Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

Background: Limited knowledge of stem cell therapies‘ mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. Methods: We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. Findings: PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. Interpretation: Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. Funding: Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Healt

METHOD OF CALCULATION OF EXTENDED LARGE-PANEL BUILDINGS SUBJECTED TO FORCE AND TEMPERATURE ACTION

This paper presents the results of the developed method of calculation of large-panel ex- tended buildings subjected to the temperature action with taking into account inserted floor

Patient's perceptions of the cannabis-psychosis link--a systematic review

Over the past years a growing research effort has investigated the relation between cannabis use and schizophrenia at a neurobiological, epidemiological and clinical level. A number of systematic reviews and meta analyses have summarized the available evidence in the field. Conversely the patient's perception of the link between cannabis use and psychosis has been under investigation. Since patient's beliefs and attitudes strongly correlate with adherence to all forms of treatment, we conducted a systematic PUBMED database search for any English and German-language articles published until January 2012 that addressed patient's perception of a cannabis psychosis link. Six studies including psychotic subjects met inclusion criteria yielding a total sample of 97. The vast majority of patients with either schizophrenia or a recent psychosis disagreed with a causal link between cannabis use and their mental illness. We qualitatively reviewed the explanatory models underlying their views, which were multi-factorial, psychological, social, biological, esoteric and irrational factors. Most patient's believed that the temporal sequence of events did not clearly indicate a causal relationship for them. They thus discarded the hypothesis of a causal link between cannabis use and psychosis. Despite the heterogeneity of the included studies, findings are comparable and support the robustness of this review. Limitations and implications for clinicians and psychosis research are discussed

Antifibrotic Effects of Amyloid-Beta and Its Loss in Cirrhotic Liver

The function and regulation of amyloid-beta (A beta) in healthy and diseased liver remains unexplored. Because A beta reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. A beta and key proteins that generate (beta-secretase 1 and presenilin-1) and degrade it (neprilysin and myelin basic protein) were decreased in human cirrhotic liver. In culture, activated hepatic stellate cells (HSC) internalized A beta more efficiently than astrocytes and HSC degraded A beta leading to suppressed expression of alpha-smooth muscle actin (alpha-SMA), collagen 1 and transforming growth factor beta (TGF beta). A beta also upregulated sinusoidal permeability marker endothelial NO synthase (eNOS) and decreased TGF beta in cultured human liver sinusoidal endothelial cells (hLSEC). Liver A beta levels also correlate with the expression of eNOS in transgenic Alzheimer's disease mice and in human and rodent cirrhosis/fibrosis. These findings suggest a previously unexplored role of A beta in the maintenance of liver sinusoidal permeability and in protection against cirrhosis/fibrosis via attenuation of HSC activation

High dose methylphenidate treatment in adult Attention Deficit Hyperactivity Disorder: a case report

INTRODUCTION: Stimulant medication improves hyperactivity, inattention, and impulsivity in both pediatric and adult populations with Attention Deficit Hyperactivity Disorder (ADHD). However, data regarding the optimal dosage in adults is still limited. CASE PRESENTATION: We report the case of a 38-year-old Caucasian patient who was diagnosed with ADHD when he was nine years old. He then received up to 10mg Ritalinand 20mg Ritalin SR daily. When he was 13, his medication was changed to desipramine (Norpramin), and both Ritalin and Ritalin SR were discontinued; and at age 18, when he developed obsessive-compulsive symptoms, his medication was changed to clomipramine (Anafranil) 75mg/d. Still suffering from inattention and hyperactivity, the patient began college when he was 19, but did not receive stimulant medication until three years later, when Ritalin 60mg/d was re-established. During the 14 months that followed, he began to use Ritalin excessively, both orally and rectally, in dosages from 4800-6000mg/d. Four years ago, he was referred to our outpatient service, where his ADHD was re-evaluated. At that point, the patient's daily Ritalin dosage was reduced to 200mg/d orally, but he still experienced pronounced symptoms of ADHD, so this dosage was raised again. The patient's plasma levels consistently remained between 60-187 nmol/l--within the recommended range--and signs of his obsessive-compulsive symptoms diminished with fluoxetine 40mg/d. Finally, on a dosage of 378mg Concerta, his symptoms of ADHD have improved dramatically and no further use of methylphenidate has been recorded during the 24 months preceding this report. CONCLUSION: Symptoms of ADHD in this adult patient, who also manifested a co-occurring obsessive compulsive disorder, dramatically improved only after application of a higher-than-normal dose of methylphenidate. We therefore suggest that clinicians consider these findings in relation to their adherence to current therapeutic guidelines