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- Lewis, Cathryn M, et al.
(författare)
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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II : Schizophrenia
- 2003
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 73:1, s. 34-48
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
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- Shoenfeld, Yehuda, et al.
(författare)
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Features associated with epilepsy in the antiphospholipid syndrome
- 2004
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Ingår i: Journal of Rheumatology. - 0315-162X. ; 31:7, s. 1344-1348
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the frequency of epilepsy in primary and secondary antiphospholipid syndrome (APS); to analyze the clinical and laboratory features characterizing those with epilepsy in a cohort of 538 patients with APS; and to find associated features that would suggest risk factors for epilepsy in APS. METHODS: We analyzed the clinical features of patients with APS who had epilepsy and compared them to the clinical features of non-epileptic APS patients. RESULTS: Of 538 APS patients, 46 (8.6%) had epilepsy. Epilepsy was more prevalent among APS secondary to systemic lupus erythematosus (SLE) compared to primary APS (13.7% vs 6%; p < 0.05). The patients with epilepsy had a higher prevalence of central nervous system (CNS) manifestations including focal ischemic events (strokes or transient ischemic events, 54.3% vs 24.6%; p < 0.0001) and amaurosis fugax (15.2% vs 4.9%; p < 0.05). APS patients with epilepsy had a higher frequency of valvular pathology (30.4% vs 14.6%; p < 0.01), thrombocytopenia (43.5% vs 25%; p < 0.05), and livedo reticularis (26.1% vs 11.5%; p < 0.01). The multivariate logistic regression analysis found CNS thromboembolic events as the most significant factor associated with epilepsy, with an odds ratio (OR) of 4.05 (95% confidence interval, CI: 2.05-8), followed by SLE (OR 1.4, 95% CI 1.2-4.7), and valvular vegetations (OR 2.87, 95% CI 1-8.27). CONCLUSION: Epilepsy is common in APS and most of the risk seems to be linked to vascular disease as manifested by extensive CNS involvement, valvulopathy, and livedo reticularis and to the presence of SLE. These factors, however, explain only part of the increased occurrence of epilepsy in APS and other causes such as direct immune interaction in the brain should be investigated.
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- Yang, Jia Jin, et al.
(författare)
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Internalization of proteinase 3 is concomitant with endothelial cell apoptosis and internalization of myeloperoxidase with generation of intracellular oxidants
- 2001
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Ingår i: American Journal of Pathology. - 1525-2191. ; 158:2, s. 581-592
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Tidskriftsartikel (refereegranskat)abstract
- The important issue addressed by the studies presented here is the mechanism of neutrophil-mediated damage to endothelial and epithelial cells during inflammation. Binding of neutrophil-released granule proteins to endothelial cells may be involved in vascular damage in patients with inflammatory vascular diseases. We have determined whether granule proteins proteinase 3(PR3) and/or myeloperoxidase (MPO) are internalized into endothelial cells, as examined by UV light, confocal, and electron microscopy. Coincident induction of apoptosis and/or the generation of intracellular oxidants were monitored. The results indicate that human endothelial cells (human umbilical vein endothelial cells, human umbilical arterial endothelial cells, human lung microvascular endothelial cells) internalize both PR3 and MPO, which are detected on the cell surface, in the cytoplasm, and possibly nuclear. Epithelial cells (small airway epithelial cells) internalized MPO but not PR3, implying that the mechanism of PR3 internalization may be cell-type specific and different from that of MPO. Internalization of PR3, but not MPO, correlated with activation of apoptosis. Internalization of MPO correlated with an increase in intracellular oxidant radicals. The requirement for the proteolytic activity of PR3 for the induction of apoptosis was examined by generating PR3-truncated fragments that did not contain the components of the catalytic triad. An apoptotic function was localized to the C-terminal portion of PR3. These studies reveal novel mechanisms by which the neutrophil granule proteins PR3 and MPO contribute to tissue injury at sites of inflammation.
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- Bornehag, Carl-Gustaf, et al.
(författare)
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The association between asthma and allergic symptoms in children and phthalates in house dust : a nested case-control study
- 2004
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Ingår i: Journal of Environmental Health Perspectives. - : National Institute of Environmental Health Sciences (NIEHS). - 0091-6765 .- 1552-9924. ; 112:14, s. 1393-1397
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Tidskriftsartikel (refereegranskat)abstract
- Global phthalate ester production has increased from very low levels at the end of World War II to approximately 3.5 million metric tons/year. The aim of the present study was to investigate potential associations between persistent allergic symptoms in children, which have increased markedly in developed countries over the past three decades, and the concentration of phthalates in dust collected from their homes. This investigation is a case-control study nested within a cohort of 10,852 children. From the cohort, we selected 198 cases with persistent allergic symptoms and 202 controls without allergic symptoms. A clinical and a technical team investigated each child and her or his environment. We found higher median concentrations of butyl benzyl phthalate (BBzP) in dust among cases than among controls (0.15 vs. 0.12 mg/g dust). Analyzing the case group by symptoms showed that BBzP was associated with rhinitis (p = 0.001) and eczema (p = 0.001), whereas di(2-ethylhexyl) phthalate (DEHP) was associated with asthma (p = 0.022). Furthermore, dose-response relationships for these associations are supported by trend analyses. This study shows that phthalates, within the range of what is normally found in indoor environments, are associated with allergic symptoms in children. We believe that the different associations of symptoms for the three major phthalates-BBzP, DEHP, and di-n-butyl phthalate-can be explained by a combination of chemical physical properties and toxicologic potential. Given the phthalate exposures of children worldwide, the results from this study of Swedish children have global implications.
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- Bragdon, Charles R, 1959, et al.
(författare)
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Comparison of two digital radiostereometric analysis methods in the determination of femoral head penetration in a total hip replacement phantom
- 2004
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Ingår i: J Orthop Res. - : Wiley. - 0736-0266. ; 22:3, s. 659-64
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Tidskriftsartikel (refereegranskat)abstract
- Radiostereometric analysis (RSA) has been used extensively to evaluate the magnitude and direction of penetration of the femoral head into the acetabular component of a total hip replacement as a result of polyethylene wear and creep. The accuracy and precision of an RSA study depends on several factors, including the radiographic technique, the analytical software, and the positioning of the tantalum markers. This study had three sequential purposes. First, an in vitro phantom model was used to quantify the accuracy and precision of digital images versus conventional radiography in RSA measurements of penetration of the femoral head into the acetabular shell in a total hip replacement. The Umea RSA software package was used for analysis of both the conventional films, which were digitized at a resolution of 300 DPI, and digital radiographs, which were converted from a DICOM format at a resolution of 218 DPI. Digital radiography was found to be superior. Next, two methods of RSA analysis currently in use for determining femoral head penetration into polyethylene of total joint replacements were compared. Using the phantom model, we compared the Umea RSA system (Biomedical Innovations AB) to the RSA-CMS (RSA Clinical Measurement Solution) and in both cases used the digital radiographs. The Umea RSA system was found to be superior. Finally, two methods of marking the position of the acetabular component with tantalum beads were compared: one in which beads were inserted into previously described towers protruding from the back of the acetabular shell and another in which beads were placed into the peripheral flange of the polyethylene liner using the Umea RSA analysis system of the digital radiographs. The results using the two marker configurations were similar.
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- Griffith, May, et al.
(författare)
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Artificial human corneas - Scaffolds for transplantation and host regeneration
- 2002
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Ingår i: Cornea. - : Lippincott, Williams andamp; Wilkins. - 0277-3740 .- 1536-4798. ; 21:7, s. S54-S61
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Tidskriftsartikel (refereegranskat)abstract
- Purpose. To review the development of artificial corneas (prostheses and tissue equivalents) for transplantation, and to provide recent updates on our tissue-engineered replacement corneas. Methods. Modified natural polymers and synthetic polymers were screened for their potential to replace damaged portions of the human cornea or the entire corneal thickness. These polymers, combined with cells derived from each of the three main corneal layers or stem cells, were used to develop artificial corneas. Functional testing was performed in vitro. Trials of biocompatibility and immune and inflammatory reactions were performed by implanting the most promising polymers into rabbit corneas. Results. Collagen-based biopolymers, combined with synthetic crosslinkers or copolymers, formed effective scaffolds for developing prototype artificial corneas that could be used as tissue replacements in the future. We have previously developed an artificial cornea that mimicked key morphologic and functional properties of the human cornea. The addition of synthetic polymers increased its toughness as it retained transparency and low light scattering, making the matrix scaffold more suitable for transplantation. These new composites were implanted into rabbits without causing any acute inflammation or immune response. We have also fabricated full-thickness composites that can be fully sutured. However, the long-term effects of these artificial corneas need to be evaluated. Conclusions. Novel tissue-engineered corneas that comprise composites of natural and synthetic biopolymers together with corneal cell lines or stem cells will, in the future, replace portions of the cornea that are damaged. Our results provide a basis for the development of both implantable temporary and permanent corneal replacements.
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| 9. |
- Hua, Jianyi, et al.
(författare)
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Oxi4503, a novel vascular targeting agent: effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate.
- 2003
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Ingår i: Anticancer research. - 1791-7530. ; 23:2B, s. 1433-1440
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Tidskriftsartikel (refereegranskat)abstract
- Oxi4503, which is the diphosphate prodrug of combretastatin A1, is a novel vascular targeting agent from the combretastatin family. Another member of this family, Combretastatin A-4 phosphate (CA4P), is a well-characterized vascular targeting agent already being evaluated in clinical trials. The potential for tumor vascular targeting by Oxi4503 was assessed in a mouse system. This approach aims to shut down the established tumor vasculature, leading to the development of extensive tumor cell necrosis. The vascular effects of Oxi4503 were assessed in the s.c. implanted MDA-MB-231 adenocarcinoma and the MHEC5-T hemangio-endothelioma in SCID mice and in a range of normal tissues. Blood flow was measured by i.v. injection of fluorescence beads, while quantitative fluorescence microscopy was used to measure the spatial heterogeneity of blood flow in tumor sections. Oxi4503 induced the shutdown of tumor blood vessels in a dose-dependent pattern with an ED50 at 3 mg/kg in contrast to 43 mg/kg of CA4P. Quantitative fluorescence microscopy showed that Oxi4503 increased the spatial heterogeneity in tumor blood flow. Oxi4503 affected peripheral tumor regions less than central regions, although this was not as pronounced as seen with CA4P, where only central regions were affected. The vascular shutdown induced by administration of Oxi4503 at a dose of 6 mg/kg resulted in extensive cell loss 24 hours following treatment, which translated into a significant effect on tumor growth. Tumor growth was completely repressed at doses above 12.5 mg/kg of Oxi4503, while doses above 25 mg/kg showed tumor regression and even complete regression in some animals. These results are promising for the use of Oxi4503 as a tumor vascular targeting agent. Moreover the potent antitumor effect when administered as a single agent suggests a different activity profile than CA4P.
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