Changes in characteristics of hospitalized heart failure patients in ten years: a single-center study

SummaryBackgroundProgress in therapy and the ageing patients hospitalized with heart failure may have impacted the characteristics of this patients.AimsWe compared epidemiological data of patients admitted with heart failure during two periods separated by a 10 year interval.MethodsCharacteristics of 353 heart failure patients recruited between 2002 and 2004 with those of 304 heart failure patients recruited between 1992 and 1994 were compared retrospectively.ResultsThere is now a majority of male patients (56.4%) not found ten years ago. The average age is unchanged (75.1±11 then 76.4±11 years) even though the proportion of patients aged over 70 years has increased (75% versus 70%). Hospital length of stay has fallen from 14±9 to 10±7 days. Hospital mortality (8%) are identical. The two main etiologies remain coronary and hypertensive heart disease at 29 and 24% respectively but these proportions are lower than ten years ago (42 and 28% respectively). The ejection fraction is more often preserved (56%) than before (44%). Increased prescription of inhibitors of the renin-angiotensin system and beta-blockers is confirmed. Post-hospital and total mortality has fallen by 50 and 30% from 30 to 16% and 35 to 24% respectively at the expense of a 25% increase in the frequency of hospital readmissions from 29 to 38%.ConclusionEven if mortality has declined, heart failure remains a major public health burden with a significant number of hospital readmissions. Other approaches such as therapeutic education must therefore be developed

Vortex Waves and Channel Capacity: Hopes and Reality

Several recent contributions have envisioned the possibility of increasing currently exploitable maximum channel capacity of a free space link, both at optical and radio frequencies, by using vortex waves, i.e. carrying Orbital Angular Momentum (OAM). Our objective is to disprove these claims by showing that they are in contradiction with very fundamental properties of Maxwellian fields. We demonstrate that the Degrees of Freedom (DoF) of the field cannot be increased by the helical phase structure of electromagnetic vortex waves beyond what can be done without invoking this property. We also show that the often-advocated over-quadratic power decay of OAM beams with distance does not play any fundamental role in the determination of the channel DoF.Comment: 8 pages, 7 figure

How clusters create shared value in rural areas: An examination of six case studies

The main aim of this paper is to demonstrate that clusters can support the sustainable development of rural areas through the creation of shared value. This is done via the close examination of six different cases of rural clusters in Greece, Italy, Germany, Poland, Denmark, and Sweden. Qualitative as well as quantitative data were taken from the clusters, which demonstrated that their main business approaches naturally coincided with the creation of economic, social, and environmental benefits for the local communities in which they operated. The case clusters were created in a top-down manner, aimed at boosting regional R&D activities and making the local economy more competitive and more sustainable. However, private initiative took over and al-lowed these clusters to flourish because meeting the regions’ economic, social, and environmental needs successfully coincided with the target of the clusters’ own development and profitability. The results show that clusters, with their potential for shared value creation, can constitute a powerful engine for the revitalisation and development of rural areas, addressing the significant challenges which they are currently facing

Structural Amyloid Plaque Polymorphism is Associated with Distinct Lipid Accumulations Revealed by Trapped Ion Mobility Mass Spectrometry Imaging (TIMS MSI)

Understanding of Alzheimer’s disease (AD) pathophysiology, requires molecular assessment of how key pathological factors, specifically amyloid β (Aβ) plaques, influence the surrounding microenvironment. Here, neuronal lipids have been implicated in Aβ) plaque pathology, though the lipid microenvironment in direct proximity to Aβ plaques are still not fully resolved. A further challenge is the microenvironmental molecular heterogeneity, across structurally polymorphic Aβ features - such as diffuse, immature and mature, fibrillary aggregates, whose resolution requires the integration of advanced, multimodal chemical imaging tools. Herein, we used matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) trapped ion mobility spectrometry Time-of-Flight (TIMS TOF) in combination with hyperspectral confocal microscopy to probe the lipidomic microenvironment associated with structural polymorphism of Aβ plaques in transgenic Alzheimer’s disease mice (tgAPPSWE). Using on tissue and ex situ validation, TIMS MS/MS facilitated unambiguous identification of isobaric lipid species that showed plaque pathology associated localizations. Integrated multivariate imaging data analysis revealed multiple, Aβ plaque enriched lipid patterns for gangliosides (GM), phosphoinositols (PI), phosphoethanolamines (PE) and phosphatidic acids (PA). Conversely, sulfatides (ST), cardiolipins (CL) and polyunsaturated fatty acid conjugated -phosphoserines (PS) and - PE were depleted at plaques. Hyperspectral amyloid imaging further delineated unique distribution of PA, PE to mature plaque core regions, while PI, LPI, GM2 and GM3 localized to immature Aβ aggregates present within the periphery of individual Aβ plaques. Finally, we followed AD pathology associated lipid changes over time, identifying plaque growth and maturation to be characterized by peripheral accumulation of PI (18:0/22:6). Together, these data demonstrate the potential of multimodal imaging approaches to overcome limitations associated with conventional advanced MS imaging applications. This allowed for differentiation of both distinct lipid components in a complex micro environment, as well as their correlation to disease relevant amyloid plaque polymorphs

Chemical traits of cerebral amyloid angiopathy in familial British-, Danish-, and non-Alzheimerʼs dementias

Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant forms of dementia caused by mutations in the integral membrane protein 2B (ITM2B, also known as BRI2) gene. Secretase processing of mutant BRI2 leads to secretion and deposition of BRI2-derived amyloidogenic peptides, ABri and ADan that resemble APP/β-amyloid (Aβ) pathology, which is characteristic of Alzheimer's disease (AD). Amyloid pathology in FBD/FDD manifests itself predominantly in the microvasculature by ABri/ADan containing cerebral amyloid angiopathy (CAA). While ABri and ADan peptide sequences differ only in a few C-terminal amino acids, CAA in FDD is characterized by co-aggregation of ADan with Aβ, while in contrast no Aβ deposition is observed in FBD. The fact that FDD patients display an earlier and more severe disease onset than FBD suggests a potential role of ADan and Aβ co-aggregation that promotes a more rapid disease progression in FDD compared to FBD. It is therefore critical to delineate the chemical signatures of amyloid aggregation in these two vascular dementias. This in turn will increase the knowledge on the pathophysiology of these diseases and the pathogenic role of heterogenous amyloid peptide interactions and deposition, respectively. Herein, we used matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) in combination with hyperspectral, confocal microscopy based on luminescent conjugated oligothiophene probes (LCO) to delineate the structural traits and associated amyloid peptide patterns of single CAA in postmortem brain tissue of patients with FBD, FDD as well as sporadic CAA without AD (CAA+) that show pronounced CAA without parenchymal plaques. The results show that CAA in both FBD and FDD consist of N-terminally truncated- and pyroglutamate-modified amyloid peptide species (ADan and ABri), but that ADan peptides in FDD are also extensively C-terminally truncated as compared to ABri in FBD, which contributes to hydrophobicity of ADan species. Further, CAA in FDD showed co-deposition with Aβ x-42 and Aβ x-40 species. CAA+ vessels were structurally more mature than FDD/FBD CAA and contained significant amounts of pyroglutamated Aβ. When compared with FDD, Aβ in CAA+ showed more C-terminal and less N-terminally truncations. In FDD, ADan showed spatial co-localization with Aβ3pE-40 and Aβ3-40 but not with Aβx-42 species. This suggests an increased aggregation propensity of Aβ in FDD that promotes co-aggregation of both Aβ and ADan. Further, CAA maturity appears to be mainly governed by Aβ content based on the significantly higher 500/580 patterns observed in CAA+ than in FDD and FBD, respectively. Together this is the first study of its kind on comprehensive delineation of Bri2 and APP-derived amyloid peptides in single vascular plaques in both FDD/FBD and sporadic CAA that provides new insight in non-AD-related vascular amyloid pathology. (Figure presented.

γ-Secretase modulators show selectivity for γ-secretase–mediated amyloid precursor protein intramembrane processing

The aggregation of β-amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 that are produced as a result of γ-secretase–mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ-Secretase modulators (GSMs) represent a promising class of Aβ42-lowering anti-amyloidogenic compounds for the treatment of AD. Gamma-secretase modulators change the relative proportion of secreted Aβ peptides, while sparing the γ-secretase–mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ-secretase cleavage of three γ-secretase substrates, E-cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ-secretase–dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ-secretase processing of EphA4 and EphB2 results in the release of several Aβ-like peptides, but that only the production of Aβ-like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ-secretase–mediated Aβ production

Première observation malienne d’histoplasmose africaine disséminée à prédominance osseuse chez un enfant VIH négatif. Revue de la littérature

Endemic deep fungal infections are still under recognised diseases in daily medical practice because of their rarity in sub-Saharan area. The African histoplasmosis Histoplasma capsulatum var. duboisii (H. capsulatum duboisii) is the most frequent variety described in Mali through limited studies in adult patients, since the first case described by Catanei and Kervran (1945). Our case report is a disseminated histoplasmosis in a young 6-year-old african child. He was male and rural. The infectious localisations were mucosae, skin, lymphnodes, urinary tract and bones. Evolution has been marred by an episode of worsening of symptoms despite initial clinical improvement with ketoconazole. After healing of mucocutaneous lesions, we noticed a limitation of ampliation of both wrists. The radiographic bone lesions were lysis of the right lower end of the right radius and cubitus and fragmentation of cubital epiphysis of the same arm. Lacunes were present on the fifth right finger in metatarsus and phalanx; lacune and blowing aspect of the second phalanx of the left third finger was noted. The disseminated form of African histoplasmosis may occur in HIV-negative subject. The prognosis depends on early diagnosis and administration of appropriate and well-conducted therapy

Astroglial excitability and gliotransmission: an appraisal of Ca2+ as a signalling route

Astroglial cells, due to their passive electrical properties, were long considered subservient to neurons and to merely provide the framework and metabolic support of the brain. Although astrocytes do play such structural and housekeeping roles in the brain, these glial cells also contribute to the brain's computational power and behavioural output. These more active functions are endowed by the Ca2+-based excitability displayed by astrocytes. An increase in cytosolic Ca2+ levels in astrocytes can lead to the release of signalling molecules, a process termed gliotransmission, via the process of regulated exocytosis. Dynamic components of astrocytic exocytosis include the vesicular-plasma membrane secretory machinery, as well as the vesicular traffic, which is governed not only by general cytoskeletal elements but also by astrocyte-specific IFs (intermediate filaments). Gliotransmitters released into the ECS (extracellular space) can exert their actions on neighbouring neurons, to modulate synaptic transmission and plasticity, and to affect behaviour by modulating the sleep homoeostat. Besides these novel physiological roles, astrocytic Ca2+ dynamics, Ca2+-dependent gliotransmission and astrocyte–neuron signalling have been also implicated in brain disorders, such as epilepsy. The aim of this review is to highlight the newer findings concerning Ca2+ signalling in astrocytes and exocytotic gliotransmission. For this we report on Ca2+ sources and sinks that are necessary and sufficient for regulating the exocytotic release of gliotransmitters and discuss secretory machinery, secretory vesicles and vesicle mobility regulation. Finally, we consider the exocytotic gliotransmission in the modulation of synaptic transmission and plasticity, as well as the astrocytic contribution to sleep behaviour and epilepsy

Activin/Nodal Inhibition Alone Accelerates Highly Efficient Neural Conversion from Human Embryonic Stem Cells and Imposes a Caudal Positional Identity

Background Neural conversion from human embryonic stem cells (hESCs) has been demonstrated in a variety of systems including chemically defined suspension culture, not requiring extrinsic signals, as well as in an adherent culture method that involves dual SMAD inhibition using Noggin and SB431542 (an inhibitor of activin/nodal signaling). Previous studies have also determined a role for activin/nodal signaling in development of the neural plate and anterior fate specification. We therefore sought to investigate the independent influence of SB431542 both on neural commitment of hESCs and positional identity of derived neural progenitors in chemically defined substrate-free conditions. Methodology/Principal Findings We show that in non-adherent culture conditions, treatment with SB431542 alone for 8 days is sufficient for highly efficient and accelerated neural conversion from hESCs with negligible mesendodermal, epidermal or trophectodermal contamination. In addition the resulting neural progenitor population has a predominantly caudal identity compared to the more anterior positional fate of non-SB431542 treated cultures. Finally we demonstrate that resulting neurons are electro-physiologically competent. Conclusions This study provides a platform for the efficient generation of caudal neural progenitors under defined conditions for experimental study