title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. | The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury. | 18,988,856 |
Quebec platelet disorder is linked to the urokinase plasminogen activator gene (PLAU) and increases expression of the linked allele in megakaryocytes. | Quebec platelet disorder (QPD) is an autosomal dominant disorder with high penetrance that is associated with increased risks for bleeding. The hallmark of QPD is a gain-of-function defect in fibrinolysis due to increased platelet content of urokinase plasminogen activator (uPA) without systemic fibrinolysis. We hypothesized that increased expression of uPA by differentiating QPD megakaryocytes is linked to PLAU. Genetic marker analyses indicated that QPD was significantly linked to a 2-Mb region on chromosome 10q containing PLAU with a maximum multipoint logarithm of the odds (LOD) score of +11 between markers D10S1432 and D10S1136. Analysis of PLAU by sequencing and Southern blotting excluded mutations within PLAU and its known regulatory elements as the cause of QPD. Analyses of uPA mRNA indicated that QPD distinctly increased transcript levels of the linked PLAU allele with megakaryocyte differentiation. These findings implicate a mutation in an uncharacterized cis element near PLAU as the cause of QPD. | 18,988,861 |
Endothelial nitric oxide deficiency reduces MMP-13-mediated cleavage of ICAM-1 in vascular endothelium: a role in atherosclerosis. | Lack of endothelial nitric oxide synthase worsens atherosclerosis at least by increasing monocyte adhesion to endothelial cells. The purpose of this study was to elucidate the molecular mechanism elicited by NO. We evaluated atherosclerosis in apoE and NOS3/apoE-deficient mice fed with high-cholesterol diet. We found significant increase in aortic lesion size, and infiltration of macrophages in NOS3/apoE-null mice when compared to apoE-deficient animals. To test the relevance of cellular adhesion as well as extracellular matrix degradation, we evaluated ICAM-1, VCAM-1, PECAM-1, MMP-2, MMP-9, MMP-12, MT1-MMP, and MMP-13 levels in mouse aortas. Lack of NO inhibits MMP-13 and increases ICAM-1 levels in atherosclerosis as compared to apoE-null mice. Ectopically expression of ICAM-1 in eukaryotic cells revealed that extracellular domain of ICAM-1 harbors a substrate recognized by MMP-13. Incubation of COS-7 cells expressing ectopic ICAM-1 in the presence of active MMP-13 induced inhibition of RAW 264.7 cell adhesion to COS-7 monolayers. MALDI-TOF MS analysis combined to Liquid chromatography coupled to Ion Trap MS on ICAM-1 incubated with MMP-13 allowed us to determine the cleavage sites of MMP-13 at positions E61 and G98 of ICAM-1. G98 is part of a PDGQS moiety, which shows homology with the consensus PDGLS substrate located at the MMP-13 cleaved site of type II collagen I-alpha. Taking together, these results point toward MMP-13 as a mechanism for the NO-mediated protection of atherosclerosis. | 18,988,893 |
p53 impairs endothelium-dependent vasomotor function through transcriptional upregulation of p66shc. | The transcription factor, p53, and the adaptor protein, p66shc, both play essential roles in promoting oxidative stress in the vascular system. However, the relationship between the two in the context of endothelium-dependent vascular tone is unknown. Here, we report a novel, evolutionarily conserved, p53-mediated transcriptional mechanism that regulates p66shc expression and identify p53 as an important determinant of endothelium-dependent vasomotor function. We provide evidence of a p53 response element in the promoter of p66shc and show that angiotensin II-induced upregulation of p66shc in endothelial cells is dependent on p53. In addition, we demonstrate that downregulation of p66shc expression, as well as inhibition of p53 function in mice, mitigates angiotensin II-induced impairment of endothelium-dependent vasorelaxation, decrease in bioavailable nitric oxide, and hypertension. These findings reveal a novel p53-dependent transcriptional mechanism for the regulation of p66shc expression that is operative in the vascular endothelium and suggest that this mechanism is important in impairing endothelium-dependent vascular relaxation. | 18,988,897 |
Cardiogenic differentiation and transdifferentiation of progenitor cells. | In recent years, cell transplantation has drawn tremendous interest as a novel approach to preserving or even restoring contractile function to infarcted hearts. A typical human infarct involves the loss of approximately 1 billion cardiomyocytes, and, therefore, many investigators have sought to identify endogenous or exogenous stem cells with the capacity to differentiate into committed cardiomyocytes and repopulate lost myocardium. As a result of these efforts, dozens of stem cell types have been reported to have cardiac potential. These include pluripotent embryonic stem cells, as well various adult stem cells resident in compartments including bone marrow, peripheral tissues, and the heart itself. Some of these cardiogenic progenitors have been reported to contribute replacement muscle through endogenous reparative processes or via cell transplantation in preclinical cardiac injury models. However, considerable disagreement exists regarding the efficiency and even the reality of cardiac differentiation by many of these stem cell types, making these issues a continuing source of controversy in the field. In this review, we consider approaches to cell fate mapping and establishing the cardiac phenotype, as well as the present state of the evidence for the cardiogenic and regenerative potential of the major candidate stem cell types. | 18,988,903 |
Extrapulmonary manifestations of chronic obstructive pulmonary disease in a mouse model of chronic cigarette smoke exposure. | Cigarette smoking is the most commonly encountered risk factor for chronic obstructive pulmonary disease (COPD), reflected by irreversible airflow limitation, frequently associated with airspace enlargement and pulmonary inflammation. In addition, COPD has systemic consequences, including systemic inflammation, muscle wasting, and loss of muscle oxidative phenotype. However, the role of smoking in the development of these extrapulmonary manifestations remains rather unexplored. Mice were exposed to cigarette smoke or control air for 6 months. Subsequently, emphysema was assessed by morphometry of lung tissue, and blood cytokine and chemokine levels were determined by a multiplex assay. Soleus, plantaris, gastrocnemius, and tibialis muscles were dissected and weighed. Muscle fiber typing was performed based on I, IIA, IIB, and IIX myosin heavy-chain isoform composition. Lungs of the smoke-exposed animals showed pulmonary inflammation and emphysema. Moreover, circulating levels of primarily proinflammatory proteins, especially TNF-alpha, were elevated after smoke exposure. Despite an attenuated body weight gain, only the soleus showed a tendency toward lower muscle weight after smoke exposure. Oxidative fiber type IIA proportion was significantly reduced in the soleus. Muscle oxidative enzyme activity was slightly reduced after smoke exposure, being most prominent for citrate synthase in the soleus and tibialis. In this mouse model, chronic cigarette smoke exposure resulted in systemic features that closely resemble the early signs of the extrapulmonary manifestations observed in patients with COPD. | 18,988,919 |
Graphical histories for visualization: supporting analysis, communication, and evaluation. | Interactive history tools, ranging from basic undo and redo to branching timelines of user actions, facilitate iterative forms of interaction. In this paper, we investigate the design of history mechanisms for information visualization. We present a design space analysis of both architectural and interface issues, identifying design decisions and associated trade-offs. Based on this analysis, we contribute a design study of graphical history tools for Tableau, a database visualization system. These tools record and visualize interaction histories, support data analysis and communication of findings, and contribute novel mechanisms for presenting, managing, and exporting histories. Furthermore, we have analyzed aggregated collections of history sessions to evaluate Tableau usage. We describe additional tools for analyzing users' history logs and how they have been applied to study usage patterns in Tableau. | 18,988,963 |
Geometry-based edge clustering for graph visualization. | Graphs have been widely used to model relationships among data. For large graphs, excessive edge crossings make the display visually cluttered and thus difficult to explore. In this paper, we propose a novel geometry-based edge-clustering framework that can group edges into bundles to reduce the overall edge crossings. Our method uses a control mesh to guide the edge-clustering process; edge bundles can be formed by forcing all edges to pass through some control points on the mesh. The control mesh can be generated at different levels of detail either manually or automatically based on underlying graph patterns. Users can further interact with the edge-clustering results through several advanced visualization techniques such as color and opacity enhancement. Compared with other edge-clustering methods, our approach is intuitive, flexible, and efficient. The experiments on some large graphs demonstrate the effectiveness of our method. | 18,988,974 |
Perceptual organization in user-generated graph layouts. | Many graph layout algorithms optimize visual characteristics to achieve useful representations. Implicitly, their goal is to create visual representations that are more intuitive to human observers. In this paper, we asked users to explicitly manipulate nodes in a network diagram to create layouts that they felt best captured the relationships in the data. This allowed us to measure organizational behavior directly, allowing us to evaluate the perceptual importance of particular visual features, such as edge crossings and edge-lengths uniformity. We also manipulated the interior structure of the node relationships by designing data sets that contained clusters, that is, sets of nodes that are strongly interconnected. By varying the degree to which these clusters were "masked" by extraneous edges we were able to measure observers' sensitivity to the existence of clusters and how they revealed them in the network diagram. Based on these measurements we found that observers are able to recover cluster structure, that the distance between clusters is inversely related to the strength of the clustering, and that users exhibit the tendency to use edges to visually delineate perceptual groups. These results demonstrate the role of perceptual organization in representing graph data and provide concrete recommendations for graph layout algorithms. | 18,988,981 |
Spatially ordered treemaps. | Existing treemap layout algorithms suffer to some extent from poor or inconsistent mappings between data order and visual ordering in their representation, reducing their cognitive plausibility. While attempts have been made to quantify this mismatch, and algorithms proposed to minimize inconsistency, solutions provided tend to concentrate on one-dimensional ordering. We propose extensions to the existing squarified layout algorithm that exploit the two-dimensional arrangement of treemap nodes more effectively. Our proposed spatial squarified layout algorithm provides a more consistent arrangement of nodes while maintaining low aspect ratios. It is suitable for the arrangement of data with a geographic component and can be used to create tessellated cartograms for geovisualization. Locational consistency is measured and visualized and a number of layout algorithms are compared. CIELab color space and displacement vector overlays are used to assess and emphasize the spatial layout of treemap nodes. A case study involving locations of tagged photographs in the Flickr database is described. | 18,988,983 |
Size-based transfer functions: a new volume exploration technique. | The visualization of complex 3D images remains a challenge, a fact that is magnified by the difficulty to classify or segment volume data. In this paper, we introduce size-based transfer functions, which map the local scale of features to color and opacity. Features in a data set with similar or identical scalar values can be classified based on their relative size. We achieve this with the use of scale fields, which are 3D fields that represent the relative size of the local feature at each voxel. We present a mechanism for obtaining these scale fields at interactive rates, through a continuous scale-space analysis and a set of detection filters. Through a number of examples, we show that size-based transfer functions can improve classification and enhance volume rendering techniques, such as maximum intensity projection. The ability to classify objects based on local size at interactive rates proves to be a powerful method for complex data exploration. | 18,988,987 |
Visualizing particle/flow structure interactions in the small bronchial tubes. | Particle deposition in the small bronchial tubes (generations six through twelve) is strongly influenced by the vortex-dominated secondary flows that are induced by axial curvature of the tubes. In this paper, we employ particle destination maps in conjunction with two-dimensional, finite-time Lyapunov exponent maps to illustrate how the trajectories of finite-mass particles are influenced by the presence of vortices. We consider two three-generation bronchial tube models: a planar, asymmetric geometry and a non-planar, asymmetric geometry. Our visualizations demonstrate that these techniques, coupled with judiciously seeded particle trajectories, are effective tools for studying particle/flow structure interactions. | 18,988,991 |
Visualizing temporal patterns in large multivariate data using textual pattern matching. | Extracting and visualizing temporal patterns in large scientific data is an open problem in visualization research. First, there are few proven methods to flexibly and concisely define general temporal patterns for visualization. Second, with large time-dependent data sets, as typical with today's large-scale simulations, scalable and general solutions for handling the data are still not widely available. In this work, we have developed a textual pattern matching approach for specifying and identifying general temporal patterns. Besides defining the formalism of the language, we also provide a working implementation with sufficient efficiency and scalability to handle large data sets. Using recent large-scale simulation data from multiple application domains, we demonstrate that our visualization approach is one of the first to empower a concept driven exploration of large-scale time-varying multivariate data. | 18,988,998 |
Effective visualization of short routes. | In this work we develop a new alternative to conventional maps for visualization of relatively short paths as they are frequently encountered in hotels, resorts or museums. Our approach is based on a warped rendering of a 3D model of the environment such that the visualized path appears to be straight even though it may contain several junctions. This has the advantage that the beholder of the image gains a realistic impression of the surroundings along the way which makes it easy to retrace the route in practice. We give an intuitive method for generation of such images and present results from user studies undertaken to evaluate the benefit of the warped images for orientation in unknown environments. | 18,988,996 |
Sinus endoscopy--application of advanced GPU volume rendering for virtual endoscopy. | For difficult cases in endoscopic sinus surgery, a careful planning of the intervention is necessary. Due to the reduced field of view during the intervention, the surgeons have less information about the surrounding structures in the working area compared to open surgery. Virtual endoscopy enables the visualization of the operating field and additional information, such as risk structures (e.g., optical nerve and skull base) and target structures to be removed (e.g., mucosal swelling). The Sinus Endoscopy system provides the functional range of a virtual endoscopic system with special focus on a realistic representation. Furthermore, by using direct volume rendering, we avoid time-consuming segmentation steps for the use of individual patient datasets. However, the image quality of the endoscopic view can be adjusted in a way that a standard computer with a modern standard graphics card achieves interactive frame rates with low CPU utilization. Thereby, characteristics of the endoscopic view are systematically used for the optimization of the volume rendering speed. The system design was based on a careful analysis of the endoscopic sinus surgery and the resulting needs for computer support. As a small standalone application it can be instantly used for surgical planning and patient education. First results of a clinical evaluation with ENT surgeons were employed to fine-tune the user interface, in particular to reduce the number of controls by using appropriate default values wherever possible. The system was used for preoperative planning in 102 cases, provides useful information for intervention planning (e.g., anatomic variations of the Rec. Frontalis), and closely resembles the intraoperative situation. | 18,989,001 |
Predictors of operative mortality following primary coronary artery bypass surgery. | Although quality assessment of coronary artery patients can be done by 30 days risk-adjusted operative mortality, it is still insufficient to study the outcome after primary coronary artery bypass graft surgery (CABG). In our study, we attempted to determine the factors, which can help predict operative mortality before and after CABG. The study population consisted of 1000 prospective patients who underwent primary isolated CABG. Assessment was done by dividing the patients into two groups, i.e. non-survivors ( n= 12) and survivors ( n= 988). Data were analyzed using both univariate and multivariate models. On univariate analysis, recent acute myocardial infarction, intra-aortic balloon counterpulsation (IABC), left ventricular ejection fraction (LVEF) <25%, ventilator-associated pneumonia (VAP), tracheostomy, re-exploration, ventricular arrhythmias, low cardiac output (CO), multiple blood transfusions, post-operative renal dysfunction and longer intensive care unit and hospital stay were found as risk factors for mortality. Multivariate analysis showed that LVEF <25%,VAP, ventricular arrhythmias and low CO independently predicted mortality. Prior knowledge of these risk factors can help not only in predicting the outcome and the risks but also helps to plan the surgical and post-operative course of the patients to improve the morbidity and mortality. Our data suggest that operative mortality can be predicted prior to and after surgery considering factors such as LVEF, use of IABC, onset of ventricular arrhythmias and low CO. | 18,989,059 |
A novel cadmium(II) coordination polymer with a four-connected (4,4)-net based on a trinuclear cadmium(II) node. | In the title cadmium(II) coordination polymer, poly[tri-mu(4)-adipato-bis(2-phenyl-1H-1,3,7,8-tetraazacyclopenta[l]phenanthrene-kappa(2)N(7),N(8))tricadmium(II)], [Cd(3)(C(6)H(8)O(4))(3)(C(19)H(12)N(4))(2)](n), one of the Cd atoms is in a distorted pentagonal bipyramidal coordination environment, surrounded by five O atoms from three adipate (adip) ligands and two N atoms from one 2-phenyl-1H-1,3,7,8-tetraazacyclopenta[l]phenanthrene (L) ligand. A second Cd atom occupies an inversion center and is coordinated by six O atoms from six adip ligands in a distorted octahedral geometry. The carboxylate ends of the adip ligands link Cd(II) atoms to form unique trinuclear Cd(II) clusters, which are further bridged by the adip linkers to produce a two-dimensional layer structure. Topologically, each trinuclear Cd(II) cluster is connected to four others through six adip ligands, thus resulting in a unique two-dimensional four-connected framework of (4,4)-topology. This work may help the development of the coordination chemistry of 1,10-phenanthroline derivatives. | 18,989,077 |
Technologies for transporter drug discovery. | Transporters represent attractive targets for drug discovery and are implicated in the pathophysiology of disorders across several therapeutic areas including asthma, cardiovascular disease, diabetes and neuroscience. However, the intrinsic mechanistic properties of transporters present significant challenges to the development of high-throughput screening methodologies. This review provides an update on potential transporter targets and evaluates the impact of available technologies to enable transporter screening, lead optimization and assessment of pharmacokinetics. | 18,989,100 |
New approaches to the treatment of frontotemporal lobar degeneration. | Treatment approaches for frontotemporal lobar degeneration (FTLD) are rapidly evolving with improved understanding of the disease. This brief review highlights recent advances. Early-onset dementia has a devastating impact on families and rids its victims of their most productive and rewarding years. Over the past 10 years, FTLD has emerged as the commonest cause of dementia under the age of 60 years, outstripping even Alzheimer's disease in prevalence. Remarkable progress has occurred in our understanding of FTLD both as a set of distinctive clinical syndromes and as a set of disorders with unique genetic and pathological profiles. Although there are no Food and Drug Administration-approved medications for FTLD, new evidence of specific genetic and neurochemical defects is beginning to provide a strong rationale for pharmacological treatment. Behavioral changes, which are common in behavioral variant frontotemporal dementia and semantic dementia, often respond to treatment with selective serotonin reuptake inhibitors. Memantine also holds promise to treat neuropsychiatric symptoms, but more prospective trials are needed.With better understanding of pathogenic molecular pathways involving microtubule-associated protein tau, progranulin and TDP-43, potential disease-modifying therapies are being studied in animal models and approaching human trials. | 18,989,117 |
What is the place of bevacizumab and irinotecan in the treatment of glioblastoma and other malignant gliomas? | To critically assess the role of irinotecan (Camptosar, CPT-11) and bevacizumab (Avastin) as a new treatment for glioblastoma and other malignant gliomas (anaplastic forms of astrocytomas and oligodendrogliomas). Two prospective phase II trials of bevacizumab and irinotecan have been reported. The observed high response rates (30-60%) had never been seen in this disease before. Gains in progression-free survival and overall survival (OS) were less impressive (6-month progression-free survival 30-50%; median OS: 9-10 months), but are still superior to historical controls. Bevacizumab is a welcome new weapon in the treatment of malignant gliomas and should be favored as a salvage treatment over cytotoxic chemotherapy for recurrent disease. However, survival results remain far from satisfactory. Once failure to treatment with bevacizumab is diagnosed by conventional radiographic methods, most patients experience rapid deterioration and die shortly afterward. New methods and radiographic criteria for detecting disease progression are needed. Patients willing to explore new treatment strategies through participation in clinical trials should do so prior to starting bevacizumab, as this may not be an option once treatment fails. Cost-effectiveness of bevacizumab in gliomas deserves further investigation. The role of irinotecan in this combination remains unclear. At this time, bevacizumab should only be used in newly diagnosed malignant gliomas in the setting of a clinical trial. | 18,989,118 |
Hormone replacement therapy post Women's Health Initiative study: where do we stand? | The aim of this review is to look at all publications from the past 18 months, which deal with the impact of the Women's Health Initiative Trial on hormone replacement therapy. There is a definite decline in the use of hormone replacement therapy among menopausal women. More research needs to be done on the long-term effects of hormone replacement therapy, especially with regard to ultra-low dose hormone therapy. | 18,989,125 |
Thromboembolism in pregnancy: recurrence risks, prevention and management. | The purpose of this review is to summarize the epidemiology of thromboembolism in pregnancy and describe strategies to prevent and treat it. The main reason for the increased risk of thrombosis in pregnancy is hypercoagulability. Other risk factors include a history of thrombosis, inherited and acquired thrombophilia, certain medical conditions, and complications of pregnancy and childbirth. The hypercoagulability of pregnancy is present as early as the first trimester and so is the increased risk of thrombosis. Candidates for anticoagulation are women with a current thrombosis, a history of thrombosis, thrombophilia and a history of poor pregnancy outcome, or risk factors for postpartum thrombosis. For fetal reasons, the preferred agents for anticoagulation in pregnancy are heparins. There are no large trials of anticoagulants in pregnancy and recommendations are based on case series and the opinion of experts. Nonetheless, anticoagulants are believed to improve the outcome of pregnancy for women and their fetuses. | 18,989,130 |
Oesophageal bolus transit and clearance by secondary peristalsis in normal individuals. | Secondary peristalsis is important for the clearance of retained refluxate or material from the oesophagus. Combined impedance and manometry can directly detect both oesophageal contraction and bolus transit. To apply combined impedance and manometry to characterize oesophageal bolus transit and clearance by secondary peristalsis in healthy individuals. Eleven healthy volunteers underwent combined impedance and manometry with a catheter containing seven impedance-measuring segments and eight water-perfusion pressure transducers. Saline and solid agar boluses of 5 ml were applied for primary peristalsis and secondary peristalsis was stimulated by rapid mid-oesophageal injections of saline. The rate for complete bolus clearance of secondary peristalsis with saline injections was less than that of primary peristalsis with saline swallows (69 vs. 95%, P=0.02). No statistical difference in bolus propagation time between primary and secondary peristalsis was observed (P=0.45). Bolus presence time of secondary peristalsis was significantly longer than that of primary peristalsis for all impedance-measuring segments (all P<0.05). Solid swallows differed from saline swallows with lower rate of complete bolus transit and longer bolus transit time. Our data show that the impedance technique can successfully characterize oesophageal bolus transit and clearance by secondary peristalsis. These findings suggest that secondary peristalsis may be less effective than primary peristalsis regarding oesophageal transit and clearance of a liquid bolus. | 18,989,139 |
Antimicrobial host defense in the upper gastrointestinal tract. | With the exception of fungi, microbial infections are rare in the oesophagus. Herein, we aimed to systematically assess the distribution and quantity of different antimicrobial host factors as well as, for the first time, functional mucosal antimicrobial activity in the upper gastrointestinal tract. We investigated biopsies from the healthy oesophagus, three different locations in the stomach and the duodenum in a total of 12 individuals. Using real-time PCR with external standards, we compared absolute expression of mRNA encoding antimicrobial peptides including defensins, cathelicidin, bactericidal/permeability-increasing protein, psoriasin, and elafin. In addition, we performed immunostaining for human-beta-defensin-1 (HBD1), elafin, and psoriasin. To test functional relevance, we assessed antimicrobial as well as antifungal activity of cationic extracts from biopsies against E. coli ATCC 25922 and a clinical isolate of Candida albicans. In contrast to HBD1 which was similarly expressed in all tissues, inducible beta-defensins in the healthy oesophagus were much higher compared with the stomach and duodenum (for HBD2-4: P<0.01). In addition, the antiproteases elafin and psoriasin were also predominantly expressed in the oesophagus (P<0.005). In contrast, LL-37 and bactericidal/permeability-increasing protein were only marginally expressed. Cationic tissue extracts from both the oesophagus as well as the stomach showed potent antibacterial activity against E. coli. Consistent with susceptibility to Candida infection, the esophageal extracts exhibited a weaker activity against C. albicans (P=0.026). Despite dominant expression of antimicrobial host peptides, oesophageal tissue shows a weakened potency to kill C. albicans. These data suggest an important role of yet unknown antimicrobial molecules. | 18,989,140 |
Acute lymphoblastic leukemia in a patient with Miller-Dieker syndrome. | A 15-month-old girl with Miller-Dieker syndrome, a contiguous gene deletion syndrome involving chromosome 17p13.3 and resulting in lissencephaly, was diagnosed with precursor B-cell acute lymphoblastic leukemia. Cytogenetic analysis identified both the previously detected 17p13.3 deletion and additional complex numerical and structural abnormalities, including loss of chromosome 9, isochromosome 9q and interstitial deletion of 20q. This is, to our knowledge, the first report of acute leukemia in the setting of Miller-Dieker syndrome. Herein we review the literature regarding Miller-Dieker syndrome, with particular attention to the presence of several candidate tumor suppressor genes within the deleted material. | 18,989,166 |
CD4+ T-cell count monitoring does not accurately identify HIV-infected adults with virologic failure receiving antiretroviral therapy. | CD4 T-lymphocyte (CD4) counts are widely used to monitor response to antiretroviral therapy (ART) in resource-limited settings. However, the utility of such monitoring in terms of predicting virologic response to therapy has been little studied. We studied participants aged 18 years and older who initiated ART in Tororo, Uganda. CD4 counts, CD4 percentages, and viral load (VL) were examined at 6-monthly intervals. Various definitions of immunologic failure were examined to identify individuals with VLs>or=50, >or=500, >or=1000, or >or=5000 copies per milliliter at 6, 12, and 18 months after treatment initiation. One thousand sixty-three ART-naive persons initiated ART. The proportion of individuals with virologic failure ranged between 1.5% and 16.4% for each time point. The proportion with no increase in CD4 count from baseline did not differ between those with suppressed or unsuppressed VLs at 6, 18, and 24 months after ART initiation. No increase in CD4 cell counts at 6 months had a sensitivity of 0.04 [95% confidence interval (CI) 0.00 to 0.10] and a positive predictive value of 0.03 (95% CI 0.00 to 0.09) for identifying individuals with VL>or=500 copies per milliliter at 6 months. The best measure identified was an absolute CD4 cell count<125 cells per microliter at 21 months for predicting VL>or=500 copies per milliliter at 18 months which had a sensitivity of 0.13 (95% CI 0.01 to 0.21) and a positive predictive value of 0.29 (95% CI 0.10 to 0.44). CD4 cell count monitoring does not accurately identify individuals with virologic failure among patients taking ART. | 18,989,232 |
The relationship between obesity and blood pressure differs by ethnicity in Sydney school children. | The objective of this study was to investigate the relationship between obesity and high systolic blood pressure (SBP) in Southeast Asian (SEAsian) and Australian children living in Australia. SBP, country of birth, and obesity indices (body mass index (BMI), waist circumference (WC), and percent body fat (%TBF)) were recorded in 1,232 9-year-old children from Sydney schools and remeasured 3 years later (n = 628). The relationship between SBP and obesity (both at baseline and longitudinally) was investigated by regression analyses. Children of SEAsian origin had a significantly higher risk of high SBP with increases in obesity indices compared to those of Australian origin. At 9 years old, SBP increased 1.51 mm Hg for each of BMI increase for SEAsian children compared to 1.05 mm Hg for Australian children (P(interaction) = 0.03). These same significant analysis of variance (ANOVA) interactions were seen with WC (P(interaction) = 0.02) and %TBF (P(interaction) = 0.04) as predictors of SBP. These differences by ethnic background were also reflected in the 3-year longitudinal analysis where SEAsian children showed higher risk of increasing SBP with BMI increase (SBP increased 1.70 mm Hg for each unit of BMI increase for SEAsian children compared to 0.80 mm Hg for Australian children (P(interaction) = 0.02)) or with WC increase (P(interaction) = 0.01), whereas these increases were small and nonsignificant in Australian children. These findings suggest that SEAsian children living in Australia are at higher risk of increasing SBP than their Australian counterparts when they become overweight or obese. | 18,989,256 |
Sustained moderate visual loss as a predictive end point for visual loss in non-proliferative diabetic retinopathy. | In PKC-DRS2, the efficacy of the oral PKC-beta inhibitor, ruboxistaurin 32 mg/day, was measured by the primary end point of sustained moderate visual loss (SMVL: a > or = 15 letter decrease from baseline on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart sustained at least for the last 6 months of study participation). We now evaluate whether SMVL is more accurate than moderate visual loss (MVL: a single occurrence of a decrease from baseline of > or = 15 ETDRS letters) for predicting future visual loss. Study eyes with moderately severe to very-severe non-proliferative diabetic retinopathy, best-corrected visual acuity of at least 45 letters on the ETDRS chart (approximately Snellen 20/125), and no prior pan retinal photocoagulation were evaluated in 506 patients (869 eyes) who completed 36 months of treatment. Sixty-five percentage (26/40) of study eyes with the onset of SMVL within 24 months of enrolment still had SMVL at study completion (36 months). In comparison, only 24% (30/126) with MVL within 24 months had SMVL at study completion. Analyses based on data from 6, 12, and 18 months of treatment were similar. SMVL is a more predictable measure of subsequent visual loss than is a single time point measure of MVL. | 18,989,348 |
Privilege revisited: an evaluation of the eye's defence mechanisms. | Immune privilege has been considered for many years to be an interesting phenomenon associated with certain specialised tissues such as the eye and the brain. In recent years however, it has become clear that the active and passive mechanisms which underpin immune privilege are in fact a form of tissue-based immunological tolerance, perhaps of equal importance in providing defence against antigenic attack as the well established mechanisms based on the thymus (central tolerance) and circulating regulatory cells (peripheral tolerance). It would appear that each tissue possesses a degree of intrinsic immunological resistance which varies depending on the tissues and provides some degree of protection. In some tissues, such as the eye, this is protection from 'danger' has been developed to a high level of sophistication, but at a price. The mechanisms involved are presented in his lecture. | 18,989,350 |
A precise Bicoid gradient is nonessential during cycles 11-13 for precise patterning in the Drosophila blastoderm. | During development, embryos decode maternal morphogen inputs into highly precise zygotic gene expression. The discovery of the morphogen Bicoid and its profound effect on developmental programming in the Drosophila embryo has been a cornerstone in understanding the decoding of maternal inputs. Bicoid has been described as a classical morphogen that forms a concentration gradient along the antero-posterior axis of the embryo by diffusion and initiates expression of target genes in a concentration-dependent manner in the syncytial blastoderm. Recent work has emphasized the stability of the Bicoid gradient as a function of egg length and the role of nuclear dynamics in maintaining the Bicoid gradient. Bicoid and nuclear dynamics were observed but not modulated under the ideal conditions used previously. Therefore, it has not been tested explicitly whether a temporally stable Bicoid gradient prior to cellularization is required for precise patterning. Here, we modulate both nuclear dynamics and the Bicoid gradient using laminar flows of different temperature in a microfluidic device to determine if stability of the Bicoid gradient prior to cellularization is essential for precise patterning. Dramatic motion of both cytoplasm and nuclei was observed prior to cellularization, and the Bicoid gradient was disrupted by nuclear motion and was highly abnormal as a function of egg length. Despite an abnormal Bicoid gradient during cycles 11-13, Even-skipped patterning in these embryos remained precise. These results indicate that the stability of the Bicoid gradient as a function of egg length is nonessential during syncytial blastoderm stages. Further, presumably no gradient formed by simple diffusion on the scale of egg length could be responsible for the robust antero-posterior patterning observed, as severe cytoplasmic and nuclear motion would disrupt such a gradient. Additional mechanisms for how the embryo could sense its dimensions and interpret the Bicoid gradient are discussed. | 18,989,373 |
A model of brain circulation and metabolism: NIRS signal changes during physiological challenges. | We construct a model of brain circulation and energy metabolism. The model is designed to explain experimental data and predict the response of the circulation and metabolism to a variety of stimuli, in particular, changes in arterial blood pressure, CO(2) levels, O(2) levels, and functional activation. Significant model outputs are predictions about blood flow, metabolic rate, and quantities measurable noninvasively using near-infrared spectroscopy (NIRS), including cerebral blood volume and oxygenation and the redox state of the Cu(A) centre in cytochrome c oxidase. These quantities are now frequently measured in clinical settings; however the relationship between the measurements and the underlying physiological events is in general complex. We anticipate that the model will play an important role in helping to understand the NIRS signals, in particular, the cytochrome signal, which has been hard to interpret. A range of model simulations are presented, and model outputs are compared to published data obtained from both in vivo and in vitro settings. The comparisons are encouraging, showing that the model is able to reproduce observed behaviour in response to various stimuli. | 18,989,392 |
Genome-wide analysis of human disease alleles reveals that their locations are correlated in paralogous proteins. | The millions of mutations and polymorphisms that occur in human populations are potential predictors of disease, of our reactions to drugs, of predisposition to microbial infections, and of age-related conditions such as impaired brain and cardiovascular functions. However, predicting the phenotypic consequences and eventual clinical significance of a sequence variant is not an easy task. Computational approaches have found perturbation of conserved amino acids to be a useful criterion for identifying variants likely to have phenotypic consequences. To our knowledge, however, no study to date has explored the potential of variants that occur at homologous positions within paralogous human proteins as a means of identifying polymorphisms with likely phenotypic consequences. In order to investigate the potential of this approach, we have assembled a unique collection of known disease-causing variants from OMIM and the Human Genome Mutation Database (HGMD) and used them to identify and characterize pairs of sequence variants that occur at homologous positions within paralogous human proteins. Our analyses demonstrate that the locations of variants are correlated in paralogous proteins. Moreover, if one member of a variant-pair is disease-causing, its partner is likely to be disease-causing as well. Thus, information about variant-pairs can be used to identify potentially disease-causing variants, extend existing procedures for polymorphism prioritization, and provide a suite of candidates for further diagnostic and therapeutic purposes. | 18,989,397 |
Isolation of mononuclear cells from the central nervous system of rats with EAE. | Whether studying an autoimmune disease directed to the central nervous system (CNS), such as experimental autoimmune encephalomyelitis (EAE, 1), or the immune response to an infection of the CNS, such as poliomyelitis, Lyme neuroborreliosis, or neurosyphilis, it is often necessary to isolate the CNS-infiltrating immune cells.In this video-protocol we demonstrate how to isolate mononuclear cells (MNCs) from the CNS of a rat with EAE. The first step of this procedure requires a cardiac perfusion of the rodent with a saline solution to ensure that no blood remains in the blood vessels irrigating the CNS. Any blood contamination will artificially increase the number of apparent CNS-infiltrating MNCs and may alter the apparent composition of the immune infiltrate. We then demonstrate how to remove the brain and spinal cord of the rat for subsequent dilaceration to prepare a single-cell suspension. This suspension is separated on a two-layer Percoll gradient to isolate the MNCs. After washing, these cells are then ready to undergo any required procedure. Mononuclear cells isolated using this procedure are viable and can be used for electrophysiology, flow cytometry (FACS), or biochemistry. If the technique is performed under sterile conditions (using sterile instruments in a tissue culture hood) the cells can also be grown in tissue culture medium. A given cell population can be further purified using either magnetic separation procedures or a FACS. | 18,989,401 |
A sterol-regulatory element binding protein is required for cell polarity, hypoxia adaptation, azole drug resistance, and virulence in Aspergillus fumigatus. | At the site of microbial infections, the significant influx of immune effector cells and the necrosis of tissue by the invading pathogen generate hypoxic microenvironments in which both the pathogen and host cells must survive. Currently, whether hypoxia adaptation is an important virulence attribute of opportunistic pathogenic molds is unknown. Here we report the characterization of a sterol-regulatory element binding protein, SrbA, in the opportunistic pathogenic mold, Aspergillus fumigatus. Loss of SrbA results in a mutant strain of the fungus that is incapable of growth in a hypoxic environment and consequently incapable of causing disease in two distinct murine models of invasive pulmonary aspergillosis (IPA). Transcriptional profiling revealed 87 genes that are affected by loss of SrbA function. Annotation of these genes implicated SrbA in maintaining sterol biosynthesis and hyphal morphology. Further examination of the SrbA null mutant consequently revealed that SrbA plays a critical role in ergosterol biosynthesis, resistance to the azole class of antifungal drugs, and in maintenance of cell polarity in A. fumigatus. Significantly, the SrbA null mutant was highly susceptible to fluconazole and voriconazole. Thus, these findings present a new function of SREBP proteins in filamentous fungi, and demonstrate for the first time that hypoxia adaptation is likely an important virulence attribute of pathogenic molds. | 18,989,462 |
Induction of ICAM-1 and VCAM-1 on the mouse lingual lymphatic endothelium with TNF-alpha. | This study investigated the TNF-alpha-induced ICAM-1 and VCAM-1 expression on mouse lingual lymphatic vessels. All podoplanin-positive lymphatic vessels expressed PECAM-1. In the lamina propria mucosae of TNF-alpha-treated tongue, almost all initial lymphatics expressed ICAM-1. There were initial lymphatics with the VCAM-1 expression and also the vessels without the expression. In the tunica muscularis of TNF-alpha-treated tongue, collecting lymphatic vessels expressed ICAM-1, but rarely expressed VCAM-1 whereas blood vessels simultaneously expressed ICAM-1 and VCAM-1. The ICAM-1-positive rate increased with TNF-alpha to 75% from 10% on initial lymphatics, and to 40% from 0% on collecting lymphatic vessels while it increased to 90% from 45% on blood vessels. The VCAM-1-positive rate increased with TNF-alpha to 30% from 0% on initial lymphatics, and to 5% from 0% on collecting lymphatic vessels while it increased to 75% from 5% on blood vessels. These findings suggest that the lingual lymphatic endothelium has the ability to express ICAM-1, and VCAM-1 to a lesser extent than the ICAM-1 induction with TNF-alpha, and that the ICAM-1 and VCAM-1 induction predominantly occurs in the initial lymphatics compared with collecting lymphatic vessels. | 18,989,464 |
Photochemical cooperativity in photosystem II. Characterization of oxygen evolution discontinuities in the light-response curves. | In two previous papers (Fragata et al., J. Phys. Chem. B, 2005, 109, 14707-14714; Fragata et al., J. Phys. Chem. B, 2007, 111, 3315-3320), it was shown that the variation of oxygen evolution with the light intensity (I) in photosystem II (PSII) in steady state conditions can be formulated according to the Langmuir adsorption isotherm for heterogeneous catalysis. This yielded the expression OEth = OEth(max) I/(L1/2 + I), where OEth is the theoretical oxygen evolution, OEth(max) the maximum oxygen evolution, and L1/2 the irradiance giving OEth(max)/2. In this approximation, the photons interaction with the chlorophylls in the PSII reaction center is assumed to be a heterogeneous reaction in which the light is represented as a stream of particles instead of an electromagnetic wave. That is, the chlorophyll molecules are the adsorption surfaces (or heterogeneous catalysts), and the incident (or exciting) photons are the substrate, or the reagent. Recently, the examination of new experimental data obtained with 2,6-dichloro-p-benzoquinone (DCBQ) and p-benzoquinone (pBQ) as exogenous electron acceptors, disclosed the presence of oxygen evolution discontinuities (or transitions) in the light-response curves. The new data were fitted with a mathematical summation of hyperbola of order n(i) > 1, OEth = Sigma(i) [OEth(max)]iIn(i)/[(L1/2)i(n(i)) + I(n(i))], where the n(i)'s are the number of sites used by the incident photons in their interaction with the photosynthetic pigments in each population i of PSII centers open for photochemistry. The mathematical simulations yielded only three distinct n(i)'s, that is, 1.8, 4.8, 8.5 and 1.8, 4.2, 8.4 for isolated PSII particles incubated with DCBQ and pBQ, respectively. Implicitly, this means the simultaneous excitation of each PSII reaction center with more than one photon, that is, the excitation of more than one pigment molecule. It is suggested that these transitions have their origin in the cooperative interaction of the photons and the chlorophylls, and most likely also the pheophytins. This indicates that the discontinuities (or transitions) observed in the light-response curves of oxygen evolution are consistent with the hypothesis of photochemical cooperativity in photosystem II. | 18,989,471 |
Mental health professionals' perceived barriers and benefits, and personal concerns in relation to psychiatric research. | Mental health professionals can contribute to generating a strong evidence base for policy and practice in psychiatry. An insight into their perception of psychiatric research is important for planning support strategies. This study explored healthcare professionals' perceptions of barriers, benefits and concerns about psychiatric research in a Singapore psychiatric hospital. Self-administered questionnaire was employed to collect socio-demographic data and opinions on research. Likert scale was used for the responses and descriptive statistics and ordinal regression were used for data analysing. 93.8% respondents perceived "contribution to medical knowledge/public health" to be a major benefit of conducting research. 86.7% respondents felt that "learning experience" was important. "Prestige/publication" (52.7%) and "financial gain" (76%) were perceived to be unimportant. "Clinical load of patients", "lack of skilled personnel to assist in research" and "insufficient funding" were identified as important barriers by 72.4%, 70.6% and 68.9% respondents. "Time constraints", "patient and family readiness to research participation", "insufficient training" and "concerns about patient welfare" are major concerns while conducting research. To the study team's best knowledge, this is the only study of mental health professionals' perceptions on psychiatric research. It is useful for strategising research planning and enhancing the research culture in the hospital. | 18,989,488 |
Evidence-based medicine (EBM) for undergraduate medical students. | Teaching evidence-based medicine (EBM) to practitioners and residents will improve their performance. There is insufficient evidence regarding the teaching of EBM in undergraduate medical education. We aimed to determine whether an EBM workshop would improve undergraduate medical student's ability to form clinical questions and search databases, as well as their attitudes towards EBM. This was a quasi-experimental study on fifth- and sixth-year medical students of Isfahan University of Medical Sciences. In a 4- day workshop, students learned and practised how to form clinical questions, perform literature searches and carry out critical appraisals. We assessed the student's ability to form a clinical question and their performance in searching and identifying the best clinical literature to answer the question, before and after the workshop. Students' attitudes were assessed using the Likert scale 15-item questionnaire on the last day of the workshop. Wilcoxon signed ranks test was performed to compare pre- and post-tests. The workshop increased students' scores in developing clinical questions (P = 0.004, mean rank = 14) and search skills (P <0.001, mean rank = 12.50). It also improved students' attitudes towards EBM [mean = 3.76, (standared deviation = 0.7)]. The course allowed students (79.2%) to appreciate the need for EBM education for medical students. The students also commented that the course showed them the importance of EBM knowledge in effective clinical performance. EBM workshop for undergraduate medical students increased their ability to form clinical questions and carry out appropriate literature searches. It also improved their attitudes towards learning and applying EBM. | 18,989,493 |
Comparison of the two-year outcomes and costs of prophylaxis in medical patients at risk of venous thromboembolism. | A decision-analytic model incorporating a Markov process to assess the incremental cost and effectiveness of venous thromboembolism (VTE) prevention strategies was used. Modeling was carried out using a hypothetical cohort of medical patients at risk of VTE. The model compared clinical effectiveness (primary and recurrent VTE, death), safety (adverse events), and direct medical costs between patients receiving enoxaparin prophylaxis, unfractionated heparin (UFH) prophylaxis, and no prophylaxis (n = 10,000 for each arm). Monte Carlo simulation was performed to identify changes in inputs that would affect the results. The estimated incidence ofVTE at two years (including recurrent VTE) was 6.8% with enoxaparin prophylaxis, 7.9% with UFH prophylaxis, and 17.9% with no prophylaxis. Two-year mortality occurred in 15.7% of enoxaparin patients and 16.0% of UFH patients, with the incidences of major bleeding in these groups being 0.7% and 1.2%, respectively. However, both enoxaparin and UFH prophylaxis were associated with higher rates of major bleeds than no prophylaxis (0.6%). Total average costs per patient were (US dollars) $1,264 (for enoxaparin prophylaxis, $1,585 for UFH prophylaxis, and $2,245 for no prophylaxis). No realistic parameter changes resulted in enoxaparin prophylaxis being more costly than UFH prophylaxis. For the healthcare payer, considering all direct medical costs associated with VTE up to two years after an admission for acute illness, prophylaxis with enoxaparin was more effective and less costly than UFH. This identifies enoxaparin as a potentially favorable VTE prophylaxis regimen compared with UFH and no prophylaxis in at-risk medical patients. | 18,989,525 |
The INSIG1 gene, not the INSIG2 gene, associated with coronary heart disease: tagSNPs and haplotype-based association study. The Beijing Atherosclerosis Study. | Dyslipidemia, especially hypercholesterolemia, is a major risk factor of coronary heart disease (CHD). The insulin induced gene 1 (INSIG1) and insulin induced gene 2 (INSIG2) encode two proteins which mediate feedback control of cholesterol synthesis. We conducted a case-control study to investigate whether the common variants in INSIG genes were associated with CHD in Chinese Han population. Three single nucleotide polymorphisms (SNPs) of the INSIG1 gene and four SNPs of the INSIG2 gene were chosen as haplotype-tagging SNPs (htSNPs) and genotyped in 853 patients with CHD and 948 unrelated control subjects. Haplotype analysis showed that the haplotype Hap4 (TTA) of the INSIG1 gene significantly increased the risk of CHD (adjusted odds ratio [OR]1.59, 95% confidence interval [CI] 1.22-2.06, p = 0.0006), while the haplotype Hap3 (TGA) significantly decreased the risk of CHD (adjusted OR 0.74, 95%CI 0.60-0.92, p = 0.006) compared with the reference haplotype Hap1 (GGA). No significant associations were found between polymorphisms of INSIG2 gene and CHD. In addition, the single polymorphism analysis showed that rs9769826 of the INSIG1 gene was associated with glucose in controls. The G-allele (minor allele) carriers had higher glucose level (5.74 +/- 2.03 mM) than AA genotype carriers (5.45 +/- 1.37 mM, p = 0.015). The present study indicated that the INSIG1 gene, but not the INSIG2 gene, was associated with CHD in the Chinese population. | 18,989,534 |
Expression, purification and mass spectrometric analysis of LIM mineralization protein-1 in human lung epithelial cells. | LIM mineralization protein-1 (LMP-1) is a novel osteoinductive protein that has been cloned and shown to induce bone formation both in vitro and in vivo. Detection and evaluation of the possible presence of carbohydrate structures in LMP-1 is an important regulatory consideration for the therapeutic use of recombinantly expressed protein. The sequence of LMP-1 contains a highly conserved N-terminal PDZ domain and three C-terminal LIM domains. The sequence analysis of LMP-1 predicts two potential N-glycosylation sites and several O-glycosylation sites. Here, we report the cloning and overexpression of LMP-1 in human lung carcinoma (A549) cells. Even though our group already reported the sequence of LMP-1 cDNA, we undertook this work to clarify whether or not the overexpressed protein undergoes any glycosylation in vivo. The expressed full-length recombinant protein was purified and subjected to chemical analysis and internal sequencing. The absence of any hexosamines (N-acetyl glucosamine or N-acetyl galactosamine) in chemical composition analysis of LMP-1 protein revealed that there is little or no post-translational glycosylation of the LMP-1 polypeptide in lung carcinoma cells (A549). We performed in-gel trypsin digestion on purified LMP-1, and the resulting peptide digests were analyzed further using matrix-assisted laser desorption and ionization mass spectrometry for peptide mass finger printing, which produced several exact matches with the corresponding LMP-1 peptides. Separation by high performance liquid chromatography and purification of the desired peptides followed by N-terminal sequencing resulted in many exact LMP-1 matches for several purified peptides, thus establishing the identity of the purified protein as LMP-1. | 18,989,571 |
[Breast cancer and endothelial dysfunction]. | The main cause of death among Brazilian women is cardiovascular disease followed by cancer with breast cancer as the most incident. The relationship between cancer and thrombosis is well known, although its association with other cardiovascular events is poorly understood. In order to study these events from the earliest findings such as endothelial injury and dysfunction and the evolving atherosclerotic plaque, many methods are currently being used. Among these methods, E- and P-selectin and the von Willebrand factor have been associated, either with cardiovascular risk or with breast cancer growth and metastasis. Brachial artery flow-mediated dilatation is a tool available that emerged in the last decade due to its noninvasive nature and its clear association with endothelial dysfunction and cardiovascular risk. The aim of this revision is to bring the newest and most relevant updates about the association of breast cancer, endothelial injury and cardiovascular risk. | 18,989,570 |
The N-terminal cellulose-binding domain of EGXA increases thermal stability of xylanase and changes its specific activities on different substrates. | A full-length EGXA enzyme from a mollusk, Ampullaria crossean, was cloned into pFastBac vector and then heterogeneously expressed in insect Tn5 cells. Its natural N-terminal signal peptide worked well in the insect Tn5 cells. The recombinant EGXA was a 63 kDa protein and had active endo-beta-1,4-glucanase (EC 3.2.1.4) and endo-beta-1,4-xylanase (EC 3.2.1.8). The specific activity of endo-beta-1,4-xylanase was higher than in the EGX, which was purified from the stomach tissues of Ampullaria crossen. The N-terminal cellulose-binding domain of EGXA made it bind to cellulose and xylan more efficiently. This cellulose-binding domain also increased the thermal stability of this recombinant enzyme and decreased the recombinant EGXA's specific activities on p-nitrophenyl-beta-D-cellobioside and sodium carboxymethyl cellulose. | 18,989,576 |
[Study on oral Candida albicans apoptosis in vitro]. | Candida albicans is one of the main opportunistic pathogen for human , the aim of this study is to investigate the phenomena of apoptosis in oral Candida albicans induced by acetic acid. The Candida albicans of clinical strains were induced to apoptosis by using a weak acid acetic acid.The apoptosis was detected by flow cytometry and TEM. The data were processed for Chi-square test using SPSS11.5 software package. Oral Candida albicans had classic apoptosis when induced by proper concentration of acetic acid, and different concentrations of acetic acid had variable ability of inducing apoptosis of Candida albicans. Apoptosis can be detected in clinical strains of Candida albicans, the mechanism of apoptosis needs further research for the purpose of developing new antifungal drugs. Supported by National Natural Science Foundation of China(Grant No.30400498) and 2007 National College Student Innovative Planning Project. | 18,989,590 |
[Construction of recombinant plasmid vector pIRES-CD and its expression in ACC-2 cells]. | To clone CD gene, construct its eukaryotic expression vector pIRES-CD and obtain positive ACC-2 cells expressing E.coli CD gene stably. PCR amplification was performed using primers based on E.coli CD gene sequence from Genebank, E.coli genomic DNA as template. PCR product was inserted into pMD18-T. After sequence confirmation, the gene was subcloned to pIRES to construct recombinant eukaryotic expression vector pIRES-CD. Then the combinant plasmid was conducted into ACC-2 cell by electroporation. ACC-2 cells stably expressing CD was obtained by 10-day positive selection with 400 mug/mL G418. Total RNA was extracted and the expression of the CD gene in transfected ACC-2 cells was identified by RT-PCR. PCR yielded a fragment of 1280bp and CD was verified by sequence analysis. A fragment of 6.1kb and inserted fragment of 1280bp were obtained by cutting positive recombinant plasmid of pIRES-CD with XbaI and NotI. RT-PCR analysis demonstrated that CD gene could be effectively expressed in ACC-2 cells. The CD gene is successfully amplified and the eukaryotic expression plasmid containing E.coli CD is successfully constructed.The positive ACC-2 cell clones expressing CD gene stably are obtained, which provide a basis for further study of adenoid cystic carcinoma gene therapy with CD/5-FC suicide gene system. Supported by Natural Science Foundation of Shandong Province(Grant No.Z2003C03). | 18,989,593 |
[Application of autologous bone fresh-frozen and re-implantation in treatment of cranio-maxillofacial bone tumors: report of 4 cases]. | To evaluate the application of autologous bone fresh-frozen and re-implantation in treatment of cranio-maxillofacial bone tumors. Four cases with cranio-maxillofacial bone tumors, including one in the frontal bone and three in the mandible, underwent osteoectomy, autologous diseased bone fresh-frozen by nitrogen, re-implantation of the bone and internal fixation by titanium plate to treat the bone tumor and reconstruct the bone defect. All four cases had one-stage healing 10-14 days after operation. One patient had pathological bone fracture 2 months postoperatively, the other three patients were well-cured without tumor recurrence and gained satisfied cosmetic appearance during 6 months to 3 years of follow-up. The X-ray films showed that the frozen bone was substituted by new bone formation. Autologous bone fresh-frozen and re-implantation is a feasible method in cranio-maxillofacial bone tumor treatment, especially for young patients. It make possible to do radical surgery and reconstruct the bone defect simultaneously, and is thus worthy of clinical application. | 18,989,601 |
[Clinical application of custom-made key-key attachment in the restoration of maxillofacial defect]. | To evaluate the usefulness of custom-made key-key attachment in restoration of maxillofacial defect. Using key-key attachment, facial prostheses and intraoral prostheses were combined to restore dentition, maxilla and right facial defects in a female patient. Good retention of maxillofacial prostheses and intraoral prostheses were obtained. The appearance of the patient was remarkably improved. The function of mastication was improved. Good result can be obtained by using custom-made key-key attachment in restoration of complex maxillofacial defect. Supported by Shanghai Leading Academic Discipline Project(Grant No.T0202). | 18,989,605 |
Functional characterization of tzn1 and tzn2-zinc transporter genes in Neurospora crassa. | Previous work from our laboratory involved the description of the Neurospora metal transportome, which included seven hypothetical zinc transporters belonging to the ZIP family. The aim of the present study was to make a comparative functional evaluation of two hypothetical zinc transporters named tzn1 (NCU07621.3) and tzn2 (NCU11414.3). Phenotypic analysis of tzn1 and tzn2 mutants and a double mutant (tzn1tzn2) revealed that the deletion of tzn1 causes aconidiation and a greater defect in growth than the single deletion of tzn2. Supplementation with zinc restores growth but not conidiation in tzn1 and tzn1tzn2. TZN1 complemented a zinc-uptake-deficient Saccharomyces cerevisiae mutant (zrt1zrt2) in zinc-deficient conditions, while tzn2 restored growth upon supplementation with zinc (0.05 mM). Furthermore, the Deltatzn1 mutant was found to have severely reduced zinc content indicating that tzn1 functions as a key regulator of intracellular zinc levels in Neurospora crassa. Zinc uptake studies indicate tzn1 is a specific transporter of zinc, while tzn2 transports both zinc and cadmium. Quantitative RT-PCR showed up-regulation of tzn1 (128-fold) under zinc-depleted conditions and down-regulation (>1,000-fold) in zinc-replete conditions. The present study indicates that the zinc transport proteins encoded by tzn1 and tzn2 are members of the zinc uptake system regulated by zinc status in N. crassa. | 18,989,627 |
Systemic PCD occurs in TMV-tomato interaction. | In hypersensitive response (HR), programmed cell death (PCD) is reported as a powerful defense mechanism in plant immune responses to pathogen. However, little is known about the PCD in systemic acquired resistance (SAR). Using tobacco mosaic virus (TMV) to infect the tomato (Lycopersicon esculentum cv. Jiafen 16) we found that localized TMV-infection could induce cell death in the uninoculated parts of the tomatoes, where the enzyme-linked immunosorbent assay (ELISA) showed no spreading virus. The biological and molecular characterization of this cell death was shown as following: chromatin condensed and formed peripheral conglomeration in nuclei; cell nucleus were TUNEL positive labeled; genomic DNA was fragmented and showed DNA laddering; mitochondria and chloroplast were disrupted; tonoplast and plasma membrane were shrunk and degradated. These results suggested that with an absence of TMV spread, the local TMV-infection on certain tomato leaves could induce systemic PCD in the root-tips, stem-apices and uninoculated leaves. The systemic PCD has various initiation and synchronization in such tissues and is distinct in inducement and exhibition from HR-PCD and SAR. | 18,989,644 |
[Sepsis-associated Guillain-Barré syndrome]. | This article reports on the case of a multiple trauma patient, who was admitted to the intensive care unit with haemorrhagic shock and severe hypoxaemia. Following posttraumatic septic shock the patient developed quadriplegia 3 weeks after admittance. After having excluded any traumatic and cerebral origins, an analysis of the cerebrospinal fluid was performed and revealed a"dissociation albuminocytologique". This finding in association with limb quadriplegia led to the diagnosis of Guillain-Barré syndrome. Therapy with high-dose i.v. immunoglobulins led to a complete recovery. | 18,989,649 |
Mapping and validation of quantitative trait loci for resistance to Cercospora zeae-maydis infection in tropical maize (Zea mays L.). | Breeding for resistance to gray leaf spot, caused by Cercospora zeae-maydis (Cz) is paramount for many maize environments, in particular under warm and humid growing conditions. In this study, we mapped and characterized quantitative trait loci (QTL) involved in the resistance of maize against Cz. We confirmed the impact of the QTL on disease severity using near-isogenic lines (NILs), and estimated their effects on three major agronomic traits using their respective near isogenic hybrids (NIHs), which we obtained by crossing the NILs with an inbred from a complementary heterotic pool. We further validated three of the four QTL that were mapped using the Multiple Interval Mapping approach and showed LOD values>2.5. NILs genotype included all combinations between favorable alleles of the two QTL located in chromosome 1 (Q1 in bin 1.05 and Q2 in bin 1.07), and the allele in chromosome 3 (Q3 in bin 3.07). Each of the three QTL separately significantly reduced the severity of Cz. However, we found an unfavorable epistatic interaction between Q1 and Q2: presence of the favorable allele at one of the QTL allele effectively nullified the effect of the favorable allele at the other. In contrast, the interaction between Q2 and Q3 was additive, promoting the reduction of the severity to a greater extent than the sum of their individual effects. When evaluating the NIH we found significant individual effects for Q1 and Q3 on gray leaf spot severity, for Q2 on stalk lodging and grain yield, and for Q3 on grain moisture and stalk lodging. We detected significant epitasis between Q1 and Q2 for grain moisture and between Q1 and Q3 for stalk lodging. These results suggest that the combination of QTL impacts the effectiveness of marker-assisted selection procedures in commercial product development programs. | 18,989,654 |
Rare occurrence of Hb Lepore-Baltimore in African Americans: molecular characteristics and variations of Hb Lepores. | Hb Lepore is the hybrid hemoglobin (Hb) composed of two alpha-globin chains and two deltabeta hybrid chains and is associated with the clinical findings of thalassemia minor in its heterozygous form. Hb Lepore can be found in many ethnic groups, commonly in southern European countries, but rarely in African Americans. The first Hb Lepore case in an African-American individual was named Hb Lepore-The Bronx (Hb Lepore-Boston). Hb Lepore-Washington-Boston and Hb Lepore-Baltimore with a breakpoint of (delta50Ser/beta86Ala) were later reported. In this paper, we describe an Hb Lepore-Baltimore (delta68Leu/beta84Thr) deltabeta-fusion gene with a different breakpoint detected for the first time in an African-American female. We have used state-of-the-art technology, combining protein- and DNA-based methods, in the analysis of the hybrid hemoglobin and discuss its molecular characteristics. | 18,989,669 |
Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter? | The purpose of this study was to determine the potential utility of alternative weight descriptors in the Cockcroft-Gault equation to more accurately predict carboplatin clearance in underweight, normal weight, overweight and obese patients. Clearance values obtained from individual fits using NONMEM were compared to predicted carboplatin clearances calculated using the modified Calvert formula in which creatinine clearance was calculated with the Cockcroft-Gault equation using diverse weight descriptors. This study indicated that lean body mass was the best weight descriptor in underweight and normal weight patients, while adjusted ideal body weight was the best weight descriptor in overweight and obese patients. However, a flat dose based on the population carboplatin clearance performed better in all weight categories than the use of the Cockcroft-Gault equation with diverse weight descriptors. These results suggest that in overweight and obese patients, with a normal renal function, a flat carboplatin dose should be administered, based on the population carboplatin clearance (8.38 l/h = 140 mL/min). Thus, in case an AUC of 5 mg min/mL is desired, the appropriate dose for carboplatin would be 5 x 140 = 700 mg. | 18,989,671 |
Size of ornament is negatively correlated with baseline corticosterone in males of a socially monogamous colonial seabird. | The Goymann-Wingfield model predicts that glucocorticoid levels in social animals reflect the costs of acquiring and maintaining social status. The crested auklet is one of the few avian colonial species where a mutual ornament in males and females is used in both sexual and aggressive displays. Previous studies of the crested auklet support the notion that the crest ornament is a badge of status in this species. Here, we examined the relationship between the crest ornament size and the adrenocortical function in breeding crested auklets. Crest length was negatively correlated with corticosterone at baseline in males, but not in females. Baseline corticosterone in females (but not in males) was negatively correlated with body condition index. Although male and female crested auklets are monomorphic in their ornamental traits, our results suggest that the socially mediated physiological costs associated with status signaling may differ between the sexes. | 18,989,678 |
Comparison of topical versus parenteral testosterone in children with microphallic hypospadias. | Surgical correction of genital defects was formerly proposed when the size of the penis was sufficient to permit easy surgical repair. To enlarge penile size, temporary stimulation with testosterone either topical or parenteral has been reported. Parenteral testosterone has been found to be effective; however, variable results have been reported with topical testosterone. This study was taken up as an attempt to compare the efficacy of parenteral versus topical testosterone application. Twenty-one consecutive children with microphallic hypospadias were randomized to receive either topical or parenteral testosterone prior to surgery. Penile length, glans circumference and secondary effects were recorded before and after therapy by the same observer. Significant penile growth was noticed in both the groups of children when compared with pre-therapy size. The desired therapeutic effect of significant penile growth following testosterone was achieved in both the groups of children. There was no significant difference between the two routes of administration. | 18,989,681 |
The role of angiotensin II type 1a receptor on intestinal epithelial cells following small bowel resection in a mouse model. | We have previously shown that inhibition of angiotensin converting enzyme (ACE) significantly reduced intestinal epithelial cell (EC) apoptosis and improved morphometric intestinal adaptation in a mouse model of massive small-bowel resection (SBR). This study attempted to further examine the downstream signaling factors in this system by blocking the action of angiotensin II (ATII), hypothesizing that this would lead to similar improvement of intestinal adaptation after SBR. Two groups of mice (C57BL/6J) underwent either a 60% mid-intestinal resection (SBR group) or a transection/re-anastomosis (Sham group). Because real-time PCR studies showed that only ATII receptor type 1a (ATII-1a) expression was significantly increased after SBR, compared to SHAM mice, we decided to use the specific ATII-1a receptor antagonist Losartan to block this signaling pathway. An additional two groups of mice received daily i.p. injections of Losartan (SBR + Losartan and Sham + Losartan group). At 7 days, the adaptive response was assessed in the remnant gut including villus height, crypt depth, EC apoptosis (TUNEL staining) and proliferation (BrdU incorporation). The apoptotic and proliferation signaling pathways were addressed by analysis of EC mRNA expression. SBR (with and without Losartan) led to a significant increase in villus height and crypt depth. Losartan treatment did not significantly change EC proliferation, but did significantly reduce EC apoptosis rates as compared to the non-treated SBR group. Losartan treatment was associated with a significant reduction of the bax-to-bcl-2 ratio and TNF-alpha expression after SBR compared to non-treated groups. Interestingly, Losartan-treated groups showed a tremendous increase in proliferation of signaling factors EGFR, KGFR and IL7R, which may indicate an expanded potential for further intestinal adaptation also beyond 7 days after SBR. This study showed that the ATII-1a receptor may be of crucial importance for the modulation of intestinal EC apoptosis, and for regulating the post-resectional EC adaptive response. | 18,989,682 |
Daptomycin in bone and joint infections: a review of the literature. | To review the pharmacology, pharmacokinetics, efficacy, and safety of daptomycin, a novel antibiotic for the treatment of bone and joint infections, a literature search of relevant articles was conducted. A PubMed/MEDLINE search (1990-April 2008) to identify relevant English-language literature was conducted. Search terms included bone and joint infection, osteomyelitis, daptomycin, and methicillin-resistant Staphylococcus aureus (MRSA). Additional articles were identified by reviewing the bibliographies of articles cited. Programs and abstracts from infectious disease meetings were searched, and prescribing information of antibiotics indicated for bone and joint infections consulted. All articles identified from data sources published in English were evaluated. Caused primarily by Gram-positive pathogens such as S. aureus and, to a lesser extent, Enterococcus faecalis, bone and joint infections are difficult to treat successfully. Surgical intervention and prolonged courses of antibiotics are frequently required, and failure of first-line antibiotic therapy is common. The emergence of S. aureus strains with reduced susceptibility to vancomycin, the longstanding gold standard for bone and joint infections, has complicated the clinical scenario. Few randomized trials comparing the efficacy of different antibiotics for bone and joint infections exist. Daptomycin, a novel intravenous lipopeptide antibiotic, has shown potent in vitro activity against a broad spectrum of Gram-positive bacteria, including many resistant pathogens commonly associated with bone and joint infections such as MRSA and vancomycin-resistant E. faecalis. Early clinical investigation of daptomycin in bone and joint infections unresponsive to antibiotics, such as vancomycin, has found a cure rate of approximately 80%, with a low incidence of adverse events and drug resistance. Further studies are warranted to determine if limited clinical evidence, described in individual case reports and a daptomycin-specific retrospective registry, suggests daptomycin is a promising option for patients with bone and joint infections such as MRSA osteomyelitis. | 18,989,686 |
Modulation of heart rate variability by estrogen in young women undergoing induction of ovulation. | Estrogens are involved in the modulation of the cardiovascular system, yet their effects in young women remains largely unknown. Women who undergo ovulation induction treatments attain extremely high estrogen concentrations during a very short time period. The aim of the present study was to evaluate the effects of an acute increase in estrogens on the autonomic nervous system modulation of heart rate variability (HRV). A total of 27 women undergoing ovulation induction and 14 normally menstruating women were prospectively studied. HRV was assessed during nadir and peak estrogen using time domain and power spectral density analyses. A significant increase in high-frequency spectral power (243 +/- 77 vs. 188 +/- 73 ms(2)/Hz, P < 0.01) with a significant decrease in the ratio of low to high-frequency power was observed during estrogen peak in women undergoing induction of ovulation. The acute increase in estrogen in women undergoing ovulation induction was associated with vagal activation and altered sympathovagal balance. | 18,989,692 |
Regulation of mitochondrial respiration by inorganic phosphate; comparing permeabilized muscle fibers and isolated mitochondria prepared from type-1 and type-2 rat skeletal muscle. | ADP is generally accepted as a key regulator of oxygen consumption both in isolated mitochondria and in permeabilized fibers from skeletal muscle. The present study explored inorganic phosphate in a similar regulatory role. Saponin permeabilized fibers and isolated mitochondria from type-I and type-II muscle from male Wistar rats were prepared. Respiration was measured while the medium P(i) concentration was gradually increased. The apparent K(m) values for P(i) were 607 +/- 17 microM and 405 +/- 15 microM (P < 0.0001) for type-I and type-II fibers, respectively. For isolated mitochondria the values were significantly lower than type-1 permeabilized fibers, 338 +/- 130 microM and 235 +/- 30 microM (P < 0.05), but not different with respect to fiber type. The reason for this difference in K(m) values in the permeabilized muscle is unknown, but a similar pattern has been observed for K(m) of ADP. Our data indicate that phosphate may play a role in regulation of oxygen consumption in vitro and in vivo. | 18,989,695 |
Active Ca(2+) reabsorption in the connecting tubule. | The kidney plays a crucial role in the maintenance of the body calcium (Ca(2+)) balance. Ca(2+) is an essential ion in all organisms and participates in a large variety of structural and functional processes. In mammals, active tubular Ca(2+) reabsorption is restricted to the distal part of the nephron, i.e., the late distal convoluted (DCT2) and the connecting tubules (CNT), where approximately 10-15% of the total Ca(2+) is reabsorbed. This active transcellular transport is hallmarked by the transient receptor potential vanilloid 5 (TRPV5) epithelial Ca(2+) channel, regulated by an array of events, and mediated by hormones, including 1,25-dihydroxyvitamin D(3), parathyroid hormone, and estrogen. Novel molecular mechanisms have been identified, such as the direct regulatory effects of klotho and tissue kallikrein on the abundance of TRPV5 at the apical membrane. The newly discovered mechanisms could provide potential pharmacological targets in the therapy of renal Ca(2+) wasting. This review discusses the three basic molecular steps of active Ca(2+) reabsorption in the DCT/CNT segments of the nephron, including apical entry, cytoplasmic transport, and basolateral extrusion of Ca(2+). In addition, an overview of the recently identified mechanisms governing this active Ca(2+) transport through the DCT2/CNT epithelial cells will be presented. | 18,989,697 |
Parasites, info-disruption, and the ecology of fear. | There is growing interest in the ecological consequences of fear, as evidenced by the numerous studies on the nonconsumptive, trait-mediated effects of predators. Parasitism, however, has yet to be fully integrated into research on the ecology of fear, despite it having direct negative and often lethal effects on hosts and being the most common life history strategy on the planet. This might at least be partly due to the traditional, but untested, assumption that anti-parasite responses are weak relative to anti-predator responses. To test this hypothesis, we quantified the activity and location responses of Bufo americanus tadpoles to one of six chemical cues: water; cercariae of Echinostoma trivolvis, a trematode which infects and can kill amphibians; a snail releasing E. trivolvis cercariae; an uninfected snail; food; or conspecific alarm chemicals signaling predation. There is also literature encouraging research on the context dependency and pollution-induced disruption of fear responses. Consequently, before quantifying responses to the chemical cues, half of the B. americanus were exposed to the herbicide atrazine (201 microg/l for 4 days), a reported inhibitor of fear responses in fish. Tadpoles were attracted to food, were indifferent to an uninfected snail, avoided alarm chemicals, and exhibited avoidance and elevated activity in response to a snail shedding cercariae and cercariae alone. Atrazine had no detectable effects on B. americanus' responses to the tested cues despite the use of a higher concentration and longer exposure duration than has been repeatedly shown to inhibit chemical cue detection in fish. The magnitude of anti-parasite and anti-predator responses were qualitatively similar, suggesting that the fear of disease and its ecological consequences could be comparable to that of predation. Consequently, we call for a greater integration of parasites into research on the ecology of fear and trait-mediated indirect effects. | 18,989,706 |
Co-metabolic degradation of dimethoate by Raoultella sp. X1. | A bacterium Raoultella sp. X1, based on its 16S rRNA gene sequence, was isolated. Characteristics regarding the bacterial morphology, physiology, and genetics were investigated with an electron microscopy and conventional microbiological techniques. Although the isolate grew and degraded dimethoate poorly when the chemical was used as a sole carbon and energy source, it was able to remove up to 75% of dimethoate via co-metabolism. With a response surface methodology, we optimized carbon, nitrogen and phosphorus concentrations of the media for dimethoate degradation. Raoultella sp. X1 has a potential to be a useful organism for dimethoate degradation and a model strain for studying this biological process at the molecular level. | 18,989,739 |
Interleukin13 haplotypes and susceptibility of Iranian women to breast cancer. | Interleukin-13 (IL-13) is a TH2 cytokine with direct and indirect immunoregulatory functions on cancer cells. The cytokine has been reported to have some polymorphic variations at the gene level associated with some immune related diseases including asthma and allergy. In the present study, association of three IL13 gene polymorphisms at positions -1512 A/C and -1055 C/T in the promoter and +2044 G/A in exon-4 was investigated in Iranian women with breast cancer and healthy controls. Genotyping of IL13 gene polymorphisms were performed by PCR-RFLP methods. Serum level of IL-13 was assessed by ELISA. Haplotypes were constructed from genotypic data using Arlequin 3.1 software package. Haplotype analysis revealed higher frequency of a three-locus haplotype, ACA (-1512A/-1055C/+2044A), in normal women than breast cancer patients (P < 0.025). Haplotype CCA, from the other hand, was observed with more frequency among patients than controls (P < 0.03). No statistically significant differences were found in the frequency of genotypes and alleles between patients and control group. No association was observed between investigated genotypes and other prognostic factors including tumor type, lymph node involvement and tumor size. IL-13 serum level was undetectable in both patients and control subjects. Despite observing no association between breast cancer and the single SNPs, results of this investigation suggest that the presence of CCA haplotype of IL13 gene may be associated with susceptibility of Iranian women to breast cancer. | 18,989,750 |
The method of single-nucleotide variations detection using capillary electrophoresis and molecular beacons. | We demonstrate that single-nucleotide variations in a DNA sequence can be detected using capillary electrophoresis (CE) and molecular beacons (MBs). In this method, the region surrounding the site of a nucleotide variation was amplified in a polymerase chain reaction, then hybridize PCR products with each of MBs. The sequences of the PCR products are different at the site of 2,044 in exon of interleukin (IL)-13 which to be identified. Through denaturation, the PCR product became single strand and hybridized with the completely complementary MB. The MB-target duplexes were separated using CE and solution-based fluorescence techniques. The results show that in each reaction a fluorescent response was elicited from the molecular beacon which was perfectly complementary to the amplified DNA, but not from the other MB whose probe sequence mismatched the target sequence. The method of CE based on MBs is able to identify single-nucleotide variations in a DNA sequence and can discriminate the genotyping of the SNP between the homo- and heteroduplexes of DNA fragments. | 18,989,751 |
Prevalence of celiac disease among patients with Behcet's disease in Iran. | Behcet's disease and Celiac disease, both common in Iran, share many immunopathogenic and clinical features. Based on the possible association between these two diseases, this study is designed to determine the frequency of non-diagnosed celiac disease in patients with Behcet's disease. The sera of 288 consecutive patients with Behcet's disease were screened with anti-endomysial antibody and anti-tissue transglutaminase antibody for celiac disease. Those with a positive test underwent upper gastrointestinal endoscopy and duodenal biopsies to confirm the diagnosis of celiac disease. The patients with celiac disease were put on a gluten free diet to evaluate its efficacy on the improvement of their lesions. Fourteen patients had positive anti-tissue transglutaminase antibody test (two with positive anti-endomysial antibody as well). Duodenal biopsies showed findings compatible with Marsh 3 in one and Marsh 1 in three other patients. All the diagnosed patients with celiac disease responded to the gluten free diet. Our findings didn't support any association between celiac disease and Behcet's disease in Iranian patients compared to the general population of Iran. | 18,989,774 |
Endoscopic retrograde cholangiopancreatography with single-balloon enteroscopy is feasible in patients with a prior Roux-en-Y anastomosis. | The purpose of this study is to describe the feasibility of using single-balloon enteroscopy (SBE) to perform endoscopic retrograde cholangiopancreatography (ERCP) in patients who had a prior Roux-en-Y (RY) anastomosis. This case series describes four patients, one with RY gastric bypass, two with RY due to bile duct injury, and one with RY after liver transplantation, who underwent ERCP with SBE. Cholangiography was successful in three of the four patients. In the procedure that was not successful, the enteroenterostomy site could not be located. The successful procedures ranged from 65-91 min in duration. Medication doses were higher than with typical ERCPs. No procedural complications occurred. SBE for ERCP is a feasible option for endoscopic access to the biliary tree in patients with prior RY anastomoses. Limitations of this technique include the time requirement, delay in identification of the enteroenterostomy site, potential learning curve, and immature technology lacking accessories. | 18,989,776 |
Expression of alkaline sphingomyelinase in yeast cells and anti-inflammatory effects of the expressed enzyme in a rat colitis model. | Alkaline sphingomyelinase (Alk-SMase) is a key enzyme in the intestinal tract for digestion of dietary sphingomyelin (SM), which generates lipid messengers with cell-cycle regulating effects. The enzyme is significantly decreased in ulcerative colitis and colon cancer. Based on this information, we wanted to investigate whether the enzyme had preventive effects against murine colitis. We report herein a method to express a biologically active Alk-SMase from Pichia pastoris yeast cells. By using the expressed enzyme to treat a rat colitis model induced by dextran sulfate sodium, we found that intrarectal instillation of Alk-SMase once daily for 1 week significantly reduced the inflammation score and protected the colonic epithelium from inflammatory destruction. We found a tendency for decreased tumor necrosis factor (TNF)-alpha expression in the Alk-SMase-treated group. This study, for the first time, provides a method to produce the enzyme and shows the potential applicability of the enzyme in the treatment of inflammatory bowel diseases. | 18,989,780 |
Formation of inhalable rifampicin-poly(L-lactide) microparticles by supercritical anti-solvent process. | Formation of inhalable microparticles containing rifampicin and poly(L-lactide) (L-PLA) by using supercritical anti-solvent process (SAS) was investigated. The solutions of drug and polymer in methylene chloride were sprayed into supercritical carbon dioxide. The effect of polymer content and operating conditions, temperature, pressure, carbon dioxide molar fraction, and concentration of solution, on product characteristics were studied. The prepared microparticles were characterized with respect to their morphology, particle size and size distribution, drug content, drug loading efficiency, and drug release characteristic. Discrete, spherical microparticles were obtained at high polymer:drug ratios of 7:3, 8:2, and 9:1. The shape of L-PLA microparticles became more irregular and agglomerated with decreasing polymer content. Microparticles with polymer content higher than 60% exhibited volumetric mean diameter less than 5 microm, but percent drug loading efficiency was relatively low. Drug-loaded microparticles containing 70% and 80% L-PLA showed a sustainable drug release property without initial burst release. Operating temperature level influenced on mean size and size distribution of microparticles. The operating pressure and carbon dioxide molar fraction in the range investigated were unlikely to have an effect on microparticle formation. An increasing concentration of feed solution provided larger size microparticles. Rifampicin-loaded L-PLA microparticles could be produced by SAS in a size range suitable for dry powder inhaler formulation. | 18,989,787 |
Potentiation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- currents by the chemical solvent tetrahydrofuran. | The chemical solvent tetrahydrofuran (THF) increases short-circuit current (I(sc)) in renal epithelia endogenously expressing the cystic fibrosis transmembrane conductance regulator (CFTR). To understand how THF increases I(sc), we employed the Ussing chamber and patch-clamp techniques to study cells expressing recombinant human CFTR. THF increased I(sc) in Fischer rat thyroid (FRT) epithelia expressing wild-type CFTR with half-maximal effective concentration (K(D)) of 134 mM. This THF-induced increase in I(sc) was enhanced by forskolin (10 microM), inhibited by the PKA inhibitor H-89 (10 microM) and the thiazolidinone CFTR(inh)-172 (10 microM) and attenuated greatly in FRT epithelia expressing the cystic fibrosis mutants F508del- and G551D-CFTR. By contrast, THF (100 mM) was without effect on untransfected FRT epithelia, while other solvents failed to increase I(sc) in FRT epithelia expressing wild-type CFTR. In excised inside-out membrane patches, THF (100 mM) potentiated CFTR Cl(-) channels open in the presence of ATP (1 mM) alone by increasing the frequency of channel openings without altering their duration. However, following the phosphorylation of CFTR by PKA (75 nM), THF (100 mM) did not potentiate channel activity. Similar results were obtained with the triangle upR-S660A-CFTR Cl(-) channel that is not regulated by PKA-dependent phosphorylation and using 2'deoxy-ATP, which gates wild-type CFTR more effectively than ATP. Our data suggest that THF acts directly on CFTR to potentiate channel gating, but that its efficacy is weak and dependent on the phosphorylation status of CFTR. | 18,989,824 |
Response properties of mouse trigeminal ganglion neurons. | We used controlled whisker deflections to examine the response properties of 208 primary afferent neurons in the trigeminal ganglion of adult mice. Proportions of rapidly adapting (RA, 47%) and slowly adapting (SA, 53%) neurons were equivalent, and most cells had low or no spontaneous activity. We quantified angular tuning and sensitivity to deflection amplitude and velocity. Both RA and SA units fired more frequently to larger deflections and faster deflections, but RA units were more sensitive to differences in velocity whereas SA units were more sensitive to deflection amplitudes. Almost all neurons were tuned for deflection angle, and the average response to the maximally effective direction was more than fourfold greater than the average response in the opposite direction; SA units were more tuned than RA units. Responses of primary afferent whisker-responsive neurons are qualitatively similar to those of the rat. However, average firing rates of both RA and SA neurons in the mouse are less sensitive to differences in deflection velocity, and RA units, unlike those in the rat, display amplitude sensitivity. Subtle observed differences between mice and rats may reflect greater mechanical compliance in mice of the whisker hairs and of the tissue in which they are embedded. | 18,989,828 |
A comparative presentation of implementation of ISO 22000 versus HACCP and FMEA in a small size Greek factory producing smoked trout: a case study. | ISO 22000 is the new standard bound to replace HACCP on issues related to food safety. Although several companies, especially the big ones, have either implemented or are on the point of implementing ISO 22000, there are many others which are rather timid and/or reluctant to implement it. The main reason behind that is the lack of information and the fear that the new standard is too demanding in terms of bureaucratic work. This paper aims at making a comparative presentation of how the two systems can be applied to a small smoked salmon producing company thereby facilitating the emergence of the differences. The main difference is that in ISO 22000 systems like Good Manufacturing Practice and Good Hygiene Practice are prerequisites thus leading to lower number of CCPs. In this case study for example, the number of CCPs dropped from eight (8) in HACCP to four (4) in ISO 22000. Furthermore, the Failure Mode and Effect Analysis was applied to the smoked trout manufacturing process in an attempt to calculate quantitatively the Risk Priority Number (RPN) and to find out whether it can be effectively correlated to ISO 22000 and/or HACCP. RPN was found to be higher than 130 for eight steps, in close agreement with HACCP, thereby indicating that corrective actions will have to be undertaken. | 18,989,836 |
Population differences in immune marker profiles associated with human T-lymphotropic virus type I infection in Japan and Jamaica. | The natural history of human T-lymphotropic virus type I (HTLV-I) has been shown to differ markedly by geographic area. The differences include contrasting patterns of risk of adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which may be due in part to differences in host immune response to infection. To characterize variations in host immunity across populations, we compared serologic immune marker patterns in HTLV-I-endemic populations in Japan and Jamaica. We matched 204 participants with archived blood from the Miyazaki Cohort Study (Japan) and the Food Handlers Study (Jamaica)-i.e., 51 HTLV-I-positive ("carriers") and 51 HTLV-I-negative individuals ("noncarriers") from each population-by age, sex and blood collection year. We compared plasma concentrations of markers of T-cell-mediated (antigen-specific) and nonspecific immunity using regression models and correlation coefficients. Compared to Jamaican HTLV-I noncarriers, Japanese noncarriers had higher covariate-adjusted mean levels of T-cell activation markers, including antibody to Epstein-Barr virus nuclear antigen-1 (reciprocal titer 27 vs. 71, respectively, p=0.005), soluble interleukin-2 receptor-alpha (477 vs. 623 pg/mL, p=0.0008) and soluble CD30 (34 vs. 46 U/mL, p=0.0001) and lower levels of C-reactive protein (1.1 vs. 0.43 microg/mL, p=0.0004). HTLV-I infection was associated with activated T-cell immunity in Jamaicans but with diminished T-cell immunity in Japanese persons. The observed population differences in background and HTLV-I-related host immunity correspond closely to the divergent natural histories of infection observed among HTLV-I carriers in Japan and Jamaica and corroborate a role for host immune status in the contrasting patterns of ATL and HAM/TSP risk. | 18,989,900 |
Ultralow fouling zwitterionic polymers grafted from surfaces covered with an initiator via an adhesive mussel mimetic linkage. | In this work, nonfouling zwitterionic polymers were grafted via surface-initiated atom transfer radical polymerization (ATRP) from surfaces covered with an adhesive catechol initiator. The catechol initiator was attached to both bare gold and amino-functionalized surfaces, and the nonfouling performances of the resulting polymer brushes were compared. Under optimal conditions, ultralow protein adsorption from both single-protein solutions of fibrinogen and lysozyme and complex media of 10% blood serum and 100% blood plasma/serum was achieved. Furthermore, the 3-day accumulation of Pseudomonas aeruginosa on the treated glass surfaces was studied in situ using a laminar flow chamber. The results showed that these zwitterionic coatings dramatically reduced the biofilm formation of P. aeruginosa as compared to the reference bare glass. | 18,989,905 |
DNA closed nanostructures: a structural and Monte Carlo simulation study. | DNA nanoconstructs are obtained in solution by using six unique 42-mer DNA oligonucleotides, whose sequences have been designed to form a pseudohexagonal structure. The required flexibility is provided by the insertion of two non-base-paired thymines in the middle of each sequence that work as flexible hinges and constitute the corners of the nanostructure when formed. We show that hexagonally shaped nanostructures of about 7 nm diameter and their corresponding linear open constructs are formed by self-assembly of the specifically designed linear oligonucleotides. The structural and dynamical characterization of the nanostructure is obtained in situ for the first time by using dynamic light scattering (DLS), a noninvasive method that provides a fast dynamic and structural analysis and allows the characterization of the different synthetic DNA nanoconstructs in solution. A validation of the LS results is obtained through Monte Carlo (MC) simulations and atomic force microscopy (AFM). In particular, a mesoscale molecular model for DNA, developed by Knotts et al., is exploited to perform MC simulations and to obtain information about the conformations as well as the conformational flexibilities of these nanostructures, while AFM provides a very detailed particle analysis that yields an estimation of the particle size and size distribution. The structural features obtained by MC and AFM are in good agreement with DLS, showing that DLS is a fast and reliable tool for characterization of DNA nanostructures in solution. | 18,989,907 |
Exploiting distinct molecular architectures of ultrathin films made with iron phthalocyanine for sensing. | The possibility of generating distinct film properties from the same material is crucial for a number of applications, which can only be achieved by controlling the molecular architecture. In this paper we demonstrate as a proof-of-principle that ultrathin films produced from iron phthalocyanine (FePc) may be used to detect trace amounts of copper ions in water, where advantage was taken of the cross sensitivity of the sensing units that displayed distinct electrical properties. The ultrathin films were fabricated with three methods, namely physical vapor deposition (PVD), Langmuir-Blodgett (LB), and electrostatic layer-by-layer (LbL) techniques, where for the latter tetrasulfonated phthalocyanine was used (FeTsPc). PVD and LB films were more homogeneous than the LbL films at both microscopic and nanoscopic scales, according to results from micro-Raman spectroscopy and atomic force microscopy (AFM), respectively. From FTIR spectroscopy data, these more homogeneous films were found to have FePc molecules oriented preferentially, tilted in relation to the substrate surface, while FeTsPc molecules were isotropically distributed in the LbL films. Impedance spectroscopy measurements with films adsorbed onto interdigitated gold electrodes indicated that the electrical response depends on the type of film-forming method and varies with incorporation of copper ions in aqueous solutions. Using principal component analysis (PCA), we were able to exploit the cross sensitivity of the sensing units and detect copper ions (Cu(2+)) down to 0.2 mg/L, not only in ultrapure water but also in distilled and tap water. This level of sensitivity is sufficient for quality control of water for human consumption, with a fast, low-cost method. | 18,989,908 |
Self-assembled nanostructures of oligopyridine molecules. | The high potential of self-assembly processes of molecular building blocks is reflected in the vast variety of different functional nanostructures reported in the literature. The constituting units must fulfill several requirements like synthetic accessibility, presence of functional groups for appropriate intermolecular interactions and depending on the type of self-assembly processsignificant chemical and thermal stability. It is shown that oligopyridines are versatile building blocks for two- and three-dimensional (2D and 3D) self-assembly. They can be employed for building up different architectures like gridlike metal complexes in solution. By the appropriate tailoring of the heterocycles, further metal coordinating and/or hydrogen bonding capabilities to the heteroaromatic molecules can be added. Thus, the above-mentioned architectures can be extended in one-step processes to larger entities, or in a hierarchical fashion to infinite assemblies in the solid state, respectively. Besides the organizational properties of small molecules in solution, 2D assemblies on surfaces offer certain advantages over 3D arrays. By precise tailoring of the molecular structures, the intermolecular interactions can be fine-tuned expressed by a large variety of resulting 2D patterns. Oligopyridines prove to be ideal candidates for 2D assemblies on graphite and metal sufaces, respectively, expressing highly ordered structures. A slight structural variation in the periphery of the molecules leads to strongly changed 2D packing motifs based on weak hydrogen bonding interactions. Such 2D assemblies can be exploited for building up host-guest networks which are attractive candidates for manipulation experiments on the single-molecule level. Thus, "erasing" and "writing" processes by the scanning tunneling microscopy (STM) tip at the liquid/solid interface are shown. The 2D networks are also employed for performing coordination chemistry experiments at surfaces. | 18,989,910 |
Structural and dynamic properties of water within the solvation layer around various conformations of the glycine-based polypeptide. | Several conformations of the solvated glycine-based polypeptides were investigated using molecular dynamics simulations. Some properties of water in the neighboring space around these molecules were investigated. It was found that water forms a well-defined layer-the first solvation shell-around the peptide molecule, and thickness of this layer is independent of the peptide structure and is equal to approximately 0.28 nm. Within this layer, water molecules show marked orientations relative to a peptide surface. Using the two-particle contribution to entropy as a measure of structural ordering of water, we found that the first solvation shell contributes 95% or more to the total water ordering around the peptide molecule. In investigating the dynamic properties of water, diffusion coefficients and lifetime of the hydrogen bond, clear differences between solvation layer and the bulk water were observed. It was found that the translational diffusion coefficient, D(T), decreases by 30% or more compared to bulk water; also, the lifetime of the water-water hydrogen bond clearly increases. The rotational diffusion coefficient, however, decreases only slightly, no more than approximately 10%. These differences correspond to the slightly higher energy of the hydrogen bond, and to its slightly distorted geometry. Analyzing the translational dynamics of water in the vicinity of the peptide molecule, it was deduced that the structure of the first solvation shell becomes more rigid than the structure of the bulk water. Investigation of a "pure hydrophobic" form of the polypeptide shows that the structure and the properties of water within the solvation shell are predominantly determined by the hydrophobic effect. The specific interactions between water molecules and various charge groups of the peptide molecule modifies this effect only slightly. | 18,989,911 |
Ordering rigid rod conjugated polymer molecules for high performance photoswitchers. | Molecules of a rigid rod conjugated polymer, a derivative of poly(para-phenylene ethynylene)s with thioacetyl end groups (TA-PPE), were well aligned by drop-casting the polymer solution onto the friction-transferred poly(tetrafluoroethylene) substrates. TA-PPE molecules were found to be exactly oriented with their conjugated backbones along the PTFE sliding direction. Photoresponse characteristics based on the uniaxially ordered film were significantly improved compared to those of devices with the disordered film. For example, the switch on/off ratio of the photoswitchers with aligned molecules was as high as 330-400, while that of devices without alignment was only 8-12. It was due to the efficient carrier transport along the highly aligned polymer films, in which the molecules of TA-PPE oriented along the carrier transport direction of the devices. | 18,989,943 |
Dehydrative cyclocondensation reactions on hydrogen-terminated Si(100) and Si(111): an ex situ tool for the modification of semiconductor surfaces. | Dehydrative cyclocondensation processes for semiconductor surface modification can be generally suggested on the basis of well-known condensation schemes; however, in practice this approach for organic functionalization of semiconductors has never been investigated. Here we report the modification of hydrogen-terminated silicon surfaces by cyclocondensation. The cyclocondensation reactions of nitrobenzene with hydrogen-terminated Si(100) and Si(111) surfaces are investigated and paralleled with selected cycloaddition reactions of nitro- and nitrosobenzene with Si(100)-2x1. Infrared spectroscopy is used to confirm the reactions and verify an intact phenyl ring and C-N bond in the reaction products as well as the depletion of surface hydrogen. High resolution N 1s X-ray photoelectron spectroscopy (XPS) suggests that the major product for both cyclocondensation reactions investigated is a nitrosobenzene adduct that can only be formed following water elimination. Both IR and XPS are augmented by density functional theory (DFT) calculations that are also used to investigate the feasibility of several surface reaction pathways, which are insightful in understanding the relative distribution of products found experimentally. This novel surface modification approach will be generally applicable for semiconductor functionalization in a highly selective and easily controlled manner. | 18,989,960 |
New approaches to the treatment of inflammatory disease : focus on small-molecule inhibitors of signal transduction pathways. | This 'state-of-the-art' review specifically focuses on alternative signalling pathways deeply involved in acute and chronic inflammatory responses initiated by various pathological stimuli. The accumulated scientific knowledge has already revealed key biological targets, such as COX-2, and related pro-inflammatory mediators (cytokines and chemokines, interleukins [ILs], tumour necrosis factor [TNF]-alpha, migration inhibition factor [MIF], interferon [IFN]-gamma and matrix metalloproteinases [MMPs]) implicated in uncontrolled, destructive inflammatory reaction. A number of physiologically active agents are currently approved for market or are under active investigation in different clinical trials. However, recent findings have exposed the fatal adverse effects directly associated with drug therapy based on COX-2 inhibition. Given these possible harmful outcomes, a range of novel therapeutically relevant biological targets that include nuclear transcription factor (NF-kappaB), p38 mitogen-activated protein kinases (MAPK) and Janus protein tyrosine kinases and signal transducers and activators of transcription (JAK/STAT) signalling pathways has received growing attention. Here we discuss recent progress in the identification and development of novel, clinically approved or evaluated small-molecule regulators of these signalling cascades as promising anti-inflammatory drugs. | 18,989,991 |
Pharmacokinetic-pharmacodynamic interaction between nebicapone, a novel catechol-o-methyltransferase inhibitor, and controlled-release levodopa/carbidopa 200 mg/50 mg : randomized, double-blind, placebo-controlled, crossover study in healthy subjects. | Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) inhibitor. Nebicapone is a new COMT inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet((R)) CR 200/50) in healthy subjects (n = 16). This was a randomized, double-blind, placebo-controlled, four-way crossover study in healthy subjects, with at least 5 days of washout between treatment periods. There was a dose-dependent and significant increase in levodopa extent of exposure (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)]) without a significant change in peak exposure (maximum plasma concentration; [C(max)]). Using placebo as a reference, levodopa geometric mean ratios (GMRs) and 90% CIs following nebicapone 50 mg, 100 mg and 200 mg were, respectively, 1.13 (0.98, 1.30), 1.04 (0.90, 1.19) and 1.10 (0.96, 1.27) for C(max) and 1.26 (1.16, 1.34), 1.37 (1.27, 1.75) and 1.47 (1.42, 1.65) for AUC(infinity). For 3-O-methyldopa (3-OMD), the GMRs and 90% CIs were, respectively, 0.61 (0.55, 0.67), 0.45 (0.41, 0.50) and 0.33 (0.30, 0.36) for C(max) and 0.69 (0.61, 0.78), 0.53 (0.41, 0.61) and 0.41 (0.37, 0.47) for AUC(infinity). Nebicapone dose dependently and significantly decreased COMT activity. Maximum COMT inhibition occurred at 1.5-2.4 hours post-dose and ranged from 56% to 73% with nebicapone 50 mg and 200 mg, respectively. There was a good correlation between plasma concentrations of nebicapone and inhibition of S-COMT activity. Treatments were well tolerated. Following concomitant administration with levodopa/carbidopa CR 200 mg/50 mg, single doses of nebicapone 50 mg, 100 mg and 200 mg significantly and dose-dependently inhibited S-COMT activity, increased systemic exposure to levodopa, and reduced 3-OMD formation. | 18,989,992 |
Effect of genetic predisposition on the risk of gallbladder cancer in Hungary. | A CYP1A1 polymorphism has been associated with an increased risk for gallbladder cancer (GBC) in Japanese women. However, genetic risk factors for GBC in Hungary, where the population has a relatively high GBC incidence, has not been well studied. We therefore tested associations between CYP1A1 T3801C, CYP1A1 Ile462Val, GSTM1deletion, and TP53 Arg72Pro and GBC in Hungary. Genomic DNA was extracted from peripheral blood of 100 controls (52 men and 48 women) and from the tissue embedded in paraffin of 43 cases (6 men and 37 women). The case-control analysis was limited to females due to a small number of males. Of 37 female cases, 21 (56.8%) were diagnosed as adenocarcinoma, and the remaining 16 (43.2%) were classified as non-adenocarcinoma. The odds ratios (ORs) for the Ile/Val genotype and the Val allele were 8.9 (95% CI: 2.9-27.4) and 4.4 (95% CI: 1.7-11.1), respectively. The occurrence of the combined variant genotypes of CYP1A1 Ile462Val and GSTM1 (37.8% vs. 8.3%) or CYP1A1 Ile462Val and TP53 Arg72Pro (24.3% vs. 0%) was significantly higher in the cases than in the controls. The Ile/Val genotype was significantly associated with an increased risk of adenocarcinoma (OR 9.2; 95% CI: 2.6-32.6) and non-adenocarcinoma (OR 8.4; 95% CI: 2.2-32.4). Additionally, the Arg/Pro genotype increased risk of non-adenocarcinoma (OR 3.8; 95% CI: 1.2-12.8). The Val allele may contribute to the development of GBC not only in Japanese but also in Hungarian women. Our results provide a rationale for further studies of genetic variation on the risk of GBC in Hungary. | 18,990,008 |
Statistical comparison of survival models for analysis of cancer data. | The Cox Proportional Hazard model is the most popular technique to analysis the effects of covariates on survival time but under certain circumstances parametric models may offer advantages over Cox's model. In this study we use Cox regression and alternative parametric models such as: Weibull, Exponential and Lognormal models to evaluate prognostic factors affecting survival of patients with stomach cancer. Comparisons were made to find the best model. To determine independent prognostic factors reducing survival time for stomach cancer, we compared parametric and semi-parametric methods applied to patients who registered in one cancer registry center located in southern Iran using the Akaike Information Criterion. Of a total of 442 patients, 266 (60.2%) died. The results of data analysis using Cox and parametric models were approximately similar. Patients with ages 60-75 and >75 years at diagnosis had an increased risk for death followed by those with poor differentiated grade and presence of distant metastasis (P<0.05). Although the Hazard Ratios in the Cox model and parametric ones are approximately similar, according to Akaike Information Criterion, the Weibull and Exponential models are the most favorable for survival analysis. | 18,990,013 |
The cost-effectiveness of a quadrivalent human papillomavirus vaccine in Taiwan. | A quadrivalent human papillomavirus (HPV 6/11/16/18) vaccine has recently received regulatory approval in Taiwan for the prevention of cervical carcinoma, high-grade cervical dysplasia (cervical intraepithelial neoplasia 2/3 [CIN 2/3]), low-grade cervical dysplasia (CIN 1), high-grade vulvar and vaginal dysplasia, and external genital warts. To examine the potential long-term epidemiologic and economic consequences of a quadrivalent HPV (6/11/16/18) vaccination program in Taiwan. A transmission dynamic model was used to estimate the long-term epidemiologic and economic consequences of quadrivalent HPV vaccination. Two vaccination strategies were evaluated in conjunction with current cervical cancer screening: 1) vaccination of 12-year-old girls and 2) vaccination of 12-year-old girls with a temporary 5-year catch-up vaccination of females aged 12-24 years (catch-up). From an epidemiologic perspective, both vaccination strategies reduce the overall incidence of HPV 16/18-related cervical cancer relative to no vaccination by 91% during year 100 following vaccine introduction. Likewise, both vaccination strategies reduce the incidence of CIN 2/3, CIN 1, and genital warts by approximately 90%, 86%, and 94%, respectively, at this time point. However, the catch-up program consistently achieves greater benefit earlier than the 12-year-old program. The catch-up strategy is both more effective and efficient than the strategy that vaccinates 12-year-old girls only, with an incremental cost-effectiveness ratio of New Taiwan dollars (NT$) 410,477 per quality-adjusted life-year gained. The results from this model suggest that in Taiwan, prophylactic HPV 6/11/16/18 vaccination of females can: 1) substantially reduce genital warts, CIN, and cervical cancer; 2) improve quality of life and survival; and 3) be cost-effective when implemented as a vaccination strategy that includes a temporary catch-up program. | 18,990,021 |
Acute schistosomiasis outbreak: clinical features and economic impact. | Acute schistosomiasis (AS) is a systemic hypersensitivity reaction that has been recognized mostly in nonimmune travelers. Although the condition is self-limited, it can be severe. We describe an outbreak of AS in a group of travelers returning from Tanzania and estimate the disease burden. After we identified the index case, we initiated an epidemiological investigation of the entire group. Diagnosis was established on the basis of symptoms, serologic data, and ova detection. Relevant clinical information was documented with use of a structured questionnaire, and the patient's economic burden was recorded. Health-related quality of life was assessed during the illness and 3 months later. Of 34 group members, 27 had a single exposure to a fresh water pond, 22 (81%) of whom were infected. AS developed in 19 (86%) of the 22 infected travelers. Cough (78% of patients), fever (68%), and fatigue (58%) were the most common symptoms, with mean durations (+/- standard deviation) of 22 +/- 11, 11 +/- 7, and 37 +/- 16 days, respectively. The total number of medical encounters was 258 (mean no. of encounters per patient, 11), and 152 work and school days were missed (mean, 8 days per patient). During the acute phase of illness, there was a significant decline in health-related quality of life that returned to expected norms after 3 months. A single, short exposure of travelers to an infected pond led to a high infection rate. The illness had a significant impact on the patients' daily functions, and patients extensively used medical resources. Education to avoid exposure to fresh water remains the most effective method of schistosomiasis prevention. | 18,990,059 |
Coccidioidomycosis in elderly persons. | Coccidioidomycosis is a fungal infection acquired via inhalation of airborne fungal arthrospores of Coccidioides species in regions of endemicity in the deserts of the southwestern United States and northern Mexico. In recent years, the incidence of coccidioidomycosis has increased in areas of endemicity, and previous studies have found the highest incidence of coccidioidal infection in Arizona among persons in older age groups. We conducted a retrospective review of data for all patients with coccidioidomycosis who were treated at our institution that compared clinical manifestations of coccidioidomycosis in patients aged >or=60 years with those in patients aged <60 years. We compared 210 patients aged >or=60 years with 186 patients aged <60 years. No significant differences were observed with regard to manifestations of coccidioidomycosis, even after adjustment for comorbid conditions, excluding immunosuppression. Regardless of age, when coccidioidal illnesses in immunosuppressed patients were compared with those in nonimmunosuppressed patients, immunosuppressed patients were significantly more likely to have extrapulmonary dissemination of infection, to require hospitalization, and to have progressive infection or to die of coccidioidomycosis. Univariate logistic regression identified immunosuppression as the only marker that increased risk of extrapulmonary dissemination of infection (odds ratio, 2.13;P=.05), hospitalization (odds ratio, 2.68; P<.001), and death (odds ratio, 8.39; P<.001). Multivariate analysis revealed that neither age nor an interaction of age and immunosuppression had a significant impact on coccidioidal manifestations. Coccidioidomycosis is a serious illness in all patients, but its different manifestations in older-aged persons, compared with those in younger-aged persons, may be related to immunosuppression rather than age alone. | 18,990,061 |
The effect of interferon beta-1b on size of short-lived enhancing lesions in patients with multiple sclerosis. | Contrast enhancing lesions (CELs) in MRI represent inflammatory events in multiple sclerosis (MS). IFN-beta-1b decreases the formation of CELs. However, the ability of IFN-beta-1b to reduce the size of CELs arising during therapy has not been extensively investigated. Thirty patients with relapsing-remitting (RR) MS were followed for a 3-month pre-therapy phase then for a 6-month therapy phase during which treatment with IFN-beta-1b at a dosage of 250 microg subcutaneously injected every other day was employed. Each patient underwent monthly clinical and MRI examinations. For all patients, CELs were identified on postcontrast T1-weighted MRIs. CEL number, size, and volume were computed using Medx software. The average number and total lesion volume of CELs visible during the therapy phase were significantly lower than the number and total lesion volume of CELs observed in the pre-therapy phase. However, there was no significant reduction between pre-therapy and therapy phases in the mean size of individual lesions arising during the respective phases. Since size of CELs has been related to severity of tissue damage, the lack of size decrease during therapy suggested a limited therapeutic effect of IFN-beta-1b if a blood-brain barrier breakdown has occurred. | 18,990,070 |
Competency measurements: testing convergent validity for two measures. | This paper is a report of a study to investigate whether the Australian National Competency Standards for Registered Nurses demonstrate correlations with the Finnish Nurse Competency Scale. Competency assessment has become popular as a key regulatory requirement and performance indicator. The term competency, however, does not have a globally accepted definition and this has the potential to create controversy, ambiguity and confusion. Variations in meaning and definitions adopted in workplaces and educational settings will affect the interpretation of research findings and have implications for the nursing profession. A non-experimental cross-sectional survey design was used with a convenience sample of 116 new graduate nurses in 2005. The second version of the Australian National Competency Standards and the Nurse Competency Scale was used to elicit responses to self-assessed competency in the transitional year (first year as a Registered Nurse). Correlational analysis of self-assessed levels of competence revealed a relationship between the Australian National Competency Standards (ANCI) and the Nurse Competency Scale (NCS). The correlational relation between ANCI domains and NCS factors suggests that these scales are indeed used to measure related dimensions. A statistically significant relationship (r = 0.75) was found between the two competency measures. Although the finding of convergent validity is insufficient to establish construct validity for competency as used in both measures in this study, it is an important step towards this goal. Future studies on relationships between competencies must take into account the validity and reliability of the tools. | 18,990,106 |
The experience of life after burn injury: a new bodily awareness. | This paper is a report of a study to describe the injured body of people who have survived a major burn and seeks to understand the essence of their lived experience. The burden of a burn-injured body, including loss of function, altered appearance and psychological distress, can threaten return to preburn state of life and successful return to society. Fourteen participants (three women and 11 men; mean age 46 years) who had survived a major burn were interviewed in 2005-2006 an average 14 months after injury. A Husserlian phenomenological approach was adopted. A new and demanding bodily awareness, disclosing both limitations and potentials, emerged as the essence of the burn survivors' experience of their injured bodies. This was supported by a descriptive structure of the body as telling a new story, being unfamiliar to watch and sense, vulnerable and in need of protection, more present with a variety of nuisances, having brakes on and resisting habitual actions, as well as being insecure when distrusting own abilities. Participants typically experienced losing the familiarity of their bodies as anonymous and unconsciously at hand for all possible actions in everyday life. Significant others served as buffers, extensions of participants' injured bodies, reducing obstacles and insecurity in all aspects of life. The lived experience of people who have sustained a burn injury should be recognized and valued by nurses in all phases of burn care. Nurses have an important role in facilitating the presence and involvement of family and friends in the recovery and rehabilitation of burn survivors. | 18,990,107 |
Neurological aspects of obstructive sleep apnea. | Obstructive sleep apnea is often regarded as a structural disorder causing narrowing of the airway. This article reviews the neurological aspects of obstructive sleep apnea, including the upper airway reflex, cortical arousal thresholds, and motor function as they pertain to the pathophysiology of disease. We also discuss the relationship of obstructive sleep apnea to other neurological diseases. | 18,990,120 |
High nuclear Livin expression is a favourable prognostic indicator in renal cell carcinoma. | To assess the protein expression of Livin, an apoptosis inhibitor, in renal cell carcinoma (RCC) and to determine its prognostic relevance. Immunohistochemical staining for Livin was performed in tissue microarrays (TMAs), including tumour tissue cores, from patients with RCC who had undergone renal surgery. In 682 TMAs cytoplasmatic staining intensity and nuclear staining quantity were evaluated, and the association of Livin expression with progression-free survival (PFS) and cancer-specific survival (CSS) was analysed with a multivariate Cox regression model. Over a median (range) follow-up of 5.2 (0-16.1) years, 204 patients (28%) had died from their disease. The CSS rates at 1 and 5 years for the entire cohort was 88% and 71%. Cytoplasmatic Livin staining was absent in 516 (76%) specimens; staining was positive in 166 (24%) specimens. Weak nuclear Livin staining (<or=25%) was present in 571 (84%) specimens, strong nuclear staining (26-100%) in 111 (16%). In multivariate analysis, high (>25%) nuclear Livin expression was a favourable independent predictor of PFS and CSS even after adjusting for tumour stage, Fuhrman grade, age, sex and Karnofsky severity rating. Cytoplasmatic Livin expression did not offer additional prognostic information. High nuclear Livin expression is a favourable independent predictor of PFS and CSS in patients with RCC. | 18,990,137 |
Brachytherapy for prostate cancer: is the pretreatment prostate volume important? | To prospectively determine the effect of prostate volume on lower urinary tract symptoms (LUTS) in terms of changes in the International Prostate Symptom Score (IPSS), and to determine whether prostate volume affects the retention rate after brachytherapy, as there is concern that patients with larger prostates might develop more troublesome LUTS after brachytherapy. We prospectively identified 100 consecutive patients who had brachytherapy for prostate cancer, using a real-time three-dimensional seed implantation technique, at one institution. At each follow-up review the IPSS was recorded. To determine the effect of prostate volume on the IPSS after treatment the patients were divided into two groups according to prostate volume at brachytherapy (<50 and >or=50 mL). The median patient age was 62 years, the overall median prostate volume was 42 mL and the median intraoperative D90 was 190 Gy. The pretreatment IPSS was 4 and 8 for the <50 and >or=50 mL groups, respectively, and at 3 months after brachytherapy the median IPSS increased to 18 and 20 for the two groups, respectively. Eleven patients went into acute retention of urine after brachytherapy (six in the >or=50 mL group). This study shows that patients with prostates of >or=50 mL have an IPSS comparable with those who have prostates of <50 mL. Large prostates should not be considered an exclusion criterion when an intraoperative planning technique is used for brachytherapy. | 18,990,138 |
P-cadherin as a prognostic indicator and a modulator of migratory behaviour in bladder carcinoma cells. | To identify changes associated with P-cadherin expression in bladder cancer and evaluate the potential role of such events in determining the clinical outcome and cell behaviour, as the function of P-cadherin in normal epithelium is unknown, as is its potential role in neoplastic progression in different cancers. In all, 536 bladder tumour specimens from 408 patients were assembled in seven tissue microarrays. Paraffin sections from each array were processed for immunohistochemistry to assess the expression of P-cadherin. The expression of P-cadherin was forced using lipofectin, followed by an assessment of migration and invasion potential using standard in vitro assays. The absence of P-cadherin staining was associated with muscle-invasive disease, grade 3 (P < 0.001) and nodal disease (P = 0.009). Similar results were obtained when considering cytoplasmic and unrestricted localization of P-cadherin (P < 0.001), except for nodal involvement. The group with cytoplasmic location of P-cadherin showed a shorter cancer-specific survival than the group with membrane location of P-cadherin (P = 0.03). Forced expression of P-cadherin in EJ and UM-UC-3 cells, that constitutively lack P-cadherin expression, resulted in modulation of catenin expression and enhanced migration of EJ and UM-UC-3/P-cadherin transfectants (>200%). These results showed that loss of expression, cytoplasmic relocation or unrestricted tissue location of P-cadherin was associated with a poor clinical outcome and prognosis in bladder cancer. From the in vitro work it is evident that P-cadherin plays a role in regulating the migration potential of bladder carcinoma cells. | 18,990,147 |
Assessment of urodynamic and detrusor contractility variables in patients with overactive bladder syndrome treated with botulinum toxin-A: is incomplete bladder emptying predictable? | To assess whether incomplete bladder emptying and the need for clean intermittent self-catheterization (CISC) is predictable, by analysing urodynamic and detrusor contractility variables in patients treated with botulinum toxin-A (BTX-A) for refractory idiopathic detrusor overactivity (IDO). Sixty-seven patients (mean age 50.3) with IDO, from two centres, had bladder injections of 200 U BTX-A. Patients with difficulty in emptying their bladder and/or persistent overactive bladder symptoms, with postvoid residual volumes (PVR) of >150 mL after treatment were started on CISC. Urodynamics were conducted at baseline, 4 and 12-16 weeks after injection with BTX-A. Detrusor contractility was assessed using the projected isovolumetric pressure (PIP1) in women and bladder contractility index (BCI) in men. There were improvements in the mean maximum cystometric capacity, bladder compliance and maximum detrusor pressures during filling cystometry after BTX-A injections. The PVR was significantly increased at 4 but not at 12 weeks. Nineteen patients required CISC and when compared with those not needing CISC their pretreatment maximum flow rate (15 vs 22 mL/s, P = 0.003), PIP1 (43 vs 58, P = 0.02) and BCI (113 vs 180, P = 0.001) were lower. Receiver operator characteristic curve analysis suggested that a PIP1 of < or =50 in women (sensitivity 0.83; specificity 0.70; area under the curve 0.822) and BCI < or =120 (sensitivity 0.7; specificity 0.79; area 0.879) might predict the need for CISC. The maximum flow rate, PIP1 and BCI were significantly lower in patients who required CISC after BTX-A treatment than in those who did not. A PIP1 of < or =50 in women and a BCI of < or =120 might be predictive of a need for CISC in this setting, and might help when counselling patients. | 18,990,156 |
Stage-specific effect of nodal metastases on survival in patients with non-metastatic renal cell carcinoma. | To quantify the survival disadvantage related to the presence of exclusive nodal metastases (eNM) in patients with otherwise non-metastatic (M0) renal cell carcinoma (RCC). Data were retrieved from 12 institutional databases and yielded 3507 patients with T1-3N1-2M0 RCC treated with partial or radical nephrectomy. Cox regression analyses relied on T stage, Fuhrman grade and presence of eNM. Data were analysed using univariable, multivariable and stratified analyses. Overall 165 (4.7%) patients had eNM; of 2023 patients of stage T1, 23 (1.1%) had eNM, vs 20 of 448 (4.5%) for T2 and 122 of 993 (12.3%) for T3. In univariable analyses the presence of eNM increased the rate of cancer specific mortality (CSM) by 7.1 times. After adjusting for T stage and Fuhrman grade, in all patients eNM increased the rate of CSM by 3.2 times. In stratified analyses adjusted for Fuhrman grade, the increase in CSM related to the presence of eNM was 28.9, 4.3 and 2.5 times (all P < 0.001) for stages T1, T2 and T3, respectively. From the prognostic perspective, staging lymphadenectomy appears of most value in patients with T1-2 RCC, but the low prevalence of eNM questions the practical applicability of nodal staging in those patients. Conversely, in patients with T3 RCC, the prevalence and the prognostic impact of eNM might make a staging lymphadenectomy worthwhile. | 18,990,161 |
The significance of lymphovascular invasion in transurethral resection of bladder tumour and cystectomy specimens on the survival of patients with urothelial bladder cancer. | To test the hypothesis that patients with bladder cancer who had evidence of lymphovascular invasion (LVI) in their transurethral resection of bladder tumour (TURBT) and radical cystectomy (RC) specimens would have a worse prognosis and higher likelihood of clinical understaging, and to assess the effect of LVI discovered at RC on subsequent disease-related mortality, as the prognostic significance of LVI in TURBT or RC specimens of patients treated for urothelial carcinoma of the bladder is not completely established. We retrospectively reviewed the records of 163 patients with urothelial carcinoma of the bladder seen at our institution, and who had TURBT (69) or RC (94) between 1995 and 2005. We compared patients with LVI on TURBT and/or RC specimens to a group of controls who did not have LVI on TURBT (34) or RC (32). Patients with LVI present in their TURBT specimen had a shorter disease-specific survival than those without LVI, with a 5-year survival of 33.6% vs 62.9% (log-rank test P = 0.027; hazard ratio 2.21). LVI at TURBT varied with clinical stage (P = 0.049). Patients with LVI and who were clinical stage I or II had lower survival than those without LVI (P = 0.049; hazard ratio 2.68). LVI did not affect survival among those with clinical stage III or IV (P = 0.29). There was a trend for patients with LVI at TURBT to be clinically understaged compared to those without LVI (75% vs 46%) but the difference was not significant (P = 0.086). Patients with LVI detected in their RC specimen were significantly more likely to have cancer recurrence than were those with no evidence of LVI (48% vs 19%, P = 0.006). For the RC group there was also a significant difference in survival distribution between patients with evidence of LVI vs those without (5-year survival 45.5% vs 78.4%, P = 0.017). Those with LVI were significantly more likely to die from the disease than those without LVI (P = 0.017; hazard ratio 2.92). Our findings suggest that LVI is a histological feature that might be associated with a poorer prognosis in patients with urothelial carcinoma of the bladder. The presence of LVI in TURBT specimens predicts shorter survival for patients with stage I or II disease. The presence of LVI in RC specimens predicts recurrence of disease and shorter survival. Further studies are needed to determine whether this group of patients would benefit from early RC and/or perioperative chemotherapy to improve clinical outcomes. | 18,990,174 |
A novel streptococcal integrative conjugative element involved in iron acquisition. | In this study, we determined the function of a novel non-ribosomal peptide synthetase (NRPS) system carried by a streptococcal integrative conjugative element (ICE), ICESe2. The NRPS shares similarity with the yersiniabactin system found in the high-pathogenicity island of Yersinia sp. and is the first of its kind to be identified in streptococci. We named the NRPS product 'equibactin' and genes of this locus eqbA-N. ICESe2, although absolutely conserved in Streptococcus equi, the causative agent of equine strangles, was absent from all strains of the closely related opportunistic pathogen Streptococcus zooepidemicus. Binding of EqbA, a DtxR-like regulator, to the eqbB promoter was increased in the presence of cations. Deletion of eqbA resulted in a small-colony phenotype. Further deletion of the irp2 homologue eqbE, or the genes eqbH, eqbI and eqbJ encoding a putative ABC transporter, or addition of the iron chelator nitrilotriacetate, reversed this phenotype, implicating iron toxicity. Quantification of (55)Fe accumulation and sensitivity to streptonigrin suggested that equibactin is secreted by S. equi and that the eqbH, eqbI and eqbJ genes are required for its associated iron import. In agreement with a structure-based model of equibactin synthesis, supplementation of chemically defined media with salicylate was required for equibactin production. | 18,990,191 |
Mycotic aneurysm of the posterior tibial artery -- a rare complication of bacterial endocarditis: a case report. | Distal arterial embolisation and subsequent aneurysm formation are rare occurrences and most are secondary to trauma. We have found no case reports that describe posterior tibial aneurysm formation secondary to bacterial endocarditis. We report the case of a 47-year-old Caucasian man who, 2 years after an episode of subacute bacterial endocarditis, presented with signs and symptoms consistent with posterior tibial aneurysm formation. Posterior tibial aneurysm formation is a rare occurrence, most commonly occurring after trauma and, although other causes have been described, to our knowledge, endocarditis has not been implicated before, and as such should therefore be borne in mind when dealing with cases where no obvious aetiology is evident. | 18,990,208 |
A new 500 kb haplotype associated with high CD8+ T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis. | Hereditary Hemochromatosis(HH) is a common genetic disorder of iron overload where the large majority of patients are homozygous for one ancestral mutation in the HFE gene. In spite of this remarkable genetic homogeneity, the condition is clinically heterogeneous, varying from a severe disease to an asymptomatic phenotype with only abnormal biochemical parameters. The recent recognition of the variable penetrance of the HH mutation in different large population studies demands the need to search for new modifiers of its phenotypic expression. The present study follows previous observations that MHC class-I linked genetic markers, associated with the setting of CD8+ T-lymphocyte numbers, could be clinically relevant modifiers of the phenotypic expression in HH, and aimed to find new markers that could be used as more reliable prognostic variables. Haplotype analysis, including seven genetic markers within a 1 Mb region around the microsatellite D6S105 was performed in a group of 56 previously characterized C282Y homozygous Portuguese patients. Parameters analyzed in this study were total body iron stores, clinical manifestations related with HH and immunological parameters (total lymphocyte numbers, CD4+ and CD8+ T-lymphocyte numbers). An independent group of 10 C282Y homozygous patients from Vancouver, Canada, were also included in this study and analyzed for the same parameters. A highly conserved ancestral haplotype defined by the SNP markers PGBD1-A, ZNF193-A, ZNF165-T (designated as A-A-T) was found associated with both abnormally low CD8+ T-lymphocyte numbers and the development of a severe clinical expression of HH. In a small proportion of patients, another conserved haplotype defined by the SNP markers PGBD1-G, ZNF193-G, ZNF165-G (designated as G-G-G) was found associated with high CD8+ T-lymphocyte numbers and a milder clinical expression. Remarkably, the two conserved haplotypes defined in Portuguese patients were also observed in the geographically different population of Canadian patients, also predicting CD8+ T-lymphocyte numbers and the severity of disease. These results may have important implications not only for approaching the question of the penetrance of the hemochromatosis gene in different world populations but also to further narrow the region of interest to find a candidate gene involved in the setting of CD8+ T-lymphocyte numbers in humans. | 18,990,219 |
Stability of multiple alignments and phylogenetic trees: an analysis of ABC-transporter proteins family. | Sequence-based phylogeny reconstruction is a fundamental task in Bioinformatics. Practically all methods for phylogeny reconstruction are based on multiple alignments. The quality and stability of the underlying alignments is therefore crucial for phylogenetic analysis. In this short report, we investigate alignments and alignment-based phylogenies constructed for a set of 22 ABC transporters using CLUSTAL W and DIALIGN. Comparing the 22 "one-out phylogenies" one can obtain for this sequence set, some intrinsic phylogenetic instability is observed - even if attention is restricted to branches with high bootstrapping frequencies, the so-called safe branches. We show that this instability is caused by the fact that both, CLUSTAL W as well as DIALIGN, apparently get "confused" by sequence repeats in some of the ABC-transporter. To deal with such problems, two new DIALIGN options are introduced that prove helpful in our context, the "exclude-fragment" (or "xfr") and the "self-comparison" (or "sc") option. "One-out strategies", known to be a useful tool for testing the stability of all sorts of data-analysis procedures, can successfully be used also in testing alignment stability. In case instabilities are observed, the sequences under consideration should be carefully checked for putative causes. In case one suspects sequence repeats to be the cause, the new "sc" option can be used to detect such repeats, and the "xfr" option can help to resolve the resulting problems. | 18,990,223 |
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