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OBJECTIVE: The aim of the study was to assess the potential association between serum 25-hydroxyvitamin D (25(OH)D) and whole-body bone mineral density (BMD) among 16-year-old adolescents and to study the prevalence of 25(OH)D insufficiency, defined as concentration under 50 nmol/l. DESIGN: A cross-sectional study. SETTING: Reykjavik, Iceland, latitude 64°08'N. Measurements took place in the Icelandic Heart Association's research lab during April-June 2015. PARTICIPANTS: In total, 411 students in Reykjavik, Iceland, were invited to participate, 315 accepted the invitation (76·6 %) and 289 had valid data (mainly Caucasian). RESULTS: 25(OH)D < 50 nmol/l was observed in 70 % of girls and 66·7 % of boys. 25(OH)D ≥ 50 nmol/l was significantly associated with higher whole-body BMD after adjusting for the influence of sex, height, fat mass and lean mass. A linear relationship between 25(OH)D and whole-body BMD was significant for 25(OH)D < 50 nmol/l (n 199, P < 0·05) but NS for 25(OH)D ≥ 50 nmol/l (n 86, P = 0·48). CONCLUSIONS: Our results are in line with some but not all previous studies on the relationship between BMD and 25(OH)D in adolescents. The observed difference in BMD between those with above v. below a 25(OH)D concentration of 50 nmol/l was of about a fifth of one SD, which may have a clinical relevance as one SD decrease in volumetric BMD has been associated with a 89 % increase in 2 years risk of fracture. Icelandic adolescents should be encouraged to increase their vitamin D intake as it is possible that their current intake is insufficient to achieve optimal peak bone mass.
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Densidad Ósea , Deficiencia de Vitamina D/epidemiología , Vitamina D/análogos & derivados , Adolescente , Estudios Transversales , Femenino , Fracturas Óseas , Humanos , Islandia/epidemiología , Modelos Lineales , Masculino , Estado Nutricional , Factores Sexuales , Vitamina D/sangre , Deficiencia de Vitamina D/sangreRESUMEN
Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.
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Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Predisposición Genética a la Enfermedad/genética , Esquizofrenia/genética , Psicología del Esquizofrénico , Alelos , Pueblo Asiatico/genética , Encéfalo/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Estudios de Casos y Controles , Cognición , Bases de Datos Genéticas , Regulación hacia Abajo , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Personalidad/genética , Polimorfismo de Nucleótido Simple/genética , Mapas de Interacción de Proteínas/genética , Población Blanca/genéticaRESUMEN
Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).
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Trastorno Bipolar/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 16/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genética , Adulto , Anciano , Anciano de 80 o más Años , Trastorno Bipolar/complicaciones , Trastorno Bipolar/epidemiología , Europa (Continente) , Femenino , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Cooperación Internacional , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Análisis de Secuencia por Matrices de Oligonucleótidos , Factores de Riesgo , Esquizofrenia/complicaciones , Esquizofrenia/epidemiología , Adulto JovenRESUMEN
Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
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Aberraciones Cromosómicas , Cromosomas Humanos Par 16 , Variaciones en el Número de Copia de ADN , Esquizofrenia/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Mapeo Cromosómico , Femenino , Humanos , Masculino , Valores de Referencia , Duplicaciones Segmentarias en el Genoma/genética , Eliminación de Secuencia/genética , Adulto JovenRESUMEN
A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).
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Trastornos de Ansiedad/genética , Trastorno Bipolar/genética , Variaciones en el Número de Copia de ADN/genética , Factores de Transcripción de Tipo Kruppel/genética , Esquizofrenia/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Valores de ReferenciaRESUMEN
Inhibition of cerebral amyloid beta-protein deposition seems to be an important target for Alzheimer's disease therapy. Amyloidogenesis could be inhibited by short synthetic peptides designed as beta-sheet breakers. Here we demonstrate a 5-residue peptide that inhibits amyloid beta-protein fibrillogenesis, disassembles preformed fibrils in vitro and prevents neuronal death induced by fibrils in cell culture. In addition, the beta-sheet breaker peptide significantly reduces amyloid beta-protein deposition in vivo and completely blocks the formation of amyloid fibrils in a rat brain model of amyloidosis. These findings may provide the basis for a new therapeutic approach to prevent amyloidosis in Alzheimer's disease.
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Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/metabolismo , Amiloidosis/prevención & control , Encéfalo/metabolismo , Fragmentos de Péptidos/metabolismo , Péptidos/farmacología , Péptidos beta-Amiloides/farmacología , Péptidos beta-Amiloides/toxicidad , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/toxicidad , Ratas , Ratas Endogámicas F344 , Células Tumorales CultivadasRESUMEN
OBJECTIVE: The aim of this study was to construct regression-based norms for 3 executive-function tests: the Trail Making Test, Stroop, and Verbal Fluency. METHOD: A sample of 1,034 healthy Icelandic adults (18-64 years) was used to calculate predicted scores for test measures from all 3 tests, controlled for the effects of age, gender, and education, as well as the interaction between these variables. RESULTS: The 3 demographic variables showed significant effects on most test measures and were included in the final equation for estimating predicted scores. An older age and less education predicted worse cognitive performances in most cases, and women tended to outperform men. CONCLUSION: These results highlight the importance of adjusting for age, gender, and educational level when constructing normative data. Controlling for age alone may be insufficient or misleading in clinical-practice settings. A simple, user-friendly program for predicting executive-function test scores is provided.
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Función Ejecutiva , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Valores de Referencia , Prueba de Secuencia AlfanuméricaRESUMEN
The majority of clinical trials targeting the tau protein in Alzheimer's disease and other tauopathies are tau immunotherapies. Because tau pathology correlates better with the degree of dementia than amyloid-ß lesions, targeting tau is likely to be more effective in improving cognition than clearing amyloid-ß in Alzheimer's disease. However, the development of tau therapies is in many ways more complex than for amyloid-ß therapies as briefly outlined in this review. Most of the trials are on humanized antibodies, which may have very different properties than the original mouse antibodies. The impact of these differences are to a large extent unknown, can be difficult to decipher, and may not always be properly considered. Furthermore, the ideal antibody properties for efficacy are not well established and can depend on several factors. However, considering the varied approaches in clinical trials, there is a general optimism that at least some of these trials may provide functional benefits to patients suffering of various tauopathies. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
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Enfermedad de Alzheimer/terapia , Inmunoterapia , Proteínas tau/inmunología , Enfermedad de Alzheimer/inmunología , Animales , Anticuerpos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Tauopatías/inmunología , Tauopatías/terapiaRESUMEN
The antisaccade (AS) task is considered a prominent measure of inhibitory control, but it is still unclear which cognitive processes are used for successful performance of the task. Previous results have provided evidence for the involvement of several processes, including working memory (WM), inhibition and attention. Thus, the aim of this study was to explore, using a range of neuropsychological tests, which cognitive factors predict individual differences in AS performance. To do so, 143 healthy participants underwent a battery including tests measuring inhibition, working memory, cognitive flexibility, sustained attention, IQ and fluency. Hierarchical stepwise regression analyses were conducted to assess the association with AS performance. Performance on the Trail-Making-Test, version B (TMT-B), a test measuring flexibility, divided attention and WM, was found to significantly predict AS latency. Rapid Visual Information Processing (RVIP), used to assess sustained attention and WM, significantly predicted AS error rate. Other cognitive measures, however, did not significantly predict AS performance. Bayesian Model Averaging supported these conclusions and showed that non-significant predictors are unlikely to be associated with AS outcomes. Several explanations are provided for the associations of TMT-B and RVIP with AS performance; as the tests measure a range of different cognitive processes, interpretation of these results remains less clear. For a better understanding of the cognitive mechanisms underlying AS performance, future research should make use of a wider range of attention and WM tests.
RESUMEN
BACKGROUND AND AIMS: Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate-release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. METHODS: A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. RESULTS: Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (p<0.0001). The viscosity of the disintegrated MPH was significantly higher for MPH OROS and MPH OCR and the preparation was significantly more time-consuming than for the other MPH samples. No differences were observed between users and non-users. CONCLUSIONS: To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations.
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Metilfenidato/administración & dosificación , Metilfenidato/metabolismo , Abuso de Sustancias por Vía Intravenosa/metabolismo , Abuso de Sustancias por Vía Intravenosa/psicología , Administración Intravenosa , Administración Oral , Adulto , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/metabolismo , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/metabolismo , Consumidores de Drogas/psicología , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Abuso de Sustancias por Vía Intravenosa/diagnóstico , Comprimidos , Resultado del Tratamiento , ViscosidadRESUMEN
Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.
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Cognición/fisiología , Variaciones en el Número de Copia de ADN/genética , Discalculia/genética , Dislexia/genética , Discapacidad Intelectual/genética , Adolescente , Adulto , Anciano , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Par 15/genética , Discapacidades del Desarrollo/genética , Femenino , Neuroimagen Funcional/métodos , Neuroimagen Funcional/normas , Heterocigoto , Humanos , Islandia/epidemiología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas/normas , Fenotipo , Lóbulo Temporal/anatomía & histología , Lóbulo Temporal/diagnóstico por imagen , Adulto JovenRESUMEN
Non-fibrillar soluble oligomeric forms of amyloid-ß peptide (oAß) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAß initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aß, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAß levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAß to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aß on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aß and tau pathology.
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Potenciación a Largo Plazo , Memoria , Agregado de Proteínas , Agregación Patológica de Proteínas , Multimerización de Proteína , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Espacio Extracelular/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Ratones , Neuronas/metabolismo , Proteínas tau/químicaRESUMEN
OBJECTIVES: We sought to evaluate the prognostic value and clinical characteristics associated with electrocardiographic (ECG) ST-T changes among men without other manifestations of coronary heart disease. BACKGROUND: Recent achievements in secondary prevention and treatment of coronary heart disease have highlighted the importance of early diagnosis of both symptomatic and silent forms of the disease. The prognostic and clinical importance of ST-T changes in men with no other manifestations of coronary heart disease is still unclear. Do they reflect silent coronary heart disease or hypertension, or both, and what is their independent contribution to prognosis? METHODS: The subjects were 9,139 men born in the years 1907 to 1934 and followed up for 4 to 24 years. On initial visit they were assigned to different categories of coronary heart disease on the basis of Rose chest pain questionnaire, hospital records, 12-lead ECG, history and physical examination. RESULTS: The prevalence of silent ST-T changes among men without overt coronary heart disease was strongly influenced by age, increasing from 2% at age 40 years to 30% at age 80 years. Men with such ST-T changes were older and had higher serum triglyceride levels and worse glucose tolerance than men without such changes or other evidence of coronary heart disease. Their blood pressure was higher, and they more often had an enlarged heart or left ventricular hypertrophy and more often took antihypertensive medication, digitalis or diuretic drugs. Serum cholesterol levels were not different between the two groups. After adjustment for other risk factors, these silent ST-T changes had a risk ratio of 2.0 for death from coronary heart disease and 1.6 for subsequent myocardial infarction or angina pectoris. CONCLUSIONS: Silent ST-T changes that are ischemic by the Minnesota code are probably both a marker of silent coronary heart disease and high blood pressure. They define a distinct group of patients with highly abnormal risk factor profile. Although not specific for coronary heart disease and often transient, they are associated with the development of every clinical manifestation of coronary heart disease and are independent predictors of reduced survival.
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Enfermedad Coronaria/epidemiología , Ecocardiografía , Hipertensión/epidemiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Enfermedad Coronaria/fisiopatología , Humanos , Hipertensión/fisiopatología , Islandia/epidemiología , Masculino , Persona de Mediana Edad , Pronóstico , Factores de RiesgoRESUMEN
In recent years major outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP(C) (prion protein cellular), to a toxic and infectious form, PrP(Sc) (prion protein scrapie). None of the prionoses currently have an effective treatment. A limited number of active immunization approaches have been shown to slightly prolong the incubation period of prion infection. Active immunization in wild-type animals is hampered by auto-tolerance to PrP and potential toxicity. Here we report that mucosal vaccination with an attenuated Salmonella vaccine strain expressing the mouse PrP, is effective at overcoming tolerance to PrP and leads to a significant delay or prevention of prion disease in mice later exposed orally to the 139A scrapie strain. This mucosal vaccine induced gut anti-PrP immunoglobulin (Ig)A and systemic anti-PrP IgG. No toxicity was evident with this vaccination approach. This promising finding suggests that mucosal vaccination may be a useful method for overcoming tolerance to PrP and preventing prion infection among animal and potentially human populations at risk.
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Inmunoterapia , Membrana Mucosa/inmunología , Proteínas PrPC/inmunología , Enfermedades por Prión/inmunología , Enfermedades por Prión/prevención & control , Vacunación , Administración Oral , Análisis de Varianza , Animales , Western Blotting/métodos , Femenino , Regulación Viral de la Expresión Génica/fisiología , Inmunoglobulina A/metabolismo , Inmunoglobulina G/metabolismo , Ratones , Proteínas PrPC/química , Enfermedades por Prión/virología , Conformación Proteica , Factores de TiempoRESUMEN
Cerebral amyloid-beta (Abeta) deposition is central to the neuropathological definition of Alzheimer disease (AD) with Abeta related toxicity being linked to its beta-sheet conformation and/or aggregation. We show that a beta-sheet breaker peptide (iAbeta5) dose-dependently and reproducibly induced in vivo disassembly of fibrillar amyloid deposits, with control peptides having no effect. The iAbeta5-induced disassembly prevented and/or reversed neuronal shrinkage caused by Abeta and reduced the extent of interleukin-1beta positive microglia-like cells that surround the Abeta deposits. These findings suggest that beta-sheet breakers, such as iAbeta5 or similar peptidomimetic compounds, may be useful for reducing the size and/or number of cerebral amyloid plaques in AD, and subsequently diminishing Abeta-related histopathology.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Amígdala del Cerebelo/patología , Péptidos beta-Amiloides/farmacología , Fragmentos de Péptidos/farmacología , Enfermedad de Alzheimer/inducido químicamente , Animales , Masculino , Microglía/metabolismo , Ovillos Neurofibrilares/química , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Neuronas/metabolismo , Neuronas/patología , Estructura Secundaria de Proteína , Ratas , Ratas Endogámicas F344 , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
We have observed that single amyloid-beta 25-35 (A beta) injections (5.0 nmol) into the right amygdala of rats produce progressive cytoskeletal and astrogliotic reactions not only within the amygdala, but also in distal brain regions that project to the amygdala. To determine if these effects are potentiated by bilateral injections, we injected A beta (5.0 nmol) into the left and right amygdala of young male Fischer rats. Animals were sacrificed 32 days postoperatively. Bilateral infusions of A beta induced significant neuronal shrinkage, tau-2 neuronal staining, and reactive astrocytosis within the right amygdala and/or hippocampus, compared with vehicle-treated rats. Surprisingly, the same brain regions within the left hemisphere were significantly less affected even though no differences were observed between the left and right amygdala in the size of Congored-positive A beta deposits. Unilateral injections of A beta into the left amygdala led to significant histological changes in the right amygdala and hippocampus, but not in the same brain regions within the left hemisphere. These results suggest a laterality in the histopathological effects of A beta in male Fischer rats. Identification of the cause for the lateralized effect of A beta may prove valuable for understanding the etiology of Alzheimer disease and provide possible therapeutic strategies designed to slow the progression of the disease.
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Amígdala del Cerebelo/efectos de los fármacos , Péptidos beta-Amiloides/farmacología , Fragmentos de Péptidos/farmacología , Amígdala del Cerebelo/patología , Animales , Lateralidad Funcional , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
To determine if amyloid-beta (A beta) induces tau-immunoreactivity (IR) and reactive astrocytosis in vivo, we injected A beta 25-35 (5.0 nmol) into the right amygdala of rats. At 8 days postinjection, the peptide induced tau-2 IR in neuronal cell bodies and processes ipsilaterally in the amygdala, cingulate cortex, and hippocampus. At 32 days postinjection, the intensity of tau-2 IR was greater than at 8 days in the amygdala and hippocampus, but not in the cingulate cortex. Induction of Alz-50 IR also was progressive but the morphology and distribution was different from tau-2 IR. Beaded fibers with occasional neuronal perikarya were visualized with Alz-50, and the IR was primarily observed in the ipsilateral amygdala. In addition, amygdaloid injections of A beta 25-35 induced reactive astrocytosis, particularly in the ipsilateral hippocampus at 32 days postoperatively. To our knowledge, this is the first study to show that in vivo injections of A beta 25-35 induce progressive transsynaptic cytoskeletal and astrogliotic reactions, that gradually spread from the area of injection to brain regions that have prominent efferent connections with that area. These findings also suggest a direct association between plaque and tangle formation in Alzheimer's disease.
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Amígdala del Cerebelo/fisiología , Péptidos beta-Amiloides/toxicidad , Encéfalo/patología , Neurotoxinas/toxicidad , Fragmentos de Péptidos/toxicidad , Péptidos beta-Amiloides/administración & dosificación , Animales , Antígenos/metabolismo , Benzoxazinas , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Masculino , Microinyecciones , Neurotoxinas/administración & dosificación , Oxazinas , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Endogámicas F344 , Proteínas tau/metabolismoRESUMEN
To examine the time course of the histopathological effects of bilateral injections of amyloid-beta 25-35 (A beta) and to determine if these effects are associated with a reduction in choline acetyltransferase activity and behavioral impairments, we injected A beta (5.0 nmol) into the amygdala of young male Fischer rats. Control rats received vehicle infusions. For histological analysis, animals were sacrificed at 8, 32, 64, 96, and 128 days postoperatively (n = 21-33 per timepoint). A beta induced neuronal tau-2 staining in the right, but not the left amygdala and hippocampus. A beta also induced reactive astrocytosis and neuronal shrinkage within the right hippocampus and amygdala, respectively. As with tau-2, these same brain regions within the left hemisphere in the A beta-treated rats were significantly less affected. In addition, A beta appeared to induce microglial and neuronal interleukin-1beta staining. The histopathological effects of A beta peaked at 32 days postoperatively but were not associated with a reduction in amygdaloid choline acetyltransferase activity. In a separate experiment, behavioral effects of bilateral intra-amygdaloid injections of A beta were analyzed at 34-52 days postoperatively. In an open field test, the treatment groups differed only in the numbers of rears emitted (p = 0.016). There was no effect of A beta in the Morris water maze or in the acquisition and retention of a one-way conditioned avoidance response. These data suggest a laterality in the histopathological effects of A beta and that the effects of single injections are in part transient. These findings also suggest a direct association between plaque and tangle formation in Alzheimer's disease, and support the use of this rat model to screen drugs that may alter the initial pathological events associated with Alzheimer's disease, that occur before the manifestations of extensive behavioral impairments become evident.
Asunto(s)
Amígdala del Cerebelo/fisiología , Péptidos beta-Amiloides/farmacología , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Encéfalo/patología , Fragmentos de Péptidos/farmacología , Péptidos beta-Amiloides/administración & dosificación , Animales , Benzoxazinas , Rojo Congo , Proteína Ácida Fibrilar de la Glía/metabolismo , Histocitoquímica , Interleucina-1/metabolismo , Masculino , Oxazinas , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Endogámicas F344 , Factores de Tiempo , Proteínas tau/metabolismoRESUMEN
The Reykjavik Study is a large population-based cohort study, starting in 1967. A total of 9,139 men, born in the years 1907 to 1934, have been followed for 4 to 24 years. Heart size was determined by chest roentgenogram in 2 planes and cardiomegaly, defined as a relative heart size exceeding 550 ml/m2, was detected in 517. Multivariate Cox regression analysis was used to estimate the independent contribution of variables measured at each participant's first visit to the risk of both all-cause and coronary artery disease (CAD) mortality. Cardiomegaly was detected in 3.7% of men aged < 40 years and in 21.2% of those > 75 years. One half of these men had hypertension, one third had manifestations of CAD, and 37% had neither. Among men with cardiomegaly, the presence of CAD had marked deleterious effect on prognosis. Serum total cholesterol and systolic blood pressure were significant independent risk factors of CAD mortality with risk ratio of 1.008 per mg/dl serum cholesterol (95% confidence interval 1.00 to 1.01; p = 0.004) and 1.015/mm Hg (95% confidence interval 1.000 to 1.300; p = 0.043), respectively. Smoking > 25 cigarettes/day carried a 2.3-fold risk (95% confidence interval 1.3 to 4.4; p = 0.008) of all-cause mortality. The traditional risk factors for CAD, serum cholesterol, high blood pressure, and smoking maintain their detrimental effect on prognosis among patients with cardiomegaly. These findings have implications for secondary prevention, signifying that in the presence of cardiomegaly, complacency is not justified in controlling major risk factors for CAD.
Asunto(s)
Cardiomegalia/complicaciones , Enfermedad Coronaria/etiología , Adulto , Factores de Edad , Anciano , Presión Sanguínea , Cardiomegalia/mortalidad , Causas de Muerte , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Análisis de Regresión , Factores de RiesgoRESUMEN
BACKGROUND: While coronary heart disease (CHD) is a serious and often fatal disease the prognosis is variable and major effort has been invested in risk stratification. The purpose of this study was to examine the relation between long-term prognosis and risk factors in different clinical categories of CHD. METHODS: A general population sample of 9141 men, aged 34-79 at entry into the study was divided into six groups with respect to manifestations of CHD at entry: I. Symptomatic infarction. II. Silent or unrecognized infarction. III. Angina pectoris with ischaemic changes on ECG. IV. Angina without ischaemic changes. V. Angina by Rose questionnaire but not confirmed by a physician. VI. No manifestations of CHD. RESULTS: The risk factor profile varied considerably between the different categories and by life-table analysis marked differences in survival were demonstrated between the groups. The risk factors maintained their detrimental effects on prognosis in the presence of CHD. Thus, age, serum total cholesterol, impaired glucose tolerance and smoking were found by Cox's regression to be statistically significant independent risk factors of CHD mortality among men having manifestations of CHD (groups I-V). Furthermore, the composite risk score, a measure of the overall risk factor exposures had marked effect on the prognosis of the various CHD groups. When the comprehensive risk factor score for both CHD mortality and all-cause mortality was accounted for marked differences persisted in the long-term prognosis. Compared to those without CHD the infarct groups had about a 7.6- and 3.7-fold risk of dying from CHD and all causes respectively. Those with angina had from 2.5- to 3.2-fold risk of CHD mortality and 1.7- to 2.2-fold risk of all-cause mortality depending on the subgroup of angina, again compared to those without manifestations of CHD. CONCLUSION: Different categories of CHD had different risk factor profiles and the long-term prognosis resulted from a complex interplay between those factors and the diagnostic category of CHD. The risk factors maintained their detrimental effects on prognosis in the presence of CHD and after accounting for the comprehensive risk factor score marked differences persisted in the long-term prognosis, being worst for those having suffered a myocardial infarction, either symptomatic or silent.