RESUMEN
Extramedullary hematopoiesis (EMH) suggests the presence of hematopoietic stem cells (HSC) outside bone marrow. EMH has been reported, albeit rarely, in pyogenic granuloma (PG), a polypoid lobular capillary hemangioma. However, statistical data have hitherto been lacking on the actual incidence of EMH in PG. Therefore, we here reviewed 157 consecutive cases using routine diagnostic surgical slides and found unequivocal EMH in 17 (10.8%). This indicates that EMH is a rather common finding in PG, which could thus have strong potential to be an important resource for the study of HSC.
Asunto(s)
Granuloma Piogénico/complicaciones , Hematopoyesis Extramedular , Adolescente , Adulto , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
We evaluated the pharmacological profile of ritobegron [KUC-7483; (-)-ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)-2,5-dimethylphenyloxy]acetate monohydrochloride] and its effects on the bladder in cynomolgus monkeys by in vitro and in vivo experiments. In vitro, ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50) 8.2 ± 2.3 × 10(-7) M; maximal relaxation 88.7 ± 3.7%). The ß(3)-adrenoceptor (AR) antagonist 3-(2-allylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR58894A) produced a rightward shift of this concentration-response curve without altering the maximal response (pK(B) value 6.56 ± 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC(50) 6.5 ± 1.2 × 10(-5) M). Ritobegron had no effect on tracheal contraction at concentrations from 10(-9) to 10(-4) M, and even at the highest concentration tested, 10(-3) M, the maximal relaxation it induced was only 26.7 ± 8.1%. Tests of the selectivity of ritobegron for the bladder gave values of 79.3- and 1200-fold higher versus atria and trachea, respectively. In the in vivo study ritobegron significantly decreased intravesical pressure (ED(50) 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective ß(3)-AR agonistic activity and relaxed the monkey isolated bladder, and in vivo it decreased intravesical pressure without affecting cardiovascular parameters. These results suggest that ritobegron may be a promising potential agent for the treatment of overactive bladder.
Asunto(s)
Acetatos/farmacología , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Vejiga Urinaria/efectos de los fármacos , p-Hidroxianfetamina/análogos & derivados , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Femenino , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Macaca fascicularis , Masculino , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Tráquea/efectos de los fármacos , Vejiga Urinaria/fisiología , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , p-Hidroxianfetamina/farmacologíaRESUMEN
An 85-year-old man complained of macroscopic hematuria and painful urination. Cytoscopy revealed a non-papillary tumor at the bladder neck extending to the trigone. Abdominal computed tomography revealed thickening of the bladder wall in the same area but did not reveal lymph node swelling. Urinary cytology was class IIIb. We conducted a transurethral resection of the bladder tumor (TURBT) after which a histopathological examination showed urothelial carcinoma, G3, INFγ, pT2. From 6 days after TURBT, severe fever persisted despite the administration of various antibiotics and his general condition deteriorated. He died of acute myocardial infarction at 37 days after TURBT. Histopathological examination at autopsy revealed extensive urothelial carcinoma, a plasmacytoid variant, of the bladder which had invaded into the entire body including the lungs, liver, kidneys, adrenal glands, and veins, although tumor cells were not identified in lymph nodes. We review the literature and report this rare case of urothelial carcinoma, a plasmacytoid variant, of the bladder.
Asunto(s)
Carcinoma de Células Transicionales/patología , Neoplasias de la Vejiga Urinaria/patología , Anciano de 80 o más Años , Carcinoma de Células Transicionales/cirugía , Progresión de la Enfermedad , Humanos , Masculino , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
A 53-year-old female developed epigastric discomfort and back pain in 2007. Diagnostic imaging studies demonstrated a soft tissue tumor with heterogeneous enhancement in the anterior mediastinum and multiple nodules in the right lung. She underwent expanded thymectomy with subtotal resection of the right lung. The pathological diagnosis was primary thymic mucosa-associated lymphoid tissue (MALT) lymphoma. The patient complained of ocular discomfort, oral dryness and continuous nasal bleeding in 2007. Detailed examination led to a diagnosis of Sjögren syndrome and acquired von Willebrand syndrome. Rituximab treatment for residual disease achieved not only a reduction of the lung MALT lymphoma but also clinical and hematological remission of both syndromes. This is, to our knowledge, the first reported case of primary thymic MALT lymphoma accompanied by Sjögren and acquired von Willebrand syndromes.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/complicaciones , Linfoma de Células B de la Zona Marginal/complicaciones , Síndrome de Sjögren/complicaciones , Neoplasias del Timo/complicaciones , Enfermedades de von Willebrand/complicaciones , Femenino , Humanos , Neoplasias Pulmonares/terapia , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B de la Zona Marginal/terapia , Persona de Mediana Edad , Neumonectomía , Rituximab , Síndrome de Sjögren/terapia , Timectomía , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/patología , Neoplasias del Timo/terapia , Resultado del Tratamiento , Enfermedades de von Willebrand/terapiaRESUMEN
PURPOSE: This study was performed to characterize the α1-adrenoceptor subtypes in mouse ureters as regards gene expressions and contractile functions. METHODS: The mRNAs for these subtypes were quantified by the real-time quantitative reverse transcription polymerase chain reaction. In a functional study, α1-adrenoceptor antagonists were evaluated against the noradrenaline-induced contraction in mouse isolated ureteral preparations. RESULTS: In mouse ureter, the relative mRNA expression levels for α1a-, α1b- and α1d-adrenoceptors were 74.5, 14.3 and 11.2%, respectively. Adrenaline and noradrenaline each produced a concentration-dependent phasic contraction (pD 2 values, 5.73±0.05 and 5.69±0.06, respectively). Prazosin (non-selective α1-adrenoceptor antagonist), silodosin (selective α1A-adrenoceptor antagonist), and BMY-7378 (selective α1D-adrenoceptor antagonist) all shifted the concentrationresponse curve for noradrenaline to the right, the rank order of potencies (apparent pA 2 values) being silodosin (9.32±0.11)>prazosin (8.55±0.10)>BMY-7378 (6.06±0.15). The α1A-adrenoceptor antagonist silodosin was thus much more effective than the α1D-adrenoceptor antagonist BYM-7378. CONCLUSIONS: Our results demonstrate that in mouse ureters: the mRNA for the α1A-adrenoceptor was more prevalent than those for the α1B- and α1D-adrenoceptors, and that among these subtypes, the α1A-adrenoceptor plays the major role in noradrenaline-induced contraction.
Asunto(s)
Contracción Muscular/fisiología , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/fisiología , Uréter/fisiología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Animales , Epinefrina/farmacología , Expresión Génica/fisiología , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Contracción Muscular/efectos de los fármacos , Norepinefrina/farmacología , Piperazinas/farmacología , Prazosina/farmacología , ARN Mensajero/metabolismo , Uréter/efectos de los fármacosRESUMEN
1. Using rats, we examined the muscarinic receptor subtype mediating pilocarpine-induced parotid salivary secretion and the contributions of ion transporter systems (effluxes of K+ and Cl(-)) and aquaporin-5 (AQP5) translocation to this response in parotid glands in irradiated-induced xerostomia. 2. Salivary secretion was significantly lower in irradiated compared with sham-irradiated (normal) rats. In xerostomia rats, 0.4 and 0.8 mg/kg pilocarpine significantly increased parotid salivary secretion, although the salivary volume was still significantly less than in normal rats after the same dose of pilocarpine. 3. Pirenzepine (1 x 10(-6) to 1 x 10(-1) mol/L), AF-DX 116 (3 x 10(-6) to 3 x 10(-2) mol/L) and N-2-chloroethyl-4-piperidinyl diphenylacetate (4-DAMP; 1 x 10(-8) to 1 x 10(-2) mol/L) dose-dependently displaced radioligand binding to M(1), M(2) and M(3) receptors, respectively, in parotid membranes from both normal and irradiated rats. In each group of rats, 4-DAMP had the highest binding affinity. Pretreatment with 4-DAMP or pirenzepine dose-dependently inhibited pilocarpine-induced parotid secretion in both normal and irradiated rats, with 4-DAMP being markedly more potent than pirenzepine. 4. Normal and irradiated-rat parotid cells did not differ significantly in terms of pilocarpine-induced changes in [Ca2+](i), [K+](i) and [Cl(-)](i). Pilocarpine markedly increased the amount of AQP5 in the apical plasma membrane of parotid cells isolated from normal but not irradiated rats. 5. Thus, pilocarpine induces parotid salivary secretion mainly via the M(3) receptor subtype in both irradiated and normal rats. The reduction in this pilocarpine-induced secretion seen in irradiated rats is due not to disturbances of intracellular Ca2+ mobilization or ion transporter systems, but rather to a disturbance of AQP5 translocation, which may be involved in the pathogenesis of X-ray irradiation-induced xerostomia.
Asunto(s)
Acuaporina 5/fisiología , Pilocarpina/farmacología , Salivación/efectos de los fármacos , Salivación/efectos de la radiación , Irradiación Corporal Total , Animales , Acuaporina 5/metabolismo , Calcio/metabolismo , Masculino , Agonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacología , Glándula Parótida/efectos de los fármacos , Glándula Parótida/metabolismo , Glándula Parótida/efectos de la radiación , Piperidinas/farmacología , Transporte de Proteínas/efectos de los fármacos , Traumatismos Experimentales por Radiación/etiología , Traumatismos Experimentales por Radiación/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Saliva/efectos de los fármacos , Saliva/metabolismo , Irradiación Corporal Total/efectos adversos , Xerostomía/etiología , Xerostomía/metabolismoRESUMEN
AIM: The aim of this study was to investigate the preventive actions of bezafibrate against non-alcoholic steatohepatitis (NASH), the activation of hepatic stellate cells (HSC), and fibrogenesis by using a model of NASH and an in vitro model. METHODS: Male KK-A(y)/TaJcl (KK-A(y)) mice were fed a methionine and choline-deficient (MCD) diet or a MCD diet containing bezafibrate or pioglitazone for 7 weeks, after which biochemical parameters, pathological changes, and hepatic mRNA levels were assessed. An in vitro HSC model was designed by using a previously described RI-T cell line stimulated by transforming growth factor-beta1 (TGF-beta1). RESULTS: MCD diet-fed KK-A(y) mice developed hepatic steatosis, oxidative stress, inflammation, and hepatic fibrosis. Bezafibrate markedly decreased the hepatic content of triglyceride accumulation of fatty droplets within hepatocytes, and increased the expression of hepatic fatty acid beta-oxidative genes in MCD diet-fed KK-A(y) mice. Bezafibrate markedly inhibited the increases in the plasma alanine aminotransferase level and hepatic content of thiobarbituric acid-reactive substances in this model. Moreover, it dramatically reduced hepatic inflammatory changes and fibrosis concomitantly with marked reductions in the mRNA levels for inflammatory cytokine, chemokine, and profibrogenic genes. Importantly, both bezafibrate and pioglitazone markedly reduced the mRNA levels of profibrogenic and fibrogenic genes in TGF-beta1-stimulated cells. CONCLUSION: Bezafibrate improved hepatic steatosis and potently prevented inflammation, oxidative stress, HSC activation, and fibrogenesis in the liver. Moreover, this study was the first to demonstrate that bezafibrate directly inhibits hepatic fibrogenic response induced by TGF-beta1 in vitro. Hence bezafibrate may be a new therapeutic strategy against NASH and hepatic fibrosis.
RESUMEN
AIM AND METHODS: A decreased function of multidrug-resistance 3 P-glycoprotein (MDR3), limiting the rate of biliary phospholipid secretion, predisposes individuals to cholestasis and/or cholangitis. Fibrates induce the expression of mdr2 (homolog of human MDR3) in rodents. To investigate the effects of bezafibrate (BF) on the expression levels of MDR3 in cultured human hepatocytes and human livers, the amount of protein and subcellular localization of MDR3 was assessed in HepG2 cells treated with BF and humanized livers of BF-treated chimeric mice. RESULTS: In HepG2 cells, while treatment with BF did not increase the protein levels of MDR3, the treatment caused a redistribution of MDR3 in the bile canaliculi. In humanized livers of chimeric mice, oral administration of BF induced a large increase in the protein amount of MDR3 and its redistribution in the bile canaliculi. Moreover, the modulatory effects of BF on key factors involved in hepatic cholesterol and bile acid metabolism in human subjects were traced in the humanized livers of BF-treated chimeric mice. CONCLUSION: BF causes an induction of MDR3 expression in human livers. This provides a rationale for the beneficial role of BF in improving cholestasis and/or cholangitis associated with defective MDR3 expression and function in various types of cholestatic hepatobiliary diseases.
RESUMEN
The effects of exposure of pregnant rats to methyl methanesulfonate (MMS), an alkylating agent, during the pregastrulation period on embryonic and placental development were investigated. SD rats were treated orally with a single dose of MMS (200 mg/kg) in the morning of gestation days 0, 1, 2, 3, 4, 5, or 6 (GD0 to GD6 groups, respectively). The uterine contents including fetuses and placentas of the dams were examined on gestation day 20. The individual fetuses and placentas were weighed, and the fetuses were examined for external, visceral and skeletal anomalies. The progress of ossification was also evaluated. Both pre- and postimplantation embryonic mortalities were higher in the GD0 group than in the control group. The postimplantation loss was also increased for the GD3, GD4 and GD6 groups. Fetal malformations were rare in survivors of all the MMS-treated groups. Intrauterine growth retardation was apparent for fetuses in groups GD5 and GD6. In addition, placental weight was reduced in the GD6 group, but it was increased in the GD0 group. Effects of MMS on embryonic mortality or on fetal or placental growth were absent or minimal in the GD1 and GD2 groups. These results suggest that the susceptibility of rat embryos to MMS varies during the pregastrulation period.
Asunto(s)
Antineoplásicos Alquilantes/toxicidad , Blastocisto/efectos de los fármacos , Pérdida del Embrión/inducido químicamente , Retardo del Crecimiento Fetal/inducido químicamente , Metilmetanosulfonato/toxicidad , Placenta/efectos de los fármacos , Anomalías Inducidas por Medicamentos , Administración Oral , Animales , Antineoplásicos Alquilantes/administración & dosificación , Huesos/anomalías , Huesos/efectos de los fármacos , Cesárea , Embrión de Mamíferos/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Femenino , Fertilidad/efectos de los fármacos , Peso Fetal/efectos de los fármacos , Edad Gestacional , Humanos , Metilmetanosulfonato/administración & dosificación , Osteogénesis/efectos de los fármacos , Placenta/patología , Embarazo , Ratas , Ratas Sprague-Dawley , Vísceras/anomalías , Vísceras/efectos de los fármacosRESUMEN
Over 16 months, we evaluated the effects of ovariectomy (OVX) and bisphosphonate clodronate (CLO) on bone in 48 cynomolgus monkeys (9-15 years old) fed a normal calcium diet. We established three OVX groups (oral CLO at 0 [OVX control], 12, or 60 mg/kg per day) and one sham-operated (SHAM) group. At 16 months, the bone mineral density (BMD) values (percentage of group baseline; OVX control vs. SHAM) for lumbar bone (L3-L5), proximal femur, midfemur, radius, and tibia were -2.6% versus 11.2%, -3.5% versus 8.9%, -3.0% versus 9.0%, -5.5% versus 15.7%, and -6.7% versus 13.9%, respectively. In OVX control (i) tibia showed significant loss of bone mineral content (BMC; vs. baseline), (ii) urinary deoxypyridinoline (DPD) and serum osteocalcin (OC) levels increased (peak = 182% and 168%, respectively, of SHAM), (iii) in lumbar bone and midfemur, ultimate load (UL) was reduced (vs. SHAM), (iv) in lumbar bone, trabecular bone-formation rates (BFRs) were not changed significantly, but tibial endocortical and intracortical bone formation rates were significantly raised (vs. SHAM), (v) the volumetric BMD (vBMD) and geometry of the tibial cortex (measured by peripheral quantitative computed tomography [pQCT]) were significantly reduced (vs. SHAM). CLO, 60 mg/kg per day but not 12 mg/kg per day, significantly inhibited OVX-induced changes, age-dependent increases in bone mass, and ability to maintain structure. Thus, in OVX mature cynomolgus monkeys (possibly, a unique model of the cortical bone loss secondary to estrogen deficiency), the post-OVX increases in systemic bone markers were slight, but stimulation of local turnover in the cortical envelope was enough to cause bone loss (more so in tibia than in lumbar trabecular bone). High-dose CLO prevented these changes.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Ácido Clodrónico/farmacología , Aminoácidos/orina , Animales , Biomarcadores/análisis , Fenómenos Biomecánicos , Remodelación Ósea/efectos de los fármacos , Femenino , Fémur/efectos de los fármacos , Fémur/fisiología , Vértebras Lumbares/efectos de los fármacos , Vértebras Lumbares/fisiología , Macaca fascicularis , Ovariectomía , Factores de TiempoRESUMEN
We investigated the direct effects of various bisphosphonates on osteoblasts. At 10(-5) M, clodronate increased alkaline phosphatase activity in cultured MC3T3-E1 (osteoblast-like line) and ST2 (pluripotent mesenchymal line) cells. Etidronate significantly increased alkaline phosphatase activity at 10(-5) M only in MC3T3-E1 cells. These effects were due to an increase in alkaline phosphatase-positive cell numbers, and the differentiation-enhanced cells were capable of mineralization (von Kossa stain). Other bisphosphonates (pamidronate, alendronate, and incadronate) did not increase alkaline phosphatase activity in either cell line. In cultured rat calvariae, clodronate stimulated the expression of genes for alkaline phosphatase and osteocalcin (osteoblast-differentiation markers), but decreased the expression of the gene for tartrate-resistant acid phosphatase (osteoclast marker). Clodronate, etidronate, and incadronate inhibited protein Tyr phosphatase and Ser/Thr phosphatase activities in MC3T3-E1 cells. These data suggest that clodronate acts directly on mesenchymal cells to enhance osteoblast differentiation, and this effect may be partly expressed through inhibition of protein Tyr phosphatase and/or Ser/Thr phosphatase activity.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Ácido Clodrónico/farmacología , Osteoblastos/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Animales , Northern Blotting , Diferenciación Celular/genética , Células Cultivadas , Ácido Clodrónico/química , Femenino , Feto , Ratones , Técnicas de Cultivo de Órganos , Osteoblastos/enzimología , Osteoblastos/fisiología , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Cráneo/efectos de los fármacos , Cráneo/metabolismo , Células Madre/efectos de los fármacos , Células Madre/enzimología , Células Madre/fisiología , Factores de TiempoRESUMEN
We compared the effects of nonaminobisphosphonate (nonamino-BP; clodronate) and amino-BP (alendronate) on the changes in local and systemic bone metabolism associated with chronic inflammation in adjuvant-arthritis rats. A given rat received one of the BPs orally each day for 28 days from the day of adjuvant inoculation. Hindpaw swelling was observed from day 10 after adjuvant inoculation up to day 28 (peak, day 21). Clodronate slightly decreased the hindpaw swelling at doses of 12.5 and 25 mg/kg, p.o./day; however, alendronate (0.125-0.5 mg/kg) did not. Radiological examination of the distal limb joints revealed that only clodronate decreased bone deformation. Urinary deoxypyridinoline increased as arthritis developed, and it was decreased by clodronate. On day 29, pQCT analysis of the 5th lumbar vertebra revealed trabecular bone loss and cortical bone thinning in the arthritis control group, leading to compressive strength being reduced. Both BPs prevented this bone loss and strength reduction. These data suggest that only clodronate decreases inflammation and local bone deformation, while both BPs inhibit the arthritis-related decreases in systemic bone mass and bone strength. Clodronate would be useful in the treatment of inflammation-induced bone deformation and osteopenia.
Asunto(s)
Alendronato/farmacología , Artritis Experimental/metabolismo , Huesos/efectos de los fármacos , Ácido Clodrónico/farmacología , Alendronato/uso terapéutico , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/fisiopatología , Huesos/metabolismo , Huesos/fisiopatología , Ácido Clodrónico/uso terapéutico , Masculino , Osteogénesis/efectos de los fármacos , Ratas , Ratas Endogámicas LewRESUMEN
We describe a patient wih subacute cor pulmonale caused by tumor emboli in the lungs. A 64-year-old female suffering from a subacute progressive cough and shortness of breathing died of severe pulmonary hypertension seven days after admission. Neither chest CT scans nor lung perfusion scintigraphy showed any abnormal findings. Microscopic examination after an autopsy revealed diffuse intravascular tumor emboli occluding not only the small pulmonary arteries and arterioles, but also the lymphatic vessels, which were suggested to be metastases of a breast carcinoma resected five years previously. Thus, pulmonary tumor embolism should be considered in the differential diagnosis of primary pulmonary hypertension, particularly in patients with a past history of cancers.
Asunto(s)
Hipertensión Pulmonar/diagnóstico , Neoplasias Pulmonares/diagnóstico , Células Neoplásicas Circulantes/patología , Embolia Pulmonar/diagnóstico , Enfermedad Cardiopulmonar/diagnóstico , Autopsia , Biopsia con Aguja , Diagnóstico Diferencial , Resultado Fatal , Femenino , Humanos , Hipertensión Pulmonar/complicaciones , Inmunohistoquímica , Neoplasias Pulmonares/complicaciones , Persona de Mediana Edad , Embolia Pulmonar/complicaciones , Enfermedad Cardiopulmonar/complicaciones , Radiografía Torácica , Cintigrafía/métodos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos XRESUMEN
Primary mediastinal seminoma is a relatively rare tumor usually located in the anterior mediastinum. We report here an extremely rare case of a 66-year-old man with primary seminoma in the middle mediastinum. A physical examination showed lymphadenopathy in the right supraclavicular area. A chest CT confirmed the presence of a tumor occupying the retrotracheal space. A histological examination demonstrated metastatic seminoma from the open biopsy of the lymph node. Abdominal, pelvis, and cerebral CT scan and testicular ultrasound were negative. Thus, primary mediastinal seminoma in the middle mediastinum with supraclavicular lymph node metastasis was diagnosed.
Asunto(s)
Neoplasias del Mediastino/diagnóstico , Seminoma/diagnóstico , Anciano , Humanos , Metástasis Linfática , Masculino , Neoplasias del Mediastino/patología , Seminoma/secundarioRESUMEN
Diagnosis of mucosa-associated lymphoid tissue (MALT) lymphoma based on histological examination alone is difficult. We report three patients with histologically suspected MALT lymphoma who developed lymphoproliferative lesions of the sublingual gland. Seminested polymerase chain reaction (PCR) analysis applied to formalin-fixed and paraffin-embedded specimens showed clonal rearrangement of immunoglobulin heavy chain genes in two patients and a polyclonal characteristic in one. The clinical findings and Southern blot analysis confirmed the accuracy of the diagnosis. The molecular method described can be applied routinely to processed specimens to obtain helpful information for the diagnosis of low-grade malignancies of lymphoproliferative disorders, such as MALT lymphoma.
Asunto(s)
Linfoma de Células B de la Zona Marginal/diagnóstico , Neoplasias de la Boca/diagnóstico , Anciano , Anciano de 80 o más Años , Linfocitos B/patología , Células Clonales/patología , Femenino , Reordenamiento Génico , Genes de Inmunoglobulinas/genética , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Persona de Mediana Edad , Suelo de la Boca/patología , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Neoplasias de la Glándula Sublingual/diagnóstico , Neoplasias de la Glándula Submandibular/diagnósticoRESUMEN
Wistar Hannover rats have been utilized as one of major strains in regulatory toxicology studies. This study was performed to verify the appropriate age of male sexual maturity in the development and reproductive toxicity (DART) study in Wistar Hannover rats (RccHan:WIST) by comparing reproductive endpoints between 8, 10 and 12 weeks of ages. Although fertility showed a tendency toward decrease in 8-week-old males, copulation index was not different among three ages. Testis weights reached a plateau at 10 weeks of age, whereas weights of other reproductive organs developed until 12 weeks of age. Indices of spermatogenesis (sperm motility, number of sperm in the epididymis and testis and contents of morphologically abnormal sperm) showed age-related progress and did not fully develop except for 12-week-old. For histology, epididymal tubules in 8-week-old animals showed immaturity with tall epithelium. At cesarean section, dams mated with 8-week-old males showed high incidence of preimplantation loss and the number of live fetuses was less than 10. In conclusion, although reproductive performance attained maturity by age of 10 weeks, spermatogenesis was not fully established at 10-week-old, which could result in a low fertility index. Therefore, we recommend that Wistar Hannover male rats at 12-week-old or older are used to conduct DART study properly and evaluate any adverse effects on dams and embryo-fetal development.
Asunto(s)
Envejecimiento/fisiología , Genitales Masculinos/crecimiento & desarrollo , Reproducción/fisiología , Maduración Sexual/fisiología , Pruebas de Toxicidad , Toxicología/métodos , Animales , Femenino , Fertilidad/fisiología , Humanos , Masculino , Embarazo , Ratas , Ratas Wistar , Organismos Libres de Patógenos Específicos , Espermatogénesis/fisiologíaRESUMEN
The objective of this study was to investigate the effects of the ß3-adrenoceptor (AR) agonist ritobegron on rat bladder function following partial bladder outlet obstruction and on rat salivary secretion. In addition, the effects of ritobegron were compared with those of the anti-muscarinic agent tolterodine. After a 6-week partial bladder outlet obstruction (BOO), drug effects on bladder functions were evaluated using cystometrography. Effects on carbachol (CCh)-induced salivary secretion were evaluated in urethane-anesthetized rats. Ritobegron significantly decreased the frequency of non-voiding contractions (NVC), while both ritobegron and tolterodine each significantly decreased the amplitude of NVC. Ritobegron had no effect on either the micturition pressure (MP) or the residual volume (RV). In contrast, tolterodine dose-dependently decreased MP and increased RV. Ritobegron had no effect on CCh-induced salivary secretion, whereas tolterodine dose-dependently decreased it. Ritobegron decreased both the frequency and amplitude of NVC, which is similar to its effect on the contractions associated with detrusor overactivity (DO) in patients with an overactive bladder (OAB), without affecting MP, RV, or CCh-induced salivary secretion. Although tolterodine reduced the amplitude of NVC, it also markedly increased RV and significantly inhibited CCh-induced salivary secretion. These results suggest that use of ritobegron, a ß3-AR agonist, is unlikely to lead to the residual urine and dry mouth symptoms that are associated with anti-muscarinic drugs, and that ritobegron may hold promise as a safe and effective agent for OAB treatment.
Asunto(s)
Acetatos/farmacología , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Compuestos de Bencidrilo/farmacología , Cresoles/farmacología , Antagonistas Muscarínicos/farmacología , Fenilpropanolamina/farmacología , Saliva/metabolismo , Obstrucción del Cuello de la Vejiga Urinaria/tratamiento farmacológico , Obstrucción del Cuello de la Vejiga Urinaria/fisiopatología , Vejiga Urinaria/fisiopatología , p-Hidroxianfetamina/análogos & derivados , Animales , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Tartrato de Tolterodina , p-Hidroxianfetamina/farmacologíaRESUMEN
We herein report a case of intrapelvic gastrointestinal stromal tumor (GIST) of undetermined origin in a 48-year-old male who presented with dysuria. An enlarged tumor was detected on digital rectal examination. Imaging studies showed a solid and lobular homogenous tumor of 7.0 cm in diameter. The tumor was attached to the right dorsal aspect of the prostate with compression of the seminal vesicles and rectum. It was considered that the tumor had arisen from the prostate, although the patient's serum prostate-specific antigen level was low (0.436 ng/mL). The histological diagnosis by prostate needle biopsy was a spindle cell tumor. At cystoprostatectomy, the tumor was confirmed to be separated from the prostate by a fibrous band, and showed spindle cells with a fascicular growth pattern, but without necrotic areas. Mitotic figures were noted in 12 of 50 high-power fields. The tumor cells were immunoreactive for the KIT protein (CD117), CD34, Discovered on GIST-1 (DOG-1), and vimentin. In contrast, they were negative for desmin, α-smooth muscle actin, pancytokeratin (AE1/AE3), and S100 protein. The Ki-67 labeling index was 5%. The genetic analyses targeting the c-kit gene revealed a point mutation at codon 559 (GTTâGAT). The diagnosis of GIST was confirmed on the basis of the morphological features, immunoprofile, and results of the molecular analyses. Since extraintestinal GIST can resemble a prostatic tumor clinically, KIT (CD117) and DOG-1 should be considered for inclusion in the immunohistochemical panel for spindle cell tumors obtained by prostate needle biopsy.
Asunto(s)
Tumores del Estroma Gastrointestinal/diagnóstico , Neoplasias Primarias Desconocidas/diagnóstico , Próstata/patología , Anoctamina-1 , Antígenos CD34/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biopsia con Aguja , Canales de Cloruro/metabolismo , Análisis Mutacional de ADN , ADN de Neoplasias/análisis , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/metabolismo , Pelvis , Mutación Puntual , Próstata/metabolismo , Prostatectomía , Proteínas Proto-Oncogénicas c-kit/genética , Resultado del TratamientoRESUMEN
We performed in vitro and in vivo experiments to evaluate the pharmacological profile of ritobegron and its effects on the bladder in rats. ß(3)-AR selectivity was assessed using CHO cells expressing various subtypes of the human ß-adrenoceptor (AR). Effects on isolated organs were evaluated using the organ-bath method. Effects on intravesical pressure, heart rate, and mean blood pressure were evaluated in urethane-anesthetized rats. Ritobegron increased cAMP accumulation in a concentration-dependent manner in CHO cells expressing any one of three human ß-AR, its selectivity for ß(3)-AR being 301-fold and 32-fold higher versus ß(1)-AR and ß(2)-AR, respectively. Ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50), 7.7 × 10(-8) mol/L; maximal relaxation, 97.0 %), and the ß(3)-AR antagonist SR58894A produced a parallel rightward-shift of this concentration-response curve without altering the maximal response [pK(B) value, 6.43]. Ritobegron concentration-dependently increased atrial rate and decreased myometrial contractions in vitro, and its selectivity for the bladder was 2,078-fold higher versus the atria and 14-fold higher versus the uterus. In vivo, ritobegron induced a dose-dependent decrease in intravesical pressure (ED(50) 0.4 mg/kg), without affecting heart rate and only slightly lowering mean blood pressure. Thus, ritobegron displayed potent and selective ß(3)-AR agonistic activity toward transfected human ß-AR and exhibited a high selectivity for the bladder versus other organs in rats. Moreover, it decreased intravesical pressure with minimal effects on the cardiovascular system in anesthetized rats. These results suggest that ritobegron shows promise as a potential agent for the treatment of overactive bladder.
Asunto(s)
Acetatos/farmacología , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Vejiga Urinaria/efectos de los fármacos , p-Hidroxianfetamina/análogos & derivados , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Agonistas Adrenérgicos beta/farmacología , Animales , Células CHO , Colforsina/farmacología , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Técnicas In Vitro , Isoproterenol/farmacología , Masculino , Relajación Muscular/efectos de los fármacos , Especificidad de Órganos , Ratas , Ratas Sprague-Dawley , Especificidad por Sustrato , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , p-Hidroxianfetamina/farmacologíaRESUMEN
OBJECTIVE: To compare the effects of four α(1)-adrenoceptor (AR) subtype-selective antagonists on ejaculatory function in rats to investigate whether the differences in their modes of action-based on their selectivities for the α(1A)-AR subtype-would be related to the prevalence of ejaculation disorder (EjD). METHODS: The effects of α(1)-AR antagonists on noradrenaline-induced contractions were studied in rat isolated seminal vesicles, vas deferens, bladder trigone, and prostate. Male rats were given α(1)-AR antagonists orally and, 1 hour after the drug administration they were cohoused in pairs for 1 hour with untreated female rats certified to be in estrus. The number of copulatory plugs (NP) present after mating was measured as a marker of EjD. Drug effects on ejaculatory function (ie, on NP) were compared with those on the prostatic urethra (ie, phenylephrine-induced increase in intraurethral pressure [IUP]). RESULTS: All α(1)-AR antagonists concentration-dependently inhibited noradrenaline-induced contraction in all 4 tissues, and there were no differences in the rank order of potencies (tamsulosin > silodosin > alfuzosin > naftopidil) among the tissues. All α(1)-AR antagonists dose-dependently decreased NP and inhibited the phenylephrine-induced increase in IUP. There was little difference in the dose ratio ID(50) value (dose required to produce 50% inhibition) for NP/ID(50) value for IUP response among the four drugs. Drug potencies associated NP and IUP correlated closely with affinities for the human α(1A)-AR. CONCLUSION: α(1)-AR antagonists cause EjD as a class effect that depends on affinity for α(1A)-AR. Differences in α(1A)-AR selectivity would be unlikely to be related to the incidence of EjD.