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1.
Asian J Neurosurg ; 19(3): 369-373, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39205897

RESUMEN

Introduction Job satisfaction is a professional aspect that contributes to the achievement of objectives in general and in the health sector; it is a golden standard for having quality care. The satisfaction of nurses is a path toward humanized nursing. This article aims to evaluate the job satisfaction among nurses of the neurosurgery department at Bantane Hospital. Materials and Methods We conducted a cross-sectional study including 74 nurses at Bantane Hospital in Nagoya Japan in August 2023. Nurses responded to a questionnaire relating to job satisfaction. Univariate analysis was supported by bivariate analyses at the 95% significance level. Results The survey revealed that nurses aged between 18 and 29 were mostly represented (62.2%). Drip-injection medication was the most preferred activity (15 times) by Bantane nurses. The satisfaction rate was 63.5% and the fact of considering nurses point of view, good interpersonal relationships, and a considerable lunchtime period was statistically significant ( p < 0.05). Conclusion Transcendental motivation is a priority in the approach to humanize nursing by considering both monetary and nonmonetary incentives to motivate nurses.

2.
Heliyon ; 10(11): e32028, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38882350

RESUMEN

Objectives: Exploring the effects of swallowing function on sleep quality could provide valuable insights into the potential impact of reduced swallowing function on sleep. However, pertinent studies are limited. Therefore, this study aimed to investigate the relationship between dysphagia risk and sleep health in community-dwelling older adults. Methods: Data for this cross-sectional study were obtained from the Shizuoka and Daiko studies conducted as part of the Japan Multi-Institutional Collaborative Cohort Study. Information on demographics, overall lifestyle, dysphagia risk, as well as sleep quality, duration, satisfaction, and regularity, was obtained using a self-administered questionnaire. Dysphagia risk and sleep quality were assessed using the Dysphagia Risk Assessment Questionnaire for the Community-dwelling Elderly and the Japanese version of the Pittsburgh Sleep Questionnaire Index, respectively. Multivariate logistic regression, adjusted for covariates, was employed to assess the association between dysphagia risk and sleep health. Results: Among the 3058 participants (1633 males, 1425 females) aged ≥60 years, 28.0 % exhibited dysphagia risk, and 19.1 % reported poor sleep quality. Those with dysphagia risk were more likely to experience poor sleep quality than those without dysphagia risk. In male participants, dysphagia was significantly associated with poor sleep quality, unsatisfactory sleep, and sleep irregularity, but was not significantly associated with unsatisfactory or irregular sleep in female participants. The Japanese version of the Pittsburgh Sleep Questionnaire Index components-subjective sleep quality, sleep latency, sleep disturbances, and daytime dysfunction-were associated with dysphagia risk in both sexes. Conclusions: Dysphagia risk is associated with sleep quality in older individuals in Japan. Thus, preserving swallowing function may contribute to enhancing sleep quality.

3.
Cureus ; 16(2): e54760, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38523985

RESUMEN

BACKGROUND AND OBJECTIVE: In December 2019, COVID-19 spread rapidly across the globe. Throughout the pandemic, SARS-CoV-2 repeatedly mutated, transitioning from the alpha variant to the omicron variant. The severity and mortality of COVID-19 have been linked to age, sex, and the presence of underlying diseases (respiratory, cerebrovascular, cardiovascular, metabolic, and immune diseases, as well as cancer). The clinical features of patients infected with COVID-19 following a stroke, however, are fully unknown. Therefore, it is significant to explore the appropriate treatment for these patients based on their clinical features. METHODS: Of the 6175 patients who visited Asahi Hospital (Tokyo, Japan) between November 2022 and February 2023, 206 were admitted. Of these 206 patients, the 44 that contracted COVID-19 while hospitalized for strokes were retrospectively analyzed. RESULTS: Six (13.6%) of these patients died; four expired due to coagulopathy associated with ischemic heart failure and recurrent ischemic cerebrovascular disease. The mean D-dimer level increased to 3.53 in the deceased patients, while it was 1.64 in all patients. The platelet count was low in three of the deceased patients, while it was high in two patients. The severity of COVID-19 was significantly correlated with a high modified Rankin Scale (mRS) score and a high National Institute of Health Stroke Scale (NIHSS) score. The timing of vaccination is inversely correlated with COVID-19 severity. CONCLUSION: Patients with COVID-19 after a stroke have high mortality rates due to coagulopathy. Stroke patients with high mRS scores and high NIHSS scores are more likely to develop severe COVID-19. Anticoagulant therapy should be administered to COVID-19 patients with high mRS scores following a stroke.

4.
Biomolecules ; 13(7)2023 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-37509118

RESUMEN

The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a major regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). We have previously synthesized vitamin D derivatives with large adamantane (AD) rings at position 24, 25, or 26 of the side chain to study VDR agonist and/or antagonist properties. One of them-ADTK1, with an AD ring and 23,24-triple bond-shows a high VDR affinity and cell-selective VDR activity. In this study, we synthesized novel vitamin D derivatives (ADKM1-6) with an alkyl group substituted at position 25 of ADTK1 to develop more cell-selective VDR ligands. ADKM2, ADKM4, and ADKM6 had VDR transcriptional activity comparable to 1,25(OH)2D3 and ADTK1, although their VDR affinities were weaker. Interestingly, ADKM2 has selective VDR activity in kidney- and skin-derived cells-a unique phenotype that differs from ADTK1. Furthermore, ADKM2, ADKM4, and ADKM6 induced osteoblast differentiation in human dedifferentiated fat cells more effectively than ADTK1. The development of vitamin D derivatives with bulky modifications such as AD at position 24, 25, or 26 of the side chain is useful for increased stability and tissue selectivity in VDR-targeting therapy.


Asunto(s)
Colecalciferol , Vitamina D , Humanos , Vitamina D/farmacología , Colecalciferol/farmacología , Regulación de la Expresión Génica , Diferenciación Celular
5.
BMJ Open Sport Exerc Med ; 7(1): e000896, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33520254

RESUMEN

OBJECTIVES: To compare the mortality of Japanese athletes in the 1964 Tokyo Olympic Games with that of the Japanese population, and to elucidate factors associated with their mortality. METHODS: We obtained from the Japan Sport Association study subjects' biographical information, information on lifestyles and medical data. Missing data were obtained from online databases. Standardised mortality ratio (SMR) was calculated to compare athletes' mortality with the Japanese population. Cox proportional hazards model was applied to estimate the HR for each category of body mass index (BMI), smoking history and handgrip strength. This analysis was limited to male athletes due to the small number of female athletes. RESULTS: Among 342 (283 men, 59 women) athletes, deaths were confirmed for 70 (64 men, 6 women) athletes between September 1964 and December 2017. Total person years was 15 974.8, and the SMR was 0.64 (95% CI 0.50 to 0.81). Multivariate analysis performed on 181 male athletes. Mortality was significantly higher for BMI≥25 kg/m2 than for 21-23 kg/m2 (HR: 3.03, 95% CI 1.01 to 9.07). We found no statistically significant associations between smoking history and mortality; the HR (95% CI) for occasional and daily smokers were 0.82 (0.26 to 2.57) and 1.30 (0.55 to 3.03) compared with never smokers. We also found no statistically significant associations between handgrip strength and mortality (P for trend: 0.51). CONCLUSION: Japanese athletes in the 1964 Tokyo Olympic Games lived longer than the Japanese population. BMI≥25 kg/m2 was associated with higher mortality, but smoking history and handgrip strength were not associated with mortality.

6.
J Cachexia Sarcopenia Muscle ; 12(2): 339-349, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33463012

RESUMEN

BACKGROUND: This study aimed to determine how increased muscle mass and athletic performance in adolescence contribute to the prevention of sarcopenia in old age, accounting for the type of sport and the continuation of exercise habits. We compared the prevalence of sarcopenia, its components (low appendicular skeletal muscle mass, low muscle strength, and low physical function), and musculoskeletal pain using data from two cohorts: former athletes who competed in the 1964 Tokyo Olympics and general community-dwelling older adults living in Kashiwa City, Chiba Prefecture. METHODS: We analysed the data from 101 former Olympic athletes (mean age ± SD: 75.0 ± 4.4 years; 26% female) and 1529 general community-dwelling older adults (74.1 ± 5.5 years; 49% women). We assessed sarcopenia (defined by the Asian Working Group for Sarcopenia revised in 2019) and musculoskeletal pain and considered potential confounding factors such as demographic characteristics, for example, sex and exercise habits. RESULTS: The prevalence of sarcopenia was significantly lower in former Olympic athletes than general older adults (odds ratios [OR], 0.49; 95% confidence interval [CI], 0.20-0.94), especially with regard to superior appendicular skeletal muscle mass and muscle strength. This effect was more pronounced in individuals who continued their exercise and in athletes whose sporting discipline was classified as having a high exercise intensity. Conversely, low physical function (OR, 2.60; 95% CI, 1.16-6.07) and musculoskeletal pain (OR, 2.22; 95% CI, 1.24-3.97) were more prevalent in former Olympic athletes and in athletes who competed in sports with physical contact. CONCLUSIONS: We observed a lower prevalence of sarcopenia and superior appendicular skeletal muscle mass and strength in the former Olympic athletes, especially among those that continued their exercise habits and those in sports with high exercise intensity. Conversely, low physical function and higher musculoskeletal pain scores were more prevalent in former Olympic athletes, especially among athletes who competed in sports with physical contact. Our results warrant further promotion of exercise in adolescence and beyond as well as providing safety education, which is required to prevent the development of sarcopenia and musculoskeletal pain in old age.


Asunto(s)
Sarcopenia , Anciano , Atletas , Femenino , Humanos , Vida Independiente , Masculino , Prevalencia , Sarcopenia/epidemiología , Tokio/epidemiología
7.
J Med Chem ; 61(15): 6658-6673, 2018 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-29989817

RESUMEN

Both 25 R- and 25 S-25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3 (4a and 4b) were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki-Miyaura coupling between enol-triflate 7 and alkenyl-boronic ester 8. The 25 S isomer (4b) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1α,25-dihydroxyvitamin D3, 1) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell-type selectivity for kidney cells (HEK293, CYP24A1 160% of 1), bone cells (MG63, osteocalcin 64%), and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1 8%) and skin (HaCaT, CYP24A1 7%) cells. The X-ray crystal structural analysis of 4b in complex with rat VDR-ligand binding domain (LBD) showed the highest Cα positional shift from the 1/VDR-LBD complex at helix 11. Helix 11 of the 4b and 1 VDR-LBD complexes also showed significant differences in surface properties. These results suggest that 4b should be examined further as another candidate for a mild preventive osteoporosis agent.


Asunto(s)
Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Transporte Biológico , Técnicas de Química Sintética , Cristalografía por Rayos X , Células HEK293 , Humanos , Receptores de Calcitriol/genética , Estereoisomerismo , Transcripción Genética/efectos de los fármacos , Vitamina D/síntesis química , Vitamina D/química , Vitamina D/metabolismo , Vitamina D/farmacología
8.
Acad Radiol ; 25(12): 1632-1639, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29573936

RESUMEN

RATIONALE AND OBJECTIVES: To investigate the accuracy of dual-energy virtual monochromatic computed tomography (CT) numbers obtained by two typical hardware and software implementations: the single-source projection-based method and the dual-source image-based method. MATERIALS AND METHODS: A phantom with different tissue equivalent inserts was scanned with both single-source and dual-source scanners. A fast kVp-switching feature was used on the single-source scanner, whereas a tin filter was used on the dual-source scanner. Virtual monochromatic CT images of the phantom at energy levels of 60, 100, and 140 keV were obtained by both projection-based (on the single-source scanner) and image-based (on the dual-source scanner) methods. The accuracy of virtual monochromatic CT numbers for all inserts was assessed by comparing measured values to their corresponding true values. Linear regression analysis was performed to evaluate the dependency of measured CT numbers on tissue attenuation, method, and their interaction. RESULTS: Root mean square values of systematic error over all inserts at 60, 100, and 140 keV were approximately 53, 21, and 29 Hounsfield unit (HU) with the single-source projection-based method, and 46, 7, and 6 HU with the dual-source image-based method, respectively. Linear regression analysis revealed that the interaction between the attenuation and the method had a statistically significant effect on the measured CT numbers at 100 and 140 keV. CONCLUSIONS: There were attenuation-, method-, and energy level-dependent systematic errors in the measured virtual monochromatic CT numbers. CT number reproducibility was comparable between the two scanners, and CT numbers had better accuracy with the dual-source image-based method at 100 and 140 keV.


Asunto(s)
Imagen Radiográfica por Emisión de Doble Fotón/métodos , Tomografía Computarizada por Rayos X/métodos , Humanos , Modelos Lineales , Fantasmas de Imagen , Imagen Radiográfica por Emisión de Doble Fotón/instrumentación , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos X/instrumentación
9.
J Steroid Biochem Mol Biol ; 172: 136-148, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28736297

RESUMEN

The nuclear receptors liver X receptor (LXR) α and LXRß are involved in the regulation of lipid metabolism, inflammation, immunity, cellular proliferation, and apoptosis. Oxysterols are endogenous LXR ligands, and also interact with other nuclear and membrane receptors. We previously reported that a phytosterol derivative with a 1α-hydroxy group acts as a potent LXR agonist with intestine-selective action and that 25-hydroxy and 26/27-hydroxy metabolites of 7-dehydrocholesterol (7-DHC) exhibit partial LXR agonism. In this study, we report that 1α-hydroxy derivatives of 7-DHC, 1α-OH-7-DHC and 1,25-(OH)2-7-DHC, act as LXR modulators. Luciferase reporter gene assays showed that 1α-OH-7-DHC activates LXRα and LXRß and that 1,25-(OH)2-7-DHC activates both LXRs and vitamin D receptor. Examination of cofactor peptide association showed that the 1α-hydroxy derivatives, specifically 1,25-(OH)2-7-DHC, induce association of coactivator/corepressor peptide in a different manner from the agonist T0901317. Docking modeling and alanine mutational analysis of LXRα demonstrated that 1,25-(OH)2-7-DHC interacts with LXRα residues in a manner distinct from potent agonists, such as T0901317 and 24(S),25-epoxycholesterol. 1α-OH-7-DHC and 1,25-(OH)2-7-DHC induced expression of LXR target genes in a cell type- and gene-selective manner. 1,25-(OH)2-7-DHC effectively suppressed lipopolysaccharide-stimulated proinflammatory gene expression in an LXR-dependent manner. Therefore, 1α-hydroxy derivatives, such as 1,25-(OH)2-7-DHC, are unique LXR modulators with selective agonistic activity and potent transrepression function. These oxysterols have potential as LXR-targeted therapeutics for inflammatory disease.


Asunto(s)
Calcitriol/farmacología , Colesterol/análogos & derivados , Deshidrocolesteroles/farmacología , Hidrocarburos Fluorados/farmacología , Receptores X del Hígado/genética , Sulfonamidas/farmacología , Células CACO-2 , Calcitriol/química , Línea Celular Tumoral , Colesterol/química , Colesterol/farmacología , Deshidrocolesteroles/química , Regulación de la Expresión Génica , Genes Reporteros , Células HEK293 , Células Hep G2 , Humanos , Hidrocarburos Fluorados/química , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Receptores X del Hígado/agonistas , Receptores X del Hígado/química , Receptores X del Hígado/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , Células MCF-7 , Simulación del Acoplamiento Molecular , Especificidad de Órganos , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transducción de Señal , Relación Estructura-Actividad , Sulfonamidas/química
11.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1012-1013: 178-85, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26849186

RESUMEN

Capillary electrophoresis-capacitively coupled contactless conductivity detection (CE-C4D), conducted using an in-house-developed polyvinyl alcohol (PVA)-coated capillary system, was applied for the simultaneous analysis of small anions and cations in saliva samples from wrestlers undergoing a weight training program. Use of the PVA capillary for CE provided good reproducible ion separation with minimization of the electroosmotic flow and suppression of protein adsorption onto the capillary wall. Four cations and eight anions were separated in 12min, using a background electrolyte of 20mM MES/20mM histidine and 18-crown-6 ether (pH 6) at 20kV. The relative standard deviations (n=5) of the migration times and peak areas were <1% and <8%, respectively. The detection limit at a signal-to-noise ratio of 3 ranged from 1.6 to 10µM. Using the optimized CE-C4D system, we investigated the correlations between the concentrations of salivary ions and cortisol, which is commonly used as a stress marker. Analysis of saliva samples from ten wrestlers, who were attempting rapid weight loss before a competition, showed the following trends: (1) all ion concentrations, except for Ca(2+), Na(+), and Cl(-), increased between the first and last days of weight loss; (2) Mg(2+) increased to 166% (from 0.50mM to 1.4mM) between the first and last days of weight loss, being the highest increase of all the ions; and (3) K(+), Mg(2+), NO3(-), and SCN(-) levels were strongly correlated (P<0.05) with cortisol. The CE-C4D rapidly produced useful data on saliva ion contents, with good ion recovery as determined by the standard addition method (89-110%).


Asunto(s)
Biomarcadores/análisis , Electroforesis Capilar/métodos , Iones/análisis , Saliva/química , Lucha/fisiología , Atletas , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Pérdida de Peso
12.
J Med Chem ; 58(24): 9510-21, 2015 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-26613420

RESUMEN

Novel 19-norvitamin D analogues (ADYW1-4, 5a-d) in which an adamantyl diyne side chain is attached directly to the 17-position of the D ring are designed and stereoselectively synthesized. The adamantane ring of these analogues was expected to interfere with helix 12 (H12, activation function 2) of the vitamin D receptor (VDR) to modulate its activities. The analogue 5b binds to the VDR (7% of the natural hormone) and shows significant partial agonistic activity in transactivation assay. Compound 5b showed considerable selectivity in VDR target genes expressions in vitro, it was taken up by target cells 2-3 times more readily, and its lifetime was three times longer than the natural hormone. The X-ray crystal structure of 5b in complex with VDR reveals that the ligand binds similarly to the natural hormone, but the diyne moiety is slightly bent (angles around the diyne 5° to 8°) with respect to the original diyne vitamin D compound 6 in VDR (<1°) due to steric hindrance with helix 12.


Asunto(s)
Adamantano/análogos & derivados , Adamantano/química , Calcitriol/análogos & derivados , Adamantano/farmacología , Calcitriol/química , Calcitriol/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Agonismo Parcial de Drogas , Células HEK293 , Humanos , Estructura Molecular , Especificidad de Órganos , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/antagonistas & inhibidores , Receptores de Calcitriol/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Activación Transcripcional
13.
Radiat Oncol ; 9: 168, 2014 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-25070169

RESUMEN

BACKGROUND: In radiotherapy treatment planning, intravenous administration of an iodine-based contrast agent during computed tomography (CT) improves the accuracy of delineating target volumes. However, increased tissue attenuation resulting from the high atomic number of iodine may result in erroneous dose calculations because the contrast agent is absent during the actual procedure. The purpose of this proof-of-concept study was to present a novel framework to improve the accuracy of dose calculations using dual-energy virtual unenhanced CT in the presence of an iodine-based contrast agent. METHODS: Simple phantom experiments were designed to assess the feasibility of the proposed concept. By utilizing a "second-generation" dual-source CT scanner equipped with a tin filter for improved spectral separation, four CT datasets were obtained using both a water phantom and an iodine phantom: "true unenhanced" images with attenuation values of 2 ± 11 Hounsfield Units (HU), "enhanced" images with attenuation values of 274 ± 23 HU, and two series of "virtual unenhanced" images synthesized from dual-energy scans of the iodine phantom, each with a different combination of tube voltages. Two series of virtual unenhanced images demonstrated attenuation values of 12 ± 29 HU (with 80 kVp/140 kVp) and 34 ± 10 HU (with 100 kVp/140 kVp) after removing the iodine component from the contrast-enhanced images. Dose distributions of the single photon beams calculated from the enhanced images and two series of virtual unenhanced images were compared to those from true unenhanced images as a reference. RESULTS: The dose distributions obtained from both series of virtual unenhanced images were almost equivalent to that from the true unenhanced images, whereas the dose distribution obtained from the enhanced images indicated increased beam attenuation caused by the high attenuation characteristics of iodine. Compared to the reference dose distribution from the true unenhanced images, the dose distribution pass rates from both series of virtual unenhanced images were greater than 90%, while those from the enhanced images were less than approximately 50-60%. CONCLUSIONS: Dual-energy virtual unenhanced CT improves the accuracy of dose distributions in radiotherapy treatment planning by removing the iodine component from contrast-enhanced images.


Asunto(s)
Medios de Contraste , Yopamidol , Imagen Radiográfica por Emisión de Doble Fotón/instrumentación , Imagen Radiográfica por Emisión de Doble Fotón/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Tomografía Computarizada por Rayos X/métodos , Estudios de Factibilidad , Humanos , Fantasmas de Imagen , Proyectos Piloto , Dosificación Radioterapéutica
14.
Neuro Oncol ; 16(8): 1048-56, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24860177

RESUMEN

BACKGROUND: The metabolic preference of malignant glioma for glycolysis as an energy source is a potential therapeutic target. As a result of the cellular heterogeneity of these tumors, however, the relation between glycolytic preference, tumor formation, and tumor cell clonogenicity has remained unknown. To address this issue, we analyzed the metabolic profiles of isogenic glioma-initiating cells (GICs) in a mouse model. METHODS: GICs were established by overexpression of H-Ras(V12) in Ink4a/Arf-null neural stem cells. Subpopulations of these cells were obtained by single-cell cloning, and clones differing in extracellular acidification potential were assessed for metabolic characteristics. Tumors formed after intracranial implantation of these clones in mice were examined for pathological features of glioma and expression of glycolytic enzymes. RESULTS: Malignant transformation of neural stem cells resulted in a shift in metabolism characterized by an increase in lactic acid production. However, isogenic clonal populations of GICs manifested pronounced differences in glucose and oxygen consumption, lactate production, and nucleoside levels. These differences were paralleled by differential expression of glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2, with this differential expression also being evident in tumors formed by these clones in vivo. CONCLUSIONS: The metabolic characteristics of glioma cells appear early during malignant transformation and persist until the late stages of tumor formation. Even isogenic clones may be heterogeneous in terms of metabolic features, however, suggesting that a more detailed understanding of the metabolic profile of glioma is imperative for effective therapeutic targeting.


Asunto(s)
Neoplasias Encefálicas/patología , Diferenciación Celular/fisiología , Transformación Celular Neoplásica/patología , Glioblastoma/patología , Células Madre Neoplásicas/citología , Animales , Neoplasias Encefálicas/metabolismo , Modelos Animales de Enfermedad , Glioblastoma/metabolismo , Humanos , Ratones , Células Tumorales Cultivadas
15.
Trends Pharmacol Sci ; 35(7): 324-37, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24865943

RESUMEN

The vitamin D receptor (VDR), a receptor for the secosteroid 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a promising drug target in the treatment of bone and mineral disorders, cancer, autoimmune disease, infection, and cardiovascular disease. Indeed, approximately 100 nonsecosteroidal VDR modulators (VDRMs) have been developed. Analysis of X-ray crystal structures reveals: (i) nonsecosteroidal VDRMs bind to VDR in a position similar to 1,25(OH)2D3; (ii) hydrogen bond interactions between ligands and VDR are the most important for VDR binding; (iii) hydrophobic interactions and CH-π interactions in aromatic ligands are also important for VDR binding; and (iv) exchange of C-O-C linkage to C-CH2-C linkage in VDRMs increases transactivation activity, probably as a result of an entropic effect of solvation/desolvation of molecules. Several VDRMs have better therapeutic efficacy when compared to 1,25(OH)2D3 in experimental models of cancer and osteoporosis with less induction of hypercalcemia, a major potential adverse effect in the clinical application of VDR ligands.


Asunto(s)
Derivados del Benceno/química , Derivados del Benceno/farmacología , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Acetatos/química , Acetatos/farmacología , Animales , Arilsulfonatos/química , Arilsulfonatos/farmacología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología
16.
J Med Chem ; 57(10): 4073-87, 2014 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-24773565

RESUMEN

Vitamin D receptor (VDR) ligands are therapeutic agents that are used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism and have immense potential as therapeutic agents for autoimmune diseases, cancers, and cardiovascular diseases. However, the major side effect of VDR ligands, the development of hypercalcemia, limits their expanded use. To develop tissue-selective VDR modulators, we have designed vitamin D analogues with an adamantane ring at the side chain terminal, which would interfere with helix 12, the activation function 2, and modulate the VDR potency. Here we report 25- or 26-adamantyl-23,23,24,24-tetradehydro-19-norvitamin D derivatives (ADTK1-4, 4b,a and 5a,b). These compounds showed high VDR affinities (90% at maximum), partial agonistic activities (EC50 10(-9)-10(-8) M with 40-80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure-activity relationships of these compounds on the basis of their X-ray crystal structures.


Asunto(s)
Adamantano/análogos & derivados , Receptores de Calcitriol/agonistas , Vitamina D/análogos & derivados , Cristalografía por Rayos X , Células HEK293 , Humanos , Receptores de Calcitriol/química , Relación Estructura-Actividad
17.
PLoS One ; 9(2): e89135, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24586548

RESUMEN

Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.


Asunto(s)
Proteína Morfogenética Ósea 7/antagonistas & inhibidores , Proteína Morfogenética Ósea 7/metabolismo , Podocitos/metabolismo , Proteínas/metabolismo , Animales , Diferenciación Celular/fisiología , Células Cultivadas , Glomérulos Renales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nefronas/metabolismo , Transducción de Señal/fisiología , Proteínas Smad/metabolismo
18.
Igaku Butsuri ; 34(2): 35-46, 2014.
Artículo en Japonés | MEDLINE | ID: mdl-25693290

RESUMEN

An iterative reconstruction (IR) technique in computed tomography (CT) is expected to play an important role in reducing the radiation dose while preserving both spatial resolution and contrast-to-noise ratio. However, images obtained by using the IR technique are known to have different visual appearances from those obtained by using the traditional filtered back-projection (FBP) reconstruction. This appearance is often figuratively described as "blocky," but it has not been objectively characterized further. In this paper, we propose a novel image quality metric, called "perceptual image dissimilarity" (PID), to characterize the visual dissimilarity between FBP and IR images. The PID was formulated as a grayscale transformation and subsequent structural similarity (SSIM)-based image quality measurement. The PID metric was validated using phantom images with three different modules. Sixty datasets, each consisting of an IR image and its corresponding noise-level-equivalent FBP image, were visually assigned "subjective dissimilarity scores" on a five level scale by six observers. The data sets were then quantitatively analyzed using both the PID and the traditional mean squared error (MSE) metrics. Our results show that the PID is highly consistent with the subjective dissimilarity score and thus delivers superior performance, whereas the MSE fails to quantify the observers' visual perception.


Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Tomografía Computarizada por Rayos X/métodos , Percepción Visual/fisiología , Humanos , Variaciones Dependientes del Observador , Fantasmas de Imagen , Relación Señal-Ruido
19.
Free Radic Biol Med ; 65: 1005-1011, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23994770

RESUMEN

Here we developed a new cell-permeative lucigenin derivative, 10,10'-dimethyl-9,9'-biacridinium bis(monomethyl terephthalate) (MMT), to detect intracellular superoxide production. Both MMT and lucigenin were specific to superoxide among reactive oxygen species tested. Although lucigenin barely penetrated into cells, MMT accumulated in mitochondria in a variety of cells such as neutrophils. By employing MMT, we found that, upon activation of neutrophils with phorbol myristate acetate, superoxide was generated extracellularly as well as intramitochondrially and that such intramitochondrial superoxide production was dependent on oxidative phosphorylation. We also found that, during apoptosis, superoxide was gradually produced in mitochondria in association with phosphatidylserine exposure and that the kinetics of superoxide production was very heterogeneous at the single-cell level. Thus this study demonstrates that MMT could serve as a specific probe for intramitochondrial superoxide in either activated or apoptotic cells.


Asunto(s)
Acridinas/metabolismo , Apoptosis , Sustancias Luminiscentes/metabolismo , Mitocondrias/metabolismo , Ácidos Ftálicos/metabolismo , Superóxidos/metabolismo , Animales , Células Cultivadas , Ratones Endogámicos C57BL , Neutrófilos/fisiología , Imagen de Lapso de Tiempo
20.
J Appl Clin Med Phys ; 14(5): 173-86, 2013 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-24036870

RESUMEN

The monochromatic images acquired by Gemstone spectral imaging (GSI) mode on the GE CT750 HD theoretically determines the computed tomography (CT) number more accurately than that of conventional scanner. Using the former, the CT number is calculated from (synthesized) monoenergetic X-ray data. We reasoned that the monochromatic image might be applied to radiotherapy treatment planning (RTP) to calculate dose distribution more accurately. Our goal here was to provide CT to electron density (ED) conversion curves with monochromatic images for RTP. Therefore, we assessed the reproducibility of CT numbers, an important factor on quality assurance, over short and long time periods for different substances at varying energy. CT number difference between measured and theoretical value was investigated. The scanner provided sufficient reproducibility of CT numbers for dose calculation over short and long time periods. The CT numbers of monochromatic images produced by this scanner had reasonable values for dose calculation. The CT to ED conversion curve becomes linear with respect to the relationship between CT numbers and EDs as the energy increases. We conclude that monochromatic imaging from a fast switching system can be applied for the dose calculation, keeping Hounsfield units (HU) stability.


Asunto(s)
Electrones , Interpretación de Imagen Radiográfica Asistida por Computador/instrumentación , Planificación de la Radioterapia Asistida por Computador , Tomografía Computarizada por Rayos X/instrumentación , Algoritmos , Humanos , Órganos en Riesgo/efectos de la radiación , Fantasmas de Imagen , Radiometría , Dosificación Radioterapéutica
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