Treatment of hereditary amyotrophic lateral sclerosis.

Currently, only four molecules can be prescribed for amyotrophic lateral sclerosis (ALS), of which only one is approved worldwide for this indication, riluzole. Although progress in the therapeutic field remains unsatisfactory, we have to notice that genetics have undergone impressive improvements over the last three decades and, by extension, our knowledge of ALS cases linked to a pathogenic mutation that accounts for 10% of all cases (either sporadic or familiar) and is currently called hereditary ALS (hALS). In many neurological diseases treatment targeting pathogenic genes have significatively improved the natural profile of the disease: this is perfectly illustrated for familial amyloid neuropathy and spinal muscular atrophy. Because of these findings and the urgent need to find a cure for ALS, many trials have focused on familial ALS targeting the four most important genes linked to the disease: C9orf72, SOD1, TARDBP and FUS. We propose in this review an update on the perspectives of treatment that may be available in mid-term in hALS and will discuss in the last part the potential consequences for asymptomatic relatives of patients with a hALS and for ALS patients.

Loperamide exerts a direct bactericidal effect against M. tuberculosis, M. bovis, M. terrae and M. smegmatis.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis. TB is highly prevalent, characterized by the constant occurrence of drug-resistant cases, and confounded by the incidence of respiratory disease caused by non-tuberculous mycobacteria (NTB). Expanding the spectrum of drugs for the treatment of TB is indispensable. Loperamide, an antidiarrhoeal drug, enhances immune-driven antimycobacterial activity, and we aimed to evaluate its bactericidal activity against M. tuberculosis, Mycobacterium bovis BCG, Mycobacterium terrae and Mycobacterium smegmatis. Loperamide exhibited an inhibitory effect against all mycobacterial species tested, with MICs of 100 and 150 µg ml-1 . Thus, loperamide is a mycobactericidal drug with potential as adjunctive therapy for TB and NTB infections.

Therapeutic news in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by death of motor neurons in the cortex and the spinal cord. This loss of motor neurons causes progressive weakness and amyotrophy. To date, the median duration of survival in patients with ALS, from first symptoms to death, is estimated to be 36 months. Currently the treatment is limited to two options: riluzole which prolongs survival for a few months and edaravone which is available in only a few countries and also has a small impact on disease progression. There is an urgent need for more effective drugs in this disease to significantly improve progression. Over the last 30 years, all trials have failed to find a curative drug for ALS. This is due, partially, to the heterogeneity of the clinical features and the pathophysiology of motor neuron death. We present in this review the various treatment options currently being developed for ALS, with an emphasis on the range of therapeutic approaches being explored, from old drugs tested in a new indication to innovative drugs obtained via biotechnology or gene therapy.

Interventions for infantile haemangiomas of the skin: abridged Cochrane systematic review and GRADE assessments.

BACKGROUND: Infantile haemangiomas (IH) are soft swellings of the skin that occur in 3-10% of infants. When haemangiomas occur in high-risk areas or when complications develop, active intervention is necessary. OBJECTIVE: To update a Cochrane Review assessing the interventions for the management of IH in children. METHODS: We searched for randomized controlled trials in CENTRAL, MEDLINE, Embase, LILACS, AMED, PsycINFO, CINAHL and six trials registers up to February 2017. We included 28 trials (1728 participants) assessing 12 interventions. RESULTS: We downgraded evidence from high to moderate/low for issues related to risk of bias and imprecision. Oral propranolol (3 mg kg-1 daily) probably improves clinician-assessed clearance vs placebo [risk ratio (RR) 16·61, 95% confidence interval (CI) 4·22-65·34; moderate quality of evidence (QoE)]; we found no evidence of a difference in terms of serious adverse events (RR 1·05, 95% CI 0·33-3·39; low QoE). We found the chance of reduction of redness may be improved with topical timolol maleate (0·5% gel applied twice daily) when compared with placebo (RR 8·11, 95% CI 1·09-60·09; low QoE). We found no instances of bradycardia or hypotension for this comparison. CONCLUSIONS: Our key results indicate that oral propranolol and topical timolol maleate are more beneficial than placebo in terms of clearance or other measures of resolution, or both, without an increase in harm.

Staging amyotrophic lateral sclerosis: A new focus on progression.

Amyotrophic lateral sclerosis (ALS) is a heterogenous motoneuronal neurodegenerative condition with a panel of phenotypes exhibiting different clinical patterns. Two compounds are currently available for the treatment of ALS but the majority of trials have failed to show a positive effect on prognosis. One of the explanations which could be put forward involves the way efficacy is evaluated: clinicians agree that the ALSFRS-revised scale used in all trials does not fit with highlighting a positive effect. So, the development and validation of new tools allowing a reliable assessment of ALS has become a key issue in clinical research. Over the last three years, two functional scales (the King's College and MiToS staging systems) have been proposed. These scales rely on two different approaches to ALS: an anatomical and prognostic concept, and loss of autonomy. Both scales propose five stages. We will discuss below the contribution of these two scales to clinical evaluation and the questions which remain to be resolved in the future.

Genetics of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by upper and lower motor neuron damage in the bulbar and spinal territories. Although the pathophysiology of ALS is still unknown, the involvement of genetic factors is no longer a subject of debate. Familial ALS (fALS) accounts for 10-20% of cases. Since the identification of the SOD1 gene, more than 20 genes have been described, of which four can explain >50% of familial cases. This review is an update focused on major aspects of the field of ALS genetics concerning both causative and susceptibility factors.

Diagnosis and optimization of WWTPs using the PWM library: full-scale experiences.

Given the shift in perception of wastewater treatment plants as water resource recovery facilities, conventional mathematical models need to be updated. The resource recovery perspective should be applied to new processes, technologies and plant layouts. The number and level of models proposed to date give an overview of the complexity of the new plant configurations and provides a wide range of possibilities and process combinations in order to construct plant layouts. This diversity makes the development of standard, modular and flexible tools and model libraries that allow the incorporation of new processes and components in a straightforward way a necessity. In this regard, the plant-wide modelling (PWM) library is a complete model library that includes conventional and advanced technologies and that allows economic and energetic analyses to be carried out in a holistic way. This paper shows the fundamentals of this PWM library that is built upon the above-mentioned premises and the application of the PWM library in three different full-scale case studies.

Biomarkers in amyotrophic lateral sclerosis: combining metabolomic and clinical parameters to define disease progression.

BACKGROUND AND PURPOSE: The objectives of this study were to define the metabolomic profile of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS) patients, to model outcome through combined clinical and metabolomic parameters and independently to validate predictive models. METHODS: In all, 74 consecutive newly diagnosed patients were enrolled into training (Tr, n = 49) and test (Te, n = 25) cohorts. Investigators recorded clinical data and the metabalomic profile of cerebrospinal fluid at baseline was analyzed with (1)H nuclear magnetic resonance spectroscopy. Markers of disease progression, collected in 1-year prospective follow-up, included change in ALS Functional Rating Scale (var_ALSFRS), change in weight (var_weight) and survival time. Stepwise multiple regression selected from metabolomic and clinical parameters to model rate of progression in the Tr cohort. Best fit models were validated independently in the Te cohort. RESULTS: The best-fit statistical models, using both metabolomic and clinical covariates, predicted outcome with 70.8% (var_weight), 72% (var_ALSFRS) and 76% (survival) accuracy in the Te cohort. Models that used metabolomics or clinical data alone predicted outcome less well. Highlighted metabolites are involved in pathophysiological pathways previously described in ALS. CONCLUSION: Cerebrospinal fluid metabolomics can aid in predicting the clinical course of ALS and tap into pathophysiological processes. The precision of predictive models, independently reproduced in this study, is enhanced through inclusion of both metabolomic and clinical parameters. The findings bring the field closer to a clinically meaningful disease marker.

Ultraviolet and extreme ultraviolet spectroscopy of the solar corona at the Naval Research Laboratory.

We review the history of ultraviolet and extreme ultraviolet spectroscopy with a specific focus on such activities at the Naval Research Laboratory and on studies of the extended solar corona and solar-wind source regions. We describe the problem of forecasting solar energetic particle events and discuss an observational technique designed to solve this problem by detecting supra-thermal seed particles as extended wings on spectral lines. Such seed particles are believed to be a necessary prerequisite for particle acceleration by heliospheric shock waves driven by a coronal mass ejection.

Lessons learnt from the application of a multi-variable controller for nitrogen removal in the Mekolalde wastewater treatment plant: good simulation practices in control.

Although often perceived as tools for use by scientists, mathematical modelling and simulation become indispensable when control engineers have to design controllers for real-life wastewater treatment plants (WWTPs). Nonetheless, the design of effective controllers in the wastewater domain using simulations requires effects, such as the nonlinearity of actuators, the time response of sensors, plant model uncertainties, etc. to have been reproduced beforehand. Otherwise, control solutions verified by simulation can completely underperform under real conditions. This study demonstrates that, when all the above effects are included at the outset, a systematic use of simulations guarantees high quality controllers in a relatively short period of time. The above is exemplified through the Mekolalde WWTP, where a comprehensive simulation study was conducted in order to develop a control product for nitrogen removal. Since its activation in May 2011, the designed controller has been permanently working in the plant which, from this time onwards, has experienced significant improvements in the quality of water discharges combined with a lower utilization of electricity for wastewater treatment.

Degradation kinetics of sugars (glucose and xylose), amino acids (proline and aspartic acid) and their binary mixtures in subcritical water: Effect of Maillard reaction.

A systematic kinetic study was conducted in subcritical water medium in the temperature range from 150 to 200 °C for pure glucose, xylose, proline and aspartic acid as well as binary mixtures of sugars + amino acids to understand the reaction kinetics and interactions among biomass components and to discern the influence of Maillard reaction (MR) on the overall reaction kinetics. The main degradation products identified for glucose and xylose were the respective dehydration products, hydroxymethyl furfural and furfural, yielding an increasing solid residue with temperature (15.9 wt% at 200 °C) with an augmented heating value. The degradation of sugars and amino acids in binary systems was faster compared to pure compounds due to MR and the production of dehydration products was delayed when considering total sugar conversion. Higher relative reactivity in MR was observed for xylose over glucose showing also higher antioxidant activity.

Association between CD4 lymphocyte count and the incidence of comorbidities in Human immunodeficiency virus positive patients with virological suppression after antiretroviral treatment.

BACKGROUND: The incidence of comorbidities is higher in HIV-positive patients than in the general population due to factors, such as HIV-related chronic inflammation. There is no consensus on whether a low CD4 lymphocyte count after virological suppression at long-term follow-up increases the risk of comorbidities. This study evaluates the association between CD4 lymphocyte count and the incidence of comorbidities during the first 5 years of virological suppression after highly active antiretroviral treatment. METHODS: We conducted a cohort study of HIV-positive adults who achieved virological suppression in an HIV program between 2002 and 2016 in Colombia. A generalized equation estimation model was used to estimate the association between CD4 lymphocyte count and the incidence of comorbidities. RESULTS: A follow-up period of at least 1 year was completed in 921 HIV-positive patients with virological suppression. We found 71 comorbidities during a maximum of 5 years of follow-up; 41 (59%) were AIDS-defining comorbidities and 19 (46%) of them occurred during the first semester. Thirty cases of non-AIDS- defining comorbidities were diagnosed.We did not find any association between CD4 lymphocyte count and the incidence of comorbidities (OR 0.92, CI 95% 0.45 -1.91 for CD4 201-499 cells/µL vs CD4 ≤200 cells/µL, and OR 0.55, 95% CI 0.21-1.44 for CD4 ≥500 cells/µL vs CD4 ≤200 cells/µL). CONCLUSION: No association was found between CD4 lymphocyte count and the incidence of AIDS-defining or non-AIDS-defining comorbidities in patients with virological suppression. Further studies are needed to assess the risk of comorbidities in this population to design interventions aimed at improving their prognosis.

Do parasites adopt different strategies in different intermediate hosts? Host size, not host species, influences Coitocaecum parvum (Trematoda) life history strategy, size and egg production.

Host exploitation induces host defence responses and competition between parasites, resulting in individual parasites facing highly variable environments. Alternative life strategies may thus be expressed in context-dependent ways, depending on which host species is used and intra-host competition between parasites. Coitocaecum parvum (Trematode) can use facultative progenesis in amphipod intermediate hosts, Paracalliope fluviatilis, to abbreviate its life cycle in response to such environmental factors. Coitocaecum parvum also uses another amphipod host, Paracorophium excavatum, a species widely different in size and ecology from P. fluviatilis. In this study, parasite infection levels and strategies in the two amphipod species were compared to determine whether the adoption of progenesis by C. parvum varied between these two hosts. Potential differences in size and/or egg production between C. parvum individuals according to amphipod host species were also investigated. Results show that C. parvum life strategy was not influenced by host species. In contrast, host size significantly affected C. parvum strategy, size and egg production. Since intra-host interactions between co-infecting parasites also influenced C. parvum strategy, size and fecundity, it is highly likely that within-host resource limitations affect C. parvum life strategy and overall fitness regardless of host species.

Vertebrate host protective immunity drives genetic diversity and antigenic polymorphism in Schistosoma mansoni.

Schistosomes are gonochoric blood parasites with a complex life cycle responsible for a disease of considerable medical and veterinary importance in tropical and subtropical regions. Understanding the evolution of schistosome genetic diversity is clearly of fundamental importance to interpreting schistosomiasis epidemiology and disease transmission patterns of this parasite. In this article, we investigated the putative role of the host immune system in the selection of male genetic diversity. We demonstrated the link between genetic dissimilarity and the protective effect among male worms. We then compared the proteomes of three male clones with different genotypes and differing by their capacity to protect against reinfection. The identified differences correspond mainly to antigens known or supposed to be involved in the induction of protective immunity. These results underline the role played by host immune system in the selection of schistosome genetic diversity that is linked to antigenic diversity. We discuss the evolutionary consequences in the context of schistosome infection.

Automatic characterisation of primary, secondary and mixed sludge inflow in terms of the mathematical generalised sludge digester model.

This paper presents the characterisation procedure of different types of sludge generated in a wastewater treatment plant to be reproduced in a mathematical model of the sludge digestion process. The automatic calibration method used is based on an optimisation problem and uses a set of mathematical equations related to the a priori knowledge of the sludge composition, the experimental measurements applied to the real sludge, and the definition of the model components. In this work, the potential of the characterisation methodology is shown by means of a real example, taking into account that sludge is a very complex matter to characterise and that the models for digestion also have a considerable number of model components. The results obtained suit both the previously reported characteristics of the primary, secondary and mixed sludge, and the experimental measurements specially done for this work. These three types of sludge have been successfully characterised to be used in complex mathematical models.