Maternal neurofascin-specific autoantibodies bind to structures of the fetal nervous system during pregnancy, but have no long term effect on development in the rat

Neurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum. Results: Immunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody. Conclusions: We show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children

Proceedings of the second "international Traveling Workshop on Interactions between Sparse models and Technology" (iTWIST'14)

The implicit objective of the biennial "international - Traveling Workshop on Interactions between Sparse models and Technology" (iTWIST) is to foster collaboration between international scientific teams by disseminating ideas through both specific oral/poster presentations and free discussions. For its second edition, the iTWIST workshop took place in the medieval and picturesque town of Namur in Belgium, from Wednesday August 27th till Friday August 29th, 2014. The workshop was conveniently located in "The Arsenal" building within walking distance of both hotels and town center. iTWIST'14 has gathered about 70 international participants and has featured 9 invited talks, 10 oral presentations, and 14 posters on the following themes, all related to the theory, application and generalization of the "sparsity paradigm": Sparsity-driven data sensing and processing; Union of low dimensional subspaces; Beyond linear and convex inverse problem; Matrix/manifold/graph sensing/processing; Blind inverse problems and dictionary learning; Sparsity and computational neuroscience; Information theory, geometry and randomness; Complexity/accuracy tradeoffs in numerical methods; Sparsity? What's next?; Sparse machine learning and inference.Comment: 69 pages, 24 extended abstracts, iTWIST'14 website: http://sites.google.com/site/itwist1

Consensus Statement Immunonutrition and Exercise.

In this consensus statement on immunonutrition and exercise, a panel of knowledgeable contributors from across the globe provides a consensus of updated science, including the background, the aspects for which a consensus actually exists, the controversies and, when possible, suggested directions for future research

Consensus statement immunonutrition and exercise

In this consensus statement on immunonutrition and exercise, a panel of knowledgeable contributors from across the globe provides a consensus of updated science, including the background, the aspects for which a consensus actually exists, the controversies and, when possible, suggested directions for future research

Pathogenic T cell responses against aquaporin 4

Inflammatory lesions in the central nervous system of patients with neuromyelitis optica are characterized by infiltration of T cells and deposition of aquaporin-4-specific antibodies and complement on astrocytes at the glia limitans. Although the contribution of aquaporin-4-specific autoantibodies to the disease process has been recently elucidated, a potential role of aquaporin-4-specific T cells in lesion formation is unresolved. To address this issue, we raised aquaporin-4-specific T cell lines in Lewis rats and characterized their pathogenic potential in the presence and absence of aquaporin-4-specific autoantibodies of neuromyelitis optica patients. We show that aquaporin-4-specific T cells induce brain inflammation with particular targeting of the astrocytic glia limitans and permit the entry of pathogenic anti-aquaporin-4-specific antibodies to induce NMO-like lesions in spinal cord and brain. In addition, transfer of aquaporin-4-specific T cells provoked mild (subclinical) myositis and interstitial nephritis. We further show that the expression of the conformational epitope, recognized by NMO patient-derived aquaporin-4-specific antibodies is induced in kidney cells by the pro-inflammatory cytokine gamma-interferon. Our data provide further support for the view that NMO lesions may be induced by a complex interplay of T cell mediated and humoral immune responses against aquaporin-4

Acquired and genetic thrombotic risk factors in the athlete

While athletes are often considered the epitome of health due to their physique and lowered potential for metabolic and cardiovascular diseases, they may also be at risk for the onset and development of venous thromboembolism (VTE). In an attempt to achieve and remain competitive, athletes are frequently exposed to numerous athlete-specific risk factors, which may predispose them to VTE through the disruption of factors associated with Virchow's triad (i.e., hypercoagulability, venous stasis, and vessel wall injury). Indeed, hypercoagulability within an athletic population has been well documented to occur due to a combination of multiple factors including exercise, dehydration, and polycythemia. Furthermore, venous stasis within an athletic population may occur as a direct result of prolonged periods of immobilization experienced when undertaking long-distance travels for training and competition, recovery from injury, and overdevelopment of musculature. While all components of Virchow's triad are disrupted, injury to the vessel wall has emerged as the most important factor contributing to thrombosis formation within an athletic population, due to its ability to influence multiple hemostatic mechanisms. Vessel wall injury within an athletic population is often related to repetitive microtrauma to the venous and arterial walls as a direct result of sport-dependent trauma, in addition to high metabolic rates and repetitive blood monitoring. Although disturbances to Virchow's triad may not be detrimental to most individuals, approximately 1 in 1,000 athletes will experience a potentially fatal post-exercise thrombotic incidence. When acquired factors are considered in conjunction with genetic predispositions to hypercoagulability present in some athletes, an overall increased risk for VTE is present

Deep vein thrombosis in a well-trained masters cyclist, is popliteal vein entrapment syndrome to blame?

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Whilst athletes are the epitome of health, venous thromboembolisms (VTE) including deep vein thrombosis and pulmonary embolism have been demonstrated to occur in well-trained athletes. VTE is frequently misdiagnosed and poorly treated within this population, often resulting in career or life-threatening ramifications. Furthermore, VTE risk rises with increasing age (> 40 years), potentially affecting masters athletes. A 44-year-old well-trained male cyclist volunteered to participate in a research project investigating the influence of exercise on haemostasis in well-trained athletes. The cyclist presented with elevated d-Dimer levels both pre- (2251 ng/mL) and post-exercise (2653 ng/mL). The cyclist reported constant mild-pain in the left mid-calf region, with a cold tingling sensation in their left foot. Diagnosis of DVT was confirmed via a DVT squeeze test and Doppler ultrasound, with the clot located in the left popliteal vein. During the research project, the cyclist was exposed to numerous thrombogenic risk factors including travel, dehydration, prolonged sitting and exercise. The DVT in the popliteal vein may have resulted from repetitive movements associated with cycling. Additionally, hypertrophy of the gastrocnemius muscle may have impinged the vein. When diagnosing DVT within a cycling population, PVES should not be overlooked as a contributing factor

kitic

Sideritis raeseri spp. raeseri Boiss & Heldr is a native plant from the Mediterranean region that is used due to its medicinal and culinary properties. The aim of this study was to evaluate the effects of ethanol extract of S. raeseri on the blood pressure, vascular and cardiac contractions. Arterial blood pressure was registered directly from the carotid artery in the anaesthetized rabbits. Aortic rings and the spontaneously beating atria were mounted in tissue bath. An intravenous injection of extract of S. raeseri (0.025-7.5 mg/kg) caused a dose dependent decrease of the arterial pressure and heart rate, with EC 50 value of 24.31±3.87 mg/kg and 88.14±7.51 mg/kg, respectively. In aortic preparations precontracted with KCl (80 mM), the extract of S. raeseri (0.005-1.5 mg/ml) elicited a vasodilatator action (EC 50 0.11±0.008 mg/ml). In spontaneously beating rat atria, the extract of S. raeseri (0.005-1.5 mg/ml) produced decrease of chronotropic and inotropic activity (with EC 50 value of 0.63±0.03 mg/ml and 0.40±0.08 mg/ml). Administration of verapamil induced inhibition of force and rate of the atrial contraction. These results demonstrate that the ethanol extract of Sideritis raeseri spp. raeseri Boiss & Heldr can produce hypotension, vasodilatation, negative chronotropic and inotropic effects. K e y w o r d s : Sideritis raeseri, hypotension, vasorelaxation, cardiodepressant, blood pressure, isolated aorta, phenols, flavonoids MATERIALS AND METHODS Reagents Heparine sodium salt (Hemofarm, Serbia) and urethane (Pliva, Croatia) were used. Verapamil was obtained from the Sigma Chemical Company, St. Louis, MO, USA. All drugs were dissolved in distilled water. Vegetal material The aerial parts of cultivated S. raeseri spp. raeseri were collected in the phase of full flowering, from the experimental field at the Institute for Medicinal Plants Research in Pancevo, Serbia. Preparation of plant extract Upper 20 cm of the plants were harvested and open-air dried in the shadow. Air-dried and powdered aerial parts were extracted with 96% ethanol in Soxhlet apparatus. The extracts were filtered and evaporated in vacuum to dryness. For experimental purposes the plant extract was first dissolved in ethanol (20% m/m), than diluted with distilled water to the appropriate concentration. Ethanol, at the same concentrations, had no effect on blood pressure and contractility of isolated vessels and atria in the control experiments. Animals and treatment In this study, rabbits (around 1 kg) and Wistar albino rats (200-250 g) were used obtained from the Animal Research Center of Medical Faculty, University of Nis, Serbia. The animals were housed in stainless steel cages under standard laboratory conditions. These animals were maintained at 20-24°C with a 12 h light-dark cycle at least 1 week before the experiment. All animals had free access to food and water. All experimental procedures with animals were in compliance with the European Council Directive of November 24, 1986 (86/609/EEC). Blood pressure measurement in anaesthetized rabbits The rabbits were anesthetized intravenously with urethane (750 mg/kg). The animals were implanted with carotid arterial catheter for blood pressure recording. The arterial catheter was connected to a blood pressure transducer (P-1000-A) coupled with a Narcophysiograph (NARCO Bio system, Houston, USA) for measurement arterial pressure. The blood pressure and heart rate were recorded before and after the administration of the plant extract. Arterial pressure was allowed to return to the resting level between injections. Changes in blood pressure were recorded as the difference between the steady state values before and the peak readings after the injection. Animals were treated with S. raeseri ethanol extract, which was administered in a rising concentrations (0.025-7.5 mg/kg) at intervals of 15-20 min. Isolation of the rat aorta and recording of contractions The thoracic aorta ring preparations from rats were used. Aortic rings were mounted in 10 ml tissue bath containing a Krebs solution at 37°C and aerated with carbogen. The composition of the Krebs solution was (mM): NaCl 118.2, KCl 4.7, CaCl 2 2.5, MgSO 4 1.2, KH 2 PO 4 1.3, NaHCO 3 25.0, glucose 11.7. Before the experiments, an equilibrium period of 60 min was given. High K + (80 mM) doses were used to induce sustained contractions. The extract of S. raeseri (0.005-1.5 mg/ml) was than added to the organ bath, and the relaxation was evaluated as percentage of the induced vasoconstriction. In the second experimental series, the aortic rings were precontracted with high K + , and verapamil was then added (0.015-1.5 µg/ml). Tension changes in the tissue were recorded using a transducer (TSZ-04-E, Experimetria Ltd, Budapest, Hungary) and analyzed with a SPEL Advanced ISOSYS Data Acquisition System (Experimetria Ltd, Budapest, Hungary). Isolation of the rat atria and recording of contractions Rat atria were dissected out cleaned off fatty tissue. The spontaneously beating atria were suspended in 10 ml tissue baths, containing Krebs solution for isolated atria, maintained at 36±1°C and continuously aerated with a carbogen. The composition of Krebs solution was (mM): NaCl 137, KCl 2.81, CaCl 2 1.8, MgCl 2 0.1, NaH 2 PO 4 0.417, NaHCO 3 11.9, glucose 11.1. The force and rate of isolated atria were recorded using a transducer (TSZ-04-E, Experimetria Ltd, Budapest, Hungary) and analyzed with a SPEL Advanced ISOSYS Data Acquisition System (Experimetria Ltd, Budapest, Hungary). In the first experimental series, after an equilibrium period of 30 min, the extract of S. raeseri (0.005-1.5 mg/ml) was added cumulatively. In the second experimental series, rat atria were incubated with verapamil (0.3-3 µM). The effect on force and rate of contractions was determined as percent of the pretreated control. Statistical analysis The results were expressed as mean ±standard deviation of six determinations. Statistical evaluation was performed using the Student`s t-test. A probability value of p<0.05 was considered to be significant. The mean effective doses EC 50 that is the concentration which elicited 50% of maximal response, was established by regression analysis. RESULTS Effects of the extract on blood pressure In anaesthetized rabbits the baseline mean blood pressure did not vary, and the value of the pressure was 97.84±3.14 mmHg. Intravenous administration of the ethanol extract of S. raeseri (0.025-7.5 mg/kg) immediately caused dose-dependent decreases in systolic, diastolic and mean arterial blood pressure. The plant extract at doses of 7.5 mg/kg induced a significant fall in the blood pressure of 35.02±5.28% (p<0.01), with EC 50 value of 24.31±3.87 mg/kg Effects of the extract on isolated aorta In isolated rat aorta preparations cumulative addition of the ethanol extract of S. raeseri (0.005-1.5 mg/ml) caused the relaxation of the sustained contractions induced by KCl in a concentration-dependent manner. The plant extract at the concentration of 1.5 mg/ml caused an inhibitory effect of 79.13±6.85%, with EC 50 0.11±0.008 mg/ml 532 Effects of the extract on isolated atria The administrations of the ethanol extract of S. raeseri (0.005-1.5 mg/ml) to the spontaneously beating atria, caused negative inotropic and chronotropic effects. In isolated rat atria the plant extract at the concentration of 1.5 mg/ml decreased the rate of contraction for 69.59±5.11% (with EC 50 value of 0.63±0.03 mg/ml) and the force for 72.95±6.45% (with EC 50 value of 0.40±0.08 mg/ml) DISCUSSION The study demonstrates that the ethanol extract of S. raeseri has a hypotensive effect in rabbits, a negative inotropic and chronotropic effect in isolated rat atria and a vasorelaxant effect in isolated rat aorta. The intravenous injection of the ethanol extracts of S. raeseri induced a dose-dependent decrease of the blood pressure and heart rate of anaesthetized rabbits. The hypotensive effect was short-term and the blood pressure reached the basal value in about 2-3 min. The blood pressure is a product of cardiac output and vascular resistance hence the extract of S. raeseri was studied for its possible inhibitory effects on isolated rat aorta and atria. When tested on the high K + induced contractions of rat aorta, extract of S. raeseri showed a dose dependent vasorelaxant effect. The high KCl induced contraction is due to membrane depolarization, leading to the increase of the calcium influx through voltage-dependent channels The results demonstrated that the plant extract induced a negative chronotropic and inotropic effects on the spontaneously contracting cardiac tissues of atria. The cardio-inhibitory effect of the extract of S. raeseri was concentration dependent and reversible after washing, suggesting that the inhibition was not due to the damage of the myocardial cells by the extract. The phytochemical analysis on the samples of the genus Sideritis revealed the presence of flavones and terpenoids Literature data report that flavones and terpenoids, in other plants, to exhibit activities in cardiovascular system. Presence of such compounds in S. raeseri might possibly contribute in the hypotensive and cardio-inhibitory effects of plant extract. It was known that the aglycones apigenin exhibited endotheliumdependent vasodilatatory activities in isolated rat aorta (24). The sesquiterpene extracted from the medicinal plant Petasites formosanus in anesthetized rats produced a dose-dependent hypotensive effect (25). The hypotensive effect of other plants of Lamiaceae family has been reported. The essential oil from aerial parts of Mentha x villosa in rats induced endothelium-dependent hypotensive and vasorelaxing effects (26). Matsubara et al. (27) shown that compound from Orthosiphon aristatus (Lamiaceae) caused hypotensive, negative chronotropic and vasodilatory effects. The results demonstrate that the ethanol extract of Sideritis raeseri spp. raeseri Boiss & Heldr can produce hypotension, vasodilatation, negative chronotropic and inotropic effects. Vasorelaxant, negative chronotropic and inotropic actions can be responsible for the hypotensive effect of the ethanol extract of Sideritis raeseri. Based on our results, Sideritis raeseri may be phytotherapeutically used, after full pharmacological and toxicological evaluation, as an alternative drug to synthetic hypotensive agents