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Journal articles on the topic "CDAII"
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Bianchi, Paola, Klaus Schwarz, Elisa Fermo, Katja Heinrich, Cristina Vercellati, Anna Paola Maria Luisa Marcello, Richard van Wijk, et al. "Molecular Analysis of the SEC23B Gene In Patients Affected by Congenital Dyserythropoietic Anemia Type II (CDAII)." Blood 116, no. 21 (November 19, 2010): 4227. http://dx.doi.org/10.1182/blood.v116.21.4227.4227.
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Abstract Abstract 4227 CDAII, the most frequent type of congenital dyserythropoietic anemia, is an autosomal recessive disease characterized by ineffective erythropoiesis, peripheral hemolysis, erythroblast morphological abnormalities and hypoglycosylation of some RBC membrane proteins. Last year we and others identified SEC23B as the gene responsible for CDAII (Schwarz et al, 2009, Bianchi et al, 2009). SEC23B is a member of the SEC23/SEC24 family, a component of COPII coat protein complex which is involved in protein trafficking through membrane vesicles from the endoplasmic reticulum to the Golgi apparatus. The gene, localized on chromosome 20p11, is split in 20 exons and codifies for a 767 aa protein. The aim of the study was to characterize the molecular defect in a large series of CDAII patients of Caucasian origin. Fifty-one CDAII patients from 49 unrelated families (17 Italians, 20 German or Swiss, 4 Dutch, 2 British, 2 Czech and 1 Greek, Turkish, Bulgarian and Irish origin) were analyzed by direct exon sequencing. We identified 36 different mutations, 25 of which were not described before. Eighteen were disruptive and 18 were missense mutations. The patients' molecular data are summarized in the Figure (novel mutations are reported in bold). All the missense mutations affected highly conserved aminoacids and were not found in 200 normal alleles examined. The c.325G>A mutation was identified in 15 homozygous patients and in two cases in combination with other mutations. The change c.40C>T was detected in 16 unrelated patients as heterozygous mutation and, for the first time, at the homozygous level in one patient only. Considering the entire series of patients (including previously published cases) characterized by our groups (86 CDAII patients from 77 unrelated families) c.325G>A and c.40C>T mutations account for 49% (76/154) of the unrelated mutated alleles and therefore should be firstly screened during molecular diagnosis of CDAII. A c.325G>A mutation usually results in a mild to moderate clinical picture at homozygous level, whereas it may cause a very severe clinical pictures when combined with other mutations (Fermo, et al 2010). Despite the sequencing of all exons and flanking intronic regions, 5 patients displayed only one mutation, suggesting the possibility that mutations could be located in regulatory regions or that a second gene could be involved in the pathogenesis of CDAII. P. Bianchi and K. Schwarz contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.
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Barcellini, Wilma, Anna Ines Gregorini, Giulia Soverini, Anna Zaninoni, Juri A. Giannotta, Cristina Vercellati, Valeria Ferri, Paola Bianchi, Agostino Cortelezzi, and Maria Domenica Cappellini. "Iron Overload and Cytokine Serum Levels in Congenital Hemolytic Anemias." Blood 128, no. 22 (December 2, 2016): 2458. http://dx.doi.org/10.1182/blood.v128.22.2458.2458.
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Abstract Background: Congenital hemolytic anemias (CHAs) are a heterogeneous group of inherited RBC disorders including membrane and enzyme defects and dyserythropoietic anemias. Iron overload is a well recognized complication of hereditary hemoglobinopathies, both in transfusion-dependent and independent cases. However, little is known in congenital hemolytic anemias, with the exception of anecdotic reports in pyruvate kinase deficiency and dyserythropoietic anemias. Aim: to describe the clinical and hematological features at diagnosis and enrolment, to investigate iron overload by hepatic and cardiac T2* MRI, and to study inflammatory/regulatory cytokine profiles (IL-6, TNF-alpha, IFN-gamma, IL-10, IL-17) and hepcidin levels in patients with CHAs. Confounding factors such as hemocromatosis genotyping, metabolic syndrome, and hepatic viral profile were also considered. Methods: Between July 2015 and April 2016, 38 patients were enrolled (13 hereditary spherocytosis -HS, 3 hereditary stomatocytosis - HSt, 8 congenital dyserythropoietic anemia type II - CDAII, 13 pyruvate kinase deficiency - PKD, 1 glucose-phosphate isomerase deficiency). HS cases were enrolled on the basis of ferritin >300 ng/mL at diagnosis. Cytokine levels were detected in serum by ELISA. Comparisons were made by Students T test (continuous) and Fisher's exact test (categorical), and correlations by Pearson's linear coefficient. Results: The main clinical and hematological findings are shown in table. Median Hb values progressively decreased in the 4 groups considered, being close to normal in HS and moderately reduced in CDAII patients, whereas hemolytic parameters were comparable among groups. Consistently with clinical severity, ferritin values were particularly high in CDAII (together with transferrin saturation-TfS) and PKD patients, notwithstanding chelation in about half cases of both groups. Of note, only 2 PKD patients were transfusion-dependent, suggesting that other factors are involved in iron overload. Splenectomy had been performed in 17/38 (44.7%), mainly CDAII. Liver iron concentration (LIC) showed a great heterogeneity in all groups, with a trend towards higher values in CDAII; 16/36 (44%) patients had a LIC>4 mg/g DW (23%, 33%, 38% and 88% in HS, HSt, PKD and CDAII, respectively). Cardiac T2* value was normal in all subjects, with the exception of a HS and a CDAII case. Regarding possible cofactors, 12/16 displayed at least one of the following: 1 homozygous for HFE C282Y and 1 for H63D mutations, 3 HCV+, 4 BMI>25, 2 alcohol abuse, 3 heterozygous for HFE mutations. The following positive correlations were observed at enrolment: LIC and ferritin (r=0.68, p<0.05), LIC and TfS (r=0.34, p=0.05), and cardiac T2* and TfS (r=0.34, p<0.05). Moreover Hb values at diagnosis negatively correlated with LIC (r=0.37, p<0.05). Interestingly, among the 28 cases with ferritin <800 ng/mL, 10 (36%) displayed liver iron overload (LIC>4), of whom 5 with the above listed cofactors. As regards cytokine levels, IL-10 was significantly increased in HS, PKD and CDAII groups compared with normal cases; TNF-alpha was decreased in HS and PKD, and IFN-gamma increased in HS and CDAII. Ferritin values were positively correlated with IL-6 and IFN-gamma, and TfS negatively with IL-6 (r= -0.38, p<0.05). Hepcidin values were slightly increased in CHAs compared with normal controls, and correlated positively with ferritin (r=0.33; p<0.05), and negatively with TfS (r= -0.56; p<0.001). Finally, hepcidin levels were positively correlated with IL-6 (r=0.62; p<0.001), and negatively with IFN-gamma (r=0.3; p<0.05). Conclusion: Iron overload is highly prevalent in CHAs, particularly in PKD and CDAII, is independent from transfusion support, and is also observed in cases with ferritin <800 ng/mL. T2* MRI is the gold standard approach to evaluate iron overload in CHAs (as in other congenital anemias) and its use is advisable, particularly in the presence of cofactors, for early chelation. Cytokine studies suggest the existence of a positive loop among ferritin, hepcidin, and inflammatory cytokines such as IL-6 and IFN-gamma, and of a negative loop among TfS, hepcidin, and the same inflammatory cytokines. These findings disclose important hints to understand the multiple biological mechanisms of iron overload, and support the rationale for new emerging therapies. Table Table. Disclosures Barcellini: Agios: Consultancy.
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Khoriaty, Rami, Angela Weyand, Geoffrey Hesketh, Amélie Bernard, Lesley Everett, Guojing Zhu, Beth McGee, et al. "Overlap of SEC23A and SEC23B Function Suggests a Novel Therapeutic Approach for Congenital Dyserythropoietic Anemia Type II." Blood 130, Suppl_1 (December 7, 2017): 80. http://dx.doi.org/10.1182/blood.v130.suppl_1.80.80.
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Abstract Congenital Dyserythropoietic Anemia type II (CDAII) is an autosomal recessive disease characterized by anemia and increased bone marrow (BM) bi/multi-nucleated erythroblasts. CDAII results from loss of function mutations in SEC23B encoding a core component of coat complex protein II (COPII) vesicles, which transport secretory proteins from the endoplasmic reticulum to the Golgi apparatus. Despite the identification of the genetic cause of CDAII, the pathophysiology of the disease remains unknown. Morpholino-induced SEC23B deficiency in zebrafish (ZF) has been previously reported to result in an erythroid phenotype mimicking CDAII (Shwartz et al, Nature genetics 2009), suggesting conservation of the underlying CDAII mechanism from fish to humans. Thus, we were puzzled to observe the absence of anemia or other CDAII characteristics in mice with erythroid specific (EpoR -Cre) and pan-hematopoietic (Vav1 -Cre) SEC23B deficiency (Khoriaty et al, MBC and Khoriaty et al, Sci Rep). To re-examine the ZF phenotype, we injected the morpholino targeting Sec23b into one-cell stage ZF embryos demonstrating no increase in circulating bi-nucleated erythroid cells, in contrast to the previous report. Given the variable knock-down that can result from morpholinos, we next generated ZF heterozygous for a 53 bp deletion (Sec23b+/-) using CRISPR/Cas9 genome editing. Intercrosses between Sec23b+/- ZF demonstrated lethality of Sec23b-/- ZF between days 17-21. However, the percentage of circulating bi-nucleated erythrocytes observed at day 16 was indistinguishable between Sec23b-/- ZF and wildtype (WT) clutch mate controls. Mammals and fish express two paralogs for SEC23, SEC23A and SEC23B, encoding highly related (~85%) proteins. To investigate the different functions of SEC23A and SEC23B, we defined the SEC23A and SEC23B interactomes using "BioID" (proximity dependent biotinylation) in HEK293 cells expressing BirA*-tagged SEC23A, SEC23B, or GFP control. Surprisingly, SEC23A and SEC23B exhibit indistinguishable interactomes. We also demonstrated that both mouse and human SEC23 paralogs can complement SEC23 deficiency in yeast. Similarly, rescue of the Sec23b-/- lethal phenotype in ZF by a Sec23a transgene demonstrated at least partial functional overlap of SEC23A/SEC23B function in vertebrates. To extend these observations to mammals, we genetically engineered the murine Sec23a cDNA into the endogenous mouse genomic locus of Sec23b . We demonstrated that SEC23B-deficient mice (previously shown to die perinatally from pancreatic degeneration) are rescued by SEC23A, exhibiting normal survival and pancreas histology, with no abnormalities apparent on detailed hematologic and anatomic examination. The expression of SEC23A and SEC23B mRNAs in human and mouse BMs were examined by qRT-PCR. SEC23B is the predominantly expressed paralog in human BM, with greater levels of SEC23A and reduced SEC23B in mouse BM. We therefore hypothesized that mice with erythroid deficiency of SEC23A alone or combined SEC23A/SEC23B deficiency might exhibit an erythroid defect. We first generated mice with erythroid-specific SEC23A deficiency, with the latter mice exhibiting no anemia or other CDAII characteristic. In contrast, mice with combined erythroid SEC23A and SEC23B deficiency die at ~E12.5, exhibiting reduced size and appear white in color compared to their WT litter mate controls, consistent with requirement of SEC23 in the erythroid compartment. Taken together, these data suggest complete (or near complete) overlap in function between SEC23A and SEC23B, and suggest that therapies that increase the expression of either SEC23 paralog might prove effective in treating CDAII. This paradigm might also apply to other disorders due to mutations in paralogous genes. Finally, our findings also suggest that a switch in paralog expression could account for other disparate disease phenotypes observed between animal models and humans. Disclosures No relevant conflicts of interest to declare.
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Khoriaty, Rami, Matthew P. Vasievich, and David Ginsburg. "The COPII pathway and hematologic disease." Blood 120, no. 1 (July 5, 2012): 31–38. http://dx.doi.org/10.1182/blood-2012-01-292086.
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Abstract Multiple diseases, hematologic and nonhematologic, result from defects in the early secretory pathway. Congenital dyserythropoietic anemia type II (CDAII) and combined deficiency of coagulation factors V and VIII (F5F8D) are the 2 known hematologic diseases that result from defects in the endoplasmic reticulum (ER)–to–Golgi transport system. CDAII is caused by mutations in the SEC23B gene, which encodes a core component of the coat protein complex II (COPII). F5F8D results from mutations in either LMAN1 (lectin mannose-binding protein 1) or MCFD2 (multiple coagulation factor deficiency protein 2), which encode the ER cargo receptor complex LMAN1-MCFD2. These diseases and their molecular pathogenesis are the focus of this review.
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Khoriaty, Rami, Lesley Everett, Jennifer Chase, Guojing Zhu, Bin Zhang, Mark Hoenerhoff, Ivan Maillard, and David Ginsburg. "SEC23A Functionally Compensates for SEC23B Deficiency in Mice." Blood 126, no. 23 (December 3, 2015): 935. http://dx.doi.org/10.1182/blood.v126.23.935.935.
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Abstract Congenital Dyserythropoietic Anemia type II (CDAII) is a disease of ineffective erythropoiesis characterized by moderate anemia and increased bone marrow (BM) bi/multi-nucleated erythroid precursors. CDAII is an autosomal recessive disease resulting from mutations in SEC23B. SEC23 is a core component of COPII vesicles, which transport secretory proteins from the endoplasmic reticulum (ER) to the Golgi. Despite identification of the underlying genetic defect, the molecular mechanism by which SEC23B deficiency produces the unique CDAII phenotype remains unknown. We previously reported that mice homozygous for a Sec23b null allele die perinatally, exhibiting massive pancreatic degeneration, precluding evaluation of the adult erythroid compartment. To examine the impact of SEC23B deficiency on adult murine hematopoiesis, we generated mice with erythroid specific and pan-hematopoietic deficiency for SEC23B by crossing a second, conditional Sec23b allele (Sec23bfl), in which exons 5 and 6 are flanked by loxP sites, to an EpoR-Cre and Vav1-Cre, respectively. These mice did not exhibit anemia or any other CDAII characteristic. Similarly, mice transplanted with SEC23B-deficient fetal liver cells harvested from E17.5 embryos also failed to recapitulate any features of the CDAII phenotype. We next generated mice deficient in SEC23B exclusively in the pancreas by crossing the Sec23bfl allele to either p48-Cre or Pdx1-Cre. These mice exhibit a phenotype indistinguishable from mice with germline deletion of Sec23b, indicating that loss of pancreatic SEC23B is sufficient to explain the perinatal-lethality of global SEC23B deficiency in mice. The mammalian genome contains two paralogs for SEC23, SEC23A and SEC23B. These paralogs are highly identical at the amino acid level (~85%). We examined the relative expression of SEC23B/SEC23A in WT tissues from both humans and mice. This ratio is higher in human BM compared to pancreas, while it was higher in mouse pancreas compared to BM. In order to determine if SEC23A can rescue the phenotype of SEC23B deficient mice when expressed under the regulatory control of Sec23b, we genetically engineered the Sec23a cDNA into the endogenous genomic locus of Sec23b (Sec23a-b) in mouse embryonic stem cells via recombinase mediated cassette exchange. A heterozygous Sec23a-b intercross yielded the expected number of mice homozygous for the Sec23a-b allele. These mice exhibited normal survival, development, and fertility. Pancreas tissues dissected from Sec23a-b/a-b mice had normal weights, were histologically indistinguishable from WT controls, and did not exhibit dilated ER by transmission electron microscopy. Western blot analysis confirmed the absence of SEC23B in pancreata of Sec23a-b/a-b mice, with high levels of SEC23A expression. These data demonstrate that the SEC23A and SEC23B proteins overlap significantly (or completely) at the level of protein function, and suggest that the distinct phenotypes of human and mouse SEC23 deficiency are the result of an evolutionary shift in the tissue-specific gene expression programs of SEC23A and SEC23B. These findings also suggest that therapies that increase the expression of either SEC23 paralog in erythroid cells might be effective in CDAII. Disclosures No relevant conflicts of interest to declare.
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Russo, Roberta, Immacolata Andolfo, Luigia De Falco, Francesco Manna, Antonella Gambale, Mariasole Bruno, Gianluca De Rosa, Domenico Girelli, Lucia De Franceschi, and Achille Iolascon. "Erfe-Encoding FAM132B in Congenital Dyserythropoietic Anemia Type II." Blood 126, no. 23 (December 3, 2015): 535. http://dx.doi.org/10.1182/blood.v126.23.535.535.
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Abstract Recessive mutations in SEC23B gene cause congenital dyserythropoietic anemia type II (CDAII), a rare hereditary disorder hallmarked by ineffective erythropoiesis, iron overload, and reduced expression of hepatic hormone hepcidin (Iolascon, 2013). The most recently described hepcidin regulator is the erythroblast-derived hormone erythroferrone (ERFE), a member of TNF-α superfamily that specifically inhibits hepcidin production in experimental models (Kautz, 2014). However, the function of ERFE in humans remains to be investigated. To determine whether dysregulation of ERFE expression is associated with ineffective erythropoiesis and iron-loading in CDAII, we studied the ERFE-encoding FAM132B gene expression in 48 SEC23B-related CDAII patients and 29 age and gender matched healthy controls (HCs). Twelve new cases and four novel SEC23B mutations were described. Samples were obtained after informed consent, according to the Declaration of Helsinki. Genomic DNA, mutational screening, RNA isolation, cDNA preparation, and qRT-PCR were performed as previously described (Russo, 2013). All patients were young adults (17.0±2.5 years at diagnosis), with increased serum ferritin (395.4±67.6 ng/mL) and transferrin saturation (71.9±5.4 %). We observed a statistically significant overexpression of FAM132B gene in peripheral blood mononuclear cells from CDAII patients (9.09±0.08) compared to HCs (8.32±0.12, p<0.0001). A similar trend was obtained when evaluating FAM132B expression in reticulocytes from a subset of patients and HCs. Of note, a statistically significant correlation between peripheral blood and reticulocyte FAM132B expression from the same patients was observed (Spearman ρ= 0.78, p=0.02). Although the role of ERFE in peripheral blood is still unknown, our observations suggested that the evaluation of FAM132B mRNA in peripheral blood is a reliable and easy-to-measure marker of ERFE levels. When we divided CDAII patients into two sub-groups accordingly to FAM132B gene expression, we observed a statistically significant reduction in hemoglobin (Hb) level in the high-FAM132B subset (8.6±0.4 g/dL) respect to low-FAM132B one (10.1±0.5 g/dL, p=0.02). Of note, the expression level of FAM132B did not correlate with the transfusion regimen. The higher amount of ERFE reflects the increased iron demand for Hb production as well as the expanding abnormal erythropoiesis, as attested by the increased RDW and sTfR (although not significant) in high-FAM132B patients. This in turn leads to reduced hepcidin in high-FAM132B group (4.2±1.8 nM) compared to low-FAM132B one (5.9±1.8 nM, p=0.05), resulting in augmented iron delivery to the erythron. Although the iron balance data do not differ significantly between the two groups, a tendency to decreased hepcidin/ferritin ratio and increased transferrin saturation was observed in high-FAM132B patients. Thus, FAM132B overexpression seems to contribute to the inappropriate suppression of hepcidin with subsequent hemosiderosis observed in CDAII. Consistent with our previous studies, we observed a reduced SEC23B expression in our patients compared to HC. Indeed, FAM132B and SEC23B gene expression exhibited an inverse correlation (Spearman ρ=-0.36, p=0.01). We confirmed the ex vivo data about inverse correlation between FAM132B and SEC23B expression observed in our patients by establishing K562 SEC23B-silenced cells. To knockdown SEC23B gene expression in K562 cells two different pGIPZ Lentiviral shRNAmir for SEC23B (shSEC23B-70/-74) were used. We observed a higher expression of FAM132B at 5 days of erythroid differentiation in K562 SEC23B-silenced cell compared to not-silenced ones. Conversely, SEC23B expression was lower in both shSEC23B compared to sh-CTR at 2 and 5 days of differentiation. Although the mechanisms of hemin-induced differentiation are quite different from EPO-induced ones, we can hypothesize that FAM132B over-expression is related to the maturative arrest and the subsequent increased number of erythroid precursors. This study provides the first analysis on ERFE regulation in humans. Our data suggest that ERFE over-expression in CDAII patients is the result of both physiological and pathological mechanisms leading to hepcidin suppression in condition of dyserythropoiesis. Nevertheless, it seems that ERFE cannot be the main erythroid regulator of hepcidin suppression, at least in CDAII patients. Disclosures No relevant conflicts of interest to declare.
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Khoriaty, Rami, Matthew Vasievich, Morgan Jones, Jennifer Chase, Lesley Everett, Bin Zhang, Ivan Maillard, and David Ginsburg. "SEC23B Deficiency Results in Different Phenotypes in Humans and Mice." Blood 124, no. 21 (December 6, 2014): 1341. http://dx.doi.org/10.1182/blood.v124.21.1341.1341.
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Abstract SEC23B mutations in humans result in the autosomal recessive disease Congenital Dyserythropoietic Anemia type-II (CDAII). CDAII is characterized by moderate anemia in increased bone marrow (BM) bi/multi-nucleated erythroblasts. Despite the identification of the genetic defect underlying CDAII, the pathophysiology of this disease remains unknown. SEC23A and SEC23B are paralogous components of the coat protein complex II (COPII)-coated vesicles, which transport secretory proteins from the Endoplasmic Reticulum to the Golgi apparatus. We generated SEC23B-deficient mice and demonstrated that these animals die perinatally exhibiting massive pancreatic degeneration (Tao et. al PNAS). To examine the impact of SEC23B-deficiency on adult murine hematopoiesis, we harvested fetal liver cells (FLC), which contain hematopoietic stem cells, from SEC23B-deficient or wild-type (WT) control E17.5 embryos and transplanted them into lethally irradiated C57BL/6J mice. Recipients of SEC23B-deficient FLC did not exhibit anemia or any other CDAII characteristic (Khoriaty et. al, Mol Cell Biol), and SEC23B deficient FLC competed effectively with WT FLC at reconstituting hematopoiesis when transplanted into lethally irradiated recipient mice (Khoriaty et. al, Mol Cell Biol). A Sec23bfl conditional-allele was also generated. Mice with hematopoietic-specific SEC23B-deficiency, generated by crossing Vav1-Cre into Sec23bfl mice, also exhibited normal hematopoiesis. In contrast, mice with pancreas-specific Sec23b deficiency generated by crossing the Sec23bfl allele to a p48-Cre or Pdx1-Cre resulted in a phenotype indistinguishable from complete SEC23B-deficiency, demonstrating that loss of pancreatic Sec23b expression is sufficient to explain the perinatal lethality of SEC23B-deficient mice. To investigate different phenotypes of SEC23B deficiency in humans and mice, the SEC23B/SEC23A expression ratio was examined in murine and human tissues. This ratio is higher in mouse pancreas (12.7) compared to BM (2.6), whereas it is higher in human BM (7.8) relative to pancreas (5.5). Taken together with the high degree of amino-acid identity between SEC23A and SEC23B (~85%), these data suggest that the tissue-specific functions of SEC23A and SEC23B have shifted during evolution between humans and mice. To determine if Sec23a can rescue the lethality of SEC23B-deficient mice, we have engineered Sec23a cDNA into the endogenous genomic locus of Sec23b (Sec23A-B) via recombinase-mediated cassette exchange. A heterozygous Sec23A-B intercross is in progress. Rescue of the SEC23B deficient phenotype by SEC23A protein expressed under control of Sec23b regulatory sequences would suggest that increasing the expression of either paralog in erythroid cells might be effective in the treatment of CDAII. Disclosures No relevant conflicts of interest to declare.
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Fermo, Elisa, Paola Bianchi, Cristina Vercellati, Wilma Barcellini, Carla Boschetti, Anna Paola Marcello, and Alberto Zanella. "Two Atypical Severe Cda Forms Presenting as Hydrops Foetalis Are Caused by Mutations in the SEC23B Gene." Blood 114, no. 22 (November 20, 2009): 1981. http://dx.doi.org/10.1182/blood.v114.22.1981.1981.
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Abstract Abstract 1981 Poster Board I-1003 Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of disorders characterized by ineffective erythropoiesis with prominent dysplastic features of the erythroid precursors in the bone marrow. Three main subtypes (I, II and III) have been identified, but several variants or atypical forms have been reported over the years. CDA are rarely associated with hydrops foetalis. In the past we described two cases presenting with hydrops foetalis and very severe anemia that were classified as atypical CDAs since they presented CDAII-like erythroblastic morphological features lacking other diagnostic CDAII markers. Very recently we and others (Bianchi et al, Human Mutat 2009, in press; Schwarz et al, Nat Genet 2009, in press) demonstrated that mutations in SEC23B gene, coding for a protein involved in the coat protein complex responsible for vesicle budding from the endoplasmic reticulum, cause CDA II. The aim of this work was to ascertain whether atypical CDAII-like forms presenting as hydrops foetalis could be caused by mutations in SEC23B gene and reclassified as CDAII. Two patients (Cantù-Rajnoldi et al, Br J Haematol 1997, 96: 530-3; Bianchi et al, Blood 1999, 94, suppl 1, 8b) from unrelated families with a history of intrauterine death of hydropic foetuses in previous pregnancies were referred at 20th week gestation following ultrasonic diagnosis of foetal hydrops and severe anemia (2.0 and 1.3 g/dL Hb respectively). In both cases intrauterine transfusions enabled the delivery of the babies. At birth both of them underwent extensive laboratory evaluation (including red cell metabolism and membrane proteins analysis) that was not informative on the causes of anemia. Ham test was repeatedly normal as for Western blotting analysis for GRP78 and glycoslylation pattern of red cell band 3. The bone marrow examination revealed the presence of 30 and 48% of bi- or multinucleated erythroblasts, some of whom presenting typical double outer membranes at transmission electron microscopy. Both babies became transfusion dependent. The 20 exons and intronic flanking regions of SEC23B gene were analyzed by direct sequencing. Both patients displayed mutations in SEC23B gene, in particular mutations c.325 G>A/ c.2101 C>T in patient 1 and c.325 G>A/ c.197G>A in patient 2 (Glu109Lys/ Arg701Cys and Glu109Lys/ Cys66Tyr respectively). c.325 G>A is the most frequent mutation so far described in CDAII and at homozygous level is usually associated with mild anemia. When found in compound heterozygosity with a second missense mutation as in these cases it may result in a very severe clinical pattern, although we cannot exclude that factors other than SEC23B mutations may contribute to worsening the clinical picture. In conclusion, SEC23B gene analysis allowed the correct classification of two very severe CDA cases associated with hydrops foetalis. This finding indicates that CDAII may result in intrauterine death and its frequency may therefore be underestimated. These cases may present as “atypical” for the lack of band3 hypoglycosylation likely due to the early sequestration of the more severely affected cells. Disclosures: No relevant conflicts of interest to declare.
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Khoriaty, Rami, Matthew Vasievich, Morgan Jones, Bin Zhang, Lesley Everett, Jiayi Tao, Ivan Maillard, and David Ginsburg. "Disparate Phenotypes Of SEC23B Deficiency In Humans and Mice." Blood 122, no. 21 (November 15, 2013): 312. http://dx.doi.org/10.1182/blood.v122.21.312.312.
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Abstract Congenital dyserythropoietic anemia type-II (CDAII) is an autosomal recessive disease characterized by moderate anemia and increased bone marrow (BM) bi/multi-nucleated erythroblasts. CDAII results from mutations in SEC23B, one of two closely related mammalian SEC23 paralogs. SEC23 is a core component of COPII coated vesicles, which transport secretory proteins from the Endoplasmic Reticulum (ER) to the Golgi apparatus. Bone marrow transplantation cures CDAII, suggesting that the pathologic defect in this disease is restricted to the hematopoietic compartment. However, the mechanism by which SEC23B-deficiency results in CDAII remains unknown. We previously reported that mice homozygous deficient for SEC23B (Sec23bgt/gt) exhibit massive pancreatic degeneration. The latter resulted in perinatal mortality precluding evaluation of the adult hematopoietic compartment. To examine the impact of SEC23B-deficiency on adult murine hematopoiesis, fetal liver cells (FLC) were harvested from Sec23bgt/gt or wildtype (WT) control E17.5 embryos and transplanted into lethally irradiated C57BL/6J mice. Recipients of Sec23bgt/gt FLC had normal peripheral blood counts and were indistinguishable from recipients of WT FLC. To test for a more subtle hematopoietic defect, Sec23bgt/gt FLCs were tested directly against WT FLC for their ability to reconstitute hematopoiesis in a competitive repopulation assay. SEC23B deficient FLC exhibited no competitive disadvantage at reconstituting erythropoiesis relative to WT FLC over 18 weeks of follow-up. Transplant of marrow from these chimeric animals into secondary recipients demonstrated continued equivalence of Sec23bgt/gt and WT hematopoietic stem cells. We also generated a second, conditional Sec23b allele, in which exons 5 and 6 are flanked by loxP sites (Sec23bfl). Deletion of exons 5 and 6 with Cre-recombinase results in a frame shift leading to a stop codon in exon 7. Mice with erythroid-specific SEC23B deficiency were generated by crossing the Sec23bfl allele to an EpoR-Cre transgene. Sec23bfl/-/EpoR-CreTg+ mice maintained normal erythropoiesis indistinguishable from their WT littermates. Pancreas-specific knock-out generated by crossing the Sec23bfl allele to p48-Cre or Pdx1-Cre transgenes generated phenotypes indistinguishable from complete SEC23B deficiency, demonstrating that loss of pancreatic Sec23b expression alone is sufficient to explain the perinatal lethality observed in Sec23bgt/gt and Sec23b-/- mice. Our results conclusively demonstrate that in contrast to humans, SEC23B-deficiency results in massive pancreatic degeneration in mice, but no CDAII in these animals. To investigate the cause of the disparate human and mouse SEC23B-deficient phenotypes, SEC23B/SEC23A expression ratios were examined in endogenous tissues from both species. This ratio (normalized to the ratio in liver mRNA as 1.0) was higher in mouse pancreas (12.7) compared to BM (2.6), with the reverse pattern observed in human BM (7.8) relative to pancreas (5.5). These data, taken together with the high degree of identity between SEC23A and SEC23B (∼ 85% amino acid identity), suggest that the tissue-specific functions of SEC23A and SEC23B may have shifted during evolution between humans and mice. To test the role of SEC23A, we generated a mouse with a conditional Sec23a allele, in which exon 3 is flanked by loxP sites (Sec23afl). Cre-recombinase mediated deletion of exon 3 results in a frame shift leading to a stop codon in exon 7 (Sec23a-). Mice with erythroid-specific SEC23A-deficiency (Sec23afl/-/EpoR-CreTg+) maintained normal red blood cell counts indistinguishable from their WT littermates. In summary, we have shown that SEC23B-deficient humans and mice exhibit disparate phenotypes. We have also demonstrated variations in the gene expression programs for SEC23A and SEC23B potentially explaining the pancreatic phenotype of SEC23B-deficiency in mice and the erythroid phenotype in humans. These results suggest that the two SEC23 paralogs have overlapping functions and that therapeutic strategies that increase the expression of either SEC23A or SEC23B in erythroid cells might be effective in CDAII. Further studies of the overlapping functions of SEC23A and SEC23B and their relevant protein cargos should provide new insight into the pathogenesis of CDAII. Disclosures: No relevant conflicts of interest to declare.
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Villanueva, Melanie A., Carol J. Saunders, David Zwick, Laurie Smith, Darrell Dinwiddie, Emily Farrow, Neil Miller, Stephen Kingsmore, and Keith J. August. "An Unusual Presentation of Congenital Dyserythropoietic Anemia Type II (CDAII) Associated with Severe Anemia in a Patient with a Novel Mutation of the SEC23B Gene." Blood 120, no. 21 (November 16, 2012): 990. http://dx.doi.org/10.1182/blood.v120.21.990.990.
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Abstract Abstract 990 CDAII is an autosomal recessive disorder characterized by ineffective erythropoiesis, anemia, hemolysis, hepatosplenomegaly and morphologic abnormalities. While rare, more than 300 cases of CDAII have been described worldwide, making it the most common form of congenital dyserythropoietic anemia. In patients with CDAII, bone marrow specimens often demonstrate hypercellularity, erythroid hyperplasia and the presence of 10–45% bi- and multinucleated erythroid precursors. Generally, all patients will have a positive serum acid hemolysin test. The clinical picture includes a mild to moderate anemia and hemolysis with typical hemoglobin levels that range from 8 to 11 g/dL. In less than 10 percent of reported cases, severe anemia is seen requiring frequent red blood cell transfusions. Mutations in SEC23B are the underlying defect in the majority of patients with CDAII. SEC23B encodes an essential component of coat protein complex II coated vesicles, resulting in ineffective trafficking of secretory proteins from the endoplasmic reticulum to the Golgi apparatus. Here we report a patient with a severe presentation of CDA II associated with a novel nonsense mutation in the SEC23Bgene. Our patient was born at 36 weeks estimated gestational age with IUGR and hypospadias. The family history included a brother born with severe anemia, severe hypospadias and hydrops fetalis who died at 4 days of life. Parents were of nonconsanguinious Samoan decent. The initial hemoglobin was 7 g/d; red blood cell transfusions were required on days of life 1, 10 and 15. Total bilirubin peaked at 3.3 and phototherapy was unnecessary. Now 20 months of age, he continues to be transfusion-dependent. Reticulocytopenia is pronounced with absolute reticulocyte counts consistently <20000/mL. Treatment with glucocorticoids produced a minimal increase in reticulocytes without a decrease in frequency of transfusions. Additional laboratory evaluation demonstrated mild indirect hyperbilirubinemia (1–3.4 mg/dL) that presented around one year of age, normal LDH and decreased haptoglobin. Bone marrow evaluation revealed dyserythropoiesis and reticulin fibrosis. Bi- and multinucleated cells were present and comprised 6% of the erythrocyte precursors. Exome sequencing was performed using Illumina hybrid capture, HiSeq sequencing and a full analysis pipeline. Sequencing revealed compound heterozygosity for two mutations in the SEC23B gene: c.53G>A (p.Arg18His) and c.1507C>T (p.Arg503X). The p.Arg18His has been previously reported in patients with CDAII. The p.Arg503X is a novel nonsense mutation that is expected to be pathogenic, likely resulting in nonsense-mediated decay of the mRNA. These mutations were confirmed clinically by Sanger sequencing and each parent was found to carry one mutation. Compound heterozygosity including a nonsense mutation in SEC23B has been reported to result in a more severe phenotype with reticulocytopenia, a finding consistent with the presentation of our patient. This case demonstrates that exome sequencing, with confirmatory dideoxy sequencing of the affected individual and the parents, can be a powerful new diagnostic approach in inherited hematologic disorders that feature genetic heterogeneity. Disclosures: No relevant conflicts of interest to declare.
Dissertations / Theses on the topic "CDAII"
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DE, ROSA GIANLUCA. "UNRAVELING THE MOLECULAR PATHOGENESIS OF INEFFECTIVE ERYTHROPOIESIS IN CONGENITAL DYSERYTHROPOIETIC ANEMIA TYPE II: IN VITRO EVALUATION OF RAP-011 TREATMENT." Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/697529.
Full textAbstract:
Congenital Dyserythropoietic Anemias (CDAs) are subtypes of bone marrow failure syndromes, hallmarked by ineffective erythropoiesis. The most common form is CDA type II (CDAII), showing moderate/severe anemia, relative reticulocytopenia, jaundice, splenomegaly, and iron overload. It is inherited as an autosomal recessive disorder due to loss-of-function mutations in the SEC23B gene. Molecular pathogenesis of CDA II still has to be investigated because the described animal models did not recapitulate the clinical features observed in humans. To date, treatments for CDAII patients consist of supportive therapy, such as erythrocyte transfusions, or bone marrow transplantation or splenectomy in transfusion-dependent cases. Recently, members of TGF-β superfamily have been studied as potential regulators of erythropoiesis, especially the growth differentiation factor 11 (GDF11). Through the binding of specific receptors, GDF11 leads to an inhibited late-stage erythropoiesis. Indeed, two GDF11 inhibitors, ACE-011 and ACE-536, have been associated with an improvement of hematologic parameters. Studies with the mouse counterpart of ACE-011, RAP-011, on a mouse model of β-thalassemia showed increased differentiation of erythroid cells, improvement of the anemic condition and reduced iron overload in treated mice. The first aim of our study was the establishment of a cellular model of CDA II, that could reproduce the main defects of the disease, such as the lack of the erythroid differentiation due to the low or absent expression of SEC23B gene. For this aim, we selected the K562 cell line and, through short-hairpin RNA-based strategy, we obtained two different clones of K562 showing a stable silencing of SEC23B. Then, we decided to assess the effects of RAP-011 on this CDA II model, by investigating the pathway involved in the GDF11 signaling. This treatment simulated the ligand trap function played by RAP-011 towards GDF11. The administration of RAP-011 resulted in a reduction of SMAD2 phosphorylation induced by GDF11 and, moreover, in an increase of different erythroid differentiation markers.
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Rakitin, Alexander (Alexander Yurevich). "Measurement of the dipion mass spectrum in the decay X(3872) [right arrow] J/ [psi] [pi]⁺ [pi]⁻ at the CDFII experiment." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34385.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Physics, 2005.In title on t.p., "[right arrow]" is the symbol; "[psi]" is the lower-case Greek letter; and, "[pi]" is the lower-case Greek letter.
Includes bibliographical references (leaves 147-157).
We present a measurement of the dipion mass spectrum in the decay X(3872) [right arrow] J/ [psi] [pi]⁺ [pi]⁻ using a 360 pb-1 sample of pp collisions at av [square root]s = 1.96 TeV collected with the CDF II detector at the Fermnilab Tevatron Collider. As a benchmark, we also extract the dipion mass distribution for [psi] (2s) [right arrow] J/ [psi] [pi]⁺ [pi]⁻ decay. The X(3872) dipion mass spectrum is compared to QCD multipole expansion predictions for various charmonium states, as well as to the hypothesis [right arrow] J/ [psi] po. We find that the measured spectrum is compatible with 3S1 charmonium decaying to J/ [psi] [pi]⁺ [pi]⁻ - and with the X(3872) - J/po hypothesis. There is, however, no 3S1 charmonium state available for assignment to the X(3872). The multipole expansion calculations for 1P1 and 3DJ states are in clear disagreement with the X(3872) data. For the [psi] (2S) the data agrees well with previously published results and to multipole expansion calculations for 3S1 charmonium. Other, non-charmonium, models for the X(3872) are described too. We conclude that since the dipion mass spectrum for X(3872) is compatible with J/pO hypothesis, the X(3872) should be C-positive. This conclusion is supported by recent results from Belle Collaboration which observed X(3872) -+ J/7y decay. We argue that if X(3872) is a charmonium, then it should be either ... state, decaying into J/ [psi] [pi]⁺ [pi]⁻ in violation of isospin conservation. A non-charmonium assignment, such as DD* molecule, is also quite possible.
by Alexander Rakitin.
Ph.D.
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ROCHA, JÚNIOR Laurindo Ferreira da. "Determinação de citocinas da via TH17 e da atividade imunomoduladora do novo derivado Tiazolidínico LPSF/TM17, agonista do PPARy, em células do sangue periférico de pacientes portadores de artrite reumatoide." Universidade Federal de Pernambuco, 2013. https://repositorio.ufpe.br/handle/123456789/14905.
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A artrite reumatoide (AR) é uma doença autoimune inflamatória sistêmica que tem como característica principal o acometimento articular. As citocinas estão diretamente implicadas na patogênese da AR. Este trabalho objetivou determinar os níveis de citocinas da via Th17, particularmente IL-17A e IL-22 e correlacionar seus níveis séricos com dados clínicos, demográficos, radiológicos e laboratoriais de pacientes com AR, bem como avaliar a atividade imunomoduladora do novo derivado tiazolidínico LPSF/TM17. Os pacientes foram provenientes do Hospital das Clínicas da Universidade Federal de Pernambuco (UFPE). A coleta de dados clínico-demográficos foi realizada por questionário específico e os pacientes que preencheram os critérios de inclusão realizaram coleta do sangue periférico. A quantificação de citocinas foi realizada em 83 pacientes e 30 controles saudáveis por ELISA. Os níveis de IL-22 mostraram-se aumentados nos pacientes (média 432,37 pg/ml) quando comparados aos controles (67,45 pg/ml), p<0,001. Houve correlação da IL-22 com os índices clínicos de atividade de doença DAS28 (p = 0.037) e CDAI (p = 0.013). Houve correlação dos níveis desta citocina com a presença de erosões radiográficas (p = 0.0001) e com a presença do autoanticorpo fator reumatoide (p = 0.001). Visando avaliar o efeito imunomodulador do LPSF/TM17, foram dosadas citocinas em sobrenadantes de culturas de células mononucleares periféricas após estimulação com PMA e Ionomicina de parte destes pacientes com AR (IFNγ, IL-17A, IL-6 e IL-22). O LPSF/TM17 inibiu significativamente a produção de IFNγ na concentração de 100μM e de IL-17A e IL-22 nas concentrações de 1, 10 e 100 μM (p<0,05). Este estudo foi pioneiro em associar os níveis de IL-22 com a gravidade da doença implicando importante papel desta citocina na patogênese da AR. O presente estudo mostrou a associação da IL-22 na patogênese da AR e que, nessa doença, o LPSF/TM17 pode ser importante na abordagem terapêutica, uma vez que inibiu citocinas envolvidas na doença (IFNγ, IL-17ª e IL-22).
Rheumatoid Arthritis (RA) is an inflammatory systemic autoimune disease with joint involvement as main clinical feature.Cytokines are directed implicated in RA pathogenesis.This study aimed to assess the citokine profile of Th17 pathway, paticularly IL-17A and IL-22 as well as correlate these cytokines serum levels with clinical, demographic, radiographic e laboratory data from patients with Rheumatoid Arthritis (RA) and we also evaluated the immunomodulatory activity of the new thiazolidinedione LPSF/TM17. The patients were recruited at Hospital das Clínicas of Universidade Federal de Pernambuco (UFPE). Clinical and demographic data were recorded in standard questionnaire and patients who fullfilled the inclusion criteria had their blood collected. Cytokines were assayed with ELISA in 83 RA patients and 30 healthy controls. IL-22 levels were increased in patients with RA compared with controls (mean 432.37 pg/ml and 67.45 pg/ml, respectively; p < 0.001). Levels of IL-22 correlated with the composites indices of disease activity DAS28 (p=0.037) and CDAI (p=0.013). Rheumatoid factor (RF) positivity and the presence of bone erosions correlated with higher levels of IL-22 in patients with RA, p=0.001 and p=0.0001, respectively. The immunomodulatory effect of LPSF/TM17 was assessed in peripheral blood mononuclear cells (PBMCs) from RA patients after cytokines assays (IFNγ, IL-17A e IL-22) in culture supernatants after stimulation with PMA and Ionomycin. This was the first study to associate IL-22 serum levels with disease severity suggesting an important role of this cytokine in RA pathogenesis. Importantly, LPSF/TM17 significantly inhibited IFNγ productionin the concentration of 100 μM and induced lower levels of IL-17A and IL-22 in the concentrations of 1, 10 and 100 μM (p<0,05). The role of the thiazolidinediones, synthetics agonists of PPARγ, in RA and in other autoimmune diseases has been described suggesting that these compounds may be of great importance in the therapeutic approach of theses diseases.
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Herrler, Jörn Heinrich. "Diagnostik und Evaluation der Entzündungsschwere chronisch entzündlicher Darmerkrankungen durch Magnetresonanztomographie." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2004. http://dx.doi.org/10.18452/15029.
Full textAbstract:
Für die Therapie chronisch entzündlicher Darmerkrankungen (CED) ist die Diagnostik befallener Darmabschnitte und enteraler Komplikationen ebenso von Bedeutung, wie die Einschätzung der klinischen und endoskopischen Entzündungsaktivität. In einer Studie soll die Wertigkeit der Magnetresonanztomographie (MRT) untersucht werden, die Entzündungsaktivität CED anhand visueller Befunde und Komplikationen einzuschätzen. Außerdem soll überprüft werden, ob auf eine Kontrastierung des Darmes zugunsten eines höheren Patientenkomforts und einer schnelleren Untersuchung verzichtet werden kann. 64 Patienten mit bekannter oder vermuteter CED wurden vor und nach intravenöser Gd-DTPA-Injektion mit dem MR-Tomographen untersucht. Während 35 Patienten eine orale und rektale Kontrastierung mit Endoskopielösung erhielten, wurden 31 nicht enteral kontrastiert. 53 der untersuchten Patienten wurden zeitnah koloskopiert. Ein neu entwickelter MR-Aktivitätsindex (MRAI), die Kontrastmittelanreicherung in der Darmwand sowie die gemessenen Darmwanddicken wurden mit klinischen Indizes (CAI, CDAI) und dem Endoskopie-Aktivitätsindex (EAI) korreliert. Weiterhin wurden koronare Bilder aller Patienten bezüglich der Distension des Darmes und der Abgrenzbarkeit der Darmwand begutachtet. Im Vergleich mit dem EAI konnten signifikante Unterschiede für die Verteilung des Darmwand-Enhancements und der gemessenen Darmdicken nachgewiesen werden. Der MRAI zeigte eine Korrelation von Eta = 0,43 mit der klinischen Aktivität. Für Colitis ulcerosa-Patienten konnte ein Eta = 0,64 erstellt werden. Untersuchte, die eine Kontrastierung des Darmes erhielten, wiesen eine exzellente Korrelation (Eta = 0,76) zwischen MRAI und CAI / CDAI auf, während dieser Zusammenhang für Patienten ohne enterale Auffüllung fehlte. Weiterhin konnten signifikante Zusammenhänge zwischen enteraler Kontrastierung und der Distension des Darmes sowie der Abgrenzbarkeit der Darmwand gezeigt werden. Die Arbeit macht deutlich, daß es möglich ist, CED mittels MRT zuverlässig zu diagnostizieren und mit Hilfe des MRAI in ihrer klinischen und endoskopischen Entzündungsaktivität einzuschätzen. Dabei sollte auf die Anwendung eines enteralen Kontrastmittels nicht verzichtet werden. Ein Einsatz der MRT ist somit nicht nur bei der Diagnostik sondern auch zur Verlaufskontrolle der CED sinnvoll.For the therapy of Inflammatory Bowel Diseases (IBD), not only the diagnosis of affected bowel segments and enteral complications but also the assessment of the clinical and endoscopic activity is important. The value of Magnetic Resonance Imaging (MRI) to asses the activity of IBD by visual findings and complications shall be determined by a clinical study. Furthermore shall be tested how the application of enteral contrast media affects patient comfort and examination time. 64 patients with known or supposed IBD were examined by MRI before and after intravenous injection of Gd-DTPA. 35 patients received oral and rectal contrast medium (2,5% mannitol solution) while 31 patients remaining without enteral replenishment. 53 patients underwent colonoscopy.A newly developed MR Activity Index (MRAI), based on visual findings, contrast-enhancement of the bowel wall and measured wall thickness were correlated with clinical (Crohn�s Disease Activity Index, CDAI; Colitis Activity Index, CAI) and endoscopic (Endoscopy Activity Index, EAI) activity. Coronal images of all patients were evaluated referring to bowel distension and demarcation of the bowel wall. The comparision with EAI shows significant differences in the distribution for wall contrast-enhancement and wall thickness. A good correlation is determined between the MRAI and the clinical activity (Eta = 0,43). Considering only patients with Ulcerative Colitis the correlation between MRAI and CAI shows Eta = 0,64. An excellent correlation of Eta = 0,76 between MRAI and CDAI / CAI for all patients with oral and enteral replenishment was found, while there was no correlation in the group, which did not receive mannitol solution. Significant correlations were also seen between the enteral mannitol solution replenishment and bowel distension and demarcation of the bowel wall. MRI shows good accuracy in detecting the changes the of IBD. The new developed MRAI allows an assessment of the activity of IBD. The results demonstrate that oral and enteral contrast media should be applied for MR examination of the abdomen. The utilization of MRI is furthermore useful in the follow up of IBD.
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Vera, Johana Mabel, and Sergio Guillermo Fernández. "CDII Centro de desarrollo de ideas e innovación." Bachelor's thesis, 2020. http://hdl.handle.net/11086/16042.
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Trabajo final de gradoNuestro trabajo de tesis se centra en la recuperación del patrimonio industrial de la ciudad de Córdoba abordando la problemática de la evolución del trabajo frente al avance de la tecnología y la globalización, mediante la re-funcionalización del ex molino Rio de la Plata y su entorno. Aquí se plantea un Centro de Desarrollo de Ideas e Innovación, el cual es un espacio que brindaría todas las herramientas necesarias para el desarrollo de ideas, permitiéndole al usuario transitar por todas las etapas de proyecto.
Fil: Vera, Yohana Mabel. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina
Fil: Fernández, Sergio Guillermo. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina
Fil: Mondejar, Adolfo. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina
Fil: Etkin, Ana. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina
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Kreps, David Joseph. "Obesity, weight change and disease activity measures in patients with rheumatoid arthritis." Thesis, 2016. https://hdl.handle.net/2144/16819.
Full textAbstract:
BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that causes
inflammatory polyarthritis, typically of the small joints. Obesity, a serious global
epidemic, has been shown to increase systemic inflammatory biomarkers,
several of which are related to RA pathophysiology. Associations have been
observed between obesity and worsened RA disease activity outcomes in crosssectional studies. Limited longitudinal studies investigated the effects of weight
change on RA disease activity measures. Surgical interventions for weight loss in
RA patients showed marked improvement in RA disease activity measures and
outcomes but typical weight change in a clinical setting has not been
investigated.
OBJECTIVE: To investigate the impact of typical weight change on RA disease
activity measures.
METHODS: We conducted a retrospective cohort study on 178 RA patients seen in
typical clinical practice that met the inclusion criteria for the study, which included
patients with a minimum of two clinical disease activity assessments (CDAI) with
corresponding body mass index (BMI) measures. Medical record review was conducted for each clinic visit where CDAI and BMI were measured, and at each
of these visits, sociodemographic, lifestyle, medication usage, questionnaire
data, RA characteristics, laboratory values, and comorbidities were collected.
Linear regression was used to analyze the association between ΔBMI and
ΔCDAI, defined at the dates of minimum and maximum BMI for each subject,
adjusting for confounders including sex, age, disease duration, smoking status,
serologic status, and steroid usage. Logistic regression was performed to
evaluate whether ΔBMI was associated with low/remission RA disease activity
according to accepted CDAI cutoffs.
RESULTS: Unadjusted linear regression was performed on all 178 subjects to
analyze the overall trend within the sample population. For every 1 kg/m2
increase in BMI, CDAI increased by 0.49 points, but these results were not
statistically significant (p=0.155, 95%CI -0.176, 1.097). Subjects were stratified
into BMI gain, stable, and loss groups. Within the BMI loss group (defined as
those whose BMI decreased by more than 1 kg/m2), a significant association was
found with ΔCDAI (β= -2.61 [p=0.028, 95%CI -4.91, -0.298]). Unadjusted linear
regression on the BMI gain and stable groups was found to be not statistically
significant. This association remained significant after adjusting for sex, age,
disease duration, smoking status, serologic status, and steroid usage (β=-2.499
[p=0.044, 95%CI -4.94, -0.061]). There was no association between ΔBMI and
low/remission RA disease activity (OR 0.990, (95%CI 0.855, 1.146). When
stratified by BMI gain, stable, and loss groups there was no significant association with low/remission RA disease activity.
CONCLUSION: These results suggest that weight loss may be associated with
improved disease activity among patients with RA seen in a typical clinical
setting. Weight loss has the potential to be a non-pharmacologic intervention to
improve RA disease activity. Prospective studies of weight loss and RA disease
activity are necessary to replicate these results.
Books on the topic "CDAII"
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Magali, Tʻodua, and Akad. G. Ceretʻlis saxelobis aġmosavletʻmcʻodneobis instituti., eds. Sparsul-kʻartʻuli cdani. Tʻbilisi: Mecʻniereba, 1987.
Find full textBook chapters on the topic "CDAII"
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Zhao, Jishun, Shucheng Zhu, Ying Liu, and Pengyuan Liu. "CDAIL-BIAS MEASURER: A Model Ensemble Approach for Dialogue Social Bias Measurement." In Natural Language Processing and Chinese Computing, 204–15. Cham: Springer Nature Switzerland, 2022. http://dx.doi.org/10.1007/978-3-031-17189-5_17.
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Compaoré Sawadogo, Eveline M. F. W., and Natewinde Sawadogo. "Capacity Development for Agricultural Innovation Systems in Burkina Faso: What’s New with CDAIS Project?" In Innovation and Interdisciplinary Solutions for Underserved Areas, 150–55. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-72965-7_14.
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"CDAI." In Encyclopedia of Quality of Life and Well-Being Research, 631. Dordrecht: Springer Netherlands, 2014. http://dx.doi.org/10.1007/978-94-007-0753-5_100416.
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"Tafeln CCCLXXXVII-CDIII." In Bildatlas zum Sport im alten Ägypten, Teil 2 Abbildungen, Tafel CCCLXXXVII—Tafel CDIII. BRILL, 1994. http://dx.doi.org/10.1163/9789004293922_019.
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"CDVII. — A Léo d'Orfer." In Stephane Mallarme, 26. Routledge, 2017. http://dx.doi.org/10.4324/9781351199117-17.
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"1884 CDIII. — A Léo d'Orfer." In Stephane Mallarme, 25. Routledge, 2017. http://dx.doi.org/10.4324/9781351199117-16.
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Miller, Cara, Bill Torbert, Nancy Wallis, and Karen C. Yeyinmen. "Team coaching through CDAI and the GLP." In The Practitioner’s Handbook of Team Coaching, 420–31. Routledge, 2019. http://dx.doi.org/10.4324/9781351130554-31.
Full textConference papers on the topic "CDAII"
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PALMONARI, F. "THE CDFII SILICON TRACKING SYSTEM." In Proceedings of the 7th International Conference on ICATPP-7. WORLD SCIENTIFIC, 2002. http://dx.doi.org/10.1142/9789812776464_0018.
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Sasaki, Wakao, Iwao Ebina, and Tatehisa Ohta. "A Compact And Efficient He-CdII White Light Laser." In OE/LASE '89, edited by Jin J. Kim, Randy Kimball, and P. J. Wisoff. SPIE, 1989. http://dx.doi.org/10.1117/12.951238.
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Bhowmick, Kiran, Meera Narvekar, Aqsa Bhimdiwala, and Chandrasekhar Raman. "CDACI: Concept Drift Detection and Adaptation to Classify Imbalanced Data streams." In 2018 IEEE Punecon. IEEE, 2018. http://dx.doi.org/10.1109/punecon.2018.8745380.
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Khan, Samira, Christian Alvarado, Michael Wirth, Nitin Shivappa, and James R. Hebert. "Abstract C45: Development and validation of Children Dietary Inflammatory Index (CDII)." In Abstracts: Tenth AACR Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; September 25-28, 2017; Atlanta, GA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7755.disp17-c45.
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Sasaki, Wakao, and Tatehisa Ohta. "Anomalous broadening spectra due to isotope effects in the high-power He-CdII white light lasers." In OE/LASE '90, 14-19 Jan., Los Angeles, CA, edited by Petras V. Avizonis, Charles Freed, Jin J. Kim, and Frank K. Tittel. SPIE, 1990. http://dx.doi.org/10.1117/12.18500.
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Curtis, JR, S. Kafka, D. Parenti, S. Black, S. Xu, Y. Wang, and CO Bingham. "THU0672 Real world evidence comparing the patient reported outcomes measurement information system to the cdai in rheumatoid arthritis patients." In Annual European Congress of Rheumatology, 14–17 June, 2017. BMJ Publishing Group Ltd and European League Against Rheumatism, 2017. http://dx.doi.org/10.1136/annrheumdis-2017-eular.5225.
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Yosmar, Rahmi, Sindi Suija, Yoneta Srangenge, and A. Almahdy. "Differences of Clinical Disease Activity Index (CDAI) in Rheumatoid Arthritis Patients Towards the Use of Disease Modifying Anti Rheumatic Drugs (DMARD)." In 2nd International Conference on Contemporary Science and Clinical Pharmacy 2021 (ICCSCP 2021). Paris, France: Atlantis Press, 2021. http://dx.doi.org/10.2991/ahsr.k.211105.018.
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Blagoev, Kiril. "Ultraviolet laser action on nd8(n+1)s2 - nd9(n+1)p transitions of ZnIII and CdIII." In Ninth International School on Quantum Electronics: Lasers--Physics and Applications, edited by Peter A. Atanasov. SPIE, 1996. http://dx.doi.org/10.1117/12.262911.
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Curtis, J., S. Schwartzman, S. Kafka, D. Parenti, S. Black, S. Xu, W. Langholff, and C. O. Bingham. "AB0243 Real world clinical trial comparing the patient reported outcomes measurement information system short forms and profiles to cdai disease classification in rheumatoid arthritis patients." In Annual European Congress of Rheumatology, EULAR 2018, Amsterdam, 13–16 June 2018. BMJ Publishing Group Ltd and European League Against Rheumatism, 2018. http://dx.doi.org/10.1136/annrheumdis-2018-eular.1800.
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Vega, O., Y. Calvo, Z. Torres, R. Gamboa, and S. Flores. "AB0288 Levels of metalloproteinase-3 (MMP-3) correlate better with clinical disease activity index (CDAI) and simplified disease activity index (SDAI) than standard disease assessment score (DAS-28)." In Annual European Congress of Rheumatology, EULAR 2018, Amsterdam, 13–16 June 2018. BMJ Publishing Group Ltd and European League Against Rheumatism, 2018. http://dx.doi.org/10.1136/annrheumdis-2018-eular.5289.
Full textReports on the topic "CDAII"
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Lovás, Lubomír. The Bose-Einstein correlations in CDFII experiment. Office of Scientific and Technical Information (OSTI), January 2008. http://dx.doi.org/10.2172/1342204.
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Amerio, Silvia. Study of t$\bar{t}$ production in tau jets channel at CDFII using neural networks. Office of Scientific and Technical Information (OSTI), December 2005. http://dx.doi.org/10.2172/948188.
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Di Ruzza, Benedetto. Measurement of the Branching Ratio of the charmless decay Bs → φφ at CDFII. Office of Scientific and Technical Information (OSTI), January 2008. http://dx.doi.org/10.2172/1352005.
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Salamanna, Giuseppe. Study of Bs mixing at the CDFII experiment with a newly developed opposite side b-flavour tagging algorithm using kaons. Office of Scientific and Technical Information (OSTI), October 2006. http://dx.doi.org/10.2172/897034.
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