Age-related impairment of human T lymphocytes' activation: specific differences between CD4+ and CD8+ subsets

The relevance of physiological immune aging is of great interest with respect to determining disorders with pathologic immune function in aging individuals. In recent years, the relevance of changes in peripheral lymphocytes in age-associated neurologic diseases has become more evident. Due to the lack of immunological studies, covering more than one event after mitogenic activation, we envisaged a new concept in the present study, aiming to investigate several events, starting from T cell receptor (TCR) ligation up to T cell proliferation. In addition, we addressed the question whether changes are present in the subsets (CD4, CD8) with aging. Phosphorylation of tyrosine residues declines with increasing age in CD4+ cells. Fewer levels of CD69 positive cells after 4 h mitogenic activation, altered expression of cytokines (IL2, IFN-gamma and TNF-alpha; 22 h) and lower proliferation (72 h) were determined in aging. Moreover, it could be shown that CD8+ lymphocytes react more effectively to mitogenic stimulation with reference to CD69 expression and proliferation in both age groups (60 years old). These data indicate that T cell activation, mediated by TCR engagement, is significantly impaired in aging and both subsets are affected. However, bypassing the TCR does not fully restore T cell function, indicating that there are more mechanisms involved than impaired signal transduction through TCR only. The results will be discussed in relation to their relevance in neurodegenerative and psychiatric disorders

Cerebral networks linked to the event-related potential P300

Abstract.: P300 is an event-related potential that is elicited by an oddball paradigm. In several neuropsychiatric diseases, differences in latencies and amplitude compared to healthy subjects have been reported. Because of its clinical significance, several investigations have tried to elucidate the intracranial origins of the P300 component. In the present study we could demonstrate a network of P300 generators. Investigated were 15 healthy subjects with an acoustical oddball paradigm within a fMRI block design, which enabled us to exclude attention or acoustical processing effects. The inferior and middle frontal, superior temporal, lower parietal cortex, the insula and the anterior cingulum were significantly activated symmetrical in both hemisphere

Abnormal connectional fingerprint in schizophrenia: a novel network analysis of diffusion tensor imaging data

The graph theoretical analysis of structural magnetic resonance imaging (MRI) data has received a great deal of interest in recent years to characterize the organizational principles of brain networks and their alterations in psychiatric disorders, such as schizophrenia. However, the characterization of networks in clinical populations can be challenging, since the comparison of connectivity between groups is influenced by several factors, such as the overall number of connections and the structural abnormalities of the seed regions. To overcome these limitations, the current study employed the whole-brain analysis of connectional fingerprints in diffusion tensor imaging data obtained at 3 T of chronic schizophrenia patients (n = 16) and healthy, age-matched control participants (n = 17). Probabilistic tractography was performed to quantify the connectivity of 110 brain areas. The connectional fingerprint of a brain area represents the set of relative connection probabilities to all its target areas and is, hence, less affected by overall white and gray matter changes than absolute connectivity measures. After detecting brain regions with abnormal connectional fingerprints through similarity measures, we tested each of its relative connection probability between groups. We found altered connectional fingerprints in schizophrenia patients consistent with a dysconnectivity syndrome. While the medial frontal gyrus showed only reduced connectivity, the connectional fingerprints of the inferior frontal gyrus and the putamen mainly contained relatively increased connection probabilities to areas in the frontal, limbic, and subcortical areas. These findings are in line with previous studies that reported abnormalities in striatal–frontal circuits in the pathophysiology of schizophrenia, highlighting the potential utility of connectional fingerprints for the analysis of anatomical networks in the disorder

Propofol decreases the axonal excitability in rat primary sensory afferents

AIMS: The aim of this present study was to investigate the changes of peripheral sensory nerve excitability produced by propofol. MAIN METHODS: In a recently described in vitro model of rodent saphenous nerve we used the technique of threshold tracking (QTRAC®) to measure changes of axonal nerve excitability of Aβ-fibres caused by propofol. Concentrations of 10μMol, 100μMol and 1000μMol were tested. Latency, peak response, strength-duration time constant (τSD) and recovery cycle of the sensory neuronal action potential (SNAP) were recorded. KEY FINDINGS: Our results have shown that propofol decreases nerve excitability of rat primary sensory afferents in vitro. Latency increased with increasing concentrations (0μMol: 0.96±0.07ms; 1000μMol 1.10±0.06ms, P<0.01). Also, propofol prolonged the relative refractory period (0μMol: 1.79±1.13ms; 100μMol: 2.53±1.38ms, P<0.01), and reduced superexcitability (0 μMol: -14.0±4.0%; 100μMol: -9.5±5.5%) and subexcitability (0μMol: 7.5±1.2%; 1000μMol: 3.6±1.2) significantly during the recovery cycle (P<0.01). SIGNIFICANCE: Our results have shown that propofol decreases nerve excitability of primary sensory afferents. The technique of threshold tracking revealed that axonal voltage-gated ion channels are significantly affected by propofol and therefore might be at least partially responsible for earlier described analgesic effects

P300 in Schizophrenia: Interactions between Amplitudes and Topography

Low P300 amplitudes and topographical asymmetries have been reponed in schizophrenic patients, but reference-independent amplitude assessment failed to replicate reduced amplitudes. P300 amplitude is conventially assessed at midline electrodes (PZ), anti asymmetric topography as reported in schizophrenics, may conj'ound this measurement. We lnvestigated the possible Interaction between P300 ropography and assessments of amplitudes. ln 41 clinically stable schizophrenics and 31 normal controls, the generalfinding ofreduced amplitudes at the P'l electrode and topographical asymmetrles in the patient group were replicated. ln both groups, a.symmetries of the P300 field (lateralized peaks) reduced the standard amplitude assessment at the midline parletal electrode, but did not Qjfoct the reference-independent, global amplitude assessment. This shows thal asymmetry per se does not imply reduced field strength. in addition, in schizophreraics. but not in controls, there was a significcmt effect oftlae direction of asymmetry on both amplltude measures, amplitudes belng lower with increasing shift ofthe P300 peak to the right side. Considering also the slightly left-lateralized peaks in the normal controls. this suggests rhat only right lateralized P300 peaks upressfunctional deficits in schizophrenics, whereas left lateralized pealcs fall wlthin the physiological variability of the P3OO field. Tht refonnce-independent amplitude assessment is proposed for unambiguous amplitude assessment in order to better define the clinical, psychological and physiopathological mtaning of the P3OO alterations in schizophrenics

Impact of aging : sporadic, and genetic risk factors on vulnerability to apoptosis in Alzheimer's disease

The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells

Enhanced ROS-generation in lymphocytes from Alzheimer’s patients

Introduction: Reactive oxygen species (ROS) have been implicated in neurodegeneration and seem to be involved in the physiology and pathophysiology of several diseases, including normal aging and Alzheimer’s disease (AD). Enhanced ROS production in aging or AD is not restricted to the brain, but can also been seen in several peripheral tissues. The objective of the present study was to evaluate whether the mechanisms involved in the generation of oxidative stress in normal senescence and Alzheimer’s disease are identical or not. Methods: We analysed intracellular basal levels of ROS in lymphocytes from AD patients and healthy young and aged not-demented subjects as well as ROS levels following stimulation with d-ribose and staurosporine in all three groups. ROS levels were measured by flow cytometry using the intracellular fluorescence dye dihydrorhodamine123 (DHR123). Results: Our study shows that AD lymphocytes have increased basal levels of ROS, low susceptibility to ROS stimulation by 2-deoxy-D-ribose (dRib) and an increased response to staurosporine when compared with age-matched controls. Discussion: The data suggest that the defect(s) responsible for enhanced ROS production in AD may involve different or additional biological pathways than those involved in enhanced ROS generation during aging

WAO guideline for the management of hereditary angioedema

Hereditary Angioedema (HAE) is a rare disease and for this reason proper diagnosis and appropriate therapy are often unknown or not available for physicians and other health care providers. For this reason we convened a group of specialists that focus upon HAE from around the world to develop not only a consensus on diagnosis and management of HAE, but to also provide evidence based grades, strength of evidence and classification for the consensus. Since both consensus and evidence grading were adhered to the document meets criteria as a guideline. The outcome of the guideline is to improve diagnosis and management of patients with HAE throughout the world and to help initiate uniform care and availability of therapies to all with the diagnosis no matter where the residence of the individual with HAE exists

Attenuated androgen discontinuation in patients with hereditary angioedema: a commented case series

Background: Hereditary angioedema (HAE) is characterized by potentially severe and life-threatening attacks of localized swelling. Prophylactic therapies are available, including attenuated androgens. Efficacy of attenuated androgens has not been assessed in large, randomized, placebo-controlled trials and can be associated with frequent, and sometimes severe, side effects. As better tolerated targeted therapies become available, attenuated androgen withdrawal is increasingly considered by physicians and their patients with HAE. Attenuated androgens withdrawal has not been systematically studied in HAE, although examination of other disorders indicates that attenuated androgen withdrawal may result in mood disturbances and flu-like symptoms. Standardized protocols for attenuated androgen discontinuation that continue to provide control of attacks while limiting potential attenuated androgen withdrawal symptoms are not established as the outcomes of different withdrawal strategies have not been compared. We aim to describe the challenges of attenuated androgen discontinuation in patients with HAE and how these may continue into the post-androgen period. Case presentation: We present a retrospective case series of 10 patients with confirmed type I HAE who have discontinued prophylactic treatment with attenuated androgens. The most common reason for attenuated androgen discontinuation was side effects. Attenuated androgens were either immediately withdrawn, tapered and/or overlapped with another treatment. The major challenge of discontinuation was the management of an increased frequency and severity of HAE attacks in some patients. Conclusions: Healthcare teams need to undertake careful planning and monitoring after attenuated androgens discontinuation, and modify treatment strategies if HAE control is destabilized with an increased number of attacks. Discontinuation of attenuated androgens is definitively an option in an evolving HAE treatment landscape, and outcomes can be favourable with additional patient support and education

Dysfunctional long-range coordination of neural activity during Gestalt perception in schizophrenia

Recent theoretical and empirical research on schizophrenia converges on the notion that core aspects of the pathophysiology of the disorder may arise from a dysfunction in the coordination of distributed neural activity. Synchronization of neural responses in the β-band (15–30 Hz) and γ-band range (30–80 Hz) has been implicated as a possible neural substrate for dysfunctional coordination in schizophrenia. To test this hypothesis, we examined the electroencephalography (EEG) activity in 19 patients with a Diagnostic and Statistical Manual of Mental Disorder, edition IV criteria, diagnosis of schizophrenia and 19 healthy control subjects during a Gestalt perception task. EEG data were analyzed for phase synchrony and induced spectral power as an index of neural synchronization. Schizophrenia patients were impaired significantly in the detection of images that required the grouping of stimulus elements into coherent object representations. This deficit was accompanied by longer reaction times in schizophrenia patients. Deficits in Gestalt perception in schizophrenia patients were associated with reduced phase synchrony in the β-band (20 –30 Hz), whereas induced spectral power in the γ-band (40 –70 Hz) was mainly intact. Our findings suggest that schizophrenia patients are impaired in the long-range synchronization of neural responses, which may reflect a core deficit in the coordination of neural activity and underlie the specific cognitive dysfunctions associated with the disorder