Contrast Adaptation Contributes to Contrast-Invariance of Orientation Tuning of Primate V1 Cells

BACKGROUND: Studies in rodents and carnivores have shown that orientation tuning width of single neurons does not change when stimulus contrast is modified. However, in these studies, stimuli were presented for a relatively long duration (e. g., 4 seconds), making it possible that contrast adaptation contributed to contrast-invariance of orientation tuning. Our first purpose was to determine, in marmoset area V1, whether orientation tuning is still contrast-invariant with the stimulation duration is comparable to that of a visual fixation. METHODOLOGY/PRINCIPAL FINDINGS: We performed extracellular recordings and examined orientation tuning of single-units using static sine-wave gratings that were flashed for 200 msec. Sixteen orientations and three contrast levels, representing low, medium and high values in the range of effective contrasts for each neuron, were randomly intermixed. Contrast adaptation being a slow phenomenon, cells did not have enough time to adapt to each contrast individually. With this stimulation protocol, we found that the tuning width obtained at intermediate contrast was reduced to 89% (median), and that at low contrast to 76%, of that obtained at high contrast. Therefore, when probed with briefly flashed stimuli, orientation tuning is not contrast-invariant in marmoset V1. Our second purpose was to determine whether contrast adaptation contributes to contrast-invariance of orientation tuning. Stationary gratings were presented, as previously, for 200 msec with randomly varying orientations, but the contrast was kept constant within stimulation blocks lasting >20 sec, allowing for adaptation to the single contrast in use. In these conditions, tuning widths obtained at low contrast were still significantly less than at high contrast (median 85%). However, tuning widths obtained with medium and high contrast stimuli no longer differed significantly. CONCLUSIONS/SIGNIFICANCE: Orientation tuning does not appear to be contrast-invariant when briefly flashed stimuli vary in both contrast and orientation, but contrast adaptation partially restores contrast-invariance of orientation tuning

Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy

Learning and memory deficits in Alzheimer's disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABA(A) receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen-glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for restoration of synaptic function in hippocampal slices from AD-transgenic mice, reversal of cognitive deficits, and brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together, the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD

A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease.

BACKGROUND: Clinical failures singularly targeting amyloid-β pathology indicate a critical need for alternative Alzheimer's disease (AD) therapeutic strategies. The mixed pathology reported in a large population of AD patients demands a multifunctional drug approach. Since activation of cAMP response element binding protein (CREB) plays a crucial role in synaptic strengthening and memory formation, we retooled a clinical drug with known neuroprotective and anti-inflammatory activity to activate CREB, and validated this novel multifunctional drug, NMZ, in 4 different mouse models of AD. RESULTS: NMZ was tested in three mouse models of familial AD and one model of sporadic AD. In 3 × Tg hippocampal slices, NMZ restored LTP. In vivo, memory was improved with NMZ in all animal models with robust cognitive deficits. NMZ treatment lowered neurotoxic forms of Aβ in both APP/PS1 and 3 × Tg transgenic mice while also restoring neuronal plasticity biomarkers in the 3 × Tg mice. In EFAD mice, incorporation of the major genetic AD risk factor, hAPOE4, did not mute the beneficial drug effects. In a novel sporadic mouse model that manifests AD-like pathology caused by accelerated oxidative stress in the absence of any familial AD mutation, oral administration of NMZ attenuated hallmark AD pathology and restored biomarkers of synaptic and neuronal function. CONCLUSIONS: The multifunctional approach, embodied by NMZ, was successful in mouse models of AD incorporating Aβ pathology (APP/PS1), tau pathology (3xTg), and APOE4, the major human genetic risk factor for AD (EFAD). The efficacy observed in a novel model of sporadic AD (Aldh2 (-/-) ) demonstrates that the therapeutic approach is not limited to rare, familial AD genetic mutations. The multifunctional drug, NMZ, was not designed directly to target Aβ and tau pathology; however, the attenuation of this hallmark pathology suggests the approach to be a highly promising, disease-modifying strategy for AD and mixed pathology dementia

Clinical evolution of patients hospitalized due to the first episode of Acute Coronary Syndrome Evolución clínica de pacientes internados debido el primer episodio de la Síndrome Aguda de las Coronarias Evolução clinica de pacientes internados em decorrência do primeiro episódio da Síndrome Coronariana Aguda

AIM: to assess the clinical evolution of patients hospitalized due to the first episode of Acute Coronary Syndrome (ACS) according to its clinical manifestation. METHODS: data were collected from 234 patients, hospitalized between May 2006 and July 2009 due to the first episode of an ACS, by consulting their medical records. RESULTS: 234 patients were hospitalized, 140 (59.8%) due to Acute Myocardial Infarction (AMI). In the group with AMI, 19.3% presented complications, against 12.8% in the group with Unstable Angina (UA) (p=0.19). Angioplasty levels were higher among patients with AMI than with UA (p=0.02) and coronary artery bypass graft surgery was more frequent among UA patients (p=0.03). The majority (227; 97%) survived after the coronary event. Among the seven patients who died during the hospitalization, four had AMI (2.9%) and three UA (3.2%). CONCLUSIONS: A larger number of complications were found among infarction victims and the accomplishment of coronary artery bypass graft surgery differed between the groups.<br>OBJETIVO: evaluar la evolución clínica de pacientes internados por el primer episodio del Síndrome Aguda de Coronarias según su manifestación clínica. MÉTODOS: Fueron colectados datos de 234 pacientes internados entre mayo de 2006 y julio de 2009 debido el primer episodio de una ACA mediante consultas a los prontuarios. RESULTADOS: La mayoría (59,8%) internó debido al Infarto Agudo del Miocardio (IAM). En el grupo con IAM, 19,3% presentaron complicaciones y 12,8% en el grupo con Angina Inestable (AI)(p=0,19). La realización de angioplastia fue mayor entre los pacientes con IAM de lo que con AI (p=0,02) y la cirugía de revascularización fue más realizada entre los pacientes con AI (p=0,03). La mayoría (227; 97%) sobrevivió al evento de las coronarias. Entre los siete pacientes que murieron en la internación, cuatro tenían IAM (2,9%) y tres AI (3,2%). CONCLUSIONES: Hubo mayor número de complicaciones entre los infartados y la realización de revascularización del miocardio fue diferente en los dos grupos.<br>OBJETIVO: avaliar a evolução clínica de pacientes internados pelo primeiro episódio da síndrome coronariana aguda (SCA), segundo sua manifestação clínica. MÉTODOS: foram coletados dados de 234 pacientes internados entre maio de 2006 e julho de 2009, em decorrência do primeiro episódio de uma SCA, mediante consultas aos prontuários. RESULTADOS: a maioria (59,8%) foi internada devido ao infarto agudo do miocárdio (IAM). No grupo com IAM, 19,3% apresentaram complicações e 12,8% no grupo com angina instável (AI) (p=0,19). A realização de angioplastia foi maior entre os pacientes com IAM do que com AI (p=0,02) e a cirurgia de revascularização foi mais realizada entre os pacientes com AI (p=0,03). A maioria (227 - 97%) sobreviveu ao evento coronariano. Entre os sete pacientes que morreram na internação, quatro tinham IAM (2,9%) e três AI (3,2%). CONCLUSÕES: houve maior número de complicações entre os infartados e a realização de revascularização do miocárdio foi diferente nos dois grupos