Nada Lukkahatai

Association of mitochondrial dysfunction and fatigue: A review of the literature

Fatigue is often described by patients as a lack of energy, mental or physical tiredness, diminished endurance, and prolonged recovery after physical activity. Etiologic mechanisms underlying fatigue are not well understood; however, fatigue is a hallmark symptom of mitochondrial disease, making mitochondrial dysfunction a putative biological mechanism for fatigue. Therefore, this review examined studies that investigated the association of markers of mitochondrial dysfunction with fatigue and proposes possible research directions to enhance understanding of the role of mitochondrial dysfunction in fatigue. A thorough search using PubMed, Scopus, Web of Science, and Embase databases returned 1220 articles. After the application of inclusion and exclusion criteria, a total of 25 articles meeting eligibility criteria were selected for full review. Dysfunctions in the mitochondrial structure, mitochondrial function (mitochondrial enzymes and oxidative/nitrosative stress), mitochondrial energy metabolism (ATP production and fatty acid metabolism), immune response, and genetics were investigated as potential contributors to fatigue. Carnitine was the most investigated mitochondrial function marker. Dysfunctional levels were reported in all the studies investigating carnitine; however, the specific type of carnitine that was dysfunctional varied. Genetic profiles were the second most studied mitochondrial parameter. Six common pathways were proposed: metabolism, energy production, protein transport, mitochondrial morphology, central nervous system dysfunction and post-viral infection. Coenzyme Q10 was the most commonly investigated mitochondrial enzyme. Low levels of Coenzyme Q10 were consistently associated with fatigue. Potential targets for further investigation were identified as well as gaps in the current literature.

Understanding the association of fatigue with other symptoms of fibromyalgia: Development of a cluster model

To develop a symptoms cluster model that can describe factors of fibromyalgia syndrome (FMS) associated with fatigue severity as reported by the sample and to explore FMS clinical symptom subclusters based on varying symptom intensities.

Gene expression profiles of fatigued fibromyalgia patients with different categories of pain and catastrophizing: A preliminary report

BACKGROUND Fibromyalgia (FM) is a chronic condition characterized by diffused musculoskeletal pain and overwhelming fatigue. PURPOSE To compare the gene expression profiles of fatigued FM women with different levels of pain and catastrophizing. METHODS Nine women with FM enrolled in an active Medstar Research Institute protocol were included in the gene expression analyses of peripheral blood RNA via Affymetrix GeneChip Human Genome U133 Plus 2.0 array (Santa Clara, CA). Scores from Brief Pain Inventory, Pain Catastrophizing Scale, and Multidimensional Fatigue Inventory categorized the nine participants into pain (high, n = 3; low, n = 6) and catastrophizing groups (high, n = 5; low, n = 4). DISCUSSION Differential expression of 107 genes between the high and low pain groups and 139 genes between the high and low catastrophizing groups (over 2.0-fold change, p < .05) were observed. Network analyses showed interferon signaling and interferon regulatory activation factor pathways distinguished between the pain groups whereas dendritic cell maturation delineated between the catastrophizing groups. CONCLUSION Findings provide preliminary evidence that specific physiological pathways may possibly delineate pain and catastrophizing mechanisms. Further investigation via the use of a larger and more homogenous sample is warranted.

Lower brain-derived neurotrophic factor levels associated with worsening fatigue in prostate cancer patients during repeated stress from radiation therapy

Objectives. Fatigue during cancer treatment is associated with depression. Neurotrophic factors play a major role in depression and stress and might provide insight into mechanisms of fatigue. This study investigated the association between plasma concentrations of three neurotrophic factors (BDNF, brain-derived neurotrophic factor; GDNF, glial-derived neurotrophic factor; and SNAPIN, soluble N-ethylmaleimide sensitive fusion attachment receptor-associated protein) and initial fatigue intensification during external beam radiation therapy (EBRT) in euthymic non-metastatic prostate cancer men. Methods. Fatigue, as measured by the 13-item Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and plasma neurotrophic factors were collected at baseline (prior to EBRT) and mid-EBRT. Subjects were categorized into fatigue and no fatigue groups using a > 3-point change in FACT-F scores between the two time points. Multiple linear regressions analysed the associations between fatigue and neurotrophic factors. Results. FACT-F scores of 47 subjects decreased from baseline (43.95 ± 1.3) to mid-EBRT (38.36 ± 1.5, P < 0.001), indicating worsening fatigue. SNAPIN levels were associated with fatigue scores (rs = 0.43, P = 0.005) at baseline. A significant decrease of BDNF concentration (P = 0.008) was found in fatigued subjects during EBRT (n = 39). Conclusions. Baseline SNAPIN and decreasing BDNF levels may influence worsening fatigue during EBRT. Further investigations are warranted to confirm their role in the pathophysiology and therapeutics of fatigue.

Clinical predictors of fatigue in men with non-metastatic prostate cancer receiving external beam radiation therapy

BACKGROUND Fatigue is one of the most distressing symptoms experienced by people with cancer receiving radiation therapy. OBJECTIVES The goal of this study is to evaluate clinical predictors of worsening fatigue during external beam radiation therapy (EBRT) in men with non-metastatic prostate cancer. METHODS Thirty-five men with non-metastatic prostate cancer scheduled for EBRT were followed at baseline, midpoint, and completion of EBRT. The Functional Assessment of Cancer Therapy-Fatigue scale was administered. Demographic and clinical data were obtained by chart review. Paired t-tests, correlations, general linear models, and logistic regressions were used to determine associations between fatigue scores and clinical data. FINDINGS Red blood cells, hemoglobin, and hematocrit levels were highly intercorrelated and, therefore, were grouped as one composite variable termed heme. Heme levels at baseline and androgen-deprivation therapy (ADT) were significantly correlated with worsening of fatigue symptoms from baseline to midpoint and endpoint. ADT alone did not have a significant correlation with fatigue, but it indirectly affected fatigue levels by influencing heme markers as treatment progressed. These findings provide evidence that hematologic markers and the use of ADT assist in predicting radiation therapy-related fatigue and guide symptom management.

Comparing Genomic Profiles of Women With and Without Fibromyalgia

Background: Fibromyalgia syndrome (FMS), a chronic musculoskeletal condition characterized by diffuse pain, fatigue, sleep impairment, and cognitive dysfunction, is associated with significant functional disability. Its underlying biological mechanisms are unknown. This study investigated differentially expressed genes between women with FMS and healthy volunteers. Methods: Women who met the 1990 or 2010 American College of Rheumatology fibromyalgia criteria were compared to age- and race-matched pain-free healthy women. Peripheral blood samples were collected, and a full genome microarray gene expression analysis was performed. One-way analysis of variance was used to identify differentially expressed genes using the filtering criterion of 1% false discovery rate. Analysis of canonical pathways associated with these genes was performed. Confirmatory quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay verified microarray results. Independent t-tests compared gene and protein expression between groups. Result: Participants were 54 women with FMS and 25 controls. Expression arrays from a subset of women with FMS (n = 29) and controls (n = 20) showed upregulation of 12 genes (>1.8-fold change, p < .05) in the FMS sample. Differentially expressed genes were related to B-cell development, primary immunodeficiency signaling, and mitotic roles of polo-like kinase. CENPK and HSP90AA1 were the most differentially expressed genes (p < .01). Conclusion: Activity of interrelated pathways related to immune response, and homeostasis appears to be relevant to the experience of FMS. Replication and exploration of the relationship between gene expression and symptom severity will help determine clinical relevance of these findings.

Relationship of Mitochondrial Enzymes to Fatigue Intensity in Men With Prostate Cancer Receiving External Beam Radiation Therapy

Purpose: Mitochondrial dysfunction is a plausible biological mechanism for cancer-related fatigue. Specific aims of this study were to (1) describe the levels of mitochondrial oxidative phosphorylation complex (MOPC) enzymes, fatigue, and health-related quality of life (HRQOL) before and at completion of external beam radiation therapy (EBRT) in men with nonmetastatic prostate cancer (PC); (2) examine relationships over time among levels of MOPC enzymes, fatigue, and HRQOL; and (3) compare levels of MOPC enzymes in men with clinically significant and nonsignificant fatigue intensification during EBRT. Methods: Fatigue was measured by the revised Piper Fatigue Scale and the Functional Assessment of Cancer Therapy–Fatigue subscale (FACT-F). MOPC enzymes (Complexes I–V) and mitochondrial antioxidant superoxide dismutase 2 were measured in peripheral blood using enzyme-linked immunosorbent assay at baseline and completion of EBRT. Participants were categorized into high or low fatigue (HF vs. LF) intensification groups based on amount of change in FACT-F scores during EBRT. Results: Fatigue reported by the 22 participants with PC significantly worsened and HRQOL significantly declined from baseline to EBRT completion. The HF group comprised 12 men with clinically significant change in fatigue (HF) during EBRT. Although no significant changes were observed in MOPC enzymes from baseline to EBRT completion, there were important differences in the patterns in the levels of MOPC enzymes between HF and LF groups. Conclusion: Distinct patterns of changes in the absorbance of MOPC enzymes delineated fatigue intensification among participants. Further investigation using a larger sample is warranted.

Effects of Exercise on Select Biomarkers and Associated Outcomes in Chronic Pain Conditions: Systematic Review.

Background: Chronic pain is highly prevalent. Current management is challenged by lack of validated objective measures like biological markers. Clinical pain studies employing exercise interventions have evaluated biomarkers; however, it is unclear how exercise impacts biomarkers involved in pain pathways and whether these markers are associated with relevant pain-related outcomes. This systematic review evaluates data from clinical studies employing exercise interventions in chronic musculoskeletal nonmalignant pain conditions in which biomarkers in pain pathways were measured. Method: Published research studies from several databases were examined using the Jadad Scale for assessing the quality of clinical studies. Results: Twelve research studies were reviewed. Jadad scores ranged from 5 to 11 out of 13 points. Inflammatory markers were most commonly measured followed by neurotransmitter-related genes and metabolite-detecting genes. After exercise interventions, changes in biomarkers involved in neurotransmission and inflammation suggest a hypoalgesic exercise effect. Significant biomarker associations were found with pain intensity, fatigue, depression, anxiety, and quality of life. However, there were varying methodologies in the studies reviewed. Discussion: It remains a question whether biomarkers can be used as objective measures for risk assessment, diagnosis, or evaluation or as surrogate endpoints in chronic pain. Adequate sample sizes, optimal exercise dose determination, study replications, and longitudinal research studies with consistent methodologies are warranted. Regardless, the potential translational value of biomarkers in chronic pain is evident. Advancing nursing research in biomarkers is vital for moving the nursing discipline and clinical chronic pain practice forward. Developing a biobehavioral perspective in chronic pain is also necessary for comprehensive management.

Altered Cd8+ T lymphocyte Response Triggered by Arginase 1: Implication for Fatigue Intensification during Localized Radiation Therapy in Prostate Cancer Patients

Fatigue, the most common side effect of cancer treatments, is observed to intensify during external-beam radiation therapy (EBRT). The underlying molecular mechanisms remain unclear. This study investigated the differentially expressed genes/proteins and their association with fatigue intensification during EBRT. Fatigue scores measured by FACT-F and peripheral blood were collected prior to treatment (baseline D0), at midpoint (days 19-21, D21) and endpoint (days 38-42, D42) from men (n=30) with non-metastatic prostate cancer undergoing EBRT. RNA extracted from peripheral blood was used for gene expression analysis. Plasma arginase I and arginine were examined using ELISA and liquid chromatography-tandem mass spectrometry. Differences in fatigue scores, gene and protein expression between times points following EBRT were analyzed by one way ANOVA followed by Post Hoc t-test. Fatigue scores decreased significantly from baseline (44.6 ± 8.1) to midpoint (37.3 ± 10.6, p=0.000, low scores indicating high fatigue) and to endpoint (37.4 ± 10.1, p=0.001) during EBRT. ARG1 (encoding arginase type 1) was significantly up regulated from baseline to midpoint of EBRT (fold change =2.41, p<0.05) whereas genes associated with the adaptive immune functional pathway (CD28, CD27, CCR7, CD3D, CD8A and HLA-DOB) were significantly downregulated >2-fold between the study time points. The changes in gene expression were associated with patient reported fatigue intensity. Moreover, the upregulation of ARG1 was negatively correlated with the absolute lymphocyte count (R2=0.561, p=0.01) only in the high level of fatigue group (n=17) during EBRT. Increased ARG1 expression is known to result in arginine deficiency, which leads to immunosuppression by impairing lymphocyte proliferation and activation. EBRT-induced ARG1 upregulation may play an essential role in fatigue intensification via the arginine deficiency and suppression of T-cell proliferation pathways. These findings may provide novel insights into the molecular-genetic mechanisms underlying the development and intensification of cancer treatment-related fatigue.

Effect of Wearable Technology on Self-Care Behaviors, Physical Activity and Quality of Life

Background:Self-care and management have been associated with the ability to monitor behaviors. For diabetic patients, it is important to manage physical activity and diet. It is not known if self-monitoring in a Thai population improves health outcomes. Objective:The purpose of this study was to determine the effects of wearable technology on physical activity and relationships of self-care behaviors and quality of life. Methods:A randomized controlled group design was used. Thai persons aged 21 or older with diabetes from two diabetic clinics in Chiang Mai Thailand were recruited. They were randomly assigned into 3 groups: control group (no wearable devices), aware group (received wearable device with feedback) and unaware group (received wearable device with no feedback). During their first visit, participants were asked to complete questionnaires about self-care behavior and their quality of life (SF-12). Participants in the aware and unaware groups wore the device for 3 days. Data analysis was conducted using SAS software version 9.4. Results:One hundred and twenty five Thai participants with diabetes ages ranged from 39 to 75 years old were included in this analysis. The majority was female (n = 86, 69%) and married (n = 103, 82%). The number of steps taken for both aware and unaware group was positively associated with their physical functions (r = 0.225, p = 0.041) and their body pain (r = 0.300, p = 0.0059). No significant differences of self-care behaviors were found among the three groups. The number of steps in both groups was not significantly different. Conclusion:The wearable assessment device was feasible and results of steps taken was associated with better physical function and pain, but not determined by awareness of their steps taken. While the device had no significant impact on exercise more information is needed on the usefulness of this information and its relationship to pain and how it can be utilized to enhance physical activity.