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1.
Rinsho Ketsueki ; 65(3): 142-146, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38569856

RESUMO

A 27-year-old woman was diagnosed with idiopathic thrombocytopenic purpura in the neonatal period, and was admitted to our hospital after presenting with impaired consciousness, purpura, nausea and vomiting, with a platelet count of 10×109/l. Congenital thrombotic thrombocytopenic purpura (cTTP) was suspected on the basis of recurrent thrombocytopenia and impaired consciousness, so tests for ADAMTS13 activity and inhibitor were performed. ADAMTS13 activity was severely decreased, ADAMTS13 inhibitor was negative, and platelet count increased after transfusion of fresh frozen plasma. These findings and the results of genetic testing done on all family members led to a diagnosis of cTTP. cTTP requires differential diagnosis even in adults. If a patient diagnosed with ITP in childhood has a history or findings that suggest cTTP during follow-up observation, it is necessary to actively consider ADAMTS13 testing.


Assuntos
Púrpura Trombocitopênica Idiopática , Púrpura Trombocitopênica Trombótica , Adulto , Recém-Nascido , Feminino , Humanos , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/terapia , Contagem de Plaquetas , Plasma , Transfusão de Sangue , Proteína ADAMTS13/genética
2.
Immunity ; 38(6): 1105-15, 2013 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-23791645

RESUMO

How hematopoietic stem cells (HSCs) produce particular lineages is insufficiently understood. We searched for key factors that direct HSC to lymphopoiesis. Comparing gene expression profiles for HSCs and early lymphoid progenitors revealed that Satb1, a global chromatin regulator, was markedly induced with lymphoid lineage specification. HSCs from Satb1-deficient mice were defective in lymphopoietic activity in culture and failed to reconstitute T lymphopoiesis in wild-type recipients. Furthermore, Satb1 transduction of HSCs and embryonic stem cells robustly promoted their differentiation toward lymphocytes. Whereas genes that encode Ikaros, E2A, and Notch1 were unaffected, many genes involved in lineage decisions were regulated by Satb1. Satb1 expression was reduced in aged HSCs with compromised lymphopoietic potential, but forced Satb1 expression partly restored that potential. Thus, Satb1 governs the initiating process central to the replenishing of lymphoid lineages. Such activity in lymphoid cell generation may be of clinical importance and useful to overcome immunosenescence.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Linfopoese , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Linfócitos T/fisiologia , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Sobrevivência Celular/genética , Células Cultivadas , Senescência Celular/genética , Montagem e Desmontagem da Cromatina/genética , Regulação da Expressão Gênica , Humanos , Linfopoese/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transgenes/genética
3.
Br J Haematol ; 194(2): 444-452, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34046888

RESUMO

Congenital thrombotic thrombocytopenic purpura (cTTP), known as Upshaw-Schulman syndrome, is an ultrarare thrombotic disorder caused by ADAMTS13 gene mutations; however, its long-term outcomes have not been widely studied. A questionnaire survey was administered to physicians of patients in the Japanese cTTP registry to characterise these outcomes. We analysed 55 patients in remission, with 41 cases receiving prophylactic fresh frozen plasma (FFP; median dosage: 13·2 ml/kg per month) and 14 receiving on-demand FFP. Patients receiving prophylactic FFP were considered as having a more severe form of the disease and had lower platelet counts and higher serum creatinine levels than those receiving on-demand FFP (median 138 × 109 /l vs. 243 × 109 /l, P = 0·003 and 0·71 mg/dl vs 0·58 mg/dl, P = 0·009, respectively). Patients who received prophylactic FFP more commonly developed organ damage, including renal impairment, cerebral infarctions, and cardiac hypofunction, than those who did not. Adverse FFP-related events were seen in 78% of the prophylactic FFP group, with allergic reactions being most common. Since current protocols for FFP administration to the prophylactic FFP group in Japan may be insufficient for preventing cumulative organ damage, a higher dosage of ADAMTS13 supply using recombinant ADAMTS13 agent is needed in these patients.


Assuntos
Transfusão de Componentes Sanguíneos , Púrpura Trombocitopênica Trombótica/terapia , Proteína ADAMTS13/genética , Adolescente , Adulto , Transfusão de Componentes Sanguíneos/efeitos adversos , Criança , Estudos de Coortes , Feminino , Humanos , Japão/epidemiologia , Masculino , Mutação , Escores de Disfunção Orgânica , Plasma/química , Púrpura Trombocitopênica Trombótica/epidemiologia , Púrpura Trombocitopênica Trombótica/genética , Adulto Jovem
4.
Mol Cell ; 52(6): 783-93, 2013 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-24239290

RESUMO

Folding-defective proteins must be cleared efficiently from the endoplasmic reticulum (ER) to prevent perturbation of the folding environment and to maintain cellular proteostasis. Misfolded proteins engage dislocation machineries (dislocons) built around E3 ubiquitin ligases that promote their transport across the ER membrane, their polyubiquitylation, and their proteasomal degradation. Here, we report on the intrinsic instability of the HRD1 dislocon and the constitutive, rapid turnover of the scaffold protein HERP. We show that HRD1 dislocon integrity relies on the presence of HRD1 clients that interrupt, in a dose-dependent manner, the UBC6e/RNF5/p97/proteasome-controlled relay that controls HERP turnover. We propose that ER-associated degradation (ERAD) deploys autoadaptive regulatory pathways, collectively defined as ERAD tuning, to rapidly adapt degradation activity to misfolded protein load and to preempt the unfolded protein response (UPR) activation.


Assuntos
Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Resposta a Proteínas não Dobradas , Proteínas Adaptadoras de Transporte Vesicular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteínas/genética , Proteínas/metabolismo , Proteólise , Interferência de RNA , Transdução de Sinais , Fator 2 Associado a Receptor de TNF , Transcrição Gênica , Transfecção , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
5.
Mol Cell ; 47(1): 99-110, 2012 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-22607976

RESUMO

Nascent secretory proteins are extensively scrutinized at the endoplasmic reticulum (ER). Various signatures of client proteins, including exposure of hydrophobic patches or unpaired sulfhydryls, are coordinately utilized to reduce nonnative proteins in the ER. We report here the cryptic N-glycosylation site as a recognition signal for unfolding of a natively nonglycosylated protein, transthyretin (TTR), involved in familial amyloidosis. Folding and ER-associated degradation (ERAD) perturbation analyses revealed that prolonged TTR unfolding induces externalization of cryptic N-glycosylation site and triggers STT3B-dependent posttranslational N-glycosylation. Inhibition of posttranslational N-glycosylation increases detergent-insoluble TTR aggregates and decreases cell proliferation of mutant TTR-expressing cells. Moreover, this modification provides an alternative pathway for degradation, which is EDEM3-mediated N-glycan-dependent ERAD, distinct from the major pathway of Herp-mediated N-glycan-independent ERAD. Hence we postulate that STT3B-dependent posttranslational N-glycosylation is part of a triage-salvage system recognizing cryptic N-glycosylation sites of secretory proteins to preserve protein homeostasis.


Assuntos
Hexosiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Pré-Albumina/metabolismo , Processamento de Proteína Pós-Traducional , Sequência de Aminoácidos , Ácido Azetidinocarboxílico/farmacologia , Proteínas de Ligação ao Cálcio , Retículo Endoplasmático/metabolismo , Glicosilação/efeitos dos fármacos , Células HEK293 , Hexosiltransferases/genética , Humanos , Immunoblotting , Manosidases , Proteínas de Membrana/genética , Modelos Biológicos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Polissacarídeos/metabolismo , Pré-Albumina/química , Pré-Albumina/genética , Estrutura Terciária de Proteína , Desdobramento de Proteína , Interferência de RNA , Via Secretória/efeitos dos fármacos , Homologia de Sequência de Aminoácidos , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , alfa-Manosidase
6.
Int J Mol Sci ; 21(17)2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32858914

RESUMO

Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is a quality control system that induces the degradation of ER terminally misfolded proteins. The ERAD system consists of complexes of multiple ER membrane-associated and luminal proteins that function cooperatively. We aimed to reveal the role of Derlin-3 in the ERAD system using the liver, pancreas, and kidney obtained from different mouse genotypes. We performed coimmunoprecipitation and sucrose density gradient centrifugation to unravel the dynamic nature of ERAD complexes. We observed that Derlin-3 is exclusively expressed in the pancreas, and its deficiency leads to the destabilization of Herp and accumulation of ERAD substrates. Under normal conditions, Complex-1a predominantly contains Herp, Derlin-2, HRD1, and SEL1L, and under ER stress, Complex-1b contains Herp, Derlin-3 (instead of Derlin-2), HRD1, and SEL1L. Complex-2 is upregulated under ER stress and contains Derlin-1, Derlin-2, p97, and VIMP. Derlin-3 deficiency suppresses the transition of Derlin-2 from Complex-1a to Complex-2 under ER stress. In the pancreas, Derlin-3 deficiency blocks Derlin-2 transition. In conclusion, the composition of ERAD complexes is tissue-specific and changes in response to ER stress in a Derlin-3-dependent manner. Derlin-3 may play a key role in changing ERAD complex compositions to overcome ER stress.


Assuntos
Retículo Endoplasmático/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pâncreas/metabolismo , Animais , Estresse do Retículo Endoplasmático , Degradação Associada com o Retículo Endoplasmático , Genótipo , Rim/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Especificidade de Órgãos
7.
Haematologica ; 104(10): 2107-2115, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30792199

RESUMO

Congenital thrombotic thrombocytopenic purpura is an autosomal recessive inherited disease with a clinically heterogeneous course and an incompletely understood genotype-phenotype correlation. In 2006, the Hereditary TTP Registry started recruitment for a study which aimed to improve the understanding of this ultra-rare disease. The objective of this study is to present characteristics of the cohort until the end of 2017 and to explore the relationship between overt disease onset and ADAMTS13 activity with emphasis on the recurring ADAMTS13 c.4143_4144dupA mutation. Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles. By the end of 2017, 123 confirmed patients had been enrolled from Europe (n=55), Asia (n=52, 90% from Japan), the Americas (n=14), and Africa (n=2). First recognized disease manifestation occurred from around birth up to the age of 70 years. Of the 98 different ADAMTS13 mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246 alleles. We found a larger proportion of compound heterozygous than homozygous carriers of ADAMTS13 c.4143_4144dupA with overt disease onset at < 3 months of age (50% vs 37%), despite the fact that ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers. An evaluation of overt disease onset in all patients with an available sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13 activity is not the only determinant of age at first disease manifestation. Registered at clinicaltrials.gov identifier NCT01257269.


Assuntos
Proteína ADAMTS13 , Alelos , Heterozigoto , Homozigoto , Mutação , Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13/sangue , Proteína ADAMTS13/genética , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/genética
9.
J Artif Organs ; 22(4): 334-337, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31338629

RESUMO

Gastrointestinal bleeding (GIB) is among the major complications affecting implantable continuous-flow left ventricular assist device (iLVAD) recipients and is the major cause of re-hospitalization. GIB in iLVAD recipients is sometimes critical, and controlling bleeding using conventional approaches is difficult. A 35-year-old woman developed refractory GIB from multiple gastric polyps and de novo angiodysplasia after Jarvik2000® iLVAD implantation. Discontinuation of anticoagulation and antiplatelet therapies had little effect on GIB; thus, multiple endoscopic hemostatic therapies were performed. However, bleeding recurred several times, and red blood cell (RBC) transfusion in large volumes was required for progressive anemia. Furthermore, the von Willebrand factor (VWF) multimer analysis revealed loss of the high-molecular weight multimer, which may have resulted from the high-speed rotation of the axial-flow LVAD pump. To supplement VWF, cryoprecipitate was administered, but it was effective for only several days. Finally, the patient was treated with octreotide, a somatostatin analog, on post-operative day 58. After starting octreotide, tarry stool gradually decreased, and progression of anemia slowed down within the first 14 days of treatment; thus, the total RBC transfusion volume was reduced without additional hemostatic interventions, including cryoprecipitate administration. The patient developed mediastinitis on post-operative day 68 and died of sepsis on post-operative day 72. There was no adverse effect associated with octreotide use. Although the observation period was short, octreotide appears to be useful for resolving recurrent GIB after iLVAD implantation and reducing blood transfusions.


Assuntos
Hemorragia Gastrointestinal/tratamento farmacológico , Insuficiência Cardíaca/terapia , Coração Auxiliar/efeitos adversos , Octreotida/uso terapêutico , Hemorragia Pós-Operatória/tratamento farmacológico , Adulto , Feminino , Fármacos Gastrointestinais/uso terapêutico , Hemorragia Gastrointestinal/sangue , Humanos , Hemorragia Pós-Operatória/etiologia , Recidiva
10.
Biochim Biophys Acta Mol Basis Dis ; 1864(5 Pt A): 1653-1662, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29486284

RESUMO

Skeletal muscle plays a central role in insulin-controlled glucose homeostasis. The molecular mechanisms related to insulin resistance in this tissue are incompletely understood. Herpud1 is an endoplasmic reticulum membrane protein that maintains intracellular Ca2+ homeostasis under stress conditions. It has recently been reported that Herpud1-knockout mice display intolerance to a glucose load without showing altered insulin secretion. The functions of Herpud1 in skeletal muscle also remain unknown. Based on these findings, we propose that Herpud1 is necessary for insulin-dependent glucose disposal in skeletal muscle. Here we show that Herpud1 silencing decreased insulin-dependent glucose uptake, GLUT4 translocation to the plasma membrane, and Akt Ser473 phosphorylation in cultured L6 myotubes. A decrease in insulin-induced Akt Ser473 phosphorylation was observed in soleus but not in extensor digitorum longus muscle samples from Herpud1-knockout mice. Herpud1 knockdown increased the IP3R-dependent cytosolic Ca2+ response and the activity of Ca2+-dependent serine/threonine phosphatase calcineurin in L6 cells. Calcineurin decreased insulin-dependent Akt phosphorylation and glucose uptake. Moreover, calcineurin inhibition restored the insulin response in Herpud1-depleted L6 cells. Based on these findings, we conclude that Herpud1 is necessary for adequate insulin-induced glucose uptake due to its role in Ca2+/calcineurin regulation in L6 myotubes.


Assuntos
Calcineurina/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Proteínas de Membrana/metabolismo , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Calcineurina/genética , Glucose/genética , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Insulina/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/genética
11.
Arterioscler Thromb Vasc Biol ; 37(7): 1332-1338, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28495930

RESUMO

OBJECTIVE: ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) prevents microvascular thrombosis by cleaving prothrombogenic ultralarge von Willebrand factor (VWF) multimers. Clinical studies have found association between reduced ADAMTS13-specific activity, ultralarge VWF multimers, and thrombotic angiopathy in patients with diabetic nephropathy. It remains unknown, however, whether ADAMTS13 deficiency or ultralarge VWF multimers have a causative effect in diabetic nephropathy. APPROACH AND RESULTS: The extent of renal injury was evaluated in wild-type (WT), Adamts13-/- and Adamts13-/-Vwf-/- mice after 26 weeks of streptozotocin-induced diabetic nephropathy. We found that WT diabetic mice exhibited low plasma ADAMTS13-specific activity and increased VWF levels (P<0.05 versus WT nondiabetic mice). Adamts13-/- diabetic mice exhibited deterioration of kidney function (increased albuminuria, plasma creatinine, and urea; P<0.05 versus WT diabetic mice), independent of hyperglycemia and hypertension. Deterioration of kidney function in Adamts13-/- diabetic mice was concomitant with aggravated intrarenal thrombosis (assessed by plasminogen activator inhibitor, VWF, fibrin(ogen), and CD41-positive microthrombi), increased mesangial cell expansion, and extracellular matrix deposition (P<0.05 versus WT diabetic mice). Genetic deletion of VWF in Adamts13-/- diabetic mice improved kidney function, inhibited intrarenal thrombosis, and alleviated histological changes in glomeruli, suggesting that exacerbation of diabetic nephropathy in the setting of ADAMTS13 deficiency is VWF dependent. CONCLUSIONS: ADAMTS13 retards progression of diabetic nephropathy, most likely by inhibiting VWF-dependent intrarenal thrombosis. Alteration in ADAMTS13-VWF balance may be one of the key pathophysiological mechanisms of thrombotic angiopathy in diabetes mellitus.


Assuntos
Proteína ADAMTS13/metabolismo , Nefropatias Diabéticas/prevenção & controle , Glomérulos Renais/enzimologia , Trombose/prevenção & controle , Proteína ADAMTS13/deficiência , Proteína ADAMTS13/genética , Albuminúria/enzimologia , Albuminúria/prevenção & controle , Animais , Proliferação de Células , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Progressão da Doença , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrinogênio/metabolismo , Predisposição Genética para Doença , Glomérulos Renais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Glicoproteína IIb da Membrana de Plaquetas/metabolismo , Estreptozocina , Trombose/enzimologia , Trombose/genética , Trombose/patologia , Ureia/sangue , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo
12.
Transfus Apher Sci ; 57(6): 790-792, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30471945

RESUMO

Upshaw-Schulman syndrome (USS) is an inherited type of thrombotic thrombocytopenic purpura (TTP) that is extremely rare, but often diagnosed during pregnancy. Reversible cerebral vasoconstriction syndrome (RCVS) is the transient stenosis of several cerebral arteries that is frequently diagnosed post-partum. We describe a 28-year-old woman with USS complicated by RCVS after delivery that was treated by plasma exchange with a good outcome. She was referred to our hospital with thunderclap headache, anemia and thrombocytopenia that occurred immediately postpartum. She was diagnosed with TTP and multiple cerebral infarctions. Plasma exchange promptly improved her symptoms on hospital day 3. Moreover, multiple stenoses of cerebral arteries indicating RCVS were resolved. Since her sister also had an episode of thrombocytopenia during pregnancy, inherited TTP was suspected and genetic analyses confirmed USS. Pregnancy is a risk for not only TTP, but also RCVS. Endothelial damage might be an underlining cause and vasospasm after delivery is a trigger of RCVS. Plasma exchange was effective against both TTP and RCVS.


Assuntos
Cérebro/irrigação sanguínea , Complicações na Gravidez/patologia , Púrpura Trombocitopênica Trombótica/diagnóstico , Vasoconstrição , Proteína ADAMTS13/genética , Adulto , Família , Feminino , Humanos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Mutação/genética , Gravidez , Síndrome
13.
Clin Exp Nephrol ; 22(5): 1088-1099, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29511899

RESUMO

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is caused by complement overactivation, and its presentation and prognosis differ according to the underlying molecular defects. The aim of this study was to characterize the genetic backgrounds of aHUS patients in Japan and to elucidate the associations between their genetic backgrounds, clinical findings, and outcomes. METHODS: We conducted a nationwide epidemiological survey of clinically diagnosed aHUS patients and examined 118 patients enrolled from 1998 to 2016 in Japan. We screened variants of seven genes related to complement and coagulation, as well as positivity for anti-CFH antibodies, and assessed clinical manifestations, laboratory findings, and clinical course. RESULTS: The most frequent genetic abnormalities were in C3 (31%) and the frequency of CFH variants was relatively low (10%) compared to Western countries. The predominant variant in this cohort was C3 p.I1157T (23%), which was related to favorable outcomes despite frequent relapses. A total of 72% of patients received plasma therapy, while 42% were treated with eculizumab. The prognosis of Japanese aHUS patients was relatively favorable, with a total mortality rate of 5.4% and a renal mortality rate of 15%. CONCLUSIONS: The common occurrence of genotype C3, especially the p.I1157T variant was the characteristic of the genetic backgrounds of Japanese aHUS patients that differed from those of Caucasian patients. In addition, the favorable prognosis of patients with the unique C3 p.I1157T variant indicates that understanding the clinical characteristics of individual gene alterations is important for predicting prognosis and determining therapeutic strategies in aHUS.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Patrimônio Genético , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Proteínas do Sistema Complemento , Feminino , Humanos , Lactente , Japão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
14.
Blood ; 126(19): 2247-53, 2015 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-26251307

RESUMO

Protein S (PS) acts as an anticoagulant cofactor for activated protein C in regulation of blood coagulation. The K196E mutation in PS is a race-specific genetic risk factor for venous thromboembolism with a prevalence of ∼2% within the Japanese population. To evaluate the thrombosis risk of the PS-K196E mutation, we generated PS-K196E knockin mice and heterozygous PS-deficient mice. We analyzed their thrombotic states, comparing with mice carrying the factor V Leiden mutation (FV-R504Q), a race-specific genetic risk for venous thrombosis in whites. PS-K196E mice grew normally but had decreased activated protein C cofactor activity in plasma. Purified recombinant murine PS-K196E showed the same decreased activated protein C cofactor activity. A deep vein thrombosis model of electrolytic inferior vena cava injury and pulmonary embolism models induced by infusion of tissue factor or polyphosphates revealed that PS-K196E mice, heterozygous PS-deficient mice, and FV-R504Q mice were much more susceptible to venous thrombosis compared with wild-type mice. Transient middle cerebral artery ischemia-reperfusion injury model studies demonstrated that both PS-K196E mice and heterozygous PS-deficient mice had cerebral infarction similar to wild-type mice, consistent with human observations. Our in vitro and in vivo results support a causal relationship between the PS-K196E mutation and venous thrombosis and indicate that PS-K196E mice can provide an in vivo evaluation system to help uncovering racial differences in thrombotic diseases.


Assuntos
Mutação de Sentido Incorreto , Proteína S , Tromboembolia Venosa , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Fator V/genética , Fator V/metabolismo , Humanos , Camundongos , Camundongos Mutantes , Proteína C/genética , Proteína C/metabolismo , Proteína S/genética , Proteína S/metabolismo , Tromboembolia Venosa/sangue , Tromboembolia Venosa/genética
16.
Rinsho Ketsueki ; 58(8): 933-937, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28883277

RESUMO

Congenital thrombotic thrombocytopenic purpura (TTP) is a rare hereditary deficiency of ADAMTS13 (von Willebrand factor-cleaving protease) characterized by thrombocytopenia and microangiopathic hemolytic anemia. The spectrum of the clinical phenotype is wide, ranging from asymptomatic episodes of thrombocytopenia to life-threatening multiorgan failure. Reportedly, some patients develop isolated thrombocytopenia during childhood. We herein report sibling cases of congenital TTP. An 11-year-old boy with thrombocytopenia accompanied by influenza virus infection was referred to our hospital. He had a history of severe neonatal jaundice. His 15-year-old brother also had recurrent thrombocytopenia with approximately 10 episodes of recurrence since 3 years of age. Their ADAMTS13 activities were low and ADAMTS13 inhibitors were negative, and a gene analysis confirmed the diagnosis of congenital TTP. Notably, congenital TTP should be included in the differential diagnosis, and it is essential to determine the ADAMTS13 activity for pediatric patients with thrombocytopenia of unknown etiology.


Assuntos
Proteína ADAMTS13/genética , Púrpura Trombocitopênica Trombótica/congênito , Púrpura Trombocitopênica Trombótica/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Púrpura Trombocitopênica Trombótica/enzimologia , Irmãos
17.
Artif Organs ; 40(9): 877-83, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26750507

RESUMO

We have developed a rotational speed (RS) modulation system for a continuous-flow left ventricular assist device (EVAHEART) that can change RS in synchronization with a patient's electrocardiogram. Although EVAHEART is considered not to cause significant acquired von Willebrand syndrome, there remains a concern that the repeated acceleration and deceleration of the impeller may degrade von Willebrand factor (vWF) multimers. Accordingly, we evaluated the influence of our RS modulation system on vWF dynamics. A simple mock circulation was used. The circulation was filled with whole bovine blood (650 mL), and the temperature was maintained at 37 ± 1°C. EVAHEART was operated using the electrocardiogram-synchronized RS modulation system with an RS variance of 500 rpm and a pulse frequency of 60 bpm (EVA-RSM; n = 4). The pumps were operated at a mean flow rate of 5.0 ± 0.2 L/min against a mean pressure head of 100 ± 3 mm Hg. The continuous-flow mode of EVAHEART (EVA-C; n = 4) and ROTAFLOW (ROTA; n = 4) was used as controls. Whole blood samples were collected at baseline and every 60 min for 6 h. Complete blood counts (CBCs), normalized indexes of hemolysis (NIH), vWF antigen (vWF:Ag), vWF ristocetin cofactor (vWF:Rco), the ratio of vWF:Rco to vWF:Ag (Rco/Ag), and high molecular weight multimers (HMWM) of vWF were evaluated. There were no significant changes in CBCs throughout the 6-h test period in any group. NIH levels of EVA-RSM, EVA-C, and ROTA were 0.0035 ± 0.0018, 0.0031 ± 0.0007, and 0.0022 ± 0.0011 g/100 L, respectively. Levels of vWF:Ag, vWF:Rco, and Rco/Ag did not change significantly during the test. Immunoblotting analysis of vWF multimers showed slight degradation of HMWM in all groups, but there were no significant differences between groups in the ratios of HMWM to low molecular weight multimers, calculated by densitometry. This study suggests that our RS modulation system used with EVAHEART does not have marked adverse influences on vWF dynamics. The low NIH and the absence of significant decreases in CBCs indicate that EVAHEART is hemocompatible, regardless of whether it is operated with the RS modulation system.


Assuntos
Coração Auxiliar/efeitos adversos , Fator de von Willebrand/análise , Animais , Contagem de Células Sanguíneas , Bovinos , Hemodinâmica , Hemólise , Fator de von Willebrand/metabolismo
19.
Proc Natl Acad Sci U S A ; 108(12): 4864-9, 2011 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-21383147

RESUMO

The circadian clock is phase-delayed or -advanced by light when given at early or late subjective night, respectively. Despite the importance of the time-of-day-dependent phase responses to light, the underlying molecular mechanism is poorly understood. Here, we performed a comprehensive analysis of light-inducible genes in the chicken pineal gland, which consists of light-sensitive clock cells representing a prototype of the clock system. Light stimulated expression of 62 genes and 40 ESTs by >2.5-fold, among which genes responsive to the heat shock and endoplasmic reticulum stress as well as their regulatory transcription factors heat shock factor (HSF)1, HSF2, and X-box-binding protein 1 (XBP1) were strongly activated when a light pulse was given at late subjective night. In contrast, the light pulse at early subjective night caused prominent induction of E4bp4, a key regulator in the phase-delaying mechanism of the pineal clock, along with activation of a large group of cholesterol biosynthetic genes that are targets of sterol regulatory element-binding protein (SREBP) transcription factor. We found that the light pulse stimulated proteolytic formation of active SREBP-1 that, in turn, transactivated E4bp4 expression, linking SREBP with the light-input pathway of the pineal clock. As an output of light activation of cholesterol biosynthetic genes, we found light-stimulated pineal production of a neurosteroid, 7α-hydroxypregnenolone, demonstrating a unique endocrine function of the pineal gland. Intracerebroventricular injection of 7α-hydroxypregnenolone activated locomotor activities of chicks. Our study on the genome-wide gene expression analysis revealed time-of-day-dependent light activation of signaling pathways and provided molecular connection between gene expression and behavior through neurosteroid release from the pineal gland.


Assuntos
Ritmo Circadiano/fisiologia , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica/fisiologia , Proteínas de Choque Térmico/metabolismo , Luz , Transdução de Sinais/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/metabolismo , 17-alfa-Hidroxipregnenolona/análogos & derivados , 17-alfa-Hidroxipregnenolona/farmacologia , Animais , Sequência de Bases , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento Animal/efeitos da radiação , Galinhas , Colesterol/biossíntese , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/efeitos da radiação , Retículo Endoplasmático/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Estudo de Associação Genômica Ampla , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Locomoção/efeitos da radiação , Masculino , Dados de Sequência Molecular , Fatores de Transcrição de Fator Regulador X , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
20.
J Obstet Gynaecol Res ; 40(1): 247-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23937165

RESUMO

Upshaw-Schulman syndrome (USS) involves a congenital deficiency of von Willebrand factor-cleaving metalloprotease (ADAMTS13) activity due to gene mutations. Female patients develop overt thrombotic thrombocytopenic purpura (TTP) caused by a decline of ADAMTS13 activity in pregnancy. A 23-year-old nulliparous Japanese woman died due to severe, rapid progression of TTP with intrauterine fetal death at 20 weeks of gestation after its onset, even though she underwent intensive treatment which included plasma exchange. She had a history of idiopathic thrombocytopenic purpura at the age of 3 years. The patient's ADAMTS13 activity was of very low level. It should be borne in mind that there is the possibility of rapidly progressive fulminant USS during pregnancy.


Assuntos
Morte Fetal/etiologia , Complicações Hematológicas na Gravidez/fisiopatologia , Púrpura Trombocitopênica Trombótica/fisiopatologia , Proteínas ADAM/sangue , Proteínas ADAM/genética , Proteína ADAMTS13 , Adulto , Terapia Combinada , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Mutação , Troca Plasmática , Gravidez , Complicações Hematológicas na Gravidez/sangue , Complicações Hematológicas na Gravidez/genética , Complicações Hematológicas na Gravidez/terapia , Segundo Trimestre da Gravidez , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/terapia , Índice de Gravidade de Doença , Adulto Jovem
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