Influence of the LILRA3 Deletion on Multiple Sclerosis Risk: Original Data and Meta-Analysis.

BACKGROUND Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. OBJECTIVES In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. RESULTS AND CONCLUSION Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95-1.19)], even after stratification by gender and the HLA-DRB1*15:01 risk allele.

Probabilistic models to assist maintenance of multiple instruments

The paper discusses maintenance challenges of organisations with a huge number of devices and proposes the use of probabilistic models to assist monitoring and maintenance planning. The proposal assumes connectivity of instruments to report relevant features for monitoring. Also, the existence of enough historical registers with diagnosed breakdowns is required to make probabilistic models reliable and useful for predictive maintenance strategies based on them. Regular Markov models based on estimated failure and repair rates are proposed to calculate the availability of the instruments and Dynamic Bayesian Networks are proposed to model cause-effect relationships to trigger predictive maintenance services based on the influence between observed features and previously documented diagnostics

Ross procedure: is the root replacement technique superior to the sub-coronary implantation technique? Long-term results.

There is controversy over the use of the Ross procedure with regard to the sub-coronary and root replacement technique and its long-term durability. A systematic review of the literature may provide insight into the outcomes of these two surgical subvariants. A systematic review of reports between 1967 and February 2013 on sub-coronary and root replacement Ross procedures was undertaken. Twenty-four articles were included and divided into (i) sub-coronary technique and (ii) root replacement technique. The 10-year survival rate for a mixed-patient population in the sub-coronary procedure was 87.3% with a 95% confidence interval (CI) of 79.7-93.4 and 89.1% (95% CI, 85.3-92.1) in the root replacement technique category. For adults, it was 94 vs 95.3% (CI, 88.9-98.1) and in the paediatric series it was 90 vs 92.7% (CI, 86.9-96.0), respectively. Freedom from reoperation at 10 years was, in the mixed population, 83.3% (95% CI, 69.9-93.4) and 93.3% (95% CI, 89.4-95.9) for sub-coronary versus root replacement technique, respectively. In adults, it was 98 vs 91.2% (95% CI, 82.4-295.8), and in the paediatric series 93.3 vs 92.0% (95% CI, 86.1-96.5) for sub-coronary versus root replacement technique, respectively. The Ross procedure arguably has satisfactory results over 5 and 10 years for both adults and children. The results do not support the advantages of the sub-coronary technique over the root replacement technique. Root replacement was of benefit to patients undergoing reoperations on neoaorta and for long-term survival in mixed series.

Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study.

BACKGROUND: Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy (PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment. METHODS: We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay. The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment. FINDINGS: We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta. INTERPRETATION: Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation. FUNDING: Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.

Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers.

MRI tractography is the mapping of neural fiber pathways based on diffusion MRI of tissue diffusion anisotropy. Tractography based on diffusion tensor imaging (DTI) cannot directly image multiple fiber orientations within a single voxel. To address this limitation, diffusion spectrum MRI (DSI) and related methods were developed to image complex distributions of intravoxel fiber orientation. Here we demonstrate that tractography based on DSI has the capacity to image crossing fibers in neural tissue. DSI was performed in formalin-fixed brains of adult macaque and in the brains of healthy human subjects. Fiber tract solutions were constructed by a streamline procedure, following directions of maximum diffusion at every point, and analyzed in an interactive visualization environment (TrackVis). We report that DSI tractography accurately shows the known anatomic fiber crossings in optic chiasm, centrum semiovale, and brainstem; fiber intersections in gray matter, including cerebellar folia and the caudate nucleus; and radial fiber architecture in cerebral cortex. In contrast, none of these examples of fiber crossing and complex structure was identified by DTI analysis of the same data sets. These findings indicate that DSI tractography is able to image crossing fibers in neural tissue, an essential step toward non-invasive imaging of connectional neuroanatomy.

Networks in Argentine agriculture: a multiple-case study approach

Argentina is among the four largest producers of soybeans, sunflower, corn, and wheat, among other agricultural products. Institutional and policy changes during the 1990s fostered the development of Argentine agriculture and the introduction of innovative process and product technologies (no-till, agrochemicals, GMO, GPS) and new investments in modern, large-scale sunflower and soybean processing plants. In addition to technological changes, a "quiet revolution" occurred in the way agricultural production was carried out and organized: from self-production or ownership agriculture to a contract-based agriculture. The objective of this paper is to explore and describe the emergence of networks in the Argentine crop production sector. The paper presents and describes four cases that currently represent about 50% of total grain and oilseed production in Argentina: "informal hybrid form", "agricultural trust fund", "investor-oriented corporate structure", and "network of networks". In all cases, hybrid forms involve a group of actors linked by common objectives, mainly to gain scale, share resources, and improve the profitability of the business. Informal contracts seem to be the most common way of organizing the agriculture process, but using short-term contracts and sequential interfirm collaboration. Networks of networks involve long-term relationships and social development, and reciprocal interfirm collaboration. Agricultural trust fund and investor-oriented corporate structures have combined interfirm collaboration and medium-term relationships. These organizational forms are highly flexible and show a great capacity to adapt to challenges; they are competitive because they enjoy aligned incentives, flexibility, and adaptability.

Effectiveness of glatiramer acetate compared to other multiple sclerosis therapies.

OBJECTIVE To assess the effectiveness of glatiramer acetate (GA) compared to other multiple sclerosis (MS) therapies in routine clinical practice. MATERIALS AND METHODS Observational cohort study carried out in MS patients treated with GA (GA cohort) or other MS therapies -switched from GA- (non-GA cohort). Study data were obtained through review of our MS patient database. The primary endpoint was the Expanded Disability Status Scale (EDSS) scores reached at the end of treatment/last check-up. RESULTS A total of 180 patients were included: GA cohort n = 120, non-GA cohort n = 60. Patients in the GA cohort showed better EDSS scores at the end of treatment/last check-up (mean ± SD, 2.8 ± 1.8 vs. 3.9 ± 2.2; P = 0.001) and were 1.65 times more likely to show better EDSS scores compared to the non-GA cohort (odds ratio, 0.606; 95%CI, 0.436-0.843; P = 0.003). Patients in the GA cohort showed longer mean time to reach EDSS scores of 6 (209.1 [95%CI, 187.6-230.6] vs. 164.3 [95% CI, 137.0-191.6] months; P = 0.004) and slower disability progression (hazard ratio, 0.415 [95%CI, 0.286-0.603]; P < 0.001). The annualized relapse rate was lower in the GA cohort (mean ± SD, 0.5 ± 0.5 vs. 0.8 ± 0.5; P = 0.001) and patients' quality of life was improved in this study cohort compared to the non-GA cohort (mean ± SD, 0.7 ± 0.1 vs. 0.6 ± 0.2; P = 0.01). CONCLUSIONS GA may slow down the progression of EDSS scores to a greater extent than other MS therapies, as well as achieving a greater reduction in relapses and a greater improvement in patients' quality of life. Switching from GA to other MS therapies has not proved to entail a better response to treatment.

Concentrations of the enantiomers of fluoxetine and norfluoxetine after multiple doses of fluoxetine in cytochrome P4502D6 poor and extensive metabolizers.

Plasma concentrations of the enantiomers of fluoxetine (FLX) and norfluoxetine (NFLX) were measured at days 7, 14, and 23 of oral administration of 20 mg of racemic fluoxetine in 11 patients who were comedicated with risperidone. Eight patients were genotyped as being cytochrome P4502D6 extensive metabolizers (EMs) and three as cytochrome P4502D6 poor metabolizers (PMs). No statistically significant differences were calculated between EMs and PMs in the concentrations of (R)-FLX and (R)-NFLX for all days examined (day 23, mean +/- SD for (R)-FLX and (R)-NFLX in EMs, 16 +/- 5 and 29 +/- 20 ng/mL, respectively; in PMs, 16 +/- 1 and 20 +/- 2 ng/mL, respectively). However, concentrations of (S)-FLX and (S)-NFLX were higher and lower, respectively, in PMs as compared with EMs (day 7, p = 0.037 and p = 0.036; day 14, p = 0.014 and p = 0.014; day 23, p = 0.068 and p = 0.038). On day 23, mean (S)-FLX and (S)-NFLX in EMs were (mean +/- SD) 39 +/- 26 and 63 +/- 26 ng/mL, and in PMs they were 88 +/- 7 and 19 +/- 2 ng/mL. This study confirms the results of the single-dose studies showing that CYP2D6 is involved in the demethylation of FLX to NFLX, with a stereoselectivity toward the (S)-enantiomer. The data also clearly show that the CYP2D6 genotype has an important influence on the concentrations of the (S)- but not of the (R)-enantiomer of FLX and NFLX after multiple doses.

Health-related quality of life assessment in people with multiple sclerosis and their family caregivers. A multicenter study in Catalonia (Southern Europe)

Objectives: To measure the health-related quality of life (HRQoL) of multiple sclerosis (MS) patients and their caregivers, and to assess which factors can best describe HRQoL. Methods: A cross-sectional multicenter study of nine hospitals enrolled MS patients and their caregivers who attended outpatient clinics consecutively. The instruments used were the SF-36 for patients and the SF-12 and GHQ-12 for caregivers. Classification and regression tree analysis was used to analyze the explanatory factors of HRQoL. Results: A total of 705 patients (mean age 40.4 years, median Expanded Disability Status Scale 2.5, 77.8% with relapsing-remitting MS) and 551 caregivers (mean age 45.4 years) participated in the study. MS patients had significantly lower HRQoL than in the general population (physical SF-36: 39.9; 95% confidence interval [CI]: 39.1–40.6; mental SF-36: 44.4; 95% CI: 43.5–45.3). Caregivers also presented lower HRQoL than general population, especially in its mental domain (mental SF-12: 46.4; 95% CI: 45.5–47.3). Moreover, according to GHQ-12, 27% of caregivers presented probable psychological distress. Disability and co-morbidity in patients, and co-morbidity and employment status in caregivers, were the most important explanatory factors of their HRQoL. Conclusions: Not only the HRQoL of patients with MS, but also that of their caregivers, is indeed notably affected. Caregivers’ HRQoL is close to population of chronic illness even that the patients sample has a mild clinical severity and that caregiving role is a usual task in the study context

Metacognitive training for adolescents with psychosis: A multiple case study

Cognitive biases may be one of the explaining factor underlying psychotic symptoms like delusions and hallucinations. Metacognitive training (MCT) was demonstrated, in adults with schizophrenia, to reduce these cognitive biases. However, to the best of our knowledge, there has been no research on adolescents with psychosis. The current study aimed at assessing the feasibility, treatment adherence and its benefi cial effects on psychotic symptoms, depression, social functioning and self-esteem of a MCT. Participants were fi ve psychotic adolescents with psychosis, aged 16-18, who attended the Day Care Unit for Adolescents (DCUA). The MCT, delivered in group, corresponds to 2x8 modules, lasting between 45 and 60 minutes once a week. To measure MCT's effi ciency, the Positive And Negative Syndrome Scale (PANSS), the Social and Occupational Functioning Assessment Scale (SOFAS), the Health of Nation Outcome Scale for Children and Adolescent (HoNOSCA), the depression scale of Calgary and the self-esteem scale of Rosenberg have been used. The results of the 5 patients indicate that MCT is feasible and the treatment adherence is moderate. The schedule of the MCT needs to be adapted to the availability of the participants. At a descriptive level, the MCT allows to reduce psychotic and depressive symptoms (PANSS & Calgary) as well as to improve the social functioning (SOFAS & HoNOSCA) and self-esteem (Rosenberg). To sum up, MCT seem to be an interesting alternative and/or a good additional treatment to reduce cognitive bias, psychotic symptoms as well as improving social functioning

Functional calibration procedure for 3D knee joint angle description using inertial sensors.

Measurement of three-dimensional (3D) knee joint angle outside a laboratory is of benefit in clinical examination and therapeutic treatment comparison. Although several motion capture devices exist, there is a need for an ambulatory system that could be used in routine practice. Up-to-date, inertial measurement units (IMUs) have proven to be suitable for unconstrained measurement of knee joint differential orientation. Nevertheless, this differential orientation should be converted into three reliable and clinically interpretable angles. Thus, the aim of this study was to propose a new calibration procedure adapted for the joint coordinate system (JCS), which required only IMUs data. The repeatability of the calibration procedure, as well as the errors in the measurement of 3D knee angle during gait in comparison to a reference system were assessed on eight healthy subjects. The new procedure relying on active and passive movements reported a high repeatability of the mean values (offset<1 degrees) and angular patterns (SD<0.3 degrees and CMC>0.9). In comparison to the reference system, this functional procedure showed high precision (SD<2 degrees and CC>0.75) and moderate accuracy (between 4.0 degrees and 8.1 degrees) for the three knee angle. The combination of the inertial-based system with the functional calibration procedure proposed here resulted in a promising tool for the measurement of 3D knee joint angle. Moreover, this method could be adapted to measure other complex joint, such as ankle or elbow.

NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?

The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that activates caspase 1, leading to the processing and secretion of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and IL-18. The NLRP3 inflammasome is activated by a wide range of danger signals that derive not only from microorganisms but also from metabolic dysregulation. It is unclear how these highly varied stress signals can be detected by a single inflammasome. In this Opinion article, we review the different signalling pathways that have been proposed to engage the NLRP3 inflammasome and suggest a model in which one of the crucial elements for NLRP3 activation is the generation of reactive oxygen species (ROS).

131I/123I-metaiodobenzylguanidine (mIBG) scintigraphy: procedure guidelines for tumour imaging.

The aim of this document is to provide general information about mIBG scintigraphy in cancer patients. The guidelines describe the mIBG scintigraphy protocol currently used in clinical routine, but do not include all existing procedures for neuroendocrine tumours. The guidelines should therefore not be taken as exclusive of other nuclear medicine modalities that can be used to obtain comparable results. It is important to remember that the resources and facilities available for patient care may vary from one country to another and from one medical institution to another. The present guidelines have been prepared for nuclear medicine physicians and intend to offer assistance in optimizing the diagnostic information that can currently be obtained from mIBG scintigraphy. The corresponding guidelines of the Society of Nuclear Medicine (SNM) and the Dosimetry, Therapy and Paediatric Committee of the EANM have been taken into consideration, and partially integrated into this text. The same has been done with the most relevant literature on this topic, and the final result has been discussed within a group of distinguished experts.