1,721,047 research outputs found
Effecten van IL-6 en IL-8 op ventilatoire en perifere skeletspieren: gevolgen voor systemische inflammatie in COPD.
Full text linkIn my PhD project, the effects of systemic inflammation on respiratoryand peripheral skeletal muscle function were examined. In a first part, we investigated the effects of circulating IL-6 onrespiratory and peripheral skeletal muscle function in rats. Wefound that clinically relevant levels of IL-6 induced a dose-dependentrespiratory and peripheral skeletal muscle atrophy, without alterationsin diaphragm contractile properties. These alterations werelikely caused by a primary effect of IL-6 on the myocardium, as changesin blood flow were observed in both muscle types. In a second part, we examined the effects of circulating IL-8 onrespiratory and peripheral skeletal muscle function in rats. Inthis setting, no deleterious effects of IL-8 were observed withclinically relevant IL-8 plasma levels. Finally, in a last part, we explored whether increased circulatingcytokines could induce a deleterious outcome in patients suffering fromheart valve disease. We found that IL-6, IL-10 and TNF-alpha werethe most important cytokines in patients undergoing myocardial surgerywith the use of extracorporeal circulation. Moreover, the profilededuced from the correlations between IL-6 and haemodynamic variablesin these patients was similar to the type of myocardial failureobserved in rats after exogenous IL-6 administration. Therefore,therapeutic interventions might be considered.status: Publishe
Ventilatie-geïnduceerde diafragma disfunctie: naar een beter begrip
No full textMechanical ventilation is a life-saving therapy for critically ill patients with respiratory failure. However, weaning difficulties are very often encountered and are time-consuming. Although weaning failure may be due to a variety of factors ventilator-induced diaphragm dysfunction may play an important role. Many animal models have consistently shown that controlled mechanical ventilation resulted in a decrease in force-generating capacity and atrophy of the diaphragm. In addition, several alterations such as increased oxidative stress, decreased protein synthesis and increased proteolysis were found in the diaphragm of mechanically ventilated animals. These findings were recently confirmed in human studies. Measurements of transdiaphragmatic pressure during bilateral anterior magnetic stimulation of the phrenic nerve showed that diaphragm force was decreased in mechanically ventilated patients. In addition, human studies have shown a great similarity in underlying mechanisms for ventilator-induced diaphragm dysfunction with animal models. Atrophy of diaphragm fibers was found in mechanically ventilated patients and is associated with increased oxidative stress and an increase in proteolysis biomarkers. Since mechanically ventilated patients are often treated with corticosteroids and a very high dose (80mg/kg) of corticosteroids seems to be protective against ventilator-induced diaphragm dysfunction, the first aim of this thesis was to examine whether lower doses of corticosteroids would also protect the diaphragm from the deleterious effects of controlled mechanical ventilation. On the other hand, the development of preventive strategies is an important clinical issue. Therefore, two different preventive strategies were developed. First we examined whether the administration of an anti-oxidant commonly used in the clinical practice, N-acetylcysteine, would protect the diaphragm against ventilator-induced disturbances in diaphragmatic redox-balance and thereby, prevent ventilator-induced diaphragmatic contractile dysfunction and proteolysis. The last aim of this thesis was to examine whether the administration of a proteasome inhibitor, bortezomib, would protect the diaphragm from atrophy and contractile dysfunction caused by controlled mechanical ventilation. The effects of corticosteroids on the diaphragm during controlled mechanical ventilation depended on the dose administered since decreased diaphragm force and atrophy were prevented with high dose (30mg/kg) corticosteroids and worsened with low dose (5mg/kg). Administration of N-acetylcysteine, an antioxidant, concomitantly with 24h of controlled mechanical ventilation prevented diaphragm contractile dysfunction caused by controlled mechanical ventilation and inhibited calpain, caspase-3 and 20S proteasome activity. Finally, the administration of bortezomib, a selective 20S proteasome inhibitor, resulted in a partial protection against ventilator-induced diaphragm dysfunction. Bortezomib had no effect on the calpain activity, while it partially inhibited caspase-3 activity. In conclusion, this doctoral thesis showed that the deleterious effects of controlled mechanical ventilation on the diaphragm can be prevented or minimized while using different strategies. In particular, the inhibition of the calpain and the caspase-3 system seems to be the most efficient strategy to achieve this goal as shown in the study with high dose corticosteroid administration or with N-acetylcysteine. Importantly, when this system is either not inhibited as was the case with a low dose corticosteroids or not fully inhibited as was the case with bortezomib treatment, only a partial prevention is obtained. The beneficial effect of high dose corticosteroids was associated with an inhibition of calpain activity and caspase-3 activity, but to a lesser extent. Interestingly, the beneficial role of N-acetylcysteine in this model was probably related to the ability of N-acetylcysteine to inhibit calpain and caspase-3 activity together with its anti-oxidant properties. This doctoral thesis clearly demonstrated the role of Ca2+-dependent proteases in ventilator-induced diaphragm dysfunction.status: Publishe
Moleculaire screening en functie analyse van de vastus lateralis spier in patienten met een acute COPD exacerbatie
Full text linkInleiding en doelstelling Chronisch obstructief longlijden (COPD) is een traag progressieve ziekte gekenmerkt door luchtweg obstructie, inflammatie en een geleidelijk verl ies van longfunctie. Naast effecten in de long heeft COPD talrijke systemische c o-morbiditeiten, zoals ondermeer voedingsproblemen, cardiovasculaire effecten en spierzwa kte. Een acute COPD exacerbatie wordt gekenmerkt door een verdere toename van inflammatie en een verdere daling van de spierfunctie en lijdt in vele gevallen tot hospitalisatie. Na ontslag ui t het ziekenhuis is er slechts een zeer langzaam herstel van de spierfunctie. Bovendien zijn patienten waarvan de spierkracht niet herstelt meer vatba ar voor heropname voor een volgende exacerbatie. De doelstellingen van dit doctoraatsproject waren 1) een beter inzicht k rijgen in de moleculaire mechanismen betrokken bij spierfunctie verlies tijdens hospitalisatie voor een acute exacerbatie. Daartoe werden lokale express ie niveaus van anabole (insulin-like growth factor-1 (IGF-I), MyoD en myoge nine) en catabole (interleukine-6 (IL-6), IL-8 en tumor necrosis factor-α (TNF-α)) merkers gemeten in de vastus lateralis spier van patienten die gehospitaliseerd zijn voor een acute COPD exacerbatie. Tevens werd een microarray analyse uitgevoerd op spierweefsel van deze patienten. 2) Nag aan of weerstandstraining tijdens hospitalisatie verdere spierverzwakking kan tegengaan. Resultaten Expressie van MyoD en IGF-I waren gedaald in de vastus lateralis tijdens hospitalisatie. Een correlatie van MyoD expressieniveaus en spierkracht werd aangetoond. Deze resultaten vormen moleculair bewijs dat deconditionering een rol speelt in de verdere spierverzwakking tijdens hospitalisatie voor een acute exacerbat ie. Analyse van lokale expressie niveaus van IL-6, IL-8 en TNF-α leverd e geen bewijs voor lokale inflammatie in de vastus lateralis tijdens hospitalis atie. Uit de microarray analyse bleek dat expressie van genen betrokken in ubiquitine-gerelateerde eiwit afbraak, apoptose en het anti-oxidant meta bolisme opwaarts gereguleerd en genen betrokken in mitochondriale respiratie en aspartaat metabolisme neerwaarts gereguleerd waren. Real time PCR kon de ze bevindingen bevestigen door het aantonen van toegenomen expressie van de spierspecifieke E3 ubiquitine-ligases MURF-1 en MAFbx en een gedaalde expressie van COX6 C, een merker van mitochondriale respiratie. Tevens suggereerde de microarray a nalyse een toegenomen expressie van leden van de Akt/FOXO signalisatie. Dit vor mt mogelijk een link tussen gedaalde IGF-I expressie niveaus en toegenomen proteasoom-gemedieerde eiwit afbraak. Zowel deconditionering, inflammati e en het gebruik van corticosteroiden allemaal een mogelijke rol spelen in he t onstaan van de huidige resultaten. Weerstandstraining gedurende zeven dagen tijdens hospitalisatie leidde t ot een toename van de spierkracht, een daling van myostatine en een trend v oor een hogere myogenine/MyoD ratio. De anabolische catabolische index suggere erde toegenomen anabolisme in de getrainde patienten. Deze resultaten geven a an dat een kort programma van weerstandstraining tijdens hospitalizatie kan lei den tot bescherming van de spierfunctie. Besluit en toekomstige studies Hospitalisatie voor een acute exacerbatie beinvloedt meerdere moleculaire mechanismen in de spier. De invloed van deconditionering, systemische inflammatie en behandeling met corticosteroiden vormen belan grijke oorzaken. Een beter begrip van de moleculaire mechanismen betrokken bij de ontwikkeling van spierverzwakking kan leiden tot de ontwikkeling van eff iciente therapieen. Weerstandstraining tijdens hospitalisatie beschermt de spier functie en kan leiden tot een beter functioneel herstel na een exacerbatie. Bijk omende strategieen, op maat van de patient, moeten nu ontwikkeld worden om het effect van training tijdens hospitalisatie verder te optimaliseren.status: Publishe
De rol van de vitamine D pathway in de aangeboren immuunrespons in COPD
No full textChronic obstructive pulmonary disease (COPD) is a chronic lung disease affecting millions of people worldwide. Enhanced inflammatory responses within the airways is one of the key characteristics in the pathophysiology of COPD. Although cigarette smoking is the major risk factor, only around 20% of smokers actually develop COPD. Therefore, other risk factors must be involved in COPD onset and progression. We hypothesize that vitamin D deficiency, which is highly prevalent worldwide and even more so in COPD patients, could be such a risk factor for COPD onset and progression because of its anti-inflammatory and antibacterial potential.
The use of our established mouse model of CS-induced COPD allowed us to elucidate whether vitamin D deficiency is a causal contributing factor to COPD onset and progression. In Chapter 3, we demonstrate that vitamin D deficiency greatly enhances airway and parenchymal inflammation in a mouse model of subacute and chronic CS exposure, resulting in early onset of emphysema and consistent lung hyperinflation. Our data further strengthen the epidemiological associations that link vitamin D deficiency to COPD onset and progression (lung function decline, exacerbations).
Respiratory bacterial infections, such as nontypeable Haemophilus influenzae (NTHi), are the major trigger for COPD exacerbations and amplify the ongoing inflammation in COPD. In Chapter 4, we have investigated whether vitamin D deficiency may affect bacterial clearance and acute inflammatory response to a respiratory infection with NTHi. Although results are preliminary and additional research is necessary, our results suggest that vitamin D deficiency may amplify acute inflammatory responses directly following NTHi infection, leading to a more rapid clearance of the infection and accompanying inflammation.
As vitamin D deficiency is highly prevalent worldwide, our results implicate that vitamin D may be a promising strategy to prevent COPD onset and progression. However, it is currently not known whether the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), can indeed exert anti-inflammatory and antibacterial functions within CS-compromised airways. By using in vitro cell research, we have demonstrated in Chapter 5 that 1,25(OH)2D dampens levels of important inflammatory mediators (IL-8, TNF-a, MCP-1) released by alveolar macrophages from (non-) smoking subjects and released by cigarette smoke extract (CSE)-treated THP-1 macrophages (cell line model for alveolar macrophages). 1,25(OH)2D furthermore enhanced the release of the important antimicrobial peptide cathelicidin from alveolar macrophages from (non-)smoking subjects and CSE-treated THP-1 macrophages. As we have shown that vitamin D metabolism in THP-1 macrophages is not affected by CS exposure, our results suggest that 1,25(OH)2D can exert its anti-inflammatory and antibacterial functions within the airways of smoking subjects and in this way could potentially decrease susceptibility to COPD in those subjects.
Although our data support the use of vitamin D supplementation as a means for reducing COPD onset and progression, (high-dose) vitamin D supplementation may lead to high serum vitamin D levels, which have been previously associated with increased risk of adverse outcomes. In Chapter 6, we demonstrate that high serum vitamin D levels, resulting from high-dose vitamin D supplementation, enhance characteristic disease features of COPD (emphysema, lung hyperinflation, pulmonary inflammation) in our mouse model of subacute and chronic CS exposure. These results together with the results from Chapter 3 suggest that there may be an optimal range for serum vitamin D levels.
Taken together, our data demonstrate an important role for the vitamin D pathway in COPD onset and progression and support the need for more well-designed intervention studies with vitamin D supplementation.status: Publishe
Veranderingen in de plasticiteit van skeletspieren bij muizen onder invloed van roken, rookstop en vitamine D deficiëntie.
Full text linkCigarette smoking is a prime cause of morbidity and mortality worldwide. It is a major risk factor for the development of cardiovascular diseases, various cancers, respiratory disorders, and skeletal muscle dysfunction. The adverse effects of cigarette smoking beyond the respiratory system has been an area of rising interest, particularly its impact on skeletal muscles. Considering the capital role of skeletal muscles in movement, maintenance of posture, metabolism and vital functions such as respiration, a proper understanding of the manifestations and mechanisms of smoking-induced skeletal muscle dysfunction and development of strategies to curb the ensuing morbidities and mortality is necessary. In humans and animal models the manifestations of smoking-induced skeletal muscle dysfunction include: atrophy, weakness, decreased mitochondrial function and bioenergetics, reduced force and fatigue resistance, decreased protein synthesis, increased proteolysis, capillary regression, reduced vasodilation, decreased perfusion, increased inflammation and oxidative stress.
Smoking cessation is the most efficient and cheapest way to avert these deleterious alterations in skeletal muscle structure and function as a result of smoking. In fact, long term smoking cessation has been shown to restore whole body and skeletal muscle mass, increase muscle mitochondrial function, and improve muscle plasticity in humans and animal models. However, prior to our study, evidence of short-term (1 to 2 weeks) benefits of smoking cessation were lacking. Our study in mice reveals that smoking cessation for as short as 1 to 2 weeks leads to immediate benefits on the diaphragm and limb muscles demonstrated by the reversal of muscle mass loss, recovery of whole body fat and especially lean mass, and improvement of mitochondrial function. We also show that the constantly active diaphragm muscle is most affected by cigarette smoking and recovers rapidly after smoking cessation. Considering the fact that the devastating effects of smoking on skeletal muscles occur slowly and may only manifest later in life, these results are important as they could motivate smokers to stop smoking as soon as possible to avoid long term muscle wasting and weakness.
The maintenance and improvement of skeletal muscle mass and plasticity is highly recommended, especially for people suffering from muscle wasting such as patients with COPD, cancer, dystrophic muscle diseases, chronic smokers and the elderly in whom smoking and vitamin D deficiency is also prevalent. Skeletal muscle hypertrophy is a normal response of skeletal muscles to resistance training and overload which lead to increased mass and fiber cross-sectional area. It is usually accompanied by beneficial adaptations, such as muscle mitochondrial biogenesis, increased protein anabolism, reduced proteolysis, enhanced vasodilatory capacity and capillary proliferation that are associated with an increased force generating capacity and fatigue resistance of the muscle. However, cigarette smoke may impair the hypertrophic response to overload. Vitamin D plays a vital role in skeletal muscle plasticity and regeneration and vitamin D deficiency, which is highly prevalent worldwide, leads to skeletal muscle dysfunction with similar manifestations to those orchestrated by cigarette smoke such as fiber atrophy, loss of muscle mass and muscle mitochondrial dysfunction. Our second study was therefore designed to understand the impact of smoking alone, vitamin D deficiency alone or a combination of these factors on the skeletal muscle hypertrophic response in mice. Our results showed that smoking or vitamin D deficiency alone did not diminish the hypertrophic response to overload in the plantaris muscles, but this hypertrophic response was attenuated in the presence of both conditions, as indicated by the attenuated fiber hypertrophy in vitamin D-deficient smoking mice. Therefore, a combination of these risk factors impairs the skeletal muscle hypertrophic response. These data are relevant for consideration in the design and implementation of strategies to improve muscle mass, especially in smokers and vitamin D deficient individuals.
Our studies report the short-term benefits of smoking cessation that include an improved mitochondrial function and limb muscle mass. This is particularly relevant as an incentive to encourage smoking cessation in healthy smokers and individuals suffering from muscle deterioration yet struggling with smoking cessation. We also show the synergistic deleterious effect of smoking combined with vitamin D deficiency on the skeletal muscle hypertrophic response to overload. This is relevant as it may help in understanding the differences in skeletal muscle response to exercise training and could improve the interventions to restore or improve muscle mass.status: Publishe
Effects of downhill walking in pulmonary rehabilitation for patients with COPD : a randomised controlled trial
No full textThe development of contractile muscle fatigue (CMF) affects training responses in patients with chronic obstructive pulmonary disease (COPD). Downhill walking induces CMF with lower dyspnoea and fatigue than level walking. This study compared the effect of pulmonary rehabilitation (PR) comprising downhill walking training (DT) to PR comprising level walking (conventional training (CT)) in patients with COPD.
In this randomised controlled trial, 35 patients (62 +/- 8 years; forced expiratory volume in 1 s (FEV1) 50 +/- 17% predicted) were randomised to DT or CT. Exercise tolerance (6-minute walk test distance (6MWD); primary outcome), muscle function, symptoms, quality-of-life and physical activity levels were assessed before and after PR. Absolute training changes and the proportion of patients exceeding the 30 m 6MWD minimally important difference (MID) were compared between groups. Quadriceps muscle biopsies were collected after PR in a subset of patients to examine physiological responses to long-term eccentric training.
No between-group differences were observed in absolute 6MWD improvement (mean 6MWD change 77 +/- 46 m DT versus 56 +/- 47 m CT; p=0.45), however 94% of patients in DT exceeded the 6MWD MID compared to 65% in CT (p=0.03). Patients in DT tended to have larger improvements than CT in other outcomes. Muscle biopsy analyses did not differ between groups.
PR incorporating downhill walking confers similar magnitudes of effects to PR with conventional walking across clinical outcomes in patients with COPD, however, offers a more reliable stimulus to maximise the achievement of clinically relevant gains in functional exercise tolerance in people with COPD
Roken-geïnduceerd emfyseem in een muizenmodel
No full textChronic obstructive pulmonary disease (COPD) isdefined as a chronic disease characterized by airflow limitation that isprogressive, not fully reversible and associated with an abnormal inflammatoryresponse of the lungs to noxious particles or gases. Besides the presence ofthe lung disease, COPD is associated with several extrapulmonaryeffects. Of these extrapulmonary effects, skeletal muscle dysfunction is animportant contributor in COPD as it is associated with exercise limitation,reduced quality of life and poor prognosis. To better understand diseaseprogression and skeletal muscle dysfunction in COPD, animal models arefundamental. In the first part of this study, we aimed to develop a cigarettesmoke-induced emphysema mouse model in which systemic effects, in particularmuscle function, could be explored. Since pulmonary function tests areimportant in the diagnosis of human COPD, we evaluated how similar pulmonaryfunction test could be used in mouse models of different respiratory diseases.We first described some invasive pulmonary function parameters to bedisease-specific and disease-sensitive markers. Additionally, we demonstratedthat repeated measurements of lung volumes and lung compliance were useful inthe monitoring of our cigarette smoke-exposed emphysema mouse model. This mousemodel of emphysema was generated by nose-only cigarette smoke exposure and wascharacterized by mild skeletal muscle weakness and fiber-type shifts after 6months of cigarette smoke exposure. Imposing additional risk factors ortherapeutic interventions in vivo will now allow to investigate skeletal muscleweakness in more depth. There isno doubt that the adaptive immune response is involved in the pathogenesis ofCOPD. It still remains unclear against which antigen(s) the immune system isdirected. We aimed to investigate whether induced anti-elastin immunity maycontribute to COPD onset and progression in two murine models of emphysema.Although we showed that our immunization protocol against elastin fragments wassuccessful, an elastin specific immune response did not worsen diseaseprogression compared to emphysematous mice without immunization. In addition,we explored whether peripheral immunity against elastin and collagen could bedetected in human COPD. In contrast to elastin and collagen I, there was a Th1specific immune response present against collagen V in healthy smokers and inCOPD patients,which deserves more attention in the nearby future.status: Publishe
Muscle Microbiopsy to Delineate Stem Cell Involvement in Young Patients: A Novel Approach for Children With Cerebral Palsy
Full text linkCerebral palsy (CP), the single largest cause of childhood physical disability, is characterized firstly by a lesion in the immature brain, and secondly by musculoskeletal problems that progress with age. Previous research reported altered muscle properties, such as reduced volume and satellite cell (SC) numbers and hypertrophic extracellular matrix compared to typically developing (TD) children (>10 years). Unfortunately, data on younger CP patients are scarce and studies on SCs and other muscle stem cells in CP are insufficient or lacking. Therefore, it remains difficult to understand the early onset and trajectory of altered muscle properties in growing CP children. Because muscle stem cells are responsible for postnatal growth, repair and remodeling, multiple adult stem cell populations from young CP children could play a role in altered muscle development. To this end, new methods for studying muscle samples of young children, valid to delineate the features and to elucidate the regenerative potential of muscle tissue, are necessary. Using minimal invasive muscle microbiopsy, which was applied in young subjects under general anaesthesia for the first time, we aimed to isolate and characterize muscle stem cell-derived progenitors of TD children and patients with CP. Data of 15 CP patients, 3-9 years old, and 5 aged-matched TD children were reported. The muscle microbiopsy technique was tolerated well in all participants. Through the explant technique, we provided muscle stem cell-derived progenitors from the Medial Gastrocnemius. Via fluorescent activated cell sorting, using surface markers CD56, ALP, and PDGFRa, we obtained SC-derived progenitors, mesoangioblasts and fibro-adipogenic progenitors, respectively. Adipogenic, skeletal, and smooth muscle differentiation assays confirmed the cell identity and ability to give rise to different cell types after appropriate stimuli. Myogenic differentiation in CP SC-derived progenitors showed enhanced fusion index and altered myotube formation based on MYOSIN HEAVY CHAIN expression, as well as disorganization of nuclear spreading, which were not observed in TD myotubes. In conclusion, the microbiopsy technique allows more focused muscle research in young CP patients. Current results show altered differentiation abilities of muscle stem cell-derived progenitors and support the hypothesis of their involvement in CP-altered muscle growth.sponsorship: This project was funded by an internal KU Leuven grant (C24/18/103) and by Fund Scientific Research Flanders (FWO; grant G0B4619N). MC is the recipient of a predoctoral FWOSB fellowship (grant 1S78419N). DC was supported by internal funding of the KU Leuven Biomedical Science group: Fund for Translational Biomedical Research 2019. (internal KU Leuven grant|C24/18/103, Fund Scientific Research Flanders (FWO)|G0B4619N, KU Leuven Biomedical Science group: Fund for Translational Biomedical Research 2019, FWOSB fellowship|1S78419N)status: Publishe
Perifere en respiratoire spierzwakte op intensieve zorgen: Oorzaken en gevolgen
No full textCritical illness polyneuropathie (CIP) en myopathie (CIM) zijn belangrij ke verwikkelingen van ernstige kritieke ziekte en de behandeling hiervan . CIP/CIM kan bijdragen tot een vertraagd proces van ontwennen van kunst matige beademing en fysieke revalidatie gezien zowel spieren van de lede maten als ademspieren kunnen aangetast zijn. Bovendien vertonen veel pat iënten een verminderde inspanningscapaciteit en levenskwaliteit maanden tot jaren na de acute gebeurtenis. Tot voor kort bestond er geen specifi eke behandeling om CIP/CIM te voorkomen, afgezien van het verminderen va n de risicofactoren. De voornaamste risicofactoren zijn sepsis, systemis che inflammatoire respons syndroom en multipel orgaan falen. Kritiek zie ke patiënten vertonen hyperglycemie als reactie op stress, wat men ook stress diabetes noemt. Hyperglycemie voorspelt overlijden en verwikkeli ngen bij kritiek zieke patiënten. Verschillende prospectieve en retrospe ctieve studies hebben ook aangetoond dat hyperglycemie een risicofactor is voor CIP/CIM. Recent werden 2 grote gerandomiseerde en gecontroleerde studies uitgevoerd in een chirurgische en medische intensieve zorgen af deling die het effect onderzochten van intensieve insuline therapie (IIT ), waarin gestreefd werd naar normoglycemie (80-110 mg/dl), versus conve ntionele insuline therapie (CIT) waarin matige hyperglycmie werd aanvaar d (tot 215 mg/dl). De resultaten toonden een voordeel op morbiditeit en mortaliteit. Een subanalyse van de chirurgische studie toonde dat I IT de elektrofysiologische incidentie van CIP/CIM significant reduceerde , alsook de nood aan verlengde kunstmatige beademing bij patiënten die m instens 1 week op intensieve zorgen verbleven. In dit project hebben we als doel gesteld na te gaan of deze voordelige neuromusculaire effecten van IIT kunnen geëxtrapoleerd worden naar een p opulatie van medisch intensieve zorgen patiënten. Deze patiënten vertone n hogere scores van ziekte ernst bij opname, hetgeen theoretisch de moge lijkheid om preventief te werken kan beperken. Hiertoe hebben we kritiek zieke medische patiënten, die minstens 7 d op de intensieve zorgen afde ling verbleven, wekelijks gescreend dmv routine elektrofysiologisch onde rzoek, bestaande uit electromyografie en zenuwgeleidingsonderzoek. De re sultaten toonden aan dat de elektrofysiologische incidentie van CIP/CIM in de groep patiënten behandeld met IIT significant verminderde van 51% naar 39%. Multivariaat logistieke regressie analyse toonde dat, na corre ctie voor basis risicofactoren en risicofactoren optredend tijdens verbl ijf op intensieve zorgen, IIT een onafhankelijke beschermende factor was . Er werd geen klinische evaluatie van spierkracht uitgevoerd. IIT ging echter ook gepaard met een verminderde nood aan verlengde kunstmatige ve ntilatie, gedefinieerd als kunstmatige ventilatie gedurende minstens 14d , en dit van 47% naar 35%. De elektrofysiologische diagnose van CIP/CIM werd bovendien geïdentificeerd als een onafhankelijke risicofactor voor verlengde kunstmatige ventilatie. Dit suggereert dat de elektrofysiologi sche diagnose van CIP/CIM inderdaad een klinisch relevante diagnose was. Het voordeel van IIT op verlengde kunstmatige ventilatie was gerelateer d aan de totale dosis insuline toegediend. We hebben deze voordelige eff ecten van IIT op de elektrofysiologische incidentie van CIP/CIM verder b evestigd in de dagelijkse zorgen voor de kritiek zieke medische en chiru rgische patiënten, buiten de setting van een gerandomiseerde en gecontro leerde studie. In deze retrospectieve studie hebben we de resultaten ver geleken van elektrofysiologische onderzoeken uitgevoerd bij medische en chirurgische kritiek zieke patiënten, en dit van de periode voor en na d at IIT deel ging uitmaken van de routine dagelijkse praktijk. In de subg roep van langliggers die elektrofysiologisch onderzoek ondergingen, was er een vermindering van de incidentie van CIP/CIM van 74,4% naar 48,7% n a implementatie van IIT als standaard procedure. IIT was opnieuw een ona fhankelijke beschermende factor voor de nood aan verlengde kunstmatige v entilatie. Er was ook een significante vermindering in myogene patronen bij elektrofysiologisch onderzoek, alsook een significante verbetering i n de sensory nerve action potentials van de bovenste ledematen, als surr ogaat merker voor neuropathie. De pathophysiology van CIP/CIM is zeer complex, en nog niet volledig ont rafeld. De bestaande concepten bieden echter interessante behandelingsmo gelijkheden. Het volgende doel in dit project was op een systematische w ijze de evidentie afkomstig van gerandomiseerde en gecontroleerde studie s te onderzoeken, betreffende de evidentie van eender welke interventie om de incidentie van CIP/CIM te verminderen. Deze review werd uitgevoerd op verzoek van de Cochrane bibliotheek en is methodologisch conform de richtlijnen van het Cochrane Handbook for Systematic Reviews. We weerhie lden 9 relevante studies. Twee studies vergeleken IIT met CIT op een tot aal van 825 patiënten. Meta-analyse toonde aan dat IIT de elektrofysiolo gische incidentie van CIP/CIM significant reduceerde in de gescreende po pulatie [relatief risico (RR) 0.65, 95% confidentie interval (CI) 0 .55 tot 0.78] alsook in de totale gerandomiseerde populatie (RR 0. 60, 95% CI 0.49 tot 0.74). Eindpunten die potentieel gerelateerd zijn aa n een verminderde incidentie van CIP/CIM, zoals duur van kunstmatige ven tilatie, duur van verblijf op intensieve zorgen, en 180-dagen mortalitei t maar niet 30-dagen mortaliteit, waren significant verminderd met IIT i n de gescreende populatie alsook in de totaal gerandomiseerde populatie. Dit ging gepaard met een toename in het aantal hypoglycemies, aantal he rhaaldelijke hypoglycemies, maar geen toename in mortaliteit binnen de 2 4 u na hypoglycemie. Een derde studie onderzocht de effecten van cortico steroiden in een populatie van 180 patiënten met aanslepende ARDS. Er we rd geen effect gevonden op de incidentie van CIP/CIM (RR 1.09, 95% CI 0. 53 tot 2.26), mortaliteit na 180 d, nieuwe ernstige infecties, glycemie op dag 7, maar wel een trend tot minder episoden van vermoede of waarsch ijnlijk geachte longontsteking. Het aantal nieuwe episoden van shock was verminderd. In de overblijvende 6 studies ontbraken adequate diagnostis che criteria voor CIP/CIM, waardoor we het primaire eindpunt van de revi ew voor deze studies niet konden kwantificeren. Dit benadrukt de nood aa n het ontwikkelen van adequate diagnostische criteria voor CIP/CIM in he t kader van toekomstig onderzoek. Ten slotte hebben we de reproduceerbaarheid van de techniek van bilatera le anterior magnetische phrenicus stimulatie (BAMPS) geëvalueerd in de s etting van kritiek zieke, kunstmatige beademde patiënten. Wij hebben 7/1 0 kritiek zieke en kunstmatig beademde patiënten gemeten op minstens 2 m omenten. Reproduceerbaarheid van de techniek bleek gelijkaardig als deze bij gezonde vrijwilligers (between-occasion coëfficiënt van variatie 9, 7%). We vonden ook een logaritmische afname van de diafragmakracht gemet en met BAMPS, naar mate de duur van kunstmatige ventilatie toenam (R=0,6 9,p=0.038). Dit verband werd nog niet beschreven in de literatuur. Deze bevindingen passen in het concept van ventilator-geïnduceerde dysfunctie van het diafragma (VIDD). Het concept van VIDD is afkomstig uit omstand ig dierexperimenteel onderzoek dat aantoont dat gecontroleerde kunstmati ge ventilatie op zich aanleiding geeft tot atrofie en zwakte van het dia fragma. Onze resultaten laten niet toe om een causaal verband te maken, en kunnen ook het gevolg zijn van gebruik van verdovende middelen en pij nstillers, alsook van andere cofactoren.status: Publishe
Fine-needle percutaneous muscle microbiopsy technique as a feasible tool to address histological analysis in young children with cerebral palsy and age-matched typically developing children
No full textCerebral palsy (CP) is a heterogeneous group of motor disorders attributed to a non-progressive lesion in the developing brain. Knowledge on skeletal muscle properties is important to understand the impact of CP and treatment but data at the microscopic levels are limited and inconsistent. Currently, muscle biopsies are collected during surgery and are restricted to CP eligible for such treatment or they may refer to another muscle or older children in typically developing (TD) biopsies. A minimally invasive technique to collect (repeated) muscle biopsies in young CP and TD children is needed to provide insights into the early muscle microscopic alterations and their evolution in CP. This paper describes the protocol used to 1) collect microbiopsies of the medial gastrocnemius (MG) and semitendinosus (ST) in CP children and age-matched TD children, 2) handle the biopsies for histology, 3) stain the biopsies to address muscle structure (Hematoxylin & Eosin), fiber size and proportion (myosin heavy chain), counting of the satellite cells (Pax7) and capillaries (CD31). Technique feasibility and safety as well as staining feasibility and measure accuracy were evaluated. Two microbiopsies per muscle were collected in 56 CP (5.8 +/- 1.1 yr) and 32 TD (6 +/- 1.1 yr) children using ultrasound-guided percutaneous microbiopsy technique. The biopsy procedure was safe (absence of complications) and well tolerated (Score pain using Wong-Baker faces). Cross-sectionally orientated fibers were found in 86% (CP) and 92% (TD) of the biopsies with 60% (CP) and 85% (TD) containing more than 150 fibers. Fiber staining was successful in all MG biopsies but failed in 30% (CP) and 16% (TD) of the ST biopsies. Satellite cell staining was successful in 89% (CP) and 85% (TD) for MG and in 70% (CP) and 90% (TD) for ST biopsies, while capillary staining was successful in 88% (CP) and 100% (TD) of the MG and in 86% (CP) and 90% (TD) for the ST biopsies. Intraclass coefficient correlation showed reliable and reproducible measures of all outcomes. This study shows that the percutaneous microbiopsy technique is a safe and feasible tool to collect (repeated) muscle biopsies in young CP and TD children for histological analysis and it provides sufficient muscle tissue of good quality for reliable quantification.This study has been funded by a KULeuven grant C24/18/103 and by a grant from the Research foundation Flanders (FWO) G0B4619N The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript -Jorieke Deschrevel and Nathalie De Beukelaer were supported by a KU Leuven grant Belgium C24/18/103, Marlies Corvelyn was supported by a predoctoral FWO-SB fellowship 1S78419N and Domiziana Costamagna by a KU Leuven grant Fund for Translational Biomedical Research 201
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