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Major Alterations (major + alteration)
Selected AbstractsClinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome,HUMAN MUTATION, Issue 7 2008Guntram Borck Abstract Mutations in the AP1S2 gene, encoding the ,1B subunit of the clathrin-associated adaptor protein complex (AP)-1, have been recently identified in five X-linked mental retardation (XLMR) families, including the original family with Fried syndrome. Studying four patients in two unrelated families in which AP1S2 nonsense and splice-site mutations segregated, we found that affected individuals presented, in addition to previously described features, with elevated protein levels in cerebrospinal fluid (CSF). Moreover, computed tomography scans demonstrated that the basal ganglia calcifications associated with AP1S2 mutations appeared during childhood and might be progressive. Based on these observations, we propose that AP1S2 mutations are responsible for a clinically recognizable XLMR and autism syndrome associating hypotonia, delayed walking, speech delay, aggressive behavior, brain calcifications, and elevated CSF protein levels. Using the AP-2 complex, in which the , subunit is encoded by one single gene, as a model system, we demonstrated that , subunits are essential for the stability of human AP complexes. By contrast, no major alteration of the stability, subcellular localization, and function of the AP-1 complex was observed in fibroblasts derived from a patient carrying an AP1S2 mutation. Similarly, neither macro- nor microscopic defects were observed in the brain of an affected fetus. Altogether, these data suggest that the absence of an AP-1 defect in peripheral tissues is due to functional redundancy among AP-1 , subunits (,1A, ,1B, and ,1C) and that the phenotype observed in our patients results from a subtle and brain-specific defect of the AP-1-dependent intracellular protein traffic. Hum Mutat 29(7), 966,974, 2008. © 2008 Wiley-Liss, Inc. [source] Assessment of the "common" 4.8-kb mitochondrial DNA deletion and identification of several closely related deletions in the dorsal root ganglion of aging and streptozotocin ratsJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2002Kim K. Nickander Abstract The identification of several mitochondrial DNA (mtDNA) deletions and the accumulation of the "common" 4.8-kb mitochondrial DNA deletion (mtDNA4834) with aging and experimental streptozotocin-induced diabetes (STZ) were studied in the rat dorsal root ganglion (DRG). Twenty-one mtDNA deletions, including mtDNA4834, were identified in rat L4-L6 DRG mtDNA of 15-month-old Spraque-Dawley rats with 13 months of STZ and age-matched controls. These deletions were flanked by breakpoints that ranged from 16-bp direct repeats to no direct repeats. The sciatic nerve contained undetectable levels of mtDNA deletions. Levels of mtDNA4834 in rat DRG mtDNA significantly accumulated with age at a rate much higher than those reported in the brain, yet were not statistically different in STZ. Southern blot analysis demonstrated no significant accumulation of the total amount of mtDNA deletions in STZ over age-matched controls. The accumulation of mtDNA4834 has not been studied in rat peripheral nerve tissue. Our identification of several mtDNA deletions with and without direct repeats at their breakpoint support the hypothesis that deletions can occur by both the slip-replication model and random recombination. Although there is a significant increase in accumulation of mtDNA4834 associated with aging, the lack of significant accumulations of mtDNA deletions in STZ over age-matched controls indicates that this type of mtDNA damage is likely not a major alteration in STZ, although the changes could be confined to a small population of neurons that undergo apoptosis between 8 and 15 months. [source] Last Interglacial stratigraphy at Ristinge Klint, South DenmarkBOREAS, Issue 2 2000PETER KRISTENSEN Past environmental changes in the Baltic area are discussed on the basis of foraminifera and ostracods as well as pollen and spores in marine sediments in cliff sections at Ristinge Klint, Langeland, southern Denmark. The sediment succession represents Jessen & Milthers' (1928) pollen zones d,g or Andersen's (1961, 1975) zones E2,E5, and a correlation with the annually laminated Bispingen sequence indicates that the sequence spans about 3400 years. Marine conditions seem to have occurred at c. 300,365 years after the beginning of the Eemian Interglacial, close to fully marine conditions developing by c. 2500 years. This early date of the marine ingression pre-dates that of most previous studies in the region by several hundred years, but it postdates the initial marine ingression in the easternmost Baltic. A marked change in salinity at c. 650 years after the beginning of the Eemian was presumably caused by an opening of the Danish Belts. An indication of a major alteration in current activity is registered at c. 3000 years after the beginning of the interglacial. The recognition of the relative timing of these events may be significant for the understanding of the opening of connections between the North Sea, the Baltic and the White Sea. [source] Cognitive visual dysfunctions in preterm children with periventricular leukomalaciaDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 12 2009ELISA FAZZI MD PHD Aim, Cognitive visual dysfunctions (CVDs) reflect an impairment of the capacity to process visual information. The question of whether CVDs might be classifiable according to the nature and distribution of the underlying brain damage is an intriguing one in child neuropsychology. Method, We studied 22 children born preterm (12 males, 10 females; mean age at examination 8y, range 6,15y; mean gestational age 30wks, range 28,36wks) with periventricular leukomalacia, spastic diplegia, normal intelligence (mean Full-scale IQ 84; mean Verbal IQ 97; mean Performance IQ 74), and normal visual acuity, focusing on higher visual functions. Brain magnetic resonance images (MRI) were analysed to establish the presence of lesions along the primary optic pathway, in the occipitoparietal and occipitotemporal regions. Results, Most children displayed an uneven cognitive profile, with deficits in visual object recognition, visual imagery, visual,spatial skills, and visual memory, and sparing of visual associative abilities, non-verbal intelligence, and face and letter recognition. Conventional brain MRI did not document major alterations of parietal and temporal white matter, or cortical alteration of areas involved in visual associative functions. Interpretation, We suggest a widespread involvement of higher visual processing systems, involving both the ventral and dorsal streams, in preterm children with periventricular leukomalacia. The lack of major alterations on conventional MRI does not exclude the possibility of malfunctioning of higher visual processing systems, expressing itself through discrete CVDs. Possible mechanisms underlying these neuropsychological deficits are discussed. [source] White pines, Ribes, and blister rust: integration and actionFOREST PATHOLOGY, Issue 3-4 2010R. S. Hunt Summary The preceding articles in this series review the history, biology and management of white pine blister rust in North America, Europe and eastern Asia. In this integration, we connect and discuss seven recurring themes important for understanding and managing epidemics of Cronartium ribicola in the white pines (five-needle pines in subgenus Strobus). Information and action priorities for research and management of the pathogen, telial and aecial hosts, and their interactions are listed in a detailed Appendix. Syntheses focused on genetics, plant disease, invasive species or forest management have provided alternative but knowledgeable lessons on the white pine blister rust pathosystem. Two critical issues for the conservation of white pines are to sustain ecosystems affected by blister rust and to maintain genetic diversity for adaptive traits such as disease resistance. Forest genetics includes tree improvement and molecular techniques for research; their application can increase rust resistance by artificial and natural selection. Silviculture augments genetics with methods to deploy and enhance resistance as well as to regenerate and tend white pine stands. Although cultivated or wild Ribes might serve as inoculum sources, silviculture and horticulture can reduce the risk of serious impacts from blister rust using genetics for breeding and epidemiology for hazard assessment and disease control. Climate change threatens to cause major alterations in temperature and precipitation regimes, resulting in maladapted conifers succumbing to various diseases and insect outbreaks. In contrast, many white pine species have broad ecological ranges and are tolerant of harsh environments,traits that permit successful establishment and growth over wide geographic and altitudinal zones. Given appropriate management, white pines could thrive as valuable commercial and ecologically important keystone species. In an uncertain environment, adaptive management provides a learning and participatory approach for sustaining resilient ecosystems. [source] Targeted Expression of SHH Affects Chondrocyte Differentiation, Growth Plate Organization, and Sox9 Expression,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2004Sara Tavella Abstract The role of Hedgehogs (Hh) in murine skeletal development was studied by overexpressing human Sonic Hedgehog (SHH) in chondrocytes of transgenic mice using the collagen II promoter/enhancer. Overexpression caused a lethal craniorachischisis with major alterations in long bones because of defects in chondrocyte differentiation. Introduction: Hedgehogs (Hhs) are a family of secreted polypeptides that play important roles in vertebrate development, controlling many critical steps of cell differentiation and patterning. Skeletal development is affected in many different ways by Hhs. Genetic defects and anomalies of Hhs signaling pathways cause severe abnormalities in the appendicular, axial, and cranial skeleton in man and other vertebrates. Materials and Methods: Genetic manipulation of mouse embryos was used to study in vivo the function of SHH in skeletal development. By DNA microinjection into pronuclei of fertilized oocytes, we have generated transgenic mice that express SHH specifically in chondrocytes using the cartilage-specific collagen II promoter/enhancer. Transgenic skeletal development was studied at different embryonic stages by histology. The expression pattern of specific chondrocyte molecules was studied by immunohistochemistry and in situ hybridization. Results: Transgenic mice died at birth with severe craniorachischisis and other skeletal defects in ribs, sternum, and long bones. Detailed analysis of long bones showed that chondrocyte differentiation was blocked at prehypertrophic stages, hindering endochondral ossification and trabecular bone formation, with specific defects in different limb segments. The growth plate was highly disorganized in the tibia and was completely absent in the femur and humerus, leading to skeletal elements entirely made of cartilage surrounded by a thin layer of bone. In this cartilage, chondrocytes maintained a columnar organization that was perpendicular to the bone longitudinal axis and directed toward its outer surface. The expression of SHH receptor, Patched-1 (Ptc1), was greatly increased in all cartilage, as well as the expression of parathyroid hormone-related protein (PTHrP) at the articular surface; while the expression of Indian Hedgehog (Ihh), another member of Hh family that controls the rate of chondrocyte maturation, was greatly reduced and restricted to the displaced chondrocyte columns. Transgenic mice also revealed the ability of SHH to upregulate the expression of Sox9, a major transcription factor implicated in chondrocyte-specific gene expression, in vivo and in vitro, acting through the proximal 6.8-kb-long Sox9 promoter. Conclusion: Transgenic mice show that continuous expression of SHH in chondrocytes interferes with cell differentiation and growth plate organization and induces high levels and diffuse expression of Sox9 in cartilaginous bones. [source] FGFR1/PI3K/AKT signaling pathway is a novel target for antiangiogenic effects of the cancer drug Fumagillin (TNP-470)JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2007Gregory J. Chen Abstract Fibroblast growth factor-1 (FGF1), a prototypic member of the FGF family, is a potent angiogenic factor. Although FGF-stimulated angiogenesis has been extensively studied, the molecular mechanisms regulating FGF1-induced angiogenesis are poorly understood in vivo. Fumagillin, an antiangiogenic fungal metabolite, has the ability to inhibit FGF-stimulated angiogenesis in the chicken chorioallantoic membrane (CAM). In the current study, chicken CAMs were transfected with a signal peptide-containing version of the FGF1 gene construct (sp-FGF1). Transfected CAMs were then analyzed in the presence and absence of fumagillin treatment with respect to the mRNA expression levels and protein activity of the FGF1 receptor protein (FGFR1), phosphatidylinositol 3-kinase (PI3K), and its immediate downstream target, AKT-1 (protein kinase B). Treatment of sp-FGF1-transfected CAMs with fumagillin showed downregulation for both PI3K and AKT-1 proteins in mRNA expression and protein activity. In contrast, no major alterations in FGFR1 mRNA expression level were observed. Similar patterns of mRNA expression for the above three proteins were observed when the CAMs were treated with recombinant FGF1 protein in place of sp-FGF1 gene transfection. Investigation using biotin-labeled fumagillin showed that only the FGF1 receptor protein containing the cytoplasmic domain demonstrated binding to fumagillin. Furthermore, we demonstrated endothelial-specificity of the proposed antiangiogenic signaling cascade using an in vitro system. Based on these findings, we conclude that the binding of fumagillin to the cytoplasmic domain of the FGF1 receptor inhibited FGF1-stimulated angiogenesis both in vitro and in vivo. J. Cell. Biochem. 101: 1492,1504, 2007. © 2007 Wiley-Liss, Inc. [source] Gangliosides in rat femoral injury: Early effect on intimal hyperplasiaMICROSURGERY, Issue 4 2001Leonardo C. Castro Previous studies demonstrated that some immunosupressive agents inhibit arterial intimal hyperplasia. Our previous studies demonstrated that gangliosides (Gang) have an immunosuppressive effect on as well as an anti-inflammatory role in the wound-healing process. Therefore, we decided to examine the effect of Gang on intimal hyperplasia. Twenty Wistar isogenic rats received a transverse division of the anterior wall of the femoral artery, followed by suturing using mononylon 10-0 under surgical microscopy and were then divided into two groups: Gang group, 3 mg/kg per day of Gang, and control group, vehicle, intramuscularly from surgery to death (1 and 3 weeks, respectively). Concentric intimal hyperplasia was observed in arteries stained by hematoxylin-eosin in control and Gang groups. However, the media layer did not demonstrate any major alterations. After 3 weeks, the Gang group showed more intimal hyperplasia than the control group. Therefore, because intimal hyperplasia worsened in the presence of Gang after 3 weeks, further studies will be necessary to clarify its role in intimal proliferation. © 2001 Wiley-Liss, Inc. MICROSURGERY 21:170,172 2001 [source] Onset of Apoptosis in the Cystic Duct During Metamorphosis of a Japanese Lamprey, Lethenteron reissneriTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 7 2010Mayako Morii Abstract A nonparasitic lamprey in Japan, Lethenteron reissneri, stops feeding prior to the commencement of metamorphosis. Resumption of feeding cannot take place due to major alterations in the digestive system, including loss of the gall bladder (GB) and biliary tree in the liver. This degeneration of bile ducts is considered to depend on programmed cell death or apoptosis, but molecular evidence of apoptosis remains lacking. Using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and immunohistochemistry with an antibody against active caspase-3, we showed that epithelial cells of the cystic duct (CD) and GB became TUNEL-positive by the early metamorphosing stage. Immunohistochemical staining of active caspase-3, a key mediator in the apoptotic cascade, showed that the apoptotic signal was initiated in the region around the CD in the late larval phase. In later stages, active caspase-3-positive epithelial cells were also observed in the large intrahepatic bile duct (IHBD) and peripheral small IHBDs. At the early metamorphosing stage, bile canaliculi between hepatocytes were dilated and displayed features resembling canaliculi in cholestasis. Onset of apoptosis around the CD, which is the pathway for the storage of bile juice, and progression of apoptosis towards the large IHBD, which is the pathway for the secretion of bile juice, may lead to temporary intrahepatic cholestasis. The present study represents the first precise spatial and temporal analysis of apoptosis in epithelial cells of the biliary tract system during metamorphosis of any lamprey species. Anat Rec 293:1155,1166, 2010. © 2010 Wiley-Liss, Inc. [source] Orthotopic, but Reversed Implantation of the Liver Allograft in Situs Inversus Totalis,A Simple New Approach to a Difficult ProblemAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2009S. C. Rayhill Situs inversus totalis is a rare congenital anomaly in which the heart and abdominal organs are oriented in a mirror image of normal. It provides a unique challenge as there is no established technique for liver transplantation in these patients. Employing two major alterations from our standard technique, a liver was transplanted in the left subphrenic space of a patient with situs inversus totalis. First, the liver was flipped 180° from right to left (facing backward). Second, a reversed cavaplasty (anterior, not posterior, donor suprahepatic caval incision) was performed. Otherwise, it was standard, with end-to-end anastomoses of the portal vein, hepatic artery and bile duct. Three years after the entirely uneventful transplant, the recipient continues to enjoy the benefits of a normally functioning liver. The described technique prevented torsion, kinking and tension on the anastomosed structures by allowing the liver to sit naturally in an anatomical position in the left hepatic fossa. As it required no special measurements or maneuvers, the technique was easy to execute and required no donor liver size restrictions. This novel technique, with a reversed cavaplasty and a 180° right-to-left flip of the liver into a left-sided hepatic fossa, may be ideal for situs inversus totalis. [source] A morphometric analysis of bulbar urethral stricturesBJU INTERNATIONAL, Issue 2 2007Andre G. Cavalcanti In a beautifully descriptive paper, authors from Rio de Janeiro and San Francisco report a quantitative and qualitative histological analysis of spongiosal tissue in patients with bulbar urethral strictures. They found that stricture formation was characterised by major alterations in extracellular matrix features. OBJECTIVE To report a quantitative and qualitative histological analysis of spongiosum tissue in patients with bulbar urethral strictures. MATERIALS AND METHODS Urethral specimens from 15 patients who had end-to-end anastomotic urethroplasty were evaluated; the control group comprised five bulbar urethras from cadavers. The collagen content, elastic fibres, smooth muscle and vessels were analysed using stereological methods. RESULTS There was complete loss of the relationship between smooth muscle, extracellular matrix and sinusoids in the peri-luminal area (PLA), with collagen replacement. The extension of the fibrotic area was greater in those with a traumatic than in those with an atraumatic stricture. The content of smooth muscle and collagen in the peripheral spongiosum (PS) area was similar for the stricture and control groups, and results were comparable for traumatic and atraumatic groups and those with suprapubic cystostomy diversion or not before surgery. There was a remarkably lower vascular density in the traumatic than in the atraumatic group. There was an increase in type III collagen in the PLA and in type I collagen in the PS; collagen type III in the PLA was greater in the group with no suprapubic cystostomy diversion before surgery. There were fewer elastic fibres in both stricture areas (PLA and PS) than in the control group. CONCLUSIONS Urethral stricture formation is characterized by marked changes in extracellular matrix features, with consequent changes in organ function. [source] | |||||||||||||