Fluxomics reveals cellular and molecular basis of increased renal ammoniagenesis.

The kidney plays a critical role in excreting ammonia during metabolic acidosis and liver failure. The mechanisms behind this process have been poorly explored. The present study combines results of in vivo experiments of increased total ammoniagenesis with systems biology modeling, in which eight rats were fed an amino acid-rich diet (HD group) and eight a normal chow diet (AL group). We developed a method based on elementary mode analysis to study changes in amino acid flux occurring across the kidney in increased ammoniagenesis. Elementary modes represent minimal feasible metabolic paths in steady state. The model was used to predict amino acid fluxes in healthy and pre-hyperammonemic conditions, which were compared to experimental fluxes in rats. First, we found that total renal ammoniagenesis increased from 264 ± 68 to 612 ± 87 nmol (100 g body weight)-1 min-1 in the HD group (P = 0.021) and a concomitated upregulation of NKCC2 ammonia and other transporters in the kidney. In the kidney metabolic model, the best predictions were obtained with ammonia transport as an objective. Other objectives resulting in a fair correlation with the measured fluxes (correlation coefficient >0.5) were growth, protein uptake, urea excretion, and lysine and phenylalanine transport. These predictions were improved when specific gene expression data were considered in HD conditions, suggesting a role for the mitochondrial glycine pathway. Further studies are needed to determine if regulation through the mitochondrial glycine pathway and ammonia transporters can be modulated and how to use the kidney as a therapeutic target in hyperammonemia.

[Don't stop medication too abruptly: advice about the discontinuation of medication]. / Stop niet te snel, dan lukt het wél.

Polypharmacy may result in interactions and side effects that lead to morbidity and mortality. Therefore, it is important to evaluate on a regular basis the possibility to stop medication. Sometimes it is necessary to temporarily discontinue certain medication, for example when a patient is unable to swallow or suffers from a delirium. Not all drugs can be stopped abruptly, since this can result in a rebound-effect or withdrawal symptoms Especially drugs that act on the central nervous system (e.g. psychotropic drugs, dopaminergic drugs, opioids) are known to cause (severe) withdrawal symptoms when stopped abruptly In addition, beta-blockers, corticosteroids and proton-pump inhibitors cause symptoms when stopped without tapering. Gradually tapering off these medicines is needed, sometimes under guidance from a specialist. Moreover, it is important to realize that stopping medication can also introduce interactions.

Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019.

BACKGROUND: Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. METHODS: A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K-dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography. RESULTS: dp-ucMGP was elevated in COVID-19 patients compared with controls (P < .001), with even higher dp-ucMGP in patients with poor outcomes (P < .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P < .001) and with coronary artery (P = .002) and thoracic aortic (P < .001) calcification scores. CONCLUSIONS: dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.

Individual Differences in the Effects of Physical Activity on Cognitive Function in People with Mild to Moderate Dementia.

The aim of this study was to investigate whether the effect of physical activity on cognitive function in persons with dementia is moderated by patient characteristics as Apolipoprotein E and dementia type. We included 101 individuals with dementia and calculated the reliable change index to determine the change in global cognition, executive function, episodic memory, working memory, and processing speed before and after a 12-week exercise training. We found a higher treatment-related benefit in episodic memory in persons with non-Alzheimer's disease compared to persons with Alzheimer's disease, and in executive function in individuals with better baseline cognitive function.

Ranking Barriers, Motivators, and Facilitators to Promote Physical Activity Participation of Persons With Dementia: An Explorative Study.

BACKGROUND AND PURPOSE: Community-dwelling persons with dementia are inactive most of the day. The purpose of this study was to rank the barriers, motivators, and facilitators that hamper or promote physical activity (PA) participation for persons with dementia. This could provide knowledge that can be used to design effective interventions to promote PA participation for persons with dementia. METHODS: Twenty community-dwelling persons with dementia, mean (SD) age = 79 (5.4) years, 25% female, mean (SD) Mini-Mental Status Examination score = 23 (3.5); their informal caregivers, N = 20, mean (SD) age = 70 (11.5) years, 85% female; and an expert group of physiotherapists, N = 15, mean (SD) age = 41 (12.4) years, 73% female, were asked to rank preselected barriers, motivators, and facilitators of PA participation for persons with dementia. These statements were categorized at the intrapersonal, interpersonal, and community levels. RESULTS AND DISCUSSION: Persons with dementia and their informal caregivers selected only motivators and facilitators as being important for PA participation, with the motivator "beneficial health effects" considered the most important. The experts had a different perspective on PA participation; half of their ranked top 10 most important factors were barriers to PA participation for persons with dementia. This could be explained by the more critical role of a therapist, focusing on symptom control and treatment of disability; in this case, the elimination of barriers to maintain PA participation in their patients. Furthermore, all groups prioritized statements at the intrapersonal level. CONCLUSIONS: The results of this study suggest a difference in perspective between the more optimistic view of persons with dementia and their informal caregivers and the more critical view of physiotherapy experts regarding the most important factors that influence PA participation. In addition, there was a strong focus on the individual characteristics that influence PA behavior that warrant personalized interventions to promote PA in persons with dementia.

Physical Exercise Training Improves Quality of Life in Healthy Older Adults: A Meta-Analysis.

The current meta-analysis first aimed to quantify the overall effect of physical exercise training on the quality of life (QoL) in healthy older adults. Second, the effects on the social, physical, and psychological QoL were assessed. In total, 16 randomized controlled trials were included. The primary analysis showed a medium effect of physical exercise training on QoL in healthy older adults (standard mean difference [SMD] = 0.38, confidence interval, CI, [0.18, 0.59], p < .05). The secondary analyses showed a positive medium effect of physical exercise training on the physical component of QoL (SMD = 0.39, CI [0.17, 0.60], p < .05), and a positive medium effect of physical exercise training on the psychological component of QoL (SMD = 0.348, CI [0.125, 0.570], p < .05), and no significant effect of physical exercise training on the social component of QoL was observed (SMD = 0.16, CI [-0.07, 0.38], p = .17). These findings warrant implementation efforts pertaining to exercise training for older adults to improve the QoL in our aging societies.

Exergaming as a Physical Exercise Strategy Reduces Frailty in People With Dementia: A Randomized Controlled Trial.

OBJECTIVES: People with dementia are known to be physically frailer, more sedentary, and participate less in regular physical exercise compared to their healthy peers. Physical activity interventions have the potential to reduce the level of frailty in community-dwelling older adults. Exergaming combines physical exercise with cognitive stimulation in a virtual environment. It is an innovative and fun way of exercising, which may aid people with dementia to be more physically active. The primary aim of this study was to investigate the efficacy of a 12-week exergame training and equally long aerobic training, both compared to an active control group, on frailty in people with dementia. DESIGN: A 3-armed randomized controlled trial compared exergame training, aerobic training, and an active control intervention. PARTICIPANTS: 115 people with dementia [mean (standard deviation [SD]) age = 79.2 (6.9) years; mean (SD) Mini-Mental State Examination score = 22.9 (3.4)]. METHODS: Participants were randomized and individually trained 3 times a week during 12 weeks. The Evaluative Frailty Index for Physical activity (EFIP) was used to assess the level of frailty at baseline and after the 12-week intervention period. Between-group differences were analyzed with analysis of covariance. RESULTS: The exergame group showed a trend toward higher adherence compared to the aerobic group (87.3% vs 81.1%, P = .05). A significant reduction on the EFIP was found in the exergame group (EG) compared to the active control group (CG) [mean difference (95% confidence interval) between EG and CG: -0.034 [-0.062, -0.007], P = .012], with a small-to-moderate effect size (partial η2 = 0.055). CONCLUSIONS AND IMPLICATIONS: This is the first study to show that a 12-week exergame intervention reduces the level of frailty in people with dementia. This is an important and promising result, because frailty is a powerful predictor for adverse health outcomes, and its reduction may have positive effects on health status. Moreover, exergaming resulted in high adherence rates of physical exercise, which makes it an effective strategy to engage people with dementia in physical activity.

The quest for synergy between physical exercise and cognitive stimulation via exergaming in people with dementia: a randomized controlled trial.

BACKGROUND: Exercise is often proposed as a non-pharmacological intervention to delay cognitive decline in people with dementia, but evidence remains inconclusive. Previous studies suggest that combining physical exercise with cognitive stimulation may be more successful in this respect. Exergaming is a promising intervention in which physical exercise is combined with cognitively challenging tasks in a single session. The aim of this study was to investigate the effect of exergame training and aerobic training on cognitive functioning in older adults with dementia. METHODS: A three-armed randomized controlled trial (RCT) compared exergame training, aerobic training and an active control intervention consisting of relaxation and flexibility exercises. Individuals with dementia were randomized and individually trained three times a week during 12 weeks. Cognitive functioning was measured at baseline, after the 12-week intervention period and at 24-week follow-up by neuropsychological assessment. The domains of executive function, episodic memory, working memory and psychomotor speed were evaluated. Test scores were converted into standardized z-scores that were averaged per domain. Between-group differences were analysed with analysis of covariance. RESULTS: Data from 115 people with dementia (mean (SD) age = 79.2 (6.9) years; mean (SD) MMSE score = 22.9 (3.4)) were analysed. There was a significant improvement in psychomotor speed in the aerobic and exergame groups compared to the active control group (mean difference domain score (95% CI) aerobic versus control 0.370 (0.103-0.637), p = 0.007; exergame versus control 0.326 (0.081-0.571), p = 0.009). The effect size was moderate (partial η2 = 0.102). No significant differences between the intervention and control groups were found for executive functioning, episodic memory and working memory. CONCLUSIONS: To our knowledge, this is the first RCT evaluating the effects of exergame training and aerobic training on cognitive functioning in people with dementia. We found that both exergame training and aerobic training improve psychomotor speed, compared to an active control group. This finding may be clinically relevant as psychomotor speed is an important predictor for functional decline. No effects were found on executive function, episodic memory and working memory. TRIAL REGISTRATION: Netherlands Trial Register, NTR5581 . Registered on 7 October 2015.

Dementia Patients Are More Sedentary and Less Physically Active than Age- and Sex-Matched Cognitively Healthy Older Adults.

AIMS: The aim of this study was to examine physical activity and sedentary behaviour characteristics of ambulatory and community-dwelling patients with dementia compared to cognitively healthy age-, sex- and weight-matched controls. METHODS: In this cross-sectional study, we included community-dwelling dementia patients (n = 45, age 79.6 ± 5.9 years, Mini-Mental State Examination [MMSE] 22.8 ± 3.2) and matched controls (n = 49, age 80.0 ± 7.7 years, MMSE 29.0 ± 1.2). Participants wore a wrist accelerometer for 7 days to assess sedentary time, sedentary bout duration and time spent in very light, light-to-moderate and moderate-to-vigorous physical activities. RESULTS: Relative sedentary time and sedentary bout duration was significantly higher in dementia patients than in controls (median [interquartile range] 57% [49-68] vs. 55% [47-59] and 18.3 [16.4-21.1] min vs. 16.6 [15.3-18.4] min, p = 0.042 and p = 0.008, respectively). In addition, dementia patients spent a lower percentage of their waking time in light-to-moderate and moderate-to-vigorous intensity physical activities (20% [15-23] vs. 22% [18-25] and 5% [2-10] vs. 10% [5-13], p = 0.017 and p = 0.001, respectively). CONCLUSION: We revealed that dementia patients are more sedentary and perform less physical activity than cognitively healthy controls. This may have clinically important consequences, given the observation that sedentary behaviour and little physical activity independently predict all-cause mortality and morbidity.

Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis.

Combined cognitive and physical exercise interventions have potential to elicit cognitive benefits in older adults with mild cognitive impairment (MCI) or dementia. This meta-analysis aims to quantify the overall effect of these interventions on global cognitive functioning in older adults with MCI or dementia. Ten randomized controlled trials that applied a combined cognitive-physical intervention with cognitive function as an outcome measure were included. For each study effect sizes were computed (i.e., post-intervention standardized mean difference (SMD) scores) and pooled, using a random-effects meta-analysis. The primary analysis showed a small-to-medium positive effect of combined cognitive-physical interventions on global cognitive function in older adults with MCI or dementia (SMD[95% confidence interval]=0.32[0.17;0.47], p<0.00). A combined intervention was equally beneficial in patients with dementia (SMD=0.36[0.12;0.60], p<0.00) and MCI (SMD=0.39[0.15;0.63], p<0.05). In addition, the analysis showed a moderate-to-large positive effect after combined cognitive-physical interventions for activities of daily living (ADL) (SMD=0.65[0.09;1.21], p<0.01)and a small-to-medium positive effect for mood (SMD=0.27[0.04;0.50], p<0.01). These functional benefits emphasize the clinical relevance of combined cognitive and physical training strategies.