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Progressive Accumulation (progressive + accumulation)
Selected AbstractsFabry disease: overall effects of agalsidase alfa treatmentEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2004M. Beck Abstract Background, Fabry disease is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme ,-galactosidase A. Progressive accumulation of the substrate globotriaosylceramide in cells throughout the body leads to major organ failure and premature death. The Fabry Outcome Survey (FOS) is a European outcomes database which was established to collect data on the natural history of this little-known disease and to monitor the long-term efficacy and safety of enzyme replacement therapy (ERT) with agalsidase alfa. This paper presents the first analysis of the FOS database on the effects of ERT on renal function, heart size, pain and quality of life. Design, The effects of 1 and 2 years of ERT with agalsidase alfa on renal function (assessed by estimated glomerular filtration rate), heart size (assessed by echocardiography), pain (assessed by the Brief Pain Inventory) and quality of life (assessed by the European Quality of Life Questionnaire EQ-5D) were analyzed in a cohort of 545 patients, 314 of whom were receiving treatment (188 for at least 12 months and 92 for at least 24 months; mean duration of treatment, 17 months; maximum duration, 56 months). Results, Treatment with agalsidase alfa stabilized renal function in patients with a mild or moderate deterioration in renal function at baseline, reduced left ventricular size in patients who had an enlarged heart at baseline, and improved pain scores and quality of life. These improvements were similar in hemizygous men and heterozygous women with Fabry disease. Conclusions, Enzyme replacement therapy with agalsidase alfa leads to significant clinical benefits in patients with Fabry disease, and treatment is likely to alter the natural history of this disorder. [source] Psychosine-induced apoptosis and cytokine activation in immune peripheral cells of Krabbe patients,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2007Patrizia Formichi Globoid cell leukodystrophy or Krabbe disease (KD), is a hereditary disorder caused by galactosylceramidase deficiency. Progressive accumulation of psychosine is considered to be the critical pathogenetic mechanism of cell death in the Krabbe brain. Psychosine mechanism of action has not been fully elucidated. It seems to induce apoptosis in oligodendrocytes through a mitochondrial pathway and to up-regulate inflammatory cytokines production resulting in oligodendrocyte loss. Our aim was to evaluate the role of psychosine in apoptotic cell death and inflammatory response in a group of patients affected by KD using peripheral blood lymphocytes (PBLs) and peripheral blood mononuclear cells (PBMCs) as a cellular model. PBLs from KP and healthy controls were exposed to 20 µM psychosine and analysed by flow cytometry, agarose gel electrophoresis and fluorescence microscopy. Our results showed that psychosine induces apoptosis in PBLs through a mitochondrial pathway, but the apoptotic response was quite low especially KP. The role of psychosine in the up-regulation of cytokines (TNFalpha, IL8 and MCP1) has been evaluated by ELISA in PBMCs from KP and controls after stimulation with LPS and phytohemagglutinin. Both in basal condition and after LPS stimulation, cells from KP showed a significant increase in TNF-, production, reduced MCP1 levels and no modification in IL8. These results indicate that lymphomonocytes from KP had a basal proinflammatory pattern that was amplified by psychosine. In conclusion, the reduced apoptotic response and the atypical cytokine production observed in our experiments, suggest an involvement of inflammatory pattern in immune peripheral cells of KP. J. Cell. Physiol. 212:737,743, 2007. © 2007 Wiley-Liss, Inc. [source] Co-expression of C-terminal truncated alpha-synuclein enhances full-length alpha-synuclein-induced pathologyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2010Ayse Ulusoy Abstract Lewy bodies, which are a pathological hallmark of Parkinson's disease, contain insoluble polymers of alpha-synuclein (,syn). Among the different modifications that can promote the formation of toxic ,syn species, C-terminal truncation is among the most abundant alterations in patients with Parkinson's disease. In vitro, C-terminal truncated ,syn aggregates faster and sub-stoichiometric amounts of C-terminal truncated ,syn promote aggregation of the full-length ,syn (,synFL) and induce neuronal toxicity. To address in vivo the putative stimulation of ,syn-induced pathology by the presence of truncated ,syn, we used recombinant adeno-associated virus to express either ,synFL or a C-terminal truncated ,syn (1-110) in rats. We adjusted the recombinant adeno-associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of ,syn were co-expressed at these pre-determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C-terminal truncated ,syn (1-110) but only ,synFL, we demonstrated that the co-expressed truncated protein promoted the progressive accumulation of ,synFL and formation of larger pathological accumulations. Moreover, in the co-expression group, three of the eight animals showed apomorphine-induced turning, suggesting prominent post-synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C-terminal truncated ,syn can interact with and exacerbate the formation of pathological accumulations containing ,synFL in vivo. [source] SEX REVERSAL: A FOUNTAIN OF YOUTH FOR SEX CHROMOSOMES?EVOLUTION, Issue 12 2009Nicolas Perrin Nonrecombining Y chromosomes are expected to degenerate through the progressive accumulation of deleterious mutations. In lower vertebrates, however, most species display homomorphic sex chromosomes. To address this, paradox I propose a role for sex reversal, which occasionally occurs in ectotherms due to the general dependence of physiological processes on temperature. Because sex-specific recombination patterns depend on phenotypic, rather than genotypic sex, homomorphic X and Y chromosomes are expected to recombine in sex-reversed females. These rare events should generate bursts of new Y haplotypes, which will be quickly sorted out by natural or sexual selection. By counteracting Muller's ratchet, this regular purge should prevent the evolutionary decay of Y chromosomes. I review empirical data supporting this suggestion, and propose further investigations for testing it. [source] The evolution of the stress,strain fields near a fatigue crack tip and plasticity-induced crack closure revisitedFATIGUE & FRACTURE OF ENGINEERING MATERIALS AND STRUCTURES, Issue 1 2004L. G. ZHAO ABSTRACT The evolution of the stress,strain fields near a stationary crack tip under cyclic loading at selected R -ratios has been studied in a detailed elastic,plastic finite element analysis. The material behaviour was described by a full constitutive model of cyclic plasticity with both kinematic and isotropic hardening variables. Whilst the stress/strain range remains mostly constant during the cyclic loading and scales with the external load range, progressive accumulation of tensile strain occurs, particularly at high R -ratios. These results may be of significance for the characterization of crack growth, particularly near the fatigue threshold. Elastic,plastic finite element simulations of advancing fatigue cracks were carried out under plane-stress, plane-strain and generalized plane-strain conditions in a compact tension specimen. Physical contact of the crack flanks was observed in plane stress but not in the plane-strain and generalized plane-strain conditions. The lack of crack closure in plane strain was found to be independent of the material studied. Significant crack closure was observed under plane-stress conditions, where a displacement method was used to obtain the actual stress intensity variation during a loading cycle in the presence of crack closure. The results reveal no direct correlation between the attenuation in the stress intensity factor range estimated by the conventional compliance method and that determined by the displacement method. This finding seems to cast some doubts on the validity of the current practice in crack-closure measurement, and indeed on the role of plasticity-induced crack closure in the reduction of the applied stress intensity factor range. [source] Response of lung ,, T cells to experimental sepsis in miceIMMUNOLOGY, Issue 1 2004Mark Hirsh Summary ,, T cells link innate and adaptive immune systems and may regulate host defence. Their role in systemic inflammation induced by trauma or infection (sepsis) is still obscured. The present study was aimed to investigate functions of lung ,, T cells and their response to experimental sepsis. Mice were subjected to caecal ligation and puncture (CLP) to induce sepsis and acute lung injury (ALI), or to the sham operation. Animals were killed 1, 4, and 7 days postoperatively; lungs were examined by histology, and isolated cells were studied by flow cytometry. Absolute number of ,, T cells progressively increased in lungs during sepsis, and reached a seven-fold increase at day 7 after CLP (3·84 ± 0·41 × 105/lung; P,=,0·0002 versus sham). A cellular dysfunction was revealed one day after CLP, as manifested by low cytolytic activity (22·3 ± 7·1%; P,<,0·05 versus sham), low interferon-, (IFN-,; 8·5 ± 2·5%; P,<,0·05 versus control) and interleukin-10 (IL-10) expression, and high tumour necrosis factor-, expression (19·5 ± 1·7%; P,<,0·05 versus control). The restoration of cytotoxicity, and increase in IFN-, and IL-10 expression was observed at day 7 of CLP-induced sepsis. In summary, our results demonstrate significant progressive accumulation of ,, T cells in lungs during CLP-induced ALI. The temporary functional suppression of lung ,, T cells found early after CLP may influence the outcome of sepsis, possibly being associated with uncontrolled inflammatory lung damage. [source] Understanding and Modulating AgeingIUBMB LIFE, Issue 4-5 2005Suresh IS Rattan Abstract Ageing is characterized by a progressive accumulation of molecular damage in nucleic acids, proteins and lipids. The inefficiency and failure of maintenance, repair and turnover pathways is the main cause of age-related accumulation of damage. Research in molecular gerontology is aimed at understanding the genetic and epigenetic regulation of survival and maintenance mechanisms at the levels of transcription, post-transcriptional processing, post-translational modifications, and interactions among various gene products. Concurrently, several approaches are being tried and tested to modulate ageing in a wide variety of organisms. The ultimate aim of such studies is to improve the quality of human life in old age and prolong the health-span. Various gerontomodulatory approaches include gene therapy, hormonal supplementation, nutritional modulation and intervention by free radical scavengers and other molecules. A recent approach is that of applying hormesis in ageing research and therapy, which is based on the principle of stimulation of maintenance and repair pathways by repeated exposure to mild stress. A combination of molecular, physiological and psychological modulatory approaches can realize "healthy ageing" as an achievable goal in the not-so-distant future. IUBMB Life, 57: 297-304, 2005 [source] Attenuation of half sulfur mustard gas-induced acute lung injury in ratsJOURNAL OF APPLIED TOXICOLOGY, Issue 2 2006Shannon D. McClintock Abstract Airway instillation into rats of 2-chloroethyl ethyl sulfide (CEES), the half molecule of sulfur mustard compound, results in acute lung injury, as measured by the leak of plasma albumin into the lung. Morphologically, early changes in the lung include alveolar hemorrhage and fibrin deposition and the influx of neutrophils. Following lung contact with CEES, progressive accumulation of collagen occurred in the lung, followed by parenchymal collapse. The co-instillation with CEES of liposomes containing pegylated (PEG)-catalase (CAT), PEG-superoxide dismutase (SOD), or the combination, greatly attenuated the development of lung injury. Likewise, the co-instillation of liposomes containing the reducing agents, N-acetylcysteine (NAC), glutathione (GSH), or resveratrol (RES), significantly reduced acute lung injury. The combination of complement depletion and airway instillation of liposomes containing anti-oxidant compounds maximally attenuated CEES-induced lung injury by nearly 80%. Delayed airway instillation of anti-oxidant-containing liposomes (containing NAC or GSH, or the combination) significantly diminished lung injury even when instillation was delayed as long as 1 h after lung exposure to CEES. These data indicate that CEES-induced injury of rat lungs can be substantially diminished by the presence of reducing agents or anti-oxidant enzymes delivered via liposomes. Copyright © 2005 John Wiley & Sons, Ltd. [source] Proliferative drive and liver carcinogenesis: Too much of a good thing?JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2009Narci C Teoh Abstract There have been innumerable studies published in the attempt to identify gene expression signatures in hepatocellular carcinoma (HCC). When all the regulators and targets of the differentially expressed genes are analyzed from larger studies, the most striking theme is upregulation of mitosis-promoting and cell proliferation genes in HCC compared with ,liver-specific gene clusters' in non-tumorous tissue. A major limitation of expression profiling is that it only provides a ,snapshot' of what is an evolving process and thus cannot distinguish the differences in gene expression that are primary effectors of dysregulated growth from those that represent downstream consequences. The development of HCC in a chronically diseased liver, often referred to as hepatocarcinogenesis, is a multistep process characterized by the progressive accumulation and interplay of genetic alterations causing aberrant growth, malignant transformation of liver parenchymal cells, followed by vascular invasion and metastasis. This review will discuss HCC precursor lesions, draw on the ,proliferation cluster' genes highlighted from HCC expression profiling studies, relate them to a selection of regulatory networks important in liver regeneration, cell cycle control and their potential significance in the pathogenesis of HCC or primary liver cancer. [source] Ocular phenotype in a mouse gene knockout model for infantile neuronal ceroid lipofuscinosisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2006Bo Lei Abstract Mutations in the human protein palmitoyl thioesterase-1 (PPT-1) gene result in an autosomal recessive neurodegenerative disorder designated neuronal ceroid lipofuscinosis (NCL), type CLN1, or infantile NCL. Among the symptoms of the CLN1 disease are accumulation of autofluorescent lysosomal storage bodies in neurons and other cell types, seizures, motor and cognitive decline, blindness, and premature death. Development of an effective therapy for this disorder will be greatly assisted by the availability of suitable animal models. A mouse PPT-1 gene knockout model has recently been generated. Studies were performed to determine whether the mouse model exhibits ocular features of the human CLN1 disorder. A progressive accumulation of autofluorescent storage material in all layers of the retina was observed in the PPT-1 knockout mice. Accompanying the storage body accumulation was a modest loss of cells with nuclei in the outer and inner nuclear layers. As indicated by electroretinogram (ERG) responses, retinal function was only mildly impaired at 4 months of age but was severely impaired by 8 months, despite only modest changes in retinal morphology. The pupillary light reflex (PLR), on the other hand, was exaggerated in the knockout mice. The apparent anomaly between the ERG and the PLR findings suggests that disease-related PLR changes may be due to changes in extraocular signal processing. The pronounced ocular phenotype in the PPT-1 knockout mice makes these animals a good model for testing therapeutic interventions for treatment of the human CLN1 disorder. © 2006 Wiley-Liss, Inc. [source] Ubiquitin C-terminal hydrolase-L1 (PGP9.5) expression in human neural cell lines following induction of neuronal differentiation and exposure to cytokines, neurotrophic factors or heat stressNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2001J.-I. Satoh Dysfunction of the ubiquitin-dependent proteolytic pathway contributes to progressive accumulation of ubiquitinated protein inclusions in neurodegenerative disorders, such as Parkinson's disease (PD). Ubiquitin C-terminal hydrolase-L1 (UCH-L1), alternatively designated protein gene product 9.5 (PGP9.5), is a neural deubiquitinating enzyme which is identified as a principal constituent of Lewy bodies. To clarify the regulatory mechanism of UCH-L1 expression in human neural cells, we studied the constitutive, cytokine/neurotrophic factor-regulated, and heat stress-induced expression of UCH-L1 in cultured human neural cell lines by Western blot analysis. The constitutive expression of UCH-L1 was identified in SK-N-SH neuroblastoma cells, IMR-32 neuroblastoma cells, U-373MG astrocytoma cells, and NTera2 teratocarcinoma-derived differentiated neurones (NTera2-N). The levels of UCH-L1 expression were unaltered in these cell lines following treatment with TNF-,, IL-1,, BDNF, GDNF, dibutyryl cyclic AMP, or phorbol 12-myristate 13-acetate, and remained unchanged by exposure to heat stress. In contrast, its levels were elevated substantially in NTera2 teratocarcinoma cells following retinoic acid-induced neuronal differentiation, accompanied with an increased expression of ,-synuclein and synaptophysin. These results indicate that UCH-L1 is expressed constitutively in human neual cell lines, where it is upregulated following induction of neuronal differentiation, but unaffected by exposure to heat stress, cytokines, or growth/differentiation factors which are supposed to be invloved in the nigral neuronal death and survival in PD. [source] Effects of progressive drought stress on the expression of patatin-like lipid acyl hydrolase genes in Arabidopsis leavesPHYSIOLOGIA PLANTARUM, Issue 1 2008Ana Rita Matos Patatin-like genes have recently been cloned from several plant species and found to be involved in stress responses and development. In previous work, we have shown that a patatin-like gene encoding a galactolipid acyl hydrolase (EC 3.1.1.26) was stimulated by drought in the leaves of the tropical legume, Vigna unguiculata L. Walp. The aim of the present work was to study the expression of patatin-like genes in Arabidopsis thaliana under water deficit. Expression of six genes was studied by reverse transcriptase polymerase chain reaction in leaves of plants submitted to progressive drought stress induced by withholding water and also in different plant organs. Three genes, designated AtPAT IIA, AtPAT IVC and AtPAT IIIA, were shown to be upregulated by water deficit but with different kinetics, while the other patatin-like genes were either constitutive or not expressed in leaves. The accumulation of transcripts of AtPAT IIA in the early stages of the drought treatment was coordinated with the upregulation of lipoxygenase and allene oxide synthase genes. AtPAT IIA expression was also induced by wounding and methyl jasmonate treatments. The in vitro lipolytic activity toward monogalactosyldiacylglycerol, digalactosyldiacylglycerol, phosphatidylcholine and phosphatidylglycerol was confirmed by producing the recombinant protein ATPAT IIA in insect cells. The analysis of free fatty acid pools in drought-stressed leaves shows an increase in the relative amounts of trans-3-hexadecenoic acid at the beginning of the treatment followed by a progressive accumulation of linoleic and linolenic acids. The possible roles of AtPAT IIA in lipid signaling and membrane degradation under water deficit are discussed. [source] Penile Enhancement Using Autologous Tissue Engineering with Biodegradable Scaffold: A Clinical and Histomorphometric StudyTHE JOURNAL OF SEXUAL MEDICINE, Issue 9 2010Sava V. Perovic PhD ABSTRACT Introduction., Autologous tissue engineering with biodegradable scaffolds is a new treatment option for real penile girth enhancement. Aim., The aim of this article is to evaluate tissue remodeling after penile girth enhancement using this technique. Methods., Between June 2005 and May 2007, a group of 12 patients underwent repeated penile widening using biodegradable scaffolds enriched with expanded autologous scrotal dartos cells. Clinical monitoring was parallel to histological investigation of tissue remodeling. During second surgical procedure, biopsies were obtained 10,14 months after first surgery (mean 12 months, N = 6) and compared with those obtained after 22,24 months (mean 23 months, N = 6), and control biopsies from patients who underwent circumcision (N = 5). Blind evaluation of histomorphometrical and immunohistochemical finding was performed in paraffin sections. Main Outcome Measurements., Penile girth gain in a flaccid state ranged between 1.5 and 3.8 cm (mean 2.1 ± 0.28 cm) and in full erection between 1.2 and 4 cm (mean 1.9 ± 0.28 cm). Patients' satisfaction, defined by a questionnaire, was good (25%) and very good (75%). Results., In biopsies obtained 10,14 months after first surgery, highly vascularized loose tissue with collagen deposition associated with small foci of mild chronic and granulomatous inflammation surrounding residual amorphous material was observed. Fibroblast-like hyperplasia and small vessel neoangiogenesis occurred intimately associated with the progressive growth of vascular-like structures from accumulation of CD34 and alpha-smooth muscle actin-positive cells surrounding residual scaffold-like amorphous material. Capillary neoangiogenesis occurred inside residual amorphous material. In biopsies obtained after 22,24 months, inflammation almost disappeared and tissue closely resembled that of the dartos fascia of control group. Conclusions., Autologous tissue engineering using expanded scrotal dartos cells with biodegradable scaffolds is a new and promising method for penile widening that generates progressive accumulation of stable collagen-rich, highly vascularized tissue matrix that closely resemble deep dartos fascia. Perovic SV, Sansalone S, Djinovic R, Ferlosio A, Vespasiani G, and Orlandi A. Penile enhancement using autologous tissue engineering with biodegradable scaffold: A clinical and histomorphometric study. J Sex Med 2010;7:3206,3215. [source] Purification, crystallization and preliminary X-ray diffraction of wild-type and mutant recombinant human transforming growth factor ,-induced protein (TGFBIp)ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2009Kasper Runager Transforming growth factor ,-induced protein (TGFBIp) has been linked to several corneal dystrophies as certain point mutations in the protein may give rise to a progressive accumulation of insoluble protein material in the human cornea. Little is known about the biological functions of this extracellular protein, which is expressed in various tissues throughout the human body. However, it has been found to interact with a number of extracellular matrix macromolecules such as collagens and proteoglycans. Structural information about TGFBIp might prove to be a valuable tool in the elucidation of its function and its role in corneal dystrophies caused by mutations in the TGFBI gene. A simple method for the purification of wild-type and mutant forms of recombinant human TGFBIp from human cells under native conditions is presented here. Moreover, the crystallization and preliminary X-ray analysis of TGFBIp are reported. [source] 2464: Phenotype/genotype evolution in corneal dystrophiesACTA OPHTHALMOLOGICA, Issue 2010F CHIAMBARETTA Purpose The corneal dystrophies are a group of genetically determined diseases usually characterized by loss of corneal transparency, which may be caused by a progressive accumulation of abnormal material within the cornea. The genetic characterization of corneal dystrophies revealed both genetic heterogeneity, that is, different genes (KRT3 and KRT12) causing a single dystrophy phenotype (Meesmann dystrophy), and phenotypic heterogeneity with a single gene (TGFBI) causing different allelic dystrophy phenotypes (RBCD, TBCD, granular type 1, granular type 2, and lattice type 1). But less is known about the evolution of the phenotype during life. Methods We were interesting in following the corneal phénotype progressive evolution during childhood. During several years we analyzed corneal phénotype of families of Lattice type 1 and granular type 1, using Scheimpflug camera. Results We were able to follow the accumulation of abnormal material, his corneal localisation and evolution during years. Conclusion The phenotype of both Lattice type 1 and granular type 1 is totally different in childhood, with subepithelial localization. [source] | ||||||||||||||||