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Iron deficiency anemia is associated with heavy menstrual bleeding (HMB) and, by extension, a bleeding disorder (BD). It is unknown if iron deficiency without anemia is associated with a BD in adolescents. Moreover, the threshold of ferritin associated with fatigue in adolescents with HMB is unclear. In this multicenter study, we enrolled adolescents with HMB without BD. Participants underwent BD and anemia work-up in Young Women's Hematology Clinics and completed the Peds QL™ fatigue scale. BDs were defined as von Willebrand Disease, platelet function defect, clotting factor deficiencies, and hypermobility syndrome. Two hundred and fifty consecutive adolescents were enrolled, of whom 196 met eligibility criteria. Overall, 43% (95% confidence interval: 36%-50%) were diagnosed with BD. A total of 61% (n = 119) had serum ferritin levels < 15 ng/mL, 23.5% (n = 46) had iron deficiency only, and 37% (n = 73) had iron deficiency anemia. Low ferritin or ferritin dichotomized as < 15 or ≥ 15 ng/mL was not associated with BD on univariable analysis (p = .24) or when accounting for age, race, ethnicity, body mass index, and hemoglobin (p = .35). A total of 85% had total fatigue score below the population mean of 80.5, and 52% (n = 102) were > 2 SD (or < 54) below the mean, the cut-off associated with severe fatigue. A ferritin threshold of < 6 ng/mL had a specificity of 79.8% but a sensitivity of 36% for severe fatigue. In conclusion, iron deficiency without anemia is not a predictor of BD in adolescents with HMB in a specialty setting. Severe fatigue, especially sleep fatigue, is prevalent in adolescents with BD. Ferritin of < 6 ng/mL has ~80% specificity for severe fatigue in adolescents with HMB., (© 2021 Wiley Periodicals LLC.)

Background: Coeliac disease patients on a gluten-free diet experience reactions to gluten, but these are not well characterised or understood. Systemic cytokine release was recently linked to reactivation of gluten immunity in coeliac disease., Aim: To define the nature and time-course of symptoms and interleukin-2 changes specific for coeliac disease patients., Methods: 25 coeliac disease patients on a gluten-free diet and 25 healthy volunteers consumed a standardised 6 gram gluten challenge. Coeliac Disease Patient-Reported Outcome survey and global digestive symptom assessment were completed hourly up to 6 hours after gluten. Adverse events over 48 hours were recorded. Serum interleukin-2 was measured at baseline, and 2, 4 and 6 hours., Results: Serum interleukin-2 was always undetectable in healthy controls, whereas it was undetectable at baseline and elevated >0.5 pg/ml at 4 hours in 92% of coeliac disease patients. All patient-reported outcome severity scores increased significantly after gluten in coeliac disease patients (P < .001 Wilcoxon signed rank test), but not in controls. Symptoms began after 1 hour, and peaked in the third. Nausea and vomiting characterised severe reactions, but mild reactions were limited to headache and tiredness. Peak interleukin-2 correlated with symptom severity, particularly for nausea and vomiting., Conclusions: Serum interleukin-2 elevations correlate with timing and severity of symptoms after gluten in coeliac disease. Standardised bolus gluten food challenge and interleukin-2 assessment could provide a valuable clinical test to monitor and diagnose coeliac disease in patients established on a gluten-free diet., (© 2019 John Wiley & Sons Ltd.)

Cancer-related fatigue (CRF) is subjective and has wide inter-individual variability. Given that leptin is commonly associated with fatigue syndrome, its use as a potential biomarker for CRF is being investigated. The primary objective of this study was to evaluate the association between leptin and CRF in early-stage breast cancer patients receiving chemotherapy. In a prospective cohort study, patients completed assessments at baseline (T1), during chemotherapy (T2) and after chemotherapy (T3). Levels of plasma leptin and adipokines were measured using a Luminex bead-immunoassay and CRF was measured using the Multi-Dimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Data were analysed longitudinally using a generalised estimating equation incorporating clinically relevant parameters and pro-inflammatory adipokines. The analysis included 136 patients (mean age ± SD = 51.5 ± 8.8 years; 69.1% receiving anthracycline-based chemotherapy). More patients experienced CRF at T3 (23.8%) than at T2 (13.8%) compared to baseline. An increase was observed in the median plasma leptin level at T2, followed by a decrease at T3 (T1: 4.07 ng/mL, T2: 4.95 ng/mL and T3: 3.96 ng/mL). In the multivariate model, the change in leptin levels over time was significantly associated with the total MFSI-SF score (β = -0.15, P = 0.003) after adjusting for the tumour necrosis factor-α (TNF-α) level, anxiety, depression, insomnia, age, menopausal status and type of chemotherapy. This is the first study to report leptin as a biomarker that predicts the onset of CRF over time. Future studies are required to validate the findings., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment., (© 2019 Japanese Dermatological Association.)

Objectives: Parkinson's disease (PD)-related fatigue is a significant clinical problem, and the pathological processes that cause fatigue remain unknown. The aim of the present study was to explore the possible association of peripheral inflammation markers and fatigue in PD., Materials & Methods: We included 47 drug naïve, newly diagnosed PD patients with low (≤3.0) or high (>5.5) fatigue levels as evaluated by the Fatigue Severity Scale (FSS). Strict diagnostic criteria were applied for inclusion. Patients with possible confounding causes for fatigue were excluded. Serum concentrations of a panel of inflammatory markers (IL-8, TNF-α, MCP1, MIP-1β, IL-6, IL-6R, p-selectin, E-selectin-1, ICAM, VCAM-1, CCL5, IL1-Ra, and TNFR1) were measured using ELISA technology in PD patients with and without fatigue to assess the potential relationships of fatigue in newly diagnosed, treatment-naïve patients., Results: Fatigued PD patients had significantly higher levels of the IL-1 receptor antagonist (IL1-Ra) (1790 pg/mL (SD1007) vs 1262 pg/mL (SD379)) and of the adhesion molecule VCAM 1 (1071 ng/mL (SD276) vs 895 ng/mL (SD229)) than non-fatigued patients. A binary logistic regression model, including high or low FSS score as the dependent variable and UPDRS motor score, MADRS, MMSE, ESS, and IL1-Ra/VCAM-1 as independent variables, showed a significant effect both for IL1-Ra and VCAM-1., Conclusions: Higher serum levels of the inflammatory molecules IL1-Ra and VCAM-1 were associated with higher fatigue levels in patients with newly diagnosed, drug-naïve PD. These findings highlight an altered immune response as a potential contributor to PD-related fatigue, from the earliest clinical stages of the disease., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Our aim was to clarify the correlation between fatigue during the acute stage of stroke with serum glucose and homocysteine (Hcy) levels and functional disability., Materials and Methods: A case group of 214 patients and a control group of 214 subjects were recruited during the same period. The serum glucose, Hcy, blood lipid and fibrinogen (FIB) levels of patients were determined. Fatigue was assessed using the Fatigue Severity Scale (FSS). Patients with an FSS score ≥4 points were defined as having fatigue. Stroke severity and the level of functional disability were assessed with the National Institutes of Health Stroke Scale (NIHSS) and the Barthel-20 Index (BI-20), respectively., Results: The incidence of fatigue in the case group was higher than that in the control group (P < 0.001). Within the case group, the fatigue group showed higher serum levels of glucose and Hcy, and a lower BI-20 score compared to the non-fatigue group (P < 0.001). Age, gender, chronic disease history, the NIHSS score and the serum blood lipid and FIB levels were not significantly different between the two groups. In the fatigue group, the serum glucose and Hcy levels showed a positive effect and the BI-20 score showed a negative effect on the FSS score (P < 0.01). Age, gender, chronic disease history, the NIHSS score and the serum blood lipid and FIB levels did not significantly affect the FSS score., Conclusions: The serum glucose and Hcy levels and functional disability are closely related to fatigue during the acute stage of ischaemic stroke., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher-risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher-risk MDS patients. Pre-treatment patient-reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Female gender (P = 0·018), poor performance status (i.e., ECOG of 2-4) (P < 0·001) and lower levels of haemoglobin (Hb) (P = 0·026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29·2 [standard deviation (SD), 18·3] and 69·0 (SD, 18·8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient-reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue., (© 2014 John Wiley & Sons Ltd.)

Objective: Insufficient sun exposure and vitamin D deficiency have both been associated with increased risk of multiple sclerosis (MS). Depressi on, anxiety, fatigue and cognitive impairment are prevalent and disabling symptoms in MS. Our objective was to examine the associations between personal sun exposure and serum 25-hydroxyvitamin D (25(OH)D), and depression, anxiety, fatigue and cognition., Methods: A total of 198 participants with multiple sclerosis were followed prospectively for an average of 2.3 years. Assessments of serum 25(OH)D, sun exposure, depression, anxiety and fatigue were carried out biannually; cognition was assessed annually., Results: Personal reported sun exposure was inversely associated with depression scores (β -0.26 (95%CI -0.40, -0.12);P ≤ 0.001) and fatigue scores (β -0.65 (95%CI -1.23, -0.07); P = 0.028). Only high levels of 25(OH)D (>80 nm) were inversely associated depression scores (β -0.64 (95%CI -1.15, -0.13); P = 0.015), but this was not significant after adjustment for reported sun exposure. No associations were seen between reported sun exposure or serum 25(OH)D levels and anxiety or cognition scores., Conclusion: We found that higher levels reported sun exposure, rather than 25(OH)D levels, were associated with less depressive symptoms and levels of fatigue. The role of UV or light therapy will need to be evaluated in randomized controlled trials to confirm an effect on these symptoms in MS., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Fatigue is an important determinant of altered quality of life in patients affected by chronic hepatitis C or the irritable bowel syndrome (IBS)., Aim: In this study, we aimed at determining the contributory role of plasma levels of leptin and carnitine on fatigue in chronic hepatitis C and IBS., Methods: We enrolled 81 patients with chronic hepatitis C, 42 with IBS and 44 healthy subjects. Fatigue was evaluated using the Fatigue Impact Scale questionnaire. Body composition was assessed through impedance analysis. Plasma carnitine and leptin were measured., Results: Fatigue scores were significantly more elevated in patients with chronic hepatitis C and IBS than in healthy subjects. Patients with chronic hepatitis C but not IBS, had significant lower plasma levels of total and free carnitine adjusted for fat mass compared with healthy subjects. In patients with chronic hepatitis C and not with IBS, fatigue scores were negatively correlated with plasma levels of carnitine. Levels of free carnitine were significantly and independently associated with the severity of fatigue in patients with chronic hepatitis C [OR=2.019, P=0.02, CI 95% (1.01-1.23)]., Conclusions: In patients with chronic hepatitis C, the severity of fatigue is associated with a low level of carnitine, suggesting that an oral supplementation may be effective to relieve fatigue in chronic hepatitis C. The underlying mechanism of fatigue in IBS does not seem to involve carnitine., (© 2011 Blackwell Publishing Ltd.)

Objective: To identify one nuclear autoantigenic protein within a complex of DNA binding proteins that bind to GC-rich sequences in Epstein-Barr virus and cellular DNA, and to describe the clinical characteristics of patients whose sera contained autoantibodies to this novel autoantigen., Methods: Antibodies to autoantigen Sp1 were initially measured by an electrophoretic mobility shift assay to detect DNA binding proteins. Nuclear extracts and purified Sp1 protein were used in these assays. Recognition of the autoantigen by autoimmune sera was confirmed by immunoprecipitation and immunoblotting., Results: The autoantigen was identified as Sp1. Anti-Sp1 was detected in sera from 8 (3%) of 230 patients. These sera contained antinuclear antibodies, but lacked antibodies to double-stranded DNA or to several extractable nuclear antigens. The patients whose sera contained antibodies to Sp1 were white women with fatigue, arthritis, Raynaud's phenomenon, malar rash, and photosensitivity., Conclusion: Sp1 is the first described example of an RNA polymerase II transcription activator as an autoantigen. The presence of Sp1 autoantibodies is associated with undifferentiated connective tissue disease.

The role of elevations of serum cytokines in psoriasis is a provocative issue. We report two patients with psoriasis who had episodes of fever, arthritis, and general fatigue. Their symptoms seemed to be associated with increases in serum levels of interleukin (IL)-6, which paralleled the severity of clinical symptoms as well as elevated serum titers of C-reactive protein (CRP) and platelet counts. Since IL-6 is a multipotential cytokine with B-cell activating, T-cell activating, and thrombocytopoietic functions, the symptoms and abnormal laboratory findings in these patients may have been related to their increased serum levels of IL-6. Monitoring the serum level of this cytokine may thus be useful in evaluating the clinical status of patients with psoriatic arthritis.