RESUMEN
BACKGROUND: Systemic sclerosis (SSc) is divided into diffuse and limited cutaneous SSc (dcSSc and lcSSc). The dcSSc subtype has more severe internal organ damage. This study aimed to assess whether cardiovascular magnetic resonance (CMR) parametric mapping could detect early cardiac involvement and evaluate differences between these two subtypes. METHODS: Eighty SSc patients (37 dcSSc and 43 lcSSc) underwent CMR at 3.0â¯T (Philips Healthcare, Best, The Netherlands) in our hospital between July 2018 and July 2021. We analyzed myocardial damage by CMR parametric mapping and compared it with clinical data. RESULTS: The median duration of the disease was 10.2â¯months. The left ventricular ejection fraction was preserved in both groups. DcSSc had significantly higher native T1 (1333.4⯱â¯71.2â¯ms vs. 1295.0⯱â¯42.7â¯ms, pâ¯=â¯0.006) and extracellular volume fraction (32.6⯱â¯4.1â¯% vs. 30.3⯱â¯4.0â¯%, pâ¯=â¯0.018) in the mid-ventricular septum as compared to lcSSc, although there were no differences in T2 values. Native T1 values were positively correlated with the E/e' ratio and left atrial volume indices evaluated by transthoracic echocardiography in overall SSc and dcSSc, but not in lcSSc. Logistic regression analysis revealed that native T1 was an independent predictor of left ventricular diastolic dysfunction in SSc patients (odds ratio, 1.194; 95â¯% confidence interval, 1.021-1.396; pâ¯=â¯0.026). Native T1 was higher in SSc patients with progressive skin lesions. Additionally, there were positive correlations between brain natriuretic peptide, New York Heart Association functional classification, and native T1. CONCLUSIONS: CMR parametric mapping is a useful tool for detecting myocardial changes. Native T1 was the most sensitive parameter for identifying diffuse myocardial changes in the early stages of SSc and was associated with left ventricular diastolic function. DcSSc had more severe myocardial involvement than lcSSc; therefore, the use of CMR parametric mapping may aid in its prediction.
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Esclerodermia Sistémica , Función Ventricular Izquierda , Humanos , Volumen Sistólico , Esclerodermia Sistémica/diagnóstico por imagen , Esclerodermia Sistémica/complicaciones , Miocardio/patología , CorazónRESUMEN
There have been no established parameters to predict responsiveness to i.v. cyclophosphamide (IVCY) pulse therapy in combination with corticosteroids in patients with interstitial lung disease (ILD) related to systemic sclerosis (SSc). This retrospective study was conducted to determine predictive factors for efficacy of IVCY at the time of before and during the treatment. Thirty-two Japanese SSc patients, ever treated for ILD with IVCY in combination with prednisolone, were analyzed retrospectively. We performed detailed time-course analyses of parameters derived from blood samples and pulmonary function tests. With the exclusion of eight unclassified patients, 24 patients were classified into 14 good responders (GR) or 10 poor responders (PR) on the basis of changes in percent predicted diffusing capacity for carbon monoxide (DLco). Pretreatment percent predicted DLco was significantly reduced in PR compared with GR. In addition, serum parameters such as Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D) and C-reactive protein were significantly higher in PR than in GR. Furthermore, our time-course analyses revealed a transient increase in serum KL-6 levels with a peak at 3 months after the first infusion of cyclophosphamide, which showed no relation to therapeutic efficacy. Moreover, continuously high serum KL-6 levels (>2000 U/mL) and rapid decrease in SP-D levels (<200 ng/mL) during IVCY were remarkably characteristic of PR and GR, respectively. ILD severity/activity before treatment and variability of serum KL-6 and SP-D levels during treatment may be useful to predict therapeutic effects of IVCY on SSc-ILD.
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Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Esclerodermia Sistémica/complicaciones , Adulto , Anciano , Biomarcadores/sangre , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Inmunosupresores/administración & dosificación , Infusiones Intravenosas , Japón , Estudios Longitudinales , Enfermedades Pulmonares Intersticiales/sangre , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Pronóstico , Capacidad de Difusión Pulmonar , Quimioterapia por Pulso , Estudios Retrospectivos , Esclerodermia Sistémica/sangre , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Scleroderma is a chronic disease of unknown etiology characterized by skin fibrosis and is divided into two clinical entities: systemic sclerosis (SSc) and localized scleroderma (LSc). In general, LSc is rarely complicated with SSc, but a certain portion of SSc patients manifests bilateral symmetric LSc-like lesions on the trunk and extremities. OBJECTIVE: We investigated SSc patients with LSc-like lesions to clarify the underlying pathophysiology. METHODS: Nine SSc cases complicated with LSc-like lesions were clinically and histologically characterized. RESULTS: SSc patients with LSc-like lesions exhibited multiple progressive hyper- and/or hypo-pigmented plaques with mild sclerosis symmetrically distributed on the trunk and extremities, especially abdominal region. In histological assessment, epidermal IL-1α expression was elevated in both forearms and LSc-like lesions of these patients to a greater extent than in forearms of control patients (SSc patients without LSc-like lesions). Of note, the infiltration and degranulation of mast cells were evident throughout the dermis of LSc-like lesions, while detectable to a lesser extent in forearms of SSc patients with LSc-like lesions and control patients. CONCLUSION: The epidermis of SSc patients with LSc-like lesions seems to possess an inflammatory phenotype, leading to the activation of mast cells in the dermis of mechanically stressed skin. Köbner phenomenon may be involved in the induction of LSc-like lesions in a certain subset of SSc.
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Esclerodermia Localizada/etiología , Esclerodermia Sistémica/patología , Adolescente , Adulto , Degranulación de la Célula , Femenino , Humanos , Interleucina-1alfa/análisis , Mastocitos/fisiología , Persona de Mediana Edad , Esclerodermia Localizada/patología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/inmunología , Adulto JovenAsunto(s)
Complicaciones Posoperatorias/etiología , Fracturas del Radio/cirugía , Esclerodermia Localizada/etiología , Esclerodermia Sistémica/etiología , Fracturas del Hombro/cirugía , Anciano , Femenino , Humanos , Complicaciones Posoperatorias/patología , Esclerodermia Localizada/patología , Esclerodermia Sistémica/patologíaRESUMEN
OBJECTIVES: Intravenous pulse cyclophosphamide (IVCY) is the first-line treatment for systemic sclerosis-associated interstitial lung disease (SSc-ILD). So far, there is no useful predictive marker for IVCY efficacy against SSc-ILD, although potential candidates are parameters reflecting vascular activation. Since plasma levels of plasmin-α2-plasmin inhibitor complex (PIC) serve as a potential biomarker of SSc vasculopathy, we evaluated the usefulness of plasma PIC levels as an indicator for IVCY efficacy against SSc-ILD. METHODS: We measured plasma PIC levels in 23 patients with active SSc-ILD and 20 patients with stabilized SSc-ILD, and also retrospectively studied traceable data of patients with active SSc-ILD during IVCY therapy. RESULTS: Plasma PIC levels were significantly elevated in patients with active SSc-ILD as compared to patients with stabilized SSc-ILD. Among patients with active SSc-ILD, baseline plasma PIC concentrations were significantly higher in patients responsive to IVCY than in those refractory to IVCY. After the entire six infusions, plasma PIC levels were significantly decreased compared with baseline in the responders, while not in the nonresponders. In the responders, plasma PIC levels were remarkably decreased after a couple of infusions. Regarding the changes of parameters by the entire infusions, Δ plasma PIC levels correlated positively with Δ serum KL-6 levels and inversely with Δ the percentage of predicted vital capacity. CONCLUSIONS: The elevation of baseline plasma PIC levels and the rapid decrease in plasma PIC levels during a couple of infusions may predict the efficacy of the entire IVCY therapy against SSc-ILD.
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Antirreumáticos/uso terapéutico , Ciclofosfamida/uso terapéutico , Fibrinolisina/metabolismo , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Esclerodermia Sistémica/complicaciones , alfa 2-Antiplasmina/metabolismo , Biomarcadores/sangre , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/sangre , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Esclerodermia Sistémica/sangre , Resultado del TratamientoRESUMEN
Systemic sclerosis (SSc) is believed to be caused by a complex interplay between genetic factors and environmental influences. Although silicone has been considered to be a candidate of environmental agents, clinical data presented so far fail to show a significant association between silicone breast implant (SBI) and the development of SSc. Because we recently experienced two consecutive SSc patients with anti-RNA polymerase III (RNAP III) antibody who underwent SBI, we here investigated the association of SBI history with the development of SSc positive for anti-RNAP III antibody. Among 262 Japanese SSc patients, of note, the frequency of SBI history was significantly higher in the anti-RNAP III antibody group (16.0% [4/25]) than in the anti-topoisomerase I antibody group (0% [0/87], P < 0.005) and in the anticentromere antibody group (1.2% [2/150], P < 0.005). These results suggest that SBI could influence the development of SSc in a certain subset of patients with anti-RNAP III antibody.
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Implantes de Mama/efectos adversos , ARN Polimerasa III/inmunología , Esclerodermia Sistémica/inmunología , Siliconas/efectos adversos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Systemic sclerosis (SSc) is characterized by disturbed blood circulation. The effect of ambrisentan, an endothelin-A receptor-selective antagonist, on impaired peripheral circulation in SSc remains largely elusive. Here we show SSc patients, whose clinical symptoms such as cyanosis and Raynaud's phenomenon, were ameliorated by the treatment with ambrisentan. Additionally, objective evaluations with thermography showed improvement of hand coldness in steady-state and cold challenge tests. Ambrisentan might have a potential to improve peripheral circulation in SSc.
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Antagonistas de los Receptores de la Endotelina A/uso terapéutico , Fenilpropionatos/uso terapéutico , Piridazinas/uso terapéutico , Enfermedad de Raynaud/tratamiento farmacológico , Esclerodermia Sistémica/tratamiento farmacológico , Anciano , Femenino , Humanos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
AIM: To determine serum galectin-1 levels and their clinical associations in patients with systemic sclerosis (SSc). METHOD: Serum galectin-1 levels were examined by enzyme-linked immunosorbent assay in 66 patients with SSc and 24 healthy individuals. RESULTS: No significant differences were observed in serum galectin-1 levels between patients with SSc (9.4 ± 5.6 ng/mL), and healthy individuals (8.9 ± 1.3 ng/mL). Among patients with SSc, no significant differences were seen in serum galectin-1 levels between those with diffuse cutaneous SSc (8.8 ± 5.7 ng/mL; n = 31) and those with limited cutaneous SSc (10.0 ± 5.4 ng/mL; n = 35). Patients with SSc who had increased galectin-1 levels less often had pitting scars/digital ulcers than those with normal galectin-1 levels (17% vs. 49%; P < 0.01). Consistently, galectin-1 levels were significantly lower in SSc patients with pitting scars/digital ulcers than in those without pitting scars/digital ulcers (6.9 ± 4.8 vs. 10.9 ± 5.5 ng/mL; P < 0.01). CONCLUSION: These results suggest that galectin-1 is a protective factor against the development of digital vasculopathy in SSc. In addition, measurement of serum galectin-1 levels may be useful for risk stratification for the development of digital vasculopathy in the early phase of SSc.
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Cicatriz/etiología , Galectina 1/sangre , Esclerodermia Sistémica/sangre , Úlcera Cutánea/etiología , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Protectores , Factores de Riesgo , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Adulto JovenRESUMEN
Patients with systemic sclerosis (SSc) have an increased risk of malignancy compared with the general population. Recently, SSc patients with anti-RNA polymerase III antibody have been reported to have an increased risk of malignancy as compared with those with other disease-specific autoantibodies in US, European and Australian populations. Therefore, we studied the relationship between disease-specific autoantibodies and malignancy in 261 Japanese SSc patients. The prevalence of malignancy was significantly higher in patients with anti-RNA polymerase III antibody (7/22, 31.8%) than in those with anti-topoisomerase I antibody (2/82, 2.4%) and in those with anticentromere antibody (8/137, 5.8%). Importantly, among seven patients with anti-RNA polymerase III antibody and malignancy, three patients (42.9%) developed malignancy from 6 months before to 12 months after SSc onset. Thus, malignancy complication in Japanese SSc patients with anti-RNA polymerase III antibody is as high as that in other races, suggesting that SSc patients with anti-RNA polymerase III antibody share the same pathological process among different ethnic groups.
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Anticuerpos Antinucleares/sangre , Neoplasias/etnología , ARN Polimerasa III/inmunología , Esclerodermia Sistémica/sangre , ADN-Topoisomerasas de Tipo I/inmunología , Femenino , Humanos , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias/epidemiologíaRESUMEN
Previous studies have demonstrated that B cells play critical roles in autoimmune disorders including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). However, the effectiveness of rituximab (RTX), a chimeric anti-CD20 antibody, for SSc-associated interstitial lung disease (ILD) or SLE disease activity remains controversial. We herein report an SSc patient with severely progressed ILD and concomitant SLE treated by two cycles of RTX at baseline and half a year later. This treatment improved ILD and SLE activities, along with reduction of dermal sclerosis and serum anti-topoisomerase I antibody levels. In addition, our detailed time-course data indicate that half a year may be appropriate as an interval between each cycle of RTX therapy aimed at SSc-associated ILD or SLE. Overall, the current report could pave the way to establish RTX as a disease-modifying drug for patients with SSc and/or SLE showing resistance to other already approved medications.
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Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Enfermedades Pulmonares Intersticiales/terapia , Lupus Eritematoso Sistémico/terapia , Esclerodermia Sistémica/terapia , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Autoanticuerpos/sangre , Linfocitos B/inmunología , ADN-Topoisomerasas de Tipo I/inmunología , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/inmunología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/inmunología , Persona de Mediana Edad , Rituximab , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/inmunología , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the relationship between gender differences in fatty acid-binding protein7 (FABP7) and BRN2 (POU class 3 homeobox 2) expression in renal cell carcinoma (RCC) and the prognosis of patients with RCC. MATERIALS AND METHODS: immunohistochemical (IHC) staining as well as reverse transcription-polymerase chain reaction (RT-PCR) was performed in renal tissues from 103 patients (83 men, mean age = 63.6 years old; 20 women, mean age = 63.1 years old) underwent radical nephrectomy from January 1, 2001 through December 31, 2010. The probability of overall patient survival was estimated using the Kaplan-Meier method. RESULTS: FABP7 mRNA expression was more frequent in men (P = 0.07) while BRN2 protein expression was significantly more frequent in women (P = 0.029). In particular, FABP7 was expressed in 100% of G1 renal cell carcinoma both in mRNA and protein levels. In women, FABP7 (-) and BRN2 (+) groups had a worse prognosis both in mRNA level (P = 0.038) and protein level (P = 0.058). BRN2 was expressed 100% of papillary RCC both in mRNA and protein levels. CONCLUSIONS: Our results demonstrated that gender was a key factor in FABP7 and BRN2 expression in RCC, and the combination with FABP7 and BRN2 stratified by gender could be a new potential prognostic factor in patients with RCC.
RESUMEN
Systemic sclerosis (SSc) is characterized by vascular injuries, and bosentan has recently been proved to be efficacious for the prevention of new digital ulcers in SSc. We herein report a case of SSc in a patient with refractory digital ulcers and gangrene treated with bosentan. Stenosis of the ulnar artery, evaluated by magnetic resonance angiography, was attenuated by the bosentan treatment, suggesting that bosentan exerts a reverse remodeling effect against the pathological organic changes of arteries in SSc.
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Dedos/irrigación sanguínea , Flujo Sanguíneo Regional/efectos de los fármacos , Esclerodermia Difusa/tratamiento farmacológico , Úlcera Cutánea/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Antihipertensivos/uso terapéutico , Bosentán , Femenino , Dedos/patología , Gangrena/tratamiento farmacológico , Gangrena/etiología , Gangrena/patología , Humanos , Persona de Mediana Edad , Esclerodermia Difusa/complicaciones , Esclerodermia Difusa/patología , Úlcera Cutánea/etiología , Úlcera Cutánea/patologíaRESUMEN
Thalidomide is now recognized as an important agent for multiple myeloma. In this study, we retrospectively analyzed the effect of thalidomide therapy in 52 patients with relapsed/refractory multiple myeloma. Median age was 70 years. Eight patients were treated with thalidomide alone, 36 with dexamethasone, and 8 with chemotherapy. The maintenance dose of thalidomide was 100 mg/day in 42 cases. The probability of overall survival and progression-free survival one year after the start of thalidomide were 76.2% and 70.9%, respectively. Complete or partial response was obtained in 16 patients (31%). The probability of survival was better in patients who obtained a partial or complete response than in non-responders (P=0.04). Adverse effects (CTCAE criteria Grade 3-4) were somnolence (n=3), constipation (n=5), peripheral neuropathy (n=1), deep vein thrombosis (n=1), anemia (n=10), leukocytopenia (n=10), and thrombocytopenia (n=3). The high incidence of cytopenia in this study suggests that the Japanese population tends to display bone marrow suppression after thalidomide therapy. Some patients developed peripheral neuropathy at the early stage of administration and attention was necessary. In conclusion, thalidomide therapy is safe and effective in patients with refractory multiple myeloma.
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Mieloma Múltiple/tratamiento farmacológico , Talidomida/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Recurrencia , Estudios Retrospectivos , Talidomida/efectos adversos , Resultado del TratamientoRESUMEN
Activation of the immune system and abnormal growth of skin fibroblasts cause systemic sclerosis. Growth factors have various biological activities, including mediation of immune reactions. The growth factor family includes basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), and connective tissue growth factor (CTGF). CTGF, an important downstream mediator of TGF-beta in fibrosis, has been suggested to play a specific role in fibrotic disorders. We have directed our attention to the role of CTGF in sustaining skin fibrosis. To better understand its effects in vivo, we established an animal model of skin fibrosis induced by exogenous application of growth factors. In this model, bFGF transiently induced subcutaneous fibrosis. Simultaneous injection of bFGF and CTGF increased skin fibrosis compared with a single injection of bFGF. Serial injections of bFGF for 3 days followed by CTGF for 4 days, or of CTGF followed by bFGF, did not cause skin fibrosis but simultaneous injections increased macrophage chemoattractant protein-1 (MCP-1) mRNA expression levels. To further define the mechanisms of skin fibrosis in vivo, bFGF and CTGF were injected simultaneously into MCP-1 knockout mice, resulting in decreased collagen levels in granulation tissues on day 8. The number of inflammatory cells, such as mast cells, macrophages and lymphocytes, was significantly decreased in MCP-1 knockout mice compared with wild-type mice. These results suggest that bFGF induces collagen production by stimulating skin fibroblasts and CTGF cooperates with bFGF. Our results indicate that the induction of MCP-1 is necessary for infiltration of inflammatory cells.
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Quimiocina CCL2/metabolismo , Fibroblastos/metabolismo , Esclerodermia Sistémica/metabolismo , Enfermedades de la Piel/metabolismo , Piel/metabolismo , Animales , Movimiento Celular , Quimiocina CCL2/deficiencia , Quimiocina CCL2/genética , Colágeno/metabolismo , Colágeno Tipo I , Factor de Crecimiento del Tejido Conjuntivo/administración & dosificación , Modelos Animales de Enfermedad , Factor 2 de Crecimiento de Fibroblastos/administración & dosificación , Fibroblastos/inmunología , Fibroblastos/patología , Fibrosis , Tejido de Granulación/metabolismo , Tejido de Granulación/patología , Humanos , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/metabolismo , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/patología , Piel/inmunología , Piel/patología , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/patología , Factores de TiempoRESUMEN
Cell cycle regulation and biochemical responses upon nutrients and growth factors are the major regulatory mechanisms for cell sizing in mammals. Recently, we identified that the death effector domain-containing DEDD impedes mitotic progression by inhibiting Cdk1 (cyclin-dependent kinase 1) and thus maintains an increase of cell size during the mitotic phase. Here we found that DEDD also associates with S6 kinase 1 (S6K1), downstream of phosphatidylinositol 3-kinase, and supports its activity by preventing inhibitory phosphorylation of S6K1 brought about by Cdk1 during the mitotic phase. DEDD(-/-) cells showed reduced S6K1 activity, consistently demonstrating decreased levels in activating phosphorylation at the Thr-389 site. In addition, levels of Cdk1-dependent inhibitory phosphorylation at the C terminus of S6K1 were enhanced in DEDD(-/-) cells and tissues. Consequently, as in S6K1(-/-) mice, the insulin mass within pancreatic islets was reduced in DEDD(-/-) mice, resulting in glucose intolerance. These findings suggest a novel cell sizing mechanism achieved by DEDD through the maintenance of S6K1 activity prior to cell division. Our results also suggest that DEDD may harbor important roles in glucose homeostasis and that its deficiency might be involved in the pathogenesis of type 2 diabetes mellitus.
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Proteína Quinasa CDC2/metabolismo , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Mitosis , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Animales , Proteína Quinasa CDC2/genética , Tamaño de la Célula , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/genética , Diabetes Mellitus Tipo 2/genética , Activación Enzimática/genética , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Homeostasis/genética , Insulina/genética , Insulina/metabolismo , Ratones , Ratones Noqueados , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/genética , Estructura Terciaria de Proteína/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genéticaRESUMEN
Mutation of primer site for genotyping by polymerase chain reaction (PCR) may cause allele dropout and other genotyping failures. Primary hyperoxaluria type 2 (PH2) is a rare inherited disease caused by overproduction of endogenous oxalate due to mutations in the glyoxylate/hydroxypyruvate reductase (GRHPR) gene. Here, to avoid allele dropout and primer annealing to multiple sites, and given the discrepancy in intron length between GRHPR gene data, we updated the primers used in the sequence assay of the GRHPR gene. These redesigned primers show potential in reducing detection failure of GRHPR mutations. In addition, we performed a single nucleotide polymorphism (SNP) linkage analysis of the GRHPR gene using direct sequencing with PCR amplification of specific alleles (DS-PASA). Using this technique, we sequenced four common SNPs between intron E and exon 6, which show linkage disequilibrium (LD) consisting of three types of haplotypes, similar to data from the HapMap SNP database.