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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Deutscher Kongress für Orthopädie und Unfallchirurgie; 74. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 96. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 51. Tagung des Berufsverbandes der Fachärzte für Orthopädie; 20101026-20101029; Berlin; DOCIN20-1289 /20101021/
    Publication Date: 2010-10-22
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Abstract: A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A 〉 C (IVS9-2A 〉 C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A 〉 C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 x 10-8 Our data indicate that c.594-2A 〉 C is always in cis with c.641A 〉 G. The spliceogenic effect of c.[594-2A 〉 C;641A 〉 G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A 〉 C; 641A 〉 G] caused exon 10 skipping, albeit not due to c.594-2A 〉 C impairing the acceptor site but rather by c.641A 〉 G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of approximately 70-80% truncating transcripts, and approximately 20-30% of in-frame Delta9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A 〉 C;641A 〉 G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.
    Type of Publication: Journal article published
    PubMed ID: 27008870
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  44. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 30. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 26. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR); 20160831-20160903; Frankfurt am Main; DOCSP.32 /20160829/
    Publication Date: 2016-08-29
    Keywords: secukinumab ; nail psoriasis ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 4
    Publication Date: 2018-06-22
    Description: CD4 T cells and antibody are required for optimal acquired immunity to Chlamydia muridarum genital tract infection, and T cell-mediated gamma interferon (IFN-) production is necessary to clear infection in the absence of humoral immunity. However, the role of T cell-independent immune responses during primary infection remains unclear. We investigated this question by inoculating wild-type and immune-deficient mice with C. muridarum CM001, a clonal isolate capable of enhanced extragenital replication. Genital inoculation of wild-type mice resulted in transient dissemination to the lungs and spleen that then was rapidly cleared from these organs. However, CM001 genital infection proved lethal for STAT1 –/– and IFNG –/– mice, in which IFN- signaling was absent, and for Rag1 –/– mice, which lacked T and B cells and in which innate IFN- signaling was retained. In contrast, B cell-deficient muMT mice, which can generate a Th1 response, and T cell-deficient mice with intact B cell and innate IFN- signaling survived. These data collectively indicate that IFN- prevents lethal CM001 dissemination in the absence of T cells and suggests a B cell corequirement. Adoptive transfer of convalescent-phase immune serum but not naive IgM to Rag1 –/– mice infected with CM001 significantly increased the survival time, while transfer of naive B cells completely rescued Rag1 –/– mice from CM001 lethality. Protection was associated with a significant reduction in the lung chlamydial burden of genitally infected mice. These data reveal an important cooperation between T cell-independent B cell responses and innate IFN- in chlamydial host defense and suggest that interactions between T cell-independent antibody and IFN- are essential for limiting extragenital dissemination.
    Print ISSN: 0019-9567
    Electronic ISSN: 1098-5522
    Topics: Medicine
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  • 5
    Publication Date: 2018-05-08
    Description: We tested the hypothesis that oral NaHCO 3 intake stimulates splenic anti-inflammatory pathways. Following oral NaHCO 3 loading, macrophage polarization was shifted from predominantly M1 (inflammatory) to M2 (regulatory) phenotypes, and FOXP3 + CD4 + T-lymphocytes increased in the spleen, blood, and kidneys of rats. Similar anti-inflammatory changes in macrophage polarization were observed in the blood of human subjects following NaHCO 3 ingestion. Surprisingly, we found that gentle manipulation to visualize the spleen at midline during surgical laparotomy (sham splenectomy) was sufficient to abolish the response in rats and resulted in hypertrophy/hyperplasia of the capsular mesothelial cells. Thin collagenous connections lined by mesothelial cells were found to connect to the capsular mesothelium. Mesothelial cells in these connections stained positive for the pan-neuronal marker PGP9.5 and acetylcholine esterase and contained many ultrastructural elements, which visually resembled neuronal structures. Both disruption of the fragile mesothelial connections or transection of the vagal nerves resulted in the loss of capsular mesothelial acetylcholine esterase staining and reduced splenic mass. Our data indicate that oral NaHCO 3 activates a splenic anti-inflammatory pathway and provides evidence that the signals that mediate this response are transmitted to the spleen via a novel neuronal-like function of mesothelial cells.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 6
    Publication Date: 2018-05-26
    Description: A consistent approach to the dosing of aminoglycosides across the modern body size distribution has been elusive. We evaluated whether radiologically derived measures of body composition could explain more of the interpatient variability in aminoglycoside pharmacokinetics (PK) than standard body size metrics. This retrospective study included adult patients treated with gentamicin or tobramycin with at least three drug concentrations and computed tomography (CT) imaging available. Aminoglycoside volume and clearance (CL) estimates were computed using a two-compartment model by Bayesian analysis. Morphomic data were extracted from CT images using a custom algorithm. Bivariable and multivariable linear regression were used to assess relationships between PK parameters and covariates. A total of 335 patients were included with a median (minimum, maximum) of 4 (3, 16) aminoglycoside concentrations per patient. The median (minimum, maximum) age, height, and weight of included patients were 57 (21, 93) years, 170 (145, 203) centimeters, and 81 (42, 187) kilograms. Both standard and morphomic measures poorly explained variability in volume ( R 2 〈 0.06). Skeletal muscle area and volume explained more of the interpatient variability in CL than weight or sex. Higher precision was observed using a modified Cockcroft-Gault equation with skeletal muscle area at L3 ( R 2 = 0.38) or L4 ( R 2 = 0.37) than the standard Cockcroft-Gault equation using lean ( R 2 = 0.23), adjusted ( R 2 = 0.23), or total ( R 2 = 0.22) body weights. These results highlight that skeletal muscle measurements from CT images obtained in the course of care can improve the precision of aminoglycoside CL estimation over current body size scalars.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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  • 7
    Publication Date: 2018-07-10
    Description: Leukocyte-associated Ig-like receptor 1 (LAIR1) is an ITIM-bearing collagen receptor expressed by leukocytes and is implicated in immune suppression. However, using a divalent soluble LAIR1/Fc recombinant protein to block interaction of cell surface LAIR1 with matrix collagen, we found that whereas T h 1 responses were enhanced as predicted, T h 17 responses were strongly inhibited. Indeed, LAIR1 on both T cells and monocytes was required for optimal T h 17 responses to collagen type (Col)V. For pre-existing "natural" T h 17 response to ColV, the LAIR1 requirement was absolute, whereas adaptive T h 17 and T h 1/17 immune responses in both mice and humans were profoundly reduced in the absence of LAIR1. Furthermore, the addition of C1q, a natural LAIR1 ligand, decreased T h 1 responses in a dose-dependent manner, but it had no effect on T h 17 responses. In IL-17–dependent murine organ transplant models of chronic rejection, LAIR1 +/+ but not LAIR1 –/– littermates mounted strong fibroproliferative responses. Surface LAIR1 expression was higher on human T h 17 cells as compared with T h 1 cells, ruling out a receptor deficiency that could account for the differences. We conclude that LAIR1 ligation by its natural ligands favors T h 17 cell development, allowing for preferential activity of these cells in collagen-rich environments. The emergence of cryptic self-antigens such as the LAIR1 ligand ColV during ischemia/reperfusion injury and early acute rejection, as well as the tendency of macrophages/monocytes to accumulate in the allograft during chronic rejection, favors T h 17 over T h 1 development, posing a risk to long-term graft survival.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 8
    Publication Date: 2018-09-04
    Description: CD8 + T cells respond to signals via the T cell receptor (TCR), costimulatory molecules, and immunoregulatory cytokines by developing into diverse populations of effector and memory cells. The relative strength of phosphoinositide 3-kinase (PI3K) signaling early in the T cell response can dramatically influence downstream effector and memory T cell differentiation. We show that initial PI3K signaling during T cell activation results in up-regulation of the signaling scaffold B cell adaptor for PI3K (BCAP), which further potentiates PI3K signaling and promotes the accumulation of CD8 + T cells with a terminally differentiated effector phenotype. Accordingly, BCAP-deficient CD8 + T cells have attenuated clonal expansion and altered effector and memory T cell development following infection with Listeria monocytogenes . Thus, induction of BCAP serves as a positive feedback circuit to enhance PI3K signaling in activated CD8 + T cells, thereby acting as a molecular checkpoint regulating effector and memory T cell development.
    Keywords: Infectious Disease and Host Defense
    Print ISSN: 0022-1007
    Electronic ISSN: 1540-9538
    Topics: Medicine
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  • 9
    Electronic Resource
    Electronic Resource
    Chichester [u.a.] : Wiley-Blackwell
    ISSN: 0029-5981
    Keywords: Engineering ; Engineering General
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Mathematics , Technology
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Serial-passage cultures of normal human tracheobronchial (TB) epithelial cells that exhibit functional differentiation have been established in serum-free medium supplemented with bovine pituitary extract (25 μg/ml), insulin (5 μg/ml), hydrocortisone (0.5 μg/ml), EGF (5 ng/ml), 10-6M each of ethanolamine and phoshoethanolamine, and antibiotics. The cells proliferated in this medium with a population doubling time of approximately 80 hours. Further, the passaged cultures retained differentiated morphology as evidenced by secretion of glycoproteins, binding of concanavalin A lectin, and presence of alcian blue and periodic acid Schiff-positive material in their cytoplasm. Ultrastructural observations further supported the functional epithelial nature of the cultures. Most cells exhibited characteristic microvilli on cell surfaces and showed junctional complexes between them. The cytoplasm contained a large number of perinuclear secretory vesicles, a characteristic feature of the differentiated cells. These cultures provide an excellent model to study factors that regulate synthesis and secretion of glycoproteins in normal human TB cells.
    Additional Material: 14 Ill.
    Type of Medium: Electronic Resource
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