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1.
Acta Cardiol Sin ; 39(4): 619-627, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37456942

RESUMEN

Background: Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease. A97S (p.Ala117Ser) is the most common transthyretin genetic mutation in Taiwan. Tafamidis is a transthyretin stabilizer, and it has been shown to improve outcomes. However, its effect on A97S ATTR-CM subtypes remains unknown. Objectives: This study aimed to investigate the efficacy of tafamidis in patients with hereditary A97S ATTR-CM after 6 months of treatment. Methods: We retrospectively analyzed ATTR-CM patients who received tafamidis (61 mg/day) treatment at National Taiwan University Hospital. Functional status, biochemistry and echocardiography were measured at baseline and after 6 months of tafamidis treatment. The outcome measure was to compare the N-terminal pro-brain natriuretic peptide (NT-proBNP) level at baseline and after 6 months of tafamidis treatment. Results: Twenty patients were enrolled in this study. Their mean age was 63.0 ± 5.8 years and 75% were men. The baseline left ventricular (LV) mass index was 200.9 ± 63.9 g/m2, and the baseline LV ejection fraction was 58.9 ± 13.5%. After 6 months of treatment, the log NT-proBNP level significantly improved from 2.9 ± 0.6 to 2.7 ± 0.5 (p = 0.036). Subgroup analysis showed that the LV posterior wall thickness and left atrial diameter were significantly higher in the patients with improved NT-proBNP, suggesting the benefits of tafamidis for ATTR-CM patients with severe cardiac involvement. Conclusions: The patients with hereditary A97S ATTR-CM in this study had decreased levels of NT-proBNP after 6 months of tafamidis treatment, and this reduction was especially pronounced in those with more severe cardiac involvement.

2.
Mol Hum Reprod ; 27(10)2021 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-34463765

RESUMEN

There have been reports of improved pregnancy rates after performing intentional endometrial injuries, also known as endometrial scratching, in patients with recurrent implantation failure. In our previous study on intentional endometrial injury, we found an increased expression of matrix metalloproteinase (MMP)-3 following induced injuries to the mice endometrium. In the current study, we further examine whether the rise in MMP-3 could contribute to increased angiogenesis. Female C57B1/6 mice were obtained at 12 weeks of age, and intentional endometrial injuries were induced mechanically in the left uterine horns. Using the appropriate media, uterine-washes were performed on the injured and uninjured (control) horns of the harvested uteri. The uterine tissues were further processed for tissue lysates, histopathology and immunohistochemistry. The results show that intentional endometrial injuries caused an increase in secreted LPA in the injured horns, which were detected in the uterine-washes. In addition, LPA induced increased production of TNF-α in human endometrial epithelial cells (hEEpCs). Furthermore, TNF-α appeared to induce differential and cell-specific upregulation of the MMPs: MMP-3 was upregulated in the epithelial (hEEpCs), while MMP-9 was upregulated in the endothelial cells (human endometrial endothelial cells; hEEnCs). The upregulation of MMP-3 appeared to be necessary for the activation of MMP-9, whose active form stimulated the formation of vessel-like structure by the hEEnCs. The results of this study suggest that there may be enhanced angiogenesis following intentional endometrial injuries, which is mediated in part by TNF-α-induced and MMP-3-activated MMP-9 production.


Asunto(s)
Endometrio/irrigación sanguínea , Endometrio/enzimología , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Neovascularización Fisiológica , Factor de Necrosis Tumoral alfa/metabolismo , Heridas y Lesiones/enzimología , Adulto , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Endometrio/lesiones , Células Endoteliales/enzimología , Células Endoteliales/patología , Activación Enzimática , Células Epiteliales/enzimología , Células Epiteliales/patología , Femenino , Humanos , Lisofosfolípidos/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Heridas y Lesiones/genética , Heridas y Lesiones/patología
3.
Mol Hum Reprod ; 27(1)2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33543290

RESUMEN

Cyclophosphamide (CP) could cause severe gonadotoxicity via imbalanced activation of primordial follicles through PI3K/AKT/mTOR activation. Whether metformin, a widely prescribed anti-diabetes agent with mTOR inhibitory effect, could preserve ovarian function against CP toxicity is unknown. Female C57BL/6 mice were randomized into seven groups (n = 11), including control, CP-alone, CP + metformin, CP + sirolimus or everolimus, metformin-alone and sirolimus-alone groups. The duration of pharmaceutical treatment was 4 weeks. CP treatment significantly impaired ovarian function and fertility in mice. CP + metformin treatment significantly attenuated the gonadotoxicity comparing to CP-alone treatment (primordial follicle count: 17.6 ± 4.2 versus 10.3 ± 2.7 follicles/high-power field; P = 0.027). CP + metformin treatment also tended to increase antral follicular count (5.4 ± 1.1 versus 2.5 ± 1.6 follicles/section), serum AMH levels (4.6 ± 1.2 versus 2.0 ± 0.8 ng/ml) and the litter size (4.2 ± 1.3 versus 1.5 ± 1.0 mice per pregnancy), compared with CP-alone group. Expression of phospho-mTOR and the number of TUNEL-positive granulosa cells increased after CP treatment and decreased in the CP + metformin groups, suggesting the mTOR inhibitory and anti-apoptotic effects of metformin. In in-vitro granulosa cell experiments, the anti-apoptotic effect of metformin was blocked after inhibiting p53 or p21 function, and the expression of p53 mRNA was blocked with AMPK inhibitor, suggesting that the anti-apoptotic effect was AMPK/p53/p21-mediated. In conclusion, concurrent metformin treatment during CP therapy could significantly preserve ovarian function and fertility and could be a promising novel fertility preserving agent during chemotherapy. The relatively acceptable cost and well-established long-term safety profiles of this old drug might prompt its further clinical application at a faster pace.


Asunto(s)
Antineoplásicos Alquilantes/efectos adversos , Ciclofosfamida/antagonistas & inhibidores , Fertilidad/efectos de los fármacos , Hipoglucemiantes/farmacología , Metformina/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Ciclofosfamida/efectos adversos , Everolimus/farmacología , Femenino , Ratones , Ratones Endogámicos C57BL , Folículo Ovárico/efectos de los fármacos , Sustancias Protectoras/farmacología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo
4.
Biol Reprod ; 100(2): 381-389, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30247509

RESUMEN

Embryo implantation rates have been found to be enhanced by precedent endometrial injuries, but the underlying mechanism is not fully investigated. Endometrial inflammation occurs both at peri-implantation period and after endometrial injury, in which vascular reaction is a distinctive feature of inflammation. In this study, intentional endometrial injury was done with a 0.7-mm-diameter brush inserted into the left uterine horn of female ICR mice, then turned around 720° (group 2), and the right uterine horn served as the controls without endometrial injuries (group 1). Intraperitoneal equine chorionic gonadotropin 2.5 IU was injected, followed by human chorionic gonadotropin 10 IU injection, and the uterus was dissected 5 days later, roughly at the peri-implantation period. The peri-implantation endometrium was obtained, and angiogenesis protein array revealed that matrix metalloproteinase-3 (MMP-3), plasminogen activator inhibitor-1 (PAI-1), insulin-like growth factor binding protein 1 (IGFBP-1), and IL-1α were more strongly expressed in injured endometrium (group 2) than in the controls (group 1). Immunohistochemical CD34 staining was more prominently expressed in group 2 uterus, and the treatment with LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly decreased CD34 immunopositive cells. The capabilities of permeability, proliferation, tube formation, and migration of mouse endometrial endothelial cells were significantly enhanced in group 2 than in group 1. Our results demonstrate that enhanced endometrial angiogenesis is a possible mechanism accounting for the increased endometrial receptivity after endometrial injury.


Asunto(s)
Implantación del Embrión/fisiología , Endometrio/lesiones , Endometrio/fisiología , Animales , Gonadotropina Coriónica/administración & dosificación , Gonadotropina Coriónica/farmacología , Endometrio/efectos de los fármacos , Células Endoteliales/fisiología , Femenino , Ratones , Ratones Endogámicos ICR , Neovascularización Fisiológica , Embarazo
5.
J Formos Med Assoc ; 118(1 Pt 2): 249-259, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29779926

RESUMEN

BACKGROUND/PURPOSE: Abnormal folliculogenesis is one of the cardinal presentations of polycystic ovarian syndrome (PCOS) and permeability of follicular wall has been proposed to be involved in the normal follicular growth. However, whether or not there is a change in intrafollicular permeability underlies PCOS is unknown. METHODS: This was a tertiary center-based case-control study. From 2014 to 2015, thirteen patients with PCOS who underwent in vitro fertilization-embryo transfer (IVF-ET) were enrolled. Eleven normo-ovulatory patients who underwent IVF-ET due to male factor and/or tubal factor infertility were enrolled as the control group. The influence of ovarian follicular fluid (FF) on endothelial cell permeability was evaluated using a human umbilical vein endothelial cell monolayer permeability assay. The intrafollicular expression profiles of angiogenesis-related proteins were analyzed using a Human Angiogenesis Protein Array Kit. RESULTS: The FF from PCOS patients caused significantly poorer endothelial cell permeability comparing with the effect of FF from the control group (46% ± 12% vs. 58% ± 9%, P = 0.023). Among the 55 angiogenesis-related proteins tested, there was a significantly higher level of intrafollicular platelet factor 4 (PF4) and PF4/IL-8 complex in the PCOS group (p = 0.004). The anti-permeability effect of PF4 was related to the decrease in the intercellular gaps and antagonistic binding with IL-8. CONCLUSION: Our study provides the first evidence of the pathophysiologic contribution of the well-known angiostatic protein, PF4, on human reproductive biology. The increase of the intrafollicular PF4 and its anti-permeability effect might affect the formation of FF and folliculogenesis in PCOS.


Asunto(s)
Líquido Folicular/química , Infertilidad Femenina/patología , Factor Plaquetario 4/química , Síndrome del Ovario Poliquístico/patología , Adulto , Estudios de Casos y Controles , Femenino , Fertilización In Vitro , Humanos , Permeabilidad , Taiwán , Centros de Atención Terciaria
6.
J Formos Med Assoc ; 118(8): 1225-1231, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31056381

RESUMEN

BACKGROUND/PURPOSE: Genetic variant of HSD3B1 1245 is known to augment androgen production at peripheral tissue as skin. This study aimed to investigate whether women with polycystic ovary syndrome inheriting this variant exhibit specific androgenic phenotypes. METHODS: A cross-sectional study of Taiwanese women with polycystic ovary syndrome, defined by Rotterdam criteria, at the reproductive endocrinology outpatient clinic in a university affiliated hospital. RESULTS: The presence of female pattern hair loss in women with polycystic ovary syndrome was significantly associated with an increased body mass index, decreased sex hormone binding globulin and high density lipoprotein cholesterol levels, elevated triglyceride levels, and increased prevalence of hypertension. Using stepwise multivariate logistic regression analysis, body mass index, triglyceride and HSD3B1 1245 AC or CC genotype were significantly related to female pattern hair loss in women with polycystic ovary syndrome after considering other variables. Overweight women with polycystic ovary syndrome had significantly higher risk of female pattern hair loss than normal-weight women with polycystic ovary syndrome. The presence of female pattern hair loss was higher in overweight women with polycystic ovary syndrome who comprised HSD3B1 AC or CC genotype compared with wild type. CONCLUSION: Carrying the HSD3B1 1245C allele and overweight are associated with the presence of female pattern hair loss in women with polycystic ovary syndrome.


Asunto(s)
Alopecia/genética , Complejos Multienzimáticos/genética , Sobrepeso/complicaciones , Síndrome del Ovario Poliquístico/genética , Progesterona Reductasa/genética , Esteroide Isomerasas/genética , Adulto , Índice de Masa Corporal , Estudios Transversales , Femenino , Humanos , Resistencia a la Insulina , Polimorfismo Genético , Taiwán , Adulto Joven
7.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-31510052

RESUMEN

Patients with a relapse of idiopathic nephrotic syndrome have significantly increased levels of serum complement component 5a (C5a), and proteinuria has been noted in mice treated with C5a via changes in permeability of kidney endothelial cells (KECs) in established animal models. However, the apoptosis of KECs treated with high concentrations of C5a has also been observed. As mitochondrial damage is known to be important in cell apoptosis, the aim of this study was to examine the association between C5a-induced mouse KEC apoptosis and mitochondrial damage. Mouse KECs were isolated and treated with different concentrations of C5a. Cell viability assays showed that a high-concentration mouse recombinant protein C5a (rmC5a) treatment reduced mouse KEC growth. Cell cycle phase analysis, including apoptosis (sub-G1 phase) showed an increased percentage of the subG1 phase with a high-concentration rmC5a treatment. Cytochrome c and caspase 3/9 activities were significantly induced in the mouse KECs after a high-dose rmC5a (50 ng/mL) treatment, and this was rescued by pretreatment with the C5a receptor (C5aR) inhibitor (W-54011) and N-acetylcysteine (NAC). Reactive oxygen species (ROS) formation was detected in C5a-treated mouse KECs; however, W-54011 or NAC pretreatment inhibited high-dose rmC5a-induced ROS formation and also reduced cytochrome c release, apoptotic cell formation, and apoptotic DNA fragmentation. These factors determined the apoptosis of mouse KECs treated with high-dose C5a through C5aR and subsequently led to apoptosis via ROS regeneration and cytochrome c release. The results showed that high concentrations of C5a induced mouse KEC apoptosis via a C5aR/ROS/mitochondria-dependent pathway. These findings may shed light on the potential mechanism of glomerular sclerosis, a process in idiopathic nephrotic syndrome causing renal function impairment.


Asunto(s)
Apoptosis/efectos de los fármacos , Complemento C5a/farmacología , Células Endoteliales/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Recombinantes/farmacología , Acetilcisteína/farmacología , Compuestos de Anilina/farmacología , Animales , Caspasas/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Complemento C5a/genética , Citocromos c/metabolismo , Relación Dosis-Respuesta a Droga , Células Endoteliales/metabolismo , Depuradores de Radicales Libres/farmacología , Humanos , Riñón/citología , Ratones , Especies Reactivas de Oxígeno/metabolismo , Receptor de Anafilatoxina C5a/antagonistas & inhibidores , Receptor de Anafilatoxina C5a/metabolismo , Tetrahidronaftalenos/farmacología
8.
Int J Mol Sci ; 20(20)2019 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-31658764

RESUMEN

B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.


Asunto(s)
Factor Activador de Células B/metabolismo , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Hepatocitos/metabolismo , Regeneración Hepática/fisiología , FN-kappa B/metabolismo , Inductores de la Angiogénesis , Animales , Anticuerpos Neutralizantes , Factor Activador de Células B/inmunología , Proliferación Celular , Células Endoteliales , Factor 4 de Crecimiento de Fibroblastos/metabolismo , Hepatectomía , Hepatocitos/patología , Interleucina-8/metabolismo , Hígado/metabolismo , Hígado/patología , Regeneración Hepática/inmunología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL
9.
Int J Mol Sci ; 20(20)2019 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-31640178

RESUMEN

Primary aldosteronism (PA) is characterized by excess production of aldosterone from the adrenal glands and is the most common and treatable cause of secondary hypertension. Aldosterone is a mineralocorticoid hormone that participates in the regulation of electrolyte balance, blood pressure, and tissue remodeling. The excess of aldosterone caused by PA results in an increase in cardiovascular and cerebrovascular complications, including coronary artery disease, myocardial infarction, stroke, transient ischemic attack, and even arrhythmia and heart failure. Endothelial dysfunction is a well-established fundamental cause of cardiovascular diseases and also a predictor of worse clinical outcomes. Accumulating evidence indicates that aldosterone plays an important role in the initiation and progression of endothelial dysfunction. Several mechanisms have been shown to contribute to aldosterone-induced endothelial dysfunction, including aldosterone-mediated vascular tone dysfunction, aldosterone- and endothelium-mediated vascular inflammation, aldosterone-related atherosclerosis, and vascular remodeling. These mechanisms are activated by aldosterone through genomic and nongenomic pathways in mineralocorticoid receptor-dependent and independent manners. In addition, other cells have also been shown to participate in these mechanisms. The complex interactions among endothelium, inflammatory cells, vascular smooth muscle cells and fibroblasts are crucial for aldosterone-mediated endothelial dysregulation. In this review, we discuss the association between aldosterone and endothelial function and the complex mechanisms from a molecular aspect. Furthermore, we also review current clinical research of endothelial dysfunction in patients with PA.


Asunto(s)
Enfermedades Cardiovasculares/etiología , Trastornos Cerebrovasculares/etiología , Hiperaldosteronismo/metabolismo , Aldosterona/metabolismo , Enfermedades Cardiovasculares/metabolismo , Trastornos Cerebrovasculares/metabolismo , Progresión de la Enfermedad , Humanos , Hiperaldosteronismo/complicaciones , Transducción de Señal
10.
N Engl J Med ; 368(16): 1519-27, 2013 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-23594004

RESUMEN

BACKGROUND: The Patient Protection and Affordable Care Act (ACA) requires tax-exempt hospitals to conduct assessments of community needs and address identified needs. Most tax-exempt hospitals will need to meet this requirement by the end of 2013. METHODS: We conducted a national study of the level and pattern of community benefits that tax-exempt hospitals provide. The study comprised more than 1800 tax-exempt hospitals, approximately two thirds of all such institutions. We used reports that hospitals filed with the Internal Revenue Service for fiscal year 2009 that provide expenditures for seven types of community benefits. We combined these reports with other data to examine whether institutional, community, and market characteristics are associated with the provision of community benefits by hospitals. RESULTS: Tax-exempt hospitals spent 7.5% of their operating expenses on community benefits during fiscal year 2009. More than 85% of these expenditures were devoted to charity care and other patient care services. Of the remaining community-benefit expenditures, approximately 5% were devoted to community health improvements that hospitals undertook directly. The rest went to education in health professions, research, and contributions to community groups. The level of benefits provided varied widely among the hospitals (hospitals in the top decile devoted approximately 20% of operating expenses to community benefits; hospitals in the bottom decile devoted approximately 1%). This variation was not accounted for by indicators of community need. CONCLUSIONS: In 2009, tax-exempt hospitals varied markedly in the level of community benefits provided, with most of their benefit-related expenditures allocated to patient care services. Little was spent on community health improvement.


Asunto(s)
Organizaciones de Beneficencia/economía , Economía Hospitalaria , Atención al Paciente/economía , Exención de Impuesto , Relaciones Comunidad-Institución , Costos de Hospital , Hospitales Religiosos/economía , Humanos , Patient Protection and Affordable Care Act , Estados Unidos
11.
Biol Reprod ; 95(4): 87, 2016 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27605343

RESUMEN

The high serum estradiol (E2) concentrations induced during in vitro fertilization are detrimental to endometrial receptivity and may result in lower embryo implantation rates. We have previously found that high E2 concentrations inhibit the activation of nuclear factor kappa B (NF-kappa B), which led to endometrial epithelial cells (EECs) apoptosis. The objective of this study is to investigate the signaling pathways through which high E2 results in NF-kappa B downregulation in EECs. Isolated human EECs were cultured in different concentrations of E2 (10-10, 10-9, 10-8, 10-7 M). The expression of heat shock protein 70 (Hsp70) and heat shock factor 1 (HSF-1) were upregulated under supraphysiological E2 (10-7 M) concentration, whereas phosphorylated inhibitory kappa B-alpha (pI kappa B-alpha) and NF-kappa B p65 subunits were downregulated. Immunohistochemistry of C57BL/6 mouse EECs, that were exposed in vivo to high serum E2 from the administration of 20 IUs of equine chorionic gonadotropin, also demonstrated the same increase in HSF-1 and Hsp70 expression, and decrease in NF-kappa B. Immunoprecipitation of the induced Hsp70 proteins was achieved with the addition of inhibitory kappa B kinase gamma (IKK-gamma) antibodies, and elimination of this reaction occurred after addition of hsp70 siRNA. In conclusion, high E2 concentrations enhance HSF-1 and Hsp70 expression in EECs. The induced Hsp70 forms a complex with IKK-gamma and inhibits pI kappa B-alpha, which consequently suppresses NF-kappa B activation.

12.
Curr Diab Rep ; 16(6): 47, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27076180

RESUMEN

The number of available therapies for treating type 2 diabetes has grown considerably in recent years. This growth has been fueled by availability of newer medications, whose benefits and risks have not been fully established. In this study, we review and synthesize the existing literature on the uptake, efficacy, safety, and cost-effectiveness of novel antidiabetic agents. Specifically, we focus on three drug classes that were introduced in the market recently: thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. Not surprisingly, we find that the usage trends reflect the efficacy and safety profile of these novel drugs. The use of TZDs increased initially but decreased after a black-box warning was issued for rosiglitazone in 2007 that highlighted the cardiovascular risks associated with using the drug. Conversely, DPP-4 inhibitors and GLP-1 receptor agonists gained market shares due to their efficacy in glycemic control as an add-on treatment to metformin. DPP-4 inhibitors were the most commonly prescribed agents among the three novel drug classes, likely because they are relatively less expensive, have better safety profile, are administered orally, and are weight neutral. Sitagliptin was the most preferred DPP-4 inhibitor. The level of evidence on the comparative effectiveness, safety, and cost implications of using novel antidiabetic agents remains low and further studies with long-term follow-ups are needed.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Animales , Glucemia , Humanos
13.
Cell Mol Life Sci ; 72(16): 3157-71, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25790939

RESUMEN

Childhood nephrotic syndrome is mainly caused by minimal change disease which is named because only subtle ultrastructural alteration could be observed at electron microscopic level in the pathological kidney. Glomerular podocytes are presumed to be the target cells whose protein sieving capability is compromised by a yet unidentified permeability perturbing factor. In a cohort of children with non-hereditary idiopathic nephrotic syndrome, we found the complement fragment C5a was elevated in their sera during active disease. Administration of recombinant C5a induced profound proteinuria and minimal change nephrotic syndrome in mice. Purified glomerular endothelial cells, instead of podocytes, were demonstrated to be responsible for the proteinuric effect elicited by C5a. Further studies depicted a signaling pathway involving Rho/Rho-associated kinase/myosin activation leading to endothelial cell contraction and cell adhesion complex breakdown. Significantly, application of Rho-associated kinase inhibitor, Y27632, prevented the protein leaking effects observed in both C5a-treated purified endothelial cells and mice. Taken together, our study identifies a previously unknown mechanism underlying nephrotic syndrome and provides a new insight toward identifying Rho-associated kinase inhibition as an alternative therapeutic option for nephrotic syndrome.


Asunto(s)
Amidas/farmacología , Complemento C5a/efectos adversos , Síndrome Nefrótico/complicaciones , Proteinuria/tratamiento farmacológico , Piridinas/farmacología , Proteínas Recombinantes/efectos adversos , Quinasas Asociadas a rho/antagonistas & inhibidores , Análisis de Varianza , Animales , Western Blotting , Niño , Complemento C5a/metabolismo , Citocinas/análisis , Cartilla de ADN/genética , Células Endoteliales/metabolismo , Células Endoteliales/ultraestructura , Humanos , Técnicas para Inmunoenzimas , Glomérulos Renales/citología , Glomérulos Renales/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Microscopía Electrónica de Transmisión , Proteinuria/etiología , Proteinuria/metabolismo , Proteínas Recombinantes/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Quinasas Asociadas a rho/metabolismo
14.
Med Care ; 53(1): 25-31, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25373405

RESUMEN

BACKGROUND: Diabetes quality of care standards promote uniform goals and are used routinely for performance measurement and reimbursement. Diabetes health disparities have been characterized using these universal goals. However, guidelines emphasize individualized goals. OBJECTIVES: To assess diabetes care disparities using individualized goals to (1) determine their racial/ethnic distribution and (2) compare disparities using individualized versus uniform goals. RESEARCH DESIGN, SUBJECTS, AND MEASURES: A nationally representative sample of non-Hispanic white, non-Hispanic black, and Hispanic adults with self-reported diabetes aged 20 years or more in the National Health and Nutrition Examination Survey, 2007-2010. Individualized glycemic goals (A1C<6.5%, <7.0%, or <8.0%) assigned based on age, duration, complications, and comorbidity, and cholesterol goals [low-density lipoprotein cholesterol (LDL) <70 or <100 mg/dL] assigned based on cardiovascular history. RESULTS: More Hispanics were recommended an individualized A1C<7.0% compared with whites (54% vs. 42%, P=0.008). Fewer blacks and Hispanics were recommended an individualized LDL<70 mg/dL than whites (21% and 19% vs. 28%, P=0.02 and 0.001). Fewer Hispanics had adequate individualized A1C control (56% vs. 68%, P<0.001), and fewer blacks and Hispanics had adequate individualized LDL control (31% and 36% vs. 51%, P≤0.001 and P=0.004). A uniform A1C<7% goal did not reveal disparities in glycemic control; individualized A1C and LDL, blood pressure <140/90 mm Hg, and nonsmoking was achieved by few adults (18%), and fewer blacks and Hispanics than whites (6% and 11% vs. 22%, P<0.001 and P=0.005). CONCLUSIONS: Individualized goals for diabetes care may unearth greater racial/ethnic disparities in clinical performance compared with uniform goals. Diabetes performance measures should include individualized goals to prevent worsening disparities in diabetes outcomes.


Asunto(s)
Diabetes Mellitus/etnología , Diabetes Mellitus/terapia , Disparidades en Atención de Salud/etnología , Calidad de la Atención de Salud/estadística & datos numéricos , Adulto , Negro o Afroamericano/estadística & datos numéricos , Anciano , Glucemia , Presión Sanguínea , LDL-Colesterol/sangre , Comorbilidad , Complicaciones de la Diabetes , Femenino , Hemoglobina Glucada , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Encuestas Nutricionales , Prevalencia , Población Blanca/estadística & datos numéricos , Adulto Joven
15.
Int J Cancer ; 135(2): 492-501, 2014 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-24375034

RESUMEN

Radiotherapy has been integrated into the multimodal treatment of hepatocellular carcinoma (HCC), especially of localized hepatic tumor(s) refractory to conventional treatment. However, tumor control remains unsatisfactory mainly because of insufficient dose, and sublethally irradiated tumor may associate with metastasis. Our aim was to assess the effect of combining a molecularly targeted Aurora kinase inhibitor, VE-465, with radiotherapy in in vitro and in vivo models of human HCC. Human HCC cell lines (Huh7 and PLC-5) were used to evaluate the in vitro synergism of combining VE-465 with irradiation. Flow cytometry analyzed the cell cycle changes, while western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with VE-465 and/or radiotherapy for the in vivo response. VE-465 significantly enhanced radiation-induced death in HCC cells by a mechanism involving the enhanced inhibition of histone H3 phosphorylation and interruption of cell cycle change. In SCID, mice bearing ectopic HCC xenografts, pretreatment with VE-465 (20 mg/kg/day × 9 days) significantly enhanced the tumor-suppressive effect of radiotherapy (5 Gy/day × 5 days) by 54.0%. A similar combinatorial effect of VE-465 and radiotherapy was observed in an orthotopic model of Huh7 tumor growth by 17.2%. In the orthotopic Huh7 xenografts, VE-465 significantly enhanced radiation-induced tumor growth suppression by a mechanism involving the increased apoptosis. VE-465 is a potent inhibitor of Aurora kinase with therapeutic value as a radiosensitizer of HCC.


Asunto(s)
Aurora Quinasas/antagonistas & inhibidores , Carcinoma Hepatocelular/patología , Ciclo Celular , Neoplasias Hepáticas/patología , Piperazinas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Western Blotting , Carcinoma Hepatocelular/enzimología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Línea Celular Tumoral , Técnica del Anticuerpo Fluorescente , Humanos , Neoplasias Hepáticas/enzimología , Masculino , Ratones , Ratones SCID , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Cancer Cell ; 9(3): 209-23, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16530705

RESUMEN

Flt-4, a VEGF receptor, is activated by its specific ligand, VEGF-C. The resultant signaling pathway promotes angiogenesis and/or lymphangiogenesis. This report provides evidence that the VEGF-C/Flt-4 axis enhances cancer cell mobility and invasiveness and contributes to the promotion of cancer cell metastasis. VEGF-C/Flt-4-mediated invasion and metastasis of cancer cells were found to require upregulation of the neural cell adhesion molecule contactin-1 through activation of the Src-p38 MAPK-C/EBP-dependent pathway. Examination of tumor tissues from various types of cancers revealed high levels of Flt-4 and VEGF-C expression that correlated closely with clinical metastasis and patient survival. The VEGF-C/Flt-4 axis, through upregulation of contactin-1, may regulate the invasive capacity in different types of cancer cells.


Asunto(s)
Adenocarcinoma/patología , Neoplasias Pulmonares/patología , Invasividad Neoplásica/patología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adenocarcinoma/metabolismo , Animales , Moléculas de Adhesión Celular Neuronal/metabolismo , Movimiento Celular , Contactina 1 , Contactinas , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/metabolismo , Metástasis Linfática/patología , Masculino , Ratones , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
17.
Hypertens Res ; 47(3): 608-617, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37993592

RESUMEN

Primary aldosteronism is associated with various types of cardiovascular and cerebrovascular damage independently of hypertension. Although chronic hypertension and related cerebral arteriosclerosis are the main risk factors for intracerebral hemorrhage, the effects of aldosteronism remain poorly understood. We enrolled 90 survivors of hypertensive intracerebral hemorrhage, 21 of them with aldosteronism and 69 with essential hypertension as controls in this study. Clinical parameters and neuroimaging markers of cerebral small vessel disease were recorded, and its correlations with aldosteronism were investigated. Our results showed that the aldosteronism group (55.2 ± 9.7 years, male 47.6%) had similar hypertension severity but exhibited a higher cerebral microbleed count (interquartile range) (8.5 [2.0‒25.8] vs 3 [1.0‒6.0], P = 0.005) and higher severity of dilated perivascular space in the basal ganglia (severe perivascular space [number >20], 52.4% vs. 24.6%, P = 0.029; large perivascular space [>3 mm], 52.4% vs. 20.3%, P = 0.010), compared to those with essential hypertension (53.8 ± 11.7 years, male 73.9%). In multivariate models, aldosteronism remained an independent predictor of a higher (>10) microbleed count (odds ratio = 8.60, P = 0.004), severe perivascular space (odds ratio = 4.00, P = 0.038); the aldosterone-to-renin ratio was associated with dilated perivascular space (P = 0.043) and large perivascular space (P = 0.008). In conclusions, survivors of intracerebral hemorrhage with aldosteronism showed a tendency towards more severe hypertensive arteriopathy than the essential hypertension counterparts independently of blood pressure; aldosteronism may contribute to dilated perivascular space around the deep perforating arteries. Aldosteronism is associated with more severe cerebral small vessel disease in hypertensive intracerebral hemorrhage.


Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales , Hiperaldosteronismo , Hipertensión , Hemorragia Intracraneal Hipertensiva , Masculino , Humanos , Hemorragia Intracraneal Hipertensiva/diagnóstico por imagen , Hemorragia Intracraneal Hipertensiva/etiología , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico por imagen , Hipertensión/complicaciones , Hipertensión Esencial , Hiperaldosteronismo/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Imagen por Resonancia Magnética
18.
Ther Adv Chronic Dis ; 15: 20406223231222828, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38223905

RESUMEN

Background: Transthyretin cardiomyopathy (ATTR-CM) is a debilitating disease that has received much attention since the emergence of novel treatments. The Transthyretin Cardiomyopathy Clinical Trial showed that tafamidis, a transthyretin tetramer stabilizer, effectively reduced the declines in functional capacity and quality of life. However, Ala97Ser (A97S) hereditary ATTR-CM is underrepresented in major ATTR-CM tafamidis trials. Objectives: We aim to investigate the change in global longitudinal strain (GLS) of A97S ATTR-CM patients after 12 months of tafamidis treatment. Methods: We retrospectively analysed a prospective cohort of patients with A97S ATTR-CM who received tafamidis meglumine (61 mg/day) at the National Taiwan University Hospital. Echocardiography with speckle tracking strain analysis was performed at baseline and 12 months after treatment. Results: In all, 20 patients were included in the cohort. The baseline left ventricular ejection fraction (LVEF) and interventricular septum (IVS) thickness were 59.20 ± 13.23% and 15.10 ± 3.43 mm, respectively. After 12 months of tafamidis treatment, the LVEF and IVS were 61.83 ± 15.60% (p = 0.244) and 14.59 ± 3.03 mm (p = 0.623), respectively. GLS significantly improved from -12.70 ± 3.31% to -13.72 ± 3.17% (p = 0.048), and longitudinal strain (LS) in apical and middle segments significantly improved from -16.05 ± 4.82% to -17.95 ± 3.48% (p = 0.039) and -11.89 ± 4.38% to -13.58 ± 3.12% (p = 0.039), respectively. Subgroup analysis showed that patients with LVEF < 50% had a better treatment response and improvement in GLS. The patients with an IVS ⩾ 13 mm had an improvement in two-chamber LS from -10.92 ± 4.25% to -13.15 ± 3.87% (p = 0.042) and an improvement in apical left ventricular LS from -15.30 ± 5.35% to -17.82 ± 3.99% (p = 0.031). Conclusion: Tafamidis significantly improved GLS, and particularly apical and middle LS in A97S ATTR-CM patients.


Tafamidis improves myocardial longitudinal strain in A97S transthyretin cardiac amyloidosis Transthyretin cardiomyopathy (ATTR-CM) is a severe heart condition that has gained attention due to recent advancements in treatments. One of these treatments, called tafamidis, has been shown to be effective in maintaining heart function and quality of life. However, there has been limited research on a specific genetic variation of ATTR-CM: A97S. Our aim was to determine whether A97S ATTR-CM patients experienced improved heart function after one year of tafamidis treatment. We conducted this study at the National Taiwan University Hospital, where we enrolled 20 A97S ATTR-CM patients. We used echocardiography to evaluate their heart function, focusing on a parameter called global longitudinal strain. The results showed that after one year of tafamidis treatment, these patients experienced a significant improvement in their global longitudinal strain, particularly in the apical and middle regions of the heart. In conclusion, tafamidis appears to be beneficial for A97S ATTR-CM patients by enhancing their heart's global longitudinal strain, which is a positive sign for their cardiac health.

19.
J Am Heart Assoc ; 13(2): e030512, 2024 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-38214277

RESUMEN

BACKGROUND: Hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) is a progressive and fatal disease. Recent evidence indicates that bone scintigraphy may serve as a tool to monitor the effectiveness of hATTR-CM treatment. The objective of this study was to examine how eplontersen therapy influences the semiquantitative uptake of technetium-99m-pyrophosphate in individuals diagnosed with hATTR-CM. METHODS AND RESULTS: We retrospectively analyzed a prospective cohort from the NEURO-TTRansform trial, including patients with hATTR-CM receiving eplontersen (45 mg/4 weeks). A control group comprised patients with hATTR-CM who had not received eplontersen, inotersen, tafamidis, or patisiran. Technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography was conducted at baseline and during follow-up. Thirteen patients with hATTR-CM were enrolled, with 6 receiving eplontersen and 7 serving as the control group. The median follow-up time was 544 days. The eplontersen group exhibited a significant decrease in volumetric heart and lung ratio (3.774 to 2.979, P=0.028), whereas the control group showed no significant change (4.079 to 3.915, P=0.237). Patients receiving eplontersen demonstrated a significantly greater reduction in volumetric heart and lung ratio compared with the control group (-20.7% versus -3.4%, P=0.007). CONCLUSIONS: The volumetric heart and lung ratio used to quantify technetium-99m-pyrophosphate uptake showed a significant reduction subsequent to eplontersen treatment in individuals diagnosed with hATTR-CM. These findings suggest the potential efficacy of eplontersen in treating hATTR-CM and highlight the value of technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography as a tool for monitoring therapeutic effectiveness.


Asunto(s)
Neuropatías Amiloides Familiares , Cardiomiopatías , Humanos , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/tratamiento farmacológico , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/tratamiento farmacológico , Prealbúmina/genética , Prealbúmina/uso terapéutico , Estudios Prospectivos , Estudios Retrospectivos , Pirofosfato de Tecnecio Tc 99m , Tomografía Computarizada por Rayos X
20.
Front Endocrinol (Lausanne) ; 14: 1061704, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36950676

RESUMEN

Background: Primary aldosteronism (PA) is the leading cause of curable endocrine hypertension, which is associated with a higher risk of cardiovascular and metabolic insults compared to essential hypertension. Aldosterone-producing adenoma (APA) is a major cause of PA, which can be treated with adrenalectomy. Somatic mutations are the main pathogenesis of aldosterone overproduction in APA, of which KCNJ5 somatic mutations are most common, especially in Asian countries. This article aimed to review the literature on the impacts of KCNJ5 somatic mutations on systemic organ damage. Evidence acquisition: PubMed literature research using keywords combination, including "aldosterone-producing adenoma," "somatic mutations," "KCNJ5," "organ damage," "cardiovascular," "diastolic function," "metabolic syndrome," "autonomous cortisol secretion," etc. Results: APA patients with KCNJ5 somatic mutations are generally younger, female, have higher aldosterone levels, lower potassium levels, larger tumor size, and higher hypertension cure rate after adrenalectomy. This review focuses on the cardiovascular and metabolic aspects of KCNJ5 somatic mutations in APA patients, including left ventricular remodeling and diastolic function, abdominal aortic thickness and calcification, arterial stiffness, metabolic syndrome, abdominal adipose tissue, and correlation with autonomous cortisol secretion. Furthermore, we discuss modalities to differentiate the types of mutations before surgery. Conclusion: KCNJ5 somatic mutations in patients with APA had higher left ventricular mass (LVM), more impaired diastolic function, thicker aortic wall, lower incidence of metabolic syndrome, and possibly a lower incidence of concurrent autonomous cortisol secretion, but better improvement in LVM, diastolic function, arterial stiffness, and aortic wall thickness after adrenalectomy compared to patients without KCNJ5 mutations.


Asunto(s)
Adenoma , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Hipertensión , Síndrome Metabólico , Humanos , Femenino , Aldosterona/metabolismo , Hiperaldosteronismo/genética , Hiperaldosteronismo/cirugía , Hiperaldosteronismo/complicaciones , Hidrocortisona , Síndrome Metabólico/genética , Síndrome Metabólico/complicaciones , Adenoma Corticosuprarrenal/complicaciones , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/cirugía , Mutación , Hipertensión/complicaciones , Adenoma/patología , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética
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