Insulin modulates emotional behavior through a serotonin-dependent mechanism.

Type-2 Diabetes (T2D) is characterized by insulin resistance and accompanied by psychiatric comorbidities including major depressive disorders (MDD). Patients with T2D are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance is positively correlated with the severity of depressive symptoms. However, the potential contribution of central insulin signaling in MDD in patients with T2D remains elusive. Here we hypothesized that insulin modulates the serotonergic (5-HT) system to control emotional behavior and that insulin resistance in 5-HT neurons contributes to the development of mood disorders in T2D. Our results show that insulin directly modulates the activity of dorsal raphe (DR) 5-HT neurons to dampen 5-HT neurotransmission through a 5-HT1A receptor-mediated inhibitory feedback. In addition, insulin-induced 5-HT neuromodulation is necessary to promote anxiolytic-like effect in response to intranasal insulin delivery. Interestingly, such an anxiolytic effect of intranasal insulin as well as the response of DR 5-HT neurons to insulin are both blunted in high-fat diet-fed T2D animals. Altogether, these findings point to a novel mechanism by which insulin directly modulates the activity of DR 5-HT neurons to dampen 5-HT neurotransmission and control emotional behaviors, and emphasize the idea that impaired insulin-sensitivity in these neurons is critical for the development of T2D-associated mood disorders.

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids.

Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.SIGNIFICANCE STATEMENT Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.

[Architecture as experience, living differently with the philosophy of John Dewey]. / L'architecture comme expérience, habiter autrement avec la philosophie de John Dewey.

If architecture can be considered an art form, it is at the cost of reconfiguring what we consider to be an aesthetic experience. Thus conceived as processes, not finished objects, refuting the separation between the active creator and the passive spectator and between ideas, actions and affects, the architectural projects accompanied and documented by the urban and architectural experiments laboratory la Preuve par 7 engage a collective, experimental, sensitive and political understanding of their discipline.

Numerical simulations of granular dam break: Comparison between discrete element, Navier-Stokes, and thin-layer models.

Granular flows occur in various contexts, including laboratory experiments, industrial processes, and natural geophysical flows. To investigate their dynamics, different kinds of physically based models have been developed. These models can be characterized by the length scale at which dynamic processes are described. Discrete models use a microscopic scale to individually model each grain, Navier-Stokes models use a mesoscopic scale to consider elementary volumes of grains, and thin-layer models use a macroscopic scale to model the dynamics of elementary columns of fluids. In each case, the derivation of the associated equations is well-known. However, few studies focus on the extent to which these modeling solutions yield mutually coherent results. In this article, we compare the simulations of a granular dam break on a horizontal or inclined planes for the discrete model convex optimization contact dynamics (COCD), the Navier-Stokes model Basilisk, and the thin-layer depth-averaged model SHALTOP. We show that, although all three models allow reproducing the temporal evolution of the free surface in the horizontal case (except for SHALTOP at the initiation), the modeled flow dynamics are significantly different, and, in particular, during the stopping phase. The stresses measured at the flow's bottom, reflecting the flow dynamics, are in relatively good agreement, but significant variations are obtained with the COCD model due to complex and fast-varying granular lattices. Similar conclusions are drawn using the same rheological parameters to model a granular dam break on an inclined plane. This comparison exercise is essential for assessing the limits and uncertainties of granular flow modeling.

Serotonergic neurons are involved in the counter-regulatory response to hypoglycemia.

OBJECTIVES: Intensive insulin therapy provides optimal glycemic control in patients with diabetes. However, intensive insulin therapy causes so-called iatrogenic hypoglycemia as a major adverse effect. The ventromedial hypothalamus (VMH) has been described as the primary brain area initiating the counter-regulatory response (CRR). Nevertheless, the VMH receives projections from other brain areas which could participate in the regulation of the CRR. In particular, studies suggest a potential role of the serotonin (5-HT) network. Thus, the objective of this study was to determine the contribution of 5-HT neurons in CRR control. METHODS: Complementary approaches have been used to test this hypothesis in quantifying the level of 5-HT in several brain areas by HPLC in response to insulin-induced hypoglycemia, measuring the electrical activity of dorsal raphe (DR) 5-HT neurons in response to insulin or decreased glucose level by patch-clamp electrophysiology; and measuring the CRR hormone glucagon as an index of the CRR to the modulation of the activity of 5-HT neurons using pharmacological or pharmacogenetic approaches. RESULTS: HPLC measurements show that the 5HIAA/5HT ratio is increased in several brain regions including the VMH in response to insulin-induced hypoglycemia. Patch-clamp electrophysiological recordings show that insulin, but not decreased glucose level, increases the firing frequency of DR 5-HT neurons in the DR. In vivo, both the pharmacological inhibition of 5-HT neurons by intraperitoneal injection of the 5-HT1A receptor agonist 8-OH-DPAT or the chemogenetic inhibition of these neurons reduce glucagon secretion, suggesting an impaired CRR. CONCLUSION: Taken together, these data highlight a new neuronal network involved in the regulation of the CRR. In particular, this study shows that DR 5-HT neurons detect iatrogenic hypoglycemia in response to the increased insulin level and may play an important role in the regulation of CRR.

Exploratory Study on Application of MALDI-TOF-MS to Detect SARS-CoV-2 Infection in Human Saliva.

SARS-CoV-2 has caused a large outbreak since its emergence in December 2019. COVID-19 diagnosis became a priority so as to isolate and treat infected individuals in order to break the contamination chain. Currently, the reference test for COVID-19 diagnosis is the molecular detection (RT-qPCR) of the virus from nasopharyngeal swab (NPS) samples. Although this sensitive and specific test remains the gold standard, it has several limitations, such as the invasive collection method, the relative high cost and the duration of the test. Moreover, the material shortage to perform tests due to the discrepancy between the high demand for tests and the production capacities puts additional constraints on RT-qPCR. Here, we propose a PCR-free method for diagnosing SARS-CoV-2 based on matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling and machine learning (ML) models from salivary samples. Kinetic saliva samples were collected at enrollment and ten and thirty days later (D0, D10 and D30), to assess the classification performance of the ML models compared to the molecular tests performed on NPS specimens. Spectra were generated using an optimized protocol of saliva collection and successive quality control steps were developed to ensure the reliability of spectra. A total of 360 averaged spectra were included in the study. At D0, the comparison of MS spectra from SARS-CoV-2 positive patients (n = 105) with healthy healthcare controls (n = 51) revealed nine peaks that significantly distinguished the two groups. Among the five ML models tested, support vector machine with linear kernel (SVM-LK) provided the best performance on the training dataset (accuracy = 85.2%, sensitivity = 85.1%, specificity = 85.3%, F1-Score = 85.1%). The application of the SVM-LK model on independent datasets confirmed its performances with 88.9% and 80.8% of correct classification for samples collected at D0 and D30, respectively. Conversely, at D10, the proportion of correct classification had fallen to 64.3%. The analysis of saliva samples by MALDI-TOF MS and ML appears as an interesting supplementary tool for COVID-19 diagnosis, despite the mitigated results obtained for convalescent patients (D10).

Switch of serotonergic descending inhibition into facilitation by a spinal chloride imbalance in neuropathic pain.

Descending control from the brain to the spinal cord shapes our pain experience, ranging from powerful analgesia to extreme sensitivity. Increasing evidence from both preclinical and clinical studies points to an imbalance toward descending facilitation as a substrate of pathological pain, but the underlying mechanisms remain unknown. We used an optogenetic approach to manipulate serotonin (5-HT) neurons of the nucleus raphe magnus that project to the dorsal horn of the spinal cord. We found that 5-HT neurons exert an analgesic action in naïve mice that becomes proalgesic in an experimental model of neuropathic pain. We show that spinal KCC2 hypofunction turns this descending inhibitory control into paradoxical facilitation; KCC2 enhancers restored 5-HT-mediated descending inhibition and analgesia. Last, combining selective serotonin reuptake inhibitors (SSRIs) with a KCC2 enhancer yields effective analgesia against nerve injury-induced pain hypersensitivity. This uncovers a previously unidentified therapeutic path for SSRIs against neuropathic pain.

Early predictive risk factors for dimethyl fumarate-associated lymphopenia in patients with multiple sclerosis.

BACKGROUND: Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. A pronounced reduction in absolute lymphocyte counts (ALCs) early after treatment initiation has been suggested to be associated with the occurrence of lymphopenia thereafter. OBJECTIVES: To identify risk factors for DMF-induced lymphopenia and evaluate whether the degree of decrease in the ALCs three months after initiation of DMF treatment is a predictor of the subsequent development of lymphopenia. METHODS: In this real-world Spanish prospective multicenter study conducted in MS patients who started DMF between 2014 and 2019, we analyzed the association between DMF-related lymphopenia and the percentage of early ALCs decline using regression models, considering both, significant lymphopenia (grades 2 + 3) and severe lymphopenia (grade 3). The cutoff values of early ALCs declines were obtained using the ROC curve. RESULTS: Among 532 MS patients treated with DMF, 193 (36.3%) developed any grade of lymphopenia. Older age and lower ALCs at treatment onset predicted the risk for lymphopenia but the best predictive risk factor was the reduction of ALCs within the three first months of treatment. Specifically, a reduction in ALCs≥21.2% was associated with a 6.5-fold higher risk of developing significant lymphopenia, and a decrease in ALCs≥40.2% with a 12.7-fold higher risk of developing severe lymphopenia. CONCLUSIONS: A pronounced reduction in ALCs early after initiation of DMF in MS patients is the best predictive risk factor for the subsequent development of significant lymphopenia.

The impact of insulin on the serotonergic system and consequences on diabetes-associated mood disorders.

The idea that insulin could influence emotional behaviours has long been suggested. However, the underlying mechanisms have yet to be solved and there is no direct and clear-cut evidence demonstrating that such action involves brain serotonergic neurones. Indeed, initial arguments in favour of the association between insulin, serotonin and mood arise from clinical or animal studies showing that impaired insulin action in type 1 or type 2 diabetes causes anxiety- and depressive symptoms along with blunted plasma and brain serotonin levels. The present review synthesises the main mechanistic hypotheses that might explain the comorbidity between diabetes and depression. It also provides a state of knowledge of the direct and indirect experimental evidence that insulin modulates brain serotonergic neurones. Finally, it highlights the literature suggesting that antidiabetic drugs present antidepressant-like effects and, conversely, that serotonergic antidepressants impact glucose homeostasis. Overall, this review provides mechanistic insights into how insulin signalling alters serotonergic neurotransmission and related behaviours bringing new targets for therapeutic options.

Telomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae.

BACKGROUND: Telomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known. RESULTS: Here, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states. CONCLUSIONS: Replicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand.

Efficacy of non-invasive intelligent volume assured pressure support (iVAPS) and pressure support ventilation (PSV) in clinical practice.

AIMS OF THE STUDY: Noninvasive ventilation (NIV) is a well-established treatment option for hypercapnic respiratory failure; however, the best mode of ventilation remains unknown. The aim of this retrospective study was to compare patients’ adherence to NIV using either pressure support ventilation (PSV) or intelligent volume-assured pressure support (iVAPS). PATIENTS AND METHODS: In this retrospective cohort study, we assessed in- and outpatients suffering from hypercapnic respiratory failure of various aetiologies (chronic obstructive pulmonary disease [COPD], obese COPD [body mass index >30 kg/m2], obesity hypoventilation syndrome and other diseases such as amyotrophic lateral sclerosis or interstitial lung disease) after NIV initiation with PSV or iVAPS. Adherence to treatment was compared between these modes using the Wilcoxon test. Within-group differences were tested using linear regression models. Mortality and emergency hospital readmission rates were modelled using Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: Adherence to treatment was similar in both groups throughout the observation period – after 6 weeks: PSV 363 min/night (interquartile range [IQR] 200–448), iVAPS 369 min/night (IQR 310–468) (p = 0.619); after 1 year: PSV 423 (323–500), iVAPS 429 (298–475) (p = 0.901); at the last follow up: PSV 481 (395–586), iVAPS 426 (391–565) (p = 0.284). NIV reduced PaCO2 significantly compared with baseline at all follow-ups: PSV −1.29/−1.49/−1.49 kPa, iVAPS −1.47/−1.23/−1.24 kPa, p <0.001 each, PSV vs iVAPS: p = 0.250, 0.756 and 0.352, respectively. Median survival time (PSV 5.06 years, iVAPS median not reached; p = 0.800) and time to first readmission (PSV 3.6 years, iVAPS 7.33 years, p = 0.200) did not differ between groups. Obese COPD patients had a longer time to hospital readmission than lean COPD patients (3.8 vs 1.5 years, hazard ratio (HR) 0.39, 95% confidence interval [CI] 0.16–0. 74; p = 0.007). Good adherence (>4 h/night and >80% nightly usage) was associated with a lower mortality rate (HR 0.34, 95% CI 0.15–0.77; p = 0.010). CONCLUSION: In a real-world setting of a mixed population with hypercapnic respiratory failure, iVAPS and PSV seem to be similarly effective in improving gas exchange and demonstrate excellent adherence to treatment. A longer survival was noted in NIV-adherent patients. Randomised controlled studies are necessary to identify patients who might benefit more from hybrid ventilation modes.

Diagnostic precision and identification of rare diseases is dependent on distance of residence relative to tertiary medical facilities.

BACKGROUND: Diagnostic precision and the identification of rare diseases is a daily challenge, which needs specialized expertise. We hypothesized, that there is a correlation between the distance of residence to the next tertiary medical facility with highly specialized care and the diagnostic precision, especially for rare diseases. RESULTS: Using a nation-wide hospitalization database, we found a negative association between diagnostic diversity and travel time to the next tertiary referral hospital when including all cases throughout the overall International Classification of Diseases version 10 German Modification (ICD-10-GM) diagnosis codes. This was paralleled with a negative association of standardized incidence rates in all groups of rare diseases defined by the Orphanet rare disease nomenclature, except for rare teratologic and rare allergic diseases. CONCLUSION: Our findings indicate a higher risk of being mis-, under- or late diagnosed especially in rare diseases when living more distant to a tertiary medical facility. Greater distance to the next tertiary medical facility basically increases the chance for hospitalization in a non-comprehensive regional hospital with less diagnostic capacity, and, thus, impacts on adapted health care access. Therefore, solutions for overcoming the distance to specialized care as an indicator of health care access are a major goal in the future.

Animal Welfare Issues in Capture-Based Aquaculture.

Capture-based aquaculture (CBA) represents a type of intensive aquaculture production system for some economically valuable fish species, such as bluefin tuna (Thunnus thynnus), eel (Anguilla spp.) and Atlantic cod (Gadus morhua). In CBA, fish are captured from the wild in certain periods of the year, and following a recovery phase, they are kept in rearing facilities for a period of time, until they reach the market size. In this case, the fish are wild and have not gone through domestication like other fish species that are reproduced and farmed under the established farming systems. Therefore, these fish are not genetically adapted to live under the intensive farming conditions, and thus their welfare may be compromised in different manners compared to their domesticated counterparts. This review presents an overview of the current situation of CBA, while focusing on the assessment of fish welfare in CBA. The most commonly used fish welfare indicators will be discussed in relation to the different stages of CBA.

Nocturnal Cough and Sleep Quality to Assess Asthma Control and Predict Attacks.

INTRODUCTION: Objective markers for asthma, that can be measured without extra patient effort, could mitigate current shortcomings in asthma monitoring. We investigated whether smartphone-recorded nocturnal cough and sleep quality can be utilized for the detection of periods with uncontrolled asthma or meaningful changes in asthma control and for the prediction of asthma attacks. METHODS: We analyzed questionnaire and sensor data of 79 adults with asthma. Data were collected in situ for 29 days by means of a smartphone. Sleep quality and nocturnal cough frequencies were measured every night with the Pittsburgh Sleep Quality Index and by manually annotating coughs from smartphone audio recordings. Primary endpoint was asthma control assessed with a weekly version of the Asthma Control Test. Secondary endpoint was self-reported asthma attacks. RESULTS: Mixed-effects regression analyses showed that nocturnal cough and sleep quality were statistically significantly associated with asthma control on a between- and within-patient level (p < 0.05). Decision trees indicated that sleep quality was more useful for detecting weeks with uncontrolled asthma (balanced accuracy (BAC) 68% vs 61%; Δ sensitivity -12%; Δ specificity -2%), while nocturnal cough better detected weeks with asthma control deteriorations (BAC 71% vs 56%; Δ sensitivity 3%; Δ specificity -34%). Cut-offs using both markers predicted asthma attacks up to five days ahead with BACs between 70% and 75% (sensitivities 75 - 88% and specificities 57 - 72%). CONCLUSION: Nocturnal cough and sleep quality have useful properties as markers for asthma control and seem to have prognostic value for the early detection of asthma attacks. Due to the limited study duration per patient and the pragmatic nature of the study, future research is needed to comprehensively evaluate and externally validate the performance of both biomarkers and their utility for asthma self-management.

Characteristics of Asthma-related Nocturnal Cough: A Potential New Digital Biomarker.

INTRODUCTION: The nature of nocturnal cough is largely unknown. It might be a valid marker for asthma control but very few studies characterized it as a basis for better defining its role and its use as clinical marker. This study investigated prevalence and characteristics of nocturnal cough in asthmatics over the course of four weeks. METHODS: In two centers, 94 adult patients with physician-diagnosed asthma were recruited. Patient-reported outcomes and nocturnal sensor data were collected by a smartphone with a chat-based study app. RESULTS: Patients coughed in 53% of 2212 nights (range: 0-345 coughs/night). Median coughs per hour were 0 (IQR 0-1). Nocturnal cough rates showed considerable inter-individual variance. The highest counts were measured in the first 30 min in bed (4.5-fold higher than rest of night). Eighty-six percent of coughs were part of a cough cluster. Clusters consisted of a median of two coughs (IQR 2-4). Nocturnal cough was persistent within patient. CONCLUSION: To the best of the authors' knowledge, this study is the first to describe prevalence and characteristics of nocturnal cough in asthma over a period of one month, demonstrating that it was a prevalent symptom with large variance between patients and high persistence within patients. Cough events in asthmatics were 4.5 times more frequent within the first 30 min in bed indicating a potential role of positional change, and not more frequent during the early morning hours. An important next step will investigate the association between nocturnal cough and asthma control.

Three-Year Effectiveness of Dimethyl Fumarate in Multiple Sclerosis: A Prospective Multicenter Real-World Study.

BACKGROUND: Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited. OBJECTIVE: The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting. METHODS: We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated. RESULTS: Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6-41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy. CONCLUSIONS: Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies.

Tolerability and safety of dimethyl fumarate in relapsing multiple sclerosis: a prospective observational multicenter study in a real-life Spanish population.

BACKGROUND: Dimethyl fumarate (DMF) tolerability and safety in multiple sclerosis (MS) has been analyzed in randomized clinical trials. Real-life studies are needed to assess possible harms of this therapy in a wider MS population. OBJECTIVE: To evaluate DMF tolerability, safety and persistence in MS in a real-world setting. METHODS: We conducted a multicenter prospective study of patients who started DMF, attended in 16 public hospitals of Spain. A specific database was elaborated to collect data on most frequent adverse events (AE). Regression models were used to analyze the effect of demographic and clinical characteristics on risk of AEs and DMF discontinuation. RESULTS: We collected data of 886 patients (2681 patients/years-exposition) with median 39.5 (IQR 23, 51.5) months on DMF exposure; 25.3% were treatment naïve and 74.7% switched to DMF from other disease-modifying therapies. DMF was discontinued in 29.9% of patients, in 13.2% due to AEs and in 13.5% to inefficacy. AEs were experienced by 71.2%, being flushing the most frequent (44.1%), 5.4% developed grade III lymphopenia, without cases of grade IV. Females showed a higher risk of flushing and gastroenteric symptoms (OR 1.49, p = 0.011; OR 1.69, p = 0.001, respectively); lymphopenia was associated with older age (OR 1.04, p < 0.001), and a higher EDSS with lymphopenia (OR 1.10, p = 0.035) and DMF withdrawal (HR 1.43, p = 0.012). No safety problems were reported. CONCLUSIONS: Our findings confirm good tolerability and safety of DMF in real-world setting and suggest that women have an increased risk of AEs and higher baseline disability involves greater risk of drug discontinuation.

The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system.

Glial cells have emerged as key players in the central control of energy balance and etiology of obesity. Astrocytes play a central role in neural communication via the release of gliotransmitters. Acyl-CoA binding protein (ACBP)-derived endozepines are secreted peptides that modulate the GABAA receptor. In the hypothalamus, ACBP is enriched in arcuate nucleus (ARC) astrocytes, ependymocytes and tanycytes. Central administration of the endozepine octadecaneuropeptide (ODN) reduces feeding and improves glucose tolerance, yet the contribution of endogenous ACBP in energy homeostasis is unknown. We demonstrated that ACBP deletion in GFAP+ astrocytes, but not in Nkx2.1-lineage neural cells, promoted diet-induced hyperphagia and obesity in both male and female mice, an effect prevented by viral rescue of ACBP in ARC astrocytes. ACBP-astrocytes were observed in apposition with proopiomelanocortin (POMC) neurons and ODN selectively activated POMC neurons through the ODN-GPCR but not GABAA, and supressed feeding while increasing carbohydrate utilization via the melanocortin system. Similarly, ACBP overexpression in ARC astrocytes reduced feeding and weight gain. Finally, the ODN-GPCR agonist decreased feeding and promoted weight loss in ob/ob mice. These findings uncover ACBP as an ARC gliopeptide playing a key role in energy balance control and exerting strong anorectic effects via the central melanocortin system.

Desempeño del analizador de orinas Laura XL-Erba Mannheim en comparación con el iRICELL-Beckman Coulter en una población general / Performance of the Laura XL urine analyzer-Erba Mannheim in comparison with IRISCell-Beckman Coulter in a general population / Desempenho do analisador de urina Laura XL-Erba Mannheim em comparação com iRICELL-Beckman Coulter em uma população geral

Resumen Los objetivos del trabajo fueron evaluar el desempeño del analizador de orinas Laura XL® Erba Mannhein, por comparación con el analizador iRICELL® Beckman Coulter y valorar la determinación de proteínas urinarias semicuantitativas como tamizaje en su estudio, con el establecimiento de un punto de corte para su cuantificación. Se emplearon 225 muestras de orina procesadas en simultáneo. Se evaluó pH, densidad, turbidez, color, hemoglobina, glucosa, cetonas, nitritos, proteínas, número de tiras reactivas positivas; células epiteliales, leucocitos, hematíes y criterio de normalidad del sedimento por microscopía. Se cuantificaron las proteínas urinarias positivas por tiras en un Modular COBAS® 8000 (Hitachi-Roche). Se empleó el coeficiente de concordancia Kappa de Cohen (k) y el índice de correlación de Spearman. Se obtuvo escasa concordancia en turbidez (k=0,334), buena concordancia en color (k=0,681), hemoglobina (k=0,620), glucosa (k=0,677), cetonas (k=0,768), nitritos (k=0,827), tiras reactivas positivas (k=0,620), células epiteliales (k=0,783), leucocitos (k=0,745) y hematíes (k=0,609); muy buena concordancia en proteínas (k=0,842) y criterio de normalidad del sedimento (k=1,000). Correlación estadísticamente significativa en pH (r=0,8064; p<0,0001), densidad (r=1,000; p<0,0001) y proteína urinaria (rs=0,9157; p<0,0001) comparada con COBAS® 8000. Se concluyó un desempeño satisfactorio de Laura XL®; se muestra un rendimiento acorde a las necesidades y normativas de este laboratorio y se avala su utilidad como test de tamizaje para la valoración de proteínas urinarias. Se estableció, además, la cuantificación de orinas que presentaron 1+ o más por tira en Laura XL®. Se consideró realizar mejoras en el software.

Abstract The objectives of this work were to evaluate the performance of the Laura XL® Erba Mannheim urine analyzer, in comparison with the iRICELL® Beckman Coulter analyzer, and to assess the determination of semiquantitative urinary protein as screening in its study, establishing a cut-off point for its quantification. A total of 225 urine samples were simultaneously processed. pH, density, turbidity, colour, hemoglobin, glucose, ketones, nitrites, proteins, and number of positive reactive strips were evaluated; and epithelial cells, leukocytes, red blood cells and criteria for normality of the sediment were evaluated by microscopy. Positive urinary proteins per strip were quantified on a Modular COBAS® 8000 (Hitachi-Roche). Cohen's Kappa concordance coefficient (k) and Spearman's correlation index were used. Little agreement was obtained in turbidity (k=0.334), good agreement in colour (k=0.681), hemoglobin (k=0.620), glucose (k=0.677), ketones (k=0.768), nitrites (k=0.827), positive test strips (k=0.620), epithelial cells (k=0.783), leukocytes (k=0.745) and red blood cells (k=0.609); very good agreement for proteins (k=0.842) and sediment normality criteria (k=1,000). Statistically significant correlation in pH (r=0.8064; p<0.0001), density (r=1.000; p<0.0001), urinary protein (rs=0.9157; p<0.0001) compared with COBAS® 8000. A satisfactory performance of Laura XL® was concluded, showing a performance consistent with the needs and regulations of this institution, and its usefulness is endorsed as a screening test for the assessment of urinary proteins, establishing the quantification of urines that present 1+ or more per strip in Laura XL®. Software improvements are considered.

Resumo Os objetivos do trabalho foram avaliar o desempenho do analisador de urina Laura XL® Erba Mannheim, em comparação com o analisador iRICELL® Beckman Coulter, e avaliar a determinação de proteínas urinárias semiquantitativa como triagem em seu estudo, estabelecendo um ponto de corte para sua quantificação. Foram utilizadas 225 amostras de urina processadas simultaneamente. Foram avaliados pH, densidade, turbidez, cor, hemoglobina, glicose, cetonas, nitritos, proteínas, número de testes reativos positivos; células epiteliais, leucócitos, hemácias e critérios de normalidade do sedimento à microscopia. As proteínas urinárias positivas por teste foram quantificadas em um Modular COBAS® 8000 (Hitachi-Roche). Foram utilizados o coeficiente de concordância Kappa de Cohen (k) e o índice de correlação de Spearman. Escassa concordância foi obtida em turbidez (k=0,334), boa concordância em cor (k=0,681), hemoglobina (k=0,620), glicose (k=0,677), cetonas (k=0,768), nitritos (k=0,827), testes reativos positivos (k=0,620), células epiteliais (k=0,783), leucócitos (k=0,745) e hemácias (k=0,609); concordância muito boa para proteínas (k=0,842) e critérios de normalidade do sedimento (k=1,000). Correlação estatisticamente significativa em pH (r=0,8064 p<0,0001), densidade (r=1,000 p<0,0001), proteína urinária (rs=0,9157 p<0,0001) em comparação com COBAS® 8000. A conclusão é um desempenho satisfatório de Laura XL®, mostrando um rendimento consistente com as necessidades e normas deste laboratorio e sua utilidade é endossada como teste de triagem para avaliação de proteínas urinárias, estabelecendo também a quantificação de urinas que apresentaram 1+ ou mais por teste em Laura XL®. Melhorias no software são consideradas.