Increased amino acid turnover and myofibrillar protein breakdown in advanced cancer are associated with muscle weakness and impaired physical function

Muscle wasting in cancer negatively affects physical function and quality of life. This study investigates amino acid metabolism and the association with muscle mass and function in patients with cancer.In 16 patients with advanced cancer undergoing chemotherapy and 16 healthy controls, we administered an intravenous pulse and prime of stable amino acid tracers. We took blood samples to measure the Rate of appearance (Ra), whole body production (WBP), clearance (Cl), and post absorptive whole body net protein breakdown (WBnetPB). Plasma amino acid concentrations and enrichments were analysed by LC-MS/MS. We assessed muscle mass, handgrip/leg/respiratory muscle strength and reported physical activity, quality of life, and physical function.Muscle strength was lower in cancer patients than in healthy controls. Total and limb muscle mass, reported physical activity and WBnetPB were comparable. WBP and Cl of tau-methylhistidine, leucine, glutamine and taurine were higher in cancer patients as well as glycine Cl. Amino acid metabolism was correlated with low muscle mass, strength, physical function and quality of life.Myofibrillar protein breakdown and production of amino acids involved in muscle contractility are up regulated in patients with cancer undergoing chemotherapy and related to muscle weakness and reduced physical outcomes

Presence or Absence of Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease is Associated With Distinct Phenotypes

Introduction: Reduced skeletal muscle function and cognitive performance are common extrapulmonary features in Chronic Obstructive Pulmonary Disease (COPD) but their connection remains unclear. Whether presence or absence of skeletal muscle dysfunction in COPD patients is linked to a specific phenotype consisting of reduced cognitive performance, comorbidities and nutritional and metabolic disturbances needs further investigation. Methods: Thirty-seven patients with COPD (grade II–IV) were divided into two phenotypic cohorts based on the presence (COPD dysfunctional, n = 25) or absence (COPD functional, n = 12) of muscle dysfunction. These cohorts were compared to 28 healthy, age matched controls. Muscle strength (dynamometry), cognitive performance (Trail Making Test and STROOP Test), body composition (Dual-energy X-Ray Absorptiometry), habitual physical activity, comorbidities and mood status (questionnaires) were measured. Pulse administration of stable amino acid tracers was performed to measure whole body production rates. Results: Presence of muscle dysfunction in COPD was independent of muscle mass or severity of airflow obstruction but associated with impaired STROOP Test performance (p = 0.04), reduced resting O saturation (p = 0.003) and physical inactivity (p = 0.01), and specific amino acid metabolic disturbances (enhanced leucine (p = 0.02) and arginine (p = 0.06) production). In contrast, COPD patients with normal muscle function presented with anxiety, increased fat mass, plasma glucose concentration, and metabolic syndrome related comorbidities (hypertension and dyslipidemia). Conclusion: COPD patients with muscle dysfunction show characteristics of a cognitive – metabolic impairment phenotype, influenced by the presence of hypoxia, whereas those with normal muscle function present a phenotype of metabolic syndrome and mood disturbances

Second intravenous immunoglobulin dose in patients with Guillain-Barre syndrome with poor prognosis (SID-GBS):a double-blind, randomised, placebo-controlled trial

Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (>= 12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of >= 6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1.4 (95% CI 0.6-3.3; p=0.45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products. Copyright (C) 2021 Elsevier Ltd. All rights reserved

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Differential metabolic effects of casein and soy protein meals on skeletal muscle in healthy volunteers

International audienceBackground & aims: Dietary protein intake is known to affect whole body and interorgan protein turnover. We examined if moderate-nitrogen and carbohydrate casein and soy meals have a different effect on skeletal muscle protein and amino acid kinetics in healthy young subjects. Methods: Muscle protein and amino acid kinetics were measured in the postabsorptive state and during 4-h enteral intake of isonitrogenous [0.21 g protein/(kg body weight. 4 h)] protein-based test meals, which contained either casein (CAPM: n = 12) or soy protein (SOPM; n = 10) in 2 separate groups. Stable isotope and muscle biopsy techniques were used to study metabolic effects. Results: The net uptake of glutamate, serine, histidine, and lysine across the leg was larger during CAPM than during SOPM intake. Muscle concentrations of glutamate, serine, histidine, glutamine, isoleucine and BCAA changed differently after CAPM and SOPM (P < 0.05). Muscle net protein breakdown decreased significantly (P < 0.05) to zero during feeding of both CAPM and SOPM, but differences in their (net) breakdown rates were not significant. Muscle protein synthesis was not different between CAPM and SOPM. Conclusion: Moderate-nitrogen casein and soy protein meals differently alter leg amino acid uptake without a significant difference in influencing acute muscle protein metabolism. (C) 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved

Decreased Whole-Body and Splanchnic Glutamate Metabolism in Healthy Elderly Men and Patients with Chronic Obstructive Pulmonary Disease in the Postabsorptive State and in Response to Feeding

Decreased plasma and muscle glutamate concentrations have been observed in patients with chronic obstructive pulmonary disease (COPD), suggesting disturbances in glutamate metabolism. The present study was conducted to further examine glutamate metabolism in 8 male COPD patients (68 +/- 4 y) by measurement of whole-body (WB) glutamate production and splanchnic glutamate extraction in the postabsorptive state as well as in response to feeding. Because COPD is particularly prevalent in the elderly and aging per se may also affect glutamate metabolism, 2 male control groups were included: 8 healthy elderly (63 +/- 3 y) and 8 young (22 +/- 1 y) subjects. On 2 test days, the stable isotope L-15N-glutamate was infused i.v. or enterally according to a primed constant and continuous infusion protocol. After 90 min of infusion, subjects ingested a carbohydrate-protein drink (28% milk protein, 72% maltodextrin) every 20 min for 2 h. Arterialized-venous blood samples were taken at the end of the postabsorptive and feeding periods. Postabsorptive WB glutamate production and splanchnic glutamate extraction were significantly lower in the elderly and COPD patients than in the young (P < 0.01). Feeding further decreased WB endogenous glutamate production in the elderly and COPD patients, with COPD patients tending (P = 0.07) to have a greater decrease. Splanchnic glutamate extraction increased during feeding in the elderly (P < 0.05) but did not change in COPD patients. In conclusion, aging reduces postabsorptive WB endogenous glutamate production and splanchnic glutamate extraction. COPD does not affect postabsorptive WB glutamate metabolism but may influence splanchnic glutamate metabolism during feeding