Distribution by Scientific Domains
Distribution within Medical Sciences

Kinds of Diseases.

  • autoimmune diseases.
  • liver diseases.
  • neurodegenerative diseases.

  • Selected Abstracts

    Increased immature hematopoietic progenitor cells CD34+/CD38dim in myelodysplasia

    CYTOMETRY, Issue 2 2006
    Mariela B. Monreal
    Abstract Background Myelodysplastic syndromes (MDS) are clonal disorders affecting hematopoietic progenitor cells (HPC). Despite the relevance of clonal CD34+ cells in developing MDS, only few studies analyze the phenotype of this cell population. The aim of this study was to evaluate phenotypic changes on HPC in MDS that could reflect abnormalities in the differentiation process of stem cells. Methods We analyzed the expression of CD38 and HLA-DR on CD34+ cells by flow cytometry in 36 patients with MDS, as well as in healthy donors (n = 12) and patients with other hematological disorders: non-Hodgkin lymphomas and multiple myeloma, both in complete remission (CR) (n = 32); acute lymphoblastic leukemia in CR (n = 17); de novo acute myeloblastic leukemia (AML) at diagnosis (n = 22) and in CR (n = 37); and AML secondary to MDS at diagnosis (n = 19). Cases with available karyotype were grouped according to the International Prognostic Scoring System (IPSS). Results Compared to normal BM, the fraction of immature HPC, characterized as CD34+bright, intermediate FSC/SSC, and CD38dim, was significantly increased in high risk MDS and secondary AML, but not in low risk MDS, (P , 0.001, P = 0.03, and P = 0.7). De novo AML showed decreased immature HPC. High numbers of immature HPC correlated with higher IPSS risk groups (P = 0.05) and showed significant impact on disease progression (P = 0.03). Conclusion Our study confirms that evaluation of CD38 expression pattern on HPC is an easy and reproducible test that allows evaluating the immature subset of progenitor cells. Increased immature HPC in high risk MDS and secondary AML may reflect blocked differentiation of CD34+ cells in these diseases. © 2006 International Society for Analytical Cytology [source]

    ,-synuclein has a dynamic intracellular localization

    CYTOSKELETON, Issue 8 2006
    Irina Surgucheva
    Abstract ,-Synuclein is a member of the synuclein family consisting of three proteins. Within the last several years increasing attention has focused on these proteins because of their role in human diseases. ,-Synuclein relevance to Parkinson's disease is based on mutations found in familial cases of the disease and its presence in filaments and inclusion bodies in sporadic cases. ,-Synuclein is implicated in some forms of cancer and ocular diseases, while ,-synuclein may antagonize their pathological functions. In this paper we present data on the localization and properties of ,-synuclein in several neuronal and nonneuronal cell cultures. We show that contrary to the current opinion, ,-synuclein is not an exclusively cytoplasmic protein, but has a dynamic localization and can associate with subcellular structures. It is present in the perinuclear area and may be associated to centrosomes. On late steps of mitosis ,-synuclein is not found in the centrosomes, and redistributes to the midbody in telophase. Under stress conditions a translocation of ,-synuclein from the perinuclear area to the nucleus occurs exhibiting nucleocytoplasmic shuttling. ,-Synuclein overexpression reduces neurite outgrowth in a greater extent then ,-synuclein overexpression. These data support the view that ,-synuclein may change its intracellular localization and associate with subcellular structures in response to intracellular signaling or stress. Cell Motil. Cytoskeleton 2006. © 2006 Wiley-Liss, Inc. [source]

    Use of longitudinal data in genetic studies in the genome-wide association studies era: summary of Group 14

    Berit Kerner
    Abstract Participants analyzed actual and simulated longitudinal data from the Framingham Heart Study for various metabolic and cardiovascular traits. The genetic information incorporated into these investigations ranged from selected single-nucleotide polymorphisms to genome-wide association arrays. Genotypes were incorporated using a broad range of methodological approaches including conditional logistic regression, linear mixed models, generalized estimating equations, linear growth curve estimation, growth modeling, growth mixture modeling, population attributable risk fraction based on survival functions under the proportional hazards models, and multivariate adaptive splines for the analysis of longitudinal data. The specific scientific questions addressed by these different approaches also varied, ranging from a more precise definition of the phenotype, bias reduction in control selection, estimation of effect sizes and genotype associated risk, to direct incorporation of genetic data into longitudinal modeling approaches and the exploration of population heterogeneity with regard to longitudinal trajectories. The group reached several overall conclusions: (1) The additional information provided by longitudinal data may be useful in genetic analyses. (2) The precision of the phenotype definition as well as control selection in nested designs may be improved, especially if traits demonstrate a trend over time or have strong age-of-onset effects. (3) Analyzing genetic data stratified for high-risk subgroups defined by a unique development over time could be useful for the detection of rare mutations in common multifactorial diseases. (4) Estimation of the population impact of genomic risk variants could be more precise. The challenges and computational complexity demanded by genome-wide single-nucleotide polymorphism data were also discussed. Genet. Epidemiol. 33 (Suppl. 1):S93,S98, 2009. © 2009 Wiley-Liss, Inc. [source]

    Activation of PPAR-, and PTEN cascade participates in lovastatin-mediated accelerated differentiation of oligodendrocyte progenitor cells

    GLIA, Issue 14 2010
    Ajaib S. Paintlia
    Abstract Previously, we and others documented that statins including-lovastatin (LOV) promote the differentiation of oligodendrocyte progenitor cells (OPCs) and remyelination in experimental autoimmune encephalomyelitis (EAE), an multiple sclerosis (MS) model. Conversely, some recent studies demonstrated that statins negatively influence oligodendrocyte (OL) differentiation in vitro and remyelination in a cuprizone-CNS demyelinating model. Therefore, herein, we first investigated the cause of impaired differentiation of OLs by statins in vitro settings. Our observations indicated that the depletion of cholesterol was detrimental to LOV treated OPCs under cholesterol/serum-deprived culture conditions similar to that were used in conflicting studies. However, the depletion of geranylgeranyl-pp under normal cholesterol homeostasis conditions enhanced the phenotypic commitment and differentiation of LOV-treated OPCs ascribed to inhibition of RhoA-Rho kinase. Interestingly, this effect of LOV was associated with increased activation and expression of both PPAR-, and PTEN in OPCs as confirmed by various pharmacological and molecular based approaches. Furthermore, PTEN was involved in an inhibition of OPCs proliferation via PI3K-Akt inhibition and induction of cell cycle arrest at G1 phase, but without affecting their cell survival. These effects of LOV on OPCs in vitro were absent in the CNS of normal rats chronically treated with LOV concentrations used in EAE indicating that PPAR-, induction in normal brain may be tightly regulated-providing evidences that statins are therapeutically safe for humans. Collectively, these data provide initial evidence that statin-mediated activation of the PPAR-,-PTEN cascade participates in OL differentiation, thus suggesting new therapeutic-interventions for MS or related CNS-demyelinating diseases. © 2010 Wiley-Liss, Inc. [source]

    Anandamide enhances IL-10 production in activated microglia by targeting CB2 receptors: Roles of ERK1/2, JNK, and NF-,B

    GLIA, Issue 2 2010
    Fernando Correa
    Abstract The endocannabinoid system exhibits anti-inflammatory properties by regulating cytokine production. Anandamide (AEA) down-regulates proinflammatory cytokines in a viral model of multiple sclerosis (MS). However, little is known about the mechanisms by which AEA exerts these effects. Microglial cells are the main source of cytokines within the brain and the first barrier of defense against pathogens by acting as antigen presenting cells. IL-10 is a key physiological negative regulator of microglial activation. In this study we show that AEA enhances LPS/IFN,-induced IL-10 production in microglia by targeting CB2 receptors through the activation of ERK1/2 and JNK MAPKs. AEA also inhibits NF-,B activation by interfering with the phosphorylation of I,B,, which may result in an increase of IL-10 production. Moreover, endogenously produced IL-10 negatively regulates IL-12 and IL-23 cytokines, which in its turn modify the pattern of expression of transcription factorsinvolved in Th commitment of splenocytes. This suggeststhat by altering the cytokine network, AEA could indirectly modify the type of immune responses within the central nervous system (CNS). Accordingly, pharmacological modulation of AEA uptake and degradation might be a useful tool for treating neuroinflammatory diseases. © 2009 Wiley-Liss, Inc. [source]

    Oxidized low-density lipoprotein induces matrix metalloproteinase-9 expression via a p42/p44 and JNK-dependent AP-1 pathway in brain astrocytes

    GLIA, Issue 1 2009
    Hui-Hsin Wang
    Abstract Upregulation of matrix metalloproteinases (MMPs), especially MMP-9, by oxidized low-density lipoprotein (oxLDL) is implicated in many inflammatory diseases including brain injury. However, the signaling mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes largely remain unknown. Here we report that oxLDL induces expression of proMMP-9 via a MAPK-dependent AP-1 activation in rat brain astrocyte (RBA)-1 cells. Results revealed by gelatin zymography, RT-PCR, and Western blotting analyses showed that oxLDL-induced proMMP-9 gene expression was mediated through Akt, JNK1/2, and p42/p44 MAPK phosphorylation in RBA-1 cells. These responses were attenuated by inhibitors of PI3K (LY294002), JNK (SP600125), and p42/p44 MAPK (PD98059), or transfection with dominant negative mutants and short hairpin RNA. Moreover, we demonstrated that AP-1 (i.e., c-Fos/c-Jun) is crucial for oxLDL-induced proMMP-9 expression which was attenuated by pretreatment with AP-1 inhibitor (curcumin). The regulation of MMP-9 gene transcription by AP-1 was confirmed by oxLDL-stimulated MMP-9 luciferase activity which was totally lost in cells transfected with the AP-1 binding site-mutated MMP-9 promoter construct (mt-AP1-MMP-9). These results suggested that oxLDL-induced proMMP-9 expression is mediated through PI3K/Akt, JNK1/2, and p42/p44 MAPK leading to AP-1 activation. Understanding the regulatory mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes might provide a new therapeutic strategy of brain injuries and diseases. © 2008 Wiley-Liss, Inc. [source]

    The expression of tubulin polymerization promoting protein TPPP/p25, is developmentally regulated in cultured rat brain oligodendrocytes and affected by proteolytic stress

    GLIA, Issue 16 2008
    Olaf Goldbaum
    Abstract The tubulin polymerization-promoting protein (TPPP)/p25, was identified as a brain specific protein, is associated with microtubules (MTs) in vitro and can promote abnormal MT assembly. Furthermore it has aggregation promoting properties and is a constituent in pathological protein deposits of neurodegenerative diseases. In the brain, TPPP/p25, is present in myelinating oligodendrocytes. Here we show, using cultured rat brain oligodendrocytes, that TPPP/p25, expression is increasing during development in culture, and particularly in immature cells is associated with the centrosome. MT binding properties in oligodendrocytes are rather low, however, when MTs are disassembled by nocodazole, TPPP/p25, accumulates in the perinuclear region. Treatment of oligodendrocytes with the proteasomal inhibitor MG-132 (1 ,M; 18 h) caused an increase in the amount of TPPP/p25, by about 40%, a decrease in its solubility, and led to the appearance of TPPP/p25,-positive cytoplasmic inclusions, which stained with thioflavin S and resembled inclusion bodies. Hence, it might be speculated that acute or chronic malfunction of the proteasomal degradation system, leading to the accumulation of aggregation prone proteins and the pro-aggregatory protein TPPP/p25, or to the aggregation of TPPP/p25, on its own, is causally related to the protein aggregation process in a variety of neurodegenerative diseases. © 2008 Wiley-Liss, Inc. [source]

    New school in liver development: Lessons from zebrafish,

    HEPATOLOGY, Issue 5 2009
    Jaime Chu
    There is significant overlap in the genes and pathways that control liver development and those that regulate liver regeneration, hepatic progenitor cell expansion, response to injury, and cancer. Additionally, defects in liver development may underlie some congenital and perinatal liver diseases. Thus, studying hepatogenesis is important for understanding not only how the liver forms, but also how it functions. Elegant work in mice has uncovered a host of transcription factors and signaling molecules that govern the early steps of hepatic specification; however, the inherent difficulty of studying embryogenesis in utero has driven developmental biologists to seek new systems. The rapidly developing vertebrate zebrafish is a favorite model for embryology. The power of forward genetic screens combined with live real-time imaging of development in transparent zebrafish embryos has highlighted conserved processes essential for hepatogenesis and has uncovered some exciting new players. This review presents the advantages of zebrafish for studying liver development, underscoring how studies in zebrafish and mice complement each other. In addition to their value for studying development, zebrafish models of hepatic and biliary diseases are expanding, and using these small, inexpensive embryos for drug screening has become de rigueur. Zebrafish provide a shared platform for developmental biology and translational research, offering innovative methods for studying liver development and disease. The story of hepatogenesis has something for everyone. It involves transcriptional regulation, cell-cell interaction, signaling pathways, control of cell proliferation and apoptosis, plus morphogenic processes that sculpt vasculature, parenchymal cells, and mesenchyme to form the multifaceted liver. Decades of research on liver development in mice and other vertebrates offer valuable lessons in how the multipotent endoderm is programmed to form a functional liver. Of equal importance are insights that have illuminated the mechanisms by which hepatic progenitors are activated in a damaged liver, how the adult liver regenerates, and, possibly, the basis for engineering liver cells in vitro for cell transplantation to sustain patients with liver failure. Moreover, processes that are key to liver development are often co-opted during pathogenesis. Therefore, reviewing hepatogenesis is informative for both basic and translational researchers. In this review, we bring to light the many advantages offered by the tropical freshwater vertebrate zebrafish (Danio rerio) in studying hepatogenesis. By comparing zebrafish and mice, we highlight how work in each system complements the other and emphasize novel paradigms that have been uncovered using zebrafish. Finally, we highlight exciting efforts using zebrafish to model hepatobiliary diseases. (HEPATOLOGY 2009.) [source]

    Adipokines in liver diseases,

    HEPATOLOGY, Issue 3 2009
    Fabio Marra
    Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. While some of these molecules are expressed only by adipocytes, resident and infiltrating macrophages and components of the vascular stroma markedly contribute to expression of other adipokines. As a result, adipose tissue inflammation is associated with a modification in the pattern of adipokine secretion. Leptin, adiponectin, and resistin are the best-studied molecules in this class, but cytokines such as tumor necrosis factor or interleukin-6 are also secreted at high levels by the adipose tissue. Several other molecules have been recently identified and are actively investigated. Adipokines interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Several studies have investigated plasma levels of adiponectin in patients with nonalcoholic fatty liver disease, to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. Hepatitis C is another disease where adipokines may represent a link between viral infection, steatosis, and metabolic disturbances. Identification of the mediators secreted by expanded adipose tissue and their pathogenic role is pivotal in consideration of the alarming increase in the prevalence of obesity and of the detrimental role that this condition exerts on the course of liver diseases. (HEPATOLOGY 2009.) [source]

    Multidrug resistance,associated proteins are crucial for the viability of activated rat hepatic stellate cells,,

    HEPATOLOGY, Issue 2 2008
    Rebekka A. Hannivoort
    Hepatic stellate cells (HSCs) survive and proliferate in the chronically injured liver. ATP-binding cassette (ABC) transporters play a crucial role in cell viability by transporting toxic metabolites or xenobiotics out of the cell. ABC transporter expression in HSCs and its relevance to cell viability and/or activation have not been reported so far. The aim of this study was to investigate the expression, regulation, and function of multidrug resistance,associated protein (Mrp)-type and multidrug resistance protein (Mdr),type ABC transporters in activated rat HSCs. Rat HSCs were exposed to cytokines or oxidative stress. ABC transporter expression was determined by quantitative polymerase chain reaction and immunohistochemistry. HSCs were exposed to the Mdr inhibitors verapamil and PSC-833 and the Mrp inhibitor MK571. Mdr and Mrp transporter function was evaluated with flow cytometry. Apoptosis was determined by activated caspase-3 and acridine orange staining, and necrosis was determined by Sytox green nuclear staining. An in vivo model of carbon tetrachloride (CCl4),induced liver fibrosis was used. With respect to hepatocytes, activated HSCs expressed high levels of Mrp1 and comparable levels of Mrp3, Mrp4, Mdr1a, and Mdr1b but not the hepatocyte-specific transporters bile salt export pump, Mrp2, and Mrp6. Mrp1 protein staining correlated with desmin staining in livers from CCl4 -treated rats. Mrp1 expression increased upon activation of HSCs. Cytokines induced Mdr1b expression only. Oxidative stress was not a major regulator of Mdr and Mrp transporter expression. Activated HSCs became necrotic when exposed to the Mrp inhibitors. Conclusion: Activated HSCs contain relatively high levels of Mrp1. Mrp-type transporters are required for the viability of activated HSCs. Mrp-dependent export of endogenous metabolites is important for the survival of activated HSCs in chronic liver diseases. (HEPATOLOGY 2008.) [source]

    Increased hepatotoxicity of tumor necrosis factor,related apoptosis-inducing ligand in diseased human liver,

    HEPATOLOGY, Issue 5 2007
    Xandra Volkmann
    Tumor necrosis factor,related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. Conclusion: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases. (HEPATOLOGY 2007.) [source]

    Mitochondrial hepatopathies: Advances in genetics and pathogenesis,

    HEPATOLOGY, Issue 6 2007
    Way S. Lee
    Hepatic involvement is a common feature in childhood mitochondrial hepatopathies, particularly in the neonatal period. Respiratory chain disorders may present as neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset. In recent years, specific molecular defects (mutations in nuclear genes such as SCO1, BCS1L, POLG, DGUOK, and MPV17 and the deletion or rearrangement of mitochondrial DNA) have been identified, with the promise of genetic and prenatal diagnosis. The current treatment of mitochondrial hepatopathies is largely ineffective, and the prognosis is generally poor. The role of liver transplantation in patients with liver failure remains poorly defined because of the systemic nature of the disease, which does not respond to transplantation. Prospective, longitudinal, multicentered studies will be needed to address the gaps in our knowledge in these rare liver diseases. (HEPATOLOGY 2007;45:1555,1565.) [source]

    Hematopoietic mobilization in mice increases the presence of bone marrow,derived hepatocytes via in vivo cell fusion,

    HEPATOLOGY, Issue 1 2006
    Oscar Quintana-Bustamante
    The mechanisms for in vivo production of bone marrow,derived hepatocytes (BMDHs) remain largely unclear. We investigated whether granulocyte colony,stimulating factor (G-CSF),mediated mobilization of hematopoietic cells increases the phenomenon. Recurrent liver injury in mice expressing green fluorescent protein (EGFP) in all hematopoietic-derived cells was produced by 3 months of carbon tetrachloride (CCL4) injections. Histologically, there were necrotic foci with histiocyte-rich infiltrates, but little oval cell proliferation. Subsequently, some animals were mobilized with G-CSF for 1, 2, or 3 weeks. Animals were sacrificed 1 month after growth factor treatment. BMDH percentages were lower than previously reported, though G-CSF mobilization significantly augmented BMDH production in injured livers. BMDHs originating from in vivo fusion were evaluated by transplanting female EGFP+ cells into male mice. Binucleated, EGFP+ hepatocytes with one Y chromosome, indicating fusion, were identified. In conclusion, (1) mobilization of hematopoietic cells increases BMDH production and (2) as with the FAH-null model, the first model demonstrating hematopoietic/hepatocyte fusion, recurring CCl4 -induced injury has macrophage-rich infiltrates, a blunted oval cell response, and a predominantly in vivo fusion process for circulating cell engraftment into the liver. These findings open the possibility of using hematopoietic growth factors to treat nonhematopoietic degenerative diseases. (HEPATOLOGY 2006;43:108,116.) [source]

    Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death

    HEPATOLOGY, Issue 2 2004
    Arndt Vogel
    The murine model of hereditary tyrosinemia type 1 (HT1) was used to analyze the relationship between chronic liver disease and programmed cell death in vivo. In healthy fumarylacetoacetate hydrolase deficient mice (Fah -/- ), protected from liver injury by the drug 2-(2- nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), the tyrosine metabolite homogentisic acid (HGA) caused rapid hepatocyte death. In contrast, all mice survived the same otherwise lethal dose of HGA if they had preexisting liver damage induced by NTBC withdrawal. Similarly, Fah -/- animals with liver injury were also resistant to apoptosis induced by the Fas ligand Jo-2 and to necrosis-like cell death induced by acetaminophen (APAP). Molecular studies revealed a marked up-regulation of the antiapoptotic heat shock proteins (Hsp) 27, 32, and 70 and of c-Jun in hepatocytes of stressed mice. In addition, the p38 and Jun N-terminal kinase (JNK) stress-activated kinase pathways were markedly impaired in the cell-death resistant liver. In conclusion, these results provide evidence that chronic liver disease can paradoxically result in cell death resistance in vivo. Stress-induced failure of cell death programs may lead to an accumulation of damaged cells and therefore enhance the risk for cancer as observed in HT1 and other chronic liver diseases. (HEPATOLOGY 2004;39:433,443.) [source]

    Clinical application of measurement of hippocampal atrophy in degenerative dementias

    HIPPOCAMPUS, Issue 6 2009
    Josephine Barnes
    Abstract Hippocampal atrophy is a characteristic and early feature of Alzheimer's disease. Volumetry of the hippocampus using T1-weighted magnetic resonance imaging (MRI) has been used not only to assess hippocampal involvement in different neurodegenerative diseases as a potential diagnostic biomarker, but also to understand the natural history of diseases, and to track changes in volume over time. Assessing change in structure circumvents issues surrounding interindividual variability and allows assessment of disease progression. Disease-modifying effects of putative therapies are important to assess in clinical trials and are difficult using clinical scales. As a result, there is increasing use of serial MRI in trials to detect potential slowing of atrophy rates as an outcome measure. Automated and yet reliable methods of quantifying such change in the hippocampus would therefore be very valuable. Algorithms capable of measuring such changes automatically have been developed and may be applicable to predict decline to a diagnosis of dementia in the future. This article details the progress in using MRI to understand hippocampal changes in the degenerative dementias and also describes attempts to automate hippocampal segmentation in these diseases. © 2009 Wiley-Liss, Inc. [source]

    Factors influencing implementation of occupational safety and health management systems by enterprises in Poland

    Daniel Podgórski
    Implementing legal regulations in occupational safety and health (OSH) as well as other actions aimed at improving working conditions in industry in many countries run in parallel with promoting nonobligatory OSH management systems (OSH MS). To define a scientific basis for working out a set of guidelines for promoting OSH MS, a survey was conducted in 40 companies. This research aimed to identify motivational factors for decisions to introduce OSH MS. Four groups of professionals who participated in the decision-making process related to implementing OSH MS were interviewed: (a) the most senior managers of the enterprise, (b) representatives of top management for implementation and maintenance of OSH MS, (c) safety and health managers, and (d) workers' safety representatives. The results indicate the need for: (1) improving the efficiency of programs promoting implementation of OSH MS; (2) considering the role of economic incentives in promoting these systems; (3) developing and promoting training packages related to OSH management, adjusted particularly to the needs of employees and their representatives to increase their involvement in OSH activities; and (4) modifying legal solutions establishing a system of differentiated premium rates for social insurance against occupational accidents and diseases. © 2006 Wiley Periodicals, Inc. Hum Factors Man 16: 255,267, 2006. [source]

    Progress towards achieving new vaccine and vaccination goals

    G. Ada
    Abstract Viral and bacterial vaccines, especially for childhood use, are one of the most successful public health measures of the last two centuries and have a good safety record. However, there are still many diseases that are caused by infectious agents for which vaccines are not available. Our increasing ability to manipulate the immune system offers hope that, in the future, at least some of these infections may be prevented by vaccin­ation. A surprising recent development is the use of vaccine technology to test whether a range of other ­generally non-communicable diseases can be prevented (or at least controlled) in this way. Investigation of these diseases is still mainly at the experimental level, however the list includes different types of cancers, allergies, drug addiction and neurodegenerative diseases. (Intern Med J 2003; 33: 297,304) [source]

    Toenail selenium and risk of hepatocellular carcinoma mortality in Haimen City, China,

    Lori C. Sakoda
    Abstract Selenium (Se) is an essential trace mineral with known anticarcinogenic properties in humans. However, few studies have examined the association between Se nutrient status and risk of liver cancer. We conducted a nested case-control study comparing the Se content in toenail clippings of 166 individuals (154 men, 12 women) with hepatocellular carcinoma (HCC) to 394 healthy controls (360 men, 34 women) in Haimen City, China, where HCC is a leading cause of mortality. Toenail Se concentration was measured by inductively coupled plasma-optical emission spectroscopy. Median toenail Se was lower for HCC cases than controls (p = 0.03). Adjusted odds ratios and 95% confidence intervals for HCC mortality by increasing quartile of toenail Se were 1.00 (reference), 0.58 (0.32,1.03), 0.83 (0.48,1.42) and 0.50 (0.28,0.90), with a marginally significant trend in risk observed (p for trend = 0.06). This inverse association appeared stronger among those who did not consume alcohol and among women. Future studies are needed to examine the interrelationship between Se, viral hepatitis infection and HCC in order to better understand the etiologic mechanisms involved and evaluate the true chemopreventive potential of Se compounds for liver diseases. © 2005 Wiley-Liss, Inc. [source]

    Assessing spatial probabilistic distributional differences in the common space between schizophrenics and normal controls based on a novel automated probabilistic pattern analysis method

    Bang-Bon Koo
    Abstract Because of the complex nature of the human brain, a full understanding of its various group specific variation factors such as volume, shape, and location related to age, gender, ethnic, and disease might be provided in both structural and functional neuroimaging studies. To serve this purpose, a novel approach for characterizing the group variability information using group specific labeled probabilistic maps was introduced in this article. An automatic labeling technique was applied to encode group specific probabilistic information for each region of interests (ROIs) covering the overall cortical region and a probabilistic pattern analytic method was proposed to assess the difference in the spatial extent between 70 schizophrenics and 70 controls in the common space. From our proposed method, we found major differences in 17 ROIs that had shown large variation in schizophrenics. Most of these ROIs were in the frontal and the temporal lobe and only three ROIs were in the parietal and the occipital lobe. The ROIs highlighted through our proposed method could be connected with previous morphological findings on schizophrenia and it also might be considered in functional analysis. As a result, our method could provide intuitive information on group difference relevant to the overall anatomical variability in the substructural level. Thus, it could be used as a prompting system to search and examine the regions of the brain that are worthy of further precise analysis by various sub-cortical region based group studies in assessing specific patterns related to diseases. © 2008 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 18, 310,324, 2008 [source]

    OCT imaging of skin cancer and other dermatological diseases

    Mette Mogensen
    Abstract Optical coherence tomography (OCT) provides clinicians and researchers with micrometer-resolution, in vivo, cross-sectional images of human skin up to several millimeter depth. This review of OCT imaging applied within dermatology covers the application of OCT to normal skin, and reports on a large number of applications in the fields of non-melanoma skin cancer, malignant melanomas, psoriasis and dermatitis, infestations, bullous skin diseases, tattoos, nails, haemangiomas, and other skin diseases. (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source]

    Long-Term Outcome of Atrial Fibrillation Ablation: Impact and Predictors of Very Late Recurrence

    Long-Term Outcome of AF Ablation. Introduction: Ablation eliminates atrial fibrillation (AF) in studies with 1 year follow-up, but very late recurrences may compromise long-term efficacy. In a large cohort, we sought to describe the determinants of delayed recurrence after AF ablation. Methods and Results: Seven hundred and seventy-four patients with AF (428 paroxysmal [PAF, 55%] and 346 persistent or longstanding persistent [PersAF, 45%]) underwent wide area circumferential ablation (WACA, 62%) or pulmonary vein isolation (38%). Over 3.0 ± 1.9 years, there were 135 recurrences in PAF patients and 142 in PersAF patients. AF elimination was achieved in 61% of patients with PersAF at 2 years after last ablation and in 71% of patients with PAF (P = 0.04). This finding was related to a higher initial rate of very late recurrence in PersAF. From 1.0 to 2.5 years, the recurrence increased by 20% (from 37% to 57%) in PersAF patients versus only 12% (from 27% to 39%) in PAF patients. Independent predictors of overall recurrence included diabetes (HR 1.9 [1.3,2.9], P = 0.002) and PersAF (HR 1.6 [1.2,2.0], P < 0.001). Independent predictors of very late recurrence included PersAF (HR 1.7 [1.1,2.7], P = 0.018) and WACA (HR 1.8 [1.1,2.7], P = 0.018), while diabetes came close to significance. In PAF patients, left atrial size >45 mm was identified as an AF-type specific predictor (HR 2.4 [1.3,4.7], P = 0.009), whereas in PersAF patients, no unique predictors were identified. Conclusion: Late recurrences reduced the long-term efficacy of AF ablation, particularly in patients with PersAF and underlying cardiovascular diseases. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1071-1078) [source]

    Thrombogenic and atherogenic activities of lysophosphatidic acid

    Wolfgang Siess
    Abstract Lysophosphatidic acid (LPA) has been identified as a biologically active lipid in mildly-oxidized LDL, human atherosclerotic lesions, and the supernatant of activated platelets. The evidence that LPA has thrombogenic and atherogenic activities has increased substantially in recent years. Supporting the thrombogenic activity of LPA, analysis of the core region of human carotid plaques revealed recently the presence of alkyl- and acyl-molecular species from LPA with high platelet-activating potency (16:0 alkyl-LPA, 20:4 acyl-LPA). LPA, lipid extracts of atherosclerotic plaques, and the lipid-rich core elicited shape change and, in synergy with other platelet stimuli, aggregation of isolated platelets. This effect was completely abrogated by prior incubation of platelets with LPA receptor antagonists. Furthermore, LPA at concentrations approaching those found in vivo, induced platelet shape change, aggregation, and platelet-monocyte aggregate formation in blood. LPA-stimulated platelet aggregation was mediated by the ADP-stimulated activation of the P2Y1 and P2Y12 receptors. Supporting its atherogenic activity, LPA is a mitogen and motogen to vascular smooth muscle cells (VSMCs) and an activator of endothelial cells and macrophages. Recently, LPA has been identified as an agonist of the peroxisome proliferator activating receptor , (PPAR,), which is a key regulator of atherogenesis. LPA elicits progressive neointima formation, which is fully abolished by GW9662, an antagonist of PPAR,. We propose that LPA plays a central role in eliciting vascular remodeling and atherogenesis. Furthermore, upon rupture of lipid-rich atherosclerotic plaques, LPA may trigger platelet aggregation and intra-arterial thrombus formation. Antagonists of LPA receptors might be useful in preventing LPA-elicited thrombus formation and neointima formation in patients with cardiovascular diseases. © 2004 Wiley-Liss, Inc. [source]

    Decorin transfection in human mesangial cells downregulates genes playing a role in the progression of fibrosis

    Antonia Costacurta
    Abstract The proteoglycan decorin inhibits TGF-,; therefore, it could antagonize progression of fibrotic diseases associated with activation of TGF-,1. The effect of decorin transfection in human mesangial cells (HMCs) on the expression of genes related to kidney fibrosis was investigated. HMCs, isolated from glomeruli of healthy portions of human kidneys removed due to carcinoma, were histochemically typed. Decorin cDNA cloned in a eukaryotic expression vector was transfected into HMCs. Gene expression of fibrogenetic cytokines and fibrotic proteins TGF-,1, PDGF-,, ,1 collagen type IV, ,1 collagen type I, fibronectin, and tenascin was analyzed, by reverse transcription polymerase chain reaction (RT-PCR), 24 hr after transfection. Immunoblotting analysis of protein extracts using anti-decorin IgG, revealed a positive signal of about 52 MDa, corresponding to the molecular weight of decorin, in cultures transfected with the decorin gene. Decorin mRNA increased about 12 times in cultures transfected with the construct pCR3.1-Deco. Cells with increased decorin synthesis showed a 61% decrease of TGF-,1 mRNA, a 71% reduction of ,1 collagen type IV mRNA, and a 29% reduction of fibronectin mRNA. This study is the first to investigate decorin transfection into human mesangial cells, and supports the use of the decorin gene to control the progression of glomerular and interstitial fibrosis in kidney diseases. © 2002 Wiley-Liss, Inc. [source]

    Salivary simulation with ascorbic acid enhances sonographic diagnosis of obstructive sialadenitis

    Alessandro Bozzato MD
    Abstract Purpose. High-frequency ultrasound (US) is routinely used to evaluate various diseases of the salivary glands. Normally, the duct network of the submandibular and parotid glands is not visible during US assessment. In obstructive sialadenitis of the parotid and submandibular glands, localization of the obstacle is often difficult. Methods. In a case-control study, the sonographic visibility of the duct before and after stimulation with oral ascorbic acid (vitamin C) was compared with sialendoscopy as the gold standard. Twenty male and 23 female patients suffering from salivary gland diseases were included in this study and compared with 25 healthy volunteers. US examination of the parotid and submandibular glands was performed before and after oral ascorbic acid stimulation. Changes in visibility of the main excretory duct were recorded and US diagnoses were compared with results of sialendoscopy. Results. In 7 of 25 controls, the main duct became partially visible after stimulation. In the group of 43 patients, the main duct was depicted before stimulation in 27 patients (63%). After ascorbic acid stimulation, the main duct became visible in 41 patients (95%). Grading the stimulated duct dilation by measuring diameters at different points revealed no correlation with the underlying type of pathology. Conclusions. Application of ascorbic acid prior to diagnostic US examination facilitates the sonographic evaluation of obstructive salivary gland diseases. © 2009 Wiley Periodicals, Inc. J Clin Ultrasound 2009 [source]

    Hexokinase II gene transfer protects against neurodegeneration in the rotenone and MPTP mouse models of Parkinson's disease,

    Juan Carlos Corona
    Abstract A typical feature of Parkinson's disease is the progressive loss of dopaminergic neurons in the substantia nigra, in which inhibition of mitochondrial complex I activity may play an important role. Rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inhibit the mitochondrial complex I and they cause the death of substantia nigra dopaminergic neurons, thereby providing acute murine models of Parkinson's disease. We have found that increasing mitochondrial hexokinase II activity can prevent cell death in neuronal cultures treated with rotenone. As a result, we have studied the effects of hexokinase II gene transfer in vivo using a herpes simplex virus type 1 (HSV-1) amplicon vector. The placHK2 amplicon vector was injected into substantia nigra of mice that were subsequently administered rotenone or MPTP. Overexpression of hexokinase II prevented both rotenone and MPTP-induced dopaminergic neuronal cell death, as well as reducing the associated motor defects. Our results provide the first proof-of-principle that hexokinase II protects against dopaminergic neurodegeneration in vivo, emphasizing the role of this enzyme in promoting neuronal survival. Thus, the increase of hexokinase II expression by gene transfer or other means represents a promising approach to treat Parkinson's and other neurodegenerative diseases. © 2010 Wiley-Liss, Inc. [source]

    Adult human spinal cord harbors neural precursor cells that generate neurons and glial cells in vitro

    C. Dromard
    Abstract Adult human and rodent brains contain neural stem and progenitor cells, and the presence of neural stem cells in the adult rodent spinal cord has also been described. Here, using electron microscopy, expression of neural precursor cell markers, and cell culture, we investigated whether neural precursor cells are also present in adult human spinal cord. In well-preserved nonpathological post-mortem human adult spinal cord, nestin, Sox2, GFAP, CD15, Nkx6.1, and PSA-NCAM were found to be expressed heterogeneously by cells located around the central canal. Ultrastructural analysis revealed the existence of immature cells close to the ependymal cells, which display characteristics of type B and C cells found in the adult rodent brain subventricular region, which are considered to be stem and progenitor cells, respectively. Completely dissociated spinal cord cells reproducibly formed Sox2+ nestin+ neurospheres containing proliferative precursor cells. On differentiation, these generate glial cells and ,-aminobutyric acid (GABA)-ergic neurons. These results provide the first evidence for the existence in the adult human spinal cord of neural precursors with the potential to differentiate into neurons and glia. They represent a major interest for endogenous regeneration of spinal cord after trauma and in degenerative diseases. © 2008 Wiley-Liss, Inc. [source]

    Neural differentiation and potential use of stem cells from the human umbilical cord for central nervous system transplantation therapy

    Choon Bing Low
    Abstract The human umbilical cord is a rich source of autologous stem and progenitor cells. Interestingly, subpopulations of these, particularly mesenchymal-like cells from both cord blood and the cord stroma, exhibited a potential to be differentiated into neuron-like cells in culture. Umbilical cord blood stem cells have demonstrated efficacy in reducing lesion sizes and enhancing behavioral recovery in animal models of ischemic and traumatic central nervous system (CNS) injury. Recent findings also suggest that neurons derived from cord stroma mesenchymal cells could alleviate movement disorders in hemiparkinsonian animal models. We review here the neurogenic potential of umbilical cord stem cells and discuss possibilities of their exploitation as an alternative to human embryonic stem cells or neural stem cells for transplantation therapy of traumatic CNS injury and neurodegenerative diseases. © 2008 Wiley-Liss, Inc. [source]

    IL-1,, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-,B pathways

    Yun-Jung Kim
    Abstract In the present study we sought to examine cell,cell interactions by investigating the effects of factors released by stimulated microglia on inducible nitric oxide (NO) synthase (iNOS) induction in astrocytoma cells. After examining the temporal profiles of proinflammatory molecules induced by lipopolysaccharide (LPS) stimulation in BV2 microglial cells, iNOS and IL-1, were observed to be the first immediate-response molecules. Removal of LPS after 3 hr stimulation abrogated NO release, whereas a full induction of IL-1, was retained in BV2 cells. We observed consistently that conditioned medium (CM) from activated microglia resulted in the induction of iNOS in C6 cells, and IL-1, was shown to be a key regulator of iNOS induction. An IL-1,-neutralizing antibody diminished NO induction. Incubation with recombinant IL-1, stimulated NO release to a lesser extent compared to microglial CM; co-treatment of LPS and IL-1, had a potent, synergistic effect on NO release from C6 cells. Transient transfection with MEK kinase 1 (MEKK1) or nuclear factor-kappa B (NF-,B) expression plasmids induced iNOS, and IL-1, further enhanced the MEKK1 response. Furthermore, IL-1,-mediated NO release from C6 cells was significantly suppressed by inhibition of p38 mitogen activated protein kinase (MAPK) or NF-,B by specific chemical inhibitors. Both IL-1, and MEKK1 stimulated p38 and JNK MAPKs, as well as the NF-,B pathway, to induce iNOS in C6 cells. Microglia may represent an anti-tumor response in the central nervous system, which is potentiated by the local secretion of immunomodulatory factors that in turn affects astrocytoma (glioma) cells. A better understanding of microglia,glioma or microglia,astrocyte interactions will help in the design of novel immune-based therapies for brain tumors or neuronal diseases. © 2006 Wiley-Liss, Inc. [source]

    AUF-1 mediates inhibition by nitric oxide of lipopolysaccharide-induced matrix metalloproteinase-9 expression in cultured astrocytes

    Wenlan Liu
    Abstract Neuroinflammatory diseases are associated with increased production of matrix metalloproteinase-9 (MMP-9) and excessive generation of nitric oxide (NO). NO hasbeen reported to have variable effects on MMP-9 gene expression and activation in various cell types. Inthe present study, we investigated the effect of NOon MMP-9 expression in primary cortical astrocytes. Zymography and real-time PCR showed that lipopolysaccharide (LPS) dramatically increased latent MMP-9 gelatinolytic activity and MMP-9 mRNA expression. By using the NO donor DETA NONOate, we observed a dose-dependent inhibition of MMP-9 induction by LPS. Active forms of MMP-9 were not found by zymography after NO treatment. The MEK1/2 inhibitor U0126 completely inhibited LPS-induced MMP-9, which was partially inhibited by the p38 MAPK inhibitor SB203580. NO had no effect on LPS-stimulated ERK1/2 and p38 MAPK activation, suggesting that the inhibitory action of NO occurs downstream of MAPK cascades. Real-time PCR analysis showed that NO accelerated the degradation of MMP-9 mRNA after LPS induction. Western blotting and pull-down assay demonstrated that NO increased AUF-1 expression as well as its specific binding to the MMP-9 gene 3,-untranslated region. Knockdown of AUF-1 with siRNA partially reversed the inhibitory action of NO on LPS-stimulated MMP-9 induction. We conclude that NO does not activate MMP-9 in astrocyte cultures but reduces LPS-induced MMP-9 expression via accelerating MMP-9 mRNA degradation, which is partially mediated by AUF-1. Our results suggest that elevated NO concentrations may suppress MMP-9 and restrict the inflammatory response in neurodegenerative diseases. © 2006 Wiley-Liss, Inc. [source]

    Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer's disease

    Akihito Ishigami
    Abstract Citrullinated proteins are the products of a posttranslational process in which arginine residues undergo modification into citrulline residues when catalyzed by peptidylarginine deiminases (PADs) in a calcium ion-dependent manner. In our previous report, PAD2 expressed mainly in the rat cerebrum became activated early in the neurodegenerative process. To elucidate the involvement of protein citrullination in human neuronal degeneration, we examined whether citrullinated proteins are produced during Alzheimer's disease (AD). By Western blot analysis with antimodified citrulline antibody, citrullinated proteins of varied molecular weights were detected in hippocampal tissues from patients with AD but not normal humans. Two of the citrullinated proteins were identified as vimentin and glial fibrillary acidic protein (GFAP) by using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. Interestingly, PAD2 was detected in hippocampal extracts from AD and normal brains, but the amount of PAD2 in the AD tissue was markedly greater. Histochemical analysis revealed citrullinated proteins throughout the hippocampus, especially in the dentate gyrus and stratum radiatum of CA1 and CA2 areas. However, no citrullinated proteins were detected in the normal hippocampus. PAD2 immunoreactivity was also ubiquitous throughout both the AD and the normal hippocampal areas. PAD2 enrichment coincided well with citrullinated protein positivity. Double immunofluorescence staining revealed that citrullinated protein- and PAD2-positive cells also coincided with GFAP-positive cells, but not all GFAP-positive cells were positive for PAD2. As with GFAP, which is an astrocyte-specific marker protein, PAD2 is distributed mainly in astrocytes. These collective results, the abnormal accumulation of citrullinated proteins and abnormal activation of PAD2 in hippocampi of patients with AD, strongly suggest that PAD has an important role in the onset and progression of AD and that citrullinated proteins may become a useful marker for human neurodegenerative diseases. © 2005 Wiley-Liss, Inc. [source]