Impact of house dust mite-driven asthma on children's school performance and activity.

Evidence regarding asthma's impact on children's daily lives is limited. This prospective and cross-sectional, observational, multicenter study assessed school/work and activity impairment in children and adolescents with allergic asthma and their caregivers and allergen immunotherapy (AIT) effects. Included patients were schooled children and adolescents (5 to 17 years) with allergic asthma due to house dust mites (HDM). Impairment of school/work (i.e., absenteeism and presenteeism) and activity was measured in patients and their caregivers using the Work Productivity Impairment Questionnaire plus Classroom Impairment Questions: Allergy Specific (WPAI + CIQ:AS). HDM allergic patients with school impairment received subcutaneous AIT with a MicroCrystalline Tyrosine-associated allergoid. WPAI + CIQ:AS and effectiveness variables were compared between baseline and 1-year post-AIT. Of the 113 patients included, 59 (52.2%) and 51 (45.1%) showed school and activity impairment, respectively, missing a mean (SD) of 37.6 (24.4) % and 42.6 (25.6) % of school and activity time, respectively. Twenty-six (23%) caregivers reported activity impairment and, of the 79 (69.9%) employed, 30 (38%) reported work impairment. Of the 65 patients with school/activities impairment, 41 (63.1%) received AIT, of which 21 (51.2%) completed 1 year of treatment. Effectiveness variables and WPAI + CIQ:AS significantly improved: Mean (SD) school impairment decreased from 39.7 (26.7) to 2.1 (7.1) % (p < 0.001) and activity impairment from 46.2 (34.6) to 1.4 (3.6) % (p < 0.001). CONCLUSION: Allergic asthma due to HDMs results in school/work and activity impairment in children and adolescents and their caregivers. One year of AIT provided clinical benefits and reduced school and activity impairment. WHAT IS KNOWN: • Allergic asthma impairs children's school performance and daily activities. • Allergen immunotherapy modifies allergic disease course and ameliorates its symptoms. WHAT IS NEW: • Asthma symptoms due to allergy to house dust mites impair children's school attendance and productivity and daily activity and their caregivers' work performance and daily lives. • Allergen immunotherapy with a house dust mite MicroCrystalline Tyrosine (MCT)-associated allergoid seems to provide clinical benefits, associated with decreased school and activity impairment, supporting it as an effective treatment option.

Lycopene and Melatonin: Antioxidant Compounds in Cosmetic Formulations.

BACKGROUND: The use of antioxidants has become a common practice in the development of antiaging cosmetics. OBJECTIVE: The aim of this study was to evaluate the clinical efficacy of cosmetic formulations containing lycopene and melatonin antioxidants. METHOD: Thirty-six healthy women from 32 to 65 years were enrolled in this study. The study was carried out for 10 weeks, 2 preconditioning weeks with a control cream without antioxidants, and 8-week test with creams containing antioxidants in study. A multifunctional skin physiology monitor (Courage & Khazaka electronic GmbH®, Germany) was used to measure skin sebum content, hydration, elasticity, erythema index, and melanin index in 4 different regions of the face. RESULTS: There were significant differences between them.

Disability and quality of life in heart failure patients: a cross-sectional study.

BACKGROUND: Although both hospitalization and mortality due to heart failure (HF) have been widely studied, less is known about the impact of HF on disability and quality of life. AIM: To assess the degree of disability and quality of life in HF patients attended at family medicine centres. DESIGN AND SETTING: Cross-sectional study of a cohort of HF patients attended at family medicine centres. METHODS: Disability was assessed with the WHODAS 2 questionnaire, which provides a global and six domain scores that is understanding and communication, getting around, self-care, getting along with people, life activities and participation in society. Quality of life was assessed with the Minnesota Living with Heart Failure Questionnaire, which furnishes a global and two domain scores, physical and emotional. RESULTS: A breakdown of the results showed that 28% of patients had moderate disability and 16.7% had severe disability, with the most important areas affected being: life activities, 8.9% extreme disability and 30.3% severe disability; getting around, 34.6% severe disability and 2% extreme disability; and participation in society, 53.3% moderate-severe disability. Quality of life was mildly affected. New York Heart Association (NYHA) Functional Classification and sex were the major determinants of disability and quality of life. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists were associated with better scores in the "getting around" and "life activity" domains. CONCLUSION: HF patients in primary care show an important degree of disability and an acceptable quality of life.

Collaborative active learning: bioimpedance and anthropometry in higher education.

Research in the health sciences devotes much attention to overweight and obesity and, consequently, to body composition. In recent years, traditional body measures have been questioned as efficient variables in health sciences due to the fact that they cannot give information about body fat mass. Our aim is to teach how to analyze body composition through anthropometry and bioelectrical impedance analysis to our "Physiology of Vegetative and Reproductive Functions" students, who are studying for their degree in Biology. We proposed project-oriented-learning to promote collaborative interactions among students. Fifty-two students voluntarily formed five groups; they worked with the concepts of basal metabolic rate and body composition from a theoretical point of view and later transformed these concepts into a practical perspective by preparing a manuscript in groups with objectives proposed by our teaching team. In this research, we show a collaborative educational scenario for university students in which students are tutored from a constructivist perspective to promote social interactions, resulting in new knowledge acquisition.

Extracellular heat shock proteins protect U937 cells from H2O2-induced apoptotic cell death.

The cytoprotective role of heat shock proteins (HSPs) has been demonstrated in various cell types however, only few studies have investigated the role of extracellular exposure to HSPs in the survival of human lymphoma cell line U937. In the present study, we investigated the effect of extracellular exposure to four HSPs (HSP90, HSP70, HSP60, and HSP47) on apoptotic cell death induced by either oxidative stress (hydrogen peroxide) or endoplasmic reticulum stress-mediated intracellular calcium overload. It was found that extracellular exposure to HSPs reduced the cytotoxicity induced by hydrogen peroxide, but not that evoked by thapsigargin (a specific inhibitor of cytosolic calcium reuptake which is able to induce endoplasmic reticulum stress with subsequent intracellular calcium overload). Similarly, it was observed that exogenous HSPs were able to suppress the caspase-3 activation induced by hydrogen peroxide. These findings indicate that extracellular HSPs increase the resistance of human lymphoma cell line U937 to apoptotic cell death induced by hydrogen peroxide and diminish oxidative stress-mediated injures.

Melatonin sensitizes human cervical cancer HeLa cells to cisplatin-induced cytotoxicity and apoptosis: effects on oxidative stress and DNA fragmentation.

Melatonin has antitumor activity via several mechanisms including its antiproliferative and pro-apoptotic effects as well as its potent antioxidant actions, although recent evidence has indicated that melatonin may perform pro-oxidant actions in tumor cells. Therefore, melatonin may be useful in the treatment of tumors in association with chemotherapy drugs. This study was intended to evaluate the in vitro effect of melatonin on the cytotoxic and pro-apoptotic actions of various chemotherapeutic agents in cervical cancer HeLa cells. Herein, we found that both melatonin and three of the chemotherapeutic drugs tested, namely cisplatin (CIS), 5-fluorouracil (5-FU), and doxorubicin, induced a decrease in HeLa cell viability. Furthermore, melatonin significantly increased the cytotoxic effect of such chemotherapeutic agents. Consistently, costimulation of HeLa cells with any chemotherapeutic agent in the presence of melatonin further increased caspase-3 activation, particularly in CIS- and 5-FU-challenged cells. Likewise, concomitant treatments with melatonin and CIS significantly enhanced the ratio of cells entering mitochondrial apoptosis due to reactive oxygen species (ROS) overproduction, substantially augmented the population of apoptotic cells, and markedly enlarged DNA fragmentation compared to the treatments with CIS alone. Nonetheless, melatonin only displayed moderate chemosensitizing effects in 5-FU-stimulated HeLa cells, as suggested by slight increments in the percentage of cells stimulated for ROS production and in the proportion of early apoptotic cells compared to the treatments with 5-FU alone. In summary, our findings provided evidence that in vitro melatonin strongly enhances CIS-induced cytotoxicity and apoptosis in HeLa cells and, hence, the indoleamine could be potentially applied to cervical cancer treatment as a powerful synergistic agent.

Chemopreventive effects of resveratrol in a rat model of cerulein-induced acute pancreatitis.

In the past decades, a greater understanding of acute pancreatitis has led to improvement in mortality rates. Nevertheless, this disease continues to be a health care system problem due to its economical costs. Future strategies such as antioxidant supplementation could be very promising, regarding to beginning and progression of the disease. For this reason, this study was aimed at assessing the effect of exogenous administration of resveratrol during the induction process of acute pancreatitis caused by the cholecystokinin analog cerulein in rats. Resveratrol pretreatment reduced histological damage induced by cerulein treatment, as well as hyperamylasemia and hyperlipidemia. Altered levels of corticosterone, total antioxidant status, and glutathione peroxidase were significantly reverted to control levels by the administration of resveratrol. Lipid peroxidation was also counteracted; nevertheless, superoxide dismutase enzyme was overexpressed due to resveratrol pretreatment. Related to immune response, resveratrol pretreatment reduced pro-inflammatory cytokine IL-1ß levels and increased anti-inflammatory cytokine IL-10 levels. In addition, pretreatment with resveratrol in cerulein-induced pancreatitis rats was able to reverse, at least partially, the abnormal calcium signal induced by treatment with cerulein. In conclusion, this study confirms antioxidant and immunomodulatory properties of resveratrol as chemopreventive in cerulein-induced acute pancreatitis.

FMLP-, thapsigargin-, and H2O2-evoked changes in intracellular free calcium concentration in lymphocytes and neutrophils of type 2 diabetic patients.

Type 2 diabetic (T2DM) patients are immune-compromised having a higher susceptibility to infections and long-term complications in different parts of the body contributing to increased morbidity and mortality. A derangement in the homeostasis of intracellular free calcium concentration [Ca²âº](i) is known to be associated with several diseases in the body including T2DM. Both neutrophils and lymphocytes play active protective roles in host immune response to infection showing impairment in microbicidal functions including phagocytosis and chemotaxis which are calcium-dependent processes. This study evaluated the process of [Ca²âº]i mobilization from both neutrophils and lymphocytes taken from blood of both T2DM patients and healthy age-matched control subjects investigating the effect of N-formyl-methionyl-leucyl-phenylalanine (fMLP), thapsigargin (TG), and hydrogen peroxide (H2O2) on [Ca²âº](i) homeostasis. This study employed isolated peripheral blood neutrophils and lymphocytes from 24 T2DM patients and 24 healthy volunteers. Either neutrophils or lymphocytes were stimulated separately with fMLP, TG, or H2O2. Induced changes in [Ca²âº] in both neutrophils and lymphocytes were evaluated using spectrofluorometric methods. Stimulation of human neutrophils and lymphocytes with fMLP, TG, or H2O2 in the presence of [Ca²âº]o resulted in significant decreases in [Ca²âº](i) mobilization from T2DM patients compared with healthy controls. These data indicate that neutrophils and lymphocytes from T2DM patients are less responsive to calcium mobilizing agents compared with granulocytes from healthy controls and this is possibly due to the hyperglycemia. The results suggest that agonist-evoked decrease in [Ca²âº](i) in immune cells might be one of the possible mechanisms of impaired immunity in diabetic patients.

Nanoceria protects from alterations in oxidative metabolism and calcium overloads induced by TNFα and cycloheximide in U937 cells: pharmacological potential of nanoparticles.

The present study is aimed to determine the protective effect of a novel nanoparticle with antioxidant properties, nanoceria, on reactive oxygen species (ROS) production, and calcium signaling evoked by the tumor necrosis factor-alpha (TNFα) in combination with cycloheximide (CHX) on apoptosis in the human histiocytic lymphoma cell line U937. Our results show that treatment of U937 cells with 10 ng/mL TNFα in combination with 1 µg/mL CHX led to several Ca(2+) alterations. These stimulatory effects on calcium signals were followed by intracellular ROS production and mitochondria membrane depolarization, as well as a time-dependent increase in caspase-8 and -9 activities. Our results show that the pretreatment with well known antioxidants such as trolox and N-acetyl cysteine (NAC) partially reduced the apoptotic effects due to the administration of TNFα plus cycloheximide. Furthermore, nanoceria had a stronger protective effect than trolox or NAC. Our findings also suggest that TNFα plus cycloheximide-induced apoptosis is dependent on alterations in cytosolic concentration of calcium [Ca(2+)]c and ROS generation in human histiocytic U937 cells.

Exogenous melatonin supplementation prevents oxidative stress-evoked DNA damage in human spermatozoa.

Reactive oxygen species (ROS) are essential for sperm physiological functions such as capacitation, hyperactivation, and acrosome reaction, on the one hand, and for stimulating the apoptotic processes involved in the regulation of spermatogenesis, on the other hand. However, the imbalance between production and removal of ROS leads to oxidative stress, which is referred to as one of the main factors involved in male infertility. The pineal hormone melatonin, given its low toxicity and well-known antioxidant capacity, could be an excellent candidate to improve sperm quality. For this reason, the objective of the present work was to analyze whether long-term supplementation with melatonin to infertile men affects human sperm quality and the quality of the embryos retrieved from their couples. Our findings showed that the daily supplementation of 6 mg melatonin, as early as after 45 days of treatment, produced an increase in melatonin endogenous levels, indirectly measured as urinary 6-sulfatoxymelatonin (aMT6-s), an enhancement of both urinary and seminal total antioxidant capacity, and a consequent reduction in oxidative damage caused in sperm DNA. Moreover, couples whose men were given melatonin showed a statistically significant increase in the percentage of grade A (embryo with blastomeres of equal size; no cytoplasmic fragmentation), B (embryo with blastomeres of equal size; minor cytoplasmic fragmentation), and C (embryo with blastomeres of distinctly unequal size; significant cytoplasmic fragmentation) embryos at the expense of grade D (embryo with blastomeres of equal or unequal size; severe or complete fragmentation.) embryos which were clearly reduced. In summary, melatonin supplementation improves human sperm quality, which is essential to achieve successful natural and/or assisted reproduction outcome.

Effect of lycopene-enriched olive and argan oils upon lipid serum parameters in Wistar rats.

BACKGROUND: Lycopene has the highest antioxidant activity within carotenoids and is an effective free radical scavenger. Virgin olive oil (VOO) and argan oil (AO) contain trace amounts of a wide variety of phytochemicals which have desirable nutritional properties. The present study intended to assess the effect of various dietary VOO and AO in combination with lycopene consumption on serum biochemical parameters, including total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides (TGs) and phospholipids, as well as on hepatosomatic index (HSI) of rats. RESULTS: Results showed that ingestion of VOO and AO diminished TC, LDL-C, TGs and phospholipid levels, whereas the HDL-C levels augmented in all the groups assayed. The enrichment of VOO and AO with lycopene improved the beneficial effects derived from the consumption of both oils on serum biochemical parameters. A decrease in body weight gain and HSI was detected after the consumption of lycopene-enriched oils. CONCLUSION: These findings suggest that the inclusion of lycopene in VOO and AO may be used as a natural tool to fight against hyperlipidaemic and hypercholesterolaemic-derived disorders.

Bibliometric analysis on cannibalism/infanticide and maternal aggression towards pups in laboratory rodents.

Animal welfare has evolved during the past decades to improve not only the quality of life of laboratory rodents but also the quality and reproducibility of scientific investigations. Bibliometric analysis has become an important tool to complete the current knowledge with academic databases. Our objective was to investigate whether scientific research on cannibalism/infanticide is connected with maternal aggression towards the offspring in laboratory rodents. To carry out our research, we performed a specific search for published articles on each concept. Results were analyzed in the open-source environment RStudio with the package Bibliometrix. We obtained 253 and 134 articles for the first search (cannibalism/infanticide) and the second search (maternal aggression towards the pups) respectively. We observed that the interest in infanticide/cannibalism started in the 1950s, while researchers started showing interest in maternal aggression towards the pups 30 years later. Our analyses indicated that maternal aggression had better citations in scientific literature. In addition, although our results showed some common features (e.g. oxytocin or medial preoptic area in the brain), we observed a gap between cannibalism/infanticide and maternal aggression towards the pups with only 14 published articles in common for both the searches. Therefore, we recommend researchers to combine both concepts in further investigations in the context of cannibalism for better dissemination and higher impact in laboratory rodents' welfare research.

Melatonin Derivative-Conjugated Formulations of Pd(II) and Pt(II) Thiazoline Complexes on Mesoporous Silica to Enhance Cytotoxicity and Apoptosis against HeLa Cells.

The search for alternatives to cisplatin has led to the development of new metal complexes where thiazoline derivatives based on platinum(II) and palladium(II) stand out. In this sense, the Pt(II) and Pd(II) complexes coordinated with the thiazoline derivative ligand 2-(3,4-dichlorophenyl)imino-N-(2-thiazolin-2-yl)thiazolidine (TdTn), with formula [PtCl2(TdTn)] and [PdCl2(TdTn)], have previously shown good results against several cancer lines; however, in this work, we have managed to improve their activity by supporting them on mesoporous silica nanoparticles (MSN). The incorporation of metal compounds with a melatonin derivative (5-methoxytryptamine, 5MT), which is a well-known antioxidant and apoptosis inducer in different types of cancer, has been able to increase the cytotoxic activity of both MSN-supported and isolated complexes with only a very low amount (0.35% w/w) of this antioxidant. The covalently functionalized systems that have been synthesized are able to increase selectivity as well as accumulation in HeLa cells. The final materials containing the metal complexes and 5MT (MSN-5MT-PtTdTn and MSN-5MT-PdTdTn) required up to nine times less metal to achieve the same cytotoxic activity than their corresponding non-formulated counterparts did, thus reducing the potential side effects caused by the use of the free metal complexes.

How 'hidden hearing loss' noise exposure affects neural coding in the inferior colliculus of rats.

Exposure to brief, intense sound can produce profound changes in the auditory system, from the internal structure of inner hair cells to reduced synaptic connections between the auditory nerves and the inner hair cells. Moreover, noisy environments can also lead to alterations in the auditory nerve or to processing changes in the auditory midbrain, all without affecting hearing thresholds. This so-called hidden hearing loss (HHL) has been shown in tinnitus patients and has been posited to account for hearing difficulties in noisy environments. However, much of the neuronal research thus far has investigated how HHL affects the response characteristics of individual fibres in the auditory nerve, as opposed to higher stations in the auditory pathway. Human models show that the auditory nerve encodes sound stochastically. Therefore, a sufficient reduction in nerve fibres could result in lowering the sampling of the acoustic scene below the minimum rate necessary to fully encode the scene, thus reducing the efficacy of sound encoding. Here, we examine how HHL affects the responses to frequency and intensity of neurons in the inferior colliculus of rats, and the duration and firing rate of those responses. Finally, we examined how shorter stimuli are encoded less effectively by the auditory midbrain than longer stimuli, and how this could lead to a clinical test for HHL.

The inhibition of TNF-α-induced leucocyte apoptosis by melatonin involves membrane receptor MT1/MT2 interaction.

The pro-apoptotic signalling cascades induced by tumour necrosis factor-alpha (TNF-α) have been intensively studied in multiple cellular systems. So far, it is known that TNF-α can simultaneously activate survival and apoptotic cell death responses. The balance between these signals determines the ultimate response of the cell to TNF-α. Moreover, emerging evidence suggests that melatonin may be involved in the protection of different cell types against apoptosis. Thus, the objective of this study was to evaluate the effect of melatonin on TNF-α-induced apoptosis in human leucocytes. Cells were treated with TNF-α alone or in the presence of cycloheximide (CHX), which promotes caspase-8 activation by eliminating the endogenous caspase-8 inhibitor, c-FLIP. Treatment with TNF-α/CHX led to apoptotic cell death, as ascertained by annexin V/propidium iodide (PI) staining. Likewise, in the presence of CHX, TNF-α stimulation produced cFLIP down-regulation and subsequent caspase-8 activation, thus directly triggering caspase-3 activation and causing Bid truncation and subsequent caspase-9 activation. Conversely, pre-incubation of cells with melatonin inhibited TNF-α-/CHX-evoked leucocyte apoptosis. Similarly, pretreatment of leucocytes with melatonin increased cFLIP protein levels, thereby preventing TNF-α-/CHX-mediated caspase processing. Blockade of melatonin membrane receptor MT1/MT2 or extracellular signal-regulated kinase (ERK) pathway with luzindole or PD98059, respectively, abolished the inhibitory effects of melatonin on leucocyte apoptosis evoked by TNF-α/CHX. In conclusion, the model proposed by these findings is that the MT1/MT2 receptors, which are under the positive control of melatonin, trigger an ERK-dependent signalling cascade that interferes with the anti-apoptotic protein cFLIP modulating the cell life/death balance of human leucocytes.

Anti-inflammatory effects of melatonin in a rat model of caerulein-induced acute pancreatitis.

The purpose of our study was to evaluate the protective effect of melatonin in a rat model of caerulein-induced acute pancreatitis. For the induction of experimental acute pancreatitis, four subcutaneous injections of caerulein (20 mgkg­1 body weight) were given to Wistar rats at 2-h intervals. Melatonin was injected intraperitoneally (25 mg kg­1 body weight) 30 min before each caerulein injection. After 12 h, rats were sacrificed by decapitation. Blood and pancreas samples were collected and processed for serological and histopathological studies,respectively. Lipase, a-amylase, corticosterone, total antioxidant power and cytokines interleukin (IL)-1b, IL-4 and tumour necrosis factor(TNF)-a were determined using commercial kits. ANOVA and Tukey tests (P<0.05) were performed for the statistical analysis of the results.Results showed that the administration of melatonin reduced histological damage induced by caerulein treatment as well as the hyperamylasemia and hyperlipidemia. Corticosterone and antioxidant total power were also reverted to basal activities. Furthermore, melatonin pre-treatment reduced pro-inflammatory cytokines IL-1b and TNF-a and increased the serum levels of anti-inflammatory cytokine IL-4. In conclusion,the findings suggest that the protective effect of melatonin in caerulein-induced acute pancreatitis is mediated by the anti-inflammatory ability of this indolamine. Thus, melatonin may have a protective effect against acute pancreatitis.

Cytotoxic Effects of New Palladium(II) Complexes with Thiazine or Thiazoline Derivative Ligands in Tumor Cell Lines.

The synthesis of analogs of cisplatin, which is a widely used chemotherapeutic agent, using other metal centers could be an alternative for cancer treatment. Pd(II) could be a substitute for Pt(II) due to its coordination chemistry similarity. For that reason, six squared-planar Pd(II) complexes with thiazine and thiazoline ligands and formula [PdCl2(L)] were synthesized and characterized in this work. The potential anticarcinogenic ability of the compounds was studied via cytotoxicity assay in three different human tumor cell lines, i.e., epithelial cervix carcinoma (HeLa), promyelocytic leukemia (HL-60), and histiocytic lymphoma (U-937). Data obtained showed that complexes with methyl substitutions did not modify cell viability, while no-methyl substituted compounds had a moderate cytotoxic effect on all three cell lines. The complexes with phenyl substitutions displayed the lowest IC50 values, which ranged between 46.39 ± 3.99 µM and 62.74 ± 6.45 µM. Moreover, Pd accumulation inside the cell was observed after incubation with any of the four complexes mentioned, and the two complexes with phenyl rings were found to induce an increase in the percentage of apoptotic cells. These results suggested that the presence of bulky substitutions on the ligands such as phenyl groups may influence the cytotoxicity of the chemotherapeutic agents synthesized.

Melatonin as a Coadjuvant in the Treatment of Patients with Fibromyalgia.

Fibromyalgia syndrome (FMS) is a chronic widespread pain syndrome that is accompanied by fatigue, sleep disturbances, anxiety, depression, lack of concentration, and neurocognitive impairment. As the currently available drugs are not completely successful against these symptoms and frequently have several side effects, many scientists have taken on the task of looking for nonpharmacological remedies. Many of the FMS-related symptoms have been suggested to be associated with an altered pattern of endogenous melatonin. Melatonin is involved in the regulation of several physiological processes, including circadian rhythms, pain, mood, and oxidative as well as immunomodulatory balance. Preliminary clinical studies have propounded that the administration of different doses of melatonin to patients with FMS can reduce pain levels and ameliorate mood and sleep disturbances. Moreover, the total antioxidant capacity, 6-sulfatoxymelatonin and urinary cortisol levels, and other biological parameters improve after the ingestion of melatonin. Recent investigations have proposed a pathophysiological relationship between mitochondrial dysfunction, oxidative stress, and FMS by looking at certain proteins involved in mitochondrial homeostasis according to the etiopathogenesis of this syndrome. These improvements exert positive effects on the quality of life of FMS patients, suggesting that the use of melatonin as a coadjuvant may be a successful strategy for the management of this syndrome.

Neuronal responses to omitted tones in the auditory brain: A neuronal correlate for predictive coding.

Prediction provides key advantages for survival, and cognitive studies have demonstrated that the brain computes multilevel predictions. Evidence for predictions remains elusive at the neuronal level because of the complexity of separating neural activity into predictions and stimulus responses. We overcome this challenge by recording from single neurons from cortical and subcortical auditory regions in anesthetized and awake preparations, during unexpected stimulus omissions interspersed in a regular sequence of tones. We find a subset of neurons that responds reliably to omitted tones. In awake animals, omission responses are similar to anesthetized animals, but larger and more frequent, indicating that the arousal and attentional state levels affect the degree to which predictions are neuronally represented. Omission-sensitive neurons also responded to frequency deviants, with their omission responses getting emphasized in the awake state. Because omission responses occur in the absence of sensory input, they provide solid and empirical evidence for the implementation of a predictive process.

Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

INTRODUCTION: Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2 years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. METHODS: This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4 weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6 months for 2 years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. RESULTS: A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2 years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2 years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18 months (p = 0.004) and 29.0 (24.6) at 24 months (p = 0.002). Levels of fatigue and depression were also reduced. After 2 years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12 months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. CONCLUSION: Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2 years is effective in reducing ARR and disability progression.