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BACKGROUND: Current guidelines recommend that relatives of index patients with hypertrophic cardiomyopathy (HCM) are offered clinical investigations to identify individuals at risk of adverse disease complications and sudden cardiac death. However, the value of family screening in relatives of index patients with a normal genetic investigation of recognized HCM genes is largely unknown. OBJECTIVES: The purpose of this study was to perform family screening among relatives of HCM index patients with a normal genetic investigation to establish the frequency of familial disease and the clinical characteristics of affected individuals. METHODS: Clinical and genetic investigations were performed in consecutive and unrelated HCM index patients. Relatives of index patients who did not carry pathogenic/likely pathogenic variants in recognized HCM genes were invited for clinical investigations. RESULTS: In total, 60% (270 of 453) of HCM index patients had a normal genetic investigation. A total of 80% of their relatives (751 of 938, median age 44 years) participated in the study. Of these, 5% (34 of 751) were diagnosed with HCM at baseline, whereas 0.3% (2 of 717 [751-34]) developed the condition during 5 years of follow-up. Their median age at diagnosis was 57 years (IQR: 51-70 years). Two-thirds (22 of 36) were diagnosed following family screening, whereas one-third (14 of 36) had been diagnosed previously because of cardiac symptoms, a murmur, or an abnormal electrocardiogram. None of the affected relatives experienced adverse disease complications. The risk of SCD was low. CONCLUSIONS: Systematic family screening of index patients with HCM and normal genetic investigations was associated with a low frequency of affected relatives who appeared to have a favorable prognosis.
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Cardiomiopatía Hipertrófica , Pruebas Genéticas , Humanos , Adulto , Persona de Mediana Edad , Anciano , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/epidemiología , Cardiomiopatía Hipertrófica/genética , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , PronósticoRESUMEN
Background: Little evidence is available on the disease expression in relatives of index patients with hypertrophic cardiomyopathy (HCM). This information has important implications for family screening programs, genetic counseling, and management of affected families. Objectives: The purpose of this study was to investigate the disease expression and penetrance in relatives of index patients carrying pathogenic/likely pathogenic (P/LP) variants in recognized HCM genes. Methods: A total of 453 consecutive and unrelated HCM index patients underwent clinical and genetic investigations. A total of 903 relatives of genotype-positive index patients were invited for clinical investigations and genetic testing. Penetrance, disease expression, and incidence rates of major adverse cardiac events (MACEs) were investigated in individuals carrying P/LP variants. Results: Forty percent (183/453) of index patients carried a P/LP variant. Eighty-four percent (757/903) of all relatives of index patients with P/LP variants were available for the investigation, of whom 54% (407/757) carried a P/LP variant. The penetrance of HCM among relatives was 39% (160/407). Relatives with HCM and index patients were diagnosed at a similar age (43 ± 18 years vs 46 ± 15 years; P = 0.11). There were no differences in clinical characteristics or incidence rates of MACE during 8 years of follow-up. Conclusions: The disease expression of HCM among index patients and affected relatives carrying P/LP variants in recognized disease genes was similar, with an equal risk of experiencing MACE. These findings provide evidence to support family screening and follow-up of genotype-positive HCM families to improve management and diminish the number of adverse disease complications among relatives.
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Vascular changes are thought to contribute to the development of Alzheimer's disease, and both cerebral blood flow and its responses during neural activation are reduced before Alzheimer's disease symptoms onset. One hypothetical explanation is that capillary dysfunction reduces oxygen extraction efficacy. This study compares the morphology and hemodynamics of the microvasculature in the somatosensory cortex of 18-month-old APPSWE/PS1ΔE9 (transgenic [Tg]) mice and wild-type (WT) littermates. In particular, the extent to which their capillary transit times homogenize during functional activation was measured and compared. Capillary length density was similar in both groups but capillary blood flow during rest was lower in the Tg mice, indicating that cortical oxygen availability is reduced. The capillary hemodynamic response to functional activation was larger, and lasted longer in Tg mice than in WT mice. The homogenization of capillary transit times during functional activation, which we previously demonstrated in young mice, was absent in the Tg mice. This study demonstrates that both neurovascular coupling and capillary function are profoundly disturbed in aged Tg and WT mice.
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Envejecimiento/patología , Envejecimiento/fisiología , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/fisiopatología , Velocidad del Flujo Sanguíneo/fisiología , Capilares/patología , Capilares/fisiopatología , Circulación Cerebrovascular/fisiología , Corteza Somatosensorial/irrigación sanguínea , Enfermedad de Alzheimer/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Hemodinámica , Ratones Endogámicos C57BL , Ratones Transgénicos , Consumo de OxígenoRESUMEN
Correct function of glutamate receptors in the postsynaptic density is crucial to synaptic function and plasticity. SorCS3 (sortilin-related receptor CNS expressed 3) is a sorting receptor which previously has been shown to interact with the key postsynaptic proteins; PSD-95 and PICK1. In this study, we employed electrophysiological analyses of acute brain slices combined with immunohistochemistry to define the role of SorCS3 in hippocampal synapses in CA1 and the dentate gyrus. We analyzed a juvenile (P17-21) and a young adult (P55-65) group of animals from a Sorcs3 knockout mouse model. We show that the basal synaptic transmission is severely affected in SorCS3-deficient neurons in CA1, while only slightly reduced in the dentate gyrus. Specifically, input/output curves of CA1 synapses revealed a 20% reduction of fEPSP (field excitatory postsynaptic potential) slopes at the highest stimulation intensity in knockouts of the juvenile group, which developed to a 33% decrease in young adult animals. These impairments may be a result of changes in the postsynaptic AMPA receptors. Interestingly, repetitive afferent stimulation demonstrated that SorCS3-deficient slices respond with an enhanced synaptic facilitation and reduced synaptic depression. These changes also developed with age. A molecular mechanism underlying this relative increase during repetitive stimulations is compatible with enhanced mobility of postsynaptic AMPA receptors resulting in faster exchange of desensitized receptors in the postsynaptic density. The altered response during repetitive stimulation was characteristic for CA1 but not the dentate gyrus. Immunohistochemical analyses of parvalbumin positive neurons combined with paired-pulse tests of network inhibition and patch-clamp recordings only showed minute inhibitory changes in SorCS3-deficient slices. Our results suggest that SorCS3 serves an important role in the postsynaptic protein network, which is more pronounced in CA1 compared to the dentate gyrus. These data support a role for SorCS3 in controlling proper positioning and mobility of glutamate receptors in the postsynaptic density. © 2016 Wiley Periodicals, Inc.
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Región CA1 Hipocampal/metabolismo , Giro Dentado/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Glutamato/metabolismo , Sinapsis/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Región CA1 Hipocampal/crecimiento & desarrollo , Región CA1 Hipocampal/patología , Recuento de Células , Giro Dentado/crecimiento & desarrollo , Giro Dentado/patología , Potenciales Postsinápticos Excitadores/fisiología , Inmunohistoquímica , Potenciación a Largo Plazo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Microelectrodos , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Parvalbúminas/metabolismo , Técnicas de Placa-Clamp , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Sinapsis/patologíaRESUMEN
N-methyl-D-aspartate receptors (NMDARs) are known for their role in the induction of long-term potentiation (LTP). Here we start by reviewing the early evidence for their role in LTP at CA1 synapses in the hippocampus. We then discuss more recent evidence that NMDAR dependent synaptic plasticity at these synapses can be separated into mechanistically distinct components. An initial phase of the synaptic potentiation, which is generally termed short-term potentiation (STP), decays in an activity-dependent manner and comprises two components that differ in their kinetics and NMDAR subtype dependence. The faster component involves activation of GluN2A and GluN2B subunits whereas the slower component involves activation of GluN2B and GluN2D subunits. The stable phase of potentiation, commonly referred to as LTP, requires activation of primarily triheteromeric NMDARs containing both GluN2A and GluN2B subunits. In new work, we compare STP with a rebound potentiation (RP) that is induced by NMDA application and conclude that they are different phenomena. We also report that NMDAR dependent long-term depression (NMDAR-LTD) is sensitive to a glycine site NMDAR antagonist. We conclude that NMDARs are not synonymous for either LTP or memory. Whilst important for the induction of LTP at many synapses in the CNS, not all forms of LTP require the activation of NMDARs. Furthermore, NMDARs mediate the induction of other forms of synaptic plasticity and are important for synaptic transmission. It is, therefore, not possible to equate NMDARs with LTP though they are intimately linked. This article is part of a Special Issue entitled SI: Brain and Memory.
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Hipocampo/fisiología , Potenciación a Largo Plazo , Memoria/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Humanos , Sinapsis/fisiologíaRESUMEN
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is a fatal degenerative disease, best recognized for its debilitating neuromuscular effects. ALS however also induces cognitive impairments in as many as 50% of affected individuals. Moreover, many ALS patients demonstrate cortical hyperexcitability, which has been shown to precede the onset of clinical symptoms. The wobbler mouse is a model of ALS, and like ALS patients the wobbler mouse displays cortical hyperexcitability. Here we investigated if the neocortical aberrations of the wobbler mouse also occur in the hippocampus. Consequently, we performed extracellular field excitatory postsynaptic potential recordings in the CA1 region of the hippocampus on acute brain slices from symptomatic (P45-P60) and presymptomatic (P17-P21) wobbler mice. Significant increased excitation of hippocampal synapses was revealed by leftward shifted input/output-curves in both symptomatic and presymptomatic wobbler mice, and substantiated by population spike occurrence analyses, demonstrating that the increased synaptic excitation precedes the onset of visible phenotypic symptoms in the mouse. Synaptic facilitation tested by paired-pulse facilitation and trains in wobbler and control mice showed no differences, suggesting the absence of presynaptic defects. Immunohistochemical staining revealed that symptomatic wobbler mice have a lower number of parvalbumin positive interneurons when compared to controls and presymptomatic mice. This study reveals that the wobbler mouse model of ALS exhibits hippocampal hyperexcitability. We suggest that the hyperexcitability could be caused by increased excitatory synaptic transmission and a concomitant reduced inhibition due to a decreased number of parvalbumin positive interneurons. Thus we substantiate that wobbler brain impairments are not confined to the motor cortex, but extend to the hippocampus. Importantly, we have revealed more details of the early pathophysiology in asymptomatic animals, and studies like the present may facilitate the development of novel treatment strategies for earlier intervention in ALS patients in the future.
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Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/fisiopatología , Hipocampo/patología , Hipocampo/fisiopatología , Interneuronas/patología , Terminales Presinápticos/metabolismo , Animales , Modelos Animales de Enfermedad , Ratones , Células Piramidales/metabolismo , Células Piramidales/fisiopatología , Potenciales SinápticosRESUMEN
Long-term potentiation (LTP), a cellular model of learning and memory, is generally regarded as a unitary phenomenon that alters the strength of synaptic transmission by increasing the postsynaptic response to the release of a quantum of neurotransmitter. LTP, at CA3-CA1 synapses in the hippocampus, contains a stimulation-labile phase of short-term potentiation (STP, or transient LTP, t-LTP) that decays into stable LTP. By studying the responses of populations of neurons to brief bursts of high-frequency afferent stimulation before and after the induction of LTP, we found that synaptic responses during bursts are potentiated equally during LTP but not during STP. We show that STP modulates the frequency response of synaptic transmission whereas LTP preserves the fidelity. Thus, STP and LTP have different functional consequences for the transfer of synaptic information.
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Potentiation at synapses between CA3 and the CA1 pyramidal neurons comprises both transient and sustained phases, commonly referred to as short-term potentiation (STP or transient LTP) and long-term potentiation (LTP), respectively. Here, we utilized four subtype-selective N-methyl-d-aspartate receptor (NMDAR) antagonists to investigate whether the induction of STP and LTP is dependent on the activation of different NMDAR subtypes. We find that the induction of LTP involves the activation of NMDARs containing both the GluN2A and the GluN2B subunits. Surprisingly, however, we find that STP can be separated into two components, the major form of which involves activation of NMDARs containing both GluN2B and GluN2D subunits. These data demonstrate that synaptic potentiation at CA1 synapses is more complex than is commonly thought, an observation that has major implications for understanding the role of NMDARs in cognition.
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Región CA1 Hipocampal/fisiología , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiología , Animales , Potenciales Postsinápticos Excitadores , Células HEK293 , Humanos , Masculino , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimer's disease (AD). This is difficult to reconcile with the hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Capilares/fisiopatología , Circulación Cerebrovascular , Trastornos Cerebrovasculares/complicaciones , Trastornos Cerebrovasculares/fisiopatología , Velocidad del Flujo Sanguíneo , Humanos , Modelos NeurológicosRESUMEN
BACKGROUND: Sex hormones closely regulate development of the male genital organs during fetal life. The hypothesis that xenobiotics may disrupt endogenous hormonal signalling has received considerable scientific attention, but human evidence is scarce. OBJECTIVES: We analyse occurrence of hypospadias and cryptorchidism according to maternal and paternal occupational exposure to possible endocrine disrupting chemicals. METHODS: We conducted a follow-up study of 45,341 male singleton deliveries in the Danish National Birth Cohort during 1997-2009. Information on work during pregnancy was obtained by telephone interviews around gestational week 16. Parents' job titles were classified according to DISCO-88. A job exposure matrix for endocrine disrupting chemicals (EDCs) was implemented to assess occupational exposures. The Medical Birth and National Hospital Register provided data on congenital anomalies diagnosed at birth or during follow-up, which ended in 2009. Crude and adjusted hazard ratios (HR) were obtained from Cox regression models. RESULTS: Among all pregnancies, 6.3% were classified as possibly or probably exposed to EDCs. The most prevalent occupations conferring possible exposure were cleaners, laboratory technicians, hairdressers and agricultural workers (58% of all potentially exposed). The final cumulative incidence of cryptorchidism in boys was 2.2% (1002 cases), and of hypospadias 0.6% (262 cases). The occurrence of hypospadias increased when mothers were probably [HRa = 1.8 (95% CI 1.0-2.6)] or possibly exposed to one or more EDCs [HRa = 2.6 (95% CI 1.8-3.4). Possible paternal exposure to heavy metals increased the risk of hypospadias [HRa 2.2 (95% CI: 1.0-3.4)] and cryptorchidism [HRa 1.9 (95% CI: 1.1-2.7)]. None of the exposure groups reached statistical significance. CONCLUSION: The study provides some but limited evidence that occupational exposure to possible endocrine disrupting chemicals during pregnancy increases the risk of hypospadias.
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Criptorquidismo/inducido químicamente , Disruptores Endocrinos/efectos adversos , Hipospadias/inducido químicamente , Exposición Materna , Exposición Profesional/efectos adversos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Preescolar , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Entrevistas como Asunto , Masculino , EmbarazoRESUMEN
Amyloid ß (Aß) plays a central role in Alzheimer's disease (AD) and binds to the nicotinic α(7) receptor (α(7) nAChR). Little is known about the degree to which the binding of Aß to the α(7) nAChR influences the role of this receptor in long-term potentiation (LTP), however. We have studied the effect of the partial α(7) nAChR agonist SSR180711 on hippocampal slice preparations from normal wild type (Wt) and APP(swe)/PS1ΔE9 transgenic (Tg) mice. In the hippocampal slices from the 6 months old Wt mice, the application of both nicotine (5µM) and SSR180711 (300nM) resulted in a significant enhancement of LTP expressed in area CA1. However, in the Tg mice the application of SSR180711 did not result in an increase in LTP beyond control levels. The amount of binding of the α(7) nAChR ligand 125-I-α-bungarotoxin was not different between in Tg and Wt mice. These findings indicate that the α(7) nAChR is functionally blocked in the hippocampal neurons, downstream of the α(7) nAChR, and that this is likely due to an interaction between the receptor and Aß, which leads to changes in LTP.
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Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Receptores Nicotínicos/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Hipocampo/efectos de los fármacos , Humanos , Potenciación a Largo Plazo/efectos de los fármacos , Ratones , Ratones Transgénicos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Técnicas de Cultivo de Órganos , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
BACKGROUND: Mitral regurgitation (MR) secondary to ischemic heart disease (IHD) increases during exercise. We tested the hypothesis that the same is also true for MR due to mitral valve prolapse (MVP). METHODS: Consecutive patients with asymptomatic MR of varying severity underwent exercise test on a supine bicycle with workload up to a maximum of 100 W. Echocardiographic measurements were performed at rest and at peak exercise. The study was designed to detect an effective regurgitant orifice (ERO) change of at least 10 mm² during exercise. RESULTS: Twenty-six patients (21 male, age 56 ± 12 years (mean ± SD)) were included. Patients had an ERO of 35 ± 23 mm² (mean ± SD) and regurgitation volume of 48 ± 38 mL (mean ± SD). In these patients, ERO remained unchanged (an increase of 2 ± 15 mm² during exercise, P = 0.6). The regurgitation volume (RVol) decreased with 11 ± 16 mL (mean ± SD), P = 0.003. When calculated for 1 minute, RVol increased during exercise (P = 0.01), but in relation to the total cardiac output it decreased significantly (P = 0.02). CONCLUSION: Exercise does not increase the severity of MR due to MVP, in contrast to MR secondary to IHD. Different disease mechanisms behind these two types of MR could explain this difference.
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Prueba de Esfuerzo , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/fisiopatología , Prolapso de la Válvula Mitral/diagnóstico por imagen , Prolapso de la Válvula Mitral/fisiopatología , Esfuerzo Físico , Ecocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia de la Válvula Mitral/etiología , Prolapso de la Válvula Mitral/complicacionesRESUMEN
BACKGROUND: General practitioners (GPs) and patients find it difficult to talk about risk of future disease, especially when patients have asymptomatic conditions, and treatment options are unlikely to cause immediate perceptible improvements in well-being. Further studies in risk communication training are needed. AIM: 1) to systematically develop, describe and evaluate a complex intervention comprising a training programme for GPs in risk communication and shared decision-making, 2) to evaluate the effect of the training programme on real-life consultations between GPs and patients with high cholesterol levels, and 3) to evaluate patients' reactions during and after the consultations. METHODS/DESIGN: The effect of the complex intervention, based around a training programme, will be evaluated in a cluster-randomised controlled trial with an intervention group and an active control group with 40 GPs and 280 patients in each group.The GPs will receive a questionnaire at baseline and after 6 months about attitudes towards risk communication and cholesterol-reducing medication. After each consultation with a participating high cholesterol-patient, the GPs will complete a questionnaire about decision satisfaction (Provider Decision Process Assessment Instrument). The patients will receive a questionnaire at baseline and after 3 and 6 months. It includes questions about adherence to chosen treatment (Morisky Compliance Scale), self-rated health (SF-12), enablement (Patient Enablement Instrument), and risk communication and decision-making effectiveness (COMRADE Scale). Prescriptions, contacts to the health services, and cholesterol level will be drawn from the registers.In each group, 12 consultations will be observed and tape-recorded. The patients from these 24 consultations will be interviewed immediately after the consultation and re-interviewed after 6 months.Eight purposefully selected GPs from the intervention group will be interviewed in a focus group 6 months after participation in the training programme.The process and context of the RISAP-study will be investigated in detail using an action research approach, in order to analyse adaptation of the intervention model to the specific context. DISCUSSION: This study aims at providing GPs and patients with a firm basis for active deliberation about preventive treatment options, with a view to optimising adherence to chosen treatment. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System NCT01187056.
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Medicina General/métodos , Hipercolesterolemia , Participación del Paciente , Médicos de Familia/educación , Adulto , Actitud Frente a la Salud , Comunicación , Femenino , Humanos , Hipercolesterolemia/tratamiento farmacológico , Masculino , Proyectos de Investigación , RiesgoRESUMEN
Alzheimer's disease (AD) is characterized by progressive memory impairment and the formation of amyloid plaques in the brain. Dysfunctional excitatory synaptic transmission and synaptic plasticity are generally accepted as primary events in the development of AD, and beta-amyloid is intimately involved. Here we describe age related differences in learning, memory, synaptic transmission and long-term potentiation (LTP) in wild type and APPswe/PS1DeltaE9 mice, which produce increasing amounts of Abeta1-42 with age. The mice have both age related and age-independent deficits in radial arm water maze performance. Blind studies of hippocampal slices from transgenic and wild type mice demonstrate that transgenic mice have impaired transient LTP and that the degree of impairment is not related to age from 3 to 12 months. The deficiencies in transient LTP may be related to the behavioral deficits that did not progress with age. The accumulation of beta-amyloid and the episodic memory deficits, both of which increased with age, were not accompanied by an alteration in synaptic transmission or sustained LTP in the in vitro hippocampal slices.
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Precursor de Proteína beta-Amiloide/genética , Amiloidosis/genética , Región CA1 Hipocampal/fisiopatología , Ácido Glutámico/genética , Trastornos de la Memoria/genética , Plasticidad Neuronal/genética , Presenilina-1/deficiencia , Transmisión Sináptica/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Amiloidosis/metabolismo , Amiloidosis/fisiopatología , Animales , Región CA1 Hipocampal/metabolismo , Modelos Animales de Enfermedad , Femenino , Ácido Glutámico/fisiología , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Presenilina-1/genética , Terminales Presinápticos/metabolismo , Terminales Presinápticos/patologíaRESUMEN
Age-related changes in taste memory were evaluated in APPswe/PS1dE9 transgenic (Tg) mice and age-matched wild type littermate controls (Wt). These Tg mice produce increasing amounts of amyloid-beta in the brain with age, develop significant amounts of plaques by 9 months of age, and provide an opportunity to study the effects of Alzheimer's disease-like amyloidosis on different aspects of taste memory. In groups of mice ranging from 15-16 months of age, the neophobic response and its attenuation were similar in Tg and Wt mice. However, conditioned taste aversion (CTA), which resulted from the association between a new taste and an artificially induced gastric malaise, was significantly reduced in the 15-16 month old Tg mice compared to the Wt mice, but not in the 3-4 or 7-8 month old mice. The extinction of CTA was normal in 3-4 month old Tg mice, but occurred more rapidly in the 7-8 and 15-16 months old Tg mice than in the age-matched controls. These results provide evidence of differences in the neuronal systems involved in the attenuation of neophobia and CTA and suggest that the progressive amyloidosis that takes place in APPswe/PS1dE9 mice selectively affects the aversion component of taste memory.
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Péptidos beta-Amiloides/metabolismo , Reacción de Prevención/fisiología , Trastornos de la Memoria/genética , Gusto/genética , Factores de Edad , Precursor de Proteína beta-Amiloide/genética , Análisis de Varianza , Animales , Conducta Animal/fisiología , Peso Corporal/genética , Modelos Animales de Enfermedad , Extinción Psicológica/fisiología , Femenino , Preferencias Alimentarias/fisiología , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Transgénicos , Mutación/efectos de los fármacos , Presenilina-1/genética , Sacarina/administración & dosificación , Sacarina/farmacología , Edulcorantes/administración & dosificación , Edulcorantes/farmacología , Factores de TiempoRESUMEN
The chronic mild stress (CMS) protocol is widely used to evoke depressive-like behaviours in laboratory rats. The aim of the present study was to examine the effects of chronic stress on cognitive performance. About 70% of rats exposed to 7 weeks of chronic mild stress showed a gradual reduction in consumption of a sucrose solution, indicating an anhedonic-like state. The remaining rats did not reduce their sucrose intake, but appeared resilient to the stress-induced effects on sucrose intake. Cognitive profiling of the CMS rats revealed that chronic stress had a negative effect on performance in the spontaneous alternation test, possibly reflecting a deficit in working memory. This effect was independent of whether the stressed rats were anhedonic-like or stress-resilient as measured by their sucrose intake. CMS did not influence performance in passive avoidance and auditory cued fear conditioning, however, in rats displaying an anhedonic-like profile, CMS increased freezing behaviour in contextual fear conditioning.
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Cognición/fisiología , Depresión/fisiopatología , Conducta Alimentaria/psicología , Memoria/fisiología , Estrés Fisiológico , Estimulación Acústica , Análisis de Varianza , Animales , Reacción de Prevención/fisiología , Peso Corporal/fisiología , Condicionamiento Clásico/fisiología , Señales (Psicología) , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Miedo/fisiología , Miedo/psicología , Conducta Alimentaria/fisiología , Reacción Cataléptica de Congelación/fisiología , Masculino , Movimiento/fisiología , Ratas , Ratas Wistar , Sacarosa/administración & dosificaciónRESUMEN
Recent studies have demonstrated that amyloid-beta1-42 (Abeta1-42) binds to the nicotinergic alpha7 acetylcholine receptor (alpha7 nAChR) and that the application of Abeta1-42 to cells inhibits the function of the alpha7 nAChR. The in vivo consequences of the pharmacological activation of the alpha7 nAChR have not been examined. The aim of this study has been to evaluate the efficacy of alpha7 nAChR modulators in transgene mice that overexpress human amyloid precursor protein and accumulate Abeta1-40 and Abeta1-42. In accordance with observations in human Alzheimer tissues, we show here through the use of co-immunoprecipitation that human Abeta-immunoreactive peptides bind to mice alpha7 nAChR in vivo. Agonists of the alpha7 nAChR improve memory and attentional properties and increase immediate early gene expression in the prefrontal cortex and the nucleus accumbens. We show that acute systemic administration of the alpha7 nAChR agonist SSR180711 (10 mg/kg) result in a significant increase in Fos protein levels in the shell of nucleus accumbens in wild-type mice, but has no effect in the transgene mice. There were fewer cell bodies expressing Fos in the prefrontal cortex of transgene mice, and in this region no induction was achieved after administration with SSR180711 in either of the two groups. These results suggest that overexpression of human Abeta peptides perhaps via direct interaction with alpha7 nAChR, inhibit alpha7 nAChR-dependent neurotransmission in vivo and emphasize that clinical trials testing alpha7 nAChR agonists should be related to the content of Abeta peptides in the patient's nervous system.
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Péptidos beta-Amiloides/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Receptores Nicotínicos/metabolismo , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Atención/efectos de los fármacos , Atención/fisiología , Western Blotting , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunohistoquímica , Inmunoprecipitación , Inyecciones Subcutáneas , Sistema Límbico/citología , Sistema Límbico/efectos de los fármacos , Sistema Límbico/metabolismo , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/citología , Neuronas/metabolismo , Núcleo Accumbens/citología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Fragmentos de Péptidos/genética , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Synaptic potentiation induced by high frequency stimulation was investigated by recording field excitatory postsynaptic potentials (f-EPSPs) in rat hippocampal slices. Potentiation consisted of a transient period of decaying f-EPSPs (short-term potentiation, STP) that led to a plateau of continuously potentiated f-EPSPs (long-term potentiation, LTP). Here we show that a previously unknown type of transient, use-dependent, long-lasting potentiation (t-LTP) can account for STP. t-LTP could be stored for more than 6 h and its decay was caused by synaptic activation. Both the expression and the decay of t-LTP were input specific. t-LTP was induced differently from conventional LTP in that the amplitude of t-LTP was dependent upon the stimulation frequency, whereas the magnitude of LTP was dependent on the number of stimuli in the induction train. The decay of t-LTP could not be prevented by the blockage of glutamate receptors, but was prevented by the blockage of stimulus-evoked neurotransmitter release, suggesting that t-LTP is expressed presynaptically. Paired-pulse stimulation experiments showed that the decay of t-LTP was mediated by a decrease in the probability of neurotransmitter release. The decline of t-LTP could be prolonged by the activation of NMDA receptors. Hence, both single and paired-pulse stimuli prolonged the decline of the t-LTP. This decline could be prevented by high frequency burst stimulation (200 Hz). We conclude that t-LTP allows dynamic modulation of synaptic transmission by providing not only spatial association but also temporal convergence between synaptic inputs. Therefore, t-LTP might be a substrate for the encoding of synaptic memory.
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Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Neuronas/fisiología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Calcio/fisiología , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/citología , Técnicas In Vitro , Magnesio/farmacología , Masculino , Potenciales de la Membrana/fisiología , Neurotransmisores/metabolismo , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiologíaRESUMEN
OBJECTIVE: Mortality and incidence of cardiovascular disease have declined during the past 35-40 years. The dual aim of this study is to investigate whether the prevalence of electrocardiographic findings is low compared with older studies and to describe the prevalence of electrocardiographic findings in the Danish population, which has not been reported since 1981. DESIGN: Cross-sectional study based on electrocardiograms obtained from a random sample of the population in the district of Ebeltoft, Denmark, December 1991-June 1992. RESULTS: The age and sex stratified prevalence of abnormal electrocardiograms ranged from 6.8% (95% CI: 4.01-10.7%) in women to 15.0% (95% CI: 10.6-20.4%) in men aged 41-51 years. Men had significantly more electrocardiographic changes than women (p = 0.004). Frequent findings were signs of earlier myocardial infarction (3.1%; 95% CI: 2.1-4.5%), axis deviation (3.1%; 95% CI: 2.1-4.5%) and incomplete right bundle branch block (1.2%; 95% CI: 0.6-2.2%). CONCLUSION: Prevalence of ischemic electrocardiographic findings is low when compared with studies from the past 50 years.