Effect of a musical intervention on tolerance and efficacy of non-invasive ventilation in the ICU: study protocol for a randomized controlled trial (MUSique pour l’Insuffisance Respiratoire Aigue - Mus-IRA)

BackgroundNon-invasive ventilation (NIV) tolerance is a key factor of NIV success. Hence, numerous sedative pharmacological or non-pharmacological strategies have been assessed to improve NIV tolerance. Music therapy in various health care settings has shown beneficial effects. In invasively ventilated critical care patients, encouraging results of music therapy on physiological parameters, anxiety, and agitation have been reported. We hypothesize that a musical intervention improves NIV tolerance in comparison to conventional care. We therefore question the potential benefit of a receptive music session administered to patients by trained caregivers (“musical intervention”) to enhance acceptance and tolerance of NIV.Methods/designWe conduct a prospective, three-center, open-label, three-arm randomized trial involving patients in the intensive care unit (ICU) who require NIV, as assessed by the treating physician. Participants are allocated to a “musical intervention” arm (“musical intervention” applied during all NIV sessions), to a “sensory deprivation” arm (sight and hearing isolation during all NIV sessions), or to the control group. The primary endpoint is the change in respiratory comfort (measured with a digital visual scale) before the initiation and after 30 minutes of the first NIV session. The evaluation of the primary endpoint is performed blindly from the treatment group. Secondary endpoints include changes in respiratory and cardiovascular parameters during NIV sessions, the percentage of patients requiring endotracheal intubation, day-90 anxiety/depression and health-related quality of life, post-trauma stress induced by NIV, and the overall assessment of NIV.The follow-up for each participant is 90 days. We expect to randomize a total of 99 participants.DiscussionAs music intervention is a simple and easy-to-implement non-pharmacological technique, efficacious in reducing anxiety in critically ill patients, it appeared logical to assess its efficacy in NIV, one of the most stressful techniques used in the ICU. Patient centeredness was crucial in choosing the outcomes assessed.

Trial registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02265458","term_id":"NCT02265458"}}NCT02265458. Registered on 25 August 2014.

Electronic supplementary material

The online version of this article (doi:10.1186/s13063-016-1574-z) contains supplementary material, which is available to authorized users.     

The oxidative environment: a mediator of interspecies communication that drives symbiosis evolution

Symbiotic interactions are ubiquitous in nature and play a major role in driving the evolution of life. Interactions between partners are often mediated by shared signalling pathways, which strongly influence both partners'' biology and the evolution of the association in various environments. As an example of ‘common language’, the regulation of the oxidative environment plays an important role in driving the evolution of symbiotic associations. Such processes have been occurring for billions of years, including the increase in Earth''s atmospheric oxygen and the subsequent evolution of mitochondria. The effect of reactive oxygen species and reactive nitrogen species (RONS) has been characterized functionally, but the molecular dialogue between partners has not been integrated within a broader evolutionary context yet. Given the pleiotropic role of RONS in cell–cell communication, development and immunity, but also their associated physiological costs, we discuss here how their regulation can influence the establishment, the maintenance and the breakdown of various symbiotic associations. By synthesizing recent developments in redox biology, we aim to provide an interdisciplinary understanding of the influence of such mediators of interspecies communication on the evolution and stability of symbioses, which in turn can shape ecosystems and play a role in health and disease.     

Biological Characterization of Gene Response to Insulin-Induced Hypoglycemia in Mouse Retina

Glucose is the most important metabolic substrate of the retina and maintenance of normoglycemia is an essential challenge for diabetic patients. Chronic, exaggerated, glycemic excursions could lead to cardiovascular diseases, nephropathy, neuropathy and retinopathy. We recently showed that hypoglycemia induced retinal cell death in mouse via caspase 3 activation and glutathione (GSH) decrease. Ex vivo experiments in 661W photoreceptor cells confirmed the low-glucose induction of death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. We evaluate herein retinal gene expression 4 h and 48 h after insulin-induced hypoglycemia. Microarray analysis demonstrated clusters of genes whose expression was modified by hypoglycemia and we discuss the potential implication of those genes in retinal cell death. In addition, we identify by gene set enrichment analysis, three important pathways, including lysosomal function, GSH metabolism and apoptotic pathways. Then we tested the effect of recurrent hypoglycemia (three successive 4h periods of hypoglycemia spaced by 48 h recovery) on retinal cell death. Interestingly, exposure to multiple hypoglycemic events prevented GSH decrease and retinal cell death, or adapted the retina to external stress by restoring GSH level comparable to control situation. We hypothesize that scavenger GSH is a key compound in this apoptotic process, and maintaining “normal” GSH level, as well as a strict glycemic control, represents a therapeutic challenge in order to avoid side effects of diabetes, especially diabetic retinopathy.     

Identification of the gate regions in the primary structure of the secretin pIV

Secretins are a family of large bacterial outer membrane channels that serve as exit ports for folded proteins, filamentous phage and surface structures. Despite the large size of their substrates, secretins do not compromise the barrier function of the outer membrane, implying a gating mechanism. The region in the primary structure that forms the putative gate has not previously been determined for any secretin. To identify residues involved in gating the pIV secretin of filamentous bacteriophage f1, we used random mutagenesis of the gene followed by positive selection for mutants with compromised barrier function (‘leaky’ mutants). We identified mutations in 34 residues, 30 of which were clustered into two regions located in the centre of the conserved C‐terminal secretin family domain: GATE1 (that spanned 39 residues) and GATE2 (that spanned 14 residues). An internal deletion constructed in the GATE2 region resulted in a severely leaky phenotype. Three of the four remaining mutations are located in the region that encodes the N‐terminal, periplasmic portion of pIV and could be involved in triggering gate opening. Two missense mutations in the 24‐residue region that separates GATE1 and GATE2 were also constructed. These mutant proteins were unstable, defective in multimerization and non‐functional.     

Three‐dimensional (3‐D) fluorescence spectroscopy analysis of the fluorescent dissolved organic matter released by the marine toxic dinoflagellate Alexandrium catenella exposed to metal stress by zinc or lead

We investigated the effects of zinc or lead on growth and on exudation of fluorescent dissolved organic matter (FDOM) by the marine toxic dinoflagellate Alexandrium catenella (Whedon & Kofoid) Balech. The species was exposed to increasing free zinc (1.34 × 10^?7 M–3.98 × 10^?6 M) or lead (5.13 × 10^?9 M–1.82 × 10^?7 M) concentra‐tions. Low metal levels ([Zn²⁺] = 1.34 × 10^?7 M; [Pb²⁺] = 5.13 × 10^?9 M) had no effect on cell growth. Toxic effects were observed from higher metal contamination ([Zn²⁺] = 3.98 × 10^?6 M; [Pb²⁺] = 6.54 × 10^?8 M), as a conversion of vegetative cells into cysts. Analysis of the released FDOM by three‐dimensional (3‐D) fluorescence spectroscopy was achieved, using the parallel factor analysis (PARAFAC). The PARAFAC modeling revealed four components associated with two contributions: one related to the biological activity; the other linked to the organic matter decomposition in the culture medium. The C1 component combined a tryptophan peak and characteristics of humic substances, whereas the C2 component was considered as a tryptophan protein fluorophore. The two others C3 and C4 components were associated with marine organic matter production. Relea‐sed fluorescent substances were induced by low ([Zn²⁺]= 1.34 × 10^?7 M; [Pb²⁺] = 5.13 × 10^?9 M) and moderate ([Zn²⁺] = 6.21 × 10^?7 M; [Pb²⁺] = 2.64× 10^?9 M) metal concentrations, suggesting the activation of cellular mechanisms in response to metal stress, to exudate FDOM that could complex metal cations and reduce their toxicity toward A. catenella cells.     

The role of glucosinolates and the jasmonic acid pathway in resistance of Arabidopsis thaliana against molluscan herbivores

Although slugs and snails play important roles in terrestrial ecosystems and cause considerable damage on a variety of crop plants, knowledge about the mechanisms of plant immunity to molluscs is limited. We found slugs to be natural herbivores of Arabidopsis thaliana and therefore investigated possible resistance mechanisms of this species against several molluscan herbivores. Treating wounded leaves with the mucus residue (‘slime trail’) of the Spanish slug Arion lusitanicus increased wound‐induced jasmonate levels, suggesting the presence of defence elicitors in the mucus. Plants deficient in jasmonate biosynthesis and signalling suffered more damage by molluscan herbivores in the laboratory and in the field, demonstrating that JA‐mediated defences protect A. thaliana against slugs and snails. Furthermore, experiments using A. thaliana mutants with altered levels of specific glucosinolate classes revealed the importance of aliphatic glucosinolates in defending leaves and reproductive structures against molluscs. The presence in mollusc faeces of known and novel metabolites arising from glutathione conjugation with glucosinolate hydrolysis products suggests that molluscan herbivores actively detoxify glucosinolates. Higher levels of aliphatic glucosinolates were found in plants during the night compared to the day, which correlated well with the nocturnal activity rhythms of slugs and snails. Our data highlight the function of well‐known antiherbivore defence pathways in resistance against slugs and snails and suggest an important role for the diurnal regulation of defence metabolites against nocturnal molluscan herbivores.     

The dual nature of haemocyanin in the establishment and persistence of the squid–vibrio symbiosis

We identified and sequenced from the squid Euprymna scolopes two isoforms of haemocyanin that share the common structural/physiological characteristics of haemocyanin from a closely related cephalopod, Sepia officinalis, including a pronounced Bohr effect. We examined the potential roles for haemocyanin in the animal''s symbiosis with the luminous bacterium Vibrio fischeri. Our data demonstrate that, as in other cephalopods, the haemocyanin is primarily synthesized in the gills. It transits through the general circulation into other tissues and is exported into crypt spaces that support the bacterial partner, which requires oxygen for its bioluminescence. We showed that the gradient of pH between the circulating haemolymph and the matrix of the crypt spaces in adult squid favours offloading of oxygen from the haemocyanin to the symbionts. Haemocyanin is also localized to the apical surfaces and associated mucus of a juvenile-specific epithelium on which the symbionts gather, and where their specificity is determined during the recruitment into the association. The haemocyanin has an antimicrobial activity, which may be involved in this enrichment of V. fischeri during symbiont initiation. Taken together, these data provide evidence that the haemocyanin plays a role in shaping two stages of the squid–vibrio partnership.     

Proteomic analysis of human substantia nigra identifies novel candidates involved in Parkinson's disease pathogenesis

Parkinson's disease (PD) pathology spreads throughout the brain following a region‐specific process predominantly affecting the substantia nigra (SN) pars compacta. SN exhibits a progressive loss of dopaminergic neurons responsible for the major cardinal motor symptoms, along with the occurrence of Lewy bodies in the surviving neurons. To gain new insights into the underlying pathogenic mechanisms in PD, we studied postmortem nigral tissues dissected from pathologically confirmed PD cases (n = 5) and neurologically intact controls (n = 8). Using a high‐throughput shotgun proteomic strategy, we simultaneously identified 1795 proteins with concomitant quantitative data. To date, this represents the most extensive catalog of nigral proteins. Of them, 204 proteins displayed significant expression level changes in PD patients versus controls. These were involved in novel or known pathogenic processes including mitochondrial dysfunction, oxidative stress, or cytoskeleton impairment. We further characterized four candidates that might be relevant to PD pathogenesis. We confirmed the differential expression of ferritin‐L and seipin by Western blot and demonstrated the neuronal localization of gamma glutamyl hydrolase and nebulette by immunohistochemistry. Our preliminary findings suggest a role for nebulette overexpression in PD neurodegeneration, through mechanisms that may involve cytoskeleton dynamics disruption. All MS data have been deposited in the ProteomeXchange with identifier PXD000427 ( http://proteomecentral.proteomexchange.org/dataset/PXD000427 ).     

Active immunization to tumor necrosis factor-α is effective in treating chronic established inflammatory disease: a long-term study in a transgenic model of arthritis

Introduction

Chicken type II collagen (CCII) is a protein extracted from the cartilage of chicken breast and exhibits intriguing possibilities for the treatment of autoimmune diseases by inducing oral tolerance. A 24-week, double-blind, double-dummy, randomized, methotrexate (MTX)-controlled study was conducted to evaluate the efficacy and safety of CCII in the treatment of rheumatoid arthritis (RA).

Methods

Five hundred three RA patients were included in the study. Patients received either 0.1 mg daily of CCII (n = 326) or 10 mg once a week of MTX (n = 177) for 24 weeks. Each patient was evaluated for pain, morning stiffness, tender joint count, swollen joint count, health assessment questionnaire (HAQ), assessments by investigator and patient, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) by using the standard tools at baseline (week 0) and at weeks 12 and 24. Additionally, rheumatoid factor (RF) was evaluated at weeks 0 and 24. Measurement of a battery of biochemical parameters in serum, hematological parameters, and urine analysis was performed to evaluate the safety of CCII.

Results

Four hundred fifty-four patients (94.43%) completed the 24-week follow-up. In both groups, there were decreases in pain, morning stiffness, tender joint count, swollen joint count, HAQ, and assessments by investigator and patient, and all differences were statistically significant. In the MTX group, ESR and CRP decreased. RF did not change in either group. At 24 weeks, 41.55% of patients in the CCII group and 57.86% in the MTX group met the American College of Rheumatology 20% improvement criteria (ACR-20) and 16.89% and 30.82%, respectively, met the ACR 50% improvement criteria (ACR-50). Both response rates for ACR-20 and ACR-50 in the CCII group were lower than those of the MTX group, and this difference was statistically significant (P < 0.05). The DAS28 (disease activity score using 28 joint counts) values of the two treatment groups were calculated, and there was a statistically significant difference between the two treatment groups (P < 0.05). Gastrointestinal complaints were common in both groups, but there were fewer and milder side effects in the CCII group than in the MTX group. The incidence of adverse events between the two groups was statistically significant (P < 0.05).

Conclusions

CCII is effective in the treatment of RA and is safe for human consumption. CCII exerts its beneficial effects by controlling inflammatory responses through inducing oral tolerance in RA patients.

Trials Registration

Clinical trial registration number: ChiCTR-TRC-00000093.