Metabolic symbiosis between oxygenated and hypoxic tumour cells: An agent-based modelling study.

Deregulated metabolism is one of the hallmarks of cancer. It is well-known that tumour cells tend to metabolize glucose via glycolysis even when oxygen is available and mitochondrial respiration is functional. However, the lower energy efficiency of aerobic glycolysis with respect to mitochondrial respiration makes this behaviour, namely the Warburg effect, counter-intuitive, although it has now been recognized as source of anabolic precursors. On the other hand, there is evidence that oxygenated tumour cells could be fuelled by exogenous lactate produced from glycolysis. We employed a multi-scale approach that integrates multi-agent modelling, diffusion-reaction, stoichiometric equations, and Boolean networks to study metabolic cooperation between hypoxic and oxygenated cells exposed to varying oxygen, nutrient, and inhibitor concentrations. The results show that the cooperation reduces the depletion of environmental glucose, resulting in an overall advantage of using aerobic glycolysis. In addition, the oxygen level was found to be decreased by symbiosis, promoting a further shift towards anaerobic glycolysis. However, the oxygenated and hypoxic populations may gradually reach quasi-equilibrium. A sensitivity analysis using Latin hypercube sampling and partial rank correlation shows that the symbiotic dynamics depends on properties of the specific cell such as the minimum glucose level needed for glycolysis. Our results suggest that strategies that block glucose transporters may be more effective to reduce tumour growth than those blocking lactate intake transporters.

Raman micro-spectroscopy as a tool to study immunometabolism.

In the past two decades, immunometabolism has emerged as a crucial field, unraveling the intricate molecular connections between cellular metabolism and immune function across various cell types, tissues, and diseases. This review explores the insights gained from studies using the emerging technology, Raman micro-spectroscopy, to investigate immunometabolism. Raman micro-spectroscopy provides an exciting opportunity to directly study metabolism at the single cell level where it can be combined with other Raman-based technologies and platforms such as single cell RNA sequencing. The review showcases applications of Raman micro-spectroscopy to study the immune system including cell identification, activation, and autoimmune disease diagnosis, offering a rapid, label-free, and minimally invasive analytical approach. The review spotlights three promising Raman technologies, Raman-activated cell sorting, Raman stable isotope probing, and Raman imaging. The synergy of Raman technologies with machine learning is poised to enhance the understanding of complex Raman phenotypes, enabling biomarker discovery and comprehensive investigations in immunometabolism. The review encourages further exploration of these evolving technologies in the rapidly advancing field of immunometabolism.

Correction: Kujawski et al. Autonomic and Cognitive Function Response to Normobaric Hyperoxia Exposure in Healthy Subjects. Preliminary Study. Medicina 2020, 56, 172.

There was an error in the original publication [...].

Whole-body cryostimulation application with age: A review.

In this review we examine studies exploring the effects of whole-body cryostimulation (WBC) from the perspective of applications with age with subjects over the age of 55 years old. Blood based factors such as Erythropoietin and Il-3 increased in exercised trained and normal subjects after WBC while other parameters did not change. WBC treatment of patients with Rheumatoid Arthritis decreased levels of the inflammatory markers IL-6 and TNF-α with a in the elasticity of erythrocytes. In older subjects with Mild Cognitive Impairment (MCI) a significant improvement of short-term memory was noted with reduced levels of IL-6 with an increase in BDNF release when whole blood was challenged with Aß42. WBC appears to be an exciting non-pharmacological treatments with pleiotropic action. It has potential in enhancing performance and alleviating chronic conditions in older subjects as part of an active rest programme in combination with regular physical exercise. In conditions associated with cognitive dysfunction including Alzheimer's and other forms of dementia the many properties of WBC as an affordable treatment has exciting therapeutic potential.

Autonomic and Cognitive Function Response to Normobaric Hyperoxia Exposure in Healthy Subjects. Preliminary Study.

Background and objective: This is the first study to investigate the effect of high-flow oxygen therapy, using a normobaric chamber on cognitive, biochemical (oxidative stress parameters and the level of neurotrophins), cardiovascular and autonomic functioning. Materials and methods: 17 healthy volunteers, eight males and nine females, with a mean age of 37.5 years, were examined. The experimental study involved ten two-hour exposures in a normobaric chamber with a total pressure of 1500 hPa, in air adjusted to 37% oxygen, 1.079% carbon dioxide and 0.44% hydrogen. Cognitive function was assessed by using Trail Making Test parts A, B and difference in results of these tests (TMT A, TMT B and TMT B-A); California Verbal Learning Test (CVLT); Digit symbol substitution test (DSST); and Digit Span (DS). Fatigue (Fatigue Severity Scale (FSS)), cardiovascular, autonomic and baroreceptor functioning (Task Force Monitor) and biochemical parameters were measured before and after intervention. Results: After 10 sessions in the normobaric chamber, significant decreases in weight, caused mainly by body fat % decrease (24.86 vs. 23.93%, p = 0.04 were observed. TMT part A and B results improved (p = 0.0007 and p = 0.001, respectively). In contrast, there was no statistically significant influence on TMT B-A. Moreover, decrease in the number of symbols left after a one-minute test in DSST was noted (p = 0.0001). The mean number of words correctly recalled in the CVLT Long Delay Free Recall test improved (p = 0.002), and a reduction in fatigue was observed (p = 0.001). Biochemical tests showed a reduction in levels of malondialdehyde (p < 0.001), with increased levels of Cu Zn superoxide dismutase (p < 0.001), Neurotrophin 4 (p = 0.0001) and brain-derived neurotrophic factor (p = 0.001). A significant increase in nitric oxide synthase 2 (Z = 2.29, p = 0.02) and Club cell secretory protein (p = 0.015) was also noted. Baroreceptor function was significantly improved after normobaric exposures (p = 0.003). Significant effect of normobaric exposures and BDNF in CVLT Long Delay Free Recall was noted. Conclusions: This study demonstrates that 10 exposures in a normobaric chamber have a positive impact on visual information and set-shifting processing speed and increase auditory-verbal short-term memory, neurotrophic levels and baroreceptor function. A response of the respiratory tract to oxidative stress was also noted. There is a need to rigorously examine the safety of normobaric therapy. Further studies should be carried out with physician examination, both pre and post treatment.

Impact of pharmacological agents on mitochondrial function: a growing opportunity?

Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, age-associated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation.

A new approach to find biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) by single-cell Raman micro-spectroscopy.

Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME), is a debilitating disorder characterized by physical and mental exhaustion. Mitochondrial and energetic dysfunction has been investigated in CFS patients due to a hallmark relationship with fatigue; however, no consistent conclusion has yet been achieved. Single-cell Raman spectra (SCRS) are label-free biochemical profiles, indicating phenotypic fingerprints of single cells. In this study, we applied a new approach using single-cell Raman microspectroscopy (SCRM) to examine ρ0 cells that lack mitochondrial DNA (mtDNA), and peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls. The experimental results show that Raman bands associated with phenylalanine in ρ0 cells and CFS patient PBMCs were significantly higher than those of the wild-type model and healthy controls. As similar changes were observed in the ρ0 cell model with a known deficiency in the mitochondrial respiratory chain as well as in CFS patients, our results suggest that the increase in cellular phenylalanine may be related to mitochondrial/energetic dysfunction in both systems. Interestingly, phenylalanine can be used as a potential biomarker for the diagnosis of CFS by SCRM. A machine learning classification model achieved an accuracy rate of 98% correctly assigning Raman spectra to either the CFS group or the control group. SCRM combined with a machine learning algorithm therefore has the potential to become a diagnostic tool for CFS.

Correction: A new approach to find biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) by single-cell Raman micro-spectroscopy.

Correction for 'A new approach to find biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) by single-cell Raman micro-spectroscopy' by Jiabao Xu et al., Analyst, 2019, 144, 913-920.

The isolation of primary hepatocytes from human tissue: optimising the use of small non-encapsulated liver resection surplus.

Two-step perfusion is considered the gold standard method for isolating hepatocytes from human liver tissue. As perfusion may require a large tissue specimen, which is encapsulated and has accessible vessels for cannulation, only a limited number of tissue samples may be suitable. Therefore, the aim of this work was to develop an alternative method to isolate hepatocytes from non-encapsulated and small samples of human liver tissue. Healthy tissue from 44 human liver resections were graded for steatosis and tissue weights between 7.8 and 600 g were used for hepatocyte isolations. Tissue was diced and underwent a two-step digestion (EDTA and collagenase). Red cell lysis buffer was used to prevent red blood cell contamination and toxicity. Isolated hepatocyte viability was determined by trypan blue exclusion. Western blot and biochemical analyses were undertaken to ascertain cellular phenotype and function. Liver tissue that weighed ≥50 g yielded significantly higher (P < 0.01) cell viability than tissue <50 g. Viable cells secreted urea and displayed the phenotypic hepatocyte markers albumin and cytochrome P450. Presence of steatosis in liver tissue or intra-hepatocellular triglyceride content had no effect on cell viability. This methodology allows for the isolation of viable primary human hepatocytes from small amounts of "healthy" resected liver tissue which are not suitable for perfusion. This work provides the opportunity to increase the utilisation of resection surplus tissue, and may ultimately lead to an increased number of in vitro cellular studies being undertaken using the gold-standard model of human primary hepatocytes.

The Warburg effect: 80 years on.

Influential research by Warburg and Cori in the 1920s ignited interest in how cancer cells' energy generation is different from that of normal cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.

Monitoring Intracellular Oxygen Concentration: Implications for Hypoxia Studies and Real-Time Oxygen Monitoring.

The metabolic properties of cancer cells have been widely accepted as a hallmark of cancer for a number of years and have shown to be of critical importance in tumour development. It is generally accepted that tumour cells exhibit a more glycolytic phenotype than normal cells. In this study, we investigate the bioenergetic phenotype of two widely used cancer cell lines, RD and U87MG, by monitoring intracellular oxygen concentrations using phosphorescent Pt-porphyrin based intracellular probes. Our study demonstrates that cancer cell lines do not always exhibit an exclusively glycolytic phenotype. RD demonstrates a reliance on oxidative phosphorylation whilst U87MG display a more glycolytic phenotype. Using the intracellular oxygen sensing probe we generate an immediate readout of intracellular oxygen levels, with the glycolytic lines reflecting the oxygen concentration of the environment, and cells with an oxidative phenotype having significantly lower levels of intracellular oxygen. Inhibition of oxygen consumption in lines with high oxygen consumption increases intracellular oxygen levels towards environmental levels. We conclude that the use of intracellular oxygen probes provides a quantitative assessment of intracellular oxygen levels, allowing the manipulation of cellular bioenergetics to be studied in real time.

From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations.

The liver is a main metabolic organ in the human body and carries out a vital role in lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, encompassing a spectrum of conditions from simple fatty liver (hepatic steatosis) through to cirrhosis. Although obesity is a known risk factor for hepatic steatosis, it remains unclear what factor(s) is/are responsible for the primary event leading to retention of intrahepatocellular fat. Studying hepatic processes and the etiology and progression of disease in vivo in humans is challenging, not least as NAFLD may take years to develop. We present here a review of experimental models and approaches that have been used to assess liver triglyceride metabolism and discuss their usefulness in helping to understand the aetiology and development of NAFLD.

Characterization of lipid metabolism in a novel immortalized human hepatocyte cell line.

The development of hepatocyte cell models that represent fatty acid partitioning within the human liver would be beneficial for the study of the development and progression of nonalcoholic fatty liver disease (NAFLD). We sought to develop and characterize a novel human liver cell line (LIV0APOLY) to establish a model of lipid accumulation using a physiological mixture of fatty acids under low- and high-glucose conditions. LIV0APOLY cells were compared with a well-established cell line (HepG2) and, where possible, primary human hepatocytes. LIV0APOLY cells were found to proliferate and express some mature liver markers and were wild type for the PNPLA3 (rs738409) gene, whereas HepG2 cells carried the Ile(148)Met variant that is positively associated with liver fat content. Intracellular triglyceride content was higher in HepG2 than in LIV0APOLY cells; exposure to high glucose and/or exogenous fatty acids increased intracellular triglyceride in both cell lines. Triglyceride concentrations in media were higher from LIV0APOLY compared with HepG2 cells. Culturing LIV0APOLY cells in high glucose increased a marker of endoplasmic reticulum stress and attenuated insulin-stimulated Akt phosphorylation whereas low glucose and exogenous fatty acids increased AMPK phosphorylation. Although LIV0APOLY cells and primary hepatocytes stored similar amounts of exogenous fatty acids as triglyceride, more exogenous fatty acids were partitioned toward oxidation in the LIV0APOLY cells than in primary hepatocytes. LIV0APOLY cells offer the potential to be a renewable cellular model for studying the effects of exogenous metabolic substrates on fatty acid partitioning; however, their usefulness as a model of lipoprotein metabolism needs to be further explored.

Differential regulation of HIF-mediated pathways increases mitochondrial metabolism and ATP production in hypoxic osteoclasts.

Inappropriate osteoclast activity instigates pathological bone loss in rheumatoid arthritis. We have investigated how osteoclasts generate sufficient ATP for the energy-intensive process of bone resorption in the hypoxic microenvironment associated with this rheumatic condition. We show that in human osteoclasts differentiated from CD14(+) monocytes, hypoxia (24 h, 2% O2 ): (a) increases ATP production and mitochondrial electron transport chain activity (Alamar blue, O2 consumption); (b) increases glycolytic flux (glucose consumption, lactate production); and (c) increases glutamine consumption. We demonstrate that glucose, rather than glutamine, is necessary for the hypoxic increase in ATP production and also for cell survival in hypoxia. Using siRNA targeting specific isoforms of the hypoxia-inducible transcription factor HIF (HIF-1α, HIF-2α), we show that employment of selected components of the HIF-1α-mediated metabolic switch to anaerobic respiration enables osteoclasts to rapidly increase ATP production in hypoxia, while at the same time compromising long-term survival. We propose this atypical HIF-driven metabolic pathway to be an adaptive mechanism to permit rapid bone resorption in the short term while ensuring curtailment of the process in the absence of re-oxygenation.

Developing a Blood Cell-Based Diagnostic Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Peripheral Blood Mononuclear Cells.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by debilitating fatigue that profoundly impacts patients' lives. Diagnosis of ME/CFS remains challenging, with most patients relying on self-report, questionnaires, and subjective measures to receive a diagnosis, and many never receiving a clear diagnosis at all. In this study, a single-cell Raman platform and artificial intelligence are utilized to analyze blood cells from 98 human subjects, including 61 ME/CFS patients of varying disease severity and 37 healthy and disease controls. These results demonstrate that Raman profiles of blood cells can distinguish between healthy individuals, disease controls, and ME/CFS patients with high accuracy (91%), and can further differentiate between mild, moderate, and severe ME/CFS patients (84%). Additionally, specific Raman peaks that correlate with ME/CFS phenotypes and have the potential to provide insights into biological changes and support the development of new therapeutics are identified. This study presents a promising approach for aiding in the diagnosis and management of ME/CFS and can be extended to other unexplained chronic diseases such as long COVID and post-treatment Lyme disease syndrome, which share many of the same symptoms as ME/CFS.

Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome With Partial Least Squares Discriminant Analysis: Relevance of Blood Extracellular Vesicles.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic disease characterized by long-lasting persistent debilitating widespread fatigue and post-exertional malaise, remains diagnosed by clinical criteria. Our group and others have identified differentially expressed miRNA profiles in the blood of patients. However, their diagnostic power individually or in combinations seems limited. A Partial Least Squares-Discriminant Analysis (PLS-DA) model initially based on 817 variables: two demographic, 34 blood analytic, 136 PBMC miRNAs, 639 Extracellular Vesicle (EV) miRNAs, and six EV features, selected an optimal number of five components, and a subset of 32 regressors showing statistically significant discriminant power. The presence of four EV-features (size and z-values of EVs prepared with or without proteinase K treatment) among the 32 regressors, suggested that blood vesicles carry relevant disease information. To further explore the features of ME/CFS EVs, we subjected them to Raman micro-spectroscopic analysis, identifying carotenoid peaks as ME/CFS fingerprints, possibly due to erythrocyte deficiencies. Although PLS-DA analysis showed limited capacity of Raman fingerprints for diagnosis (AUC = 0.7067), Raman data served to refine the number of PBMC miRNAs from our previous model still ensuring a perfect classification of subjects (AUC=1). Further investigations to evaluate model performance in extended cohorts of patients, to identify the precise ME/CFS EV components detected by Raman and to reveal their functional significance in the disease are warranted.

Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific biomarkers. Despite patient heterogeneity linked to patient subgroups and variation in disease severity, anomalies are found in the blood and plasma of these patients when compared with healthy control groups. The seeming specificity of these "plasma factors", as recently reported by Ron Davis and his group at Stanford University, CA, United States, and observations by our group, have led to the proposal that induced pluripotent stem cells (iPSCs) may be used as metabolic sensors for FM and ME/CFS, a hypothesis that is the basis for this in-depth review. AIM: To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by iPSCs. METHODS: A PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body fluids. The MeSH terms "metabolomic" or "metabolites" in combination with FM and ME/CFS disease terms were screened against the PubMed database. Only original studies applying omics technologies, published in English, were included. The data obtained were tabulated according to the disease and type of body fluid analyzed. Coincidences across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease groups. RESULTS: Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body fluids. In vitro cell-based assays have the potential to be developed as screening platforms, providing evidence for the existence of factors in patient body fluids capable of altering morphology, differentiation state and/or growth patterns. Moreover, they can be further developed using approaches aimed at blocking or reversing the effects of specific plasma/serum factors seen in patients. The documented high sensitivity and effective responses of iPSCs to environmental cues suggests that these pluripotent cells could form robust, reproducible reporter systems of metabolic diseases, including ME/CFS and FM. Furthermore, culturing iPSCs, or their mesenchymal stem cell counterparts, in patient-conditioned medium may provide valuable information to predict individual outcomes to stem-cell therapy in the context of precision medicine studies. CONCLUSION: This opinion review explains our hypothesis that iPSCs could be developed as a screening platform to provide evidence of a metabolic imbalance in FM and ME/CFS.

Cognitive Function Changes in Older People. Results of Second Wave of Cognition of Older People, Education, Recreational Activities, NutritIon, Comorbidities, fUnctional Capacity Studies (COPERNICUS).

BACKGROUND: Cognitive reserve explains why subjects with more years of education, professional achievement, or participation in recreational activities show less cognitive decline with aging. We hypothesize that levels of recreational travel, education, occupation, systemic health, physical performance, and current cognitive activity levels affect the trajectory of cognitive function in older, healthy people in Poland. MATERIALS AND METHODS: Healthy, older people (N = 205) were examined and followed-up at 2 years. Participants completed physical and cognitive function assessments: including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and its two subtests Delayed Recall (DR) and Verbal Fluency (VF), and Trail Making Test Part B (TMT B). Factors associated with cognitive functioning were also examined. RESULTS: The MMSE result significantly decreased over 2 years. No significant decrease in other cognitive tests was noted. However, the trajectory of cognitive tests results varied between individual participants. Percentage of variance of change was explained by the following predictors: 21 in MMSE, 24 in MoCA, 8 in DR, 25 in VF, and 24 in TMT B. Age and the presence of varicose veins were significantly linked to negative changes in MMSE and MoCA scores, while working in a professional occupational status associated with a higher score. The subgroup with varicose veins did worse on the Delayed Recall subtest of MoCA. CONCLUSION: Cognitive reserve could be extended by proxies of reserve that are related to systemic health and travel activity. The latter is a combination of social, physical, and cognitive activity and potentially might serve as an intervention to improve cognitive function in older people. However, due to the limitations of this study, results should be interpreted with caution and needs to be replicated in the further studies.

Acetyl-leucine slows disease progression in lysosomal storage disorders.

Acetyl-dl-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies, acetyl-dl-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-dl-leucine and its enantiomers acetyl-l-leucine and acetyl-d-leucine in symptomatic Npc1-/- mice and observed improvement in ataxia with both individual enantiomers and acetyl-dl-leucine. When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1-/- mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not. These data are consistent with acetyl-l-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1-/- mice. When the standard of care drug miglustat and acetyl-dl-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-dl-leucine treatment, rates of disease progression were slowed, with stabilization or improvement in multiple neurological domains. A beneficial effect of acetyl-dl-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-l-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders.

Relationship between Cardiopulmonary, Mitochondrial and Autonomic Nervous System Function Improvement after an Individualised Activity Programme upon Chronic Fatigue Syndrome Patients.

BACKGROUND: The therapeutic effects of exercise from structured activity programmes have recently been questioned; as a result, this study examines the impact of an Individualised Activity Program (IAP) on the relationship with cardiovascular, mitochondrial and fatigue parameters. METHODS: Chronic fatigue syndrome (CFS) patients were assessed using Chalder Fatigue Questionnaire (CFQ), Fatigue Severity Score (FSS) and the Fatigue Impact Scale (FIS). VO2peak, VO2submax and heart rate (HR) were assessed using cardiopulmonary exercise testing. Mfn1 and Mfn2 levels in plasma were assessed. A Task Force Monitor was used to assess ANS functioning in supine rest and in response to the Head-Up Tilt Test (HUTT). RESULTS: Thirty-four patients completed 16 weeks of the IAP. The CFQ, FSS and FIS scores decreased significantly along with a significant increase in Mfn1 and Mfn2 levels (p = 0.002 and p = 0.00005, respectively). The relationships between VO2 peak and Mfn1 increase in response to IAP (p = 0.03) and between VO2 at anaerobic threshold and ANS response to the HUTT (p = 0.03) were noted. CONCLUSIONS: It is concluded that IAP reduces fatigue and improves functional performance along with changes in autonomic and mitochondrial function. However, caution must be applied as exercise was not well tolerated by 51% of patients.