RESUMEN
We investigated the molecular basis of factor VII (FVII) deficiency in a Japanese patient and identified compound heterozygous mutations. Factor VII activity and antigen levels in the patient were less than 5.0% and 6.5% of controls, respectively. All exons, exon-intron boundaries, and the 5' promoter region of F7 from genomic DNA were amplified using polymerase chain reaction (PCR). Sequencing analysis of PCR fragments revealed that the patient was heterozygous for a known T to C substitution at nucleotide position 38, which resulted in the p.Leu13Pro missense mutation (Factor VII Morioka) in the signal peptide region, and a novel mutation in the 5' promoter region (-58G>C). An electrophoretic mobility shift assay showed that the mutation in the promoter region reduced the binding of hepatocyte nuclear factor (HNF). It is presumed that the reduced binding of HNF-4 to the F7 promoter region reduces F7 transcription and thus reduces the synthesis and expression of FVII.
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Deficiencia del Factor VII , Humanos , Deficiencia del Factor VII/genética , Factor VII/genética , Factor VII/metabolismo , Mutación , Heterocigoto , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: The single-limb stance with closed eyes has been widely used to evaluate chronic ankle instability as static balance; however, there was lack of consideration of whether difference in age, frequency of previous ankle sprain or physical ability influenced single-limb stance. RESEARCH QUESTION: We hypothesized that the single-limb stance might not reflect subjective ankle instability and function on physical activity in people who perform sports activities. METHODS: In total, 102 high school basketball players were recruited to evaluate their physical performance at the beginning of the season. Participants were divided into five groups based on the frequency of previous ankle sprain. Karlsson ankle function score (K score) was considered as a subjective ankle function score, that was divided into various components. Each component and the single-limb stance test with center of pressure (COP) analysis was observed between the frequency of ankle sprains with one-way ANOVA and compared using Spearman's rank correlation coefficient to verify the relationship between the K score and COP. RESULTS: For COP parameters, no difference was observed in the history of ankle sprains. The K score was lower in participants with three previous ankle sprains than in those with a different number of ankle sprains for instability, stiffness, running, work activities, support, and total K score for all parameters. There were weak negative correlations (r = -0.19â¼-0.35) between K score and COP parameters among participants with no history of ankle sprain or only once. In contrast, there were strong positive correlations (r = 0.69â¼0.87) among history of ankle sprain at third. SIGNIFICANCE: The single-limb stance might not accurately reflect an athlete's ankle instability and function on physical activity. Clinically, therapists should choose suitable evaluation tools depending on the athlete's activity level to check for chronic ankle instability.
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Traumatismos del Tobillo/fisiopatología , Articulación del Tobillo/fisiopatología , Traumatismos en Atletas/fisiopatología , Inestabilidad de la Articulación/diagnóstico , Equilibrio Postural/fisiología , Adolescente , Traumatismos del Tobillo/complicaciones , Atletas , Traumatismos en Atletas/diagnóstico , Baloncesto/lesiones , Baloncesto/fisiología , Enfermedad Crónica , Estudios Transversales , Humanos , Inestabilidad de la Articulación/etiología , Adulto JovenRESUMEN
A 72-year-old Japanese male was diagnosed as having monoclonal gammopathy of undetermined significance and was followed up without therapy. Three years later, the patient progressed to symptomatic multiple myeloma. Melphalan + prednisolone was administered as first-line chemotherapy for ~6 years. Since the patient was judged to exhibit refractory multiple myeloma, he subsequently received radiation therapy on the lumbar spine. The patient was enrolled in a clinical trial and received lenalidomide + lowdose dexamethasone (Rd) therapy. The patient achieved very good partial remission following four cycles of Rd. At this time, large granular lymphocytes (LGLs) increased to 25-40% of peripheral blood leukocytes, however, the LGLs were present in the blood (~8%) prior to lenalidomide treatment. By flow cytometry of surface antigens, it was revealed that the LGLs were positive for cluster of differnetiation (CD)2, 7, 8, 16, 56, and 57, and human leukocyte antigen-D related, however, were negative for CD3, 4 and 5, suggesting that these LGLs predominantly exhibited an natural killer (NK) cell phenotype. T-cell receptor ß gene rearrangement was not detected by polymerase chain reaction. A 51Cr release assay was performed to investigate whether the NK cells actually possessed activity. A low level of M protein was sustained for ~15 months. This implied the enhancement of immune activation during lenalidomide treatment. The present case study suggested that LGL cells induced by lenalidomide may contribute to long-term restraint of myeloma cells. This immune system component may contribute to disease control.
RESUMEN
STUDY DESIGN: Retrospective comparative cohort study. OBJECTIVE: To elucidate the characteristics of low back pain (LBP) in adolescent patients with early-stage spondylolysis (ESS). SUMMARY OF BACKGROUND DATA: ESS is a common cause of acute LBP in adolescents. When treating patients with ESS, early diagnosis is important; however, early diagnosis is difficult without magnetic resonance imaging. METHODS: Adolescent patients (n = 77) with acute LBP showing no pathological findings on plain radiography were included (<1 m after onset). Patients were divided into ESS and nonspecific LBP (NS-LBP) groups by conducting magnetic resonance imaging; patients showing no pathological findings that explain the cause of LBP were classified as NS-LBP. LBP was evaluated using a traditional visual analogue scale (VAS; 0-10 cm), Oswestry Disability Index, and a detailed VAS scoring system in which pain is independently evaluated in 3 different postural situations (in motion, standing, and sitting); the values were compared between the 2 groups. RESULTS: Of 77 patients, 41 (mean age: 14.6 yr; 33 adolescent boys/8 adolescent girls) had ESS and 36 (mean age: 14.3 yr; 20 adolescent boys/16 adolescent girls) were considered to have NS-LBP. Respective traditional VAS and Oswestry Disability Index scores were 4.9, 16.1 in the ESS group, and 6.2, 26.3 in the NS-LBP group. Both scores were significantly higher in the NS-LBP group. The results of the detailed VAS revealed that the ESS group showed significantly greater pain intensity while in motion than while standing or sitting (4.2, 2.0, and 2.0, respectively), whereas the NS-LBP group showed similar pain intensities in all 3 postural situations (5.3, 4.0, and 4.9, respectively). CONCLUSION: This study revealed that LBP characteristics may provide important information for distinguishing ESS from other low back disorders. Because early diagnosis is essential for the treatment of ESS, MRI examination is recommended for patients showing severe pain in motion, but less pain when standing or sitting.
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Dolor de la Región Lumbar/etiología , Dimensión del Dolor/métodos , Espondilólisis/complicaciones , Espondilólisis/diagnóstico , Escala Visual Analógica , Dolor Agudo , Adolescente , Niño , Evaluación de la Discapacidad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Movimiento , Postura , Estudios RetrospectivosRESUMEN
Thrombotic complications are a major cause of death in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), which are closely associated with the JAK2 V617F activating mutation. However, whether the presence of the JAK2 V617F mutation affects thrombotic risk is currently unknown, although some reports have suggested a variable association with thrombosis. Therefore, we investigated the association between JAK2 V617F and various complications, including thrombosis, in Japanese patients with MPNs. We assessed the JAK2 V617F status in 140 patients who were diagnosed or doubted as having some type of MPN by utilizing a JAK2 V617F-specific guanine-quenching probe. JAK2 V617F was detected in 31 of 51 patients (60.8%) with essential thrombocythemia, all 16 patients (100%) with polycythemia vera, 4 of 11 patients (36.4%) with primary myelofibrosis, 2 of 18 patients (11.1%) with other types of MPNs, and none of the 44 patients with doubted MPN. In the 78 patients with classical MPN, JAK2 V617F correlated with a leukocyte count ≥10,000/µl (p=0.046). Complications of thrombosis, hemorrhage, and leukemic transformation occurred in 21 (41.2%), 4 (25.0%), and 3 (27.3%) patients with classical MPN, respectively, and thrombotic events (TE) occurred more frequently in patients with JAK2 V617F than without (p=0.047). Based on these findings, initial screening for the JAK2 mutation and careful monitoring for thrombotic events should be performed in patients with MPN.
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Janus Quinasa 2/genética , Mutación , Trastornos Mieloproliferativos/genética , Tromboembolia/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Incidencia , Japón/epidemiología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/sangre , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/enzimología , Trastornos Mieloproliferativos/epidemiología , Policitemia Vera/enzimología , Policitemia Vera/genética , Valor Predictivo de las Pruebas , Mielofibrosis Primaria/enzimología , Mielofibrosis Primaria/genética , Estudios Retrospectivos , Factores de Riesgo , Trombocitemia Esencial/enzimología , Trombocitemia Esencial/genética , Tromboembolia/sangre , Tromboembolia/enzimología , Tromboembolia/epidemiología , Adulto JovenRESUMEN
The 8p11 myeloproliferative syndrome is a rare neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 (FGFR1) gene located at chromosome 8p11-12. FGFR1 encodes a transmembrane receptor tyrosine kinase. The resultant fusion proteins are constitutively active tyrosine kinases that drive the proliferation of hematopoietic cells, whose uncontrolled growth can present as a myeloproliferative neoplasm. We report here the case of a 50-year-old man harboring the t(8;22)(p12;q11) chromosomal translocation in cells from both bone marrow and lymph nodes. He presented with acute leukemia and lymphoma with trilineage features. A novel mRNA in-frame fusion between exon 4 of the breakpoint cluster region (BCR) gene at chromosome 22q11 and exon 9 of FGFR1 gene on chromosome 8p11-12 was identified by reverse transcription polymerase chain reaction analysis and was confirmed by DNA sequencing. Because the patient was refractory to chemotherapy, cord blood transplantation was performed in progressive disease. It resulted in a successful outcome in which cytogenetic complete remission has been maintained for 2 years till date.
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Sangre Fetal/trasplante , Trastornos Mieloproliferativos/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Proteínas Proto-Oncogénicas c-bcr/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Humanos , Masculino , Persona de Mediana Edad , Translocación GenéticaRESUMEN
The small cell variant of anaplastic large cell lymphoma (ALCL) presents in a nearly identical manner to the more common ALK(+) primary ALCL, with the exception that it is more frequently associated with leukemic involvement, and the prognosis has been reported to be poor. We report a 40-year-old Japanese male who was diagnosed with small cell variant ALCL with peripheral blood involvement stage IVB, age-adjusted international prognostic index 3. Conventional cytogenetics of the bone marrow aspirate specimen showed abnormal metaphases with the following karyotype: 47, XY, +X, t(2;5)(p23;q35). The patient was treated with acute lymphoblastic leukemia-oriented intensive chemotherapy. He underwent allogeneic peripheral blood stem cell transplantation from his HLA-DR1 locus mismatch sister. Prior to transplant, the patient had residual lymphadenopathy considered to be in partial remission. As of August 2012, the patient has achieved 18 months of continuous complete remission (CCR), with a Karnofsky score of 100 %. We have identified a total of seven cases of small cell variant ALCL treated with allogeneic hematopoietic stem cell transplantation (HSCT) in the literature. Of these, no relapse was reported, and four patients were CCR more than 1 year. Allogeneic HSCT appears to represent a promising treatment option for small cell variant ALCL.
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Linfoma no Hodgkin/terapia , Trasplante de Células Madre de Sangre Periférica , Adulto , Médula Ósea/patología , Humanos , Linfocitos/patología , Linfoma no Hodgkin/diagnóstico , Masculino , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Bernard-Soulier syndrome (BSS) is an inherited bleeding disorder caused by a defect in the platelet glycoprotein (GP) Ib/IX complex. The GPIX W127X mutation is the most common genetic defect in Japanese patients with BSS, which is often misdiagnosed as immune thrombocytopenic purpura, presumably due to residual expression of GPIbα. Neither the mechanism by which this mutation leads to a mild bleeding diathesis, nor whether functional GPIbα is expressed on platelet surfaces is known. We investigated GPIbα expression and function in platelets with a GPIX W127X mutation (GPIXW127X). GPIbα complexed with GPIbß by disulfide bonding was expressed on GPIXW127X platelets and stable CHO-K1 cells lacking GPIX but expressing GPIbα and GPIbß. Expression of GPIbα/ß on GPIXW127X platelets was sufficient to support adhesion to immobilized von Willebrand factor and type III collagen and ristocetin-induced platelet agglutination. A residual amount of functional GPIbα/ß heteromer expressed on GPIXW127X platelets partially compensates for the absence of the GPIb/IX complex. This may account for the mild bleeding phenotype of the BSS variant characterized by a non-sense mutation in GPIX.
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Síndrome de Bernard-Soulier/genética , Plaquetas/metabolismo , Codón sin Sentido , Glicoproteínas de Membrana/biosíntesis , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Mutación Puntual , Adulto , Animales , Anticuerpos Monoclonales/inmunología , Síndrome de Bernard-Soulier/diagnóstico , Células CHO , Colágeno Tipo III/metabolismo , Cricetinae , Cistina/química , Errores Diagnósticos , Femenino , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Fenotipo , Adhesividad Plaquetaria , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Complejo GPIb-IX de Glicoproteína Plaquetaria/fisiología , Embarazo , Complicaciones Hematológicas del Embarazo/diagnóstico , Complicaciones Hematológicas del Embarazo/genética , Púrpura Trombocitopénica Idiopática/diagnóstico , Proteínas Recombinantes de Fusión/fisiología , Ristocetina/farmacología , Transfección , Factor de von Willebrand/metabolismoRESUMEN
We report the results of unrelated cord blood transplantation (UCBT) for patients with adult T-cell leukemia/lymphoma (ATLL) conducted in our single institute. Ten patients with ATLL (nine acute and one lymphoma-type) received UCBT during the period from August 2003 to July 2011. The median age at the time of diagnosis of ATLL was 51 years (range 37-64). The median period from diagnosis of ATLL to UCBT was 130 days (range 94-344). Conditioning regimens were myeloablative for six and reduced intensity for four. The median number of infused nucleated cells and CD34 positive cells were 2.52 × 10(7)/kg and 1.04 × 10(5)/kg, respectively. There was no engraftment failure. Three patients developed grade II acute graft versus host disease, and four developed grade III. The estimated 2-year overall survival was 40 % (95 % CI 12-67 %). Four of six chemosensitive patients prior to UCBT survived for 1035, 793, 712, and 531 days post-UCBT, respectively. There were no survivors among the four chemorefractory patients prior to UCBT. Our data indicates that UCBT is feasible and provides long-term survival in patients with chemosensitive ATLL.
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Trasplante de Células Madre de Sangre del Cordón Umbilical , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/terapia , Donante no Emparentado , Enfermedad Aguda , Adulto , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/terapia , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
To investigate the association between hepatitis C virus (HCV) and B cell proliferation, we searched for the clonal B cells by flow cytometric analysis of the surface immunoglobulin kappa (kappa):lambda (lambda) light chain ratios of the circulating B (CD19+) cells in 240 HCV-positive patients and 150 negative controls with liver diseases. Clonal B cells with light chain restriction (kappa:lambda ratio >3:1 or <1:2) were analyzed for CD5 expression and the presence of monoclonal immunoglobulin heavy-chain (IGH) gene rearrangements and the t(14;18) chromosomal translocation. Clonal B cells were detected in 7 cases with HCV (2.9%), but was never detected in the controls (p < 0.05). Of the 7 cases, all had monoclonal IGH gene rearrangements and one had the t(14;18) chromosomal translocation. These HCV-related clonal B cells are not uniform in the intensity of CD5 expression and showed no increase in the frequencies of CD5+ population compared with non-clonal B cells. No "chronic lymphocytic leukemia-phenotype" cells were found. The loss of clonality was observed in 2 cases treated with interferon and in one case treated with splenectomy. The longitudinal study is required to determine whether these circulating clonal B cells progress to lymphoproliferative disorders in future or not.
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Linfocitos B/inmunología , Hepatitis C/sangre , Hepatitis C/inmunología , Anciano , Anciano de 80 o más Años , Antígenos CD20/inmunología , Linfocitos B/citología , Linfocitos B/metabolismo , Antígenos CD5/inmunología , Estudios de Casos y Controles , Movimiento Celular , Femenino , Regulación de la Expresión Génica , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Masculino , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , EsplenectomíaRESUMEN
Periostin is a secreted protein that shares structural homology with the insect axon guidance protein fasciclin 1. Periostin is expressed predominantly in collagen-rich fibrous connective tissues that are subjected to constant mechanical stresses. We have shown previously that periostin is a novel component of subepithelial fibrosis in bronchial asthma. Here, we investigated the relationship between periostin and bone marrow (BM) fibrosis. Periostin was expressed in the stroma and stromal cells of BM fibrosis specimens and to a great extent its expression levels correlated closely to the grade of fibrosis, as estimated by silver staining. However, in the present study, we found no relationship between plasma periostin levels and the extent of BM fibrosis. We also demonstrated that periostin is secreted by human BM hTERT stromal cells and that its secretion is enhanced by TGF-beta, a cytokine produced by clonal proliferation of megakaryocytes and/or monocytes. These results indicate that periostin is a component of BM fibrosis and that it may play a role in the disease progression.
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Médula Ósea/metabolismo , Moléculas de Adhesión Celular/biosíntesis , Mielofibrosis Primaria/metabolismo , Anciano , Médula Ósea/patología , Proliferación Celular , Femenino , Humanos , Masculino , Megacariocitos/metabolismo , Megacariocitos/patología , Persona de Mediana Edad , Monocitos/metabolismo , Monocitos/patología , Mielofibrosis Primaria/patología , Células del Estroma/metabolismo , Células del Estroma/patología , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
An untreated 66-year-old woman with chronic myelogenous leukaemia (CML) in the chronic phase was initially given imatinib mesylate, rapidly achieving a good cytogenetic response with treatment. However, acute promyelocytic leukaemia complicated by a disseminated intravascular coagulation occurred 9 months after beginning imatinib treatment. Promyelocytic crisis of CML was diagnosed by demonstration of both BCR/ABL and PML/RAR alpha chimeric genes in leukaemic cells by karyotypic and fluorescence in situ hybridization analysis. Clonal evolution with addition of the PML/RAR alpha translocation may have arisen in the early chronic phase of CML, with expansion of this clone during imatinib treatment. Promyelocytic crisis of CML is rare; furthermore, we know of no previous report of promyelocytic crisis occurring during treatment with imatinib.