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Gradual Loss (gradual + loss)
Selected AbstractsA Validated Grading Scale for Forehead LinesDERMATOLOGIC SURGERY, Issue 2008ALASTAIR CARRUTHERS MD BACKGROUND As with other facial wrinkles, the gradual loss and disorganization of collagen fibers and elastin, connective tissues that provide underlying support for skin, cause horizontal forehead rhytides in large part. OBJECTIVES To develop the Forehead Lines Grading Scale for objective quantification of horizontal forehead rhytides at rest and with expression and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS The Forehead Lines Grading Scale is a 5-point photonumeric rating scale that was developed to objectively quantify resting (static) and hyperkinetic (dynamic) forehead lines. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS The agreement between the experts was highly significant. Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. CONCLUSION The 5-point photonumeric scale generated spans the severity of forehead lines for which patients commonly seek correction. The scale is well stratified for consistent rating. [source] Insect community organisation in estuaries: the role of the physical environmentECOGRAPHY, Issue 3 2002D. Dudley Williams Insects are reportedly uncommon in marine habitats and, from a spatial/temporal intercomparison perspective, estuaries are among the least studied. We examined the natural variability seen among insect community organisation in estuaries on both sides of the North Atlantic, and evaluated the role of their physical environments. Community composition was found to be strongly influenced by three physical factors: estuary size, the degree of inundation by incoming tides, and substrate size/stability. Insects formed a significant proportion (17,54%, by numbers) of the benthic community of coarse-grained-substratum estuaries, and species richness increased with estuary size. Nymphs/larvae of mayflies, stoneflies, caddisflies, elmid beetles and chironomids dominated channel sites inundated by up to 25% of all incoming tides, but a gradual loss in species richness occurred downstream. However, even the most seaward sites supported high insect densities (up to 25,016 and 5433 m,2, supporting 26 and 4 species, at sites inundated by 75 and 100% of all incoming tides, respectively). Sites covered by tides for between 3 and 5 h twice daily were dominated by orthocladine chironomids, especially of the genus Orthocladius. Chironomid larvae contribute significantly to the diets of some coastal fish species, particularly juvenile flounder and sticklebacks. We present a schematic model summarising the relationships between estuary size, degree of inundation by salt water and insect community structure. [source] A role for synGAP in regulating neuronal apoptosisEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005Irene Knuesel Abstract The brain-specific Ras/Rap GTPase-activating protein synGAP is a major component of the postsynaptic density at glutamatergic synapses. It is a target for phosphorylation by Ca2+/calmodulin-dependent protein kinase II, which up-regulates its GTPase-activating activity. Thus, SynGAP may play an important role in coupling N -methyl- d -aspartate-type glutamate receptor activation to signaling pathways downstream of Ras or Rap. Homozygous deletion of synGAP is lethal within the first few days after birth. Therefore, to study the functions of synGAP, we used the cre/loxP recombination system to produce conditional mice mutants in which gradual loss of synGAP begins at ,,1 week, and usually becomes maximal by 3 weeks, after birth. The resulting phenotypes fall into two groups. In a small group, the level of synGAP protein is reduced to 20,25% of wild type, and they die at 2,3 weeks of age. In a larger group, the levels remain higher than ,,40% of wild type, and they survive and remain healthy. In all mutants, however, an abnormally high number of neurons in the hippocampus and cortex undergo apoptosis, as detected by caspase-3 activation. The effect is cell autonomous, occurring only in neuronal types in which the synGAP gene is eliminated. The level of caspase-3 activation in neurons correlates inversely with the level of synGAP protein measured at 2 and 8 weeks after birth, indicating that neuronal apoptosis is enhanced by reduction of synGAP. These data show that synGAP plays a role in regulation of the onset of apoptotic neuronal death. [source] Timing and sequence of differentiation of embryonic rat hepatocytes along the biliary epithelial lineageHEPATOLOGY, Issue 3 2003Robbert G. E. Notenboom To study the differentiation of hepatocytes along the biliary epithelial lineage in vivo, embryonic day 14 (E14) rat hepatocytes were isolated by differential centrifugation and transplanted as single-cell suspensions into the spleen of adult syngeneic rats. Hepatocytes and cholangiocytes were identified and their maturation characterized by the level of expression of ,-fetoprotein (AFP), glutamate dehydrogenase (GDH), and carbamoyl phosphate synthetase I (CPS); annexin IV, annexin V, cytokeratin 19 (CK-19), and cystic fibrosis transmembrane conductance regulator (CFTR); and electron microscopy. By correlating morphologic changes with the timing in the expression of these markers, we show that the organization of the transplanted E14 hepatocytes into lobular structures is accompanied by the formation and maturation of bile ducts around these developing lobules. Morphologic differentiation of the emerging bile ducts was accompanied by a gradual loss of hepatocyte markers and a gradual acquisition of cholangiocyte markers, with markers identifying a large-cholangiocyte phenotype appearing latest. Once fully differentiated, the intrasplenic liver lobules developed cholestatic features. The accompanying proliferation of bile ducts was due to cholangiocyte proliferation, but ductular transformation of hepatocytes was also observed. In conclusion, (1) bile duct formation at the interface between hepatocytes and connective tissue is an inherent component of liver development and (2) the susceptibility of developing hepatocytes to bile duct-inducing signals is highest in the fetal liver but that (3) this capacity is not irreversibly lost in otherwise mature hepatocytes. [source] The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations,HUMAN MUTATION, Issue 3 2010Mia-Lisa Schmiedt Abstract Neuronal ceroid lipofuscinoses (NCLs) represent a group of children's inherited neurodegenerative disorders caused by mutations in at least eight different genes. Mutations in the CLN5 gene result in the Finnish variant late infantile NCL characterized by gradual loss of vision, epileptic seizures, and mental deterioration. The CLN5 gene encodes a lysosomal glycoprotein of unidentified function. In this study, we have used both transient and stable expression systems for the characterization of CLN5, focusing on the localization, processing, and intracellular trafficking. We show that CLN5 is proteolytically cleaved, and that the mature polypeptide is transported to the lysosomes. Our data provide the first evidence that soluble CLN5 protein can also undergo mannose-6-phosphate receptor-independent trafficking to the lysosomes. We studied the localization and maturation of the CLN5 carrying the previously uncharacterized vLINCL disease causing mutations in HeLa cells. All analyzed disease mutations disturb the lysosomal trafficking of the mutated CLN5 proteins. The level of lysosomal targeting does not correlate, however, to disease onset, indicating that CLN5 may also function outside lysosomes. This study furthers our understanding of the basic properties of the CLN5 protein, necessary for the characterization of the consequences of disease mutations and for the planning of future therapies for vLINCL. Hum Mutat 31:356,365, 2010. © 2010 Wiley-Liss, Inc. [source] Recovery of normal autologous myelopoiesis after graft rejection following allogeneic bone marrow transplant for agnogenic myeloid metaplasiaINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 2 2006S. ALKINDI Summary Allogeneic hematopoietic transplantation is the only currently available therapy that has the potential to cure agnogenic myeloid metaplasia (AMM) or primary myelofibrosis (PMF). Amelioration of fibrosis and eradication of the abnormal clone is thought to occur through the repopulation of marrow by donor-derived hematopoiesis and graft- vs. -host reaction leading to graft vs. tumor effect. We report here a 50-year-old female with AMM/PMF, conditioned with busulfan and cyclophosphamide, who rejected a single locus (HLA-B) mismatched bone marrow transplant from her daughter, but recovered normal autologous hematopoiesis with disappearance of marrow fibrosis and extramedullary hematopoiesis. Variable number tandem repeats (VNTR) analysis showed a gradual loss of donor-derived hematopoietic cells with recovery of autologous hematopoiesis. This case therefore illustrates that eradication of AMM/PMF in this patient with myeloablative chemotherapy combined with a transient allogeneic effect was sufficient to suppress the abnormal stem cell clone associated with AMM/PMF with subsequent cure. [source] Genetic structure of Hypochaeris uniflora (Asteraceae) suggests vicariance in the Carpathians and rapid post-glacial colonization of the Alps from an eastern Alpine refugiumJOURNAL OF BIOGEOGRAPHY, Issue 12 2007Patrik Mráz Abstract Aim, The range of the subalpine species Hypochaeris uniflora covers the Alps, Carpathians and Sudetes Mountains. Whilst the genetic structure and post-glacial history of many high-mountain plant taxa of the Alps is relatively well documented, the Carpathian populations have often been neglected in phylogeographical studies. The aim of the present study is to compare the genetic variation of the species in two major European mountain systems , the Alps and the Carpathians. Location, Alps and Carpathians. Methods, The genetic variation of 77 populations, each consisting of three plants, was studied using amplified fragment length polymorphism (AFLP). Results, Neighbour joining and principal coordinate analyses revealed three well-supported phylogeographical groups of populations corresponding to three disjunct geographical regions , the Alps and the western and south-eastern Carpathians. Moreover, two further clusters could be distinguished within the latter mountain range, one consisting of populations from the eastern Carpathians and the second consisting of populations from the southern Carpathians. Populations from the Apuseni Mountains had an intermediate position between the eastern and southern Carpathians. The genetic clustering of populations into four groups was also supported by an analysis of molecular variance, which showed that most genetic variation (almost 46%) was found among these four groups. By far the highest within-population variation was found in the eastern Carpathians, followed by populations from the southern and western Carpathians. Generally, the populations from the Alps were considerably less variable and displayed substantially fewer region-diagnostic markers than those from the south-eastern Carpathians. Although no clear geographical structure was found within the Alps, based on neighbour joining or principal coordinate analyses, some trends were obvious: populations from the easternmost part were genetically more variable and, together with those from the south-western part, exhibited a higher proportion of rare AFLP fragments than populations in other areas. Moreover, the total number of AFLP fragments per population, the percentage of polymorphic loci and the proportion of rare AFLP fragments significantly decreased from east to west. Main conclusions, Deep infraspecific phylogeographical gaps between the populations from the Alps and the western and south-eastern Carpathians suggest the survival of H. uniflora in three separate refugia during the last glaciation. Our AFLP data provide molecular evidence for a long-term geographical disjunction between the eastern and western Carpathians, previously suggested from the floristic composition at the end of 19th century. It is likely that Alpine populations survived the Last Glacial in the eastern part of the Alps, from where they rapidly colonized the rest of the Alps after the ice sheet retreated. Multiple founder effects may explain a gradual loss of genetic variation during westward colonization of the Alps. [source] Cadherin expression pattern in melanocytic tumors more likely depends on the melanocyte environment than on tumor cell progressionJOURNAL OF CUTANEOUS PATHOLOGY, Issue 1 2004Sven Krengel Background:, Adhesion molecules have been assigned an important role in melanocytic tumor progression. By the loss of E-cadherin, melanocytes might escape the control of neighbouring keratinocytes. Although in vitro data support this hypothesis, there are yet no conclusive immunohistochemical results on cadherin expression in melanocytic tumors. Objective:, To gain detailed insight in the expression of cadherins and their cytoplasmic binding partners, the catenins, in various types of benign and malignant melanocytic neoplasms. Methods:, Immunohistochemical analysis of the expression of E-, P-, and N-cadherin and ,-, ,-, and ,-catenin in compound and dermal nevi, Spitz nevi, blue nevi, ultraviolet B (UVB)-irradiated nevi, and malignant melanomas of various tumor thickness. Results:, In both nevi and melanomas, E-cadherin expression in melanocytic cells decreased, following a gradient from junctional to deeper dermal localization. The pattern of E-cadherin expression was more heterogeneous in melanomas than in nevi. In some melanomas, E-cadherin was only weakly positive in the epidermal tumor cells. P-cadherin expression was similar to that of E-cadherin. N-cadherin expression in melanocytic lesions was a rare finding, however, a small percentage of melanomas showed expression in some cell nests. Some Spitz nevi exhibited strong N-cadherin immunoreactivity. Most melanocytic cells were ,- and ,-catenin-positive and ,-catenin-negative. UVB irradiation did not influence the expression of cadherins and catenins in melanocytic nevi in vivo. Conclusions:, It is presumed that the gradual loss of E-cadherin expression represents a reaction of melanocytic cells to altered conditions in the dermal environment, e.g. lack of contact to keratinocytes, or new contact with dermal extracellular matrix molecules, respectively. Melanoma cells apparently are less dependent on these environmental factors and, therefore, show a more heterogeneous expression pattern. This might be of importance for the adaptation of the tumor cells to local requirements. However, in view of our results, a causative role of (loss of ) E-cadherin or (gain of ) N-cadherin for melanocytic tumor progression still remains to be proven. [source] Effects of genetic impoverishment on plant community diversityJOURNAL OF ECOLOGY, Issue 5 2003Rosemary E. Booth Summary 1Established individuals removed at random from populations of 11 long-lived herbaceous species coexisting in a local area of ancient limestone pasture at Cressbrookdale in North Derbyshire were subjected to clonal propagation to produce stocks of genetically identical individuals sufficient to create 36 model communities identical in species composition but widely contrasted in genetic diversity. 2Three levels of genetic diversity were imposed. In one treatment, all individuals of each species were genetically unique. The second contained four randomly selected genotypes of each species. In the third, there was no genetic diversity in any of the species but each community contained a unique combination of genotypes. 3Over a period of 5 years the communities were allowed to develop in microcosms containing natural rendzina soil and exposed to a standardized regime of simulated grazing and trampling. The treatments were maintained by the removal of flowers, immature seed-heads and seedlings originating from the seed-bank and seed rain. Point quadrat surveys were used to monitor changes in species composition and diversity in the three experimental treatments. 4During the experiment a distinction rapidly developed between five canopy dominants and five subordinates, a process that caused the vegetation structure to closely resemble that occurring at Cressbrookdale. 5A gradual loss of species diversity occurred in all three treatments but by the end of the fifth growing season species diversity was higher in the most genetically diverse communities. 6Ordination of the 36 communities at intervals over a 5-year period revealed a gradual convergence in the species composition of the 4-genotype and 16-genotype communities and this effect was more strongly developed in the latter. A comparable process was not observed in the 1-genotype communities, suggesting that interaction between particular genotypes of different species in local neighbourhoods may be an essential part of the mechanism that determines the predictable composition of a mature pasture community. 7It is concluded that, under the conditions of this experiment, genetic diversity within component species reduced the rate at which species diversity declined. The relative importance in this effect of factors such as greater disease resistance and moderated competitive interactions remains uncertain. [source] The neuropathogenic contributions of lysosomal dysfunctionJOURNAL OF NEUROCHEMISTRY, Issue 3 2002Ben A. Bahr Abstract Multiple lines of evidence implicate lysosomes in a variety of pathogenic events that produce neurodegeneration. Genetic mutations that cause specific enzyme deficiencies account for more than 40 lysosomal storage disorders. These mostly pre-adult diseases are associated with abnormal brain development and mental retardation. Such disorders are characterized by intracellular deposition and protein aggregation, events also found in age-related neurodegenerative diseases including (i) Alzheimer's disease and related tauopathies (ii) Lewy body disorders and synucleinopathies such as Parkinson's disease, and (iii) Huntington's disease and other polyglutamine expansion disorders. Of particular interest for this review is evidence that alterations to the lysosomal system contribute to protein deposits associated with different types of age-related neurodegeneration. Lysosomes are in fact highly susceptible to free radical oxidative stress in the aging brain, leading to the gradual loss of their processing capacity over the lifespan of an individual. Several studies point to this lysosomal disturbance as being involved in amyloidogenic processing, formation of paired helical filaments, and the aggregation of ,-synuclein and mutant huntingtin proteins. Most notably, experimentally induced lysosomal dysfunction, both in vitro and in vivo, recapitulates important pathological features of age-related diseases including the link between protein deposition and synaptic loss. [source] Succinimide formation at Asn 55 in the complementarity determining region of a recombinant monoclonal antibody IgG1 heavy chainJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2009Boxu Yan Abstract We investigated the formation and stability of succinimide, an intermediate of deamidation events, in recombinant monoclonal antibodies (mAbs). During the course of an analytical development study of an IgG1 mAbs, we observed that a specific antibody population could be separated from the main product by cation-exchange (CEX) chromatography. The cell-based bioassay measured a ,70% drop in potency for this fraction. Liquid chromatography time-of-flight mass spectrometry (LC,TOF/MS) and tandem mass spectrometry (LC,MS/MS) analyses showed that the modified CEX fraction resulted from the formation of a succinimide intermediate at Asn 55 in the complementarity determining region (CDR) of the heavy chain. Biacore assay revealed a ,50% decrease in ligand binding activity for the succinimide-containing Fab with respect to the native Fab. It was found that the succinimide form existed as a stable intermediate with a half-life of ,3 h at 37°C and pH 7.6. Stress studies indicated that mildly acidic pH conditions (pH 5) favored succinimide accumulation, causing a gradual loss in potency. Hydrolysis of the succinimide resulted in a further drop in potency. The implications of the succinimide formation at Asn 55, a highly conserved residue among IgG1 (mAbs), are discussed. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3509,3521, 2009 [source] Corticobasal degeneration as cause of progressive non-fluent aphasia: Clinical, radiological and pathological study of an autopsy caseNEUROPATHOLOGY, Issue 6 2006Masaki Takao A Japanese male developed gradual loss of spontaneous speech at age 60. Three years later meaningful speech had deteriorated to the point that it had become restricted to monotonous utterances. Neuropsychological examination at age 62 showed that he had severe non-fluent aphasia. A brain MRI demonstrated mild cortical atrophy with ischemic lesions in the cerebral white matter. He was diagnosed as having primary progressive aphasia. At age 63, he was admitted to the hospital to reevaluate the neurological condition. Neurologic examination showed severe non-fluent aphasia, hyperreflexia, snout and sucking reflexes. No alien hand was observed. He was able to walk, dress, wash himself and use chopsticks as well as name real objects. At age 65, 99mTc-hexamethylpropyleneamine oxime single photon emission computed tomography (HMPAO-SPECT) revealed diffuse cerebral hypoperfusion that was particularly prominent in the left frontal lobe. An MRI showed progressive cortical atrophy with the definite atrophy of the left paracentral gyrus. The hippocampal formation and putamen were also atrophic. He died of pneumonia at age 67. The brain weighed 810 g with atrophy of the frontal lobe, globus pallidus, enlargement of the lateral ventricles and depigmentation of the substantia nigra. Microscopic examination showed severe neuronal loss and gliosis in the cerebral cortex, globus pallidus interna and substantia nigra. Ballooned neurons were observed in the cerebral cortex. Gallyas-Braak method revealed numerous astrocytic plaques and argentophilic threads in the cerebrum. Clinical diagnosis of corticobasal degeneration sometimes is difficult in individuals with atypical clinical presentations. More exact clinical and radiological criteria may warrant a diagnosis of corticobasal degeneration. [source] Removal of N -methylpyrrolidone hydrogen-bonded to polyaniline free-standing films by protonation,deprotonation cycles or thermal heatingPOLYMER INTERNATIONAL, Issue 11 2001Eduardo A Ponzio Abstract Free-standing films of polyaniline (PANI), in an emeraldine base state, prepared by evaporation of polymer solutions in N -methylpyrrolidone (NMP) retain solvent even under dynamic vacuum drying as indicated by transmission Fourier transform infrared (FTIR) spectroscopy, where a band at 1670,cm,1 is clearly observed. Upon protonation,deprotonation cycles in aqueous media the weight of the dry base film decreases indicating gradual loss of NMP. Transmission FTIR spectra shows also the washing out of NMP with a clear decrease in intensity of the hydrogen-bonded >CO stretching band (1670,cm,1) of NMP. During this process the bands between 3500 and 3200,cm,1, assigned to >NH stretching in the PANI backbone, change intensity suggesting that intermolecular hydrogen-bonded >NH, with carbonyl oxygen of NMP, is replaced by free >NH. This is clear evidence of specific interaction of NMP with the emeraldine base. A similar loss of NMP is observed during heating but evidence of polymer degradation is also present. A mechanism is proposed to account for the loss of hydrogen-bonding ability upon protonation which requires delocalization of the radical cations in the protonated films. © 2001 Society of Chemical Industry [source] Disrupted brain,immune system,joint communication during experimental arthritisARTHRITIS & RHEUMATISM, Issue 10 2008Adriana del Rey Objective To explore the hypothesis that, in parallel with alterations in the hypothalamus,pituitary,adrenal axis and the sympathetic nervous system, hypothalamic cytokine expression and monoaminergic neurotransmitter concentrations are affected during the course of arthritis development induced by type II collagen. This hypothesis was based on evidence that acute inflammatory processes induce cytokine expression in the brain and affect neuronal activity. We also studied whether depletion of hypothalamic noradrenaline can affect peripheral joint disease. Methods Hypothalamic cytokine gene expression and neurotransmitter concentration, parameters of inflammation, and joint innervation were evaluated during arthritis development in rats induced by injection of type II collagen in Freund's incomplete adjuvant. Noradrenergic neurons in the brain were depleted with 6-hydroxydopamine. Results Transiently increased corticosterone levels, followed by increased adrenaline levels and hypothalamic interleukin-1, (IL-1,) and IL-6 overexpression were observed only during the induction phase of the disease. Hypothalamic noradrenaline content was increased during the symptomatic phase and was paralleled by a gradual loss of noradrenergic fibers in the joints. The positive correlation between hypothalamic IL-1, expression and noradrenaline content in control groups was not observed in rats in which arthritis developed. Depletion of hypothalamic noradrenergic neurons when arthritis was established did not affect the course of the disease. Conclusion The dissociation between hypothalamic cytokine gene expression and noradrenergic neuronal activity, the lack of sustained stimulation of the stress axes, and the loss of sympathetic signals in the joints indicate a disruption in communication between afferent immune messages to the central nervous system and 2 main efferent antiinflammatory pathways under control of the brain during collagen-induced arthritis. [source] MALDI-TOF MS analysis of labile Lolium perenne major allergens in mixesCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2008S. G. Irańeta Summary Background It is well known that allergen extracts used for specific therapy of allergic disorders are commonly stored as mixtures, causing an alteration of its stability. Objective The aim of this report is to identify pollen allergens susceptible to degradation during storage of mixtures containing different sources of proteases in the absence of glycerol as a preserving agent. Methods Mixes containing Lolium perenne (Lol p) pollen extract with either Aspergillus fumigatus or Periplaneta americana extracts were prepared and co-incubated for 90 days at 4 °C. Samples were taken off at fixed times and comparatively tested by in vitro and in vivo assays with atopic patients. Selected pollinic allergens were subjected to MALDI-TOF MS analysis. Results ELISA inhibition evidenced the loss of potency from ryegrass extract, and immunoblotting assays showed the degradation of specific pollinic allergens during storage of mixtures containing protease-rich sources. An in vivo intradermal skin assay confirmed the gradual loss of the biological activity of L. perenne pollen extract co-incubated with non-related protease-rich extracts in comparison with that of the control pollen extract. MALDI-TOF MS analysis allowed us to determine that Lol p 1 and Lol p 5 are susceptible to proteolysis whereas Lol p 4 was found to be resistant to degradation during storage. Conclusions Lol p 1 and Lol p 5 degradation is responsible for the loss of the biological activity of L. perenne pollen extract when co-incubated with protease-rich fungal and cockroach extracts in the same vial for months in the absence of glycerol as a preserving agent. The integrity of these major allergens must be preserved to increase the vaccine stability and to assure efficacy when mixes are used for immunotherapy. [source] | |||||||||||||