RESUMEN
Prenatal exposure to alcohol causes a wide range of deficits known as fetal alcohol spectrum disorders (FASDs). Many factors determine vulnerability to developmental alcohol exposure including timing and pattern of exposure, nutrition and genetics. Here, we characterized how a prevalent single nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene (val66met) modulates FASDs severity. This polymorphism disrupts BDNF's intracellular trafficking and activity-dependent secretion, and has been linked to increased incidence of neuropsychiatric disorders such as depression and anxiety. We hypothesized that developmental ethanol (EtOH) exposure more severely affects mice carrying this polymorphism. We used transgenic mice homozygous for either valine (BDNFval/val ) or methionine (BDNFmet/met ) in residue 68, equivalent to residue 66 in humans. To model EtOH exposure during the second and third trimesters of human pregnancy, we exposed mice to EtOH in vapor chambers during gestational days 12 to 19 and postnatal days 2 to 9. We found that EtOH exposure reduces cell layer volume in the dentate gyrus and the CA1 hippocampal regions of BDNFmet/met but not BDNFval/val mice during the juvenile period (postnatal day 15). During adulthood, EtOH exposure reduced anxiety-like behavior and disrupted trace fear conditioning in BDNFmet/met mice, with most effects observed in males. EtOH exposure reduced adult neurogenesis only in the ventral hippocampus of BDNFval/val male mice. These studies show that the BDNF val66met polymorphism modulates, in a complex manner, the effects of developmental EtOH exposure, and identify a novel genetic risk factor that may regulate FASDs severity in humans.
Asunto(s)
Ansiedad/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Depresores del Sistema Nervioso Central/toxicidad , Etanol/toxicidad , Hipocampo/efectos de los fármacos , Mutación Missense , Efectos Tardíos de la Exposición Prenatal/genética , Animales , Condicionamiento Clásico , Miedo , Femenino , Hipocampo/crecimiento & desarrollo , Masculino , Ratones , Polimorfismo de Nucleótido Simple , EmbarazoRESUMEN
Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer's disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3ß, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Hipocampo/efectos de los fármacos , Litio/administración & dosificación , Trastornos de la Memoria/tratamiento farmacológico , Memoria/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Litio/uso terapéutico , Masculino , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas TransgénicasRESUMEN
OBJECTIVE: To assess the long term effects of hypertensive disorders of pregnancy on renal function. DESIGN: Cohort study where exposure was gestational hypertension or preeclampsia in the first pregnancy. Normotensive women formed the comparison group. SETTING: Aberdeen, Scotland. PARTICIPANTS: All women with date of birth on or before 30th June 1969 and at least their first singleton delivery recorded in the Aberdeen Maternity and Neonatal Databank. METHODS: Participants were linked to the Renal Biochemistry Register, Scottish Morbidity Records, Scottish Renal Registry and National Register for deaths. MAIN OUTCOME MEASURES: Occurrence of chronic kidney disease (CKD) as identified from renal function tests in later life, hospital admissions or death from kidney disease or recorded as receiving renal replacement therapy. RESULTS: CKD was diagnosed in 7.5% and 5.2% of women who previously had GH and PE respectively compared to 3.9% in normotensive women. The unadjusted odds ratio (95% confidence interval) of having CKD in PE was 2.04 (1.53, 2.71) and that for GH was 1.37 (1.15, 1.65), while the adjusted odds ratio (95% confidence interval) of CKD was 1.93 (1.44, 2.57) and 1.36 (1.13, 1.63) in women with PE and GH respectively. Kaplan-Meier curves of survival time to development of chronic kidney disease revealed that women with preeclampsia were susceptible to kidney function impairment earliest, followed by those with gestational hypertension. CONCLUSIONS: There was an increased subsequent risk of CKD associated with hypertensive disorders of pregnancy. Women with GH and PE were also found to have CKD earlier than normotensive women.
Asunto(s)
Hipertensión Inducida en el Embarazo/epidemiología , Insuficiencia Renal Crónica/epidemiología , Adulto , Estudios de Cohortes , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , Registro Médico Coordinado , Preeclampsia/epidemiología , Embarazo , Sistema de Registros , Factores de Riesgo , Escocia/epidemiología , Factores de Tiempo , Adulto JovenRESUMEN
Computer modelling has emerged as a particularly useful tool in understanding the physiology and pathophysiology of cardiac tissues. Models of ventricular, atrial and nodal tissue have evolved and include detailed ion channel kinetics and intercellular Ca(2+) handling. Purkinje fibre cells play a central role in the electrophysiology of the heart and in the genesis of cardiac arrhythmias. In this study, a new computational model has been constructed that incorporates the major membrane currents that have been isolated in recent experiments using Purkinje fibre cells. The model, which integrates mathematical models of human ion channels based on detailed biophysical studies of their kinetic and voltage-dependent properties, recapitulates distinct electrophysiological characteristics unique to Purkinje fibre cells compared to neighbouring ventricular myocytes. These characteristics include automaticity, hyperpolarized voltage range of the action potential plateau potential, and prolonged action potential duration. Simulations of selective ion channel blockade reproduce responses to pharmacological challenges characteristic of isolated Purkinje fibres in vitro, and importantly, the model predicts that Purkinje fibre cells are prone to severe arrhythmogenic activity in patients harbouring long QT syndrome 3 but much less so for other common forms of long QT. This new Purkinje cellular model can be a useful tool to study tissue-specific drug interactions and the effects of disease-related ion channel dysfunction on the cardiac conduction system.
Asunto(s)
Simulación por Computador , Síndrome de QT Prolongado/fisiopatología , Modelos Neurológicos , Ramos Subendocárdicos/fisiología , Potenciales de Acción/efectos de los fármacos , Arritmias Cardíacas/fisiopatología , Humanos , Canales Iónicos/efectos de los fármacos , Canales Iónicos/fisiología , Moduladores del Transporte de Membrana/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Ramos Subendocárdicos/efectos de los fármacosRESUMEN
Hypereosinophilia may be associated with any of several underlying diseases. Atopy or allergic drug reactions are the most common causes, but infections with bacteria and parasites should also be considered in the differential diagnosis. When thorough evaluation of a patient with chronic hypereosinophilia fails to reveal an underlying disease, the diagnosis of idiopathic hypereosinophilic syndrome (HES) should be considered. We report a patient with unexplained persistent hypereosinophilia associated with a chronic pruritic rash and an underlying diagnosis of HES (lymphocytic variant).
Asunto(s)
Síndrome Hipereosinofílico/patología , Ciclosporina/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Quimioterapia Combinada , Humanos , Síndrome Hipereosinofílico/tratamiento farmacológico , Linfocitos , Masculino , Persona de Mediana Edad , Esteroides/uso terapéutico , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Mastocitos/ultraestructura , Mastocitosis Sistémica/patología , Anciano , Forma de la Célula , Progresión de la Enfermedad , Femenino , Humanos , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/genética , Mutación Missense , Mutación Puntual , Proteínas Proto-Oncogénicas c-kit/genética , Urticaria Pigmentosa/patologíaRESUMEN
Long QT syndrome variant 3 (LQT-3) is a channelopathy in which mutations in SCN5A, the gene coding for the primary heart Na(+) channel alpha subunit, disrupt inactivation to elevate the risk of mutation carriers for arrhythmias that are thought to be calcium (Ca(2+))-dependent. Spontaneous arrhythmogenic diastolic activity has been reported in myocytes isolated from mice harboring the well-characterized Delta KPQ LQT-3 mutation but the link to altered Ca(2+) cycling related to mutant Na(+) channel activity has not previously been demonstrated. Here we have investigated the relationship between elevated sarcoplasmic reticulum (SR) Ca(2+) load and induction of spontaneous diastolic inward current (I(TI)) in myocytes expressing Delta KPQ Na(+) channels, and tested the sensitivity of both to the antianginal compound ranolazine. We combined whole-cell patch clamp measurements, imaging of intracellular Ca(2+), and measurement of SR Ca(2+) content using a caffeine dump methodology. We compared the Ca(2+) content of Delta KPQ(+/-) myocytes displaying I(TI) to those without spontaneous diastolic activity and found that I(TI) induction correlates with higher sarcoplasmic reticulum (SR) Ca(2+). Both spontaneous diastolic I(TI) and underlying Ca(2+) waves are inhibited by ranolazine at concentrations that preferentially target I(NaL) during prolonged depolarization. Furthermore, ranolazine I(TI) inhibition is accompanied by a small but significant decrease in SR Ca(2+) content. Our results provide the first direct evidence that induction of diastolic transient inward current (I(TI)) in Delta KPQ(+/-) myocytes occurs under conditions of elevated SR Ca(2+) load.
Asunto(s)
Acetanilidas/farmacología , Señalización del Calcio/efectos de los fármacos , Calcio/metabolismo , Diástole/efectos de los fármacos , Activación del Canal Iónico/efectos de los fármacos , Síndrome de QT Prolongado/fisiopatología , Piperazinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ratones , Mutación/genética , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , RanolazinaRESUMEN
In order to determine the influence of noise sensitivity on sleep, subjective sleep quality, annoyance, and performance after nocturnal exposure to traffic noise, 12 women and 12 men (age range, 19-28 years) were observed during four consecutive nights over a three weeks period. After a habituation night, the participants were exposed with weekly permuted changes to air, rail and road traffic noise. Of the four nights, one was a quiet night (32 dBA), while three were noisy nights with exposure to equivalent noise levels of 39, 44, and 50 dBA in a permuted order. The traffic noise caused alterations of most of the physiological parameters, subjective evaluation of sleep, annoyance, and performance. Correlations were found between noise sensitivity and subjective sleep quality in terms of worsened restoration, decreased calmness, difficulty to fall asleep, and body movements. The results suggest that alterations of subjective evaluation of sleep were determined by physical parameters of the noise but modified by individual factors like noise sensitivity.
Asunto(s)
Ruido del Transporte/efectos adversos , Sueño/fisiología , Adulto , Femenino , Alemania , Humanos , Masculino , PolisomnografíaRESUMEN
OBJECTIVE: To discuss the successes and challenges associated with the implementation of a post-traumatic stress disorder (PTSD) screening tool in two pediatric emergency departments (ED). METHODS: The STEPP screening tool has been developed previously on an inpatient population of motor vehicle trauma patients. It was applied here to the general ED population at two different pediatric trauma centers. Nurse screeners were trained and a convenience sample of patients with unintentional injuries who met study criteria were screened in the ED. Feedback from nurse screeners was obtained. RESULTS: The process of implementing a screening tool to identify patients and their families significantly at risk for PTSD symptomatology presented some barriers, but overall acceptability of the process was high for both the emergency department staff and the patient. Recommendations for others considering implementation of screening programs in the ED are offered. CONCLUSIONS: Future research using screening protocols in the ED should, in their design, attempt to capitalize on the successes identified in the current protocol and circumvent barriers also encountered.
Asunto(s)
Accidentes de Tránsito/psicología , Servicio de Urgencia en Hospital/organización & administración , Trastornos por Estrés Postraumático/prevención & control , Niño , Medicina de Emergencia/educación , Retroalimentación , Humanos , Personal de Enfermería en Hospital/educación , Factores de Riesgo , Encuestas y Cuestionarios , Centros TraumatológicosRESUMEN
BACKGROUND: The human secondary sex ratio reportedly falls in populations subjected to exogenous stressors such as earthquakes or political and social upheavals. Explanations of the association include reduced conception of males and increased fetal deaths among males. The latter explanation has been supported by research reporting that the sex ratio in California fell 3 months, but not 8, 9 or 10 months, after the terrorist attacks of September 11, 2001. California's distance from the attacks raises the questions of whether the results arose from chance and would be found elsewhere. We contribute to the literature by testing the association between the secondary sex ratio and the events of September 11 in New York City. METHODS: We replicate the California tests by applying interrupted time-series methods, which control for secular trends, seasonality and other forms of autocorrelation, to 91 cohorts born in New York City during 28-day periods from January 1996 to June 2002. RESULTS: As hypothesized, the sex ratio in New York City in the period 1 January to 28 January 2002 fell to 1, which was the lowest observed value during the test period and significantly (i.e. P < 0.01, two-tailed test) below the value expected from history. CONCLUSIONS: Our findings support the male fetal loss explanation of the association between exogenous population shocks and the secondary sex ratio.
Asunto(s)
Tasa de Natalidad , Razón de Masculinidad , Choque/etiología , Terrorismo , Tasa de Natalidad/tendencias , Femenino , Muerte Fetal/epidemiología , Humanos , Masculino , Ciudad de Nueva York , Choque/epidemiologíaRESUMEN
S100beta is a calcium-binding peptide produced mainly by astrocytes that exerts paracrine and autocrine effects on neurons and glia. We have previously shown that S100beta is markedly elevated at the mRNA level in the spinal cord following peripheral inflammation, intraplantar administration of complete Freund's adjuvant in the rat. The purpose of the present study was to further investigate the role of astrocytic S100beta in mediating behavioral hypersensitivity in rodent models of persistent pain. First, we assessed the lumbar spinal cord expression of S100beta at the mRNA and protein level using real-time RT-PCR, Western blot and immunohistochemistry analysis following L5 spinal nerve transection in rats, a rodent model of neuropathic pain. Second, we assessed behavioral hypersensitivity (mechanical allodynia) in wild type and genetically modified mice lacking or overexpressing S100beta following L5 spinal nerve transection. Third, we assessed the expression level of S100beta protein in the CD1 wild type mice after nerve injury. We report that lumbar spinal S100beta mRNA steadily increased from days 4-28 after nerve injury. S100beta protein in the lumbar spinal cord was significantly increased in both rats and mice at day 14 following nerve injury as compared with sham control groups. S100beta genetically deficient mice displayed significantly increased tactile thresholds (reduced response to non-noxious stimuli) after nerve injury as compared with the wild type group. S100beta overexpressing mice displayed significantly decreased tactile threshold responses (enhanced response to non-noxious stimuli). Together, these results from both series of experiments using a peripheral nerve injury model in two different species implicate the involvement of glial-derived S100beta in the pathophysiology of neuropathic pain.
Asunto(s)
Astrocitos/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Neuralgia/metabolismo , Enfermedades del Sistema Nervioso Periférico/metabolismo , Células del Asta Posterior/metabolismo , Proteínas S100/metabolismo , Nervios Espinales/lesiones , Animales , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/genética , Gliosis/metabolismo , Gliosis/fisiopatología , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Inmunohistoquímica , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Factores de Crecimiento Nervioso/genética , Neuralgia/genética , Neuralgia/fisiopatología , Umbral del Dolor/fisiología , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Estimulación Física , Células del Asta Posterior/fisiopatología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Subunidad beta de la Proteína de Unión al Calcio S100 , Proteínas S100/genética , Regulación hacia Arriba/genéticaRESUMEN
Previously we have shown that inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are abundantly expressed in the atria of rat hearts. Since arrangement of atria is very heterogeneous, in this work we focused on the precise localization of IP3 receptors in the left atrium, where the gene expression of the type 1 IP3R was the highest. The mRNA levels of the IP3 type 1 receptors in the left atrium, left ventricle and myocytes were determined using real-time polymerase chain reaction and Taqman probe. For precise localization, immunohistochemistry with the antibody against type 1 IP3Rs was performed. The mRNA of type 1 IP3 receptor was more than three times higher in the left atrium than in the left ventricle, as determined by real-time PCR. Expression of the type 1 IP3 receptor mRNA was higher in the atria, especially in parts containing cardiac ganglion cells. The atrial auricles, which are particularly free of ganglion cells, and the ventricles (wall of the right and left ventricle and ventricular septum) contained four to five times less IP3 receptors than atrial samples with ganglia. IP3R type 1 immunoreactivity detected by a confocal microscope attributed the most condensed signal on ganglionic cells, although light immunoreactivity was also seen in cardiomyocytes. These results show that type 1IP3 receptors predominate in intrinsic neuronal ganglia of cardiac atria.
Asunto(s)
Canales de Calcio/genética , Ganglios Parasimpáticos/citología , Ganglios Parasimpáticos/metabolismo , Corazón/inervación , Receptores Citoplasmáticos y Nucleares/genética , Animales , Canales de Calcio/análisis , Ganglios Parasimpáticos/química , Expresión Génica , Atrios Cardíacos/inervación , Inmunohistoquímica , Receptores de Inositol 1,4,5-Trifosfato , Masculino , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores Citoplasmáticos y Nucleares/análisisRESUMEN
The analysis of oligodendrocyte (OL) lineage development has been facilitated by the immunocytochemical characterization of OL-specific antigens and definition of the phenotypes sequentially acquired by differentiating OLs. The purpose of the present study was to address an enduring discrepancy between several reported cases of S100B immunodetection in CNS myelin and myelinating OLs on the one hand, and the systematic use of the S100B protein as an alleged astrocytic marker in studies of the mammalian CNS on the other. To resolve this discrepancy, we have compared the developmental distribution of EGFP+ cells in the CNS of s100b-enhanced green fluorescent protein (EGFP) (Vives et al., 2003) and cnp-EGFP (Yuan et al., 2002) mice, and examined the degree of overlap between EGFP expression and that of stage-specific markers of OL differentiation during the embryonic and postnatal phases of development. We demonstrate that the S100B protein is expressed in postnatal and adult populations of NG2+ progenitors of mouse brain, as well as in immature and mature myelinating OLs present in the brain and spinal cord of embryonic and adult mice, respectively. Comparison between EGFP and endogenous S100B expression in the s100b-EGFP and cnp-EGFP mice indicates that S100B protein expression is upregulated in immature and mature OLs. These results argue against the current view that S100B expression is restricted to the astrocytic lineage in the CNS, and indicate that the use of S100B in combination with other molecular markers will help discriminate oligodendrocytes from astrocytes.
Asunto(s)
Diferenciación Celular/fisiología , Sistema Nervioso Central/embriología , Sistema Nervioso Central/crecimiento & desarrollo , Factores de Crecimiento Nervioso/metabolismo , Oligodendroglía/metabolismo , Proteínas S100/metabolismo , Células Madre/metabolismo , Envejecimiento/metabolismo , Animales , Animales Recién Nacidos , Astrocitos/citología , Astrocitos/metabolismo , Biomarcadores/metabolismo , Linaje de la Célula/fisiología , Sistema Nervioso Central/citología , Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/metabolismo , Técnica del Anticuerpo Fluorescente , Ratones , Ratones Transgénicos , Vaina de Mielina/metabolismo , Oligodendroglía/citología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100 , Células Madre/citología , Factores de Tiempo , Regulación hacia Arriba/fisiologíaRESUMEN
BACKGROUND: We seek to determine whether dietary and supplement intake of specific micronutrients (zinc and folate) and antioxidants (vitamins C, E and beta-carotene) is associated with semen quality. METHODS: Ninety-seven healthy, non-smoking men provided semen and were interviewed. Average daily nutrient intake from food and supplements was derived from a self-administered food frequency questionnaire. Intake levels were summarized as low, moderate and high. Semen volume, sperm concentration, total sperm count, motility, progressive motility and total progressively motile sperm count (TPMS) were measured. RESULTS: After controlling for covariates, a high intake of antioxidants was associated with better semen quality but, in almost all cases, there was no clear dose relationship in that moderate intake groups had the poorest semen quality. For example, positive associations were observed between vitamin C intake and sperm number as reflected in the higher mean count (P=0.04), concentration (P=0.05) and TPMS (P = 0.09); between vitamin E intake and progressive motility (P = 0.04) and TPMS (P = 0.05); and between beta-carotene intake and sperm concentration (P = 0.06) and progressive motility (P = 0.06). Folate and zinc intake were not associated with improved semen quality. CONCLUSIONS: In a convenience sample of healthy non-smoking men from a non-clinical setting, higher antioxidant intake was associated with higher sperm numbers and motility.
Asunto(s)
Envejecimiento/fisiología , Antioxidantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Infertilidad Masculina/tratamiento farmacológico , Semen/efectos de los fármacos , Motilidad Espermática/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Suplementos Dietéticos , Ácido Fólico/administración & dosificación , Humanos , Infertilidad Masculina/dietoterapia , Masculino , Persona de Mediana Edad , Evaluación Nutricional , Vitamina E/administración & dosificación , Zinc/administración & dosificación , beta Caroteno/administración & dosificaciónRESUMEN
S100A6 (calcyclin), a member of the S100 family of EF-hand Ca2+ binding proteins, has been implicated in the regulation of cell growth and proliferation. We have previously shown that S100B, another member of the S100 family, is induced postinfarction and limits the hypertrophic response of surviving cardiac myocytes. We presently report that S100A6 expression is also increased in the periinfarct zone of rat heart postinfarction and in cultured neonatal rat myocytes by treatment with several trophic agents, including platelet-derived growth factor (PDGF), the alpha1-adrenergic agonist phenylephrine (PE), and angiotensin II (AII). Cotransfection of S100A6 in cultured neonatal rat cardiac myocytes inhibits induction of the cardiac fetal gene promoters skeletal alpha-actin (skACT) and beta-myosin heavy chain (beta-MHC) by PDGF, PE, AII, and the prostaglandin F2alpha (PGF2alpha), induction of the S100B promoter by PE, and induction of the alpha-MHC promoter by triiodothyronine (T3). By contrast, S100B cotransfection selectively inhibited only PE induction of skACT and beta-MHC promoters. Fluorescence microscopy demonstrated overlapping intracellular distribution of S100B and S100A6 in transfected myocytes and in postinfarct myocardium but heterodimerization of the two proteins could not be detected by co-immunoprecipitation. We conclude that S100A6 may function as a global negative modulator of differentiated cardiac gene expression comparable to its putative role in cell cycle progression of dividing cells.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas S100/metabolismo , Actinas/genética , Animales , Secuencia de Bases , Proteínas de Ciclo Celular/genética , Células Cultivadas , ADN/genética , Regulación de la Expresión Génica/efectos de los fármacos , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Factores de Crecimiento Nervioso , Fenilefrina/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteína A6 de Unión a Calcio de la Familia S100 , Subunidad beta de la Proteína de Unión al Calcio S100 , Proteínas S100/genética , Transfección , Miosinas Ventriculares/genéticaRESUMEN
Defective calcium (Ca2+) signaling and impaired contractile function have been observed in skeletal muscle secondary to impaired myocardial function. However, the molecular basis for these muscle defects have not been identified. In this study, we evaluated the alterations of the ryanodine-sensitive Ca2+ release channels (RyR1) by analyzing global and local Ca2+ signaling in a rat postmyocardial infarction (PMI) model of myocardial overload. Ca2+ transients, measured with multiphoton imaging in individual fibers within a whole extensor digitorum longus (EDL) muscle, exhibited significantly reduced amplitude and a prolonged time course in PMI. Spatio-temporal properties of spontaneous Ca2+ sparks in fibers isolated from PMI EDL muscles were also significantly altered. In addition, RyR1 from PMI skeletal muscles were PKA-hyperphosphorylated and depleted of the FK506 binding protein (FKBP12). These data show that PMI skeletal muscles exhibit altered local Ca2+ signaling, associated with hyperphosphorylation of RyR1. The observed changes in Ca2+ signaling may contribute to defective excitation-contraction coupling in muscle that can contribute to the reduced exercise capacity in PMI, out of proportion to the degree of cardiac dysfunction.
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Señalización del Calcio , Calcio/metabolismo , Músculo Esquelético/metabolismo , Infarto del Miocardio/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Insuficiencia Cardíaca/metabolismo , Modelos Biológicos , Fibras Musculares Esqueléticas/metabolismo , Ratas , Retículo Sarcoplasmático/metabolismoRESUMEN
Rapamycin (sirolimus) was initially developed as an antibiotic, then as an immunosuppressant, and recently has been identified as one of the most promising novel agents for prevention of coronary artery stent restenosis. The story of how rapamycin was developed for the prevention of stent restenosis involves the discovery of its antiproliferative and antimigratory actions in vascular smooth muscle and ultimately the demonstration that it inhibits neointimal hyperplasia in a large animal model of restenosis. Rapamycin upregulates the cyclin-dependent kinase inhibitor p27(kip1), resulting in cell-cycle arrest at the G1 to S transition. Rapamycin also inhibits other important cellular functions, including protein translation. The precise mechanisms underlying rapamycin's actions have not been fully elucidated. However, its ability to potently inhibit vascular smooth muscle cell migration and proliferation has been the basis for developing rapamycin-eluting coronary artery stents that have reduced in-stent restenosis from about 30% to less than 5% in large clinical trials.
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Músculo Liso Vascular/fisiología , Transducción de Señal/fisiología , Sirolimus/farmacología , Animales , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Humanos , Modelos Animales , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Unión Proteica , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacocinética , Proteína 1A de Unión a Tacrolimus/metabolismoRESUMEN
The sympathetic nervous system controls the force and rate of contraction of the heart. The rapid response to stress and exercise mediated by increased sympathetic nervous system (SNS) activity requires the coordinated regulation of several ion channels in response to activation of beta-adrenergic receptors. The microenvironment of target channels is mediated by the assembly of macromolecular signaling complexes in which targeting proteins recruit phosphatases and kinases and in turn bind directly to the channel protein via highly conserved leucine/isoleucine zippers (LIZs). Disruption of local signaling by disease-associated LIZ mutations unbalances the physiologic response to SNS stimulation and increases the risk of arrhythmia in mutation carriers.
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Corazón/efectos de los fármacos , Corazón/fisiopatología , Canales Iónicos/fisiología , Isoleucina/fisiología , Leucina Zippers/fisiología , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Humanos , Isoleucina/genética , Leucina Zippers/genética , Sustancias Macromoleculares , Contracción Miocárdica/fisiología , Receptores Adrenérgicos beta/fisiología , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
Regions on chromosomes 7 and 19 were recently reported to contain susceptibility loci that regulate tumor aggressiveness of prostate cancer. To confirm these findings, we analyzed genome scan data from 161 pedigrees affected with prostate cancer. Using the Gleason score as a quantitative measure of tumor aggressiveness, we regressed the squared trait difference, as well as the mean-corrected cross product, on the estimated proportion of alleles shared identical-by-descent at each marker position. Our results confirm the previous linkage results for chromosome 19q (D19S902, P<.00001). In addition, we report suggestive evidence for linkage on chromosome 4 (D4S403, P=.00012). The results of previous findings, together with our results, provide strong evidence that chromosome 19 harbors a gene for tumor aggressiveness.