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991.
Huemer M Födinger M Bodamer OA Mühl A Herle M Weigmann C Ulmer H Stöckler-Ipsiroglu S Möslinger D 《Molecular genetics and metabolism》2008,94(1):46-51
Hyperhomocysteinemia has occasionally been reported in patients with phenylketonuria (PKU) and B-vitamin deficiency. In our study total homocysteine (tHcy) and B-vitamins were measured in treated PKU patients and healthy controls. In the patients, dietary parameters and genetic polymorphisms affecting the Hcy pathway were investigated to identify parameters modulating tHcy. A case control study including 37 PKU patients and 63 healthy controls was conducted. t-Tests for independent samples were used to test between groups. Multiple regressions with tHcy as dependent variable were calculated. Hardy-Weinberg expectations were tested against the observed distribution of genotypes applying the Chi-square goodness-of-fit method. THcy concentrations were not significantly different (p=0.059) while folate and cobalamin (Cbl) concentrations were significantly higher in PKU patients compared to controls. However, 29.7% of patients had tHcy concentrations >97th centile. THcy did not vary with age nor correlate with folate and Cbl concentrations probably due to high saturatory levels. The presence of genetic polymorphisms had no impact on tHcy. In conclusion, in PKU patients treated with amino acid mixtures enriched with B-vitamins, tHcy is not significantly higher than in healthy controls, but tHcy concentrations exceed the 97th centile in about one third of patients. Even higher B-vitamin saturation may be required to further decrease tHcy concentrations and factors generally influencing tHcy such as betaine are to be investigated in PKU patients in the future. 相似文献
992.
Jankovicová K Kudlová MT Kolácková M Kunes P Mand'ák J Lonský V Vlásková D Andrýs C Krejsek J 《Acta medica (Hradec Králové) / Universitas Carolina, Facultas Medica Hradec Králové》2008,51(1):25-29
BACKGROUND: Cardiac surgery using cardiopulmonary bypass (CPB) is associated with some adverse postoperative complications caused by an altered immune response. An alternative approach to cardiac surgery, operating without the use of CPB (i.e. off-pump surgery), seems to display less adverse impacts on the immune response. Patients and METHODS: Peripheral blood lymphocytes in 40 patients undergoing cardiac surgery either with CPB ("on-pump") or without CPB ("off-pump") were followed using flow cytometry. The samples of peripheral blood were taken at five intervals: preoperatively, after termination of the surgery, on the first, on the third and on the seventh postoperative day, respectively. RESULTS: The most substantial changes appeared on the first postoperative day in both subgroups of patients. While the percentage of both total T cells and CD4+ T cells were decreased, the percentage of HLA-DR+ activated lymphocytes was increased. These changes were more profound in the "on-pump" subgroup compared to the "off-pump" subgroup. CONCLUSION: Our results may suggest that the "off-pump" surgical approach reveals less adverse impact on adaptive immune responses. 相似文献
993.
994.
Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor 总被引:1,自引:0,他引:1
Kurzik-Dumke U Hörner M Czaja J Nicotra MR Simiantonaki N Koslowski M Natali PG 《International journal of molecular medicine》2008,21(1):19-31
Recently, we identified htid-1, the human counterpart of the Drosophila tumor suppressor gene lethal(2)tumorous imaginal discs [l(2)tid], as a direct molecular ligand of the adenomatous polyposis coli (APC) tumor suppressor. The gene encodes three cytosolic (Tid50, Tid48 and Tid46) and three mitochondrial (Tid43, Tid40 and Tid38) proteins. In the colorectal epithelium the cytosolic forms hTid50/hTid48 interact under physiological conditions with the N-terminal region of APC. This complex which associates with additional proteins such as Hsp70, Hsc70, Actin, Dvl and Axin defines a novel physiological state of APC unrelated to beta-catenin degradation. Here we show that the expression of the genes htid-1 and APC was altered in colorectal tumors. These changes concerned both the localization and the expression level of all three htid-1 splice variants and of APC. Furthermore, we showed that the protein products of the two tumor suppressors co-localized in the basal and apical region of normal colon epithelia and that loss of differentiation capacity of colorectal cancers correlated with a shift in their expression patterns from compartmentalized to diffuse cytoplasmic. These findings support our hypothesis that the building of the multi-component complex mentioned above is associated with the maintenance of the polarity of cells and tissues. In addition, we provide evidence that colon cancer progression correlates with up-regulation of htid-1 and its ligand Hsp70. Since the Tid proteins are members of the DnaJ-like protein family, an essential component of the Hsp70/Hsc70 chaperone machinery, our findings describe a novel, causal link between the function of chaperone machines, APC-mediated Wg/Wnt signaling and tumor development. 相似文献
995.
Ruptures of the anterior cruciate ligament (ACL) are common knee injuries that do not heal, even with surgical repair. Our research is directed towards developing novel, biological approaches that enable suture repair of this ligament. One promising strategy involves the insertion of a collagen hydrogel between the severed ends of the ACL. Cells migrate from the damaged ligament into the hydrogel and produce repair tissue. Here we have investigated the potential for augmenting this process by the transfer of insulin like growth factor (IGF) 1 cDNA to the repair cells using an adenovirus vector. The goal is to achieve direct, in situ gene delivery by loading the hydrogel with vector prior to its insertion into the defect. In a step-wise approach towards evaluating this process, we confirmed that monolayers of ACL fibroblasts were efficiently transduced by adenovirus vectors and continued to express transgenes when subsequently incorporated into the hydrogel; indeed, transgene expression persisted longer within collagen gels than in monolayer culture. Transfer of IGF-1 cDNA increased the cellularity of the gels and led to the synthesis and deposition of increased amounts of types I and III collagen, elastin, tenascin, and vimentin. The cells remained viable, even when subjected to high viral loads. Similar results were obtained when collagen hydrogels were preloaded with adenovirus prior to insertion into an experimental ACL lesion in vitro. These data confirm the promise of using vector-laden hydrogels for the in situ delivery of genes to cells within damaged ligaments and suggest novel possibilities for the biological repair of the ACL. 相似文献
996.
Biocompatibility of poly(D,L-lactide-co-glycolide) nanoparticles conjugated with alendronate 总被引:2,自引:0,他引:2
Cenni E Granchi D Avnet S Fotia C Salerno M Micieli D Sarpietro MG Pignatello R Castelli F Baldini N 《Biomaterials》2008,29(10):1400-1411
Nanoparticles made of a conjugate of poly(D,L-lactide-co-glycolide) with alendronate (PLGA-ALE NPs), were prepared by emulsion/solvent evaporation technique. The conjugation yield, determined by MALDI TOF analysis, was 30-35%. PLGA-ALE NPs size, evaluated by photon correlation spectroscopy, was 198.7+/-0.2 nm. Haemocompatibility studies using different concentrations of PLGA-ALE NPs did not show any significant effect on haemolysis, leukocyte number, platelet activation, APTT and complement consumption, in comparison with blood incubated with phosphate buffered saline (PBS). A significant reduction of the prothrombin activity was demonstrated after incubation with 560 microg/ml of PLGA-ALE NPs; a significant increase was observed at the highest dilutions. The viability of human umbilical vein endothelial cells and bone marrow stromal cells (BMSC), evaluated through the neutral red test, was not affected by PLGA-ALE NPs. There were no significant differences in cell-associated alkaline phosphatase between BMSC incubated with PLGA-ALE NP- and PBS-added media. These results demonstrated that PLGA-ALE NPs had an acceptable degree of blood compatibility and were not cytotoxic; therefore, they may be considered suitable for intravenous administration. 相似文献
997.
Schmucker S Argentini M Carelle-Calmels N Martelli A Puccio H 《Human molecular genetics》2008,17(22):3521-3531
Deficiency in the nuclear-encoded mitochondrial protein frataxin causes Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associating spinocerebellar ataxia and cardiomyopathy. Although the exact function of frataxin is still a matter of debate, it is widely accepted that frataxin is a mitochondrial iron chaperone involved in iron-sulfur cluster and heme biosynthesis. Frataxin is synthesized as a precursor polypeptide, directed to the mitochondrial matrix where it is proteolytically cleaved by the mitochondrial processing peptidase to the mature form via a processing intermediate. The mature form was initially reported to be encoded by amino acids 56-210 (m(56)-FXN). However, two independent reports have challenged these studies describing two different forms encoded by amino acids 78-210 (m(78)-FXN) and 81-210 (m(81)-FXN). Here, we provide evidence that mature human frataxin corresponds to m(81)-FXN, and can rescue the lethal phenotype of fibroblasts completely deleted for frataxin. Furthermore, our data demonstrate that the migration profile of frataxin depends on the experimental conditions, a behavior which most likely contributed to the confusion concerning the endogenous mature frataxin. Interestingly, we show that m(56)-FXN and m(78)-FXN can be generated when the normal maturation process of frataxin is impaired, although the physiological relevance is not clear. Furthermore, we determine that the d-FXN form, previously reported to be a degradation product, corresponds to m(78)-FXN. Finally, we demonstrate that all frataxin isoforms are generated and localized within the mitochondria. The clear identification of the N-terminus of mature FXN is an important step for designing therapeutic approaches for FRDA based on frataxin replacement. 相似文献
998.
The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment
Van Laer L Van Eyken E Fransen E Huyghe JR Topsakal V Hendrickx JJ Hannula S Mäki-Torkko E Jensen M Demeester K Baur M Bonaconsa A Mazzoli M Espeso A Verbruggen K Huyghe J Huygen P Kunst S Manninen M Konings A Diaz-Lacava AN Steffens M Wienker TF Pyykkö I Cremers CW Kremer H Dhooge I Stephens D Orzan E Pfister M Bille M Parving A Sorri M Van de Heyning PH Van Camp G 《Human molecular genetics》2008,17(2):159-169
Age-related hearing impairment (ARHI) is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. The contribution of various environmental factors has been relatively extensively studied. In contrast, investigations to identify the genetic risk factors have only recently been initiated. In this paper we describe the results of an association study performed on 2418 ARHI samples derived from nine centers from seven European countries. In 70 candidate genes, a total of 768 tag single nucleotide polymorphisms (SNPs) were selected based on HAPMAP data. These genes were chosen among the monogenic hearing loss genes identified in mice and men in addition to several strong functional candidates. After genotyping and data polishing, statistical analysis of all samples combined resulted in a P-value that survived correction for multiple testing for one SNP in the GRHL2 gene. Other SNPs in this gene were also associated, albeit to a lesser degree. Subsequently, an analysis of the most significant GRHL2 SNP was performed separately for each center. The direction of the association was identical in all nine centers. Two centers showed significant associations and a third center showed a trend towards significance. Subsequent fine mapping of this locus demonstrated that the majority of the associated SNPs reside in intron 1. We hypothesize that the causative variant may change the expression levels of a GRHL2 isoform. 相似文献
999.
1000.
Geiser M Casaulta M Kupferschmid B Schulz H Semmler-Behnke M Kreyling W 《American journal of respiratory cell and molecular biology》2008,38(3):371-376
The role of macrophages in the clearance of particles with diameters less than 100 nm (ultrafine or nanoparticles) is not well established, although these particles deposit highly efficiently in peripheral lungs, where particle phagocytosis by macrophages is the primary clearance mechanism. To investigate the uptake of nanoparticles by lung phagocytes, we analyzed the distribution of titanium dioxide particles of 20 nm count median diameter in macrophages obtained by bronchoalveolar lavage at 1 hour and 24 hours after a 1-hour aerosol inhalation. Differential cell counts revealing greater than 96% macrophages and less than 1% neutrophils and lymphocytes excluded inflammatory cell responses. Employing energy-filtering transmission electron microscopy (EFTEM) for elemental microanalysis, we examined 1,594 macrophage profiles in the 1-hour group (n = 6) and 1,609 in the 24-hour group (n = 6). We found 4 particles in 3 macrophage profiles at 1 hour and 47 particles in 27 macrophage profiles at 24 hours. Model-based data analysis revealed an uptake of 0.06 to 0.12% ultrafine titanium-dioxide particles by lung-surface macrophages within 24 hours. Mean (SD) particle diameters were 31 (8) nm at 1 hour and 34 (10) nm at 24 hours. Particles were localized adjacent (within 13-83 nm) to the membrane in vesicles with mean (SD) diameters of 592 (375) nm at 1 hour and 414 (309) nm at 24 hours, containing other material like surfactant. Additional screening of macrophage profiles by conventional TEM revealed no evidence for agglomerated nanoparticles. These results give evidence for a sporadic and rather unspecific uptake of TiO(2)-nanoparticles by lung-surface macrophages within 24 hours after their deposition, and hence for an insufficient role of the key clearance mechanism in peripheral lungs. 相似文献