Efficacy of Anti-Inflammatory Therapy in a Model of Acute Seizures and in a Population of Pediatric Drug Resistant Epileptics

Targeting pro-inflammatory events to reduce seizures is gaining momentum. Experimentally, antagonism of inflammatory processes and of blood-brain barrier (BBB) damage has been demonstrated to be beneficial in reducing status epilepticus (SE). Clinically, a role of inflammation in the pathophysiology of drug resistant epilepsies is suspected. However, the use anti-inflammatory drug such as glucocorticosteroids (GCs) is limited to selected pediatric epileptic syndromes and spasms. Lack of animal data may be one of the reasons for the limited use of GCs in epilepsy. We evaluated the effect of the CG dexamethasone in reducing the onset and the severity of pilocarpine SE in rats. We assessed BBB integrity by measuring serum S100β and Evans Blue brain extravasation. Electrophysiological monitoring and hematologic measurements (WBCs and IL-1β) were performed. We reviewed the effect of add on dexamethasone treatment on a population of pediatric patients affected by drug resistant epilepsy. We excluded subjects affected by West, Landau-Kleffner or Lennox-Gastaut syndromes and Rasmussen encephalitis, known to respond to GCs or adrenocorticotropic hormone (ACTH). The effect of two additional GCs, methylprednisolone and hydrocortisone, was also reviewed in this population. When dexamethasone treatment preceded exposure to the convulsive agent pilocarpine, the number of rats developing status epilepticus (SE) was reduced. When SE developed, the time-to-onset was significantly delayed compared to pilocarpine alone and mortality associated with pilocarpine-SE was abolished. Dexamethasone significantly protected the BBB from damage. The clinical study included pediatric drug resistant epileptic subjects receiving add on GC treatments. Decreased seizure frequency (≥50%) or interruption of status epilepticus was observed in the majority of the subjects, regardless of the underlying pathology. Our experimental results point to a seizure-reducing effect of dexamethasone. The mechanism encompasses improvement of BBB integrity. Our results also suggest that add on GCs could be of efficacy in controlling pediatric drug resistant seizures

Appropriate model use for predicting elevations and inundation extent for extreme flood events

Flood risk assessment is generally studied using flood simulation models; however, flood risk managers often simplify the computational process; this is called a “simplification strategy”. This study investigates the appropriateness of the “simplification strategy” when used as a flood risk assessment tool for areas prone to flash flooding. The 2004 Boscastle, UK, flash flood was selected as a case study. Three different model structures were considered in this study, including: (1) a shock-capturing model, (2) a regular ADI-type flood model and (3) a diffusion wave model, i.e. a zero-inertia approach. The key findings from this paper strongly suggest that applying the “simplification strategy” is only appropriate for flood simulations with a mild slope and over relatively smooth terrains, whereas in areas susceptible to flash flooding (i.e. steep catchments), following this strategy can lead to significantly erroneous predictions of the main parameters—particularly the peak water levels and the inundation extent. For flood risk assessment of urban areas, where the emergence of flash flooding is possible, it is shown to be necessary to incorporate shock-capturing algorithms in the solution procedure, since these algorithms prevent the formation of spurious oscillations and provide a more realistic simulation of the flood levels

Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine .

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH

Integrated high-content quantification of intracellular ROS levels and mitochondrial morphofunction

Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and their removal by cellular antioxidant systems. Especially under pathological conditions, mitochondria constitute a relevant source of cellular ROS. These organelles harbor the electron transport chain, bringing electrons in close vicinity to molecular oxygen. Although a full understanding is still lacking, intracellular ROS generation and mitochondrial function are also linked to changes in mitochondrial morphology. To study the intricate relationships between the different factors that govern cellular redox balance in living cells, we have developed a high-contentmicroscopy-based strategy for simultaneous quantification of intracellular ROS levels and mitochondrial morphofunction. Here, we summarize the principles of intracellular ROS generation and removal, and we explain the major considerations for performing quantitative microscopy analyses of ROS and mitochondrial morphofunction in living cells. Next, we describe our workflow, and finally, we illustrate that a multiparametric readout enables the unambiguous classification of chemically perturbed cells as well as laminopathy patient cells

Neuromarketing and consumer neuroscience:contributions to neurology

Background: 'Neuromarketing' is a term that has often been used in the media in recent years. These public discussions have generally centered around potential ethical aspects and the public fear of negative consequences for society in general, and consumers in particular. However, positive contributions to the scientific discourse from developing a biological model that tries to explain context-situated human behavior such as consumption have often been neglected. We argue for a differentiated terminology, naming commercial applications of neuroscientific methods 'neuromarketing' and scientific ones 'consumer neuroscience'. While marketing scholars have eagerly integrated neuroscientific evidence into their theoretical framework, neurology has only recently started to draw its attention to the results of consumer neuroscience.Discussion: In this paper we address key research topics of consumer neuroscience that we think are of interest for neurologists; namely the reward system, trust and ethical issues. We argue that there are overlapping research topics in neurology and consumer neuroscience where both sides can profit from collaboration. Further, neurologists joining the public discussion of ethical issues surrounding neuromarketing and consumer neuroscience could contribute standards and experience gained in clinical research.Summary: We identify the following areas where consumer neuroscience could contribute to the field of neurology:. First, studies using game paradigms could help to gain further insights into the underlying pathophysiology of pathological gambling in Parkinson's disease, frontotemporal dementia, epilepsy, and Huntington's disease.Second, we identify compulsive buying as a common interest in neurology and consumer neuroscience. Paradigms commonly used in consumer neuroscience could be applied to patients suffering from Parkinson's disease and frontotemporal dementia to advance knowledge of this important behavioral symptom.Third, trust research in the medical context lacks empirical behavioral and neuroscientific evidence. Neurologists entering this field of research could profit from the extensive knowledge of the biological foundation of trust that scientists in economically-orientated neurosciences have gained.Fourth, neurologists could contribute significantly to the ethical debate about invasive methods in neuromarketing and consumer neuroscience. Further, neurologists should investigate biological and behavioral reactions of neurological patients to marketing and advertising measures, as they could show special consumer vulnerability and be subject to target marketing

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Lunar samples record an impact 4.2 billion years ago that may have formed the Serenitatis Basin

Impact cratering on the Moon and the derived size-frequency distribution functions of lunar impact craters are used to determine the ages of unsampled planetary surfaces across the Solar System. Radiometric dating of lunar samples provides an absolute age baseline, however, crater-chronology functions for the Moon remain poorly constrained for ages beyond 3.9 billion years. Here we present U–Pb geochronology of phosphate minerals within shocked lunar norites of a boulder from the Apollo 17 Station 8. These minerals record an older impact event around 4.2 billion years ago, and a younger disturbance at around 0.5 billion years ago. Based on nanoscale observations using atom probe tomography, lunar cratering records, and impact simulations, we ascribe the older event to the formation of the large Serenitatis Basin and the younger possibly to that of the Dawes crater. This suggests the Serenitatis Basin formed unrelated to or in the early stages of a protracted Late Heavy Bombardment