Oxidative stress involves phenotype modulation of morbid soreness symptoms in fibromyalgia.

OBJECTIVES: Muscle soreness occurs after exercise and also in musculoskeletal diseases, such as fibromyalgia (FM). However, the nosography and pathoetiology of morbid soreness in FM remain unknown. This study aimed to investigate the morbid soreness of FM, evaluate its therapeutic responses and probe its pathophysiology with metabolomics profiling. METHODS: Patients with newly diagnosed FM were prospectively recruited and completed self-report questionnaires pertaining to musculoskeletal symptoms. The phenotypes and metabotypes were assessed with variance, classification and correlation analyses. RESULTS: Fifty-one patients and 41 healthy controls were included. Soreness symptoms were prevalent in FM individuals (92.2%). In terms of manifestations and metabolomic features, phenotypes diverged between patients with mixed pain and soreness symptoms (FM-PS) and those with pain dominant symptoms. Conventional treatment for FM did not ameliorate soreness severity despite its efficacy on pain. Moreover, despite the salient therapeutic efficacy on pain relief in FM-PS cases, conventional treatment did not improve their general disease severity. Metabolomics analyses suggested oxidative metabolism dysregulation in FM, and high malondialdehyde level indicated excessive oxidative stress in FM individuals as compared with controls (p=0.009). Contrary to exercise-induced soreness, lactate levels were significantly lower in FM individuals than controls, especially in FM-PS. Moreover, FM-PS cases exclusively featured increased malondialdehyde level (p=0.008) and a correlative trend between malondialdehyde expression and soreness intensity (r=0.337, p=0.086). CONCLUSIONS: Morbid soreness symptoms were prevalent in FM, with the presentation and therapeutic responses different from FM pain conditions. Oxidative stress rather than lactate accumulation involved phenotype modulation of the morbid soreness in FM. TRIAL REGISTRATION NUMBER: NCT04832100.

Association between proteinuria and the development of malignant middle cerebral artery infarction: A retrospective cohort study.

A disrupted blood-brain barrier (BBB) with extravasation of macromolecules plays a critical role in the development of malignant middle cerebral artery infarction (MMI). Proteinuria is considered a marker of generalized endothelial dysfunction, including BBB disruption. This study aimed to clarify whether proteinuria identified in the acute stage of stroke is associated with MMI development. Patients with infarctions involving the middle cerebral artery territory were reviewed. Urine samples collected within 8 hours after stroke were analyzed using urine dipsticks. Patients were divided into proteinuria (urine dipstick reading of 1 + to 4+) and nonproteinuria groups. MMI was present if either signs of uncal herniation or a progressive conscious disturbance were recorded along with a midline shift > 5 mm identified on follow-up computed tomography (CT). Among the 1261 patients identified between January 2010 and June 2019, 138 were eligible for final analyses. Patients in the MMI group had lower Alberta Stroke Program Early CT Scores (ASPECTS), higher National Institutes of Health Stroke Scale scores, and a greater proportion of proteinuria than those in the non-MMI group. Four multivariate logistic regression models were used to clarify the role of proteinuria in MMI development. In model 1, proteinuria was significantly associated with MMI after adjusting for age, sex, dyslipidemia and ASPECTS (OR = 2.987, 95% CI = 1.329-6.716, P = .0081). The risk of developing MMI in patients with proteinuria remained significant in model 2 (OR = 3.066, 95% CI = 1.349-6.968, P = .0075) after adjusting for estimated glomerular filtrate rate (eGFR) < 60ml/min/1.73 m2 in addition to variables in model 1. In model 3, proteinuria was still significantly associated with MMI after adjusting for age, sex, dyslipidemia, ASPECTS, hypertension, diabetes, and atrial fibrillation (OR = 2.521, 95% CI = 1.075-5.912, P = .0335). In model 4, the risk of developing MMI in patients with proteinuria remained significant (OR = 2.579, 95% CI = 1.094-6.079, P = .0304) after adjusting for eGFR < 60ml/min/1.73 m2 in addition to variables in model 3. Proteinuria is independently associated with MMI development. Proteinuria may be a clinically accessible predictor of MMI development.

Activation of acid-sensing ion channel 3 by lysophosphatidylcholine 16:0 mediates psychological stress-induced fibromyalgia-like pain.

OBJECTIVES: Fibromyalgia is commonly considered a stress-related chronic pain disorder, and daily stressors are known triggers. However, the relation between stress and pain development remains poorly defined by clinical approaches. Also, the aetiology remains largely unknown. METHODS: We used a newly developed mouse model and lipidomic approaches to probe the causation and explore the biological plausibility for how perceived stress translates into chronic non-inflammatory pain. Clinical and lipidomic investigations of fibromyalgia were conducted for human validation. RESULTS: Using non-painful sound stimuli as psychological stressors, we demonstrated that mice developed long-lasting non-inflammatory hyperalgesia after repeated and intermittent sound stress exposure. Elevated serum malondialdehyde level in stressed mice indicated excessive oxidative stress and lipid oxidative damage. Lipidomics revealed upregulation of lysophosphatidylcholine 16:0 (LPC16:0), a product of lipid oxidisation, in stressed mice. Intramuscular LPC16:0 injection triggered nociceptive responses and a hyperalgesic priming-like effect that caused long-lasting hypersensitivity. Pharmacological or genetic inhibition of acid-sensing ion channel 3 impeded the development of LPC16:0-induced chronic hyperalgesia. Darapladib and antioxidants could effectively alleviate the stress-induced hyperalgesia by inhibiting LPC16:0 synthesis. Clinical investigations showed that excessive oxidative stress and LPC16:0 expression also exist in patients with fibromyalgia. Moreover, LPC16:0 expression was correlated with pain symptoms in patients with high oxidative stress and disease severity. CONCLUSIONS: Our study provides experimental evidence for the causal effect of psychological stressors on chronic pain development. The findings identify a possible pathophysiological mechanism of stress-induced chronic non-inflammatory pain at molecular, behavioural and clinical levels that might indicate a new therapeutic approach for fibromyalgia.

Electronegative Low-Density Lipoprotein L5 Impairs Viability and NGF-Induced Neuronal Differentiation of PC12 Cells via LOX-1.

There have been striking associations of cardiovascular diseases (e.g., atherosclerosis) and hypercholesterolemia with increased risk of neurodegeneration including Alzheimer's disease (AD). Low-density lipoprotein (LDL), a cardiovascular risk factor, plays a crucial role in AD pathogenesis; further, L5, a human plasma LDL fraction with high electronegativity, may be a factor contributing to AD-type dementia. Although L5 contributing to atherosclerosis progression has been studied, its role in inducing neurodegeneration remains unclear. Here, PC12 cell culture was used for treatments with human LDLs (L1, L5, or oxLDL), and subsequently cell viability and nerve growth factor (NGF)-induced neuronal differentiation were assessed. We identified L5 as a neurotoxic LDL, as demonstrated by decreased cell viability in a time- and concentration-dependent manner. Contrarily, L1 had no such effect. L5 caused cell damage by inducing ATM/H2AX-associated DNA breakage as well as by activating apoptosis via lectin-like oxidized LDL receptor-1 (LOX-1) signaling to p53 and ensuring cleavage of caspase-3. Additionally, sublethal L5 long-termly inhibited neurite outgrowth in NGF-treated PC12 cells, as evidenced by downregulation of early growth response factor-1 and neurofilament-M. This inhibitory effect was mediated via an interaction between L5 and LOX-1 to suppress NGF-induced activation of PI3k/Akt cascade, but not NGF receptor TrkA and downstream MAPK pathways. Together, our data suggest that L5 creates a neurotoxic stress via LOX-1 in PC12 cells, thereby leading to impairment of viability and NGF-induced differentiation. Atherogenic L5 likely contributes to neurodegenerative disorders.

Highly electronegative low-density lipoprotein L5 evokes microglial activation and creates a neuroinflammatory stress via Toll-like receptor 4 signaling.

Atherogenic risk factors, such as hypercholesterolemia, are associated with increased risk of neurodegeneration, especially Alzheimer's dementia. Human plasma electronegative low-density lipoprotein [LDL(-)], especially L5, may serve as an important contributing factor. L5 promoting an inflammatory action in atherosclerosis has been extensively studied. However, the role of L5 in inducing neuroinflammation remains unknown. Here, we examined the impact of L5 on immune activation and cell viability in cultured BV-2 microglia. BV-2 cells treated with lipopolysaccharide or human LDLs (L1, L5, or oxLDL) were subjected to molecular/biochemical assays for measuring microglial activation, levels of inflammatory factors, and cell survival. A transwell BV-2/N2a co-culture was used to assess N2a cell viability following BV-2 cell exposure to L5. We found that L5 enables the activation of microglia and elicits an inflammatory response, as evidenced by increased oxygen/nitrogen free radicals (nitric oxide, reactive oxygen species, and peroxides), elevated tumor necrosis factor-α levels, decreased basal interleukin-10 levels, and augmented production of pro-inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase-2). L5 also triggered BV-2 cell death primarily via apoptosis. These effects were markedly disrupted by the application of signaling pathway inhibitors, thus demonstrating that L5 interacts with Toll-like receptor 4 to modulate multiple pathways, including MAPKs, PI3K/Akt, and NF-κB. Decreased N2a cell viability in a transwell co-culture was mainly ascribed to L5-induced BV-2 cell activation. Together, our data suggest that L5 creates a neuroinflammatory stress via microglial Toll-like receptor 4, thereby leading to the death of BV-2 microglia and coexistent N2a cells. Atherogenic L5 possibly contributes to neuroinflammation-related neurodegeneration.

Increased risk of benign prostate hyperplasia in sleep apnea patients: a nationwide population-based study.

BACKGROUND: Sleep apnea (SA) is a common sleep disorder characterized by chronic intermittent hypoxia (IH). Chronic IH induces systemic inflammatory processes, which can cause tissue damage and contribute to prostatic enlargement. The purpose of this study was to evaluate the association between benign prostate hyperplasia (BPH) and SA in a Taiwanese population. METHODS: The study population was identified from Taiwan's National Health Insurance Research Database (NHIRD) and contained 202 SA patients and 1010 control patients. The study cohort consisted of men aged ≥ 30 years who were newly diagnosed with SA between January 1997 and December 2005. Each patient was monitored for 5 years from the index date for the development of BPH. A Cox regression analysis was used to calculate the hazard ratios (HRs) for BPH in the SA and control patients. RESULTS: During the 5-year follow-up, 18 SA patients (8.9%) and 32 non-SA control patients (3.2%) developed BPH. The adjusted HR for BPH was 2.35-fold higher in the patients with SA than in the control patients (95% confidence interval (CI) 1.28-4.29, P<.01). We further divided the SA patients into 4 age groups. After adjusting for potential confounding factors, the highest adjusted HR for BPH in the SA patients compared with the control patients was 5.59 (95% CI = 2.19-14.31, P<.001) in the patients aged between 51 and 65 years. CONCLUSION: Our study results indicate that patients with SA are associated with increased longitudinal risk of BPH development, and that the effects of SA on BPH development are age-dependent.

Timing of stroke onset determines discharge-functional status but not stroke severity: a hospital-based study.

Circadian variation of the onset time of acute ischemic stroke has been well studied. However, little is mentioned about the circadian variation of discharge-stroke severity and discharge-functional status. This study evaluated the impact of onset time on discharge-stroke severity and the functional status of acute ischemic stroke. Brain magnetic resonance imaging was performed on 274 acute ischemic stroke patients (66.42% male; mean age = 64.81 ± 12.80 years). All times of onset were assigned to 4-hourly periods (six groups) starting from midnight. Stroke severity/functional status was evaluated on admission and discharge using the National Institute of Health Stroke Scale (NIHSS) score/modified Rankin Scale (mRS) and Barthel Index (BI), respectively. Using mRS, but not NIHSS score and BI, it was possible to differentiate the best and worst groups on discharge. Patients in group 2 (4 to <8 am) and group 6 (8 to <12 pm) had best and worst functional status, respectively. To control other stroke risk factors, multiple logistic regression analyses were conducted to examine the role of onset time in discharge mRS. Aside from age, onset time was a significant indicator in mRS, while gender, hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and current smoking were not. In conclusion, there is also circadian variation of discharge-functional status in patients with acute ischemic stroke when assessed by mRS.

Application of AD8 questionnaire to screen very mild dementia in Taiwanese.

The AD8 questionnaire developed by Washington University in St Louis is a screening tool with 8 questions to reliably differentiate nondemented from demented individuals even at the very mild stage. We recruited 239 participants, including 114 cognitively normal, 73 very mild dementia, and 52 mild dementia to validate its application in Taiwanese. The cut-off value of AD8 was 2 in discriminating cognitively normal from demented individuals with the area under curve (AUC) = 0.961, sensitivity = 97.6%, specificity = 78.1%, positive likelihood ratio (PLR) = 4.5, and negative likelihood ratio (NLR) = 0.03. The cut-off value also was 2 in discriminating nondemented from very mild dementia with the AUC = 0.948, sensitivity = 95.9%, specificity = 78.1%, PLR = 4.4, and NLR = 0.05. The Chinese AD8 is effective in discriminating individuals with dementia, even at its mildest stages from those without dementia with properties identical to the original English version. The cAD8 is a quick dementia screening tool that can be applied across cultures.

Riboflavin-responsive glutaric aciduria type II with recurrent pancreatitis.

A 22-year-old woman had suffered from several episodes of acute pancreatitis since the age of 11. Other than exercise intolerance since early childhood, her psychomotor development was normal. At age 21, she experienced two episodes of generalized muscle weakness including acute respiratory failure and hepatomegaly. Liver biopsy indicated fatty metamorphosis, and muscle biopsy revealed vacuolar myopathy with lipid accumulation. Biochemical investigations demonstrated elevated serum creatine kinase and elevated 2-hydroxylglutaric, pyruvic, ethylmalonic, hippuric, adipic, and seburic acids in urinary organic acid analysis. These findings confirmed the diagnosis of glutaric aciduria type II. Although acute pancreatitis in glutaric aciduria type II has been reported previously, this is the first reported case of recurrent pancreatitis occurring in glutaric aciduria type II. We treated the patient with l-carnitine and riboflavin. As of the latest follow-up 2.5 years later, the patient has had no further episodes of muscle weakness or pancreatitis. We suggested analyzing urine organic acid when lipid storage myopathy is suspected.