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G q proteins are universally important for signal transduction in mammalian cells. The underlying kinetics and transformation from extracellular stimuli into intracellular signaling, however could not be investigated in detail so far. Here we present the human Neuropsin (hOPN5) for specific and repetitive manipulation of G q signaling in vitro and in vivo with high spatio-temporal resolution. Properties and G protein specificity of hOPN5 are characterized by UV light induced IP 3 generation, Ca 2+ transients and inhibition of G IRK channel activity in HEK cells. In adult hearts from a transgenic animal model, light increases the spontaneous beating rate. In addition, we demonstrate light induced contractions in the small intestine, which are not detectable after pharmacological G q protein block. All-optical high-throughput screening for TRPC6 inhibitors is more specific and sensitive than conventional pharmacological screening. Thus, we demonstrate specific G q signaling of hOPN5 and unveil its potential for optogenetic applications. Gq proteins are one of four major classes of G proteins; optogenetic receptors for selective and repetitive activation of Gq proteins with fast kinetics are lacking. Here the authors report UV light-dependent Gq signalling using human Neuropsin (hOPN5) and demonstrate its potential as an optogenetic tool.

Intensive care unit-acquired weakness (ICUAW) is one of the most common causes of muscle atrophy and functional disability in critically ill intensive care patients. Clinical examination, manual muscle strength testing and monitoring are frequently hampered by sedation, delirium and cognitive impairment. Many different attempts have been made to evaluate alternative compliance-independent methods, such as muscle biopsies, nerve conduction studies, electromyography and serum biomarkers. However, they are invasive, time-consuming and often require special expertise to perform, making them vastly impractical for daily intensive care medicine. Ultrasound is a broadly accepted, non-invasive, bedside-accessible diagnostic tool and well established in various clinical applications. Hereby, neuromuscular ultrasound (NMUS), in particular, has been proven to be of significant diagnostic value in many different neuromuscular diseases. In ICUAW, NMUS has been shown to detect and monitor alterations of muscles and nerves, and might help to predict patient outcome. This narrative review is focused on the recent scientific literature investigating NMUS in ICUAW and highlights the current state and future opportunities of this promising diagnostic tool.

Patients suffering from critical illness are at risk to develop critical illness neuromyopathy (CINM). The underlying pathophysiology is complex and controversial. A central question is whether soluble serum factors are involved in the pathogenesis of CINM. In this study, smooth muscle preparations obtained from the colon of patients undergoing elective surgery were used to investigate the effects of serum from critically ill patients. At the time of blood draw, CINM was assessed by clinical rating and electrophysiology. Muscle strips were incubated with serum of healthy controls or patients in organ baths and isometric force was measured. Fifteen samples from healthy controls and 98 from patients were studied. Ratios of responses to electric field stimulation (EFS) before and after incubation were 118% for serum from controls and 51% and 62% with serum from critically ill patients obtained at day 3 and 10 of critical illness, respectively (p = 0.003, One-Way-ANOVA). Responses to carbachol and high-K + were equal between these groups. Ratios of post/pre-EFS responses correlated with less severe CINM. These results support the existence of pathogenic, i.e. neurotoxic factors in the serum of critically ill patients. Using human colon smooth muscle as a bioassay may facilitate their future molecular identification.

Antral peristalsis is responsible for gastric emptying. Its failure is called gastroparesis and often caused by dysfunction of enteric neurons and interstitial cells of Cajal (ICC). Current treatment options, including gastric electrical stimulation, are non-satisfying and may improve symptoms but commonly fail to restore gastric emptying. Herein, we explore direct optogenetic stimulation of smooth muscle cells (SMC) via the light-gated non-selective cation channel Channelrhodopsin2 (ChR2) to control gastric motor function. We used a transgenic mouse model expressing ChR2 in fusion with eYFP under the control of the chicken-β-actin promoter. We performed patch clamp experiments to quantify light-induced currents in isolated SMC, Ca imaging and isometric force measurements of antral smooth muscle strips as well as pressure recordings of intact stomachs to evaluate contractile responses. Light-induced propulsion of gastric contents from the isolated stomach preparation was quantified in video recordings. We furthermore tested optogenetic stimulation in a gastroparesis model induced by neuronal- and ICC-specific damage through methylene blue photo-toxicity. In the stomachs, eYFP signals were restricted to SMC in which blue light (460 nm) induced inward currents typical for ChR2. These depolarizing currents led to contractions in antral smooth muscle strips that were stronger than those triggered by supramaximal electrical field stimulation and comparable to those evoked by global depolarization with high K concentration. In the intact stomach, panoramic illumination efficiently increased intragastric pressure achieving 239±46% (n=6) of the pressure induced by electrical field stimulation and triggered gastric transport. Within the gastroparesis model, electric field stimulation completely failed but light still efficiently generated pressure waves. We demonstrate direct optogenetic stimulation of SMC to control gastric contractility. This completely new approach could allow for the restoration of motility in gastroparesis in the future.

Spasticity, one of the main symptoms of multiple sclerosis (MS), can affect more than 80% of MS patients during the course of their disease and is often not treated adequately. δ-9-Tetrahydrocannabinol-cannabidiol (THC-CBD) oromucosal spray is a plant-derived, standardized cannabinoid-based oromucosal spray medicine for add-on treatment of moderate to severe, resistant multiple sclerosis-induced spasticity. This article reviews the current evidence for the efficacy and safety, with dizziness and fatigue as the most common treatment-related adverse events, being mostly mild to moderate in severity. Results from both randomized controlled phase III studies involving about,1600 MS patients or 1500 patient-years and recently published studies on everyday clinical practice involving more than 1000 patients or more than,1000 patient-years are presented.

Qualitative assessment by the Heckmatt scale (HS) and quantitative greyscale analysis of muscle echogenicity were compared for their value in detecting intensive care unit-acquired weakness (ICU-AW). We performed muscle ultrasound (MUS) of eight skeletal muscles on day 3 and day 10 after ICU admission. We calculated the global mean greyscale score (MGS), the global mean z-score (MZS) and the global mean Heckmatt score (MHS). Longitudinal outcome was defined by the modified Rankin scale (mRS) and Barthel index (BI) after 100 days. In total, 652 ultrasound pictures from 38 critically ill patients (18 with and 20 without ICU-AW) and 10 controls were analyzed. Patients with ICU-AW had a higher MHS on day 10 compared to patients without ICU-AW (2.6 (0.4) vs. 2.2 (0.4), p = 0.006). The MHS was superior to ROC analysis (cut-off: 2.2, AUC: 0.79, p = 0.003, sensitivity 86%, specificity 60%) in detecting ICU-AW compared to MGS and MZS on day 10. The MHS correlated with the Medical Research Council sum score (MRC-SS) (r = −0.45, p = 0.004), the mRS (r = 0.45; p = 0.007) and BI (r = −0.38, p = 0.04) on day 100. Qualitative MUS analysis seems superior to quantitative greyscale analysis of muscle echogenicity for the detection of ICU-AW.

Background: Intensive care unit-acquired weakness (ICU-AW) is associated with poorer outcome of critically ill patients. Microcirculatory changes and altered vascular permeability of skeletal muscles might contribute to the pathogenesis of ICU-AW. Muscular ultrasound (MUS) displays increased muscle echogenicity, although its pathogenesis is uncertain. Objective: We investigated the combined measurement of serum and ultrasound markers to assess ICU-AW and clinical patient outcome. Methods: Fifteen patients and five healthy controls were longitudinally assessed for signs of ICU-AW at study days 3 and 10 using a muscle strength sum score. The definition of ICU-AW was based on decreased muscle strength assessed by the muscular research council-sum score. Ultrasound echogenicity of extremity muscles was assessed using a standardized protocol. Serum markers of inflammation and endothelial damage were measured. The 3-month outcome was assessed on the modified Rankin scale. Results: ICU-AW was present in eight patients, and seven patients and the control subjects did not develop ICU-AW. The global muscle echogenicity score (GME) differed significantly between controls and patients (mean GME, 1.1 ± 0.06 vs. 2.3 ± 0.41; p = 0.001). Mean GME values significantly decreased in patients without ICU-AW from assessment 1 (2.30 ± 0.48) to assessment 2 (2.06 ± 0.45; p = 0.027), which was not observed in patients with ICU-AW. Serum levels of syndecan-1 at day 3 significantly correlated with higher GME values at day 10 (r = 0.63, p = 0.012). Furthermore, the patients’ GME significantly correlated with mRS at day 100 (r = 0.67, p = 0.013). Conclusion: The combined use of muscular ultrasound and inflammatory biomarkers might be helpful to diagnose ICU-AW and to predict long-term outcome in critical illness. Utiliser l’échographie des muscles et les niveaux sériques de CD138 et de procalcitonine pour évaluer des patients atteints du syndrome de faiblesse acquise aux soins intensifs. Contexte: Le syndrome de faiblesse acquise aux soins intensifs est associé, chez des patients gravement malades, à une évolution davantage défavorable de leur état de santé. À cet effet, il est possible que des modifications de nature microcirculatoire ainsi qu’une perméabilité vasculaire altérée des muscles squelettiques contribuent à la pathogénèse de ce syndrome. Des échographies des muscles peuvent certes indiquer une échogénicité accrue des muscles ; cela dit, la pathogénèse de ce signe clinique demeure incertaine. Objectif: Nous avons analysé la capacité combinée de mesure d’un sérum et de marqueurs utilisés lors d’échographies afin d’évaluer, chez des patients, le syndrome de faiblesse acquise aux soins intensifs ainsi que l’évolution de leur état de santé. Méthodes: Aux jours 3 et 10 de cette étude, quinze patients et cinq témoins en santé ont été évalués de façon longitudinale afin de détecter des signes de faiblesse, et ce, en utilisant un score global mesurant leur force musculaire : le Muscular Research Council-Sum Score (MRC-SS). L’échogénicité de l’extrémité des muscles a été mesurée au moyen d’un protocole normalisé. De plus, des marqueurs sériques d’inflammation et de lésions endothéliales ont été eux aussi mesurés. Au bout de 3 mois, l’évolution de l’état de santé des patients a été évaluée à l’aide de l’échelle de Rankin modifiée. Résultats: Le syndrome de faiblesse acquise aux soins intensifs s’est révélé présent chez huit patients; aucun témoin ne l’a par ailleurs développé. Le score global d’échogénicité des muscles (SGEM) des témoins a différé de façon notable de celui des patients (SGEM moyen 1,1 ± 0,06 contre 2,3 ± 0,41 ; p = 0,001). Les valeurs moyennes au SGEM ont par ailleurs diminué de façon significative chez les patients non atteints par ce syndrome si on compare le jour 3 (2,30 ± 0,48) au jour 10 (2,06 ± 0,45 ; p = 0,027), ce qui n’a pas été observé chez les patients qui en étaient atteints. Les niveaux sériques de protéine CD138 au jour 3 sont apparus étroitement liés à des valeurs plus élevées au SGEM au jour 10 (r = 0,63 ; p = 0,012). En terminant, soulignons que le SGEM des patients est apparu nettement corrélé à l’échelle de Rankin modifiée au jour 100 (r = 0,67 ; p = 0,013). Conclusion: L’utilisation combinée d’échographies des muscles et de biomarqueurs inflammatoires pourrait donc s’avérer utile pour diagnostiquer le syndrome de faiblesse acquise aux soins intensifs et prédire l’évolution de santé à long terme de patients atteints de graves maladies.

Although fatigue is a common symptom in multiple sclerosis (MS), its pathomechanisms are incompletely understood. Glatiramer acetate (GA), an immunomodulatory agent approved for treatment of relapsing-remitting MS (RRMS), possesses unique mechanisms of action and has been shown to exhibit beneficial effects on MS fatigue. The objective of this study was to correlate clinical, neuropsychological, and immunological parameters in RRMS patients with fatigue before and during treatment with GA. In a prospective, open-label, multicenter trial, 30 patients with RRMS and fatigue were treated with GA for 12 months. Inclusion criterion was the presence of fatigue as one of the most frequent and disabling symptoms. Before and during treatment, fatigue was assessed using the Fatigue Severity Scale (FSS), the MS-FSS, and the Modified Fatigue Impact Scale (MFIS). In addition, fatigue and quality of life were assessed using the Visual Analog Scales (VAS). Laboratory assessments included screening of 188 parameters using real-time PCR microarrays followed by further analysis of several cytokines, chemokines, and neurotrophic factors. Fatigue self-assessments were completed in 25 patients. After 12 months of treatment with GA, 13 of these patients improved in all three scales (with the most prominent effects on the MFIS), whereas 5 patients had deteriorated. The remaining 7 patients exhibited inconsistent effects within the three scales. Fatigue and overall quality of life had improved, as assessed via VAS. Laboratory assessments revealed heterogeneous mRNA levels of cytokines, chemokines, and neurotrophic factors. In conclusion, we were not able to correlate clinical and molecular effects of GA in patients with RRMS and fatigue.

Mitochondria are key structures providing most of the energy needed to maintain homeostasis. They are the main source of adenosine triphosphate (ATP), participate in glucose, lipid and amino acid metabolism, store calcium and are integral components in various intracellular signaling cascades. However, due to their crucial role in cellular integrity, mitochondrial damage and dysregulation in the context of critical illness can severely impair organ function, leading to energetic crisis and organ failure. Skeletal muscle tissue is rich in mitochondria and, therefore, particularly vulnerable to mitochondrial dysfunction. Intensive care unit-acquired weakness (ICUAW) and critical illness myopathy (CIM) are phenomena of generalized weakness and atrophying skeletal muscle wasting, including preferential myosin breakdown in critical illness, which has also been linked to mitochondrial failure. Hence, imbalanced mitochondrial dynamics, dysregulation of the respiratory chain complexes, alterations in gene expression, disturbed signal transduction as well as impaired nutrient utilization have been proposed as underlying mechanisms. This narrative review aims to highlight the current known molecular mechanisms immanent in mitochondrial dysfunction of patients suffering from ICUAW and CIM, as well as to discuss possible implications for muscle phenotype, function and therapeutic approaches.