We survey the literature that has explored the implications of decision-making under ambiguity for financial market outcomes, such as portfolio choice and equilibrium asset prices. This ambiguity ...literature has led to a number of significant advances in our ability to rationalize empirical features of asset returns and portfolio decisions, such as the failure of the two-fund separation theorem in portfolio decisions, the modest exposure to risky securities observed for a majority of investors, the home equity preference in international portfolio diversification, the excess volatility of asset returns, the equity premium and the risk-free rate puzzles, and the occurrence of trading break-downs.
Treatment of pediatric-onset multiple sclerosis (POMS) has been tailored after observational studies and data obtained from clinical trials in adult-onset multiple sclerosis (AOMS) patients. There ...are an increasing number of new therapeutic agents for AOMS, and many will be formally studied for use also in POMS. However, there are important efficacy and safety concerns regarding the use of these therapies in children and young adults. This review will discuss the current state of the art of POMS therapy and will focus on the newer therapies (oral and infusion disease-modifying drugs) and on those still currently under investigation.
Introduction Microglia (MG) is suggested to play an immunopathological role of in Multiple Sclerosis (MS). Since hyper-reflective foci (HRF) might mark MG activation, in vivo analysis by Optic ...Coherence Tomography (OCT) in MS patients under disease modifying therapies may help to clarify MS immunopathology as well as drug’s mechanism of intrathecal action. Objective To analyze HRF in patients treated with Natalizumab (NTZ), a high efficacy therapy for MS. Materials and methods The effect of NTZ on the retina of 36 Relapsing-Remitting MS patients was investigated in a prospective, single-center study. OCT was performed immediately before the first infusion and then between infusion 3 and 4, infusion 6 and 7, infusion 11 and 13. Peripapillary and macular scans were acquired, evaluating peripapillary RNFL thickness, macular volumes (vertical scans), and HRF count (horizontal scan) in Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL) and Inner Nuclear Layer (INL). Clinical examination was performed every six months. Results HRF count significantly increased under NTZ therapy (p<0.001) in both GCL (18.85 ± 6.93 at baseline, 28.24 ± 9.55 after 12 months) and IPL (25.73 ± 7.03 at baseline, 33.21 ± 8.50 after 12 months) but remained stable in INL (33.65 ± 7.76 at baseline, 36.06 ± 6.86 after 12 months, p=0.87), while no relevant modification of pRNFL and macular volumes were observed during the study. EDSS remained stable and no clinical relapse was observed between month 6 and 12. Conclusion In RRMS NTZ affects HRF count in GCL and IPL, but not in INL, suggesting that NTZ does not impact on some aspects of MS immunopathology.
Cystic echinococcosis(CE) is a complex, chronic and neglected disease with a worldwide distribution. The liver is the most frequent location of parasitic cysts. In humans, its clinical spectrum ...ranges from asymptom-atic infection to severe, potentially fatal disease. Four approaches exist in the clinical management of CE: surgery, percutaneous techniques and drug treatment for active cysts, and the "watch and wait" approach for inactive cysts. Allocation of patients to these treat-ments should be based on cyst stage, size and location, available clinical expertise, and comorbidities. However, clinical decision algorithms, efficacy, relapse rates, and costs have never been properly evaluated. This paper reviews recent advances in classification and diagnosisand the currently available evidence for clinical deci-sion-making in cystic echinococcosis of the liver.
Objective
Clinical and neuroimaging parameters predictive of the changing clinical course of multiple sclerosis (MS) from relapsing–remitting to secondary progressive have not been clarified yet. We ...specifically designed a prospective 5‐year longitudinal study aimed at assessing demographic, clinical, and magnetic resonance imaging (MRI) parameters that could predict the changing clinical course of MS.
Methods
At study entry and after 5 years, clinical and MRI (ie, gray matter and white matter lesions, including spinal cord lesions, and global and regional cortical thinning) parameters were assessed in a training set of 334 consecutive relapsing–remitting MS patients and in an independent validation set of 84 relapsing–remitting MS patients.
Results
Sixty‐six (19.7%) relapsing–remitting MS patients changed their clinical course during the study and entered into the secondary progressive phase. Age (p = 0.001, odds ratio OR = 1.2), cortical lesion volume (p < 0.001,OR = 1.7), and cerebellar cortical volume (p < 0.001, OR = 0.2) at study entry were found to predict the changing clinical course. The model including only these 3 variables correctly identified 252 of 268 (94.0%) patients who maintained the relapsing–remitting course and 58 of 66 (87.8%) patients who became secondary progressive (cross‐validated error rate = 7.2%). When applied on the validation set, the model obtained a similar error rate (8.4%).
Interpretation
A prediction model based on age, cortical lesion load, and cerebellar cortical volume suitably explains the probability of relapsing–remitting MS patients evolving into the progressive phase. Gray matter damage appears to play a pivotal role in determining the changing clinical course of MS. Ann Neurol 2013;74:76–83
A 27-year-old woman was admitted to our hospital for fever, associated with headache, nausea, and vomiting, and she rapidly developed mild left facial nerve palsy and diplopia. Neurological ...examination revealed mild meningitis associated with bilateral VI cranial nerve palsy and mild left facial palsy. As central nervous system (CNS) infection was suspected, a diagnostic lumbar puncture was performed, which revealed 1,677 cells/μl, 70% of which were
polymorphonuclear
leukocytes. Moreover, multiplex PCR immunoassay was positive for
Neisseria meningitidis
, supporting the diagnosis of bacterial meningitis. Finally, IgG oligoclonal bands (IgGOB) were absent in serum and cerebrospinal fluid (CSF). Therefore, ceftriaxone antibiotic therapy was started, and in the following days, the patient’s signs and symptoms improved, with complete remission of diplopia and meningeal signs within a week. On the contrary, left facial nerve palsy progressively worsened into a severe bilateral deficit. A second lumbar puncture was therefore performed: the CSF analysis revealed a remarkable decrease of pleocytosis with a qualitative modification (only lymphocytes), and oligoclonal IgG bands were present. A new brain MRI was performed, showing a bilateral gadolinium enhancement of the intrameatal VII and VIII cranial nerves bilaterally. Due to suspicion of para-infectious etiology, the patient was treated with oral steroid (prednisolone 1 mg/kg/day), with a progressive and complete regression of the symptoms. We suggest that in this case, after a pathogen-driven immunological response (characterized by relevant CSF mixed pleocytosis and no evidence of IgGOB), a para-infectious adaptive immunity-driven reaction (with mild lymphocyte pleocytosis and pattern III IgGOB) against VII and VIII cranial nerves started. Indeed, steroid administration caused a rapid and complete restoration of cranial nerve function.
Improved methods for detailed characterization of complex glycoproteins are required in the growing sector of biopharmaceuticals. Hydrophilic interaction liquid chromatography (HILIC) coupled to high ...resolution (HR) time-of-flight mass spectrometric (TOF-MS) detection was examined for the characterization of intact neo-glycoproteins prepared by chemical conjugation of synthetic saccharides to the lysine residues of selected recombinant proteins. The separation performances of three different amide HILIC columns (TSKgel Amide-80, XBridge BEH and AdvanceBio Glycan Mapping) were tested. Water-acetonitrile gradients and volatile eluent additives have been explored. Addition of 0.05% (v/v) trifluoroacetic acid to the mobile phase appeared to be essential for achieving optimum resolution of intact glycoforms and minimal ion suppression effects. Gradient elution conditions were optimized for each protein on every column. HILIC stationary phases were evaluated for the analysis of highly heterogeneous semi-synthetic derivatives of the same protein (ribonuclease A), and in the enhanced characterization of TB10.4 and Ag85B glycoconjugates, selected antigens from Mycobacterium tuberculosis (MTB). HILIC-MS results indicated that the HILIC selectivity is predominantly governed by size of the conjugated glycans and number of glycans attached, providing efficient glycoform separation. Moreover, HILIC separation prior to HRMS detection allowed assignment of several product impurities. Additional top-down MS/MS experiments confirmed conjugation at the N-terminus of TB10.4 next to its lysine residue. Overall, the obtained results demonstrate that amide-stationary-phase based HILIC coupled to MS is highly useful for the characterization of intact neo-glycoproteins allowing assessment of the number, identity and relative abundance of glycoforms present in the semi-synthetic products.
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•New potential glycoconjugate vaccines are characterized by HILIC-UV and HILIC-MS.•Amide HILIC stationary phases can provide efficient separation of intact protein glycoforms.•HILIC-MS allows reliable glycoform assignment of intact semi-synthetic glycoproteins.•Intact glycoform fragmentation in HILIC-MS/MS detects N-terminal glycosylation.
The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from
(
UP) and a purine nucleoside phosphorylase from
(
PNP), was ...re-designed under continuous-flow conditions. Glyoxyl-agarose and EziG
1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of
UP and
PNP, the results obtained pave the way to the use of the
UP/
PNP-based bioreactor for the preparation of other purine nucleosides.
Increasing evidence suggest that neuronal damage is an early and diffuse feature of Multiple Sclerosis (MS) pathology. Analysis of the optic pathway may help to clarify the mechanisms involved in ...grey matter damage in MS. Purpose of our study was to investigate the relationship between inflammation and neurodegeneration and to achieve evidence of trans-synaptic degeneration in the optic pathway in MS at clinical onset.
50 clinically isolated syndromes/early relapse-onset MS (CIS/eRRMS) with mean disease duration of 4.0±3.5 months, 28 MRI healthy controls (HC) and 31 OCT-HC were studied. Ten patients had optic neuritis at presentation (MSON+), 40 presented with other symptoms (MSON-). MRI examination included 3D-T1, 3D-FLAIR and 3D-DIR sequences. Global cortical thickness (gCTh), pericalcarin CTh (pCTh) and white matter volume (WMV) were analysed by means of Freesurfer on 3D-T1 scans. Optic radiation morphology (OR) and volume (ORV) were reconstructed on the base of the Jülich's Atlas. White matter lesion volume (WMLV), OR-WMLV and percent WM damage (WMLV/WMV = WMLV% and OR-WMLV/ORV = ORWMLV%) were obtained by 3D-FLAIR image segmentation. 3D-DIR sequences were applied to identify inflammatory lesions of the optic nerve. Optic coherence tomography (OCT) protocol included the analysis of global peripapillary retinal nerve fiber layer (g-RNFL) and the 6 fundus oculi's sectors (temporal, T-RNFL; temporal superior, TS-RNFL; nasal superior, NS-RNFL; nasal, N-RNFL; nasal inferior, NI-RNFL, temporal inferior, TI-RNFL). The retina of both eyes was analyzed. The eyes of ON+ were further divided into affected (aON+) or not (naON+).
No difference in CTh was found between CIS/eRRMS and HC, and between MSON+ and MSON-. Moreover, MSON+ and MSON- did not differ for any WM lesion load parameter. The most significant correlations between RNFL thickness and optic radiation WM pathology were found in MSON+. In these patients, the temporal RNFL inversely correlated to ipsilateral optic radiation WM lesion load (T-RNFL: r -0.7, p<0.05; TS-RNFL: r -0.7, p<0.05), while nasal RNFL inversely correlated to contralateral optic radiation WM lesion load (NI: r -0.8, p<0.01; NS-RNFL: r -0.8, p<0.01).
Our findings suggest that in MSON+ the optic pathway is site of a diffuse pathological process that involves both directly and via trans-synaptic degeneration the RNFL.
•New insights in application of polyHIPE materials to analytical sample treatment.•Application of CNT/polyHIPE composite as sorbent phase in biological matrix.•µSPE of trace fluoroquinolones in raw ...human urine prior to HPLC-MS/MS.•Proof-of-concept analysis of real-life urine samples.
Aim of this study stands in the evaluation of a carbon nanotubes-based polymerized high internal phase emulsion composite (CNT/polyHIPE) as sorptive phase in biological sample preparation. A micro-solid-phase extraction procedure (µSPE) was developed for trace fluoroquinolone (FQ) antimicrobials, namely Ciprofloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Norfloxacin and Sparfloxacin, in human urine samples. PolyHIPEs modified by incorporation of different concentrations of nanotubes (0.2–0.8 wt %) were one-pot synthesized and applied in the packed-cartridge setting. The sorption affinity for the drugs was investigated in tap water and buffered aqueous solutions, demonstrating the key role of the nanotubes embedded in the polymer. The 0.5 wt % CNT composite was selected to develop a straightforward µSPE procedure directly in raw urine (1 mL sample), followed by HPLC-MS/MS. Targets were retained on the sorbent at near neutral pH and, after an aqueous washing (0.1 % v/v formic acid), eluted in a single-step with 4 % v/v ammonia aqueous solution (15 % v/v acetonitrile), thus combining extraction and clean-up. The method allowed accurate quantification of FQs, as evidenced by the recoveries (74–116 %, n = 3) obtained on blank pooled urine samples spiked with 40, 75, 150 µg L−1, accompanied by good inter-day precision (RSD < 14 %, n = 3). To confirm the applicability of the analytical method, some real-life blind samples were processed as a proof of concept.
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