R. K. Elswick

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.

Comparison of Biomarkers in Blood and Saliva in Healthy Adults

Researchers measure biomarkers as a reflection of patient health status or intervention outcomes. While blood is generally regarded as the best body fluid for evaluation of systemic processes, substitution of saliva samples for blood would be less invasive and more convenient. The concentration of specific biomarkers may differ between blood and saliva. The objective of this study was to compare multiple biomarkers (27 cytokines) in plasma samples, passive drool saliva samples, and filter paper saliva samples in 50 healthy adults. Demographic data and three samples were obtained from each subject: saliva collected on filter paper over 1 minute, saliva collected by passive drool over 30 seconds, and venous blood (3 mL) collected by venipuncture. Cytokines were assayed using Bio-Rad multiplex suspension array technology. Descriptive statistics and pairwise correlations were used for data analysis. The sample was 52% male and 74% white. Mean age was 26 (range = 19–63 years, sd = 9.7). The most consistent and highest correlations were between the passive drool and filter paper saliva samples, although relationships were dependent on the specific biomarker. Correlations were not robust enough to support substitution of one collection method for another. There was little correlation between the plasma and passive drool saliva samples. Caution should be used in substituting saliva for blood, and relationships differ by biomarker.

Early, single chlorhexidine application reduces ventilator-associated pneumonia in trauma patients

BACKGROUND Ventilator-associated pneumonia (VAP) is an important complication of mechanical ventilation and is particularly common in trauma, burn, and surgical patients. Interventions that kill bacteria in the oropharynx reduce the pool of viable organisms available for translocation to the lung and thereby lessen the likelihood of developing VAP. Repeated administration of chlorhexidine (CHX) to the mouth and oropharynx has been shown to reduce the incidence of VAP, but use of a single dose has not been studied. This randomized, controlled clinical trial tested an early (within 12 hours of intubation) application of CHX by swab versus control (no swab) on oral microbial flora and VAP. METHODS A total of 145 trauma patients requiring endotracheal intubation were randomly assigned to the intervention (5 mL CHX) or control group. VAP (Clinical Pulmonary Infection Score [CPIS] ≥ 6) was evaluated on study admission and at 48 and 72 hours after intubation. RESULTS A total of 145 patients were enrolled; 71 and 74 patients were randomized to intervention and control groups, respectively. Seventy percent of the patients were male, and 60% were white; their mean age was 42.4 years (±18.2). A significant treatment effect was found on CPIS both from admission to 48 hours (P = .020) and to 72 hours (P = .027). In those subjects without pneumonia at baseline (CPIS < 6), 55.6% of the control patients (10/18) had developed VAP by 48 or 72 hours versus only 33.3% of the intervention patients (7/21). CONCLUSION an early, single application of CHX to the oral cavity significantly reduces CPIS and thus VAP in trauma patients.

Randomized, prospective, clinical evaluation of prosthodontic modalities for mandibular implant overdenture treatment

STATEMENT OF PROBLEM Mandibular implant overdentures provide improved treatment outcome than conventional denture therapy, but there is controversy as to which overdenture treatment is the best choice. PURPOSE This study evaluated 3 different mandibular implant overdenture treatments with respect to prosthesis retention and stability, tissue response, patient satisfaction and preference, and complications to determine treatment outcomes. MATERIAL AND METHODS In a prospective, randomized clinical trial, using a crossover design, 30 subjects (mean age, 58.9; 63% male) received 4 implants in the anterior mandible. For each subject, 3 different overdenture attachment types were fabricated and/or fitted to the implants. These included a 4-implant bar attachment fitted to all 4 implants, a 2-implant bar attachment, and 2 independent ball attachments. Subjects were randomly assigned to 1 of 6 possible treatment sequences and received all 3 attachment types each for approximately 1 year. Data were collected at baseline, and at 6 and 12 months for treatment types. Denture retention and stability and parameters of soft tissue response were recorded. Complications were documented and questionnaires were used to identify subject masticatory ability, denture complaints, and preferences. Data were analyzed to determine statistical equivalence among the 3 different treatments using the Schuirmanns two one-sided test (TOST) procedure, and the Wilcoxon-Mann-Whitney TOST procedure (α=.05). RESULTS Force gauge prosthesis retention measurements showed that the 3 treatment types were not statistically equivalent, with the 4-implant bar demonstrating the greatest retention. Criterion-based retention scores were statistically equivalent for all treatments. Both the force gauge and criterion-based prosthesis stability measurements were statistically equivalent among all 3 treatment types. Analysis of all other multiple criterion-based scoring systems indicated the majority of these variables demonstrated equivalence. Where equivalence was not identified, the most favorable responses were typically found with the O-ring treatment, and the least favorable with the 4-implant bar treatment. From the small percentage of treatment visits demonstrating minor complications, no single treatment presented with greater complications than the others. For the treatment preference among subjects, 52% selected the independent ball attachment, 32% the 4-implant bar, and 16% the 2-implant bar (P=.10). CONCLUSIONS The 2-implant independent treatment used in this study provided equivalent or more favorable treatment outcomes for most measured parameters relative to the more complex and costly 2- and 4-implant bar attachments. The 4-implant bar treatment provided greater prosthesis retention than the other treatment types in this study, but after experience with all systems, subjects were more satisfied with and preferred the independent implant treatment.

Fatigue in Adolescents and Young Adults With Sickle Cell Disease Biological and Behavioral Correlates and Health-Related Quality of Life

This descriptive, correlational study examined fatigue and potential biological and behavioral correlates in adolescents and young adults with sickle cell disease. Sixty adolescents and young adults with sickle cell disease completed the Brief Fatigue Inventory, Multidimensional Fatigue Symptom Inventory–Short Form, Patient Reported Outcomes Measurement Information System (PROMIS) fatigue short form and measures of pain, sleep quality, anxiety, depressive mood, stress, disease severity, and quality of life. Blood samples were obtained for hemoglobin and cytokines. Fatigue scores were mostly moderate in severity. Fatigue interfered to a moderate degree with daily activities and correlated significantly with pain, sleep quality, state and trait anxiety, depressive mood, stress, and quality of life. Fatigue was correlated with hemoglobin on the PROMIS measure. Fatigue was not correlated with cytokines or age, nor differed by disease severity. Fatigue was common in these adolescents and young adults, interfered with daily activities such as school, work and exercise, and significantly correlated with several potentially modifiable factors. As life expectancy increases in sickle cell disease, research is needed to test interventions to reduce fatigue.

Psychoneuroimmunological Relationships in Women With Fibromyalgia

Introduction: The purpose of this pilot study was to characterize the relationships among perceived stress, pain, fatigue, depression, anxiety, biomarkers, and functional status in women with fibromyalgia syndrome (FMS) using a psychoneuroimmunological (PNI) framework. Materials and Method: Using a cross-sectional, correlational design, the authors asked 50 women diagnosed with FMS to complete the Perceived Stress Scale (PSS), Brief Pain Inventory (BPI), Brief Fatigue Inventory (BFI), Center for Epidemiological Studies—Depression scale, State–Trait Anxiety Inventory (STAI), and Functional Impact Questionnaire. The authors analyzed plasma levels of 17 cytokines using a BioPlex® assay and levels of C-reactive protein (CRP) using a high-sensitivity enzyme-linked immunosorbent assay (ELISA). Results: Compared to published guidelines (>3 mg/L reflects high inflammation), CRP levels were elevated in participating women. Perceived stress demonstrated positive correlations with pain, fatigue, depression, anxiety, and functional status and negative correlations with monocyte chemotactic protein (MCP)-1(r = −.30) and interleukin-1 beta (IL-1β; r = −.29). Pain severity correlated with macrophage inflammatory protein (MIP)-1β (r = .29), and pain interference negatively correlated with IL-1β (r = −.30). Fatigue negatively correlated with IL-1β (r = −.32), interleukin-10 (IL-10; r = −.31), and granulocyte colony-stimulating factor (G-CSF; r = −.31). Depressive symptoms correlated with CRP (r = .31). Discussion: Relationships among perceived stress and symptoms supported the PNI framework. Study findings are similar to previous studies showing that cytokines in persons with FMS do not show a consistent pattern. The elevated CRP levels suggest higher levels of generalized inflammation in the sample and provide evidence for continued development of biobehavioral interventions to address both symptoms and their biological markers over time.

Opioid withdrawal signs and symptoms in children: Frequency and determinants

OBJECTIVES The purpose of this study was to, in a pediatric population, describe the frequency of opioid withdrawal signs and symptoms and to identify factors associated with these opioid withdrawal signs and symptoms. BACKGROUND Opioids are used routinely in the pediatric intensive care population for analgesia, sedation, blunting of physiologic responses to stress, and safety. In children, physical dependence may occur in as little as 2-3 days of continuous opioid therapy. Once the child no longer needs the opioid, the medications are reduced over time. METHODS A prospective, descriptive study was conducted. The sample of 26 was drawn from all patients, ages 2 weeks to 21 years admitted to the Childrens Hospital of Richmond pediatric intensive care unit (PICU) and who have received continuous infusion or scheduled opioids for at least 5 days. Data collected included: opioid withdrawal score (WAT-1), opioid taper rate (total dose of opioid per day in morphine equivalents per kilogram [MEK]), pretaper peak MEK, pretaper cumulative MEK, number of days of opioid exposure prior to taper, and age. RESULTS Out of 26 enrolled participants, only 9 (45%) had opioid withdrawal on any given day. In addition, there was limited variability in WAT-1 scores. The most common symptoms notes were diarrhea, vomit, sweat, and fever. CONCLUSIONS For optimal opioid withdrawal assessments, clinicians should use a validated instrument such as the WAT-1 to measure for signs and symptoms of opioid withdrawal. Further research is indicated to examine risk factors for opioid withdrawal in children.

Potential epigenetic mechanism(s) associated with the persistence of psychoneurological symptoms in women receiving chemotherapy for breast cancer: a hypothesis.

Due to recent treatment advances, there have been improvements in the proportion of women surviving a diagnosis of breast cancer (BC). However, many of these survivors report persistent adverse side effects following treatment, such as cognitive dysfunction, depressive symptoms, anxiety, fatigue, sleep disturbances, and pain. Investigators have examined circulating levels of inflammatory markers, particularly serum cytokines, for a potential causal relationship to the development/persistence of these psychoneurological symptoms (PNS). While inflammatory activation, resulting from perceived stress or other factors, may directly contribute to the development of PNS, we offer an alternative hypothesis, suggesting that these symptoms are an early step in a cascade of biological changes leading to epigenetic alterations at the level of deoxyribonucleic acid (DNA) methylation, histone modifications, and/or chromatin structure/chromosomal instability. Given that epigenetic patterns have plasticity, if this conjectured relationship between epigenomic/acquired genomic alterations and the development/persistence of PNS is confirmed, it could provide foundational knowledge for future research leading to the recognition of predictive markers and/or treatments to alleviate PNS in women with BC. In this article, we discuss an evolving theory of the biological basis of PNS, integrating knowledge related to inflammation and DNA repair in the context of genetic and epigenetic science to expand the paradigm for understanding symptom acquisition/persistence following chemotherapy.

Psychoneuroimmunology-Based Stress Management during Adjuvant Chemotherapy for Early Breast Cancer

Objective. In a randomized trial of women with early stage breast cancer undergoing adjuvant chemotherapy, two stress management interventions, tai chi training and spiritual growth groups, were compared to a usual care control group, to evaluate psychosocial functioning, quality of life (QOL), and biological markers thought to reflect cancer- and treatment-specific mechanisms. Method. The sample consisted of 145 women aged 27–75 years; 75% were Caucasian and 25% African American. A total of 109 participants completed the study, yielding a 75% retention rate. Grounded in a psychoneuroimmunology framework, the overarching hypothesis was that both interventions would reduce perceived stress, enhance QOL and psychosocial functioning, normalize levels of stress-related neuroendocrine mediators, and attenuate immunosuppression. Results. While interesting patterns were seen across the sample and over time, the interventions had no appreciable effects when delivered during the period of chemotherapy. Conclusions. Findings highlight the complex nature of biobehavioral interventions in relation to treatment trajectories and potential outcomes. Psychosocial interventions like these may lack sufficient power to overcome the psychosocial or physiological stress experienced during the chemotherapy treatment period. It may be that interventions requiring less activity and/or group attendance would have enhanced therapeutic effects, and more active interventions need to be tested prior to and following recovery from chemotherapy.

A pilot exploration of symptom trajectories in adolescents with cancer during chemotherapy.

Background: Chemotherapy is frequently administered in repetitive cycles. Adolescents with cancer have multiple symptoms related to chemotherapy, but knowledge of symptom trajectories across a cycle is limited. Examining trajectories over a cycle may reveal key periods to manage symptoms. Objectives: The aims of this pilot were to describe the trajectory of symptoms (pain, sleep, appetite, nausea, fatigue) and biological and behavioral variables (anxiety, stress, hematologic function) across 1 cycle and examine relationships between variables. Methods: Nine adolescents with cancer within 6 months of diagnosis participated. Data were collected by surveys, chart review, and biologic measures on days 1 and 2 of the cycle, 1 week later (nadir), and day 1 of the following cycle. To evaluate the trajectory, a simple random-effects repeated-measures analysis was computed. Results: The significant trajectories were fatigue (P = .003), difficulty sleeping (P = .032), and nausea (P = .04). Most of the adolescents reported some anticipatory anxiety about receiving chemotherapy. Significant correlations between symptoms and biobehavioral variables included anticipatory anxiety and nausea (r = .86, P = .003), trait anxiety and fatigue (r = −0.82, P < .001), and stress and pain (r = 0.78, P = .039). Conclusions: Multiple symptoms were experienced across the cycle. Three symptoms displayed significant trajectories indicating that patterns of symptoms may be anticipated. Implications for Practice: Pilot findings suggest that monitoring symptoms, stress, and anxiety across a cycle is important, not only during chemotherapy administration, but also prior to being admitted for chemotherapy.