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OBJECTIVES: To determine the availability of bioelectrical impedance analysis (BIA), computed tomography (CT), and magnetic resonance imaging (MRI) for measurement of skeletal muscle mass in patients with rheumatic diseases and quantitatively assess skeletal muscle loss after glucocorticoid (GC) treatment. METHODS: The data from 22 patients with rheumatic diseases were retrospectively obtained. The muscle mass of body segments was measured with a BIA device in terms of skeletal muscle mass index (SMI). Cross-sectional area (CSA) was obtained from CT and MRI scans at the mid-thigh level using the image analysis program. We further assessed the data of three different measurements before and after GC treatment in 7 patients with rheumatic diseases. RESULTS: SMI of whole body was significantly correlated with estimated muscle volume and mid-thigh muscle CSA with CT and MRI (p < 0.01). Significant correlations between SMI and mid-thigh muscle CSA of each leg were also found (p < 0.01). All the three measurements were negatively correlated with GC dosage (p < 0.01). Significant decline in mid-thigh muscle CSA with CT and MRI was found after GC treatment in 7 patients (p < 0.02). Those patients showed significant decline in SMI of whole body after GC treatment, but not in SMI of each leg. On the other hand, significant correlations between mid-thigh muscle CSA with CT and MRI were found before and after GC treatment (p < 0.01). CONCLUSIONS: GC-related skeletal muscle loss could be quantitatively assessed with BIA, CT, or MRI in patients with rheumatic diseases, and CT and MRI appeared to be more accurate than BIA.
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Composición Corporal/fisiología , Glucocorticoides/uso terapéutico , Músculo Esquelético/patología , Enfermedades Reumáticas/tratamiento farmacológico , Enfermedades Reumáticas/patología , Adulto , Anciano , Impedancia Eléctrica , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/fisiopatología , Tamaño de los Órganos , Radiografía , Enfermedades Reumáticas/diagnóstico por imagen , Enfermedades Reumáticas/fisiopatología , Muslo/diagnóstico por imagen , Muslo/patología , Muslo/fisiopatología , Resultado del TratamientoRESUMEN
Insulinomas can present with neuroglycopenic symptoms suggesting neuropsychiatric disorders, delaying diagnosis and treatment. We recently treated a 65-year-old woman with insulinoma who was misdiagnosed at her nearby psychiatric clinic as having schizophrenia because of personality changes and memory impairment; she was treated with brexpiprazole, which was discontinued due to persistence of the symptoms. Despite her relatively low casual plasma glucose (70 mg/dL), the physician at the psychiatric clinic did not investigate the possibility of hypoglycemia, partly because her HbA1c level (5.2%) was within normal range. After skipping lunch one day, she was found by her family to be unable to communicate properly. She was transported to the emergency room of our hospital, where intermittently scanning continuous glucose monitoring (isCGM) use permitted detection of the hypoglycemia and led to a diagnosis of insulinoma and successful resection. A 72-h fasting test established hyperinsulinemic hypoglycemia. Contrast-enhanced computed-tomography and endoscopic ultrasonography together with selective arterial calcium stimulation test revealed an insulin-secreting tumor in the tail of the pancreas. Surgical resection of the tumor corrected her glucose and insulin levels as well as eliminated the insulinoma neuropsychiatric symptoms. Pathological examination showed that the tumor was positive for chromogranin A, synaptophysin and insulin. It is, therefore, important for physicians to be aware that insulinomas can manifest as neuroglycopenic symptoms and to consider the possibility of hypoglycemia by careful medical interview and isCGM, especially when patients suspected of psychiatric disorders do not show the expected response to antipsychotic drugs. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00722-9.
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OBJECTIVE: Although risk factors for intracranial aneurysm growth have been reported, studies investigating the influence of the parent artery angle are limited. In this study, we examined the relationship between intracranial aneurysm growth and parent artery angle narrowing by analyzing long-term follow-up magnetic resonance angiography data. METHODS: We retrospectively reviewed data of patients with untreated aneurysms and those treated by simple coil embolization, who were followed up by magnetic resonance angiography for over 24 months at the Steel Memorial Yawata Hospital between August 2007 and March 2023. We investigated the relationship of aneurysm growth with parent artery angle narrowing, age, sex, follow-up duration, previous subarachnoid hemorrhage, hypertension, smoking, aneurysm location, aneurysm type, maximum size, and neck size. RESULTS: A total of 180 aneurysms of 162 patients (women, n=113; untreated, n=136) were included. The median age at aneurysm diagnosis was 71 (63.8-76) years and the median follow-up duration was 69 (45-120) months. Among the 180 aneurysms, 41 (untreated, n=30; treated by simple coil embolization, n=11) showed growth during the follow-up period, with a risk of 4.4%/patient-year. In the univariable analysis, the parent artery angles on the initial and last follow-up images and angle change were significantly associated with aneurysm growth. However, in the multivariable analysis, the association remained significant only for angle change (odds ratio, 2.21; 95% confidence interval, 1.42-3.45). The cutoff value of parent artery angle change for intracranial aneurysm growth was -3.4°. CONCLUSION: Parent artery angle narrowing was significantly associated with intracranial aneurysm growth. This parameter may be useful for the monitoring of patients with unruptured intracranial aneurysms and may contribute to discerning the mechanism of intracranial aneurysm growth.
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BACKGROUND: Transnasal esophagogastroduodenoscopy (EGD) using an ultrathin endoscope is less stressful to the cardiovascular system with less elevation of systolic blood pressure (BP) than oral procedures. To elucidate the mechanism of such beneficial cardiovascular responses, we performed a prospective patient-centered randomized study in which BP and pulse rate (P), as well as autonomic nervous functions, were estimated during transnasal EGD compared with those in oral procedures using the same ultrathin endoscope. METHODS: The study involved 781 patients, among whom 55 and 56 cases were assigned to transnasal and oral EGD groups, respectively. The autonomic nervous responses were determined employing power spectral analysis (PSA) of heart-rate variations on electrocardiogram. PSA data were based on two peaks in low frequency (LF) and high-frequency (HF) ranges. HF power and the ratio of LF power/HF power represented parasympathetic and sympathetic nervous activities, respectively. RESULTS: Our study confirmed the lesser elevation of BP and P in patients undergoing transnasal EGD than in those undergoing oral procedures. PSA revealed a lower increase in LH power/HF power in transnasal EGD than in oral EGD. However, both endoscopic procedures equally suppressed HF power. Significant correlations were found between the parameters of cardiovascular response (P and BP) and autonomic functions (LF power/HF power ratio and HF power). CONCLUSIONS: This is the first study demonstrating less sympathetic stimulation in patients undergoing transnasal EGD, leading to lesser elevation of BP and P.
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Sistema Nervioso Autónomo/fisiología , Presión Sanguínea/fisiología , Endoscopía Gastrointestinal/métodos , Enfermedades Gastrointestinales/diagnóstico , Frecuencia Cardíaca/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Electrocardiografía , Femenino , Estudios de Seguimiento , Enfermedades Gastrointestinales/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Boca , Nariz , Pacientes Ambulatorios , Estudios ProspectivosRESUMEN
BACKGROUND: Cardiac autonomic neuropathy, representing decreased parasympathetic nerve activity and predominance of sympathetic tone, is often encountered in diabetic patients, and leads to an increased risk of cardiovascular events including arrhythmia. To evaluate the potential cardiovascular risk of diabetics in performing esophagogastroduodenoscopy (EGD), we compared the autonomic function and cardiovascular parameters during EGD between diabetic and nondiabetic patients. METHODS: The autonomic nervous responses in 86 consecutive outpatients (42 type 2 diabetics and 44 nondiabetics) were determined by power spectral analysis (PSA) of heart-rate variations on an electrocardiogram. PSA data were based on two peaks in the low-frequency (LF) and high-frequency (HF) ranges. HF power and the ratio of LF power/HF power represented parasympathetic and sympathetic nerve activities, respectively. RESULTS: Diabetic patients showed significantly lower DeltaHF power and significantly higher DeltaLF power/HF power than nondiabetics, suggesting enhanced predominance of sympathetic activity and marked suppression of parasympathetic function. Significant correlations were found between these autonomic parameters and the diabetic duration. A slightly higher incidence of ventricular premature contractures was observed in diabetics during EGD. However, no significant difference was found in pulse or blood pressure increments during EGD between the two groups. CONCLUSIONS: This is the first study demonstrating an imbalance of autonomic function in diabetics during EGD, which may be linked to a slightly higher risk of arrhythmia.
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Arritmias Cardíacas/fisiopatología , Vías Autónomas/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Endoscopía Gastrointestinal/métodos , Anciano , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Diabetes Mellitus Tipo 2/fisiopatología , Electrocardiografía , Femenino , Estudios de Seguimiento , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
AIM: To investigate if transnasal endoscopic retrograde cholangiopancreatography (n-ERCP) using an ultrathin forward-viewing scope may overcome the disadvantages of conventional oral ERCP (o-ERCP) related to the large-caliber side-viewing duodenoscope. METHODS: The study involved 50 patients in whom 25 cases each were assigned to the o-ERCP and n-ERCP groups. We compared the requirements of esophagogastroduodenoscopy (EGD) prior to ERCP, rates and times required for successful cannulation into the pancreatobiliary ducts, incidence of post-procedure hyperamylasemia, cardiovascular parameters during the procedure, the dose of a sedative drug, and successful rates of endoscopic naso-biliary drainage (ENBD). RESULTS: Screening gastrointestinal observations were easily performed by the forward-viewing scope and thus no prior EGD was required in the n-ERCP group. There was no significant difference in the rates or times for cannulation, or incidence of hyperamylasemia between the groups. However, the cannulation was relatively difficult in n-ERCP when the scope appeared U-shape under fluoroscopy. Increments of blood pressure and the amount of a sedative drug were significantly lower in the n-ERCP group. ENBD was successfully performed succeeding to the n-ERCP in which mouth-to-nose transfer of the drainage tube was not required. CONCLUSION: n-ERCP is likely a well-tolerable method with less cardiovascular stress and no need of prior EGD or mouth-to-nose transfer of the ENBD tube. However, a deliberate application is needed since its performance is difficult in some cases and is not feasible for some endoscopic treatments such as stenting.
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Colangiopancreatografia Retrógrada Endoscópica/instrumentación , Colangiopancreatografia Retrógrada Endoscópica/métodos , Endoscopios Gastrointestinales , Adulto , Anciano , Anciano de 80 o más Años , Presión Sanguínea/fisiología , Cateterismo , Enfermedades del Sistema Digestivo/sangre , Enfermedades del Sistema Digestivo/diagnóstico , Enfermedades del Sistema Digestivo/fisiopatología , Endoscopios Gastrointestinales/efectos adversos , Femenino , Humanos , Hiperamilasemia/etiología , Hipnóticos y Sedantes/uso terapéutico , Incidencia , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
AIM: One of the pitfalls in managing multiple liver tumors is the difficulty in identifying individual tumors on ultrasonography. Computed tomography (CT)-assisted virtual sonography has been shown to improve sonographic diagnosis, however it requires additional equipment and software. We have developed a simple reconstruction method of virtual sonography (SRVS). METHODS: We reconstructed SRVS mimicking ultrasonographic images, utilizing a workstation software attached to a multi-detector row CT system without any additional program. RESULTS: We have performed SRVS in 32 patients with 41 liver tumors that could hardly be identify on ultrasonography. SRVS assisted the identification of malignant form non-pathologic ones and thereby contributed to the appropriate clinical strategy including RFA (18 tumors), liver biopsy (2 tumors), other therapies (4 tumors) and follow-up (17 tumors). CONCLUSION: We have developed virtual sonography using conventional CT software. SRVS seems useful in the clinical practice in managing liver tumors.
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Neoplasias Hepáticas/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Ultrasonografía/métodos , Interfaz Usuario-Computador , HumanosRESUMEN
Biloma is an infrequent complication of nonsurgical treatments of hepatocellular carcinoma (HCC), including transarterial embolization (TAE), and it is often associated with ischemic injuries of the biliary tract after therapy. We here report on a case featuring successful internal drainage of an extrahepatic biloma into the duodenum by a route via the cholecyst, cholecystic duct, and common bile duct under fluoroscopic control. An extrahepatic biloma developed after urgent TAE for ruptured HCC and became contaminated. Radiography with contrast medium through the percutaneous drainage tube revealed a fistula between the biloma and gallbladder. The drainage catheter was introduced into the gallbladder through the fistula, from where it subsequently reached the duodenum via the cholecystic and common bile ducts. The internal drainage route played a major role in the rapid elimination of the biloma, which did not recur after the tube was withdrawn. To our knowledge, this is the first report of internal drainage of a biloma through the cholecystic and common bile ducts.
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Enfermedades de los Conductos Biliares/cirugía , Conductos Biliares Extrahepáticos/lesiones , Carcinoma Hepatocelular/terapia , Cateterismo Periférico/efectos adversos , Drenaje/métodos , Embolización Terapéutica/efectos adversos , Neoplasias Hepáticas/terapia , Anciano , Bilis , Enfermedades de los Conductos Biliares/diagnóstico por imagen , Enfermedades de los Conductos Biliares/etiología , Carcinoma Hepatocelular/diagnóstico por imagen , Embolización Terapéutica/métodos , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Rotura Espontánea , Tomografía Computarizada por Rayos XRESUMEN
Glucose concentration may be an important factor in breast cancer cell proliferation, and the prevalence of breast cancer is high in diabetic patients. Leptin may also be an important factor since plasma levels of leptin correlated with TNM staging for breast cancer patients. The effects of glucose and leptin on breast cancer cell proliferation were evaluated by examining cell doubling time, DNA synthesis, levels of cell cycle related proteins, protein kinase C (PKC) isozyme expression, and peroxisome proliferator-activated receptor (PPAR) subtypes were determined following glucose exposure at normal (5.5 mM) and high (25 mM) concentrations with/without leptin in MCF-7 human breast cancer cells. In MCF-7 cells, leptin and high glucose stimulated cell proliferation as demonstrated by the increases in DNA synthesis and expression of cdk2 and cyclin D1. PKC-alpha, PPARgamma, and PPARalpha protein levels were up-regulated following leptin and high glucose treatment in drug-sensitive MCF-7 cells. However, there was no significant effect of leptin and high glucose on cell proliferation, DNA synthesis, levels of cell cycle proteins, PKC isozymes, or PPAR subtypes in multidrug-resistant human breast cancer NCI/ADR-RES cells. These results suggested that hyperglycemia and hyperleptinemia increase breast cancer cell proliferation through accelerated cell cycle progression with up-regulation of cdk2 and cyclin D1 levels. This suggests the involvement of PKC-alpha, PPARalpha, and PPARgamma.
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Quinasas CDC2-CDC28 , Glucosa/farmacología , Isoenzimas/metabolismo , Leptina/farmacología , Proteína Quinasa C/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Neoplasias de la Mama , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Ciclina D1/análisis , Ciclina D1/metabolismo , Quinasa 2 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/análisis , Quinasas Ciclina-Dependientes/metabolismo , ADN/biosíntesis , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos , Humanos , Proteína Quinasa C-alfa , Proteínas Serina-Treonina Quinasas/análisis , Proteínas Serina-Treonina Quinasas/metabolismo , Timidina/metabolismo , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
A bioinformatics approach has lead to the identification of FcRY, a new Fc receptor related gene. FcRY is predicted to encode a protein with three immunoglobulin (Ig) domains followed by a mucin-like domain containing a proline-rich stalk and a C-terminal leucine rich region. The predicted protein lacks a hydrophobic domain for insertion into the plasma membrane, suggesting that FcRY is an intracellular or secreted protein. This feature is shared with the product of the FcRX/FCRL/FREB gene that is closely linked to FcRY in both human and mouse genomes. Fcry transcripts are first detectable among mouse B lineage cells at the pre-B cell stage. Splenic B cells of the newly formed, follicular, and marginal zone subsets express Fcry, as do germinal center B cells to a lesser extent. FcRY is also expressed in subpopulations of human B cells. A consistent characteristic of FcRY in both species is low level gene expression, which can be further downregulated in normal mouse B cells by signaling through the B cell receptor (BCR) or CD40, thereby suggesting a correlation between cell cycle entrance and diminished FcRY expression. Fcry is upregulated by short-term treatment with BAFF/BLyS, which promotes B cell survival rather than proliferation. LPS induces very rapid but transient enhancement. We observed a pronounced upregulation of Fcry expression in WEHI 231 cells induced by BCR crosslinking to undergo cell cycle arrest prior to apoptosis, consistent with the possible regulation of Fcry expression by cell cycle status.
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Linfocitos B/citología , Activación de Linfocitos , Receptores Fc/genética , Secuencia de Aminoácidos , Animales , Linfocitos B/inmunología , Secuencia de Bases , Clonación Molecular , Cartilla de ADN , ADN Complementario , Humanos , Inmunofenotipificación , Ratones , Datos de Secuencia Molecular , Receptores Fc/química , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de AminoácidoRESUMEN
The existence of a direct action of acetylcholine and gastrin on muscarinic M3 and cholecystokinin2 (CCK2) receptors on gastric parietal cells has not yet been convincingly established because these stimulated acid secretions are remarkably inhibited by histamine H2 receptor antagonists. In the present study, we investigated the necessity of intracellular cyclic AMP in inducing gastric acid secretion via muscarinic M3 and CCK2 receptors on parietal cells using an isolated mouse stomach preparation. Bethanechol (10-300 microM) produced a marked increase in acid output and this increase was completely blocked by famotidine (10 microM). In the presence of famotidine, bethanechol (1-30 microM) augmented the acid secretory response to dibutyryl AMP (200 microM) in a concentration-dependent manner. The augmentation was blocked by atropine (1 microM), 4-DAMP (0.1 microM), a muscarinic M3-selective antagonist, and by Ca2+ exclusion from the serosal nutrient solution. Pentagastrin (0.3-3 microM) also concentration-dependently stimulated gastric acid secretion, but the effect was completely inhibited by famotidine. In the presence of famotidine, pentagastrin (0.1-0.3 microM) elicited a definite potentiation of the acid secretory response to dibutyryl cyclic AMP (200 microM). This potentiation was inhibited by YM022 (1 microM), a CCK2 receptor antagonist, and by exclusion of Ca2+ from the serosal nutrient solution. The present results suggest that gastric acid secretion via the activation of muscarinic M3 and CCK2 receptors on the parietal cells is induced by activation of the cyclic AMP-dependent secretory pathway.
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AMP Cíclico/metabolismo , Ácido Gástrico/metabolismo , Células Parietales Gástricas/metabolismo , Receptor de Colecistoquinina B/metabolismo , Receptor Muscarínico M3/metabolismo , Análisis de Varianza , Animales , Benzodiazepinas/farmacología , Betanecol/antagonistas & inhibidores , Betanecol/metabolismo , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Famotidina/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Masculino , Ratones , Pentagastrina/antagonistas & inhibidores , Pentagastrina/metabolismoRESUMEN
Skeletal muscle has a pleiotropic role in organismal energy metabolism, for example, by storing protein as an energy source, or by excreting endocrine hormones. Muscle proteolysis is tightly controlled by the hypothalamus-pituitary-adrenal signalling axis via a glucocorticoid-driven transcriptional programme. Here we unravel the physiological significance of this catabolic process using skeletal muscle-specific glucocorticoid receptor (GR) knockout (GRmKO) mice. These mice have increased muscle mass but smaller adipose tissues. Metabolically, GRmKO mice show a drastic shift of energy utilization and storage in muscle, liver and adipose tissues. We demonstrate that the resulting depletion of plasma alanine serves as a cue to increase plasma levels of fibroblast growth factor 21 (FGF21) and activates liver-fat communication, leading to the activation of lipolytic genes in adipose tissues. We propose that this skeletal muscle-liver-fat signalling axis may serve as a target for the development of therapies against various metabolic diseases, including obesity.
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Tejido Adiposo/metabolismo , Metabolismo Energético , Factores de Crecimiento de Fibroblastos/metabolismo , Hígado/metabolismo , Músculo Esquelético/metabolismo , Receptores de Glucocorticoides/genética , Adaptación Fisiológica , Alanina/sangre , Animales , Hipertrofia , Lipólisis/genética , Ratones , Ratones Noqueados , Músculo Esquelético/patología , Proteolisis , Receptores de Glucocorticoides/metabolismo , Transducción de SeñalRESUMEN
A 50-year-old woman was admitted because of severe exophthalmos associated with Graves disease. She underwent methimazole (MMI) and methylprednisolone pulse therapy against exophthalmos. She noticed photophobia and blurred vision 3 weeks after the start of pulse therapy and she was diagnosed as having uveitis. Methylprednisolone pulse therapy was performed again for both exophthalmos and uveitis, followed by daily administration of 20 mg of prednisolone and instillation of betamethasone for 2 weeks and the uveitis was improved. Western blot analysis confirmed that human T lymphotropic virus type 1 (HTLV-1) antibody was present in her serum. Propylthiouracil was substituted for MMI and HTLV-1-associated uveitis (HAU) has not recurred. Six months after the beginning of administration of PTU, anti-neutrophil cytoplasmic antibody-related vasculitis developed in the patient. We review 43 cases of HAU with Graves disease, including the present case, in the literature. Only 2 of 27 cases (except unknown cases) (7.4%) had Graves ophthalmopathy. To the best of our knowledge, there has been no investigation of HAU and Graves ophthalmopathy.
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Anticuerpos Anticitoplasma de Neutrófilos/sangre , Enfermedad de Graves/complicaciones , Infecciones por HTLV-I/complicaciones , Uveítis/complicaciones , Vasculitis/complicaciones , Antiinflamatorios/administración & dosificación , Antitiroideos/administración & dosificación , Femenino , Enfermedad de Graves/tratamiento farmacológico , Infecciones por HTLV-I/diagnóstico , Infecciones por HTLV-I/tratamiento farmacológico , Humanos , Imagen por Resonancia Magnética , Metimazol/administración & dosificación , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Prednisolona/administración & dosificación , Propiltiouracilo/administración & dosificación , Índice de Severidad de la Enfermedad , Hormonas Tiroideas/sangre , Factores de Tiempo , Resultado del Tratamiento , Uveítis/diagnóstico , Uveítis/tratamiento farmacológico , Uveítis/virología , Vasculitis/tratamiento farmacológico , Vasculitis/inmunologíaAsunto(s)
Colangitis/patología , Hígado/patología , Vena Porta/patología , Enfermedad Aguda , Anciano , Angiografía , Colangitis/terapia , Colecistectomía , Drenaje , Femenino , Arteria Hepática/diagnóstico por imagen , Arteria Hepática/patología , Humanos , Hígado/irrigación sanguínea , Circulación Hepática , Vena Porta/diagnóstico por imagen , Flujo Sanguíneo Regional , SupuraciónRESUMEN
Right ventricular hypertrophy (RVH) and right ventricular (RV) contractile dysfunction are major determinants of prognosis in pulmonary arterial hypertension (PAH) and PAH remains a severe disease. Recently, direct interruption of left ventricular hypertrophy has been suggested to decrease the risk of left-sided heart failure. Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is a negative regulator of positive transcription elongation factor b (P-TEFb), which activates RNA polymerase II (RNAPII)-dependent transcription and whose activation is strongly associated with left ventricular hypertrophy. We hypothesized that during the progression of PAH, increased P-TEFb activity might also play a role in RVH, and that HEXIM1 might have a preventive role against such process. We revealed that, in the mouse heart, HEXIM1 is highly expressed in the early postnatal period and its expression is gradually decreased, and that prostaglandin I(2), a therapeutic drug for PAH, increases HEXIM1 levels in cardiomyocytes. These results suggest that HEXIM1 might possess negative effect on cardiomyocyte growth and take part in cardiomyocyte regulation in RV. Using adenovirus-mediated gene delivery to cultured rat cardiomyocytes, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced phosphorylation of RNAPII, cardiomyocyte hypertrophy, and mRNA expression of hypertrophic genes, whereas a HEXIM1 mutant lacking central basic region, which diminishes P-TEFb-suppressing activity, could not. Moreover, we created cardiomyocyte-specific HEXIM1 transgenic mice and revealed that HEXIM1 ameliorates RVH and prevents RV dilatation in hypoxia-induced PAH model. Taken together, these findings indicate that cardiomyocyte-specific overexpression of HEXIM1 inhibits progression to RVH under chronic hypoxia, most possibly via inhibition of P-TEFb-mediated enlargement of cardiomyocytes. We conclude that P-TEFb/HEXIM1-dependent transcriptional regulation may play a pathophysiological role in RVH and be a novel therapeutic target for mitigating RVH in PAH.
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Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/etiología , Hipertrofia Ventricular Derecha/complicaciones , Hipertrofia Ventricular Derecha/prevención & control , Hipoxia/complicaciones , Miocitos Cardíacos/metabolismo , Proteínas de Unión al ARN/genética , Animales , Progresión de la Enfermedad , Endotelina-1/sangre , Expresión Génica , Regulación de la Expresión Génica , Humanos , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Masculino , Ratones , Ratones Transgénicos , Miocitos Cardíacos/patología , Especificidad de Órganos , Factor B de Elongación Transcripcional Positiva/metabolismo , Ratas , Factores de TranscripciónRESUMEN
Maintenance of skeletal muscle mass relies on the dynamic balance between anabolic and catabolic processes and is important for motility, systemic energy homeostasis, and viability. We identified direct target genes of the glucocorticoid receptor (GR) in skeletal muscle, i.e., REDD1 and KLF15. As well as REDD1, KLF15 inhibits mTOR activity, but via a distinct mechanism involving BCAT2 gene activation. Moreover, KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1 and MuRF1 genes and negatively modulates myofiber size. Thus, GR is a liaison involving a variety of downstream molecular cascades toward muscle atrophy. Notably, mTOR activation inhibits GR transcription function and efficiently counteracts the catabolic processes provoked by glucocorticoids. This mutually exclusive crosstalk between GR and mTOR, a highly coordinated interaction between the catabolic hormone signal and the anabolic machinery, may be a rational mechanism for fine-tuning of muscle volume and a potential therapeutic target for muscle wasting.
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Músculo Esquelético/metabolismo , Receptores de Glucocorticoides/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Proteínas Musculares/metabolismo , Unión Proteica , Ratas , Receptores de Glucocorticoides/genética , Proteínas Represoras/metabolismo , Proteínas Ligasas SKP Cullina F-box/metabolismo , Factores de Transcripción , Transcripción Genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
DNA polymerase theta (Poltheta) is a family A polymerase that contains an intrinsic helicase domain. To investigate the function of Poltheta in mammalian cells, we have inactivated its polymerase activity in CH12 mouse B lymphoma cells by targeted deletion of the polymerase core domain that contains the catalytic aspartic acid residue. Compared to parental CH12 cells, mutant cells devoid of Poltheta polymerase activity exhibited a slightly reduced growth rate, accompanied by increased spontaneous cell death. In addition, mutant cells showed elevated sensitivity to mitomycin C, cisplatin, etoposide, gamma-irradiation and ultraviolet (UV) radiation. Interestingly, mutant cells were more sensitive to the alkylating agent methyl methanesulfonate (MMS) than parental cells. This elevated MMS sensitivity relative to WT cells persisted in the presence of methoxyamine, an inhibitor of the major base excision repair (BER) pathway, suggesting that Poltheta is involved in tolerance of MMS through a mechanism that appears to be different from BER. These results reveal an important role for Poltheta in preventing spontaneous cell death and in tolerance of not only DNA interstrand cross-links and double strand breaks but also UV adducts and alkylation damage in mammalian lymphocytes.