Blarcamesine for the treatment of Early Alzheimer's Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial.

Background: There are no approved oral disease-modifying treatments for Alzheimer's disease (AD).

Objectives: The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement.

Design: ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial.

NFTsim: Theory and Simulation of Multiscale Neural Field Dynamics.

A user ready, portable, documented software package, NFTsim, is presented to facilitate numerical simulations of a wide range of brain systems using continuum neural field modeling. NFTsim enables users to simulate key aspects of brain activity at multiple scales. At the microscopic scale, it incorporates characteristics of local interactions between cells, neurotransmitter effects, synaptodendritic delays and feedbacks.

Spatiotemporally varying visual hallucinations: I. Corticothalamic theory.

The thalamus is introduced to a recent model of the visual cortex to examine its effect on pattern formation in general and the generation of temporally oscillating patterns in particular. By successively adding more physiological details to a basic corticothalamic model, it is determined which features are responsible for which effects. In particular, with the addition of a thalamic population, several changes occur in the spatiotemporal power spectrum: power increases at resonances of the corticothalamic loop, while the loop acts as a spatiotemporal low-pass filter, and synaptic and dendritic dynamics temporally low-pass filter the activity more generally.

Spatiotemporally varying visual hallucinations: II. Spectral classification and comparison with theory.

In order to better understand the nature of visual hallucinations, and to test predictions of spatiotemporally oscillating hallucinations from a recent corticothalamic model of visual dynamics, clinical descriptions of hallucinations are used to establish boundaries on the spatiotemporal frequencies observed in various disorders. Detailed comparisons with hallucinations during migraine aura demonstrate that key features are consistent with corticothalamic origin and specific abnormalities, but underline the need for more detailed quantitative data to be obtained on temporally oscillating hallucinations more generally.

The mixed-discipline aged-care student clinic: an authentic interprofessional learning initiative.

This paper describes the development, methods and results of a novel interprofessional student-led aged care clinic. The clinic was established to facilitate the interprofessional education of students approaching graduation in dietetics, medicine, nursing, occupational therapy, pharmacy, physiotherapy, podiatry, social work, and speech pathology. Students worked together in a primary care clinic established to support patients >70 years old who had recently been discharged home from an acute hospital admission.

Spatiotemporal hemodynamic response functions derived from physiology.

Probing neural activity with functional magnetic resonance imaging (fMRI) relies upon understanding the hemodynamic response to changes in neural activity. Although existing studies have extensively characterized the temporal hemodynamic response, less is understood about the spatial and spatiotemporal hemodynamic responses. This study systematically characterizes the spatiotemporal response by deriving the hemodynamic response due to a short localized neural drive, i.

Hemodynamic traveling waves in human visual cortex.

Functional MRI (fMRI) experiments rely on precise characterization of the blood oxygen level dependent (BOLD) signal. As the spatial resolution of fMRI reaches the sub-millimeter range, the need for quantitative modelling of spatiotemporal properties of this hemodynamic signal has become pressing. Here, we find that a detailed physiologically-based model of spatiotemporal BOLD responses predicts traveling waves with velocities and spatial ranges in empirically observable ranges.

Spatiotemporal BOLD dynamics from a poroelastic hemodynamic model.

A quantitative theory is developed for the relationship between stimulus and the resulting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal, including both spatial and temporal dynamics for the first time. The brain tissue is modeled as a porous elastic medium, whose interconnected pores represent the vasculature. The model explicitly incorporates conservation of blood mass, interconversion of oxygenated and deoxygenated hemoglobin, force balance within the blood and of blood pressure with vessel walls, and blood flow modulation due to neuronal activity.

Spatiotemporal dynamics of pattern formation in the primary visual cortex and hallucinations.

The existence of visual hallucinations with prominent temporal oscillations is well documented in conditions such as Charles Bonnett Syndrome. To explore these phenomena, a continuum model of cortical activity that includes additional physiological features of axonal propagation and synapto-dendritic time constants, is used to study the generation of hallucinations featuring both temporal and spatial oscillations. A detailed comparison of the physiological features of this model with those of two others used previously in the modeling of hallucinations is made, and differences, particularly regarding temporal dynamics, relevant to pattern formation are analyzed.

Firing pattern of bursting neurons under sinusoidal drive in mean-field modeling.

Bursting has been observed in many sensory neurons, and is thought to be important in neural signaling, sleep, and some disorders of the brain. Bursting neurons have been studied via various types of conductance-based models at the single-neuron level. Important features of bursting have been reproduced by this type of model, but it is not certain how well the behavior of populations of bursting neurons can be represented solely by that of individual neurons.

Mean-field modeling of the basal ganglia-thalamocortical system. II Dynamics of parkinsonian oscillations.

Neuronal correlates of Parkinson's disease (PD) include a shift to lower frequencies in the electroencephalogram (EEG) and enhanced synchronized oscillations at 3-7 and 7-30 Hz in the basal ganglia, thalamus, and cortex. This study describes the dynamics of a recent physiologically based mean-field model of the basal ganglia-thalamocortical system, and shows how it accounts for many key electrophysiological correlates of PD. Its detailed functional connectivity comprises partially segregated direct and indirect pathways through two populations of striatal neurons, a hyperdirect pathway involving a corticosubthalamic projection, thalamostriatal feedback, and local inhibition in striatum and external pallidum (GPe).

Comparing hemodynamic models with DCM.

The classical model of blood oxygen level-dependent (BOLD) responses by Buxton et al. [Buxton, R.B.

IFN-gamma regulates Fas ligand expression in human CD4+ T lymphocytes and controls their anti-mycobacterial cytotoxic functions.

Fas and Fas Ligand (FasL) expression, activation-induced cell death (AICD) and mycobacterial antigen-specific cytotoxicity of peripheral T cells from patients with complete inherited IFN-gamma receptor 1 binding chain deficiency (IFN-gammaR1-/-) were investigated. Fas was equally expressed in both normal and deficient T lymphoblasts and they underwent apoptosis when stimulated with agonist anti-Fas mAb. By contrast, T lymphoblasts and CD4+ T cell clones (TCC) from deficient patients displayed a reduced surface FasL expression and resistance to AICD.

BOLD responses to stimuli: dependence on frequency, stimulus form, amplitude, and repetition rate.

A quantitative theory is developed for the relationship between stimulus and the resulting blood oxygen level-dependent (BOLD) functional MRI signal. The relationship of stimuli to neuronal activity during evoked responses is inferred from recent physiology-based quantitative modeling of evoked response potentials (ERPs). A hemodynamic model is then used to calculate the BOLD response to neuronal activity having the form of an impulse, a sinusoid, or an ERP-like damped sinusoid.

The physiological regulation of toll-like receptor expression and function in humans.

Eleven mammalian toll-like receptors (TLRs 1-11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood. Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers (n = 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration.

Effects of acute exhaustive exercise and chronic exercise training on type 1 and type 2 T lymphocytes.

The present study examined the effects of acute exhaustive exercise and chronic exercise training on type 1 and type 2 T lymphocyte distribution and intracellular cytokine production. Seven endurance-trained male cyclists completed exercise trials to exhaustion before, immediately after, and following 2 weeks of resting recovery from a 6-day intensified training period (ITP). During each trial, resting and post-exercise blood samples were incubated with phorbol 12-myristate 13-acetate (PMA) and ionomycin and stained for T lymphocyte surface antigens (CD3).

Lévy walks in random scattering and growth of waves.

Random spatial wave scattering and stochastic wave growth are studied where one or both of the random processes can be described by a Lévy walk. This analysis extends previous work on randomly growing and scattering waves where both the random processes are modeled by Gaussian diffusive statistics. Both random spatial scattering and stochastic wave growth modeled by Lévy walks are studied separately, together, and in combination with Gaussian processes.

Effect of prolonged exercise and carbohydrate ingestion on type 1 and type 2 T lymphocyte distribution and intracellular cytokine production in humans.

The present study was undertaken to examine the role of the exercise-induced stress hormone response on the regulation of type 1 and type 2 T lymphocyte intracellular cytokine production. Subjects performed 2.5 h of cycling exercise at 65% maximal O2 uptake while ingesting a 6.

Deregulated production of protective cytokines in response to Candida albicans infection in patients with chronic mucocutaneous candidiasis.

Patients with chronic mucocutaneous candidiasis (CMC) are selectively unable to clear the yeast Candida, which results in persistent debilitating infections affecting the skin, nails, and mucous membranes. The underlying defect is unknown. Recent animal studies highlighted the importance of type 1 cytokines in protection against Candida, and previous work suggested that CMC patients may exhibit altered cytokine production in response to Candida.

Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway.

Patients with genetic lesions in the Type-1 cytokine/cytokine receptor pathway exhibit a selective susceptibility to severe infections with poorly pathogenic mycobacteria and non-typhi salmonella spp. These experiments of nature demonstrate that IL-12-dependent IFNgamma production is critical for granuloma formation and therefore host immunity against such pathogens. The essential role of granuloma formation for protective immunity to these organisms is emphasized by the differing granuloma forming capabilities and resultant clinical sequelae observed in these patients which seems to reflect their ability to produce or respond to IFNgamma (Fig.

Diagnosis of defects in the type 1 cytokine pathway.

Patients with inherited defects in the interleukin-12 (IL-12)-dependent, 'high-output' interferon-gamma (IFN-gamma) pathway exhibit selective susceptibility to poorly pathogenic mycobacterial and salmonella infections. This review summarises the extended clinical spectrum seen in this group of patients and indicates a strategy for the identification of putative defects in the type 1 cytokine pathway.

Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.

Interferon-gamma receptor ligand-binding chain (IFN-gammaR1) or signaling chain (IFN-gammaR2) deficiency, like interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency, predispose to severe infections due to poorly virulent mycobacteria and salmonella. A child with bacille Calmette-Guérin and Salmonella enteritidis infection was investigated. Mutations in the genes for IFN-gammaR1, IFN-gammaR2, IL-12Rbeta1, and other molecules implicated in IL-12- or IFN-gamma-mediated immunity were sought.

Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency.

In humans, interferon gamma (IFN-gamma) receptor deficiency leads to a predisposition to mycobacterial infections and impairs the formation of mature granulomas. Interleukin-12 (IL-12) receptor deficiency was found in otherwise healthy individuals with mycobacterial infections. Mature granulomas were seen, surrounded by T cells and centered with epithelioid and multinucleated giant cells, yet reduced IFN-gamma concentrations were found to be secreted by activated natural killer and T cells.