RESUMEN
BACKGROUND: Within the lung, sympathetic nerve activity (SNA) has an important role in facilitating pulmonary vasodilation. As SNA is elevated in obesity, we aimed to assess the impact of sympathetic hyper-excitation on pulmonary vascular homeostasis in obesity, and its potential role in ameliorating the severity of pulmonary hypertension (PH); the well-documented 'obesity paradox' phenomenon. METHODS: Zucker obese and lean rats were exposed to normoxia or chronic hypoxia (CH-10% O2) for 2 weeks. Subsequently, pulmonary SNA (pSNA) was recorded (electrophysiology), or the pulmonary microcirculation was visualized using Synchrotron microangiography. Acute hypoxic pulmonary vasoconstriction (HPV) was assessed before and after blockade of ß1-adrenergic receptors (ARs) (atenolol, 3 mg kg(-1)) and ß1+ß2-adrenergic (propranolol, 2 mg kg(-1)). RESULTS: pSNA of normoxic obese rats was higher than lean counterparts (2.4 and 0.5 µV s, respectively). SNA was enhanced following the development of PH in lean rats, but more so in obese rats (1.7 and 6.8 µV s, respectively). The magnitude of HPV was similar for all groups (for example, ~20% constriction of the 200-300 µm vessels). Although ß-blockade did not modify HPV in lean rats, it significantly augmented the HPV in normoxic obese rats (ß1 and ß2 blockade), and more so in obese rats with PH (ß2-blockade alone). Western blots showed, while the expression of pulmonary ß1-ARs was similar for all rats, the expression of ß2-ARs was downregulated in obesity and PH. CONCLUSIONS: This study suggests that sympathetic hyper-excitation in obesity may have an important role in constraining the severity of PH and, thus, contribute in part to the 'obesity paradox' in PH.
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Hipertensión Pulmonar/fisiopatología , Obesidad/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Antagonistas Adrenérgicos beta/farmacología , Animales , Modelos Animales de Enfermedad , Hipoxia/patología , Pulmón/irrigación sanguínea , Microcirculación , Obesidad/patología , Propranolol/farmacología , Ratas , Ratas Zucker , Vasoconstricción/fisiologíaRESUMEN
PURPOSE: Human hands are excellent in performing sensory and motor function. We have hypothesized that blood flow of the hand is dynamically regulated by sympathetic outflow during concentrated finger perception. To identify this hypothesis, we measured radial blood flow (RBF), radial vascular conductance (RVC), heart rate (HR), and arterial blood pressure (AP) during Braille reading performed under the blind condition in nine healthy subjects. The subjects were instructed to read a flat plate with raised letters (Braille reading) for 30 s by the forefinger, and to touch a blank plate as control for the Braille discrimination procedure. RESULTS: HR and AP slightly increased during Braille reading but remained unchanged during the touching of the blank plate. RBF and RVC were reduced during the Braille character discrimination task (decreased by -46% and -49%, respectively). Furthermore, the changes in RBF and RVC were much greater during the Braille character discrimination task than during the touching of the blank plate (decreased by -20% and -20%, respectively). CONCLUSIONS: These results have suggested that the distribution of blood flow to the hand is modulated via sympathetic nerve activity during concentrated finger perception.
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Dedos/irrigación sanguínea , Flujo Sanguíneo Regional/fisiología , Percepción del Tacto/fisiología , Tacto/fisiología , Ceguera , Presión Sanguínea/fisiología , Discriminación en Psicología/fisiología , Dedos/inervación , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Auxiliares Sensoriales , Sistema Nervioso Simpático/fisiología , Adulto JovenRESUMEN
The present study examined the effects of acute high-intensity exercise on Ca(2+) uptake and release rates and Ca(2+)-adenosine triphosphatase (ATPase) activity of the sarcoplasmic reticulum (SR) from the costal diaphragm. The rats were run on a treadmill at an estimated requirement of 100% of maximal O2 consumption until fatigued (average time to exhaustion: 4.79 min). Muscle lactate and inorganic phosphate after exercise were increased by 65% (P < 0.05) and 35% (P < 0.05), respectively. With exercise, Ca(2+) uptake and release, which were detected in homogenates using the Ca(2+) fluorescent dye indo-1, were decreased by 24% (P < 0.05) and 22% (P < 0.05), respectively. The reduction in Ca(2+) uptake was paralleled by decreased activity of SR Ca(2+)-ATPase in both the absence and presence of Ca(2+) ionophore. These findings demonstrate that, in the diaphragm as well as in the locomotor muscles that have been explored in previous studies, the attenuations of the SR function is brought about by acute high-intensity exercise. These changes in the SR of the diaphragm may contribute, at least in part, to deteriorations in exercise tolerance and work productivity resulting from repetitive physical activities.
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Diafragma/fisiología , Condicionamiento Físico Animal/fisiología , Retículo Sarcoplasmático/fisiología , Animales , Calcio/metabolismo , ATPasas Transportadoras de Calcio/metabolismo , Glucógeno/análisis , Lactatos/análisis , Masculino , Fatiga Muscular/fisiología , Fosfatos/análisis , Ratas , Ratas WistarRESUMEN
To examine a hypothesis of whether static muscle contraction produces a release of catecholamines from the adrenal medulla via reflex stimulation of preganglionic adrenal sympathetic nerve activity induced by receptors in the contracting muscle, we compared the reflex responses in a concentration of epinephrine (Ep) and norepinephrine (NEp) in arterial plasma during static contraction and during a mechanical stretch of the hindlimb triceps surae muscle in anesthetized cats. Static contraction was evoked by electrically stimulating the peripheral ends of the cut L(7) and S(1) ventral roots at 20 or 40 Hz. Mean arterial pressure (MAP) and heart rate (HR) increased 23 +/- 3.1 mmHg and 19 +/- 4.3 beats/min during static contraction. Ep in arterial plasma increased 0.18 +/- 0.072 ng/ml over the control of 0.14 +/- 0.051 ng/ml within 1 min from the onset of static contraction, and NEp increased 0.47 +/- 0.087 ng/ml over the control of 0.71 +/- 0.108 ng/ml. Following a neuromuscular blockade, although the same ventral root stimulation failed to produce the cardiovascular and plasma catecholamine responses, the mechanical stretch of the muscle increased MAP, HR, and plasma Ep, but not plasma NEp. With bilateral adrenalectomy, the baseline Ep became negligible (0.012 +/- 0.001 ng/ml) and the baseline NEp was lowered to 0.52 +/- 0.109 ng/ml. Neither static contraction nor mechanical stretch produced significant responses in plasma Ep and NEp following the adrenalectomy. These results suggest that static muscle contraction augments preganglionic adrenal sympathetic nerve activity, which in turn secretes epinephrine from the adrenal medulla into plasma. A muscle mechanoreflex from the contracting muscle may play a role in stimulation of the adrenal sympathetic nerve activity.
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Médula Suprarrenal/inervación , Médula Suprarrenal/fisiología , Epinefrina/metabolismo , Contracción Muscular/fisiología , Norepinefrina/metabolismo , Animales , Presión Sanguínea , Gatos , Estimulación Eléctrica , Frecuencia Cardíaca , Mecanorreceptores/fisiología , Sistema Nervioso Simpático/fisiologíaRESUMEN
We report the results of cytogenetic analyses of three cases of meningiomas. The first case, a papillary meningioma, showed only one cytogenetic abnormality, 46,XX,t(1;4)(q44;q21). In contrast, the other two benign fibroblastic meningiomas showed loss of chromosome 22. Loss and/or rearrangement of chromosomes other than chromosome 22 appears to be associated with a more aggressive clinical course. It is suggested that a sole cytogenetic abnormality with a normal chromosome 22 indicates an atypical nature of meningioma.
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Cromosomas Humanos Par 1 , Cromosomas Humanos Par 4 , Meningioma/genética , Translocación Genética , Adulto , Bandeo Cromosómico , Femenino , Humanos , Cariotipificación , Masculino , Persona de Mediana EdadRESUMEN
The purpose of this study was to evaluate the relationship between onset of blood lactate accumulation (OBLA) and long-distance running performance in order to examine whether OBLA can be a good predictor of long-distance running performance even in elite male runners with similar performance levels. Eleven highly-trained male long-distance runners participated in this study. The average running velocities of the individuals' running performance were 5.918 +/- 0.084 m.s-1 and 5.672 +/- 0.095 m.s-1 for 5000 m (V5000) and 10,000 m (V10000), respectively. The blood lactate concentrations and heart rate responses were measured immediately after field running, and the average value of running velocity corresponding to OBLA (VOBLA) was 5.447 +/- 0.132 m.s-1. Variations of these three velocities expressed as a coefficient of variance (CV) ranged from 1.4 to 2.4%. A strong inverse relationship between heart rate corresponding to OBLA (HROBLA) and performance was observed (r = -0.709, p < 0.02 for V5000 and r = -0.830, p < 0.01 for V10000), while there was a lack of significant relationship between VOBLA and performance (r = 0.293, NS for V5000 and r = 0.130, NS for V10000). Furthermore, the average value of HROBLA obtained in this study (174.5 +/- 8.2 b.min-1) was quite similar to that of the heart rate threshold reported by some previous researchers. In conclusion, VOBLA alone could not explain the small variation of long-distance running performance, and HROBLA should be used in place of VOBLA for evaluating long-distance running performance in elite runners with quite similar performance levels.
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Ácido Láctico/sangre , Aptitud Física/fisiología , Carrera/fisiología , Adulto , Biomarcadores/sangre , Humanos , Modelos Lineales , Masculino , Factores de TiempoRESUMEN
PURPOSE: We tested cross-species validity of the role of the claustrum in the convulsive evolution of the visual afferent and amygdaloid seizure and the specificity of the claustral lesioning effect. METHODS: In 7 Senegalese baboons, we examined the effect of unilateral claustral lesioning on generalized convulsive seizures either kindled from the amygdaloid nucleus (AM) and cingulate cortex (CG) or induced by intermittent photic stimulation (IPS) after systemic administration of D,L-allylglycine (AG). RESULTS: A lesioned area common to all animals was the anterior half of the left claustrum. Postoperative restimulation of the kindled left AM or CG evoked only nonconvulsive seizures. When few convulsive seizures emerged in 1 CG-kindled animal, they were mirror image of the kindled seizure and arose from the nonlesioned right hemisphere. Restimulation of the kindled right AM or CG reactivated kindled seizures. An IPS-induced generalized convulsive seizure was transformed into a secondarily generalized seizure arising from the nonlesioned right hemisphere. CONCLUSIONS: The primate claustrum regulates the convulsive evolution of partial seizures originating from nonmotor structures such as the AM and CG and also regulates the convulsive development that follows IPS. Our findings suggest that predisposed susceptibility expressed at the claustrum may be involved in the clinical variation with respect to convulsive evolution of nonmotor partial seizures and convulsive susceptibility to IPS in human primates.
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Ganglios Basales/fisiología , Lateralidad Funcional/fisiología , Giro del Cíngulo/fisiología , Excitación Neurológica/fisiología , Papio/fisiología , Convulsiones/etiología , Alilglicina , Amígdala del Cerebelo/fisiología , Animales , Gatos , Electrodos Implantados , Electroencefalografía/estadística & datos numéricos , Femenino , Masculino , Estimulación Luminosa , Convulsiones/inducido químicamenteRESUMEN
An inwardly rectifying K+ current, which was heterologously expressed in Xenopus oocytes, was inhibited by isoproterenol, a fadrenergic agonist. Poly(A)+ mRNA isolated from guinea-pig brain was injected into oocytes 2-3 days before experiments. Isoproterenol inhibition of the K+ current was time-and voltage-dependent: the inhibition became faster and more pronounced as the command voltage steps were applied to more negative potentials. This inhibition was prevented by propranolol. Dibutylyl cyclic (dB-c) AMP could mimic the effect of isoproterenol, while injection of the catalytic subunit of cAMP-dependent protein kinase into the oocytes did not affect the K+ current. Inhibitors of the protein kinases, WIPTIDE and H-8, did not prevent the inhibition by dB-cAMP. Furthermore, dB-cGMP also inhibited the K+ current in a similar time- and voltage-dependent manner. We propose that the phosphorylation-independent action of cyclic nucleotides mediates beta-adrenergic inhibition of brain inwardly rectifying K+ channels expressed in Xenopus oocytes.
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Encéfalo/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Canales de Potasio de Rectificación Interna , Canales de Potasio/metabolismo , Agonistas Adrenérgicos beta/farmacología , Animales , Bario/farmacología , Bucladesina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , GMP Dibutiril Cíclico/farmacología , Cobayas , Isoproterenol/farmacología , Potenciales de la Membrana , Oocitos , Técnicas de Placa-Clamp , Fosforilación , Bloqueadores de los Canales de Potasio , XenopusRESUMEN
Kindling of the cingulate cortex in the Senegalese baboon Papio papio led to a protracted nonconvulsive seizure state characterized by immobile staring with (anterior cingulate, AC) or without (posterior cingulate, PC) widening of eyelids and neck flexion, followed by postictal visual searching behavior. Despite early bilateral spread of EEG discharges, ictal and interictal patterns remained persistently asymmetric. Secondary generalization was rapid and predictable once contralateral lower facial twitching associated with sustained adversion developed. After the primary site had been kindled, stimulation of the contralateral homotopic posterior cingulate cortex readily produced afterdischarge. However, it remained localized and kindling growth did not occur. The findings suggest that (a) the cingulate cortex can support nonconvulsive seizures; (b) cingulate seizures are accompanied by asymmetric convexity EEG discharges indicating its lateralized onset; (c) further evolution to convulsive seizures after kindling of cingulate cortex requires access to the ipsilateral frontocentral cortex responsible for facial twitching; and (d) the development of focal epileptogenesis at one cingulate site interferes with clinical seizure development at the homotopic contralateral site.
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Giro del Cíngulo/fisiología , Excitación Neurológica/fisiología , Papio/fisiología , Adolescente , Adulto , Anciano , Amígdala del Cerebelo/fisiología , Animales , Conducta Animal/fisiología , Estimulación Eléctrica , Electroencefalografía , Femenino , Lateralidad Funcional/fisiología , Humanos , Masculino , Persona de Mediana Edad , Vías Nerviosas/fisiología , Convulsiones/etiologíaRESUMEN
The clinical characteristics of eight pediatric and five adult patients with Chiari malformation were evaluated. Six pediatric and five adult patients had associated syringomyelia. All patients initially underwent a suboccipital craniectomy with upper cervical (C-1 and/or C-2) laminectomy and duraplasty, and/or shunting procedures. The clinical characteristics of the pediatric and adult groups were compared. The mean interval between onset of symptoms and operation was shorter in the pediatric group (3 yrs 6 mos) than in the adult group (7 yrs 1 mo). Pediatric patients without syringomyelia had the shortest mean interval of 1 year 8 months. Preoperatively, the clinical features were more severe in the adult patients than in the pediatric patients. Postoperatively, seven of eight pediatric patients improved and one stabilized, while two of five adult patients improved, one stabilized, and in two the disease continued to progress despite multiple corrective procedures. Cine magnetic resonance imaging revealed correction of the abnormal cerebrospinal fluid (CSF) flow at the craniovertebral junction and decreased to-and-fro movement in the syrinx after posterior fossa decompression, which were closely correlated with the improvement of clinical features in pediatric patients. However, adult patients required further procedures because of the multifactorial nature of the disease. Evaluation of abnormal CSF pathways at the craniovertebral junction is important for investigating the pathogenesis of Chiari malformation and associated syringomyelia.
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Malformación de Arnold-Chiari/fisiopatología , Defectos del Tubo Neural , Adolescente , Adulto , Malformación de Arnold-Chiari/complicaciones , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Siringomielia/etiologíaRESUMEN
PAF decreases cardiac contractility and blood pressure. To characterize the cardiac PAF receptor, we screened a human ventricular cDNA library in a low stringency condition, using a PCR product derived from guinea pig lung PAF receptor as a probe. Four clones were obtained and named HV1-4. In Xenopus oocytes injected with cRNA derived from HV3 or 4 but not from HV1 or 2, PAF elicited a Ca(2+)-activated Cl- current. HV3 and HV4 were duplicate clones, encoding a 342 amino-acid polypeptide which was identical to that of the human leukocyte PAF receptor. However, a portion of the 5' untranslated region of HV3 (or 4) was different from that of the leukocyte receptor cDNA. Northern blotting of human ventricles and atria using the HV3 insert showed a single band of approximately 4 kb. These results suggest a tissue-specific translational mechanism responsible for regulation of the expression of the PAF receptor mRNA in these tissues.
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Corazón/fisiología , Factor de Activación Plaquetaria/farmacología , Glicoproteínas de Membrana Plaquetaria , Receptores de Superficie Celular/genética , Receptores Acoplados a Proteínas G , Secuencia de Aminoácidos , Animales , Azepinas/farmacología , Secuencia de Bases , Northern Blotting , Clonación Molecular/métodos , ADN/genética , Electrofisiología , Expresión Génica , Ventrículos Cardíacos , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Oocitos/efectos de los fármacos , Oocitos/fisiología , Factor de Activación Plaquetaria/antagonistas & inhibidores , Factor de Activación Plaquetaria/metabolismo , Reacción en Cadena de la Polimerasa/métodos , ARN/genética , ARN/aislamiento & purificación , Receptores de Superficie Celular/efectos de los fármacos , Receptores de Superficie Celular/fisiología , Triazoles/farmacología , XenopusRESUMEN
The clinical and pathological aspects of two large arteriovenous malformations which were removed totally after preoperative embolization using ethylene vinyl alcohol copolymer (EVAL) were studied. The material, which is not adhesive, is handled easily during the procedure of embolization. However, it involves some risks because it might migrate to and occlude the normal branches of the brain and pass through the nidus to the venous system. Histopathological study of AVM nidus which was removed showed embolic materials within the vessels and inflammatory reaction of the vessel wall and its surrounding tissue. There were patchy hemorrhages within the AVM nidus and its surrounding brain tissue. Recanalization was also found within the occluded vessels. These findings suggest that preoperative embolization has some risk of causing intracerebral hemorrhage after the embolization. AVM should be removed surgically as a radical treatment if the patient is able to tolerate the operation.
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Embolización Terapéutica , Malformaciones Arteriovenosas Intracraneales/terapia , Polivinilos/uso terapéutico , Adolescente , Adulto , Hemorragia Cerebral/etiología , Terapia Combinada , Embolización Terapéutica/efectos adversos , Humanos , Malformaciones Arteriovenosas Intracraneales/patología , Malformaciones Arteriovenosas Intracraneales/cirugía , Masculino , Cuidados PreoperatoriosRESUMEN
Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein hormone which stimulates the proliferation and differentiation of a subset of granulocyte precursors and enhances some functional activities of mature neutrophils. We tested the effects of G-CSF on a patient with intractable infective endocarditis. The white blood cell count was increased 3-fold and the inflammatory reactions such as C-reactive protein and erythrocyte sedimentation rate were completely normalized without any side effects. This is the first report describing the use of G-CSF for infective endocarditis. Administration of G-CSF might be suitable for treating intractable infections which cannot be controlled by antibiotics alone.
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Endocarditis Bacteriana/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Anciano , Antibacterianos , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Quimioterapia Combinada/uso terapéutico , Endocarditis Bacteriana/sangre , Humanos , Recuento de Leucocitos , MasculinoRESUMEN
We report the clinical features, radiological studies, operative procedures and results, and follow-up data in 29 patients with meningiomas of the tentorium and its surrounding structures. The cases represented 22.5% of all the intracranial meningiomas operated on in a 15 year period and were divided into three groups, depending on their main attachments, tentorial, cerebellopontine angle (dorsal aspect of the petrous ridge) and others. Tumor size was generally large and 13 cases were larger than 5 cm. The most common tumor site was along or near the superior petrosal sinus and transverse-sigmoid junction in cases involving the tentorium, and medial to the porus acousticus in cases involving the cerebellopontine angle. Different operative approaches to these tumors were carried out, depending on their location. The tumors in the lateral or medial petrous ridge were approached mainly with a suboccipital craniectomy using a retromastoid incision. Total removal was carried out in 80% of the tentorial cases, in 46.2% of cerebellopontine angle cases, and in the 83.3% in the others. Total operative mortality rate was zero. Follow-up periods ranged up to 5 years 5 months in the tentorial cases, 4 years 6 months in cerebellopontine angle cases, and 7 years 1 month in the others. Long-term results were good in 21 cases (72.4%), fair in 3 cases (10.3%) and poor in 2 (6.9%). Three patients died due to tumor recurrence. One of them suffered lung metastasis, and two of them suffered extensive local recurrences. We recommend the retromastoid approach combined with the petrosal approach, if the CPA tumor is large enough and extends to the retroclival region.
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Meningioma/patología , Neoplasias Supratentoriales/patología , Adulto , Anciano , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/cirugía , Ángulo Pontocerebeloso , Femenino , Estudios de Seguimiento , Humanos , Masculino , Meningioma/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Reoperación , Neoplasias Supratentoriales/cirugíaRESUMEN
Adult rabbit smooth muscles contain two types of myosin heavy chain (MHC) isoforms, SM1 and SM2 which are generated through alternative RNA splicing from a single gene (Nagai, R., Kuro-o, M., Babij, P. & Periasamy, M. (1989) J. Biol. Chem. 264, 9734-9737). We previously reported that the expression of SM1 and SM2 during vascular development is differentially regulated at the level of RNA splicing, whereby SM1 is constitutively expressed from early development but SM2 appear after birth (Kuro-o, M., Nagai, R., Tsuchimochi, H., Katoh, H., Yazaki, Y., Ohkubo, A. & Takaku, F. (1989) J. Biol. Chem. 264, 18272-18275). We also demonstrated that embryonic vascular smooth muscles contain a third type of MHC isoform, referred to as SMemb in this report, which comigrates on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with SM2. In the present study we have isolated and characterized a cDNA clone (FSMHC34) for SMemb. FSMHC34 encodes the light meromyosin region including the carboxyl terminus and showed 70% amino acid sequence identity with SM1 or SM2. SMemb is a nonmuscle-type MHC and identical with brain MHC, but clearly distinct from 196-kDa nonmuscle MHC in cultured smooth muscle cells. The expression of SMemb was predominant in embryonic and perinatal aortas, but down-regulated with vascular development. Interestingly SMemb was reexpressed in proliferating smooth muscle cells of arteriosclerotic neointimas. These results suggest that smooth muscle proliferation is coupled to the expression of SMemb and that dedifferentiation of smooth muscles toward the embryonic phenotype is involved in the mechanisms underlying atherosclerosis.
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Arteriosclerosis/metabolismo , Vasos Sanguíneos/metabolismo , ADN/genética , Músculo Liso/metabolismo , Miosinas/genética , Envejecimiento/genética , Secuencia de Aminoácidos , Animales , Western Blotting , Clonación Molecular , Embrión de Mamíferos , Técnica del Anticuerpo Fluorescente , Complejo Mayor de Histocompatibilidad/genética , Datos de Secuencia Molecular , Empalme del ARN , ARN Mensajero/análisis , Conejos , Homología de Secuencia de Ácido NucleicoRESUMEN
Twenty-five patients receiving surgical treatment for brain metastasis from lung cancer were retrospectively studied to evaluate the prognostic factors for survival time. Twenty-two patients had died of respiratory distress by April, 1989. Favorable prognostic factors derived from the median survival time (MST) in these patients included; 1) resection of primary tumor (MST 10 months); 2) total or subtotal removal of metastatic tumor (MST 6.5 months); 3) adenocarcinoma (MST 13 months); 4) metachronous onset of brain metastasis (MST 12 months); 5) single metastasis (MST 8 months). These results suggest that therapy for the primary lung cancer is important before surgery for metastatic brain tumor.
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Adenocarcinoma/cirugía , Neoplasias Encefálicas/cirugía , Carcinoma de Células Escamosas/cirugía , Neoplasias Pulmonares/cirugía , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/secundario , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/secundario , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Tomografía Computarizada por Rayos XRESUMEN
We have identified and functionally characterized DNA sequences that regulate the expression of the human ventricular/slow twitch isoform of myosin alkali light chain (VLC1) gene. By using primer extension and S1 nuclease mapping techniques, we have shown that the VLC1 gene is transcribed from the identical site in the ventricular and slow twitch skeletal muscles. Comparison of the VLC1 sequences from +1 to -1296 in the genes for human and mouse showed that the 5'-proximal flanking region, up to about 220 nucleotides, was highly conserved (83% homology). To determine the location of sites that may be important for the function of the VLC1 promoter, a series of transient expression vectors containing progressive deletions of the VLC1 gene 5'-flanking sequence fused to the bacterial chloramphenicol acetyltransferase (CAT) gene was introduced into myogenic and nonmyogenic cells. Deletion mutagenesis of sequences between -357 and +40 revealed the presence of positive and negative activity in all the cells tested. We demonstrated that the minimal promoter sequence required to generate muscle cell-specific expression is the region between -94 to -64 upstream from the cap site and a sequence element located between -107 and -94 was found to have a positive effect in both myogenic cells and nonmyogenic cells. These two proximal regions located between -107 and -64 appear to act together to determine the cell type-specific high level expression of the VLC1 gene in muscle cells. Competition gel retardation assays revealed that the CArG sequence located between -96 and -87 interacts specifically with nuclear extracts from myogenic and nonmyogenic cells and compete for binding with the CArG sequence present in the human cardiac alpha-actin gene and with the serum response element of the c-fos gene. These results strongly suggested that similar, if not identical, the CArG box binding proteins interact with the functionally different promoter element in the VLC1, cardiac alpha-actin, and c-fos genes.
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Miocardio/metabolismo , Miosinas/genética , Regiones Promotoras Genéticas , Secuencias Reguladoras de Ácidos Nucleicos , Transcripción Genética , Animales , Secuencia de Bases , Vectores Genéticos , Biblioteca Genómica , Ventrículos Cardíacos/metabolismo , Humanos , Sustancias Macromoleculares , Ratones , Datos de Secuencia Molecular , Sondas de Oligonucleótidos , ARN/genética , ARN/aislamiento & purificación , Mapeo Restrictivo , Homología de Secuencia de Ácido NucleicoRESUMEN
Cardiac hypertrophy is associated with qualitative as well as quantitative changes in myocardial cells. To analyze the molecular basis of isozymic transitions of cardiac myosins in response to pressure overload, we have constructed and characterized two types of myosin heavy chain (MHC) cDNA clones, specifying alpha- and beta-MHCs, and two types of myosin alkali light chain cDNA clones, complementary to atrial type (ALC1) and ventricular type (VLC1) mRNAs from a human fetal heart cDNA library. Using the S1 nuclease mapping procedure, we showed that the MCH isozymic transitions from alpha- to beta-MHC in the pressure overloaded atria are produced by changes in the relative level of alpha- and beta-MHC gene expression. In addition, we observed that the expression of VLC1 gene is also induced in the atria subjected to severe pressure overload. Thus, it appears that the increased expression of VLC1 gene, together with the isogene switch from alpha- to beta-MHC gene, may participate in the adaptation of myocardium to new functional requirement. Then, to get a better understanding of the genetic mechanisms involved in the regulation of isogene expression, we have isolated and sequenced genomic clone for VLC1 isoform. Sequence analysis has identified multiple potential cis regulatory elements within a 686-bp upstream region. This region includes 28-bp alternating purine/pyrimidine sequences and two segment exhibiting homology to consensus sequence proposed for viral and cellular enhancer elements. In particular, a comparison of the VLC1 upstream gene sequence with those available for several muscle-specific genes revealed that CC(A + T-rich)6GG elements and CATTCCT sequence are conserved. These results suggested that CArG box (-96 to -87) has an important role in the positive regulation of the VLC1 gene and this element may be involved in the co-regulation of VLC1 and cardiac alpha-actin genes.
Asunto(s)
Cardiomegalia/genética , Genes de Cambio , Miosinas/genética , Adaptación Fisiológica/genética , Adulto , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Presión Sanguínea , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Clonación Molecular , Femenino , Expresión Génica , Regulación de la Expresión Génica , Atrios Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , ARN Mensajero/metabolismo , Estrés MecánicoRESUMEN
Evidence has accumulated that T cell-mediated autoimmunity plays an important role in the pathogenesis of viral myocarditis. T lymphocytes are known to recognize antigen-presenting cells, such as virus-infected cells, being restricted by syngeneic major histocompatibility complex (MHC) antigens. To clarify in more detail the immunological mechanisms involved, we induced acute viral myocarditis in C3H/He mouse ventricles with coxsackievirus B3 (CVB3) and examined, by immunofluorescence, the expression of MHC class I and II antigens, previously reported not to be expressed by normal cardiac myocytes. Furthermore, to confirm the expression of MHC class I (H-2Kk) antigens at the cellular level, we treated cultured cardiac myocytes with interferon gamma and examined the antigen expression by immunofluorescence and Northern blot hybridization, using an antisense RNA probe for MHC messenger RNA. Our observations demonstrated 1) CVB3-induced myocarditis resulted in the enhanced expression of MHC class I (H-2Kk) gene product on the surface of cardiac myocytes but low or undetectable levels of MHC class II or H-2Dk gene products, and moderate focal transient (days 5-7) expression of both MHC class I (Kk + Dk) region gene products and MHC class II antigens were induced on capillary endothelial cells; 2) murine fetal cardiac myocytes cultured in vitro in the presence of interferon gamma similarly were shown to express marked levels of MHC class I (H-2Kk) but low to undetectable levels of the H-2Dk gene product; however, weak to moderate MHC Class II antigens were expressed by these cultured myocytes; and 3) the expression of MHC antigens in cardiac myocytes was modulated at the transcriptional level.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Infecciones por Coxsackievirus/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Miocardio/inmunología , Animales , Anticuerpos Monoclonales , Células Cultivadas , ADN/genética , Enterovirus Humano B , Fibroblastos/inmunología , Expresión Génica , Genes MHC Clase I , Ventrículos Cardíacos/inmunología , Antígenos de Histocompatibilidad Clase I/análisis , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C3H , Hibridación de Ácido NucleicoRESUMEN
Recent studies suggest that beta-blocker treatment may attenuate cardiac hypertrophy induced by pressure overload in the spontaneously hypertensive rat (SHR), but the effect of this therapy on the reconstitution of the intracellular constituents in the heart that occurs during the development of cardiac hypertrophy has not been examined. In this study, we investigated the effect of chronic administration of carteolol (4 mg/kg/day p.o.) or propranolol (20 mg/kg/day p.o.), beta-blockers with distinct modes of action, on the composition of cardiac myosin isozymes and histological findings as well as heart weight. Therapeutic periods were 4, 12 or 30 weeks. Though blood pressure was not significantly reduced, the development of cardiac hypertrophy was suppressed as evidenced by left ventricular weight in both groups of carteolol- and propranolol-treated SHR for all therapeutic periods. Again, beta-blocker treatment for 12 weeks alleviated myocardial degeneration and reactive fibrosis which were observed in all cases of age-matched untreated SHR. However the extent of the transition of cardiac myosin isozymes from V1 to V2 or V3 were essentially the same among all groups including untreated SHR. These results indicate that chronic administration of beta-blockers attenuates the development of cardiac hypertrophy and degeneration without affecting the transition of myosin isozymes which is thought to be a kind of biochemical adaptation of the myocardium to overload.