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Svatoš, Michal, Jiří Chudoba, and Petr Vokáč. "Updates on usage of the Czech national HPC center." EPJ Web of Conferences 251 (2021): 02008. http://dx.doi.org/10.1051/epjconf/202125102008.
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The distributed computing of the ATLAS experiment at LHC has used computing resources of the Czech national HPC center IT4Innovations for several years. The submission system is based on ARC-CEs installed at the Czech Tier2 site (praguelcg2). Recent improvements of this system will be discussed here. First, there was a migration of the ARC-CE from version 5 to 6 which improves the reliability and scalability. A shared filesystem built on top of sshfs 3.7 no longer represents performance bottleneck. It provided an order of magnitude better transfer performance. New Singularity containers with full software stack can easily fit default resource limits on the IT4I cluster filesystem. A new submission system, allowing sequential running of payloads in one job, was set and adapted to HPC’s environment, improving usage on worker nodes with very high number of cores. Overall, the whole infrastructure provides significant contribution to resources provided by praguelcg2.
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Umemura, Takashi, and Yumi Wako. "Pathogenesis of Osteomalacia in Itai-itai Disease." Journal of Toxicologic Pathology 19, no. 2 (2006): 69–74. http://dx.doi.org/10.1293/tox.19.69.
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Gourtsoyiannis, Nickolas. "Yuji Itai." European Radiology 13, no. 5 (2003): 1195–96. http://dx.doi.org/10.1007/s00330-003-1872-1.
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AOSHIMA, Keiko. "Recent Advances in Studies of Itai-itai Disease." Eisei kagaku 43, no. 6 (1997): 317–30. http://dx.doi.org/10.1248/jhs1956.43.317.
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AOSHIMA, Keiko. "Itai-Itai Disease: Cadmium-Induced Renal Tubular Osteomalacia." Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene) 67, no. 4 (2012): 455–63. http://dx.doi.org/10.1265/jjh.67.455.
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Morikawa, Yuko, Hideaki Nakagawa, Masaji Tabata, et al. "Study of an Outbreak of Itai-itai Disease." Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene) 46, no. 6 (1992): 1057–62. http://dx.doi.org/10.1265/jjh.46.1057.
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Kawano, Shunichi, Hideaki Nakagawa, Yoshiharu Okumura, and Kenichiro Tsujikawa. "A mortality study of patients with Itai-itai disease." Environmental Research 40, no. 1 (1986): 98–102. http://dx.doi.org/10.1016/s0013-9351(86)80085-8.
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Inaba, Takeya, Etsuko Kobayashi, Yasushi Suwazono, et al. "Estimation of cumulative cadmium intake causing Itai–itai disease." Toxicology Letters 159, no. 2 (2005): 192–201. http://dx.doi.org/10.1016/j.toxlet.2005.05.011.
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Bryan, R. Nick. "Yuji Itai, MD." Radiology 228, no. 3 (2003): 905. http://dx.doi.org/10.1148/radiol.2283032522.
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Chen, Xiao, Guoying Zhu, Taiyi Jin, et al. "Cadmium exposure induced itai-itai-like syndrome in male rats." Open Medicine 6, no. 4 (2011): 425–34. http://dx.doi.org/10.2478/s11536-011-0046-9.
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AbstractFourteen Sprague-Dawley male rats were randomly divided into 2 groups which were given CdCl2 at the doses of 0 and 1.5 mg /kg for 12 weeks. Before sacrifice, microCT scanning were performed on the proximal tibia and urine were collected for cadmium and N-acetyl-beta-D-glucosaminidase assay, then all of rats were sacrificed and blood was collected for biomarkers measurement; bone tissues were collected for bone mass, histology and biomechanical analysis. The cadmium in blood, urine, bone and kidney of rats treated with cadmium was significantly higher than those in the control group. The bone mineral density, and bone mineral ability of rats treated with cadmium were obviously decreased by 20%–50% compared to controls. Bone microstructure index and trabecular separation of rats treated with cadmium were obviously lower (−50%) and significantly higher (+150%) than that in the control group. Bone biomechanical property decreased by 30%–60% in cadmium treated rats compared to control. Tartrate-resistant acid phosphatase 5b and alkaline phosphatase levels of rats treated with cadmium were significantly higher than those in control, but serum osteocalcin level decreased greatly by cadmium. Obvious proximal tubule damage occurred after cadmium exposure. These observations gave clear and comprehensive evidence that cadmium exposure could induce itai-itai-like syndrome in male rats.
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Baba, Hayato, Koichi Tsuneyama, Tokimasa Kumada, Keiko Aoshima, and Johji Imura. "Histopathological analysis for osteomalacia and tubulopathy in itai-itai disease." Journal of Toxicological Sciences 39, no. 1 (2014): 91–96. http://dx.doi.org/10.2131/jts.39.91.
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Nogawa, Koji, and Teruhiko Kido. "Biological monitoring of cadmium exposure in itai-itai disease epidemiology." International Archives of Occupational and Environmental Health 65, S1 (1993): S43—S46. http://dx.doi.org/10.1007/bf00381306.
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Nakada, T., H. Furuta, H. Koike, T. Katayama, and H. Teranishi. "Impaired urine concentrating ability in Itai-itai (ouch-ouch) disease." International Urology and Nephrology 21, no. 2 (1989): 201–9. http://dx.doi.org/10.1007/bf02550809.
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Kasuya, M., H. Teranishi, K. Aoshima, et al. "Water Pollution by Cadmium and the Onset of Itai-itai Disease." Water Science and Technology 25, no. 11 (1992): 149–56. http://dx.doi.org/10.2166/wst.1992.0286.
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Cadmium (Cd) from a zinc mine polluted Jinzu River basin, Toyama prefecture and produced a disease with severe bone pain (Itai-itai disease), from the early part of the 20th century. Cd caused renal tubular dysfunction and osteomalacia accompanied by osteoporosis. The main symptoms of the disease were bone pain, pseud fracture (Looser's zone), fracture, and renal tubular dysfunction. The pollution of paddy-field soil by Cd still remains and our epidemio1ogica1 studies of the inhabitants living in the Cd-polluted areas show the presence of renal tubular dysfunction and decrease of bone mass; characteristic of Itai-itai disease.
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Yamashita, H., and M. Kitagawa. "Histomorphometric Study of Ribs with Looser Zones in Itai-Itai Disease." Calcified Tissue International 58, no. 3 (1996): 170–76. http://dx.doi.org/10.1007/s002239900029.
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Nakano, Masatoshi, Keiko Aoshima, Terutaka Katoh, Hidetoyo Teranishi, and Minoru Kasuya. "Elevation of urinary trehalase activity in patients of itai-itai disease." Archives of Toxicology 60, no. 4 (1987): 300–303. http://dx.doi.org/10.1007/bf01234669.
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Yamashita, H., and M. Kitagawa. "Histomorphometric study of ribs with Looser zones in Itai-itai disease." Calcified Tissue International 58, no. 3 (1996): 170–76. http://dx.doi.org/10.1007/bf02526883.
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Kasuya, M. "Recent epidemiological studies on itai-itai disease as a chronic cadmium poisoning in Japan." Water Science and Technology 42, no. 7-8 (2000): 147–54. http://dx.doi.org/10.2166/wst.2000.0563.
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Itai-itai disease is a chronic cadmium poisoning with renal tubular dysfunction followed by osteomalacia. Renal tubular dysfunction among inhabitants of the cadmium-polluted Jinzu River basin was irreversible and progressive, despite the fact that cadmium exposure had decreased. The bone mass was decreased in the inhabitants living in cadmium-polluted areas with renal tubular dysfunction, correlating with the urinary β2-microglobulin level. The decreased bone mass was diagnosed as latent renal tubular osteomalacia. Low serum erythropoietin levels were detected among the patients with itai-itai-disease, despite the presence of severe anemia. The anemia found in the end-stage of the disease was closely associated with an impaired renal function. Health surveys in cadmium-polluted areas of 8 prefectures were carried out, and many cases of renal tubular dysfunction were found in 4 prefectures, although the most severe cases were found in Toyama Prefecture. Many cases whose clinical features are completely in accord with those of itai-itai disease with severe renal tubular dysfunction and osteomalacia were reported in 3 prefectures as well as Toyama Prefecture. Mortality risks were increased in the patients with itai-itai disease, in the group suspected of having the disease, and in the groups of mild renal tubular dysfunction with 300–<1,000 μg/g creatinine. The development stage of the disease was divided into three stages. Those are the mild stage (stage of cadmium nephropathy) with the renal tubular dysfunction and decreased bone mass, the typical stage with the severe renal tubular dysfunction and pseudofracture detectable by X-ray examination, and the serious stage with severe renal dysfunction and pseudofracture and/or fracture.
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Prunzel, Jaqueline, Marcos Toebe, Alexandre Bernardino Lopes, and Virnei Silva Moreira. "MODELOS DE REGRESSÃO LINEAR MÚLTIPLA APLICADOS À AVALIAÇÃO DE TERRENOS URBANOS - CASO DO MUNICÍPIO DE ITAQUI-RS." Boletim de Ciências Geodésicas 22, no. 4 (2016): 651–64. http://dx.doi.org/10.1590/s1982-21702016000400037.
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Este trabalho teve como objetivo identificar variáveis explicativas para a modelagem e predição do valor real (ITBI) e venal de lotes urbanos no município de Itaqui-RS utilizando o Método Comparativo Direto de Dados do Mercado, desenvolvido por regressão linear múltipla. Em uma amostra de 67 lotes foram avaliadas variáveis quantitativas: área, testada, valor do m2, valor venal e valor do ITBI e variáveis qualitativas: topografia, situação e pavimentação, sendo que para cada variável foram determinados parâmetros estatísticos incluindo a distribuição de dados por assimetria, curtose, teste de normalidade de Kolmogorov-Smirnov, bem como a correlação linear de Pearson e análise de trilha, que mostra as relações de causa e efeito das variáveis explicativas sobre o valor venal e ITBI. A importância de cada variável explicativa sobre o modelo de valor venal e ITBI foi determinada pelo método stepwise. O valor venal apresentou correlação positiva, significativa (p≤0,05) e crescente com a pavimentação, testada, área e valor do m2, nessa ordem. Já o valor de ITBI apresentou correlação positiva, significativa (p≤0,05) e crescente com valor do m2e pavimentação, nessa ordem. A análise de trilha indicou que a área e o valor do m2possuem relação de causa e efeito sobre o valor venal e o valor do metro quadrado e a pavimentação apresenta relação de causa e efeito sobre o valor de ITBI. Os modelos : Y = 16,90 x área + 594,69 x valor do m 2 - 9526,54 x topografia (r2=0,91) e, Y = 868,36 x valor do m2 - 23642,19 x topografia + 33633,46 x pavimentação, (r2=0,70), são adequados para a estimação dos valores venal e de ITBI, respectivamente
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Tambo, Torben, and Jacob Filtenborg. "Digital services governance: IT4IT™ for management of technology." Journal of Manufacturing Technology Management 30, no. 8 (2019): 1230–49. http://dx.doi.org/10.1108/jmtm-01-2018-0028.
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Purpose The purpose of this paper is to present, analyse and demonstrate the impact and potentials of a pragmatically derived information technology (IT) governance framework, IT4IT™, for the discipline of management of technology (MoT) especially within the IT industry. Design/methodology/approach This paper is based on an extensive literature study working with the limitations of the relatively recent publication of IT4IT™ and the normative character of IT4IT™. A mixed-method case study is presented based on an IT service provider organisation. Both a qualitative method and a systems and design oriented method are being used. Findings IT4IT™ can provide value and a clearer understanding of the service delivery framework if the technological core of the focal organisation is adapted to a value stream thinking. This suggests a more operational character of all IT processes and analogue to general MoT frameworks and corporate governance models. Research limitations/implications Given the recent publication of the IT4IT™ framework, this study is primarily ex ante and suggests further full-scale ex post research in the future. Practical implications Validation and successful implementation of the IT4IT™ framework will give companies better opportunities for safe and controlled value creation using IT. Control connects with risk reduction and less risk can encourage innovation and “tame” development complexity. Using value streams will align IT better with manufacturing and services. Originality/value Companies are striving to seek governance and risk minimisation in IT development and operations. This paper is discussing the applicability of the IT4IT™ framework for finding a better understanding of the value creation and value proposition delivered by introducing controlled processes minimising risk.
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Dargemont, C., D. Dunon, J. Salamero, M. A. Deugnier, J. Davoust, and J. P. Thiery. "Overproduction and secretion of beta 2-microglobulin by a rat thymic epithelial cell line that expresses MHC class I heavy chain." Journal of Cell Science 98, no. 4 (1991): 559–65. http://dx.doi.org/10.1242/jcs.98.4.559.
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Major histocompatibility complex (MHC) class I antigens are constituted of dimers consisting of a peripheral light chain, beta 2-microglobulin (beta 2m) and a transmembrane heavy chain whose cell surface expression depends on its assembly with beta 2m. In contrast, soluble beta 2m can be secreted in the absence of heavy chain expression. The presence of beta 2m in medium conditioned by a rat thymic epithelial cell line, IT45-R1 (IT45) prompted us to investigate whether beta 2m could be secreted by cells that express MHC class I antigens. IT45 cells produce three to five times more beta 2m in the culture supernatant than another rat thymic epithelial cell line, IT26-R21 (IT26). The IT45 cell line exported beta 2m through a constitutive pathway of secretion, as indicated by the kinetics of production and localization of intracellular beta 2m. Although cells from the IT45 cell line expressed a much higher amount of beta 2m as compared to IT26 and NBT II cells (a rat bladder epithelial cell line), all three of these cell lines expressed the same amount of membrane and intracellular MHC class I heavy chain. These data are thus consistent with a constitutive secretion of beta 2m dependent upon an overexpression of MHC class I light chain as compared to the heavy chain. The amount of beta 2m mRNA and the ratio of beta 2m versus MHC class I heavy chain transcripts were higher in IT45 than in IT26 cells, indicating that overexpression of beta 2m in IT45 cells could be due to an enhanced level of beta 2m mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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Yasuda, Masanori, Atsuo Miwa, and Masanobu Kitagawa. "Morphometric Studies of Renal Lesions in Itai-itai Disease: Chronic Cadmium Nephropathy." Nephron 69, no. 1 (1995): 14–19. http://dx.doi.org/10.1159/000188354.
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Ødum, Lars, Torben E. Jessen та Claus Yding Andersen. "Glycosaminoglycan-bound and free inter-α-trypsin inhibitor components of follicular fluid". Zygote 9, № 4 (2001): 283–88. http://dx.doi.org/10.1017/s0967199401001319.
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The proteinase inhibitor inter-α trypsin inhibitor (ITI) is a blood-derived protein necessary for normal female fertility. Absence of ITI leads to ovulation of naked oocytes that cannot fertilise. ITI consists of two heavy chains (ITI-HC) and bikunin linked by a chrondroitin sulphate. By binding to hyaluronate, ITI-HC stabilises the extracellular matrix, but ITI-HC also binds to proteoglycans in follicular fluid. In vivo concentrations of ITI components in preovulatory follicular fluid, free as well as bound to hyaluronate or proteoglycan, are unknown. In order to quantify these components, 58 follicular fluids and 13 blood samples were collected in connection with in vitro fertilisation and embryo transfer treatment of 13 women. Quantitation of glycosaminoglycan-bound ITI-HC was performed after separation from free ITI in agarose gel. ITI components were determined by immunoelectrophoresis and hyaluronate by an ELISA method. The follicular fluid concentration of ITI was on average 70% of that in plasma and the concentration of hyaluronate remained low despite follicular production, suggesting that the production of hyaluronate is the rate-limiting step in the formation of the extracellular matrix of the oocyte-cumulus complex. In follicular fluid, the concentration of free ITI-HC was higher than that of glycosaminoglycan-bound ITI-HC. Addition of exogeneous hyaluronate doubled the amount of hyaluronate-bound ITI-HC, further supporting the notion that ITI in follicular fluid is not rate-limiting for cumulus expansion in vivo.
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Guo, Jin, Meng Chen, Xialing Sun, Zhanzhao Wang, and Jinli Xue. "Leveraging industrial-technological innovation to achieve sustainable development: A systems thinking perspective." PLOS ONE 15, no. 12 (2020): e0242981. http://dx.doi.org/10.1371/journal.pone.0242981.
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Industrial-technological innovation (ITI) has become an important requirement for the sustainable development of China. ITI development requires a comprehensive understanding of the dynamic complexity associated with ITI systems. Previous research into ITI systems is based primarily on static methods that isolate system components, and ignore feedback on adjustments made. Based on systems thinking, this paper develop six archetypes (“Limit to Growth,” “Success to the Successful,” “Tragedy of the Commons,” “Fixes that Fail,” “Accidental Adversaries,” and “Shifting the Burden”) and an ITI system integration model. The model visualizes the ITI system as a whole and identifies bottlenecks that may affect ITI development. This conceptual model provides a more effective method of judgment, which can better explain the operational mechanism of the ITI system and improve the system’s operational characteristics. Finally, we evaluate the ITI system and propose that self-organization is a key lever of a systemic intervention framework for ITI.
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Callaghan, Michael U., Indira Warrier, Madhvi Rajpurkar, and Jeanne Lusher. "Immune Tolerance Induction in 28 Children with Hemophilia Awith Inhibitors." Blood 108, no. 11 (2006): 1046. http://dx.doi.org/10.1182/blood.v108.11.1046.1046.
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Abstract Aim: To study the characteristics, treatment, and outcome of patients with hemophilia with inhibitors who have undergone immune tolerance induction (ITI) at the Children’s Hospital of Michigan over the past 14 years. Methods: In compliance with local IRB regulations, patient charts and laboratory databases were reviewed and salient data extracted. 28 boys underwent 29 attempts at immune tolerance induction. Results: Hemophilia A 26 boys with severe hemophilia A with inhibitors underwent 27 trials of ITI. In this cohort of 26 patients the average age at which patients developed an inhibitor was 22 months and the average age at start of ITI was 5 years 4 months (range 2 months to 17 years 5 months). The average number of exposure days prior to inhibitor development was 10 (1–47). The average time between development of an inhibitor and initiation of ITI was 43 months, with no difference between those who successfully completed ITI and those who did not. Six patients had low titer inhibitors (0.8–6.5 BU) and successfully completed ITI using a modified low dose ITI regimen of factor infusions 3–7 times per week. 20 of the patients with high titer inhibitors (6.4–1280 BU) were treated with daily infusions of 50–200 units/kg/d of factor VIII (FVIII) products. For ITI, 4 patients received high purity plasma derived FVIII (PD-FVIII) and 21 received recombinant FVIII (rFVIII) and one received both. In patients who became tolerized to FVIII, the average time to achieve an inhibitor titer of 0 Bethesda Units (BU) was 211 days. In those who were unable to achieve tolerance, the average length of the trial was 263 days. 21 of the ITI trials employed a central venous catheter and in 5 patients ITI was stopped after removal of the line because of recurrent infections. 14 boys received FEIBA, rFVIIa, or porcine FVIII for bleeding episodes during ITI; 8 of them failed ITI and one is still on therapy. Seven trials of ITI were in Caucasian patients (26 %), 17 in African American (AA) (63 %), and 3 in Middle Eastern patients (11 %). 19 patients achieved complete tolerance (73 %), 6 patients failed (23 %), one failed twice, and one patient continues on therapy. All but 2 patients who successfully completed ITI went on prophylaxis with FVIII. All patients who successfully completed ITI have maintained tolerance with a mean follow-up of 101 months (range 7–168). Table I: Hemophilia A Failed ITI Successful ITI *One still ongoing Number of trials* 7 (23 %) 19 (73 %) African Americans 7 (41 %) 10 (59 %) Non-AA 0 10 (100 %) Historical Peak Titer (mean) 345 BU 47 BU Titer at Start of ITI (mean) 62 BU 5 BU Peak Titer on ITI (mean) 168 BU 46 BU Age at inhibitor development (mean) 26 months 12 months ITI with PD-FVIII 1 4 ITI with rFVIII 7 15 Hemophilia B During this time period, 2 boys with severe hemophilia B underwent ITI. Both had severe allergic reactions at the time of inhibitor development; both underwent desensitization successfully but both failed ITI. Both started ITI with plasma derived factor nine at age 15 months. One developed nephrotic syndrome while on ITI. Conclusions: Most patients with Hemophilia A were able to achieve and maintain tolerance (73%). Higher titer inhibitors, hemophilia B, younger age at development of inhibitor, AA race and treatment of bleeds with bypass agents or porcine factor while on ITI were risk factors for ITI failures. Loss of central venous access with recurrent infections was also a common reason for ITI failure.
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Vanover, Kimberly, Gretchen Snyder, Joseph Hendrick, et al. "ITI-007." International Clinical Psychopharmacology 26 (September 2011): e56. http://dx.doi.org/10.1097/01.yic.0000405728.69382.1e.
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Hsu, Chin Lin, Shyankay Jou, Ying Ji Chuang, and Ching Yuan Lin. "Hydrophobic Coating on Silicon Wafer by Use of Industrial Coating-Bar Process in Atmosphere Parameter." Advanced Materials Research 941-944 (June 2014): 1577–80. http://dx.doi.org/10.4028/www.scientific.net/amr.941-944.1577.
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Silicon wafer is chosen in this work for the study of hydrophobic coating with industrial coating bar, due to the wafer has the superior flatness. Various amounts of TS-720 hydrophobic nano-particles were mixed into ITRI hydrophobic agent (H.A.), and this liquid mixture was applied onto material surface by use of a coating bar. In this study, we added the TS-720 nanoparticle from 0 – 2.5 wt% with ITRI H.A. The contact angle is higher than 135o, when we have 2.5 wt% TS-720 nanoparticle adding in ITRI H.A.
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Predieri, Stefano, Fiorella Sinesio, Erminio Monteleone, et al. "Gender, Age, Geographical Area, Food Neophobia and Their Relationships with the Adherence to the Mediterranean Diet: New Insights from a Large Population Cross-Sectional Study." Nutrients 12, no. 6 (2020): 1778. http://dx.doi.org/10.3390/nu12061778.
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The Mediterranean diet (MD) is associated with many health benefits. The association between the MD and food neophobia (FN) is still unexplored in adults. The present cross-sectional study was aimed to explore the relationships between adherence to the MD, FN, and sociodemographic variables in a large Italian cohort. Familiarity and frequency use (FFI) of prototypical and non-prototypical Mediterranean foods were used to calculate a new adherence index: the Italian Taste Mediterranean Index (ITMI). The FFI of all Mediterranean foods increased with age, while butter, soft drinks, red/cured meat, and sweets were more common in younger people. Accordingly, ITMI increased with age (F2,2384 = 54.11; p < 0.0001). Women recorded a higher ITMI (6.70) than men (6.10). Individuals with high FN showed higher FFI for soft drinks and sweets and lower ones for most typical MD foods, than individuals with low FNs. A decrease of ITMI was recorded with the increase of the FN(F2,2384 = 22.84; p < 0.0001). With ageing, ITMI increased even in individuals with a high FN. The results suggest that FN may negatively affect adherence to the MD, lowering its potential health benefits, in the adult population. Monitoring of food habits, dietary education, and anxiety management, may be valuable tools to control FN and support the adherence to the MD.
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Carneiro, Filipe Lima Rios. "O IMPOSTO SOBRE A TRANSMISSÃO DE BENS IMÓVEIS E A SUA INCIDÊNCIA QUANDO DA AQUISIÇÃO DE TERRENOS PARA CONSTRUÇÃO FUTURA E IMÓVEIS NA PLANTA NO MUNICÍPIO DE BELO HORIZONTE." Revista de Direito Tributário e Financeiro 4, no. 1 (2018): 18. http://dx.doi.org/10.26668/indexlawjournals/2526-0138/2018.v4i1.4400.
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Este artigo abordará a estrutura do Imposto sobre a Transmissão de Bens Imóveis – ITBI, passando pela Teoria Geral do Direito Tributário, notadamente pelos aspectos da Hipótese de Incidência, utilizando-se como marco teórico o livro Hipótese de Incidência Tributária de Geraldo Ataliba. Com base nessa abordagem será analisada a compatibilidade das cobranças de ITBI e ITBI complementar com multa e juros realizadas pelo Município de Belo Horizonte em casos de aquisição de terreno para realização de futura edificação e aquisição de unidades imobiliárias autônomas para entrega futura, com aqueles elementos da estrutura e Hipótese de Incidência do tributo.
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Struecker, Klaus Almeida. "AS DIVERGÊNCIAS ENTRE MUNICÍPIOS E CONTRIBUINTES NA ESTIPULAÇÃO DA BASE DE CÁLCULO DO ITBI EM IMÓVEIS ADQUIRIDOS POR MEIO DE LEILÕES JUDICIAIS E EXTRAJUDICIAIS." Revista de Direito Tributário e Financeiro 7, no. 1 (2021): 44. http://dx.doi.org/10.26668/indexlawjournals/2526-0138/2021.v7i1.7723.
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O foco do presente trabalho é a conjuntura tributária, especificamente quanto à demonstração de que a base de cálculo do ITBI é o valor alcançado em leilão na compra e venda de um imóvel adquirido por meio de hasta pública. O ITBI é o Imposto de Transmissão de Bens Imóveis, um tributo municipal aplicado sobre transferências imobiliárias. A responsabilidade do pagamento do tributo costuma obedecer às leis municipais. No caso de bem adquirido em hasta pública, verifica-se que o ITBI deve ser calculado sobre o preço pago pelo arrematante e não sobre o valor de mercado.
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Yoshida, Fumikazu, Akio Hata, and Haruo Tonegawa. "Itai-Itai disease and the countermeasures against cadmium pollution by the Kamioka mine." Environmental Economics and Policy Studies 2, no. 3 (1999): 215–29. http://dx.doi.org/10.1007/bf03353912.
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Jimi, S., A. Takaki, S. Takebayashi, and M. Segawa. "Mitochondrial DNA deletion of proximal tubules is the result of itai-itai disease." Clinical and Experimental Nephrology 7, no. 1 (2003): 18–26. http://dx.doi.org/10.1007/s101570300002.
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Xu, Zhen Hui, Jun Yang, Wan Jun Zhang, and Zhen Jun Yang. "Regions of Interest Detection Algorithm Based on Improved Visual Attention Model." Applied Mechanics and Materials 513-517 (February 2014): 3368–71. http://dx.doi.org/10.4028/www.scientific.net/amm.513-517.3368.
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Regions of Interest (ROI) detection algorithm based on Visual Attention Model can rapidly focus the attention in the conspicuous target region, and extract the interested region. As to some complicated scenes, it is very difficult to detect the target accurately by using general target detecting method, but using Regions of Interest detection algorithm based on Itti Visual Attention Model can detect the target position very well. But pay attention to Itti Visual Attention Model, it utilizes the luminance, color and texture character of the target to detect the position of it. As little moving target, these characters of it are not obvious, so the detecting result is not satisfactory that utilizing Itti Visual Attention Model directly. According to the problem, this text proposes one Regions of Interest detection algorithm on the basis of improved Itti visual attention model by introducing movement character. The experiment shows that the improved model puts forward a new thinking of little moving target detection.
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Ahsan, N. "Intravenous infusion of total dose iron is superior to oral iron in treatment of anemia in peritoneal dialysis patients: a single center comparative study." Journal of the American Society of Nephrology 9, no. 4 (1998): 664–68. http://dx.doi.org/10.1681/asn.v94664.
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In the treatment of anemia of chronic renal failure, the most common cause of recombinant human erythropoietin (rhEPO) resistance is iron deficiency. In peritoneal dialysis (PD) patients, oral iron therapy is an accepted and convenient method of iron supplementation. The effectiveness of oral iron, however, is limited by many factors, including gastrointestinal side effects and poor gastric absorption. This study prospectively compared the efficacy of single intravenous infusion of total dose iron (ITDI group) given in an outpatient setting with oral iron (oral group) for the treatment of anemia in PD patients. Twenty-five adult stable PD patients with baseline hematocrit 25 to 35% were entered into the study. Thirteen patients with serum transferrin saturation (TSAT) < 25% received ITDI, and 12 patients with TSAT between 25 and 35% received oral iron. One patient in the oral group received emergent blood transfusion and was excluded from analysis. Hematocrit and iron indices were measured at monthly intervals. Doses of rhEPO were adjusted monthly to maintain target hematocrit at 35%. At the end of the study (6 mo), despite similar baseline mean hematocrit (31.0 +/- 0.9 versus 33.0 +/- 1.0%), comparable mean baseline weekly rhEPO dose (7886 +/- 1449 versus 6370 +/- 1553 U/wk), and significantly lower level of mean TSAT (11.3 +/- 3.5 versus 30.1 +/- 3.5%; P < 0.05), the ITDI group when compared with the oral group had significantly higher mean hematocrit (36.0 +/- 1.0 versus 31.4 +/- 1.1%; P < 0.05) and TSAT (33.7 +/- 3.7 versus 22.6 +/- 4.0%; P < 0.05) values. In addition, the final mean dose of weekly rhEPO was significantly lower in the ITDI group (4799 +/- 981 versus 9998 +/- 1027 U/wk; P < 0.05). No patient in the ITDI group developed an adverse reaction to intravenous iron. It is concluded that ITDI represents a more efficacious method of iron supplementation in PD patients receiving rhEPO. Moreover, ITDI is safe and well tolerated and can be administered in an outpatient setting.
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KACZMAREK, ŁUKASZ, and ŁUKASZ MICHALCZYK. "Thulinius itoi comb. nov. a new systematic position for Isohypsibius itoi (Tsurusaki, 1980) (Tardigrada: Eutardigrada: Hypsibiidae)." Zootaxa 1373, no. 1 (2006): 65. http://dx.doi.org/10.11646/zootaxa.1373.1.4.
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Thulinius itoi comb. nov. described by Nobuo Tsurusaki in 1980 as Hypsibius (Isohypsibius) itoi from interstitial habitat in Japan and transferred to the genus Isohypsibius by Ramazzotti and Maucci (1983) is re-examined and transferred to the genus Thulinius based on the morphology of bucco-pharyngeal apparatus.
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Li, Nanxin, Koo Wilson, Marc Botteman, Daniel Nicoloso, Sangeeta Krishnan, and Jun Su. "Economic Impact of Immune Tolerance Induction (ITI) with Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) Compared to Conventional Recombinant Factor VIII (rFVIII)." Blood 132, Supplement 1 (2018): 3520. http://dx.doi.org/10.1182/blood-2018-99-114993.
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Abstract Introduction: Hemophilia A results from a clotting protein factor VIII (FVIII) deficiency, which leads to the need for the use of exogenous FVIII. Such therapy is effective unless alloantibodies (inhibitors) develop and render FVIII replacement ineffective. Patients with high-titer inhibitors may try to eradicate the presence of these inhibitors by undergoing ITI, an often costly process that requires the prolonged use of frequent doses of FVIII to induce FVIII antigen-specific tolerance. There is no consensus on the best approach to achieve tolerance and no product has been approved by any regulatory agency for ITI treatment in hemophilia A patients with inhibitors. The Fc portion of rFVIIIFc has shown immunomodulatory properties in mice, and chart reviews and case reports suggest that tolerization with rFVIIIFc in first-attempt ITI patients can potentially be achieved rapidly (i.e., ≤18 months) and therefore may possibly offer cost savings compared to conventional rFVIII. This analysis assessed the economic consequences and budget impact of using rFVIIIFc vs. conventional rFVIII for first-attempt immune tolerance induction (ITI) in hemophilia A patients with inhibitors. Methods: A literature-based model was developed to estimate the effect of rFVIIIFc vs conventional rFVIII on drug cost of first-attempt ITI, based on modelled ITI duration and outcome (rates and time to ITI success or failure) for US patients with varying clinical profiles (e.g., historical peak titer, FVIII dose) over a 3-year period. In the model, at any given time after ITI initiation (on either rFVIIIFc or rFVIII), a patient was categorized as ongoing ITI, post-ITI as success, or post-ITI as failure. The duration and outcomes for patients treated with rFVIIIFc ITI were based on observed data for first-attempt ITI patients with varied clinical profiles and ITI regimens from in chart reviews and case reports (n = 9). In the absence of direct head-to-head observations, the duration and outcome of ITI for the exact same patients in a scenario in which they received rFVIII (instead of rFVIIIFc) at the same doses were estimated indirectly using a previously published regression model (Bojke et al. 2009, Value in Health, 12(7), A378-A379) based on data for 113 patients from international and national registries that adjusts for historical and pre-ITI titer levels, time from inhibitor diagnosis to ITI start, and ITI factor dose. To place the cost comparison results in the perspective of a third-party US payer, a budget impact analysis was undertaken on a population of typical hemophilia A patients (after adjusting for patient characteristics) who are embarking on first-attempt ITI in a plan of 10 million insured members. In this analysis, the number of patients starting ITI each year was assumed constant, and patients who successfully eradicated inhibitors with ITI would transition back to FVIII prophylaxis. Results: The model predicted that, compared to rFVIII, rFVIIIFc would result in a reduction in estimated time to ITI success (rFVIIIFc: 9.43 months, rFVIII: 16.80 months), increased success probability at 20 months (rFVIIIFc: 67%, rFVIII: 25%), and lower 3-year per-patient costs (rFVIIIFc: $1,709,000, rFVIII: $3,630,000), respectively. In the budget impact analysis for a US health plan of 10 million insured members, 11.2 patients were expected to be newly diagnosed hemophilia A patients, among whom 1.17 patients were expected to develop inhibitors to FVIII and initiate ITI each year. By year 3, the predicted number of successful ITI patients increased by 23% and the budget savings for the plan were $103,738 per patient per year (for the ~1 patient who started ITI each year) after the inclusion of rFVIIIFc for ITI and subsequent prophylaxis when patients successfully eradicated inhibitors. Conclusions: Based on this mathematical economic model of first-attempt ITI patients, the modeled faster time to tolerization with rFVIIIFc vs. rFVIII, resulted in estimated per-patient and overall budget savings in ITI from a US payer perspective. Current prospective studies (e.g. verITI-8) will provide additional evidence on the efficacy of rFVIIIFc for ITI in Hemophilia A patients with inhibitors. Disclosures Li: Bioverativ: Employment. Wilson:SOBI: Employment. Botteman:Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding; Pharmerit International: Employment, Equity Ownership, Research Funding; Celgene: Research Funding; Bioverativ: Consultancy, Other: Provided consulting to Bioverativ, Research Funding. Nicoloso:Bioverativ: Other: an employee of Pharmerit, which provided consulting to Bioverativ. Krishnan:Bioverativ: Employment. Su:Bioverativ: Employment.
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Prezotti, Alessandra Nunes Loureiro, Silmara Aparecida De Lima Montalvão, Cláudia Lorenzato, et al. "Immune Tolerance Induction Treatment Is Cost-Effective in Adult Patients with Long-Standing High-Responding Inhibitors." Blood 126, no. 23 (2015): 3530. http://dx.doi.org/10.1182/blood.v126.23.3530.3530.
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Abstract Introduction: Despite treatment of hemophilia having achieved considerable improvement over the last decades, inhibitor development remains a major complication for these patients. Inhibitors are alloantibodies that neutralize factor (F) VIII coagulation activity, and occur in approximately 25% of hemophilia A patients. Immune tolerance induction (ITI) is the choice therapy to eradicate these antibodies. There are several ITI protocols with similar success rates, approximately 70%. The presence of long-standing inhibitors in the adult population has usually been associated with poor ITI outcome. In Brazil, as in other countries with constrained resources, limited access to factor concentrates prevented the use of ITI. Thus, almost all patients with inhibitors remained a long time with this complication. Only after 2013 with increased availability of factor concentrates in the country, has assured long-term prophylaxis and ITI treatment been possible. Objective: This study aimed to describe the Brazilian experience in managing ITI in adult patients from seven Hemophilia Treatment Centers with long-standing inhibitor using bypassing agents to control bleeding episodes, considering bleeding frequency, treatment barriers and economic impact of therapy. Patients and Methods: We retrospectively analyzed clinical and laboratory data of hemophilia A patients with high-responding inhibitors (peak titer > 5 Bethesda Unit (BU), anamnestic response to FVIII) over 18 yo who underwent ITI treatment and were using bypass agents before ITI. The initial ITI protocol used was low-dose FVIII concentrate (25-50 IU/kg 3x/week) Results: In Brazil, since the availability of ITI, 39 adult hemophilia A patients with inhibitors, have been submitted to ITI for the first time. In this study, we accessed data from 26 patients, of these 13 (50%) already achieved complete ITI success criteria (inhibitor titer < 0.6 BU; FVIII recovery ≥ 66%, and half-live ≥ 6 h). Another 4 patients with ongoing ITI achieved inhibitor titer < 5 BU and are no longer using bypassing agents. Thus, 17/26 (65%) patients discontinued the bypassing agents in a median period of 2 mo (range 0 to 18 mo) after starting ITI. After 24 months of irregular treatment 2 patients abandoned ITI protocol. Analyses of the 13 patients with complete success revealed mean age at first reported inhibitor of 16.21y (SD ± 11.6; median 21y, range 0.7 to 37y), and mean age at ITI onset of 31.2y (SD ± 10.6; median 27y, range 19 to 47y). The mean period from the first inhibitor detected until starting ITI was 15y (SD ± 5.1), with a 16y median (range 7 to 22y). The historical peak inhibitor mean was 53.1 BU (SD ± 49.5; median 39.4 BU, range 5.5 to 163 BU). The mean pre ITI inhibitor titer was 6.6 BU (SD ± 5.5; median 5.5 BU, range 0.6 to 20.8 BU). Low-dose ITI protocol was initially used for all patients, however 3 patients had the dose increased during treatment (100 IU/kg from 3 to 7 x/week). During ITI, 10/13 patients received prophylaxis with bypassing agents, and 9 began prophylaxis before ITI started. The mean time to achieve inhibitor titer < 0.6 BU was 11.6 mo (SD ± 12.5; median 7 mo, range 0.5 to 44 mo). All 13 patients achieved other ITI success criteria. However, a delay was observed in the majority of patients in FVIII recovery and half-life. Regarding clinical outcome, we observed a significant reduction in both, annualized bleeding rate (ABR), and annualized joint bleeding rate (AJBR), comparing 12 months before ITI, during ITI, and after achieving complete success (figure 1). Regarding economic evaluation, we observed a significant reduction in the median cost of clotting factor consumption, comparing 12 months before starting ITI, and the following years after achieving ITI success. No significant difference was observed between the median cost of 12 months before, and ITI period (figure 2). Conclusion: This study indicated that this treatment is worthwhile even for inhibitor patients with poor prognostic factors for ITI considering both effectiveness to control and prevent bleeding episodes, and economic impact. In this group, 65% of adult hemophilia A high-responding inhibitors patients stopped using bypassing agents after a median period of 2 months after starting ITI. Despite being a high cost treatment, ITI can be cost-effective, especially for patients using bypassing agents. These results reinforce the positive impact of the ITI even in long time inhibitor adult patients. Disclosures Ozelo: Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Biogen: Research Funding.
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Nakar, Charles T., Marilyn J. Manco-Johnson, Alice Lail, et al. "Prompt Immune Tolerance Induction at Inhibitor Diagnosis Regardless of Titer May Increase Overall Success in Hemophilia A With Inhibitors: Experience of Two US Centers." Blood 122, no. 21 (2013): 575. http://dx.doi.org/10.1182/blood.v122.21.575.575.
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Abstract Introduction Immune tolerance induction (ITI) for patients (pts) with hemophilia A with inhibitors is the only modality known to effectively eradicate inhibitors with an overall reported success of ∼60-80%. One debate concerns the optimal time to start ITI; recent guidelines recommend delaying ITI until inhibitor titer is <10 Bethesda units (BU). Aim We report results of an analytic project to determine the success of ITI relative to time from inhibitor detection to ITI initiation. Methods Data was collected retrospectively at 2 US hemophilia centers on pts with severe/moderate (≤5%) factor VIII (FVIII) deficiency undergoing ITI including time interval from inhibitor detection to ITI start, inhibitor titer and outcome. High-dose ITI was practiced by both centers (i.e. ≥100 IU/kg/day). Success, partial success and failure were defined practically with success as a negative inhibitor titer and ability to use FVIII concentrate routinely for treatment and prevention of bleeding; partial success was an inhibitor titer <5 BU with ability to use FVIII concentrate to treat bleeding episodes; failure as ongoing ITI >3 years without achieving success/partial success or discontinuation of ITI. IRB approvals were obtained at both centers for this data analysis. Pts were first divided into low responding inhibitor (LRI) and high responding inhibitor (HRI) based on peak inhibitor titer; the HRI subgroup was further subdivided based on time to start ITI, including within 1 month, 1-6 months and greater than 6 months. The HRI subgroup starting ITI within 1 month was analyzed based on pre-ITI inhibitor titer. Results Fifty eight male pts with adequate ITI history documentation were included; 55 (95%) were severe (<1%), 3 moderately deficient (1-3%). Forty-seven pts (48%) were Caucasian, 6 Hispanic, 2 African American, 2 Asian and 1 Native American. Outcome is summarized in Table 1. Overall, 49 of 58 pts (84%) underwent successful ITI. Low responding Inhibitors: Among 19 (33%) pts with LRI, ITI success was 100%. Most pts with LRI 15/19 (79%) started ITI within 1 month from inhibitor detection. High responding inhibitors: Among 39 (67%) pts with HRI, 30/39 (77%) achieved tolerance, 1 achieved partial success and continued ITI, 1 was ongoing, 7 pts failed. The 39 pts with HRI were further subdivided based on time to ITI start. ITI start within 1 month of detection: Twenty three pts started ITI within 1 month from detection; 21 achieved success (91%), 1 partially succeeded and 1 failed. Eight of 10 pts (80%) with a pre-ITI titer <10 BU achieved success, 1 partially succeeded and 1 failed. All 13 pts (100%) starting ITI with pre-ITI inhibitor titer ≥ 10 BU achieved success. ITI start > 6 months: Eleven pts had an interval > 6 months until ITI start; 7 (64%) achieved success and 4 (36%) failed. Conclusions These results suggest that the time interval from inhibitor detection to start of ITI may play a critical role in outcome. A titer ≥10 BU did not influence outcome in pts where ITI was utilized within 1 month, supporting this approach in contrast to the commonly accepted practice of delaying ITI start until a titer <10 BU is achieved. Pts may benefit from prompt ITI regardless of current inhibitor titer and are not subjected to wait periods where bleeding is more likely to occur. Prompt ITI should be considered a viable therapeutic option in newly identified inhibitor pts regardless of current inhibitor titer. Disclosures: Manco-Johnson: Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Eisai: Research Funding. Maahs:Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Shapiro:Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novo Nordisck: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Biogen Idec: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Chugai Pharma: Consultancy; Kedrion Biopharma: Consultancy, Research Funding; Cangene Pharmaceuticals: Research Funding; CSL Behring: Research Funding; Octopharma: Research Funding; PTC Therapeutics: Research Funding; Eli Lilly: Research Funding.
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Park, Ji-Doo, and Il-Kwon Park. "Ecological Study of Pachynematus itoi Okutani (Hymenoptera: Tenthredinidae)." Korean journal of applied entomology 49, no. 1 (2010): 17–22. http://dx.doi.org/10.5656/ksae.2010.49.1.017.
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Abraham, Aby, Shashikant Apte, Chandrakala Shamukhaiah, et al. "Outcome of Immune Tolerance Induction Using an Extended Half-Life Clotting Factor Concentrate — Recombinant Factor VIII Fc (Eloctate™) — a Report from India." Blood 132, Supplement 1 (2018): 2494. http://dx.doi.org/10.1182/blood-2018-99-119279.
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Abstract The development of inhibitors is the most serious adverse effect of replacement theray with clotting factor concentrates (CFC) in hemophilia. Its eradication is also difficult, usually requiring months of frequent exposure to high doses of the CFC - immune tolerance induction (ITI). There is limited data on use of extended half-life (EHL) CFC for ITI. A limited program of ITI was made possible in India with some of the rFVIIIFc (Eloctate™) provided through the humanitarian aid program of the World Federation of Hemophilia. This report summarizes the interim outcome of ITI in these patients treated at three centers participating in this program. ITI with rFVIIIFc was offered to patients with hemophilia A and significant inhibitors. The CFC dose used ranged from 50 IU/kg, 3x/week, to 200 IU/kg per day, depending on the weight, convenience and early response as well as availability of rFVIIIFc. All patients completing at least 10 weeks of ITI are included in this analysis. Bethesda assay was done every 2-4 weeks. Successful ITI was defined as a negative Bethesda assay with a FVIII recovery of >60%. Patients received either FEIBA or rVIIa for breakthrough bleeds. Thirty eight patients were included in this analysis. The median age at initiation of ITI was 15 years (range:2 -39). Nine (24%) patients had a family history of inhibitors. The median age at which inhibitors developed was 11 years (range:0.6 -38). Nine (24%) patients had history of surgery prior to onset of inhibitor. Ten patients (26%) had exposure to only plasma derived factors. All patients were on episodic CFC replacement therapy except two (5%) who were receiving low-dose prophylaxis prior to inhibitor development. The median exposures to FVIII was 20 (range:2-80) and duration of inhibitors prior to ITI was 2 years (range:0.1 - 20). The median highest inhibitor titre recorded prior to ITI was 19 BU (range:4-1177). Only 3 patients had their maximum inhibitor titer below 5BU. The median inhibitor titre at the time of starting ITI was 10.4 BU (range: 0.6-1177). The median peak inhibitor titer after starting ITI was 40.4 BU (range:3.5-13933). Out of the 38, 17 (45%) patients achieved a negative inhibitor status after ITI for a median duration of 23 weeks (range: 10-64). Among the 17 patients who had successful ITI, the median duration of ITI required to achieve negative inhibitor status was 20 weeks (range:10-60). Among the other 21 patients who had persistence of inhibitors, 4 were included in other clinical trials, 3 discontinued due to personal reasons while the other 14 are continuing ITI based on availability of appropriate EHL CFC. Among these patients with persistence of inhibitors, the last inhibitor titer was 6.4 BU (range:0.9-9240) after a median of 26 weeks of ITI (range:11-64). The median number of breakthrough bleeds during ITI was 1 (range:0-12), being 1 (range:0-6) among responders and 1 (range:0-12) among those with persistence of inhibitors. A comparison of the group which responded within this duration of ITI and those who did not respond is shown in the table. Older age and the peak inhibitor titer prior to ITI were the two significant variables which affected early outcome of ITI. These data show that EHL rFVIIIFc can be effective in ITI with nearly 45% of patients achieving a negative inhibitor titer within 1 year and with responses starting as early as 1 month and nearly half of them within 4 months. There was also a relatively low median annualized bleed rate during ITI. More patients need to be treated with different doses of rFVIIIFc to assess its potential in ITI and to determine the optimal protocols but the initial data is promising. Disclosures No relevant conflicts of interest to declare.
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Sakurai, Yoshihiko, Takaji Matsutani, Takeshi Yoshioka, Tomohiro Takeda, Akira Yoshioka та Midori Shima. "Alterations of T cell receptor Vβ repertoire of CD8 T lymphocytes in immune tolerance induction in two hemophilia A patients with inhibitors". Vojnosanitetski pregled 68, № 12 (2011): 1047–50. http://dx.doi.org/10.2298/vsp1112047s.
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Background/Aim. Hemophilia A patients with inhibitors are treated effectively with immune tolerance induction (ITI) therapy. Although anti-idiotypic antibodies may play a certain role in the underlying mechanism, the detailed mechanism by which ITI produces a curative effect remains unknown. The aim of this study was to clarify the immunological aspect of ITI. Methods. Longitudinal T-cell receptor (TCR) analysis was performed during ITI. TCR variable region ?-chain and ?-chain repertoires were serially analyzed for peripheral blood mononuclear cells (PBMCs), CD4 T cells, and CD8 T cells from 2 hemophilia inhibitor patients treated with ITI (Patients 1 and 2). Furthermore, to see whether skewing observed in TCR analysis resulted from clonality alterations, T-cell clonality was investigated using complementarity-determining region 3 (CDR3) size spectratyping. Results. In the patient 1, inhibitor titer remained to be 19.6 BU/mL for 596 days after ITI commencement, and ITI was unsuccessful. In the patient 2, inhibitor titer disappeared 434 days after ITI commencement, and ITI was successful. In both cases, skewing of TCR variable region ?/?-chain repertoires was observed in CD8 T cell subset, whereas not in CD4 T cell subset. Conclusion. Alteration of TCR repertoires, especially TCR variable region ?-chain repertoire of CD8 T cells, was distinct between successful and unsuccessful cases, suggesting that immunological response in the early phase affected the ITI outcomes.
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Zozulya, N. I., V. V. Vdovin, P. V. Svirin, et al. "Results of a prospective observation on the use of a coagulation factor concentrate VIII concentrate (Octanate®) for the induction of immunological tolerance in patients with an inhibitory form of hemophilia A." Russian Journal of Pediatric Hematology and Oncology 7, no. 2 (2020): 54–63. http://dx.doi.org/10.21682/2311-1267-2020-7-2-54-63.
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Relevance. Immune tolerance induction (ITI) is the only approach proven to eradicate inhibitors in hemophilia A patients. ITI with Octanate® (human VWF-stabilized FVIII) has been shown to be effective at eradicating inhibitors, even in poor-prognosis patients. Here we report interim data from two observational, prospective studies on the use of Octanate® for ITI in patients in Russia.Purposes of research. The primary objective was to assess the efficacy of ITI. Secondary objectives included assessment of time to ITI success and inhibitor eradication.Patients and methods. Patients of any age with any severity of hemophilia A and a FVIII inhibitor 0.6 BU/mL were eligible. The ITI regimen was at the discretion of the treating physician.Results. The analysis included 73 patients. ITI outcomes were assessed in 63 patients who had completed the study, of whom 56 (89 %) had 1 poor prognostic factors. Inhibitor eradication was achieved by 77.1 % (37/48) of primary ITI patients and 71.4 % (45/63) of all patients, in a median of 2.4 months (range – 0.0–27.4) for both groups. Complete success was achieved by 72.9 % (35/48) of primary ITI patients in a median of 8.9 months (range – 2.4–28.0) and 66.7 % (42/63) of all patients in a median of 10.5 months (range – 2.4–28.0). No relapses were reported after complete or partial ITI success. Of the patients with 1 poor prognostic factors, 67.9 % achieved inhibitor eradication and 62.5 % complete success.Conclusions. ITI with Octanate® in a real-world setting showed rapid and sustained success, even in patients with poor prognostic factors.
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Bhatnagar, Neha, Kate Khair, Ri Liesner, Alice Wilkinson, and Larisa Belyanskaya. "Immune Tolerance Induction with Simoctocog Alfa (Nuwiq®) in Six Patients with Severe Haemophilia a and FVIII Inhibitors." Blood 132, Supplement 1 (2018): 5037. http://dx.doi.org/10.1182/blood-2018-99-118041.
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Abstract Introduction and Objective: Inhibitors to coagulation factor VIII (FVIII) are the most serious complication of haemophilia A treatment. Previously untreated patients (PUPs) are at the greatest risk of inhibitors, which generally occur within the first 20 exposure days (ED) to FVIII. Immune tolerance induction (ITI) is the only clinically proven strategy for eradication of inhibitors. We present a case series of six PUPs with severe haemophilia A and inhibitors who underwent ITI with simoctocog alfa (Nuwiq®), a 4th generation human cell-line-derived recombinant FVIII approved for treatment of haemophilia A. Materials and Methods: Six male PUPs with severe haemophilia A who developed FVIII inhibitors after treatment with simoctocog alfa were started on ITI with simoctocog alfa. Primarily, we assessed the success of simoctocog alfa in patients with inhibitors. Success of ITI was determined based on undetectable inhibitor titre (< 0.6 BU/ml), FVIII recovery ≥ 66% and half-life ≥ 6 hours. Secondary objectives were to assess bleeding rate, tolerability and safety in patients with inhibitors treated with simoctocog alfa ITI. Results: The age of the patients at the start of ITI ranged from 8 to 186 months. Four of the patients were Caucasian, and two were African. All patients had a F8 mutation associated with high risk of ITI failure and two patients had an additional risk factor for ITI failure. The number of EDs prior to inhibitor development ranged from 9 to 33, and the peak inhibitor titre ranged from 0.9 to 114 BU. For ITI, five patients were treated with 100 IU/kg simoctocog alfa daily, and one with 90 IU/kg every other day. One patient achieved complete tolerisation and is now on prophylaxis at normal doses, having achieved an undetectable inhibitor titre after 9 months. This was despite an inhibitor titre ≥ 10 BU/mL at ITI start, which is considered a poor prognosis factor for ITI success. Three other patients achieved an undetectable inhibitor titre after 1, 6 and 18 months of ITI, and FVIII recovery has normalised but half-life remains short and they are on weaning doses as the half-life extends. One patient discontinued ITI with simoctocog alfa after 15 months due to an increasing inhibitor level. This patient was 15 years old at ITI start, and older age is associated with poor ITI outcome. Additionally, his haemophilia A was untreated for 15 years, during which time he developed severe arthropathy. One patient, who started ITI 3 months ago, has an ongoing inhibitor titre and continues on ITI with simoctocog alfa. Conclusions: In a case series of six patients treated with simoctocog alfa for ITI, who all had poor prognosis factors for ITI success, four patients (67%) to date have achieved an undetectable inhibitor titre. These data suggest that ITI with simoctocog alfa may be an effective treatment approach in haemophilia A patients with inhibitors. Disclosures Khair: Shire, SOBI, Pfizer, Roche, Novo Nordisk, Octapharma: Speakers Bureau; shire, SOBI, Pfizer, Roche: Research Funding. Liesner:Roche: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Sobi: Speakers Bureau. Belyanskaya:Octapharma AG: Employment.
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Spotts, Gerald, Brigitt E. Abbuehl, Huong D. Luu, et al. "Safety and Efficacy Profile of rAHF-PFM for Immune Tolerance Induction as Assessed In 3 Clinical Trials (PUP ITI, PRE-PAIR, and PAIR)." Blood 116, no. 21 (2010): 3670. http://dx.doi.org/10.1182/blood.v116.21.3670.3670.
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Abstract Abstract 3670 Introduction: Development of neutralizing antibodies to FVIII is the most serious complication in the management of hemophilia A today. Eradication of the inhibitor with ITI therapy is a common treatment practice however, there are few reports of controlled studies, and much of the current ITI experience is reported from international registries and small site-based case studies. A previous case-series demonstrated successful tolerance in 9/12 (75%) patients using ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method] (rAHF-PFM). Data on the safety and efficacy of rAHF-PFM in ITI therapy have now been formally captured in the recently completed Previously Untreated Patient (PUP-ITI) study, a retrospective chart review (PRE-PAIR), and an ongoing Prospective ADVATE ITI Registry (PAIR). Objectives: To provide a critical assessment of the safety and efficacy of rAHF-PFM in ITI therapy through a review of the cumulative data from PUP-ITI, PRE-PAIR, and PAIR. Methods: PUP study was a prospective, multicenter, open-label, clinical study in PUPs <6 years of age with severe or moderately severe hemophilia (FVIII level ≤2%) who underwent on-demand or prophylactic treatment with rAHF-PFM. Subjects who developed inhibitors against rAHF-PFM could enter the PUP-ITI study and receive ITI. PRE-PAIR was a multicenter, retrospective, chart review of PTPs of any age and any severity of hemophilia A with history of ITI with rAHF-PFM. PAIR is an ongoing non-interventional safety surveillance registry of subjects prescribed rAHF-PFM for ITI. In all three studies, the choice of ITI regimen was at the discretion of the investigator; however, for the PUP-ITI study, the ITI regimen was based on site-specific ITI data and/or institutional guidelines, or as described in peer reviewed literature. The primary endpoints for PUP-ITI and PRE-PAIR were the success rate of ITI. The PAIR report was an interim safety assessment that did not examine efficacy endpoints. For PUP-ITI and PRE-PAIR, the definitions of success required the subject to have achieved 2 consecutive negative inhibitor test results and if data available, demonstrated normalized FVIII recovery. For PRE-PAIR, partial success was defined as achieving negative titer but without normalized recovery. Results: In PUP-ITI, a total of 11 subjects initiated ITI; 3 withdrew and 8 completed ITI. In PRE-PAIR, 35 subjects were enrolled, 30 of which were evaluable per protocol. Of these 30 subjects, 20 had moderately severe to severe hemophilia A (FVIII ≤2%), and high-titer (>5 BU) inhibitor. As of Sept 4, 2010, 18 subjects had been enrolled in PAIR and were included in an interim safety assessment. Over all 3 studies, most commonly prescribed initial dose regimen in subjects with high inhibitor titer prior to initiation of ITI was 100 IU/kg QD (17/37 [46%]), followed by 200 IU/kg QD (11/37 [30%]), and any dose at a frequency of <1/day (9/37 [24%]). In the low titer inhibitor subjects the most commonly prescribed regimen were various doses with a frequency of <1/day (13/22 [59%] subjects). Of the 11 subjects in the PUP study who participated in the PUP-ITI study, 3 withdrew and 8 (72.7%) achieved success (95% CI: 43.4%, 90.3%). All 8 subjects (100%) achieved success, with 1st negative titer at a median time of 1.8 months (0.0 - 4.1 months) and the 2nd negative titer at 3.0 months (1.1 – 9.0 months). In PRE-PAIR, sum of complete and partial success rates gave a total success rate of 76.7% (23/30) in subjects who met inclusion criteria (95% CI: 59.1, 88.2%). During these 3 studies, there were no SAEs related to rAHF-PFM ITI therapy and 6 non-serious AEs in 3 subjects considered to be related to rAHF-PFM (diarrhea, vomiting, pain following bleed, mild urticaria, and mild fever). Conclusions: In 2 clinical studies of rAHF-PFM therapy in ITI treatment, rAHF-PFM was found to be efficacious in a variety of dosing regimens reflective of current standards of practice in hemophilia care. Overall success rates ranged from 72.7% in PUP-ITI to 76.7% in PRE-PAIR. Success rates in these 2 rAHF-PFM studies are similar to those reported in published literature. In all 3 ITI studies, there were no product related SAEs and 6 non-serious AEs in 3 subjects considered to be related to rAHF-PFM, suggesting that rAHF-PFM used for ITI has a similar risk profile established in routine clinical use. These data suggest that ITI treatment with rAHF-PFM was both effective and safe. Disclosures: Spotts: Baxter Bioscience: Employment. Off Label Use: ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method] (rAHF-PFM)use in ITI therapy. Abbuehl:Baxter Bioscience: Employment. Luu:Baxter Bioscience: Employment. Song:Baxter Bioscience: Employment. Dyck-Jones:Baxter Bioscience: Employment. Guzman-Becerra:Baxter Bioscience: Employment. Wu:Baxter Bioscience: Employment. Oh:Baxter Bioscience: Employment. Zoerer:Baxter Bioscience: Employment. Sosa:Baxter Bioscience: Employment. Stephens:Baxter Bioscience: Employment. Yamamoto:Baxter Bioscience: Employment. Ewenstein:Baxter Bioscience: Employment.
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Jensen, Brian J., and Dennis C. Working. "LaRCTM-ITPI/Arylene Ether Copolymers." High Performance Polymers 4, no. 1 (1992): 55–62. http://dx.doi.org/10.1088/0954-0083/4/1/007.
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Hou, T. H., E. J. Siochi, N. J. Johnston, and T. L. St.Clair. "IM7/LARCTM-ITPI polyimide composites." Polymer 35, no. 23 (1994): 4956–69. http://dx.doi.org/10.1016/0032-3861(94)90650-5.
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Li, Zekun, Zhenping Chen, Xiaoling Cheng, et al. "Low-Dose Immune Tolerance Induction for Hemophilia a Children with Poor-Risk High-Titer Inhibitors." Blood 134, Supplement_1 (2019): 1122. http://dx.doi.org/10.1182/blood-2019-132021.
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Background: Low-dose immune tolerance induction (ITI) +/- immunosuppression as a practical ITI strategy in China showed a relatively satisfactory success rate and economic advantages in pilot study. However, the outcome still needs to be verified by larger cohort. Aim: To report the efficacy of this low-dose ITI +/- immunosuppression strategy in hemophilia A children ≥ 10 BU. Methods: This was a single center, prospective study in 53 hemophilia A subjects from Sep 2016 to Apr 2019. All subjects having ≥ 10 BU receiving ~50IU/kg FVIII every other day using domestic intermediate purity pdFVIII/VWF products, either alone or in combination with rituximab and prednisone judging by inhibitors and ITI response. Results: Finally, 46 subjects received this strategy at a median of 3.2 (IQR, 2.3-6.5) years old, their pre-ITI inhibitor titer was median 30.0 (range, 10.1-416) BU. Analysis at median 15.1 (range 3.0-34.4) months follow-up, success (inhibitor <0.6BU) was achieved in 32 (69.6%) subjects, partial success (inhibitor <5BU but >0.6BU) in 11 (23.9%) subjects, and failure in 5 (10.9%) subjects. Between subjects administered ITI-alone and ITI- immunosuppression, no significant difference was observed in time to success (median 8.5; IQR 6.7-11.7 vs 10.2; IQR 5.1-25.1, P=0.164). The mean monthly bleeding rate on ITI was 0.49 which declined 59.3% compared with pre-ITI period. Subjects administered ITI-immunosuppression (0.54 ± 0.46) was higher than ITI-alone (0.42 ± 0.69) although with no significantly difference (P=0.089). Seven (21.9%) subjects experienced inhibitor recurrence, 4 subjects treated with ITI-alone, 3 with ITI-immunosuppression. Recurrence occurred at a median of 4.8 (range, 2.8-10.8) months after successful ITI with inhibitor titer transiently rising to median 0.7 (range, 0.7-1.5) BU. Conclusion: This low-dose ITI +/- immunosuppression therapy in subjects with pre-ITI inhibitor ≥ 10 BU showed a success rate similar to other high/intermediate-dose regimen for the whole inhibitor patients. The subjects treated with ITI-immunosuppression did not showed higher recurrence at present, while a longer time follow-up is still needed. Disclosures Poon: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; World Federation of Hemophilia: Other: Not-for-profit organization affiliation: volunteer ; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation in sponsored research; CSL-Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Noda, Makoto, and Masanoku Kitagawa. "A quantitative study of iliac bone histopathology on 62 cases with itai-itai disease." Calcified Tissue International 47, no. 2 (1990): 66–74. http://dx.doi.org/10.1007/bf02555989.
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Baba, Hayato, Koichi Tsuneyama, Megumi Yazaki, et al. "The liver in itai-itai disease (chronic cadmium poisoning): pathological features and metallothionein expression." Modern Pathology 26, no. 9 (2013): 1228–34. http://dx.doi.org/10.1038/modpathol.2013.62.
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Nishio, Hisahide, Chiyo Hayashi, Myeong Jin Lee та ін. "Itai-itai disease is not associated with polymorphisms of the estrogen receptor α gene". Archives of Toxicology 73, № 8-9 (1999): 496–98. http://dx.doi.org/10.1007/s002040050642.
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