Fibromyalgia: transformation of views

Fibromyalgia (FM) is a mystery of modern rheumatology. Despite the high prevalence of FM according to special epidemiological studies, clinicians make this diagnosis rarely. The modern concept of fibromyalgia was created by Smythe and Moldofsky in the mid-70s. They introduced a new term «fibromyalgia», thereby emphasizing that this condition is more due to pain syndrome than inflammation of connective tissue. A disturbance of sensory information processing in the central nervous system (dysfunction of the pain system with the formation of central sensitization, CS) plays a key role in the pathogenesis of FM. Clinical manifestations of FM include chronic widespread pain associated with a wide range of psychosomatic disorders (sleep disorders, cognitive disorders [fibro fog], anxiety, depression, fatigue, morning stiffness, etc.). The diagnostic criteria for fibromyalgia have undergone significant changes. The latest FM diagnostic criteria were developed by the American College of Rheumatology (ACR) in 2016. According to the ACR (2016) FM criteria, a diagnosis of FM does not exclude the presence of other clinically important illnesses. Concomitant FM among patients with rheumatic diseases (RD) occurs 2–3 times more often than in the general population. Diagnostics and treatment of FM are extremely difficult for clinicians, it is especially difficult with comorbidity of FM with RD. Therefore, FM requires a multidisciplinary approach within a biopsychosocial model of pain syndrome: the treatment of a patient with RD and FM should combine anti-inflammatory therapy with a complex of methods (medications and nondrug therapy) used for FM therapy. The diagnostics of comorbid FM in patients with RD will allow for personalized and more effective analgesic therapy.

Laboratory Examination in Hemophagocytic Lymphohistiocytosis

Hemophagocytic Lymphohistiocytosis (HLH) is derived from the word hemophagocytosis, in which macrophagesinfiltrate tissue extensively, and unspecifically phagocyte blood and bone marrow cells. The deviant activation of cytotoxicCD8+ T-cells causing the release of inflammatory cytokines is the core pathogenesis of HLH. Hemophagocyticlymphohistiocytosis is a regulatory disorder of the immune system, with clinical signs and symptoms of extremeinflammation and cytopenia, hepatitis, and severe and life-threatening central nervous system dysfunction. The name of theHLH disorder was recently proposed to be "Hyperinflammatory Lymphohistiocytosis" (also known as HLH). Enforcement ofHLH diagnosis by the Histiocyte Society based on HLH 2004 updated diagnostic criteria consists of five of the following eightdiagnostic criteria: fever, splenomegaly, cytopenia (two or more of three lineages in peripheral blood), hypertriglyceridemiaor hypofibrinogenemia, hyperferritinemia, hemophagocytes in the bone marrow/lien/lymph, the low or non-existentactivity of Natural Killer (NK) cells, increased sCD25. H-score, MH-score, and systemic Juvenile Idiopathic Arthritis(sJIA)/Macrophage Activated Syndrome (MAS) classification criteria are also used to enforce HLH diagnoses.Hemophagocytic lymphohistiocytosis is challenging to recognize and has a high mortality rate, especially in adults, rangingfrom 42 to 88%. Therefore, immediate diagnosis and therapy are essential. The introduction of HLH triggers is criticalbecause treatment is based on the underlying trigger. Cytokine storms due to Coronavirus Disease 19 (COVID-19) infectionhave significant similarities to the clinical and laboratory findings of HLH. Secondary HLH (sHLH) is suspected in severeCOVID-19 patients, so early diagnosis is potentially made based on the H-score.

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

We here provide an overview of the pathophysiological mechanisms during heat stroke and describe similar mechanisms found in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Both conditions are characterized by disturbed homeostasis in which inflammatory pathways play a central role. Splanchnic vasoconstriction, increased gut permeability, gut-related endotoxemia, systemic inflammatory response, central nervous system dysfunction, blood coagulation disorder, endothelial-cell injury, and mitochondrial dysfunction underlie heat stroke. These mechanisms have also been documented in ME/CFS. Moreover, initial transcriptomic studies suggest that similar gene expressions are altered in both heat stroke and ME/CFS. Finally, some predisposing factors for heat stroke, such as pre-existing inflammation or infection, overlap with those for ME/CFS. Notwithstanding important differences - and despite heat stroke being an acute condition - the overlaps between heat stroke and ME/CFS suggest common pathways in the physiological responses to very different forms of stressors, which are manifested in different clinical outcomes. The human studies and animal models of heat stroke provide an explanation for the self-perpetuation of homeostatic imbalance centered around intestinal wall injury, which could also inform the understanding of ME/CFS. Moreover, the studies of novel therapeutics for heat stroke might provide new avenues for the treatment of ME/CFS. Future research should be conducted to investigate the similarities between heat stroke and ME/CFS to help identify the potential treatments for ME/CFS.

Profile of a short-acting κ-antagonist, LY2795050, on self-grooming behaviors, forced swim test and locomotor activity: sex comparison in mice

Background: Novel short-acting κ(kappa)-opioid receptor selective antagonists are translational tools to examine the impact of the κ-receptor/dynorphin system in assays related to central nervous system dysfunction (e.g., substance use disorders, anhedonia and depression). The effects of such compounds have been compared in males and females under very limited conditions. Aims: The goal of this study was to examine potential sex differences in the effects of a κ-agonist and a short-acting κ-antagonist in an ethologically relevant test of anhedonia, the “splash test” of self-grooming, and also in the forced swim test and in locomotor activity. Methods: We examined the dose-dependence of grooming deficits caused by the κ-agonist U50,488 (0.1–3.2 mg/kg intraperitoneal (i.p.)) in gonadally intact adult male and female C57BL/6J mice. We then compared the effects of the short-acting κ-antagonist LY2795050 ((3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)); 0.032–0.1 mg/kg i.p.) in blocking grooming deficits caused by U50,488 (3.2 mg/kg). The effects of LY2795050 were also studied in the forced swim test (FST). The effects of LY2795050 in blocking the locomotor depressant effects of U50,488 (10 mg/kg) were also studied. Results: U50,488 produced dose-dependent grooming deficits in male and female mice, and LY2795050 prevented these effects. In contrast, LY2795050 decreased immobility in the FST in males at a dose of 0.1 mg/kg, but not in females, up to a dose of 0.32 mg/kg. Also, LY2795050 (0.32 mg/kg) prevented and also reversed the locomotor-depressant effects of U50,488 (10 mg/kg), in males and females. Conclusions: This study further implicates the κ-receptor system in ethologically relevant aspects of anhedonia, and confirms sexual dimorphism in some behavioral effects of novel κ-antagonists.

Probing the Brain–Body Connection Using Transcranial Magnetic Stimulation (TMS): Validating a Promising Tool to Provide Biomarkers of Neuroplasticity and Central Nervous System Function

Transcranial magnetic stimulation (TMS) is a non-invasive method used to investigate neurophysiological integrity of the human neuromotor system. We describe in detail, the methodology of a single pulse TMS protocol that was performed in a large cohort of people (n = 110) with multiple sclerosis (MS). The aim was to establish and validate a core-set of TMS variables that predicted typical MS clinical outcomes: walking speed, hand dexterity, fatigue, and cognitive processing speed. We provide a brief and simple methodological pipeline to examine excitatory and inhibitory corticospinal mechanisms in MS that map to clinical status. Delayed and longer ipsilateral silent period (a measure of transcallosal inhibition; the influence of one brain hemisphere’s activity over the other), longer cortical silent period (suggestive of greater corticospinal inhibition via GABA) and higher resting motor threshold (lower corticospinal excitability) most strongly related to clinical outcomes, especially when measured in the hemisphere corresponding to the weaker hand. Greater interhemispheric asymmetry (imbalance between hemispheres) correlated with poorer performance in the greatest number of clinical outcomes. We also show, not surprisingly, that TMS variables related more strongly to motor outcomes than non-motor outcomes. As it was validated in a large sample of patients with varying severities of central nervous system dysfunction, the protocol described herein can be used by investigators and clinicians alike to investigate the role of TMS as a biomarker in MS and other central nervous system disorders.

Titanium Dioxide Nanoparticles Induce Cognitive Dysfunction of Rats with Endogenous Protective Mechanism of Increased miR-21-5p

BackgroundTitanium dioxide nanoparticles (TiO2 NPs) cause nerve cell damage and central nervous system dysfunction has been well known. However, most of the cognitive deficits occurs before the observable damage to nerve cells and the regulatory mechanism is largely unknown. Mitochondria and energy metabolism are the targets of many neurotoxic substances. ResultsHere, we showed that TiO2 NPs exposure reduced the mitochondrial membrane potential (ΔΨm) and ATP content, which is the important cause of cognitive deficits, and upregulated microRNA-21-5p (miR-21-5p) levels in rat neuron cells. Upregulated miR-21-5p promoted phosphorylation of c-Jun, consequently promoting transcription of VDAC1 (encoding voltage-dependent anion channel 1), which in turn preserved the ΔΨm and ATP content of neuron cells. ConclusionsMechanistically, upregulated VDAC1 was attributed to TiO2 NPs-induced phosphorylation of c-Jun (Ser73), which is predicted to be a transcription factor of VDAC1, while upregulation of the ΔΨm and ATP content was caused by the increased oxygen consumption rate induced by VDAC1. The results of our present study revealed an endogenous self-protection mechanism in the process of TiO2 NPs-induced cognitive deficits.

Structural basis of GABARAP-mediated GABAA receptor trafficking and functions on GABAergic synaptic transmission

GABAA receptors (GABAARs) are the primary fast inhibitory ion channels in the central nervous system. Dysfunction of trafficking and localization of GABAARs to cell membranes is clinically associated with severe psychiatric disorders in humans. The GABARAP protein is known to support the stability of GABAARs in synapses, but the underlying molecular mechanisms remain to be elucidated. Here, we show that GABARAP/GABARAPL1 directly binds to a previously unappreciated region in the γ2 subunit of GABAAR. We demonstrate that GABARAP functions to stabilize GABAARs via promoting its trafficking pathway instead of blocking receptor endocytosis. The GABARAPL1–γ2-GABAAR crystal structure reveals the mechanisms underlying the complex formation. We provide evidence showing that phosphorylation of γ2-GABAAR differentially modulate the receptor’s binding to GABARAP and the clathrin adaptor protein AP2. Finally, we demonstrate that GABAergic synaptic currents are reduced upon specific blockage of the GABARAP–GABAAR complex formation. Collectively, our results reveal that GABARAP/GABARAPL1, but not other members of the Atg8 family proteins, specifically regulates synaptic localization of GABAARs via modulating the trafficking of the receptor.