Search

Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.

Funding Acknowledgements Type of funding sources: None. Background In left atrial appendage occlusion (LAAO), pre-procedural computed tomography (CT) is pivotal to describe the complex and highly variable LAA anatomy and to guide the operator in accurate planning of the intervention. Multiplanar reconstruction and 3D rendering are used for the navigation and analysis of the 3D datasets but they share some limitations that are due to the use of 2D screens; Mixed Reality (MxR) technology aims at overcoming such limitations by allowing for real-3D visualizations with holographic replicas of anatomical models while preserving a sense of presence within the true physical environment by the operator. Purpose To develop and test a MxR platform that provides a more intuitive and informative tool for the morphological analysis during the planning phase of LAAO. Methods Patients (n = 4) were randomly selected among those referred for a CT scan prior to transcatheter aortic valve replacement, each one characterized by a specific LAA morphology (cauliflower, bilobular, chicken wing, wind-sock). CT scans were performed in diastole at 75% of the R-R interval on a 64-slice scanner, with in-plane resolution 0.38-0.64 mm and slice thickness 0.62 mm. Firstly, the acquisition was cropped to contain the left atrium, the circumflex artery, the left upper pulmonary ridge. Subsequently, an isosurface with high coincidence between the blood cavity border and the endocardium was identified by the user and processed using a marching cube algorithm to obtain the 3D model. Finally, the 3D model was optimized for a MxR platform that allows for moving, zooming and cutting the model, measuring the main LAA linear dimensions and simulating the implant of a virtual replica of a transcatheter occluder. Results The workflow was successfully applied for all the patients independently from the morphology. All the models were successfully uploaded in the MxR platform (Fig 1.a) and for all the patients the morphological analysis was performed (Fig 1.b) in less than 10 minutes. The four different morphologies of the LAA were correctly identified allowing a very detailed holographic modeling of the structure, including the neck, the landing zone, the curvature and the position and size of lobes. For both the identified ostium and landing planes, using a dedicated measuring tool (Fig. 1.c), the operator measured the minimum and maximum diameters, which were later used to define the size of the occluder device to be used in the virtual implant simulation (Fig. 1.d). Conclusions The tested MxR platform suggested the potential to overcome the limits of the standard technologies in planning of LAAO thanks to the real-3D perception, potentially leading to a more accurate and faster planning phase. Furthermore, the use of MxR technology may enhance the ability to predict the optimal device size and position within the anatomy to obtain LAA complete sealing. Abstract Figure.

A Finite Element workflow for the multiscale analysis of the aortic valve biomechanics was developed and applied to three physiological anatomies with the aim of describing the aortic valve interstitial cells biomechanical milieu in physiological conditions, capturing the effect of subject-specific and leaflet-specific anatomical features from the organ down to the cell scale. A mixed approach was used to transfer organ-scale information down to the cell-scale. Displacement data from the organ model were used to impose kinematic boundary conditions to the tissue model, while stress data from the latter were used to impose loading boundary conditions to the cell level. Peak of radial leaflet strains was correlated with leaflet extent variability at the organ scale, while circumferential leaflet strains varied over a narrow range of values regardless of leaflet extent. The dependency of leaflet biomechanics on the leaflet-specific anatomy observed at the organ length-scale is reflected, and to some extent emphasized, into the results obtained at the lower length-scales. At the tissue length-scale, the peak diastolic circumferential and radial stresses computed in the fibrosa correlated with the leaflet surface area. At the cell length-scale, the difference between the strains in two main directions, and between the respective relationships with the specific leaflet anatomy, was even more evident; cell strains in the radial direction varied over a relatively wide range ($$0.36-0.87$$ 0.36 - 0.87 ) with a strong correlation with the organ length-scale radial strain ($$R^{2}= 0.95$$ R 2 = 0.95 ); conversely, circumferential cell strains spanned a very narrow range ($$0.75-0.88$$ 0.75 - 0.88 ) showing no correlation with the circumferential strain at the organ level ($$R^{2}= 0.02$$ R 2 = 0.02 ). Within the proposed simulation framework, being able to account for the actual anatomical features of the aortic valve leaflets allowed to gain insight into their effect on the structural mechanics of the leaflets at all length-scales, down to the cell scale.

We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differentiation and bone formation in vitro and in vivo in rodents. Structurally different inhibitors that bind to specific catalytic beta subunits of the 20S proteasome stimulated bone formation in bone organ cultures in concentrations as low as 10 nM. When administered systemically to mice, the proteasome inhibitors epoxomicin and proteasome inhibitor-1 increased bone volume and bone formation rates over 70% after only 5 days of treatment. Since the ubiquitin-proteasome pathway has been shown to modulate expression of the Drosophila homologue of the bone morphogenetic protein-2 and -4 (BMP-2 and BMP-4) genes, we examined the effects of noggin, an endogenous inhibitor of BMP-2 and BMP-4 on bone formation stimulated by these compounds and found that it was abrogated. These compounds increased BMP-2 but not BMP-4 or BMP-6 mRNA expression in osteoblastic cells, suggesting that BMP-2 was responsible for the observed bone formation that was inhibited by noggin. We show proteasome inhibitors regulate BMP-2 gene expression at least in part through inhibiting the proteolytic processing of Gli3 protein. Our results suggest that the ubiquitin-proteasome machinery regulates osteoblast differentiation and bone formation and that inhibition of specific components of this system may be useful therapeutically in common diseases of bone loss.

Insomnia is one of the symptoms of inorganic mercury poisoning (IMP). The objective of this study is to analyze the chief psychological aspects in the adjustment of workers with chronic insomnia associated with IMP. For this purpose the Preventive Clinical Interview and the Ryad Simon Operational Adaptive Diagnostic Scale (Escala Diagnóstica Adaptativa Operacionalizada-EDAO) were utilized. Fifteen subjects with mean age of 40 years (10 males and 5 females) were studied. Nine were diagnosed with High Adaptive Inefficacy, five with Moderate Inefficient Adaptation and only one with Mild Inefficient Adaptation. Impairment occurred in four adaptive sectors: affective relationship, social-cultural, productivity and organic. Adaptive efficiency indicated that in all the 15 subjects studied the adaptive solutions were frustrating and led to psychic suffering and/or environmental conflict confirming the severity of the involvement in chronic IMP.Insônia é um dos sintomas da contaminação por mercúrio inorgânico. O objetivo desta pesquisa foi avaliar os principais aspectos psicológicos presentes na organização adaptativa de trabalhadores com insônia crônica associada à contaminação por mercúrio inorgânico. Utilizaram a Entrevista Clínica Preventiva e a Escala Diagnóstica Adaptativa Operacionalizada (EDAO) de Ryad Simon. Foram estudadas 15 pessoas, com média de idade de 40 anos (10M; 5 F). Nove foram diagnosticadas como tendo Adaptação Ineficaz Severa; cinco, Adaptação Ineficaz Moderada; e somente um, Adaptação Ineficaz Leve. O comprometimento na adaptação ocorreu nos quatro setores adaptativos: afetivo-emocional, sócio-cultural, da produtividade e orgânico. A eficácia adaptativa indicou que em todos as15 pessoas estudadas, as soluções adaptativas encontradas foram frustrantes e levaram a sofrimento psíquico e/ou atritos ambientais, evidenciando a severidade de comprometimento na intoxicação crônica por mercúrio inorgânico.

Osteoporosis and other diseases of bone loss are a major public health problem. Here it is shown that the statins, drugs widely used for lowering serum cholesterol, also enhance new bone formation in vitro and in rodents. This effect was associated with increased expression of the bone morphogenetic protein–2 (BMP-2) gene in bone cells. Lovastatin and simvastatin increased bone formation when injected subcutaneously over the calvaria of mice and increased cancellous bone volume when orally administered to rats. Thus, in appropriate doses, statins may have therapeutic applications for the treatment of osteoporosis.

Many studies have shown that the bad lifestyles are the major factors thought to influence susceptibility to many diseases in our society and often these habits during the adolescence begin. The aim of the study was to evaluate the health promotion intervention effect in an orthodontic adolescent sample, in particular: deterring adolescents from smoking; discourage the use and abuse of alcoholic beverages; encourage the adherence to the Mediterranean style diet. A blinded randomized controlled trial will be performed. The participants will be adolescents aged 10 to 14 years that will receive a medical examination in the Complex Unit of Orthodontics. The sample will be followed for three years. The collected evidence would be a scientific support for decisions in public health, in order to increase the health of the young generations.

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a fast and minimally invasive methodology with a crucial impact on patients’ management. It has an important and established role in the diagnosis and staging of mediastinal and abdominal malignancies, but little is discussed in the literature on the usefulness of this technique in the diagnosis of infectious diseases. In the current report, we present three different cases where EUS was essential for reaching the diagnosis of tuberculosis and paracoccidiodomicosis in cases otherwise seen as malignant. In conclusion, EUS was successful not only in obtaining enough cells for morphological analysis, but also for the production of cell blocks and assessment of the presence of the microorganisms by special stains. EUS allied to fine needle biopsy was an important tool in determining diagnoses of enlarged lymph nodes, revealing the diagnosis of infectious diseases in cases otherwise seen as malignant. The wide use of this methodology in cases such as those reported here cannot only rule out malignancy, but also aid critically ill patients by installing early proper therapy without the need for aggressive interventions.

In 2009, to date 16 human cases of West Nile neuroinvasive disease (WNND) have been reported in Italy, in three regions: Veneto, Emilia-Romagna and Lombardia. The number of cases is higher compared with last year when nine cases were identified (eight cases of WNND and one case of West Nile fever) and the geographical distribution indicates spread from east to west.

Statins stimulate bone formation in vitro and in vivo and, when given in large doses or by prolonged infusions, stimulate biomechanical strength of murine long bones with healing fractures. However, administration of statins by large oral doses or prolonged infusions to a fracture site is not a feasible therapeutic approach to hasten healing of human fractures. We administered lovastatin in biodegradable polymer nanobeads of poly(lactic-co-glycolide acid) to determine if lovastatin delivered in low doses in nanoparticles of a therapeutically acceptable scaffold could increase rates of healing in a standard preclinical model of femoral fracture. We found that these nanobeads: (1) stimulated bone formation in vitro at 5 ng/mL, (2) increased rates of healing in femoral fractures when administered as a single injection into the fracture site, and (3) decreased cortical fracture gap at 4 weeks as assessed by microcomputed tomography. These preclinical results suggest that lovastatin administered in a nanobead preparation may be therapeutically useful in hastening repair of human fractures.

The paper contains first the analysis of the strategic decision as to whether to integrate or not, in a market with differenciation of final products feeding back into the production of intermediate inputs. Cournot competition makes integration a dominant strategy, althogh it is not Pareto optimal for the industry when goods are close substitutes.Bertrand competition leaves room also for non integration and there remains the possibility of asymmetric industry organization, with non integrated firms competing with integrated rivals.The analysisis extended to an oligopoly where upstream process R&D takes place. Here, the nonintegrated part of industry may invest more in process R&D and even perform better than its integrated counterart.

According to received literature, vertical integration may enjoy a social superiority due to the ability to internalize the externality that goes back from the pricing policy of the downstream firm to the profits of the upstream firm. We challenge this result introducing process R&D in a broad set of scenarios with vertically symmetric and asymmetric R&D commitments. In some of these contexts a reversed sequence of socially desirable vertical arrangements arises, making outsourcing superior. In other circumstances disintegration is privately superior but socially inefficient. Finally, vertically asymmetric costs of R&D are considered to allow for a wider range of applications.

Nowadays organ transplantation is a life-saving procedure, or anyhow it can considerably improve the life quality of patients suffering from irreversible organ impairment. Monitoring transplantation outcome is the last step of a long process that starts with cadaver donor identification, selection and clinical management, and continues with organ allocation, patient evaluation, surgical operation and clinical follow-up. The National Transplantation Committee has been discussing many of these items and, in 1995, it set up two protocols, one on liver exchange for urgent patients and the other on transplantation in the pediatric patient. The protocols application has met many difficulties, mainly due to the uneven behaviours of the different inter-regional organizations. In this paper we comment on the two main aspects to be submitted to the next National Committee: organ allocation and transplantation outcome. As far as the last point is concerned, the enclosed data are based on the experience of the North Italy Transplant program (NITp), and on that of the major international registries. Without any doubt these data demontrate that organ transplantation is to be ascribed among the successes of medicine in the just closed century.

We analyse R&D activity in transport and communication technology (TCRD), in a Cournot duopoly. Transport and communication costs are of the iceberg type, i.e., using up some portion of the product along its path to the final buyer. Firms invest in TCRD to increase the net amount of the product that reaches consumers. A variety of equilibria arise as a result of the different levels of TCRD efficiency. If TCRD’s productivity is high, the game is a prisoner’s dilemma where both firms invest in TCRD. As the e¢ciency of the TCRD progressively fades we come across first a chicken game and, then, at lower e¢ciency, a game with an equilibrium in dominant strategies where the profits are at the highest. Social welfare is maximised by market strategies only when TCRD is very efficient.

Different market settings are considered in a free trade environment, where firms can choose technology, quality, and price or quantity. The shape of competition in prices requires the intervention of governments, via a common antidumping policy, to make firms converge on the simultaneous equilibrium which is socially optimal. In the Cournot framework, the equilibria we obtain impinge upon the kind of precommitments undertaken by firms. The coincidence between firms' behaviour and social preference obtains either when competition is tough, since income is low, or when firms must compete in quantities in the market stage, since they cannot modify qualities. The spontaneous coordination over common standards has to be contrasted with both the case of affuent consumers and Bertrand competition.

Recent developments in the field of ecotoxicological effects assessment of pollutants on aquatic systems make use of methods founded on statistical principles and requirements (Kooijman 1987; Van Straalen & Denneman 1989). Van Straalen and Kooijman methods estimate a hazardous concentration for p percent of species in a community (HCp) at a chosen protection level. Evaluations on the application of the methodology to different toxic compounds and test species using both chronic and acute toxicity data have been undertaken (Van Leeuwen 1990)., Centro de Investigaciones del Medioambiente

Tra i problemi che accompagnano i mercati finanziari in presenza di cospicui debiti da collocare va incluso in primis quello che concerne la risposta dei portafogli delle famiglie e delle imprese a variazioni dei prezzi relativi delle attività finanziarie.

In this paper we want to examine market diversification and scope of production of a firm.

We report a case of Usutu virus (USUV)-related illness in a patient that underwent an orthotropic liver transplant (OLT). Post transplant, the patient developed clinical signs of a possible neuroinvasive disease with a significant loss of cerebral functions. USUV was isolated in Vero E6 cells from a plasma sample obtained immediately before the surgery, and USUV RNA was demonstrated by RT-PCR and sequencing. This report enlarges the panel of emerging mosquito-borne flavivirus-related disease in humans.

n/a

Muovendo dall’approccio deweyano, il focus del contributo è l’importanza dell’educazione alla cittadinanza democratica (Ecd) come nesso costitutivo tra sviluppo umano, giustizia sociale e ambiente. Si soffermerà poi sul repertorio di competenze per la scuola con un’attenzione al modello di educazione sociale, emotiva, etica e accademica (SEEAE) di Cohen, e si chiude con una ricerca che si focalizza sul riconoscimento/validazione di una proposta Ecd delle competenze nei contesti locali. Building on the deweyan approach, the focus of the paper is the importance of education for democratic citizenship (Ecd) as a constitutive link between human development, social justice and the environment. It will then look at the repertoire of competencies for schooling with a focus on Cohen’s Social, Emotional, Ethical and Academic Education (SEEAE) model, and closes with research that focuses on the recognition/validation of an Ecd proposal competencies in local contexts.

OBJECTIVE:\ud We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy.\ud \ud METHODS:\ud A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered.\ud \ud RESULTS:\ud The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively.\ud \ud CONCLUSIONS:\ud This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.

West Nile virus, genus Flavivirus, is transmitted between birds and occasionally other animals by ornithophilic mosquitoes. This virus also infects humans causing asymptomatic infections in about 85% of cases and

The mosquito-borne alphavirus, chikungunya virus (CHIKV), has recently reemerged, producing the largest epidemic ever recorded for this virus, with up to 6.5 million cases of acute and chronic rheumatic disease. There are currently no licensed vaccines for CHIKV and current anti-inflammatory drug treatment is often inadequate. Here we describe the isolation and characterization of two human monoclonal antibodies, C9 and E8, from CHIKV infected and recovered individuals. C9 was determined to be a potent virus neutralizing antibody and a biosensor antibody binding study demonstrated it recognized residues on intact CHIKV VLPs. Shotgun mutagenesis alanine scanning of 98 percent of the residues in the E1 and E2 glycoproteins of CHIKV envelope showed that the epitope bound by C9 included amino-acid 162 in the acid-sensitive region (ASR) of the CHIKV E2 glycoprotein. The ASR is critical for the rearrangement of CHIKV E2 during fusion and viral entry into host cells, and we predict that C9 prevents these events from occurring. When used prophylactically in a CHIKV mouse model, C9 completely protected against CHIKV viremia and arthritis. We also observed that when administered therapeutically at 8 or 18 hours post-CHIKV challenge, C9 gave 100% protection in a pathogenic mouse model. Given that targeting this novel neutralizing epitope in E2 can potently protect both in vitro and in vivo, it is likely to be an important region both for future antibody and vaccine-based interventions against CHIKV., Author Summary CHIKV is characterized by acute and chronic polyarthritis/polyarthralgia that can be debilitating and protracted. Currently there are no FDA-approved vaccines or specific antiviral treatments for CHIKV. We thus identified and characterized human monoclonal antibodies directed against CHIKV that could be utilized in prophylactic and immediate post-exposure settings. Such patient derived monoclonal antibodies could also provide useful information on critical antigens and epitopes for development of future vaccines and other biologics. We describe here the identification of two monoclonal antibodies (C9 and E8) isolated from recovered patients. C9 potently inhibited CHIKV infection in cells and prevented viremia and arthritis in a mouse model of CHIKV disease. The epitope for this antibody includes an amino-acid residue in a key acid-sensitive region of the E2 glycoprotein of CHIKV. Rearrangement of this region following exposure to low pH is critical for uncovering portions of the companion E1 glycoprotein, required for successful entry of CHIKV into cells. We hypothesize that binding of antibodies to this region stabilizes the native complex and thus prevents such rearrangements.

West Nile virus (WNV) is currently circulating in several European countries and, over recent decades, concomitantly with enhanced surveillance studies and improved diagnostic capabilities, an increase in the geographical distribution and in the number of cases in Europe has been documented. In Italy in 2011, 14 human cases of WNV neuroinvasive infections due to lineage 1 strains were registered in several Italian regions. Here we report WNV partial sequences obtained from serum samples of two patients living in different regions of Italy (Veneto and Sardinia). Phylogenetic analysis, performed on a fragment (566 nt) of the envelope gene, showed that WNV strains circulating in Italy in 2011 belong to lineage 1a, but are different from lineage 1a strains isolated in 2008–2009.The data reported here are consistent with the hypothesis of multiple recent introductions of WNV lineage 1a strains into Italy.

Background Treponema denticola is an oral spirochete involved in the pathogenesis and progression of periodontal disease. Of its virulence factors, the major surface protein (MSP) plays a role in the interaction between the treponeme and host. To understand the possible evolution of this protein, we analyzed the sequence of the msp gene in 17 T. denticola positive clinical samples. Methods Nucleotide and amino acid sequence of MSP have been determined by PCR amplification and sequencing in seventeen T. denticola clinical specimens to evaluate the genetic variability and the philogenetic relationship of the T. denticola msp gene among the different amplified sequence of positive samples. In silico antigenic analysis was performed on each MSP sequences to determined possible antigenic variation. Results The msp sequences showed two highly conserved 5' and 3' ends and a central region that varies substantially. Phylogenetic analysis categorized the 17 specimens into 2 principal groups, suggesting a low rate of evolutionary variability and an elevated degree of conservation of msp in clinically derived genetic material. Analysis of the predicted antigenic variability between isolates, demonstrated that the major differences lay between amino acids 200 and 300. Conclusion These findings showed for the first time, the nucleotide and amino acids variation of the msp gene in infecting T. denticola, in vivo. This data suggested that the antigenic variability found in to the MSP molecule, may be an important factor involved in immune evasion by T. denticola.

The main aim of the paper is to highlight the relation between flexibility and vertical integration. To this purpose, we go through the selection of the optimal degree of vertical disintegration of a flexible firm which operates in a dynamic uncertain environment. The enterprise we model enjoys flexibility since it can switch from a certain amount of disintegration to vertical integration and viceversa. This means that the firm never loses vertical control, i.e., the ability to produce all inputs even when it buys them in the market. This sort of flexibility makes for results which are somehow contrary to the Industrial Organization recent literature and closer to the Operations Research results. In this sense we provide a bridge between the two approaches and rescue Industrial Organization from counterintuitive conclusions.

One of the reasons why workers' enterprises (WE) still represent a relevant chunk of the economy may lay in some affinities with conventional profit maximizing firms. To provide a solid basis to this presumption, we compare the entry policies of WEs and conventional firms when size is set at entry and kept fixed afterwards. Even though short run differences remain between WEs and conventional firms, a long run coincidence appears in an uncertain dynamic environment. Endogenizing size and time of entry we see that the two kinds of firms enter at the same trigger market price and size. Both of them enter earlier and choose a dimension larger than the minimum efficient scale. This generalised coincidence may be another way to explain why WEs still make for an important share of the economy (Hesse and Cihàk, 2007) despite the ongoing mantra of their imminent demise.