Application de la spectroscopie infrarouge (NIRS) dans l’évaluation des adaptations musculaires périphériques chez l’enfant cardiaque

Objective. – The purpose of this work is to study the muscular responses in children with congenital heart disease using near infrared spectroscopy during isometric exercise.Materials and methods. – Twelve healthy children and eight children with congenital heart disease (class II and III NYHA) performed an isometric knee extension on Cybex Norm. For every subject, maximal voluntary contraction (MVC) and endurance time (TE) at 50% of MVC was assessed. The near infrared spectroscopy (NIRS) has been used to assess muscular oxygenation (SmO₂) and of blood volume (VS) during exercise and recovery. Half time recovery of the SmO₂ (1/2 Trec) has been also measured.Results. – Cardiac subjects developed MVC and TE weaker than healthy subjects (MVC: 96.1 ±5.0 vs 125.1 ±6.7 N·m; P <0.01) and (TE: 60.88 ±5.7 vs 116.5 ±8.7 secondes; P <0.001). No significant difference of the SmO₂ and the VS has been noted at rest. The SmO₂ decrease rapidly to reach a plateau at 25% of TE in the healthy subjects, whereas the cardiac subjects reach this plateau at 50% of TE. During recovery, 1/2 Trec is significantly higher in cardiac subjects compared to healthy subjects (26.6 ±1.8 secondes vs 18.9 ±1.9 secondes; respectively, P <0.05).Conclusion. – A decreased muscular performance accompanied with oxygenation and blood volume abnormalities has been found in children with congenital heart diseases. The NIRS is a valuable non-invasive technique for assessment of oxygenation and blood volume during exercise.     

Effect of sensory stimulus on striatal dopamine release in humans and cats: a [(11)C]raclopride PET study

BACKGROUND: Sensory stimulation of the forelimb extremities constitutes a well-established experimental model that has consistently shown to activate dopamine (DA) neurotransmission in the mammals' forebrain. OBJECTIVES: To visualize in vivo this modification of striatal DA release in healthy human volunteers using Positron Emission Tomography (PET) and [(11)C]raclopride. Experiments in humans were paralleled by experiments in anesthetized cats. Changes in endogenous DA release were assessed through its competition with [(11)C]raclopride binding (BP(raclo)), a radioligand probing DA D2-receptors. RESULTS: In humans no significant difference of BP(raclo) in caudate (with sensory stimulation: 2.0 +/- 0.3 versus without sensory stimulation: 2.2 +/- 0.3; P = 0.3) or putamen (2.6 +/- 0.3 versus 2.6 +/- 0.2; P = 0.9) ipsilateral to the stimulus was disclosed as a result of sensory stimulation. Similarly, no change of BP(raclo) was observed contralaterally to the stimulation in the caudate nucleus (with sensory stimulation: 2.0 +/- 0.4 versus without sensory stimulation: 2.1 +/- 0.2; P = 0.5) and the putamen (2.5 +/- 0.4 versus 2.6 +/- 0.2; P = 0.4). In cats the same results were obtained in the ipsilateral to stimulation striatum (with sensory stimulation: 2.5 +/- 0.03 versus without sensory stimulation: 2.4 +/- 0.05; P = 0.7). No change was also observed contralaterally to the stimulation (2.4 +/- 0.04 versus 2.5 +/- 0.06; P = 0.6). The [(11)C]raclopride binding remained unchanged by sensory stimuli in both humans and cats. CONCLUSION: This suggests that the DA release induced by sensory stimulus is mostly extrasynaptic whereas the synaptic DA release is probably small, which fits well with the absence of [(11)C]raclopride displacement. The mechanism of this extrasynaptic DA release could be related to a local action of glutamate on dopaminergic terminals via a thalamo-cortico-striatal loop. Present results also underline homology between cat and human responses to sensory stimuli and validate the use of cat brain to find physiological concepts in humans.     

Exon identity influences splicing induced by exonic variants and in silico prediction efficacy

BackgroundMinigenes and in silico prediction tools are commonly used to assess the impact on splicing of CFTR variants. Exon skipping is often neglected though it could impact the efficacy of targeted therapies. The aim of the study was to identify exon skipping associated with CFTR variants and to evaluate in silico predictions of seven freely available software.MethodsCFTR basal exon skipping was evaluated on endogenous mRNA extracted from non-CF nasal cells and on two CFTR minigene banks. In silico tools and minigene systems were used to evaluate the impact of CFTR exonic variants on exon skipping.ResultsData showed that out of 65 CFTR variants tested, 26 enhanced exon skipping and that in silico prediction efficacy was of 50%-66%. Some in silico tools presented predictions with a bias towards the occurrence of splicing events while others presented a bias towards the absence of splicing events (non-detection including true negatives and false negatives). Classification of exons depending on their basal exon skipping level increased prediction rates up to 80%.ConclusionThis study indicates that taking basal exon skipping into account could orientate the choice of the in silico tools to improve prediction rates. It also highlights the need to validate effects using in vitro assays or mRNA studies in patients. Eventually, it shows that variant-guided therapy should also target exon skipping associated with variants.     

Leveraging Clinical Digitized Data to Understand Temporal Characteristics and Outcomes of Acute Myocardial Infarctions at a Tertiary Care Medical Centre in Pakistan from 1988–2018 – Methods and Results

Background and Objective:Few data exist on trends in acute myocardial infarction (AMI) patterns spanning recent epidemiological shifts in low middle-income countries (LMICs). To understand temporal disease patterns of AMI characteristics and outcomes between 1988–2018, we used digitized legacy clinical data at a large tertiary care centre in Pakistan.Methods:We reviewed digital health information capture systems maintained across the Aga Khan University Hospital and obtained structured elements to create a master dataset. We included index admissions of patients >18 years that were discharged between January 1, 1988, and December 31, 2018, with a primary discharge diagnosis of AMI (using ICD-9 diagnoses). The outcome evaluated was in-hospital mortality.Clinical characteristics derived from the electronic database were validated against chart review in a random sample of cases (k 0.53–1.00).Results:The final population consisted of 14,601 patients of which 30.6% (n = 4,470) were female, 52.4% (n = 7,651) had ST elevation MI and 47.6% (n = 6,950) had non-ST elevation MI. The median (IQR) age at presentation was 61 (52–70) years. Overall unadjusted in-hospital mortality was 10.3%. Across the time period, increasing trends were noted for the following characteristics: age, proportion of women, prevalence of hypertension, diabetes, proportion with NSTEMI (all p_trend < 0.001). In-hospital mortality rates declined significantly between 1988–1997 and 2008–2018 (13.8% to 9.2%, p < 0.001).Conclusions:The patterns of AMI have changed over the last three decades with a concomitant decline in in-hospital mortality at a tertiary care centre in Pakistan. Clinical digitized data presents a unique opportunity for gaining insights into disease patterns in LMICs.     

Noninvasive ventilation during exercise training improves exercise tolerance in patients with chronic obstructive pulmonary disease

PURPOSE: In patients with chronic obstructive pulmonary disease, pulmonary rehabilitation has been demonstrated to increase exercise capacity and reduce dyspnea. In the most disabled patients, the intensity of exercise during the training sessions is limited by ventilatory pump capacity. This study therefore evaluated the beneficial effect of noninvasive ventilation (NIV) support during the rehabilitation sessions on exercise tolerance. METHODS: This study included 14 patients with stabilized chronic obstructive pulmonary disease, ages 63 +/- 7 years, with a forced expiratory volume in 1 second (FEV(1)) 31.5% +/- 9.2% of predicted value. All 14 patients participated in an outpatient pulmonary rehabilitation program. Seven of the patients trained with NIV during the exercise sessions (NIV group), whereas the remaining seven patients breathed spontaneously (control group). Exercise tolerance was evaluated during an incremental exercise test and during constant work rate exercise at 75% of peak oxygen consumption (VO(2)) before and after the training program. RESULTS: The application of noninvasive ventilation increased exercise tolerance, reduced dyspnea, and prevented exercise-induced oxygen desaturation both before and after training. The pressure support was well tolerated by all the patients during the course of the training program. In the NIV group, training induced a greater improvement in peak VO(2) (18% vs 2%; P <.05) and a reduced ventilatory requirement for maximal exercise, as compared with the control group. The constant work rate exercise duration increased similarly in both groups (116% vs 81%, nonsignificant difference), and posttraining blood lactate was decreased at isotime (P <.05 in both groups), but not at the end of the exercise. CONCLUSION: In this pilot study, exercise training with noninvasive ventilation support was well tolerated and yielded further improvement in the increased exercise tolerance brought about by pulmonary rehabilitation in patients with chronic obstructive pulmonary disease. This improved exercise tolerance is partly explained by a better ventilatory adaptation during exercise.     

Retrospective Detection and Complete Genomic Sequencing of Canine morbillivirus in Eurasian Otter (Lutra lutra) Using Nanopore Technology

The Eurasian otter (Lutra lutra) is a piscivorous apex predator in aquatic habitats, and a flagship species of conservation biology throughout Europe. Despite the wide distribution and ecological relevance of the species, there is a considerable lack of knowledge regarding its virological and veterinary health context, especially in Central Europe. Canine morbillivirus (Canine distemper virus (CDV)) is a highly contagious viral agent of the family Paramyxoviridae with high epizootic potential and veterinary health impact. CDV is present worldwide among a wide range of animals; wild carnivores are at particular risk. As part of a retrospective study, lung-tissue samples (n = 339) from Eurasian otters were collected between 2000 and 2021 throughout Hungary. The samples were screened for CDV using a real-time RT-PCR method. Two specimens proved positive for CDV RNA. In one sample, the complete viral genome was sequenced using a novel, pan-genotype CDV-specific amplicon-based sequencing method with Oxford Nanopore sequencing technology. Both viral sequences were grouped to a European lineage based on the hemagglutinin-gene phylogenetic classification. In this article, we present the feasibility of road-killed animal samples for understanding the long-term dynamics of CDV among wildlife and provide novel virological sequence data to better understand CDV circulation and evolution.     

Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop

We have a previously reported that interleukin-10 (IL-10) is a potent but IL-6-unrelated growth factor for freshly explanted myeloma cells (Lu et al, Blood 85:2521, 1995). We have also shown that exogenous IL- 10 supported the growth of XG-1 and XG-2 human myeloma cell lines (HMCL) through an IL-6-independent mechanism. (Lu et al, Blood 85:2521, 1995). Because the IL-10 receptor does not involve the gp 130 IL-6 transducer, we have attempted to elucidate the mechanisms of IL-10 action on myeloma cells. Our results indicate that the myeloma cell growth factor activity of IL-10 was abrogated by an antibody to the gp 130 IL-6 transducer, indicating that it was mediated through one of the gp 130-activating cytokines. We found that myeloma cells from XG-1 and XG-2 HMCL and from 5 of 6 patients' tumoral samples produced oncostatin M (OM) constitutively but failed to produce IL-6, IL-11 and leukemia- inhibitory factor (LIF). The autocrine OM was inactive in the absence of IL-10 due to lack of a functional OM receptor on myeloma cells. IL- 10, by inducing the receptor for LIF (LIFR), produced a functional autocrine OM loop in XG-1 and XG-2 cells and in primary myeloma cells from 2 patients. We also found that some myeloma cell lines (XG-4, XG- 6, and XG-7) an fresh myeloma cells from 3 of 6 patients produced an autocrine IL-10 and that these cells constitutively expressed LIFR. One HMCL (XG-7) produced IL-10, OM, and IL-6 an expressed LIFR. The XG-7 cells used OM and IL-6 as autocrine growth factors. We have previously shown that IL-10 could induce IL-11 receptor in myeloma cells and confer on them sensitivity to IL-11 (Lu et al, FEBS Lett 377:515, 1995). Taken together, these results show that IL-10 is a key cytokine for inducing the expression of LIFR and IL-11R and possibly another uncharacterized OM coreceptor on myeloma cells and that OM and IL-10 might be produced by myeloma cells. They also emphasize that all myeloma cell growth factors reported to data involve an activation of the gp130 IL-6 transducer.