RESUMEN
We present the results of searches for nucleon decay via nâν[over ¯]π0 and pâν[over ¯]π+ using data from a combined 172.8 kt·yr exposure of Super-Kamiokande-I,-II, and-III. We set lower limits on the partial lifetime for each of these modes: τnâν[over ¯]π0>1.1×10(33) years and τpâν[over ¯]π+>3.9×10(32) years at a 90% confidence level.
RESUMEN
A search for the dinucleon decay pp â K+ K+ has been performed using 91.6 kton·yr data from Super-Kamiokande-I. This decay provides a sensitive probe of the R-parity-violating parameter λ112''. A boosted decision tree analysis found no signal candidates in the data. The expected background was 0.28±0.19 atmospheric neutrino induced events and the estimated signal detection efficiency was 12.6%±3.2%. A lower limit of 1.7×10(32) years has been placed on the partial lifetime of the decay O16 â C14K+ K+ at 90% C.L. A corresponding upper limit of 7.8×10(-9) has been placed on the parameter λ112''.
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Previous studies have suggested some interactions between muscle tissues and bone metabolism. The constitutively activating mutation (R206H) of the BMP type I receptor, activin-like-kinase 2 (ALK2), causes fibrodysplasia ossificans progressiva (FOP), which is characterized by extensive ossifications within muscle tissues. In the present study, we revealed that Tmem176b mRNA levels were upregulated by stable transfection of ALK2 (R206H) in mouse myoblastic C2C12 cells. Transient Tmem176b overexpression elevated levels of osteoblast differentiation markers, such as Osterix and alkaline phosphatase, as well as mineralization in C2C12 cells. In addition, Tmem176b overexpression elevated the levels of these markers in mouse osteoblastic MC3T3-E1 cells. On the other hand, Tmem176b overexpression suppressed the levels of myogenic markers, such as MyoD and myogenin in C2C12 cells, although it did not affect the levels of chondrogenic markers, such as type II and X collagens. In conclusion, the present study is the first to demonstrate that Tmem176b induces the differentiation of myoblasts into an osteoblast lineage.
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Receptores de Activinas Tipo I/fisiología , Diferenciación Celular/genética , Proteínas de la Membrana/fisiología , Mioblastos Esqueléticos/fisiología , Osteoblastos/fisiología , Animales , Transdiferenciación Celular/genética , Células Cultivadas , Condrocitos/fisiología , Ratones , Fibras Musculares Esqueléticas/fisiología , Osteogénesis/genética , Transducción de Señal/genética , TransfecciónRESUMEN
Super-Kamiokande atmospheric neutrino data were fit with an unbinned maximum likelihood method to search for the appearance of tau leptons resulting from the interactions of oscillation-generated tau neutrinos in the detector. Relative to the expectation of unity, the tau normalization is found to be 1.42 ± 0.35(stat)(-0.12)(+0.14)(syst) excluding the no-tau-appearance hypothesis, for which the normalization would be zero, at the 3.8σ level. We estimate that 180.1 ± 44.3(stat)(-15.2)(+17.8) (syst) tau leptons were produced in the 22.5 kton fiducial volume of the detector by tau neutrinos during the 2806 day running period. In future analyses, this large sample of selected tau events will allow the study of charged current tau neutrino interaction physics with oscillation produced tau neutrinos.
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Urokinase-type plasminogen activator (u-PA) and plasminogen play a primary role in liver repair through the accumulation of macrophages and alteration of their phenotype. However, it is still unclear whether u-PA and plasminogen mediate the activation of macrophage phagocytosis during liver repair. Herein, we investigated the morphological changes in macrophages that accumulated at the edge of damaged tissue induced by a photochemical reaction or hepatic ischaemia-reperfusion in mice with u-PA ( u-PA-/- ) or plasminogen ( Plg-/- ) gene deficiency by using transmission electron and fluorescence microscopy. In wild-type mice, the macrophages aligned at the edge of the damaged tissue and extended a large number of long pseudopodia. These macrophages clearly engulfed cellular debris and showed well-developed organelles, including lysosome-like vacuoles, nuclei, and Golgi complexes. In wild-type mice, the distribution of the Golgi complex in these macrophages was biased towards the direction of the damaged tissue, indicating the extension of their pseudopodia in this direction. Conversely, in u-PA-/- and Plg-/- mice, the macrophages located at the edge of the damaged tissue had few pseudopodia and less developed organelles. The Golgi complex was randomly distributed in these macrophages in u-PA-/- mice. Furthermore, interferon γ and IL-4 were expressed at a low level at the border region of the damaged tissue in u-PA-/- mice. Our data provide novel evidence that u-PA and plasminogen are essential for the phagocytosis of cellular debris by macrophages during liver repair. Furthermore, u-PA plays a critical role in the induction of macrophage polarity by affecting the microenvironment at the edge of damaged tissue.
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Regulación de la Expresión Génica , Hígado/metabolismo , Macrófagos/metabolismo , Plasminógeno/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Animales , Femenino , Aparato de Golgi/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica de Transmisión/métodos , Modelos Genéticos , Fagocitosis , Plasminógeno/genética , Seudópodos/metabolismo , Daño por Reperfusión , Activador de Plasminógeno de Tipo Uroquinasa/genéticaRESUMEN
Wnt-ß-catenin signaling is important for bone formation. Sclerostin inhibits bone formation mainly by suppressing this signal, and several studies suggest that the suppression of sclerostin expression contributes to the bone anabolic action of parathyroid hormone (PTH). We therefore examined serum sclerostin levels using enzyme-linked immunosolvent assay in 18 patients with postmenopausal osteoporosis, 9 postmenopausal women with primary hyperparathyroidism (pHPT) and 7 patients with osteomalacia. Serum levels of sclerostin were significantly lower in the group with pHPT, compared with those with postmenopausal osteoporosis. Moreover, serum sclerostin levels were significantly lower in the group with tumor-induced osteomalacia, but not in the group with osteomalacia without tumor, compared with those with postmenopausal osteoporosis. In patients with pHPT, serum sclerostin levels were significantly and negatively correlated to serum calcium and PTH levels. In patients with postmenopausal osteoporosis, serum levels of sclerostin levels were significantly and positively related to serum calcium and creatinine levels. In conclusion, we showed that serum sclerostin levels are decreased presumably through endogenous PTH elevation in postmenopausal women with pHPT, compared with the patients with postmenopausal osteoporosis.
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Proteínas Morfogenéticas Óseas/sangre , Hiperparatiroidismo/sangre , Osteomalacia/sangre , Osteoporosis Posmenopáusica/sangre , Proteínas Adaptadoras Transductoras de Señales , Anciano , Femenino , Marcadores Genéticos , Humanos , Persona de Mediana Edad , Hormona Paratiroidea/sangreRESUMEN
Menin promotes the commitment of pluripotent mesenchymal stem cells to the osteoblast lineage by interacting with the BMP-2 signaling molecules Smad1/5, and Runx2. However, the relationship between menin and the Wnt-ß-catenin pathway in bone is unclear. Reduction of menin expression by transfection of a menin antisense construct did not alter the levels of ß-catenin in mouse mesenchymal C2C12 and osteoblastic MC3T3-E1 cells. However, menin co-immunoprecipitated with ß-catenin as well as LEF-1 in C2C12 and MC3T3-E1 cells. Reduction of menin expression by antisense menin transfection antagonized ß-catenin-induced transcriptional activity of the pGL3-OT luciferase reporter construct in C2C12 and MC3T3-E1 cells. Antisense menin transfection antagonized the BMP-2 and ß-catenin-stimulated increases in Runx2 and alkaline phosphatase levels in C2C12 cells. The data show that menin interacts with ß-catenin in mouse mesenchymal and osteoblastic cells, and suggest that the interaction is important for osteoblast differentiation.
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Diferenciación Celular , Osteoblastos/citología , Osteoblastos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , beta Catenina/metabolismo , Animales , Proteína Morfogenética Ósea 2/metabolismo , Células Cultivadas , Células Madre Mesenquimatosas/metabolismo , Ratones , Unión Proteica , Proteínas Proto-Oncogénicas/genética , beta Catenina/genéticaRESUMEN
We present a search for differences in the oscillations of antineutrinos and neutrinos in the Super-Kamiokande-I, -II, and -III atmospheric neutrino sample. Under a two-flavor disappearance model with separate mixing parameters between neutrinos and antineutrinos, we find no evidence for a difference in oscillation parameters. Best-fit antineutrino mixing is found to be at (Δm2,sin2 2θ)=(2.0×10(-3) eV2, 1.0) and is consistent with the overall Super-K measurement.
RESUMEN
Alendronate, an aminobisphosphonate, is an effective reagent to reduce fracture risk in osteoporotic patients. Although several studies suggest that bisphosphonates affect osteoblast differentiation, how they affect the genes relating to the mineralization step remains unknown. The present study was performed to clarify the effects of alendronate on mineralization and its related genes in mouse osteoblastic MC3T3-E1 cells. Alendronate at 10 (-8) and 10 (-7) M induced mineralization in MC3T3-E1 cells. As for the genes that suppress mineralization, alendronate enhanced the level of PC-1 mRNA in a dose-dependent manner in 7-day cultures in semiquantitative RT-PCR, although it reduced the levels of PC-1 mRNA in 21-day cultures. On the other hand, alendronate did not affect the levels of ANK, osteopontin and matrix Gla protein mRNA in both 7- and 21-day cultures. Moreover, alendronate reduced the level of osteocalcin mRNA at 10 (-7) and 10 (-6) M in 14-day cultures of these cells. As for the expression of alkaline phosphatase (ALP), an important positive regulator of mineralization in osteoblasts, alendronate enhanced the levels of ALP mRNA and protein at 10 (-7)-10 (-5) M. In conclusion, low-dose alendronate induced mineralization in mouse osteoblastic cells. The regulation of PC-1, osteocalcin and ALP by alendronate might play some role in these effects.
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Alendronato/farmacología , Conservadores de la Densidad Ósea/farmacología , Calcificación Fisiológica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoblastos/fisiología , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Antraquinonas/química , Línea Celular , Indicadores y Reactivos/química , Ratones , Concentración Osmolar , Osteocalcina/genética , Osteocalcina/metabolismo , Osteoporosis/tratamiento farmacológico , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
Although increased arterial sclerosis and dyslipidemia were observed in primary hyperparathyroidism (pHPT) patients in previous studies, it still remains unclear about the relationships between lipid and bone metabolism in pHPT patients, especially about fracture risk. The present study was performed to examine the relationships between lipid metabolism parameters including body composition and bone metabolism in 116 female patients with pHPT and 116 age-matched control subjects. Bone mineral density (BMD) and body composition were measured by dual-energy x-ray absorptiometry. Serum low density lipoprotein (LDL)-cholesterol (Chol) levels were negatively related to only z-score of BMD at femoral neck and serum creatinine levels. Serum levels of LDL-Chol were significantly lower in the group with vertebral fractures in pHPT patients, although body composition parameters were not significantly different. In univariate logistic regression analyses, age, height, BMD at lumbar spine and radius, serum levels of creatinine, total-Chol and LDL-Chol were significantly selected as a predictor of vertebral fractures. LDL-Chol was related to vertebral fractures independently of the other parameters. In conclusion, the present study demonstrated that lower serum LDL-Chol levels were related to vertebral fracture risk independent of renal function, age, body size, bone metabolism parameters and the severity of the disease in pHPT women.
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Hiperparatiroidismo/sangre , Hiperparatiroidismo/complicaciones , Lipoproteínas LDL/sangre , Fracturas de la Columna Vertebral/epidemiología , Composición Corporal , Densidad Ósea , Huesos/metabolismo , Calcio/metabolismo , LDL-Colesterol/sangre , Creatinina/metabolismo , Dislipidemias/epidemiología , Femenino , Humanos , Estado Nutricional , Hormona Paratiroidea/sangre , Valores de Referencia , Factores de Riesgo , Columna Vertebral/patologíaRESUMEN
SUMMARY: Urinary deoxypyridinoline (DPD) level was associated with prevalent vertebral fractures in glucocorticoid (GC)-treated postmenopausal women independently of lumbar spine bone mineral density (BMD). INTRODUCTION: Bone metabolic indices are the potential predictors of bone fragility. However, their diagnostic efficiency for identifying the risk of GC-induced vertebral fractures is still unclear. We therefore evaluated whether bone metabolic indices would assess the risk of vertebral fractures in GC-treated women. METHODS: One hundred seventy-five women treated with GC for more than 6 months were enrolled in this study. RESULTS: Both premenopausal and postmenopausal women with vertebral fractures had significantly higher urinary DPD levels than those without vertebral fractures. When multivariable logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and each of DPD or osteocalcin level adjusted for age, weight, height, current and maximum doses of GC, duration of GC treatment, as well as lumbar spine BMD as an independent variable, DPD level was identified as a factor associated with the presence of vertebral fractures in postmenopausal women but not in premenopausal women. CONCLUSION: Urinary DPD level was significantly associated with prevalent vertebral fractures in GC-treated postmenopausal women independently of lumbar spine BMD.
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Aminoácidos/orina , Glucocorticoides/efectos adversos , Osteoporosis Posmenopáusica/complicaciones , Fracturas Osteoporóticas/diagnóstico , Fracturas de la Columna Vertebral/diagnóstico , Adulto , Anciano , Biomarcadores/orina , Densidad Ósea/fisiología , Huesos/metabolismo , Femenino , Humanos , Vértebras Lumbares/fisiopatología , Persona de Mediana Edad , Osteoporosis Posmenopáusica/orina , Fracturas Osteoporóticas/etiología , Premenopausia/fisiología , Fracturas de la Columna Vertebral/etiología , Adulto JovenRESUMEN
SUMMARY: This prospective study, in the very early phase after initiation of glucocorticoid (GC) treatment, showed that alendronate was effective in suppressing accelerated bone resorption and subsequent decrease in bone mineral density (BMD) at the lumbar spine of patients with high-dose GC treatment. INTRODUCTION: How bisphosphonates affect bone metabolism and BMD of patients with high-dose GC in the early phase, especially within 1 month is unclear. METHODS: We examined the prospective effects of daily 5 mg alendronate on bone metabolism and BMD in 20 patients with high-dose GC (at least 40 mg prednisolone/day) and compared them to 34 high-dose GC-treated patients without alendronate. RESULTS: Serum levels of calcium decreased at day 28 in the alendronate group. Urinary calcium excretion significantly increased after day 7 in both groups. The increase in serum parathyroid hormone (PTH) level at day 7 in the control group was not observed in the alendronate group, but PTH levels increased at day 28 and month 3 in the alendronate group. As for the bone turnover markers, the serum osteocalcin level decreased in both alendronate and control groups, but serum bone-type alkaline phosphatase levels did not show significant changes. Although the urinary type I collagen cross-linked N-telopeptide (NTX) level showed significant increases on days 7 and 28 in the control group; such early increases in urinary NTX were not observed in the alendronate group. Thereafter, the urinary NTX levels fell slowly in the alendronate group significantly. BMD at the lumbar spine significantly decreased from month 1 in the control group, whereas in the alendronate group, BMD at the lumbar spine maintained almost the same level at all time points observed. CONCLUSION: Alendronate was effective in suppressing bone resorption and subsequent BMD decrease at the lumbar spine in patients with high-dose GC treatment.
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Alendronato/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Glucocorticoides/efectos adversos , Osteoporosis/prevención & control , Adulto , Anciano , Biomarcadores/metabolismo , Densidad Ósea/efectos de los fármacos , Resorción Ósea/inducido químicamente , Resorción Ósea/metabolismo , Resorción Ósea/prevención & control , Calcio/metabolismo , Esquema de Medicación , Femenino , Glucocorticoides/administración & dosificación , Humanos , Vértebras Lumbares/efectos de los fármacos , Vértebras Lumbares/fisiopatología , Masculino , Persona de Mediana Edad , Osteoporosis/inducido químicamente , Osteoporosis/metabolismo , Hormona Paratiroidea/sangre , Prednisolona/administración & dosificación , Prednisolona/efectos adversos , Estudios Prospectivos , Resultado del TratamientoRESUMEN
We study B --> K(*)l+l- decays (l = e, mu) based on a data sample of 657 x 10(6) BB pairs collected with the Belle detector at the KEKB e+e- collider. We report the differential branching fraction, isospin asymmetry, K* polarization, and the forward-backward asymmetry (A(FB)) as functions of q2 = M(ll)(2)c2. The fitted A(FB) spectrum exceeds the standard model expectation by 2.7 standard deviations. The measured branching fractions are B(B --> K*l+l-) = (10.7(-1.0)(+1.1) +/- 0.9) x 10(-7) and B(B --> Kl+l-) = (4.8(-0.4)(+0.5) +/- 0.3) x 10(-7), where the first errors are statistical and the second are systematic, with the muon to electron ratios R(K*) = 0.83 +/- 0.17 +/- 0.08 and R(K) = 1.03 +/- 0.19 +/- 0.06.
RESUMEN
UNLABELLED: Eighty-seven male Japanese subjects taking prednisolone > or = 5 mg for more than 6 months and 132 age- and body mass index (BMI)-matched control subjects were examined. Multiple regression analysis adjusted for age and BMI showed that spinal bone mineral density (BMD) in the prednisolone group was not associated with prevalent vertebral fractures (VFs). INTRODUCTION: Glucocorticoid (GC) treatment is known to increase the risk for bone fractures. However, the association between VFs and BMD in GC-treated male patients remains unclear. METHODS: Eighty-seven male subjects taking prednisolone > or = 5 mg for more than 6 months and 132 age- and BMI-matched control subjects were examined using lateral thoracic and lumbar spine radiographs and spine dual energy X-ray absorptiometry. RESULTS: The presence of GC use was an independent risk factor for VFs adjusted for age and BMI (odds ratio 10.93, P < 0.001). By receiver operating characteristic analysis, the absolute BMD values for detecting VFs were higher and the sensitivity and specificity were lower in the GC group than in the control group (0.936 vs 0.825 g/cm(2) and 53.5% vs 74.0%, respectively). Multiple regression analysis adjusted for age and BMI showed that spinal BMD in the GC group was not associated with prevalent VFs, even after adding current and past maximum GC doses as independent variables. CONCLUSIONS: These results show that lumbar BMD values are not associated with prevalent VFs in GC-treated male patients, suggesting that bone fragility in male GC users is affected by bone quality rather than by BMD.
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Glucocorticoides/efectos adversos , Fracturas Osteoporóticas/inducido químicamente , Prednisolona/efectos adversos , Fracturas de la Columna Vertebral/inducido químicamente , Absorciometría de Fotón , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Densidad Ósea/efectos de los fármacos , Esquema de Medicación , Métodos Epidemiológicos , Glucocorticoides/administración & dosificación , Humanos , Vértebras Lumbares/fisiopatología , Masculino , Persona de Mediana Edad , Fracturas Osteoporóticas/fisiopatología , Prednisolona/administración & dosificación , Fracturas de la Columna Vertebral/fisiopatología , Vértebras Torácicas/fisiopatología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Oral mucositis is a major severe toxic side-effect of systemic chemotherapy and irradiation in patients with cancer. Various free radical scavengers have been shown to prevent chemotherapy-induced skin necrosis. The objective of this study was to determine the antioxidant activity of a bisbenzylisoquinoline alkaloidal compound (BIQAC) and a series of chemicals, including allopurinol, used clinically for the treatment of chemotherapy-induced mucositis. METHODS: Allopurinol, melatonin, camostat mesilate, gabexate mesilate, hydroquinone and BIQAC were tested for their radical scavenging activities on four different radical species: 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) cation radical (ABTS(*+)) using standard methods, and superoxide anion radical (O(2) (-)) and hydroxyl radical (OH(*)) using electron spin resonance. RESULTS: Allopurinol had radical scavenging activity against O(2) (-) only. Melatonin had strong radical scavenging activity against ABTS(*+), and weak activity against DPPH radical and OH(*). Camostat mesilate had weak radical scavenging activity against OH(*). Gabexate mesilate had no radical scavenging activity against any of these radicals. Hydroquinone had strong radical scavenging activity against DPPH radical and ABTS(*+), and moderate activity against both O(2) (-) and OH(*). BIQAC had moderate radical scavenging activity against DPPH radical, strong radical scavenging activity against ABTS(*+) and O(2) (-), and weak activity against OH(*). CONCLUSION: The BIQAC had the most braod-spectrum radical scavenging activity, suggesting that it may be effective against chemotherapy-induced mucositis. These findings also suggest that this radical-scavenging activity screening method, against four kinds of radicals, may be useful for the screening of radical scavenging activity of new natural and synthetic chemicals.
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Antineoplásicos/efectos adversos , Bencilisoquinolinas/química , Depuradores de Radicales Libres/química , Mucositis/inducido químicamente , Mucositis/prevención & control , Alopurinol/química , Alopurinol/farmacología , Antimetabolitos Antineoplásicos/química , Antimetabolitos Antineoplásicos/farmacología , Benzotiazoles/química , Compuestos de Bifenilo/química , Relación Dosis-Respuesta a Droga , Espectroscopía de Resonancia por Spin del Electrón , Radical Hidroxilo/química , Oxidantes/química , Picratos/química , Especies Reactivas de Oxígeno/química , Relación Estructura-Actividad , Ácidos Sulfónicos/químicaRESUMEN
We investigated the behavior of red blood cells (RBCs) in a microchannel with stenosis using a confocal micro-PTV system. Individual trajectories of RBCs in a concentrated suspension of up to 20% hematocrit (Hct) were measured successfully. Results indicated that the trajectories of healthy RBCs became asymmetric before and after the stenosis, while the trajectories of tracer particles in pure water were almost symmetric. The asymmetry was greater in 10% Hct than in 20% Hct. We also investigated the effect of deformability of RBCs on the cell-free layer thickness by hardening RBCs using a glutaraldehyde treatment. The results indicated that deformability is the key factor in the asymmetry of cell-free layer thickness. Therefore, the motions of RBCs are influenced strongly by the Hct, the deformability, and the channel geometry. These results give fundamental knowledge for a better understanding of blood flow in microcirculation and biomedical microdevices.
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Eritrocitos , Velocidad del Flujo Sanguíneo , Constricción Patológica , Salud , Hematócrito , Humanos , Masculino , Microcirculación , Reología , Agua , Adulto JovenRESUMEN
Several studies suggest that mild PTH excess does not have any deteriorative effects on bone mineral density (BMD) in several-year-longitudinal studies of patients with mild primary hyperparathyroidism (pHPT) without parathyroidectomy (PTX). However, it remains unknown about the change in bone geometry in pHPT patients without PTX. We examined the longitudinal effects of mild PTH excess on cortical bone geometry in postmenopausal patients with mild pHPT without PTX by using peripheral quantitative computed tomography (pQCT), and we compared them with normal and hypoparathyroidism women. Nine postmenopausal female patients who were diagnosed as pHPT, six postmenopausal female patients with hypoparathyroidism (3 idiopathic and 3 postoperative), and thirty postmenopausal control subjects participated in this study. Radial volumetric (v) BMD and several bone geometry parameters were measured by pQCT at basal line and after 2 years. Cortical vBMD was significantly lower in pHPT group. Moreover, total area and periosteal circumferences were significantly higher in pHPT group. Total and cortical vBMD were significantly decreased after 2 years in control group. However, they were stable in pHPT group after 2-year follow-up. As for bone geometry, cortical thickness and area were also stable in pHPT group during 2-year follow-up, although they were significantly reduced in control group and hypoparathyroidism group. In conclusion, the present longitudinal study revealed that there were no significant changes in radial vBMD and cortical bone geometry in postmenopausal women with mild pHPT, whereas age-related thinning of cortical bone as well as decrease of vBMD were observed in the control and patients with hypoparathyroidism.
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Densidad Ósea/fisiología , Huesos/fisiopatología , Antebrazo/fisiopatología , Hiperparatiroidismo Primario/fisiopatología , Posmenopausia/fisiología , Anciano , Envejecimiento/fisiología , Huesos/diagnóstico por imagen , Progresión de la Enfermedad , Femenino , Antebrazo/diagnóstico por imagen , Humanos , Hiperparatiroidismo Primario/diagnóstico por imagen , Estudios Longitudinales , Persona de Mediana Edad , Estadísticas no Paramétricas , UltrasonografíaRESUMEN
OBJECTIVE: Oral mucositis is a major toxicity in the high-dose methotrexate (HD-MTX) treatment for children with acute lymphoblastic leukemia (ALL). The first aim of this study was to evaluate the relationship between the MTX serum concentration and occurrence of oral mucositis in pediatric ALL patients. The second aim was to clarify the relationship between MTX exposure and epidermal keratinocyte cell injury using an in vitro study. METHODS: 49 patients were treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-HR02 protocol. This protocol involves HD-MTX treatment (3 g/m2 for 24-h i.v. infusion). The MTX serum concentrations were measured by a fluorescence polarization immunoassay. The relationship between oral mucositis and MTX serum concentrations 48 and 72 h after administration was determined. The cell toxicity of MTX for human epidermal keratinocytes was analyzed by using a cell viability assay (WST-1 assay). In addition, pharmacokinetic evaluation for clearance, AUC extrapolated from 48 h to infinity (AUC48h-inf) and elimination half-life (t1/2b) were done using the 1-compartmental models. RESULTS: Oral mucositis occurred in 24 patients (49.0%), in whom 20 patients (83.3% in oral mucositis group) showed WHO severity Grade 1 or 2. Only 4 patients (16.7% in oral mucositis group) showed Grade 3 severity. 22 patients (44.9%) had oral mucositis in the group with a concentration under 10-6 M 48 h after MTX administration. There was no significant deference among the cell viabilities in the concentrations of 10-6 M, 10-5 M and 10-4 M 48 h after the MTX exposure. However, the cell viability obtained 24 h after the MTX exposure was significantly different from the respective cell viability 48, 72 and 96 h after the MTX exposure. In the group with oral mucositis, the clearance decreased significantly (p = 0.042), and the t1/2b (p = 0.025) and AUC48h- yen (p = 0.025) increased significantly compared with the non-symptom group. CONCLUSIONS: It seems that there is no significant relationship between the serum MTX concentration and oral mucositis. This in vitro study has demonstrated that the cell injury was related to the duration of MTX exposure rather than a high MTX concentration.
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Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Queratinocitos/efectos de los fármacos , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estomatitis/inducido químicamente , Adolescente , Antimetabolitos Antineoplásicos/farmacocinética , Área Bajo la Curva , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Lactante , Masculino , Tasa de Depuración Metabólica , Metotrexato/farmacocinéticaRESUMEN
We report on a search for the doubly Cabibbo suppressed decay B+-->D*+pi0, based on a data sample of 657x10(6) BB pairs collected at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider. We find no significant signal and set an upper limit of B(B+-->D*+pi0)<3.6x10(-6) at the 90% confidence level. This limit can be used to constrain the ratio between suppressed and favored B-->D*pi decay amplitudes, r<0.051, at the 90% confidence level.
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Statins possess pleiotropic effects in several tissues. Among them, their bone anabolic actions have been recently noted. We have proposed that Smad3, a TGF-beta-signaling molecule, is a promoter of bone formation. However, whether statins would affect TGF-beta-Smad3 pathway in osteoblasts is still unknown. The present study was performed to examine the effects of statin on Smad3 expression and cell apoptosis by employing mouse osteoblastic MC3T3-E1 and rat osteoblastic UMR-106 cells. Statins (pitavastatin, mevastatin, and simvastatin) as well as alendronate increased the levels of Smad3 in MC3T3-E1 cells. The effects of pitavastatin on Smad3 levels were observed from 3 hours and later. Pitavastatin induced the expression of TGF-beta, and cycloheximide, a protein synthesis inhibitor, antagonized the increased levels of pitavastatin on Smad3. On the other hand, pitavastatin antagonized dexamethasone- or etoposide-induced apoptosis in a dose-dependent manner, and Smad3 inactivation by dominant negative Smad3 or an inhibition of endogenous TGF-beta action by SB431542 antagonized anti-apoptotic effects of pitavastatin, indicating that pitavastatin suppressed osteoblast apoptosis partly through TGF-beta-Smad3 pathway. In conclusion, the present study has demonstrated for the first time that statin suppressed cell apoptosis partly through TGF-beta-Smad3 pathway in osteoblastic cells.