Assessing the response of human primary macrophages to defined fibrous architectures fabricated by melt electrowriting.

The dual role of macrophages in the healing process depends on macrophage ability to polarize into phenotypes that can propagate inflammation or exert anti-inflammatory and tissue-remodeling functions. Controlling scaffold geometry has been proposed as a strategy to influence macrophage behavior and favor the positive host response to implants. Here, we fabricated Polycaprolactone (PCL) scaffolds by Melt Electrowriting (MEW) to investigate the ability of scaffold architecture to modulate macrophage polarization.

Detailed Methodology to Establish a Synovium/Cartilage-on-a-Chip Model to Investigate the Process of Monocyte Extravasation.

Microfluidics allows for recapitulating organotypic environments in miniaturized cell culture platforms. This ability paves the way to the investigation of complex biological processes in a relevant milieu. Here we describe the protocols to generate an organotypic model including a vascularized compartment mimicking the synovial membrane and designed for the study of monocyte extravasation during osteoarthritis.

Recapitulating monocyte extravasation to the synovium in an organotypic microfluidic model of the articular joint.

The synovium of osteoarthritis (OA) patients can be characterized by an abnormal accumulation of macrophages originating from extravasated monocytes. Since targeting monocyte extravasation may represent a promising therapeutic strategy, our aim was to develop an organotypic microfluidic model recapitulating this process. Synovium and cartilage were modeled by hydrogel-embedded OA synovial fibroblasts and articular chondrocytes separated by a synovial fluid channel.

Advanced Microfluidic Models of Cancer and Immune Cell Extravasation: A Systematic Review of the Literature.

Extravasation is a multi-step process implicated in many physiological and pathological events. This process is essential to get leukocytes to the site of injury or infection but is also one of the main steps in the metastatic cascade in which cancer cells leave the primary tumor and migrate to target sites through the vascular route. In this perspective, extravasation is a double-edged sword.

Inflammatory priming enhances mesenchymal stromal cell secretome potential as a clinical product for regenerative medicine approaches through secreted factors and EV-miRNAs: the example of joint disease.

Background: Mesenchymal stromal cell (MSC)-enriched products showed positive clinical outcomes in regenerative medicine, where tissue restoration and inflammation control are needed. GMP-expanded MSCs displayed an even higher potential due to exclusive secretion of therapeutic factors, both free and conveyed within extracellular vesicles (EVs), collectively termed secretome. Moreover, priming with biochemical cues may influence the portfolio and biological activities of MSC-derived factors.

Translational Application of Microfluidics and Bioprinting for Stem Cell-Based Cartilage Repair.

Cartilage defects can impair the most elementary daily activities and, if not properly treated, can lead to the complete loss of articular function. The limitations of standard treatments for cartilage repair have triggered the development of stem cell-based therapies. In this scenario, the development of efficient cell differentiation protocols and the design of proper biomaterial-based supports to deliver cells to the injury site need to be addressed through basic and applied research to fully exploit the potential of stem cells.

Call for uniform neuropsychological assessment after aneurysmal subarachnoid hemorrhage: Swiss recommendations.

Background: In a high proportion of patients with favorable outcome after aneurysmal subarachnoid hemorrhage (aSAH), neuropsychological deficits, depression, anxiety, and fatigue are responsible for the inability to return to their regular premorbid life and pursue their professional careers. These problems often remain unrecognized, as no recommendations concerning a standardized comprehensive assessment have yet found entry into clinical routines.

Methods: To establish a nationwide standard concerning a comprehensive assessment after aSAH, representatives of all neuropsychological and neurosurgical departments of those eight Swiss centers treating acute aSAH have agreed on a common protocol.

Current practice in neuropsychological outcome reporting after aneurysmal subarachnoid haemorrhage.

Background: Neuropsychological deficits (NPD) are common in patients with aneurysmal subarachnoid haemorrhage (aSAH). NPD are one of the major limiting factors for patients with an otherwise acceptable prognosis for sustained quality of life. There are only a few studies reporting outcome after aSAH, which used a standardized neuropsychological test battery as a primary or secondary outcome measure.

The orally active melanocortin-4 receptor antagonist BL-6020/979: a promising candidate for the treatment of cancer cachexia.

BACKGROUND: Under physiological conditions, the melanocortin system is a crucial part of the complex network regulating food intake and energy expenditure. In pathological states, like cachexia, these two parameters are deregulated, i.e.

Cerebellum and source memory.

We report the case of a 40-year-old right-handed German-speaking man who presented with ischemic stroke in the territories of the right superior cerebellar artery and posterior inferior cerebellar artery. The objective of the present study was to investigate the consequences of this cerebellar damage with regard to higher cognitive functions. On admission to the stroke unit, the patient presented with dysarthria, right-sided appendicular ataxia, gait ataxia, and right-sided horizontal nystagmus (National Institutes of Health Stroke Scale, NIHSS, score 4).

A genome-wide survey of human short-term memory.

Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons.

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects.

There is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain β-amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46 TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry.

Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice.

Background: Cachexia is among the most debilitating and life-threatening aspects of cancer. It represents a metabolic syndrome affecting essential functional circuits involved in the regulation of homeostasis, and includes anorexia, fat and muscle tissue wasting. The anorexigenic peptide alpha-MSH is believed to be crucially involved in the normal and pathologic regulation of food intake.

Sexual dimorphism in the parietal substrate associated with visuospatial cognition independent of general intelligence.

Sex differences in visuospatial cognition (VSC) with male advantage are frequently reported in the literature. There is evidence for sexual dimorphisms in the human brain, one of which postulates more gray matter (GM) in females and more white matter (WM) in males relative to total intracranial volume. We investigated the neuroanatomy of VSC independent of general intelligence (g) in sex-separated populations, homogenous in age, education, memory performance, a memory- and brain morphology-related gene, and g.

Prion protein M129V polymorphism affects retrieval-related brain activity.

The prion protein Met129Val polymorphism has recently been related to human long-term memory with carriers of either the 129MM or the 129MV genotype recalling 17% more words than 129(VV) carriers at 24h following learning. Here, we sampled genotype differences in retrieval-related brain activity at 30min and 24h following learning. Furthermore, genotype groups were compared regarding grey matter concentrations and cognitive profiles.

Fluoxetine protects hippocampal plasticity during conditioned fear stress and prevents fear learning potentiation.

Rationale: Contextual fear conditioning can produce both changes in hippocampal synaptic efficacy and potentiation of subsequent fear learning.

Objectives: In this study, we tested whether fluoxetine reverses these effects.

Materials And Methods: In the first experiment, we examined alterations of baseline synaptic efficacy and induction of synaptic plasticity in the CA3 region of the hippocampus during re-exposure of rats, treated with fluoxetine (7 mg/kg) or vehicle, in a context where they previously received 15 eyelid shocks or no shock (controls).

Calmodulin-binding transcription activator 1 (CAMTA1) alleles predispose human episodic memory performance.

Little is known about the genes and proteins involved in the process of human memory. To identify genetic factors related to human episodic memory performance, we conducted an ultra-high-density genome-wide screen at > 500 000 single nucleotide polymorphisms (SNPs) in a sample of normal young adults stratified for performance on an episodic recall memory test. Analysis of this data identified SNPs within the calmodulin-binding transcription activator 1 (CAMTA1) gene that were significantly associated with memory performance.

Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers.

The apolipoprotein E (APOE) epsilon4 allele is the major genetic risk factor for Alzheimer's disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE epsilon4 with better episodic memory compared with APOE epsilon2 and epsilon3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance.

Common Kibra alleles are associated with human memory performance.

Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States.

Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years.

Presenilin 1 (PSEN1) mutations cause autosomal dominant familial Alzheimer's disease (FAD). PSEN1 mutation carriers undergo the course of cognitive deterioration, which is typical for sporadic Alzheimer's disease but disease onset is earlier and disease progression is faster. Here, we sought to detect signs of FAD in presymptomatic carriers of the PSEN1 mutation (C410Y) by use of a neuropsychological examination, functional MRI during learning and memory tasks and MRI volumetry.

Implicit associative learning engages the hippocampus and interacts with explicit associative learning.

The hippocampus is crucial for conscious, explicit memory, but whether it is also involved in nonconscious, implicit memory is uncertain. We investigated with functional magnetic resonance imaging whether implicit learning engages the hippocampus and interacts with subsequent explicit learning. The presentation of subliminal faces-written profession pairs for implicit learning was followed by the explicit learning of supraliminal pairs composed of the same faces combined with written professions semantically incongruous to those presented subliminally (experiment 1), semantically congruous professions (experiment 2), or identical professions (experiment 3).

SGS742: the first GABA(B) receptor antagonist in clinical trials.

The GABA(B) receptor antagonist SGS742 (CGP36742) displays pronounced cognition enhancing effects in mice, young and old rats and in Rhesus monkeys in active and passive avoidance paradigms, in an eight-arm radial maze and a Morris water maze and in a social learning task. SGS742 blocks the late inhibitory postsynaptic potential and the paired-pulse inhibition of population spikes recorded from CA1 pyramidal neurons of the hippocampus of rats in vitro and in vivo. SGS742 significantly enhances the release of glutamate, aspartate, glycine and somatostatin in vivo.

Nonconscious formation and reactivation of semantic associations by way of the medial temporal lobe.

A successful strategy to memorize unrelated items is to associate them semantically. This learning method is typical for declarative memory and depends on the medial temporal lobe (MTL). Yet, only a small fraction of perceived items emerge into conscious awareness and receive the status of representations in declarative memory.

Cytochemical study of the involvement of cell organelles in formation and accumulation of fibrillar amyloid in the pancreas of NORbeta transgenic mice.

Phosphatase ultrastructural cytochemistry was used to evaluate the participation of cytoplasmic organelles in the accumulation of fibrillar amyloid beta (Abeta) in exocrine acinar cells and in macrophages of the pancreas of transgenic mice overexpressing a carboxy-terminal fragment of Abeta protein precursor (ABPP). Nucleoside diphosphatase (NDPase) and glucose-6-phosphatase (G6Pase) were used as cytochemical markers of the endoplasmic reticulum (ER), thiamine pyrophosphatase (TPPase) as a marker of the Golgi apparatus (GA), and acid phosphatase (AcPase) as a marker of lysosomes. Monoclonal antibody 4G8 raised against the 17-24 aa sequence of human Abeta protein was used for immunogold localization of fibrillar Abeta.

Fibrillar amyloid-beta production, accumulation, and recycling in transgenic mice pancreatic acinar cells and macrophages.

Amyloid-beta (A beta) production, accumulation, and recycling were examined by light and electron microscopy in the pancreas of transgenic mice (from 45 days to 22 months of age) that express the gene for the carboxy-terminal fragment of the human amyloid-beta protein precursor. Ultrastructural immunocytochemistry revealed four types of cells accumulating fibrillar A beta 1-40 in cytoplasmic vacuoles: acinar pancreatic cells, macrophages infiltrating stroma, epithelial cells of pancreatic ducts, and blood monocytes/macrophages in the lumen of pancreatic vessels. The ultrastructure of amyloid deposits suggests that each of these four types of cells produces fibrillar A beta.