 years, with more females in the RA group compared to the OA group. During elective knee replacement surgery, a muscle biopsy was taken from the distal musculus vastus medialis. Cell populations from four RA and eight OA patients were used for extensive phenotyping because these cell populations showed no spontaneous differentiation and myogenic purity greater than 75% after explantation.

Results

After mononuclear cell explantation, myogenic purity, viability, proliferation index, number of colonies, myogenic colonies, growth speed, maximum number of population doublings and fusion index were not different between RA and OA patients. Furthermore, the expression of proteins involved in replicative and stress-induced premature senescence and apoptosis, including p16, p21, p53, hTERT and cleaved caspase-3, was not different between RA and OA patients. Mean telomere length was shorter in the RA group compared to the OA group.

Conclusions

In the present study we found evidence that chronic inflammation in RA does not affect the in vitro regenerative potential of human satellite cells. Identification of mechanisms influencing muscle regeneration by modulation of its microenvironment may, therefore, be more appropriate.
Variants on the promoter region of PTEN affect breast cancer progression and patient survival
Authors: Heikkinen Tuomas , Greco Dario , Pelttari Liisa M , Tommiska Johanna , Vahteristo Pia , Heikkilä Päivi , Blomqvist Carl , Aittomäki Kristiina , Nevanlinna Heli
Published: December 2011

Introduction

The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer.

Methods

We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.

Results

All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.

Conclusions

Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.
Succinate Dehydrogenase (SDH) D Subunit (SDHD) Inactivation in a Growth-Hormone-Producing Pituitary Tumor: A New Association for SDH?
Authors: Xekouki Paraskevi , Pacak Karel , Almeida Madson , Wassif Christopher A. , Rustin Pierre , Nesterova Maria , de la Luz Sierra Maria , Matro Joey , Ball Evan , Azevedo Monalisa , Horvath Anelia , Lyssikatos Charalampos , Quezado Martha , Patronas Nicholas , Ferrando Barbara , Pasini Barbara , Lytras Aristides , Tolis George , Stratakis Constantine A.
Published: December 2011

Background:

Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD).

Aim:

Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma.

Patients and Methods:

A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298_301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors.

Conclusion:

We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.