bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Expression during Survival ofEscherichia coliO157:H7 in Soil and Water
Authors: Duffitt Ashley D. , Reber Robert T. , Whipple Andrew , Chauret Christian
Published: September 2010

Thein vitrosurvival ofEscherichia coliO157:H7 at15∘Cunder two experimental conditions (sterile soil and sterile natural water) was examined. DNA microarrays of the entire set ofE. coliO157:H7 genes were used to measure the genomic expression patterns after 14 days. Although the populations declined, someE. coliO157:H7 cells survived in sterile stream water up to 234 days and in sterile soil for up to 179 days. Cells incubated in soil microcosms for 14 days expressed genes for antibiotic resistance, biosynthesis, DNA replication and modification, metabolism, phages, transposons, plasmids, pathogenesis and virulence, antibiotic resistance, ribosomal proteins, the stress response, transcription, translation, and transport and binding proteins at significantly higher levels than cells grown in Luria broth. These results suggest thatE. coliO157:H7 may develop a different phenotype during transport through the environment. Furthermore, this pathogen may become more resistant to antibiotics making subsequent infections more difficult to treat.
Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of Significance
Authors: Moore Nathan , Lyle Stephen
Published: September 2010

Long-lived cancer stem cells (CSCs) with indefinite proliferative potential have been identified in multiple epithelial cancer types. These cells are likely derived from transformed adult stem cells and are thought to share many characteristics with their parental population, including a quiescent slow-cycling phenotype. Various label-retaining techniques have been used to identify normal slow cycling adult stem cell populations and offer a unique methodology to functionally identify and isolate cancer stem cells. The quiescent nature of CSCs represents an inherent mechanism that at least partially explains chemotherapy resistance and recurrence in posttherapy cancer patients. Isolating and understanding the cell cycle regulatory mechanisms of quiescent cancer cells will be a key component to creation of future therapies that better target CSCs and totally eradicate tumors. Here we review the evidence for quiescent CSC populations and explore potential cell cycle regulators that may serve as future targets for elimination of these cells.
Anti-Inflammatory Nutrition as a Pharmacological Approach to Treat Obesity
Authors: Sears Barry , Ricordi Camillo
Published: September 2010

Obesity is a multifactorial condition resulting from improper balances of hormones and gene expression induced by the diet. Obesity also has a strong inflammatory component that can be driven by diet-induced increases in arachidonic acid. The purpose of this paper is to discuss the molecular targets that can be addressed by anti-inflammatory nutrition. These molecular targets range from reduction of proinflammatory eicosanoids to the modulation of features of the innate immune system, such as toll-like receptors and gene transcription factors. From knowledge of the impact of these dietary nutrients on these various molecular targets, it becomes possible to develop a general outline of an anti-inflammatory diet that can offer a unique synergism with more traditional pharmacological approaches in treating obesity and its associated comorbidities.
The Effectiveness of Music in Pediatric Healthcare: A Systematic Review of Randomized Controlled Trials
Authors: Treurnicht Naylor Karline , Kingsnorth Shauna , Lamont Andrea , McKeever Patricia , Macarthur Colin
Published: September 2010

The aim of this study was to systematically review the effectiveness of music on pediatric health‐related outcomes. Five electronic databases were searched for randomized controlled/crossover trial designs published between 1984 and 2009. Eligible studies used music as a therapy or intervention, included participants 1 to 18 years, and focused on at least one health‐related outcome (with the exclusion of procedural pain). Seventeen studies met the inclusion criteria. Quantitative synthesis was hampered by an inability to aggregate data arising from heterogeneity of interventions, outcomes and measurement tools. Qualitative synthesis revealed significant improvements in one or more health outcomes within four of seven trials involving children with learning and developmental disorders; two of three trials involving children experiencing stressful life events; and four of five trials involving children with acute and/or chronic physical illness. No significant effects were found for two trials involving children with mood disorders and related psychopathology. These findings offer limited qualitative evidence to support the effectiveness of music on health‐related outcomes for children and adolescents with clinical diagnoses. Recommendations for establishing a consensus on research priorities and addressing methodological limitations are put forth to support the continued advancement of this popular intervention.
Microsurgical Anatomy of the Orbit: The Rule of Seven
Authors: Martins Carolina , Costa e Silva Isabel Eugênia , Campero Alvaro , Yasuda Alexandre , Aguiar Luiz Roberto , Tatagiba Marcos , Rhoton Albert
Published: September 2010

The orbits are paired structures, located on the anterior part of the face. Morphologically, each orbit is a four sided pyramid with a posterior apex and anterior base. In the orbit, all openings are arranged around the base, apex or between the orbital walls. An anatomical characteristic of the orbit is that structures are arranged in groups of seven: there are seven bones, seven intraorbital muscles and seven nerves in the orbit. Tumors confined within the periorbita in the anterior two thirds of the orbit can often be approached extracranially, but those located in the apical area, and especially those on the medial side of the optic nerve, often require a transcranial approach. Thus, knowledge of orbital osteology is paramount in adequately choosing and performing an orbital approach. Understanding the critical topographical elements in this area helps to classify an orbital lesion and provides for a solid basis in choosing the most adequate intraorbital route for its treatment.
Navigating the Human Metabolome for Biomarker Identification and Design of Pharmaceutical Molecules
Authors: Kouskoumvekaki Irene , Panagiotou Gianni
Published: September 2010

Metabolomics is a rapidly evolving discipline that involves the systematic study of endogenous small molecules that characterize the metabolic pathways of biological systems. The study of metabolism at a global level has the potential to contribute significantly to biomedical research, clinical medical practice, as well as drug discovery. In this paper, we present the most up‐to‐date metabolite and metabolic pathway resources, and we summarize the statistical, and machine‐learning tools used for the analysis of data from clinical metabolomics. Through specific applications on cancer, diabetes, neurological and other diseases, we demonstrate how these tools can facilitate diagnosis and identification of potential biomarkers for use within disease diagnosis. Additionally, we discuss the increasing importance of the integration of metabolomics data in drug discovery. On a case‐study based on the Human Metabolome Database (HMDB) and the Chinese Natural Product Database (CNPD), we demonstrate the close relatedness of the two data sets of compounds, and we further illustrate how structural similarity with human metabolites could assist in the design of novel pharmaceuticals and the elucidation of the molecular mechanisms of medicinal plants.
Acupuncture on the Endometrial Morphology, the Serum Estradiol and Progesterone Levels, and the Expression of Endometrial Leukaemia‐inhibitor Factor and Osteopontin in Rats
Authors: Fu Houju , He Yuanqiao , Gao Ying , Man Yicun , Liu Wukun , Hao Hua
Published: September 2010

Although it is well known that acupuncture has beneficial effects on a variety of medical conditions especially in pain relief, nausea, and vomiting, it remains controversial whether it has positive impact on the female reproduction. The present study aimed to evaluate whether the following endometrial receptivity factors: the endometrial morphology, the hormone concentrations, and the protein expression of endometrial leukaemia‐inhibitory factor (LIF) and osteopontin (OPN) could be improved by the acupuncture in clomiphene citrate(CC)‐induced rat model during implantation period. Results showed that, compared with the CC group, glandular development advanced, the serum estradiol levels decreased significantly, and the glandular area and endometrial LIF and OPN expression were significantly higher in acupuncture group. There were no significant differences in serum progesterone levels, endometrial thickness, and stromal area between groups. These results suggest that acupuncture can improve certain aspects of endometrial receptivity in CC‐induced rat model during implantation period, which might result in endometrial state better to female reproduction.
Recovery Effects of a 180 mT Static Magnetic Field on Bone Mineral Density of Osteoporotic Lumbar Vertebrae in Ovariectomized Rats
Authors: Xu Shenzhi , Okano Hideyuki , Tomita Naohide , Ikada Yoshito
Published: September 2010

The effects of a moderate‐intensity static magnetic field (SMF) on osteoporosis of the lumbar vertebrae were studied in ovariectomized rats. A small disc magnet (maximum magnetic flux density 180 mT) was implanted to the right side of spinous process of the third lumbar vertebra. Female rats in the growth stage (10 weeks old) were randomly divided into 4 groups: (i) ovariectomized and implanted with a disc magnet (SMF); (ii) ovariectomized and implanted with a nonmagnetized disc (sham); (iii) ovariectomized alone (OVX) and (vi) intact, nonoperated cage control (CTL). The blood serum 17‐β‐estradiol (E2) concentrations were measured by radioimmunoassay, and the bone mineral density (BMD) values of the femurs and the lumbar vertebrae were assessed by dual energy X‐ray absorptiometry. The E2 concentrations were statistically significantly lower for all three operated groups than those of the CTL group at the 6th week. Although there was no statistical significant difference in the E2 concentrations between the SMF‐exposed and sham‐exposed groups, the BMD values of the lumbar vertebrae proximal to the SMF‐exposed area statistically significantly increased in the SMF‐exposed group than in the sham‐exposed group. These results suggest that the SMF increased the BMD values of osteoporotic lumbar vertebrae in the ovariectomized rats.
Zinc Metalloproteinases and Amyloid Beta-Peptide Metabolism: The Positive Side of Proteolysis in Alzheimer's Disease
Authors: Gough Mallory , Parr-Sturgess Catherine , Parkin Edward
Published: September 2010

Alzheimer's disease is a neurodegenerative condition characterized by an accumulation of toxic amyloid beta- (A-)peptides in the brain causing progressive neuronal death. A-peptides are produced by aspartyl proteinase-mediated cleavage of the larger amyloid precursor protein (APP). In contrast to this detrimental “amyloidogenic” form of proteolysis, a range of zinc metalloproteinases can process APP via an alternative “nonamyloidogenic” pathway in which the protein is cleaved within its A region thereby precluding the formation of intact A-peptides. In addition, other members of the zinc metalloproteinase family can degrade preformed A-peptides. As such, the zinc metalloproteinases, collectively, are key to downregulating A generation and enhancing its degradation. It is the role of zinc metalloproteinases in this “positive side of proteolysis in Alzheimer's disease” that is discussed in the current paper.
Differences in Reef Fish Assemblages between Populated and Remote Reefs Spanning Multiple Archipelagos Across the Central and Western Pacific
Authors: Williams Ivor D. , Richards Benjamin L. , Sandin Stuart A. , Baum Julia K. , Schroeder Robert E. , Nadon Marc O. , Zgliczynski Brian , Craig Peter , McIlwain Jennifer L. , Brainard Russell E.
Published: September 2010

Comparable information on the status of natural resources across large geographic and human impact scales provides invaluable context to ecosystem-based management and insights into processes driving differences among areas. Data on fish assemblages at 39 US flag coral reef-areas distributed across the Pacific are presented. Total reef fish biomass varied by more than an order of magnitude: lowest at densely-populated islands and highest on reefs distant from human populations. Remote reefs (<50 people within 100 km) averaged ~4 times the biomass of “all fishes” and 15 times the biomass of piscivores compared to reefs near populated areas. Greatest within-archipelagic differences were found in Hawaiian and Mariana Archipelagos, where differences were consistent with, but likely not exclusively driven by, higher fishing pressure around populated areas. Results highlight the importance of the extremely remote reefs now contained within the system of Pacific Marine National Monuments as ecological reference areas.
Two Distinct Pathways to Development of Squamous Cell Carcinoma of the Vulva
Authors: Ueda Yutaka , Enomoto Takayuki , Kimura Toshihiro , Yoshino Kiyoshi , Fujita Masami , Kimura Tadashi
Published: September 2010

Squamous cell carcinoma (SCC) accounts for approximately 95% of the malignant tumors of the vaginal vulva and is mostly found in elderly women. The future numbers of patients with vulvar SCC is expected to rise, mainly because of the proportional increase in the average age of the general population. Two different pathways for vulvar SCC have been put forth. The first pathway is triggered by infection with a high-risk-type Human Papillomavirus (HPV). Integration of the HPV DNA into the host genome leads to the development of a typical vulvar intraepithelial neoplasia (VIN), accompanied with overexpression of and . This lesion subsequently forms a warty- or basaloid-type SCC. The HPV vaccine is a promising new tool for prevention of this HPV related SCC of the vulva. The second pathway is HPV-independent. Keratinizing SCC develops within a background of lichen sclerosus (LS) through a differentiated VIN. It has a different set of genetic alterations than those in the first pathway, including p53 mutations, allelic imbalances (AI), and microsatellite instability (MSI). Further clinical and basic research is still required to understand and prevent vulvar SCC.Capsule. Two pathway for pathogenesis of squamous cell carcinoma of the value are reviewed.
Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment
Authors: Ragusa Marco , Majorana Alessandra , Statello Luisa , Maugeri Marco , Salito Loredana , Barbagallo Davide , Guglielmino Maria Rosa , Duro Laura R. , Angelica Rosario , Caltabiano Rosario , Biondi Antonio , Di Vita Maria , Privitera Giuseppe , Scalia Marina , Cappellani Alessandro , Vasquez Enrico , Lanzafame Salvatore , Basile Francesco , Di Pietro Cinzia , Purrello Michele
Published: September 2010

The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P < 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras–mutated samples with respect to wild-type ones (Wilcoxon test, P < 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response. Mol Cancer Ther; 9(12); 3396–409. © 2010 AACR.
The Synthetic Caged Garcinia Xanthone Cluvenone Induces Cell Stress and Apoptosis and Has Immune Modulatory Activity
Authors: Batova Ayse , Altomare Diego , Chantarasriwong Oraphin , Ohlsen Kari L. , Creek Kim E. , Lin You-Chin , Messersmith Amy , Yu Alice L. , Yu John , Theodorakis Emmanuel A.
Published: September 2010

Several caged Garcinia xanthone natural products have potent bioactivity and a documented value in traditional Eastern medicine. Previous synthesis and structure activity relationship studies of these natural products resulted in the identification of the pharmacophore represented by the structure of cluvenone. In the current study, we examined the anticancer activity of cluvenone and conducted gene expression profiling and pathway analyses. Cluvenone was found to induce apoptosis in T-cell acute lymphoblastic leukemia cells (EC50 = 0.25 μmol/L) and had potent growth-inhibitory activity against the NCI60 cell panel, including those that are multidrug-resistant, with a GI50 range of 0.1 to 2.7 μmol/L. Importantly, cluvenone was approximately 5-fold more potent against a primary B-cell acute lymphoblastic leukemia compared with peripheral blood mononuclear cells from normal donors, suggesting that it has significant tumor selectivity. Comparison of cluvenone's growth-inhibitory profile to those in the National Cancer Institute database revealed that compounds with a similar profile to cluvenone were mechanistically unlike known agents, but were associated with cell stress and survival signaling. Gene expression profiling studies determined that cluvenone induced the activation of mitogen-activated protein kinase and NrF2 stress response pathways. Furthermore, cluvenone was found to induce intracellular reactive oxygen species formation. Lastly, the modulation in the expression of several genes associated with T cell and natural killer cell activation and function by cluvenone suggests a role as an immune-modulator. The current work highlights the potential of cluvenone as a chemotherapeutic agent and provides support for further investigation of these intriguing molecules with regard to mechanism and targets. Mol Cancer Ther; 9(11); 2869–78. ©2010 AACR.
Cyclin G–Associated Kinase Is Necessary for Osteosarcoma Cell Proliferation and Receptor Trafficking
Authors: Susa Michiro , Choy Edwin , Liu Xianzhe , Schwab Joseph , Hornicek Francis J. , Mankin Henry , Duan Zhenfeng
Published: September 2010

Osteosarcoma is the most frequent primary malignant bone tumor among the children. The advent of neoadjuvant chemotherapy significantly improved the prognosis of patients with osteosarcoma in the 1980s, but it has since plateaued in the past decades. Recently, one of the most researched areas in sarcoma treatment is tyrosine kinases. Here, we describe research on a serine/threonine kinase, cyclin G–associated kinase (GAK), which has not been reported in osteosarcoma previously. In this study, a lentiviral based human shRNA library was utilized to screen for kinases in KHOS and U-2OS osteosarcoma cells. The expression of GAK was examined in osteosarcoma and the effect on cell proliferation was analyzed by GAK siRNA knockdown. The level of GAK expression and its correlation to prognosis was analyzed in osteosarcoma tissue microarray. The effect of GAK depletion on insulin-like growth factor and epidermal growth factor receptor–mediated signal transduction was analyzed by Western blot. We observed that GAK was overexpressed in both osteosarcoma cell lines and tissue samples when compared with human osteoblasts. GAK knockdown by siRNA decreased cell proliferation in both drug-sensitive and multidrug-resistant osteosarcoma cell lines. Immunohistochemistry of osteosarcoma tissue microarray revealed that overexpression of GAK was associated with poor prognosis. Finally, knockdown of GAK resulted in alterations of receptor trafficking and several downstream proteins. In conclusion, our results suggest that osteosarcoma cell proliferation and survival are dependent on GAK. These findings may lead to the development of new therapeutic options for osteosarcoma. Mol Cancer Ther; 9(12); 3342–50. ©2010 AACR.
TROY (TNFRSF19) Is Overexpressed in Advanced Glial Tumors and Promotes Glioblastoma Cell Invasion via Pyk2-Rac1 Signaling
Authors: Paulino Vincent M. , Yang Zhongbo , Kloss Jean , Ennis Matthew J. , Armstrong Brock A. , Loftus Joseph C. , Tran Nhan L.
Published: September 2010

A critical problem in the treatment of malignant gliomas is the extensive infiltration of individual tumor cells into adjacent brain tissues. This invasive phenotype severely limits all current therapies, and to date, no treatment is available to control the spread of this disease. Members of the tumor necrosis factor (TNF) ligand superfamily and their cognate receptors regulate various cellular responses including proliferation, migration, differentiation, and apoptosis. Specifically, the TNFRSF19/TROY gene encodes a type I cell surface receptor that is expressed on migrating or proliferating progenitor cells of the hippocampus, thalamus, and cerebral cortex. Here, we show that levels of TROY mRNA expression directly correlate with increasing glial tumor grade. Among malignant gliomas, TROY expression correlates inversely with overall patient survival. In addition, we show that TROY overexpression in glioma cells activates Rac1 signaling in a Pyk2-dependent manner to drive glioma cell invasion and migration. Pyk2 coimmunoprecipitates with the TROY receptor, and depletion of Pyk2 expression by short hairpin RNA interference oligonucleotides inhibits TROY-induced Rac1 activation and subsequent cellular migration. These findings position aberrant expression and/or signaling by TROY as a contributor, and possibly as a driver, of the malignant dispersion of glioma cells. Mol Cancer Res; 8(11); 1558–67. ©2010 AACR.
Progenitor Radial Cells and Neurogenesis in Pejerrey Fish Forebrain
Authors: Strobl-Mazzulla Pablo H. , Nuñez Analía , Pellegrini Elisabeth , Gueguen Marie-Madeleine , Kah Olivier , Somoza Gustavo M.
Published: September 2010

The central nervous system of adult teleost fish is peculiar because of the following features: (1) the persistence of radial glial cells, (2) an important neurogenic activity and (3) a high aromatase expression by radial cells. In this study, the proliferative zones of the forebrain were described using bromodeoxyuridine (BrdU) treatment in the brain of the pejerrey, an Acanthopterygian teleost fish. These cells were shown to have morphological and immunoreactive characteristics of radial cells and to express aromatase. Three different progenitor populations were identified based on the mobility and proliferation capacity 6 weeks after BrdU treatment: transit amplifying progenitors, slowly proliferating stem cells, and cells remaining in the proliferative zones showing no signs of mitotic activity. The proliferative cells were always located in the ventricular zone and were never observed in the brain parenchyma; however, 3 weeks later they were found away from these proliferative zones and displayed acetylated tubulin immunoreactivity. Other BrdU-positive cells showed astrocyte morphology and were immunoreactive to the S100 glial marker. These results show that in this fish, radial cells are true progenitors generating neurons and possibly astrocytes.
Central Projections of Primary Sensory Afferents to the Spinal Dorsal Horn in the Long-Tailed Stingray, Himantura fai
Authors: Kitchener Peter D. , Fuller Jack , Snow Peter J.
Published: September 2010

The central projections of primary sensory afferents innervating the caudal region of the pectoral fin of the long-tailed stingray (Himantura fai) were labeled by applying the lipophilic carbocyanine dye DiI to the dorsal roots in fixed tissue. These observations were complemented by examination of hemotoxylin and eosin-stained paraffin sections of the dorsal root entry zone, and transmission electron microscopy of the dorsal horn. Transverse sections of the sensory nerve and dorsal root revealed two distinct myelinated axon sizes in the sensory nerve. Although the thick and thin axons do not appear to group together in the sensory nerves and dorsal root, they segregate into a dorsally directed bundle of thin fibers and a more horizontally directed bundle of thick fibers soon after entering the spinal cord. In DiI-labeled horizontal sections, fibers were observed to enter the spinal cord and diverge into rostrally and caudally directed trajectories. Branching varicose axons could be traced in the dorsal horn gray matter in the segment of entry and about half of the adjacent rostral and caudal segments. In transverse and sagittal sections, DiI-labeled afferents were seen to innervate the superficial and, to a lesser extent, deeper laminae of the dorsal horn, but not the ventral horn. Electron microscopy of unlabeled dorsal horn sections revealed a variety of synaptic morphologies including large presynaptic elements (some containing dense-core vesicles) making synaptic contacts with multiple processes in a glomerular arrangement; in this respect, the synaptic ultrastructure is broadly similar to that seen in the dorsal horn of rodents and other mammals.
The Organization of CRF Neuronal Pathways in Toads: Evidence that Retinal Afferents Do Not Contribute Significantly to Tectal CRF Content
Authors: Carr James A. , Lustgarten Jacob , Ahmed Nafisa , Bergfeld Nicholas , Bulin Sarah E. , Shoukfeh Omar , Tripathy Shreejoy
Published: September 2010

Previous work has suggested that the peptide corticotropin-releasing factor (CRF) acts to inhibit visually guided feeding in anurans, but little is known about potential targets for CRF within the subcortical visuomotor circuitry. Here we investigated the relationship between CRF neuronal organization and visual pathways in toads. CRF-immunoreactive (ir) neurons and fibers were widely distributed throughout the ventral subpallial telencephalon and hypothalamus, although few fibers were found in telencephalic areas, such as the striatum, that are known to project to the tectum in anurans. Large populations of CRF-ir cells were observed in the bed nucleus of the stria terminalis and preoptic area as well as in the ventral infundibular hypothalamus. CRF-ir neurons and fibers also were observed in several midbrain and brain stem areas. Colchicine treatment significantly enhanced CRF-ir neurons and fibers throughout the brain, and revealed CRF-ir cell groups in several brain areas (including the dorsal hypothalamus) that were not observed in untreated animals. Intrinsic CRF-immunoreactive neurons were routinely observed in cell layer 8 and sometimes in layer 6 of the optic tectum in both untreated and colchicine-treated animals. CRF was detected in toad optic tectum by radioimmunoassay, although tectal CRF content was less than that of the hypothalamus and forebrain. Unilateral eye ablation did not affect CRF content of the contralateral optic tectum. We conclude that CRF-producing neurons are widely distributed in several areas of the toad brain known to be involved in regulating the behavioral, autonomic and endocrine response to stressors, including the optic tectum and several brain areas known to project to the optic tectum. Furthermore, retinal afferents do not contribute significantly to tectal CRF content.
D-Dimer Levels in Combination with Clinical Risk Factors Can Effectively Predict Subsequent Thromboembolic Events in Patients with Atrial Fibrillation during Oral Anticoagulant Therapy
Authors: Sadanaga Tsuneaki , Kohsaka Shun , Ogawa Satoshi
Published: September 2010

Objectives: Atrial fibrillation (AF) is associated with hemostatic abnormality and increased risk of thromboembolic events. The aim of the present study was to evaluate whether elevated D-dimer levels in combination with clinical risk factors can adequately predict subsequent thromboembolic events in patients with AF. Method: This was a post hoc analysis of the single-center, prospective observational study. Consecutive patients with nonvalvular AF (245 patients, 74 ± 9 years) treated with warfarin were included. D-dimer levels were measured in combination with clinical risk factors to assess the relationship of this parameter with subsequent thromboembolic events. Results:D-dimer levels were elevated (≧0.5 µg/ml) in 55 (22%) patients. During an average follow-up time of 756 ± 223 days, 9 (1.8%/year) thromboembolic events occurred. Cox proportional hazard analysis showed that elevated D-dimer levels (hazard ratio, HR, 14.3, p < 0.01) as well as high CHADS2 score (≧3; HR 9.43, p < 0.01) was associated with thromboembolic events. C-statistic improved to 0.848 from 0.781 when D-dimer level was added to the predictor model based on CHADS2 score. Elevated D-dimer levels also predicted thromboembolic events in the subgroup of patients with high CHADS2 score (n = 76, HR 12.1, p = 0.021). Conclusion: CHADS2 scores and D-dimer level can be a useful marker of subsequent thromboembolic events in patients with AF during oral anticoagulant therapy and combination of these can effectively predict thromboembolic events.
Cellular Scaling Rules for the Brains of an Extended Number of Primate Species
Authors: Gabi Mariana , Collins Christine E. , Wong Peiyan , Torres Laila B. , Kaas Jon H. , Herculano-Houzel Suzana
Published: September 2010

What are the rules relating the size of the brain and its structures to the number of cells that compose them and their average sizes? We have shown previously that the cerebral cortex, cerebellum and the remaining brain structures increase in size as a linear function of their numbers of neurons and non-neuronal cells across 6 species of primates. Here we describe that the cellular composition of the same brain structures of 5 other primate species, as well as humans, conform to the scaling rules identified previously, and that the updated power functions for the extended sample are similar to those determined earlier. Accounting for phylogenetic relatedness in the combined dataset does not affect the scaling slopes that apply to the cerebral cortex and cerebellum, but alters the slope for the remaining brain structures to a value that is similar to that observed in rodents, which raises the possibility that the neuronal scaling rules for these structures are shared among rodents and primates. The conformity of the new set of primate species to the previous rules strongly suggests that the cellular scaling rules we have identified apply to primates in general, including humans, and not only to particular subgroups of primate species. In contrast, the allometric rules relating body and brain size are highly sensitive to the particular species sampled, suggesting that brain size is neither determined by body size nor together with it, but is rather only loosely correlated with body size.
Chemokines in Inflammatory Bowel Diseases
Authors: Atreya Raja , Neurath M.F.
Published: September 2010

Uncontrolled activation of mucosal effector cells has been identified as the main pathogenic mechanism involved in the initiation and perpetuation of mucosal inflammation in inflammatory bowel diseases (IBD). The sustained activation of these cells leads to the aberrant production of various pro-inflammatory mediators, which co-ordinated action amplifies the inflammatory process. In this setting a network of tissue-specific chemoattractant cytokines (chemokines) and their corresponding receptors have been implicated as main contributors in the initiation and perpetuation of the inflammatory reaction in IBD. They are produced by a variety of inflammatory cells present in IBD lesions, as well as endothelial and epithelial cells. Chemokines not only control the multistep process of leukocyte adhesion to and migration across the endothelium, but also the release of lipid mediators and oxygen radicals from leukocytes, the modulation of tumorigenesis, release of matrix metalloproteinases and tissue fibrosis. Numerous data indicate that that intestinal chemokine expression is non-selectively up-regulated in IBD and correlates with disease activity. The development of selective inhibitors for chemokines or chemokine receptors, based on a more complete understanding of the immunopathogenic role of chemokines in intestinal inflammation, will be of great interest as potential novel therapeutic strategies in IBD.
New Serologic Markers for Inflammatory Bowel Disease Diagnosis
Authors: Dotan Iris
Published: September 2010

Inflammatory bowel diseases (IBD) are chronic intestinal disorders where, in genetically susceptible hosts, an intestinal microorganism triggers an over-reactive immune response. Antibodies against luminal antigens are specifically associated with Crohn’s disease (CD). In addition to the previously described antibodies antineutrophil cytoplasmic (auto)antibodies (ANCA), anti-Saccharomyces cerevisiae antibodies (ASCA), OmpC, I2 and CBir1 Flagellin, new anti-glycan antibodies were recently added to the armamentarium of serologic markers in IBD. Glycans are sugars associated with proteins, abundant on many living cells. The anti-glycan antibodies are directed against laminaribioside, chitobioside, mannobioside and mannan residues and are designated anti-laminaribioside carbohydrate antibodies (ALCA), anti-chitobioside carbohydrate antibodies (ACCA), anti-mannobioside carbohydrate antibodies (AMCA) and gASCA, respectively. Anti-laminarin IgA (Anti-L), and anti-chitin IgA (Anti-C) are new members of this family. Laminarin and chitobioside are capable of stimulating the innate immune system, thus the finding of antibodies against these glycans suggests a connection between the adaptive and innate arms of the immune response in CD patients. The contribution of serologic markers, specifically the anti-glycan antibodies, to IBD diagnosis may be in differentiating IBD from other gastrointestinal diseases, and between CD and ulcerative colitis (UC), in better classifying undetermined colitis and for decision-making prior to proctocolectmy in UC patients. The anti-glycan antibodies are specifically important in ASCA-negative CD patients. Correlation between serologic markers and genetic variations may contribute to reclassifying IBD into new and more homogeneous subclasses. Their significance in diagnosing populations at risk, such as unaffected relatives of IBD patients and CD patients prior to diagnosis, is under current investigation.
Can Serologic Markers Help Determine Prognosis and Guide Therapy?
Authors: Dubinsky Marla
Published: September 2010

The search for biologic markers that can assess the natural history and perhaps predict the course of an individual’s disease – including response to treatments over time – has become an important focus of inflammatory bowel disease research. The knowledge of an individual’s prognosis can help physicians and patients make important management decisions and aid communication on risks and benefits of disease and treatment.
CT Enterography: Is It the Current State-of-the-Art for Small Bowel Diagnostics?
Authors: Bruining David H.
Published: September 2010

CT enterography has rapidly emerged as the preferred small bowel imaging modality at several tertiary care medical centers. It utilizes negative or neutral oral contrast agents to enhance small bowel mural assessments. A high sensitivity and specificity for active inflammation and its ability to detect extra-intestinal disease set CT enterography apart from more traditional imaging methods. It has also been shown to be of great value for the detection of occult penetrating disease, changing physician level of confidence, and altering management plans in a large proportion of patients. Concerns regarding radiation exposure will likely become less of an issue with new dose reduction techniques. CT enterography has begun to revolutionize Crohn’s disease evaluations for luminal and extraluminal disease, and its role will likely continue to expand in diagnostic and management algorithms.
Does Treatment Schedule Matter? Once Daily versus Divided Doses of 5-ASAs
Authors: Kane Sunanda
Published: September 2010

Sulfasalazine was the first 5-ASA used to treat ulcerative colitis (UC). Because of tolerability issues, it was administered in a three times a day schedule in order to try to minimize side effects. With the development of sulfa-free 5-ASA products, the controlled trials used historical clinical experience and in vitro pharmacokinetic studies to dose their therapies to perhaps be in the most favorable light possible. However, it became clear over the years that outside of the context of a clinical trial, t.i.d. or even q.i.d. dosing led to lower patient satisfaction and overall adherence. Research demonstrated that upwards of 40% of patients were not taking their maintenance 5-ASA, and many patients cited unintentional forgetfulness as the reason. It became clear that simplifying the regimen was paramount for acceptable outcomes. Early pilot data and then controlled trials demonstrated the efficacy and safety of twice daily 5-ASA for active and quiescent UC. Now several large controlled trials demonstrate the non-inferiority and increased patient adherence and satisfaction with once daily dosing. MMX mesalamine was the first 5-ASA to receive US FDA approval in a once daily regimen. Results from the PODIUM and QDIEM trials have demonstrated acceptable effectiveness rates with favorable side effect profiles. Adherence rates remain high in real-world settings when medication is given once daily and data now suggest that once daily may be more effective than more frequently. It thus appears that the majority of patients with UC, whether with active or quiescent disease, can be treated with once daily 5-ASA.
The Role of Biologics in Ulcerative Colitis
Authors: Hanauer Stephen B.
Published: September 2010

Since the introduction of anti-TNF agents for the treatment of Crohn’s disease there has been interest in the potential for treating ulcerative colitis with biological therapies. Early observational series suggested a benefit in the setting of severe, hospitalized patients. However, the recent completion of two large multi-center, double-blind placebo-controlled trials confirmed a role for infliximab for outpatients with refractory, moderate-severe disease with evidence for clinical remissions, mucosal healing, and a reduction in colectomies. Despite this evidence, there are numerous questions remaining regarding the optimal positioning in the setting of moderate-severe disease, potential benefits of concomitant immune suppression and the need for maintenance treatment after induction therapy. Additional clinical trials have demonstrated a less profound benefit for adalimumab at similar doses that are used in Crohn’s disease. Other biological agents that have targeted T cells such as visiluzimab and abatacept were not demonstrated to be effective in controlled trials.
What Options Do We Have for Induction Therapy for Crohn’s Disease?
Authors: Siegel Corey A.
Published: September 2010

The first goal of Crohn’s disease treatment is to induce a response. The choice of induction therapy depends on a number of factors. First, disease severity will dictate the level of intensity of treatment. Moderate to severely active Crohn’s disease needs to be treated more aggressively than mild disease. Second, it is important to consider the disease distribution, since some medications (e.g. 5-aminosalicylates, budesonide, antibiotics) are more effectively delivered to the small bowel or the colon. Third, prior medications need to be considered. A patient naïve to immunomodulators and anti-TNF agents will be managed very differently from a patient who has already failed two anti-TNF drugs. A fourth critical factor is considering the individual patient. The balance of benefits and risks will depend upon the patient’s expected disease course, and how much risk they are at personally for serious adverse events related to treatment. In addition, patients’ preferences for treatment need to be addressed since they will choose therapies differently based on their personal experience with symptoms, thresholds for risk taking, and fears about their disease and treatment. The basic armamentarium for induction therapy for Crohn’s disease includes: 5-aminosalicylates, antibiotics, budesonide, systemic corticosteroids, thiopurines, methotrexate, and anti-TNF agents. These drugs can be used alone or combined in difference treatment algorithms to optimize therapy. The art of treating the IBD patient is in understanding the options and being able to apply an individualized regimen based upon unique patient and disease factors.
Fistula Treatment: The Unresolved Challenge
Authors: Vavricka Stephan R. , Rogler Gerhard
Published: September 2010

In population-based studies, up to 50% of patients with Crohn’s disease suffer from fistulas. Fistulas pose a considerable morbidity including permanent sphincter and perineal tissue destruction as well as professional and personal disabilities. Treatment options have progressed in recent years and fistula closure and fibrosis of the fistula track is achieved in some patients. Depending on severity of symptoms and fistula location, different medical and surgical therapies can be chosen. Internal fistulas such as ileoileal or ileocecal fistulas are either asymptomatic and do not require intervention or they are symptomatic and need surgery alone. They always carry a risk of abscess formation. Symptomatic perianal fistulizing disease can be treated with antibiotics (i.e. metronidazole and ciprofloxacin) for three months and/or immunosuppressant therapy (6-mercaptopurine or azathioprine). More complex cases require therapy with anti-TNF agents. Only few and preliminary data exist on cyclosporine A, tacrolimus or methotrexate in fistulizing Crohn’s disease. Therefore, these therapies should mainly be used as second-line therapies. Surgery is reserved for the treatment of perianal sepsis in the presence of abscesses and refractory disease or complications of fistulas, or used in combination with pharmacological approaches. The surgical interventions in perianal disease consist of surgical drainage with or without seton placement, transient ileostomy, or in severe cases, proctectomy. The classification of fistulas in patients with Crohn’s disease remains poorly defined and largely investigator dependent. The unresolved challenges in fistula treatment warrant randomized controlled trials for existing and future treatment strategies as well as a better classification system to compare available studies.
Diffusion Tensor Imaging Changes Correlate with Cognition Better than Conventional MRI Findings in Patients with Subcortical Ischemic Vascular Disease
Authors: Xu Qun , Zhou Yan , Li Yan-Sheng , Cao Wen-Wei , Lin Yan , Pan Yuan-Mei , Chen Sheng-Di
Published: September 2010

Background/Aims: To investigate whether diffusion tensor imaging (DTI) is more sensitive than conventional MRI at detecting cognitive deterioration in patients with subcortical ischemic vascular disease (SIVD). Methods: Forty-two SIVD patients had a diagnosis of no cognitive impairment (NCI), vascular cognitive impairment/no dementia or vascular dementia (VaD). Whole-brain DTI histography and routine MRI were performed on these participants. Results: There were significant differences between cognitively impaired patients and NCI subjects in mean diffusivity and fractional anisotropy in either whole-brain white matter (WBWM) or in normal-appearing white matter (NAWM). All DTI indices within either WBWM or NAWM were found to be significantly correlated with both the attention-executive and memory measures in SIVD subjects. Lacune numbers and T2-weighted lesions correlated only with attention-executive measures, whereas hippocampal volumes correlated only weakly with memory measures. Whole-brain gray matter volumes correlated with Z scores for all cognitive domains but language. After VaD patients had been excluded from the analysis, cognitive measures remained significantly correlated with some of the DTI indices, but not with conventional MRI findings. Conclusions: Compared with conventional MRI, whole-brain DTI is a more reliable and sensitive technique for the early detection of cognitive impairment in SIVD patients.
Right Ventricular Dysfunction in Patients with End-Stage Renal Disease
Authors: Paneni Francesco , Gregori Mario , Ciavarella Giuseppino Massimo , Sciarretta Sebastiano , De Biase Luciano , Marino Laura , Tocci Giuliano , Principe Francesco , Domenici Alessandro , Luciani Remo , Punzo Giorgio , Menè Paolo , Volpe Massimo
Published: September 2010

Background: While chronic dialysis treatment has been suggested to increase pulmonary pressure values, right ventricular dysfunction (RVD) is a major cause of death in patients with end-stage renal disease. We investigated the impact of different dialysis treatments on right ventricular function. Methods: We examined 220 subjects grouped as follows: healthy controls (n = 100), peritoneal dialysis (PD; n = 26), hemodialysis (HD) with radial arteriovenous fistula (AVF; n = 62), and HD with brachial AVF (n = 32). Echocardiography including tissue Doppler imaging (TDI) of the right ventricle was performed in all patients. Results: Pulmonary pressure values progressively rose from controls across the 3 dialysis groups (21.7 ± 6.8, 29.7 ± 6.7, 37.9 ± 6.7 and 40.8 ± 6.6 mm Hg, respectively; p < 0.001). TDI indices of right ventricular function were more impaired in HD patients, particularly in those with brachial AVF. RVD, assessed by TDI myocardial performance index, was higher in HD patients compared with PD patients (71.3 vs. 34.6%, p < 0.001). Moreover, the prevalence of RVD further increased in patients with brachial AVF compared with the radial access (90.6 vs. 61.3%, p < 0.001). Conclusions: Compared to DP, HD increases the risk of RVD, particularly in the presence of brachial AVF. TDI may detect early functional failure of the right ventricle in HD patients.
Revisiting the Party Paradox of Finance Capitalism: Social Democratic Preferences and Corporate Governance Reforms in Switzerland, Sweden, and the Netherlands
Authors: Schnyder Gerhard
Published: September 2010

The “party paradox” thesis claims that in the context of the legal corporate governance reforms of the 1990s, which aimed at adjusting national corporate governance systems to the “finance capitalism” of the Anglo-American type, center-left parties promoted proshareholder corporate governance reforms, whereas center-right parties opposed such reforms. Based on case studies of Switzerland, Sweden, and the Netherlands, this article shows that this thesis does not apply to two of these cases: In Sweden and the Netherlands a broad coalition uniting center-right and center-left parties opposed— with considerable success—proshareholder reforms. Therefore, the author argues that firm-level explanations of the “party paradox” are insufficient to understand the variance in center-left preferences across different cases. Instead, the historical role of labor in different countries is critical in the formation of center-left preferences. Where labor was not excluded from the formation of corporate governance structures, center-left support for proshareholder reform was weak.