Enhancing Control of Leishmania infantum Infection: A Multi-Epitope Nanovaccine for Durable T-Cell Immunity.

Canine leishmaniosis (CanL) is a growing health problem for which vaccination is a crucial tool for the control of disease. The successful development of an effective vaccine against this disease relies on eliciting a robust and enduring T-cell immune response involving the activation of CD4+ Th1 and CD8+ T-cells. This study aimed to evaluate the immunogenicity and prophylactic efficacy of a novel nanovaccine comprising a multi-epitope peptide, known as HisDTC, encapsulated in PLGA nanoparticles against Leishmania infantum infection in the murine model. The encapsulation strategy was designed to enhance antigen loading and sustain release, ensuring prolonged exposure to the immune system. Our results showed that mice immunized with PLGA-encapsulated HisDTC exhibited a significant reduction in the parasite load in the liver and spleen over both short and long-term duration. This reduction was associated with a cellular immune profile marked by elevated levels of pro-inflammatory cytokines, such as IFN-γ, and the generation of memory T cells. In conclusion, the current study establishes that PLGA-encapsulated HisDTC can promote effective and long-lasting T-cell responses against L. infantum in the murine model. These findings underscore the potential utility of multi-epitope vaccines, in conjunction with appropriate delivery systems, as an alternative strategy for CanL control.

New insights into the pathogenesis and transmission of Brucella pinnipedialis: systemic infection in two bottlenose dolphins (Tursiops truncatus).

IMPORTANCE: Brucella spp. are zoonotic pathogens that can affect both terrestrial and marine mammals. Brucella ceti has been identified in various cetacean species, but only one sequence type (ST27) has been reported in humans. However, it is important to conduct surveillance studies to better understand the impact of marine Brucella species on marine mammals, a typically understudied host group. Here, we describe a systemic infection by two related strains of Brucella pinnipedialis (ST25) in a couple of live-stranded bottlenose dolphins, with more severe lesions in the younger animal. Furthermore, B. pinnipedialis was first detected in milk from a female cetacean that stranded with its offspring. Our study reveals novel insights into the epidemiology and pathological consequences of B. pinnipedialis infections in cetaceans, emphasizing the crucial importance of ongoing surveillance and accurate diagnosis to understand the impact of this pathogen on marine mammal populations.

Oil-in-Water Pickering Emulsions Stabilized with Nanostructured Biopolymers: A Venue for Templating Bacterial Cellulose.

Pickering emulsions (PEs) differ from conventional emulsions in the use of solid colloidal particles as stabilizing agents instead of traditional amphiphilic molecules. Nanostructured biopolymers (NBs) emerge as a promising alternative for PE stabilization owing to their remarkable biocompatibility, abundant availability, and low cost. To explore this potential, a study is herein presented, in which cellulose nanocrystals (CNCs), both type I and type II allomorphs, and chitin nanocrystals (ChNCs) were used for stabilizing oil-in-water PEs prepared by the use of ultrasound. Sunflower oil was selected as the oil phase as it offers the advantages of being edible, renewable, and inexpensive. By utilizing ζ-potential, static light diffraction, and visual observations, we determined the optimal oil/water ratio for each type of NB to obtain stable emulsions after 14 days. The optimized PEs were used to form bacterial nanocellulose composites through emulsion templating. To our knowledge, this study represents a pioneering work in exploiting oil-in-water PEs for this approach. Additionally, it entails the first utilization of nonmercerized type II CNCs as stabilizers for PEs, while also establishing a direct comparison among the most relevant NBs. The resulting composites exhibited a unique morphology, composed of larger pores compared to standard bacterial nanocellulose aerogels. These findings highlight the notable potential of NBs as stabilizers for PEs and their ability to generate green nanocomposites with tailored properties.

Antimicrobial Susceptibility and Resistance Mechanisms in Mannheimia haemolytica Isolates from Sheep at Slaughter.

Mannheimia haemolytica is the main pathogen contributing to pneumonic pasteurellosis in sheep. The aim of this study was to investigate the antimicrobial resistance levels in M. haemolytica isolates from the lungs of slaughtered sheep and to examine the genetic resistance mechanisms involved. A total of 256 M. haemolytica isolates, 169 from lungs with pneumonic lesions and 87 from lungs without lesions, were analyzed by the disk diffusion method for 12 antimicrobials, and the whole genome of 14 isolates was sequenced to identify antimicrobial resistance determinants. Levels of phenotypic resistance ranged from <2% for 10 antimicrobials (amoxicillin, amoxicillin-clavulanic, ceftiofur, cefquinome, lincomycin/spectinomycin, gentamicin, erythromycin, florfenicol, enrofloxacin, and doxycycline) to 4.3% for tetracycline and 89.1% for tylosin. Six isolates carried tetH genes and four isolates carried, in addition, the strA and sul2 genes in putative plasmid sequences. No mutations associated with macrolide resistance were identified in 23 rDNA sequences, suggesting that the M. haemolytica phenotypic results for tylosin should be interpreted with care in the absence of well-established epidemiological and clinical breakpoints. The identification of strains phenotypically resistant to tetracycline and of several resistance genes, some of which were present in plasmids, highlights the need for continuous monitoring of susceptibility patterns in Pasteurellaceae isolates from livestock.

Induced Relaxation Enhances the Cardiorespiratory Dynamics in COVID-19 Survivors.

Most COVID-19 survivors report experiencing at least one persistent symptom after recovery, including sympathovagal imbalance. Relaxation techniques based on slow-paced breathing have proven to be beneficial for cardiovascular and respiratory dynamics in healthy subjects and patients with various diseases. Therefore, the present study aimed to explore the cardiorespiratory dynamics by linear and nonlinear analysis of photoplethysmographic and respiratory time series on COVID-19 survivors under a psychophysiological assessment that includes slow-paced breathing. We analyzed photoplethysmographic and respiratory signals of 49 COVID-19 survivors to assess breathing rate variability (BRV), pulse rate variability (PRV), and pulse-respiration quotient (PRQ) during a psychophysiological assessment. Additionally, a comorbidity-based analysis was conducted to evaluate group changes. Our results indicate that all BRV indices significantly differed when performing slow-paced breathing. Nonlinear parameters of PRV were more appropriate for identifying changes in breathing patterns than linear indices. Furthermore, the mean and standard deviation of PRQ exhibited a significant increase while sample and fuzzy entropies decreased during diaphragmatic breathing. Thus, our findings suggest that slow-paced breathing may improve the cardiorespiratory dynamics of COVID-19 survivors in the short term by enhancing cardiorespiratory coupling via increased vagal activity.

Regulating Oxygen Ion Transport at the Nanoscale to Enable Highly Cyclable Magneto-Ionic Control of Magnetism.

Magneto-ionics refers to the control of magnetic properties of materials through voltage-driven ion motion. To generate effective electric fields, either solid or liquid electrolytes are utilized, which also serve as ion reservoirs. Thin solid electrolytes have difficulties in (i) withstanding high electric fields without electric pinholes and (ii) maintaining stable ion transport during long-term actuation. In turn, the use of liquid electrolytes can result in poor cyclability, thus limiting their applicability. Here we propose a nanoscale-engineered magneto-ionic architecture (comprising a thin solid electrolyte in contact with a liquid electrolyte) that drastically enhances cyclability while preserving sufficiently high electric fields to trigger ion motion. Specifically, we show that the insertion of a highly nanostructured (amorphous-like) Ta layer (with suitable thickness and electric resistivity) between a magneto-ionic target material (i.e., Co3O4) and the liquid electrolyte increases magneto-ionic cyclability from <30 cycles (when no Ta is inserted) to more than 800 cycles. Transmission electron microscopy together with variable energy positron annihilation spectroscopy reveals the crucial role of the generated TaOx interlayer as a solid electrolyte (i.e., ionic conductor) that improves magneto-ionic endurance by proper tuning of the types of voltage-driven structural defects. The Ta layer is very effective in trapping oxygen and hindering O2- ions from moving into the liquid electrolyte, thus keeping O2- motion mainly restricted between Co3O4 and Ta when voltage of alternating polarity is applied. We demonstrate that this approach provides a suitable strategy to boost magneto-ionics by combining the benefits of solid and liquid electrolytes in a synergetic manner.

Ubiquity and Diversity of Cold Adapted Denitrifying Bacteria Isolated From Diverse Antarctic Ecosystems.

Nitrogen cycle has been poorly investigated in Antarctic ecosystems. In particular, how extreme conditions of low temperature, dryness, and high radiation select the microorganisms involved in the cycle is not yet understood. Denitrification is an important step in the nitrogen cycle in which nitrate is reduced stepwise to the gases NO, N2O, and N2. Denitrification is carried out by a wide group of microorganisms spread in the phylogenetic tree. The aim of this work was to isolate and characterize denitrifying bacteria present in different cold environments from Antarctica. Bacterial isolates were obtained from lake, meltwater, sea, glacier ice, ornithogenic soil, and penguin feces samples from King George Island, Fildes peninsula in the Antarctic. Samples were taken during the deicing season in five sampling campaigns. From all the samples we were able to isolate denitrifying strains. A total of 199 bacterial isolates with the capacity to grow in anaerobic mineral media reducing nitrate at 4°C were obtained. The characterization of the isolates by 16S rRNA gene sequence analysis showed a high predominance of the genus Pseudomonas, followed by Janthinobacterium, Flavobacterium, Psychrobacter, and Yersinia. Other minor genera detected were Cryobacterium, Iodobacter, Kaistella, and Carnobacterium. The capacity to denitrify was not previously described for most of the bacteria related to our isolates and in many of them denitrifying genes were not present suggesting the presence of new genes in this extreme environment. Our work demonstrates the ubiquity of denitrification in the Maritime Antarctica and gives important information linking denitrification at cold temperature with taxa in an unequivocal way.

Spatial Learning Promotes Adult Neurogenesis in Specific Regions of the Zebrafish Pallium.

Adult neurogenesis could be considered as a homeostatic mechanism that accompanies the continuous growth of teleost fish. As an alternative but not excluding hypothesis, adult neurogenesis would provide a form of plasticity necessary to adapt the brain to environmental challenges. The zebrafish pallium is a brain structure involved in the processing of various cognitive functions and exhibits extended neurogenic niches throughout the periventricular zone. The involvement of neuronal addition as a learning-related plastic mechanism has not been explored in this model, yet. In this work, we trained adult zebrafish in a spatial behavioral paradigm and evaluated the neurogenic dynamics in different pallial niches. We found that adult zebrafish improved their performance in a cue-guided rhomboid maze throughout five daily sessions, being the fish able to relearn the task after a rule change. This cognitive activity increased cell proliferation exclusively in two pallial regions: the caudal lateral pallium (cLP) and the rostral medial pallium (rMP). To assessed whether learning impinges on pallial adult neurogenesis, mitotic cells were labeled by BrdU administration, and then fish were trained at different periods of adult-born neuron maturation. Our results indicate that adult-born neurons are being produced on demand in rMP and cLP during the learning process, but with distinct critical periods among these regions. Next, we evaluated the time course of adult neurogenesis by pulse and chase experiments. We found that labeled cells decreased between 4 and 32 dpl in both learning-sensitive regions, whereas a fraction of them continues proliferating over time. By modeling the population dynamics of neural stem cells (NSC), we propose that learning increases adult neurogenesis by two mechanisms: driving a chained proliferation of labeled NSC and rescuing newborn neurons from death. Our findings highlight adult neurogenesis as a conserved source of brain plasticity and shed light on a rostro-caudal specialization of pallial neurogenic niches in adult zebrafish.

Case Report: Eosinophilic Esophagitis in a Patient With a Novel STAT1 Gain-of-Function Pathogenic Variant.

Background: STAT1 gain-of-function (GOF) is a primary immune dysregulatory disorder marked by wide infectious predisposition (most notably chronic mucocutaneous Candidiasis), autoimmunity, vascular disease and malignant predisposition. While atopic features have been described in some STAT1 GOF patients, they are not considered a predominant feature of the disease. Additionally, while eosinophilic gastrointestinal infiltration has been reported in some cases, this has always been described in the context of pre-existing oropharyngeal and/or esophageal Candidiasis. Clinical cases: Herein, we report 3 members of a multi-generational family diagnosed with STAT1 GOF caused by a novel mutation in the N-terminal domain, c.194A>C (p.D65A). The proband presented initially with a long-standing history of treatment-refractory eosinophilic esophagitis (EoE) without preceding gastrointestinal tract fungal infections, and her mother was diagnosed with esophagitis as well. Conclusion: EoE has been previously associated with alterations to STAT6 and STAT3 signaling pathways. The current report expands the possible association between JAK/STAT-related disorders and EoE, suggesting that EoE could be a primary disease manifestation of STAT1 GOF, even in the absence of oropharyngeal and/or esophageal Candidiasis.

Monday-focused tailored rapid interactive mobile messaging for weight management 2 (MTRIMM2): results from a randomized controlled trial.

BACKGROUND: Text-messaging interventions can reach many individuals across a range of socioeconomic groups, at a low cost. Few randomized controlled trials (RCTs) of text-messaging weight loss interventions have been conducted in United States. METHODS: From September of 2016 to September of 2018, we conducted a two-parallel group, superiority, RCT of a 16-week text-messaging, weight loss intervention in Baltimore, Maryland, in overweight and obese adults younger than 71, who were able to receive text-messages. Our objective was to assess the effect of receiving the message content only (in printed documents distributed at baseline and week 8), versus receiving messages via short messaging service (SMS) on weight loss (primary outcome), body mass index, perceived exercise benefits and barriers, self-efficacy, and physical activity (PA). The random allocation sequence was equally balanced intervention groups by gender and age groups. Participants were randomized after the baseline assessment. Then, participants and most study staff were unblinded. Follow-up assessments were conducted at 8-, 16-, and 42-week post randomization. We performed intention-to-treat analysis using mixed linear regression models. RESULTS: Of the 155 adults randomized (printed messages =77, SMS =78), 87.1% were women, 53.5% were African Americans, and 93.5% non-Hispanic. Participants who completed at least one follow-up assessment were included in regression analyses (n=145, printed messages =74, SMS =71). Compared to baseline, at the 42-week assessment, the average percent weight loss was 1.23 for the SMS group (P=0.006) and 0.86 for the printed messages group (P=0.047). Both groups experienced small reductions in weight (printed messages: -0.96 kg, P=0.022; SMS: -1.19 kg, P=0.006), BMI (printed messages: -0.32, P=0.035; SMS: -0.52, P=0.002), and percent energy from fat consumption (printed messages: -1.43, P=0.021; SMS: -2.14, P≤0.001). No statistically significant between groups differences were detected for any of the study outcomes. SMS response rates were not statistically significantly associated with study outcomes. No adverse events were reported. CONCLUSIONS: A semi-tailored SMS weight loss intervention among overweight and obese adults was not statistically superior in efficacy to paper-based messaging. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04506996.

Effects of Supplemental Oxygen on Cardiovascular and Respiratory Interactions by Extended Partial Directed Coherence in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and restrictive disease characterized by fibrosis and inflammatory changes in lung tissue producing a reduction in diffusion capacity and leading to exertional chronic arterial hypoxemia and dyspnea. Furthermore, clinically, supplemental oxygen (SupplO2) has been prescribed to IPF patients to improve symptoms. However, the evidence about the benefits or disadvantages of oxygen supplementation is not conclusive. In addition, the impact of SupplO2 on the autonomic nervous system (ANS) regulation in respiratory diseases needs to be evaluated. In this study the interactions between cardiovascular and respiratory systems in IPF patients, during ambient air (AA) and SupplO2 breathing, are compared to those from a matched healthy group. Interactions were estimated by time series of successive beat-to-beat intervals (BBI), respiratory amplitude (RESP) at BBI onset, arterial systolic (SYS) and diastolic (DIA) blood pressures. The paper explores the Granger causality (GC) between systems in the frequency domain by the extended partial directed coherence (ePDC), considering instantaneous effects. Also, traditional linear and nonlinear markers as power in low (LF) and high frequency (HF) bands, symbolic dynamic indices as well as arterial baroreflex, were calculated. The results showed that for IPF during AA phase: 1) mean BBI and power of BBI-HF band, as well as mean respiratory frequency were significantly lower (p < 0.05) and higher (p < 0.001), respectively, indicating a strong sympathetic influence, and 2) the RESP → SYS interaction was characterized by Mayer waves and diminished RESP → BBI, i.e., decreased respiratory sinus arrhythmia. In contrast, during short-term SupplO2 phase: 1) oxygen might produce a negative influence on the systolic blood pressure variability, 2) the arterial baroreflex reduced significantly (p < 0.01) and 3) reduction of RSA reflected by RESP → BBI with simultaneous increase of Traube-Hering waves in RESP → SYS (p < 0.001), reflected increased sympathetic modulation to the vessels. The results gathered in this study may be helpful in the management of the administration of SupplO2.

Knowing the enemy: homoacetogens in hydrogen production reactors.

One of the bottlenecks of the hydrogen production by dark fermentation is the low yields obtained because of the homoacetogenesis persistence, a metabolic pathway where H2 and CO2 are consumed to produce acetate. The central reactions of H2 production and homoacetogenesis are catalyzed by enzyme hydrogenase and the formyltetrahydrofolate synthetase, respectively. In this work, genes encoding for the formyltetrahydrofolate synthetase (fthfs) and hydrogenase (hydA) were used to investigate the diversity of homoacetogens as well as their phylogenetic relationships through quantitative PCR (qPCR) and next-generation amplicon sequencing. A total of 70 samples from 19 different H2-producing bioreactors with different configurations and operating conditions were analyzed. Quantification through qPCR showed that the abundance of fthfs and hydA was strongly associated with the type of substrate, organic loading rate, and H2 production performance. In particular, fthfs sequencing revealed that homoacetogens diversity was low with one or two dominant homoacetogens in each sample. Clostridium carboxivorans was detected in the reactors fed with agave hydrolisates; Acetobacterium woodii dominated in systems fed with glucose; Blautia coccoides and unclassified Sporoanaerobacter species were present in reactors fed with cheese whey; finally, Eubacterium limosum and Selenomonas sp. were co-dominant in reactors fed with glycerol. Altogether, quantification and sequencing analysis revealed that the occurrence of homoacetogenesis could take place due to (1) metabolic changes of H2-producing bacteria towards homoacetogenesis or (2) the displacement of H2-producing bacteria by homoacetogens. Overall, it was demonstrated that the fthfs gene was a suitable marker to investigate homoacetogens in H2-producing reactors. KEY POINTS: • qPCR and sequencing analysis revealed two homoacetogenesis phenomena. • fthfs gene was a suitable marker to investigate homoacetogens in H2 reactors.

Sugarcane vinasse extreme thermophilic digestion: a glimpse on biogas free management.

The high temperature in which sugarcane vinasse (SV) is generated (~ 90 °C) and the positive effect of higher temperatures in biochemical reactions have motivated the evaluation of SV anaerobic digestion (AD) under extreme temperature conditions. Two-stage (acidogenic/methanogenic) and single-stage (methanogenic) AD of SV were evaluated under 70 °C in structured-bed reactors. The extreme temperature was beneficial to the acidogenic step of the two-stage AD process. The methane production, however, was hindered at 70 °C. The VMP of the single and two-stage reactors accounted, respectively, for only 13% and 7% of the production rate reported in sugarcane vinasse AD at 55 °C. At 70 °C, the main genera responsible for methane production was Methanothermobacter and the acetoclastic methanogenesis did not occur, resulting in acetic acid build up (15,800 mg L-1). These results brought a new perspective for sugarcane vinasse management, with acetic acid production alternatively to methanization. In this perspective, two-stage process would be composed of acidogenic and acetogenic reactors, and beyond acetate, hydrogen and other soluble compounds could be recovered in a complete biorefinery process.

Whole-Exome Sequencing and C9orf72 Analysis in Primary Progressive Aphasia.

Primary progressive aphasia (PPA) is mainly considered a sporadic disease and few studies have systematically analyzed its genetic basis. We here report the analyses of C9orf72 genotyping and whole-exome sequencing data in a consecutive and well-characterized cohort of 50 patients with PPA. We identified three pathogenic GRN variants, one of them unreported, and two cases with C9orf72 expansions. In addition, one likely pathogenic variant was found in the SQSTM1 gene. Overall, we found 12%of patients carrying pathogenic or likely pathogenic variants. These results support the genetic role in the pathophysiology of a proportion of patients with PPA.

ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain.

It has been suggested that some individuals may present genetic susceptibility to SARS-CoV-2 infection, with particular research interest in variants of the ACE2 and TMPRSS2 genes, involved in viral penetration into cells, in different populations and geographic regions, although insufficient information is currently available. This study addresses the apparently reasonable hypothesis that variants of these genes may modulate viral infectivity, making some individuals more vulnerable than others. Through whole-exome sequencing, the frequency of exonic variants of the ACE2, TMPRSS2, and Furin genes was analyzed in relation to presence or absence of SARS-CoV-2 infection in a familial multiple sclerosis cohort including 120 individuals from Madrid. The ACE2 gene showed a low level of polymorphism, and none variant was significantly associated with SARS-CoV-2 infection. These variants have previously been detected in Italy. While TMPRSS2 is highly polymorphic, the variants found do not coincide with those described in other studies, with the exception of rs75603675, which may be associated with SARS-CoV-2 infection. The synonymous variants rs61735792 and rs61735794 showed a significant association with infection. Despite the limited number of patients with SARS-CoV-2 infection, some variants, especially in TMPRSS2, may be associated with COVID-19.

Hemodynamic response to low-flow acute supplemental oxygen in idiopathic pulmonary fibrosis and elderly healthy subjects.

BACKGROUND: Hemodynamic response to supplemental oxygen in idiopathic pulmonary fibrosis (IPF) is still not well known. OBJECTIVE: To determine and compare the effect of low-flow acute supplemental oxygen on the hemodynamics of IPF patients and matched healthy subjects. METHODS: Descriptive and comparative study in 20 IPF-patients and 19 Control-subjects, (60-80 years old) breathing ambient air followed by acute nasal low-flow (3 L/min) supplemental oxygen. Non-invasive methods were used during the supine position to evaluate oxygen saturation, heart rate, stroke volume index, cardiac output index, total peripheral resistance and arterial blood pressure. RESULTS: Breathing ambient air, IPF (vs. Control) presented lower values in stroke volume index (38.7 [29.4-43.2] vs. 45.4 [38.4-50.9] mL•kg-1•m2; p=0.009) and cardiac output index (2.484 [2.268 - 2.946] vs. 2.857 [2.628 - 3.054] L•min-1•m-2; p=0.028), with higher total peripheral resistance (1644 [1559-2076] vs. 1505 [1366-1784] dyne•s•cm-5; p=0.017). During supplemental oxygen (vs. ambient air), both groups increased oxygen saturation above 94% (p<0.001) while heart rate decreased about 6 to 8% (p<0.001); stroke volume index increased around 7% in the Control-group (p=0.004) but only 1% in the IPF-group (p=0.017). In addition, IPF showed increments in total peripheral resistance (1644 [1559-2076] vs. 1706 [1554-2278] dyne•s•cm-5; p=0.017) with subsequent decrements in cardiac output index (2.484 [2.268 - 2.946] vs. 2.362 [2.139 - 2.664] L•min-1•m-2; p<0.001). CONCLUSION: Low-flow acute supplemental oxygen in IPF causes a meaningful decrement in cardiac output due to greater reduction in heart rate and increment in total peripheral resistance than matched healthy subjects. Knowing the hemodynamic profile of IPF patients may be helpful in determining their management with supplemental oxygen.

Effects of music therapy as an adjunct to chest physiotherapy in children with cystic fibrosis: A randomized controlled trial.

Airway clearance therapy (ACT) is considered an important approach to improve airway clearance in children with cystic fibrosis (CF). Daily ACT administration requires substantial commitments of time and energy that complicate ACT and reduce its benefits. It is crucial to establish ACT as a positive routine. Music therapy (MT) is an aspect of integrative strategies to ameliorate the psycho-emotional consequences of chronic diseases, and a MT intervention could help children with CF between the ages of 2 and 17 develop a positive response. The aim of this randomized controlled trial was to evaluate the effects of specifically composed and recorded instrumental music as an adjunct to ACT. We compared the use of specifically composed music (Treated Group, TG), music that the patient liked (Placebo Group, PG), and no music (Control Group, CG) during the usual ACT routine in children with CF aged from 2 to 17. The primary outcomes, i.e., enjoyment and perception of time, were evaluated via validated questionnaires. The secondary outcome, i.e., efficiency, was evaluated in terms of avoided healthcare resources. Enjoyment increased after the use of the specifically composed music (children +0.9 units/parents +1.7 units; p<0.05) compared to enjoyment with no music (0 units) and familiar music (+0.5 units). Perception of time was 11.1 min (±3.9) less than the actual time in the TG (p<0.05), 3.9 min (±4.2) more than the actual time in the PG and unchanged in the CG. The potential cost saving related to respiratory exacerbations was €6,704.87, while the cost increased to €33,524.35 in the CG and to €13,409.74 in the PG. In conclusion, the specifically composed, played and compiled instrumental recorded music is an effective adjunct to ACT to establish a positive response and is an efficient option in terms of avoided costs. Trial registered as ISRCTN11161411. ISRCTN registry (www.isrctn.com).

Variants of genes encoding TNF receptors and ligands and proteins regulating TNF activation in familial multiple sclerosis.

INTRODUCTION: Numerous genetic variants have been associated with susceptibility to multiple sclerosis (MS). Variants located in genes involved in specific pathways, such as those affecting TNF-α, can contribute to the risk of MS. The purpose of this study was to determine whether variants of these genes are associated with greater risk of MS. METHODS: We used whole-exome sequencing to study genes coding for TNF-α receptors and ligands, and proteins promoting TNF-α expression in 116 individuals from 19 families including at least two MS patients. We compared patients with MS, patients with other autoimmune diseases, and healthy individuals. RESULTS: Greater polymorphism was observed in several genes in families with familial MS compared to the general population; this may reflect greater susceptibility to autoimmune diseases. Pedigree analysis also revealed that LT-α variants rs1041981 and rs2229094 and LT-ß variant rs4647197 were associated with MS and that LT-ß variant rs4647183 was associated with other autoimmune diseases. The association between autoimmune disease and TNFAIP2 variant rs1132339 is particularly noteworthy, as is the fact that TNFAIP6 variant rs1046668 appears to follow a recessive inheritance pattern. CONCLUSIONS: Our findings support the idea that the risk of familial MS is associated with variants of signaling pathways, including those involving TNF-α.