Anxiolytic and antidepressive effects of electric stimulation of the paleocerebellar cortex in pentylenetetrazol kindled rats

Anxiety and depression are component of interictal behavioral deteriorations that occur as a consequence of kindling, a procedure to induce chronic epilepsy. The aim of this study was to evaluate the possible effects of electrical stimulation (ES) of paleocerebellar cortex on anxiety and depressive-like behavior in a PTZ kindled epilepsy model. Kindling was induced via pentylenetetrazol (PTZ) (25.0 mg/kg IP daily) during three weeks. Locomotion in open field, elevated plus-maze (EPM) and Porsolt forced swimming test have been used for the assessment of anxiety and depression-like behavior. ES (100 Hz) has been delivered to V–VII lobules of vermal cortex of kindled rats. ES of paleocerebellum reversed kindling-induced reduction of crossings of central squares, increased rearings, and decreased the number of defecations in open field. The duration that kindled animals spent in the open arms of the EPM increased in post- ES period, and the number of enterings into the closed arms of the EPM decreased. The duration of the immobility response in the swimming test in kindled rats was reduced after ESs of paleocerebellum. In all: ES of paleocerebellar structures suppressed anxious and depressive-like behavior in PTZ-kindled rats

Functioning and disability in multiple sclerosis from the patient perspective

Multiple sclerosis (MS) has a great impact on functioning and disability. The perspective of those who experience the health problem has to be taken into account to obtain an in-depth understanding of functioning and disability. The objective was to describe the areas of functioning and disability and relevant contextual factors in MS from the patient perspective. A qualitative study using focus group methodology was performed. The sample size was determined by saturation. The focus groups were digitally recorded and transcribed verbatim. The meaning condensation procedure was used for data analysis. Identified concepts were linked to International Classification of Functioning, Disability and Health (ICF) categories according to established linking rules. Six focus groups with a total of 27 participants were performed. In total, 1327 concepts were identified and linked to 106 ICF categories of the ICF components Body Functions, Activities and Participation and Environmental Factors. This qualitative study reports on the impact of MS on functioning and disability from the patient perspective. The participants in this study provided information about all physical aspects and areas of daily life affected by the disease, as well as the environmental factors influencing their lives

A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves' ophthalmopathy

Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital tissues associated with elevated serum levels of TSH receptor (TSHR) autoantibodies. Because previous studies have demonstrated evidence of adipogenesis within the GO orbit, we sought to determine whether M22, a human monoclonal antibody directed against TSHR, enhances adipogenesis in orbital fibroblasts from patients with GO and, if so, to identify signaling mechanisms involved. GO orbital fibroblast cultures (n=10) were treated for 10 days with bovine TSH (1 or 10·0 U/l) or M22 (1 or 10 ng/ml) in serum-free adipocyte differentiation medium. Some cultures also received a phosphoinositide 3-kinase (PI3K) inhibitor or an inhibitor of cAMP production. In other experiments, confluent cultures (n=8) were treated for between 1 and 30 min with TSH (0·1–10·0 U/l) or M22 (0·1–100 ng/ml) with measurement of cAMP production or levels of phosphorylated AKT (pAKT). We found levels of adiponectin, leptin, and TSHR mRNA to be increased in GO cultures treated for 10 days with either M22 (2·6 mean fold ±0·7; P=0·03) or TSH (13·2±5·8-fold, P=0·048). In other studies, M22 and TSH stimulated cAMP production and pAKT levels in GO cells. Inhibition of PI3K activity during 10 days in culture decreased the levels of M22-stimulated mRNA encoding adiponectin (67±12%; P=0·021), as well as adiponectin and CCAAT/enhancer-binding protein α protein levels. In conclusion, M22 is a pro-adipogenic factor in GO orbital preadipocytes. This antibody appears to act via the PI3K signaling cascade, suggesting that inhibition of PI3K signaling may represent a potential novel therapeutic approach in GO

Antibiotics for coughing in general practice: a questionnaire study to quantify and condense the reasons for prescribing

BACKGROUND: Antibiotics are being overprescribed in ambulant care, especially for respiratory tract infections (RTIs). Gaining insight into the actual reasons for prescribing remains important for the design of effective strategies to optimise antibiotic prescribing. We aimed to determine items of importance for the antibiotic prescribing decision and to make them operational for an intervention trial. METHODS: A postal questionnaire based upon focus group findings was sent to 316 Flemish general practitioners (GPs). On a verbal rating scale the GPs scored to what extent they consider the questionnaire items in decision making in case of suspected RTI in a coughing patient and how strongly the items support or counter antibiotic treatment. Factor analysis was used to condense the data. The relative importance of the yielded operational factors was assessed using Wilcoxon Matched Pairs test. RESULTS: 59.5% completed the study. Response group characteristics (mean age: 42.8 years; 65.9% men) approximated that of all Flemish GPs. Participants considered all the items included in the questionnaire: always the operational factor 'lung auscultation', often 'whether or not there is something unusual happening' – both medical reasons – and to a lesser extent 'non-medical reasons' (P < 0.001). Non-medical as well as medical reasons support antibiotic treatment, but non-medical reasons to a lesser extent (P < 0.001). CONCLUSION: This study quantified, condensed and confirmed the findings of previous focus group research. Practice guidelines and interventions to optimise antibiotic prescribing have to take non-medical reasons into account

On modelling the Fast Radio Burst population and event rate predictions

Assuming that Fast Radio Bursts (FRBs) are of extragalactic origin, we have developed a formalism to predict the FRB detection rate and the redshift distribution of the detected events for a telescope with given parameters. We have adopted FRB 110220, for which the emitted pulse energy is estimated to be E0 =5.4×1033 J, as the reference event. The formalism requires us to assume models for (a) pulse broadening due to scattering in the ionized intergalactic medium – we consider two different models for this, (b) the frequency spectrum of the emitted pulse – we consider a power-law model Eν ∝ν −α with −5 ≤ α ≤ 5, and (c) the comoving number density of the FRB occurrence rate n(E, wi, z) – we ignore the z dependence and assume a fixed intrinsic pulse width wi = 1ms for all the FRBs. The distribution of the emitted pulse energy E is modelled through (a) a delta function where all the FRBs have the same energy E = E0, and (b) a Schechter luminosity function where the energies have a spread around E0. The models are all normalized using the four FRBs detected by Thornton et al. Our model predictions for the Parkes telescope are all consistent with the inferred redshift distribution of the 14 FRBs detected there to date. We also find that scattering places an upper limit on the redshift of the FRBs detectable by a given telescope; for the Parkes telescope, this is z ~ 2. Considering the upcoming Ooty Wide Field Array, we predict an FRB detection rate of ~0.01 to ~103 d−1

The Influence of Taxation on Small Enterprise Development in Russia

Formation of adequate conditions in Russia market economy model requires the creation of a sound financial base. An important place in the mobilization of financial resources of society plays a tax system with its characteristic features of each state and the specifics of the tasks performed at a certain stage. In recent years, the negative effects of the transition period is expected to overcome through the development of small businesses, which determines the possibility of self-realization of the population in achieving the established preferences and values, as well as through the optimization of the tax system and, in particular, strengthening and stimulating social functions taxes. Formation and development of a market economy based on private property, accompanied by an expansion of business and the creation of small businesses, the activation of various financial and credit institutions, thus increasing the number of actual taxpayers. In connection with this problem is exacerbated relations between the state in the face of tax structures and small businesses as taxpayers

Money in monetary policy design: monetary cross-checking in the New-Keynesian model

In the New-Keynesian model, optimal interest rate policy under uncertainty is formulated without reference to monetary aggregates as long as certain standard assumptions on the distributions of unobservables are satisfied. The model has been criticized for failing to explain common trends in money growth and inflation, and that therefore money should be used as a cross-check in policy formulation (see Lucas (2007)). We show that the New-Keynesian model can explain such trends if one allows for the possibility of persistent central bank misperceptions. Such misperceptions motivate the search for policies that include additional robustness checks. In earlier work, we proposed an interest rate rule that is near-optimal in normal times but includes a cross-check with monetary information. In case of unusual monetary trends, interest rates are adjusted. In this paper, we show in detail how to derive the appropriate magnitude of the interest rate adjustment following a significant cross-check with monetary information, when the New-Keynesian model is the central bank’s preferred model. The cross-check is shown to be effective in offsetting persistent deviations of inflation due to central bank misperceptions. Keywords: Monetary Policy, New-Keynesian Model, Money, Quantity Theory, European Central Bank, Policy Under Uncertaint

Response to IL‐17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein‐coding and untranslated regions of the IL‐17A gene : results from a multicentre study of four European psoriasis cohorts

Background Genetic predictors for treatment response could optimize allocation of biological treatment in patients with psoriasis. There is minimal knowledge about pharmacogenetics of anti-IL-17 agents. Objectives To assess whether genetic variants in the protein-coding region or untranslated regions of the IL-17A gene are associated with response to IL-17A inhibitors in patients with psoriasis. Methods This was a multicenter European cohort study investigating pharmacogenetics of IL-17A inhibitors in patients with psoriasis. Patients with plaque psoriasis treated with secukinumab or ixekizumab in daily practice were included. For all participants, the protein-coding region and untranslated regions of the IL-17A gene were analysed using Sanger sequencing. Identified genetic variants were tested for association with response to secukinumab/ixekizumab, measured as increment PASI, after 12 weeks (primary outcome) and after 24 weeks (secondary outcome). Association was tested using a linear regression model with correction for baseline PASI as a fixed covariate and for biological naivety and body mass index as additional covariates. Results In total, 134 patients treated with secukinumab or ixekizumab were included. Genotyping of the cohort identified genetic variants present in untranslated regions and intronic DNA, but not in the protein-coding region of the IL-17A gene. Five genetic variants in non-coding DNA with a known or suspected functional effect on IL-17A expression were selected for association analyses: rs2275913, rs8193037, rs3819025, rs7747909 and rs3748067. After 12 weeks, 62% of patients achieved PASI75 and 39% achieved PASI90. At week 24, PASI75 and PASI90 response rates were 72% and 62%, respectively. No associations were found between the five genetic variants and increment PASI, PASI75 or PASI90 after 12 and 24 weeks of anti-IL-17A treatment. Conclusions Response to IL-17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein-coding and untranslated regions of the IL-17A gene. Pharmacogenetics of IL-17A inhibitors in the treatment of psoriasis requires further exploration