β-Amyloid precursor protein-b is essential for Mauthner cell development in the zebrafish in a Notch-dependent manner

Amyloid precursor protein (APP) is a transmembrane glycoprotein that has been the subject of intense research because of its implication in Alzheimer's disease. However, the physiological function of APP in the development and maintenance of the central nervous system remains largely unknown. We have previously shown that the APP homologue in zebrafish (Danio rerio), Appb, is required for motor neuron patterning and formation. Here we study the function of Appb during neurogenesis in the zebrafish hindbrain. Partial knockdown of Appb using antisense morpholino oligonucleotides blocked the formation of the Mauthner neurons, uni- or bilaterally, with an aberrant behavior as a consequence of this cellular change. The Appb morphants had decreased neurogenesis, increased notch signaling and notch1a expression at the expense of deltaA/D expression. The Mauthner cell development could be restored either by a general decrease in Notch signaling through γ-secretase inhibition or by a partial knock down of Notch1a. Together, this demonstrates the importance of Appb in neurogenesis and for the first time shows the essential requirement of Appb in the formation of a specific cell type, the Mauthner cell, in the hindbrain during development. Our results suggest that Appb-regulated neurogenesis is mediated through balancing the Notch1a signaling pathway and provide new insights into the development of the Mauthner cell

(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) - a novel cortical-preferring catecholamine transmission- and cognition-promoting agent

YesHere we describe for the first time the distinctive pharmacological profile for IRL752, a new phenyl-pyrrolidine derivative with regio-selective CNS transmission-enhancing properties. IRL752 (3.7-150 μmol/kg, s.c.) was characterised through extensive in vivo studies, using behavioural, tissue neurochemical and gene expression, as well as microdialysis methods. Behaviourally, the compound normalised tetrabenazine-induced hypoactivity, while unable to stimulate basal locomotion in normal animals or to either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across NA- and DA-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related IEGs (immediate early genes) however increased by 1.5- to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600-750% above baseline, while striatal DA remained unaltered and NA rose to ~250%; cortical and hippocampal dialysate ACh increased to ~250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also pro-cognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data, coupled to drug exposure support the hypothesis that 5‑HT7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions where these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson's Disease

Understanding the effects of a decentralized budget on physicians' compliance with guidelines for statin prescription – a multilevel methodological approach

<p>Abstract</p> <p>Background</p> <p>Official guidelines that promote evidence-based and cost-effective prescribing are of main relevance for obvious reasons. However, to what extent these guidelines are followed and their conditioning factors at different levels of the health care system are still insufficiently known.</p> <p>In January 2004, a decentralized drug budget was implemented in the county of Scania, Sweden. Focusing on lipid-lowering drugs (i.e., statins), we evaluated the effect of this intervention across a 25-month period. We expected that increased local economic responsibility would promote prescribing of recommended statins.</p> <p>Methods</p> <p>We performed two separate multilevel regression analyses; on 110 827 individual prescriptions issued at 136 <it>publicly</it>-administered health care centres (HCCs) nested within 14 administrative areas (HCAs), and on 72 012 individual prescriptions issued by 115 <it>privately</it>-administered HCCs. Temporal trends in the prevalence of prescription of recommended statins were investigated by random slope analysis. Differences (i.e., variance) between HCCs and between HCAs were expressed by median odds ratio (MOR).</p> <p>Results</p> <p>After the implementation of the decentralized drug budget, adherence to guidelines increased continuously. At the end of the observation period, however, practice variation remained high. Prescription of recommended statins presented a high degree of clustering within both publicly (i.e., MOR_HCC= 2.18 and MOR_HCA= 1.31 respectively) and privately administered facilities (MOR_HCC= 3.47).</p> <p>Conclusion</p> <p>A decentralized drug budget seems to promote adherence to guidelines for statin prescription. However, the high practice differences at the end of the observation period may reflect inefficient therapeutic traditions, and indicates that rational statin prescription could be further improved.</p

A systematic review of musculoskeletal disorders among school teachers

<p>Abstract</p> <p>Background</p> <p>Musculoskeletal disorders (MSD) represent one of the most common and most expensive occupational health problems in both developed and developing countries. School teachers represent an occupational group among which there appears to be a high prevalence of MSD. Given that causes of MSD have been described as multi-factorial and prevalence rates vary between body sites and location of study, the objective of this systematic review was to investigate the prevalence and risk factors for MSD among teaching staff.</p> <p>Methods</p> <p>The study involved an extensive search of MEDLINE and EMBASE databases in 2011. All studies which reported on the prevalence and/or risk factors for MSD in the teaching profession were initially selected for inclusion. Reference lists of articles identified in the original search were then examined for additional publications. Of the 80 articles initially located, a final group of 33 met the inclusion criteria and were examined in detail.</p> <p>Results</p> <p>This review suggests that the prevalence of self-reported MSD among school teachers ranges between 39% and 95%. The most prevalent body sites appear to be the back, neck and upper limbs. Nursery school teachers appear to be more likely to report suffering from low back pain. Factors such as gender, age, length of employment and awkward posture have been associated with higher MSD prevalence rates.</p> <p>Conclusion</p> <p>Overall, this study suggests that school teachers are at a high risk of MSD. Further research, preferably longitudinal, is required to more thoroughly investigate the issue of MSD among teachers, with a greater emphasis on the possible wider use of ergonomic principles. This would represent a major step forward in the prevention of MSD among teachers, especially if easy to implement control measures could be recommended.</p

Effects of Ferumoxides – Protamine Sulfate Labeling on Immunomodulatory Characteristics of Macrophage-like THP-1 Cells

Superparamagnetic Iron Oxide (SPIO) complexed with cationic transfection agent is used to label various mammalian cells. Labeled cells can then be utilized as an in vivo magnetic resonance imaging (MRI) probes. However, certain number of in vivo administered labeled cells may be cleared from tissues by the host's macrophages. For successful translation to routine clinical application of SPIO labeling method it is important that this mode of in vivo clearance of iron does not elicit any diverse immunological effects. The purpose of this study was to demonstrate that SPIO agent ferumoxides-protamine sulfate (FePro) incorporation into macrophages does not alter immunological properties of these cells with regard to differentiation, chemotaxis, and ability to respond to the activation stimuli and to modulate T cell response. We used THP-1 cell line as a model for studying macrophage cell type. THP-1 cells were magnetically labeled with FePro, differentiated with 100 nM of phorbol ester, 12-Myristate-13-acetate (TPA) and stimulated with 100 ng/ml of LPS. The results showed 1) FePro labeling had no effect on the changes in morphology and expression of cell surface proteins associated with TPA induced differentiation; 2) FePro labeled cells responded to LPS with slightly higher levels of NFκB pathway activation, as shown by immunobloting; TNF-α secretion and cell surface expression levels of CD54 and CD83 activation markers, under these conditions, were still comparable to the levels observed in non-labeled cells; 3) FePro labeling exhibited differential, chemokine dependent, effect on THP-1 chemotaxis with a decrease in cell directional migration to MCP-1; 4) FePro labeling did not affect the ability of THP-1 cells to down-regulate T cell expression of CD4 and CD8 and to induce T cell proliferation. Our study demonstrated that intracellular incorporation of FePro complexes does not alter overall immunological properties of THP-1 cells. The described experiments provide the model for studying the effects of in vivo clearance of iron particles via incorporation into the host's macrophages that may follow after in vivo application of any type of magnetically labeled mammalian cells. To better mimic the complex in vivo scenario, this model may be further exploited by introducing additional cellular and biological, immunologically relevant, components

Cardiotoxicity of Freon among refrigeration services workers: comparative cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Freon includes a number of gaseous, colorless chlorofluorocarbons. Although freon is generally considered to be a fluorocarbon of relatively low toxicity; significantly detrimental effects may occur upon over exposure. The purpose of the present study is to investigate whether occupational exposure to fluorocarbons can induce arterial hypertension, myocardial ischemia, cardiac arrhythmias, elevated levels of plasma lipids and renal dysfunction.</p> <p>Methods</p> <p>This comparative cross-sectional study was conducted at the cardiology clinic of the Suez Canal Authority Hospital (Egypt). The study included 23 apparently healthy male workers at the refrigeration services workshop who were exposed to fluorocarbons (FC 12 and FC 22) and 23 likewise apparently healthy male workers (unexposed), the control group. All the participants were interviewed using a pre-composed questionnaire and were subjected to a clinical examination and relevant laboratory investigations.</p> <p>Results</p> <p>There were no significant statistical differences between the groups studied regarding symptoms suggesting arterial hypertension and renal affection, although a significantly higher percentage of the studied refrigeration services workers had symptoms of arrhythmias. None of the workers had symptoms suggesting coronary artery disease. Clinical examination revealed that the refrigeration services workers had a significantly higher mean pulse rate compared to the controls, though no significant statistical differences were found in arterial blood pressure measurements between the two study groups. Exercise stress testing of the workers studied revealed normal heart reaction to the increased need for oxygen, while sinus tachycardia was detected in all the participants. The results of Holter monitoring revealed significant differences within subject and group regarding the number of abnormal beats detected throughout the day of monitoring (p < 0.001). There were no significant differences detected in the average heart rate during the monitoring period within subject or group. Most laboratory investigations revealed absence of significant statistical differences for lipid profile markers, serum electrolyte levels and glomerular lesion markers between the groups except for cholesterol and urinary β2-microglobulin (tubular lesion markers) levels which were significantly elevated in freon exposed workers.</p> <p>Conclusions</p> <p>Unprotected occupational exposure to chlorofluorocarbons can induce cardiotoxicity in the form of cardiac arrhythmias. The role of chlorofluorocarbons in inducing arterial hypertension and coronary artery diseases is unclear, although significantly elevated serum cholesterol and urinary β2-microglobulin levels raise a concern.</p

Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

BACKGROUND: The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class. METHODS: The model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4°C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest. RESULTS: The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution. CONCLUSION: If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained