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Background: Our group have recently reported that there is no evidence of an associa-tion between fibromyalgia and Borrelia-specific T lymphocytes. However, a small number of case reports has suggested that infection by the bacterial genus Borrelia may be associated with the pres-ence of antinuclear antibodies (ANAs). Objective: To test the hypothesis that those fibromyalgia patients who are ANA seropositive are more likely to show evidence of Borrelia-specific T lymphocyte reactivity than those who are sero-negative. Methods: T lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen) was assessed using the enzyme-linked immunospot and serum ANA status was assessed using immunofluores-cence in 27 fibromyalgia patients fulfilling the revised diagnostic criteria of the American College of Rheumatology. Results: The ANA seropositive and seronegative groups were matched for age, sex and ethnicity; the T lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen) in the former group (mean 5.60) was significantly higher than that in the seronegative group (mean 1.77; p < 0.05). Conclusion: This novel study points to an association of ANA seropositivity in fibromyalgia with Borrelia-specific T lymphocytes.

Background: Preliminary evidence has pointed an association of the gene HLA-DRB1 with fibromyalgia. HLA-DRB1 alleles carrying the shared or susceptibility epitope encoding the five-amino acid motif QKRAA, QRRAA or RRRAA in positions 70 to 74 of the major histocom-patibility complex class II DRβ chain are associated with several autoimmune diseases. Objective: The objective of this study was to test the hypothesis that susceptibility epitope-encoding HLA-DRB1 alleles are associated with fibromyalgia. Methods: Using a case-control design, the prevalence of susceptibility epitope-encoding HLA-DRB1 alleles in 27 white Caucasian patients fulfilling the revised diagnostic criteria for fibromyal-gia of the American College of Rheumatology was compared with that in 27 white Caucasian age- and sex-matched healthy controls. Results: 13 (48%) of the fibromyalgia patients had susceptibility epitope-coding HLA-DRB1 alleles compared with 15 (56%) of the controls (P = 0.785). The DRB1*01 allele encoding the protective epitope 70-DERAA-74 motif was found in one of the control subjects; none of the fibromyalgia patients had such a protective epitope. Conclusion: While the present study does not provide evidence supporting the potential role of HLA-DRB1 in the etiology of fibromyalgia, it does not exclude the possibility that there is a poly-genic component to a putative genetic causative role.

The pathophysiology of psychiatric and neurodegenerative disorders is complex and multifactorial. Polyphenols possess a range of potentially beneficial mechanisms of action that relate to the implicated pathways in psychiatric and neurodegenerative disorders. The aim of this review is to highlight the emerging clinical trial and preclinical efficacy data regarding the role of polyphenols in mental and brain health, elucidate novel mechanisms of action including the gut microbiome and gene expression, and discuss the factors that may be responsible for the mixed clinical results; namely, the role of interindividual differences in treatment response and the potentially pro-oxidant effects of some polyphenols. Further clarification as part of larger, well conducted randomized controlled trials that incorporate precision medicine methods are required to inform clinical efficacy and optimal dosing regimens.

SUMMARY OBJECTIVE: This study aimed to test the hypothesis that fibromyalgia is associated with a human enteroviral infection. METHODS: Venous peripheral blood samples from 27 patients fulfilling the American College of Rheumatology revised diagnostic criteria for fibromyalgia and from 26 age- and sex-matched controls, who underwent immunofluorescence assays for coxsackievirus A7 IgG, coxsackievirus B1 IgG, coxsackievirus A7 IgA, coxsackievirus B1 IgA, echovirus IgG, and echovirus IgA. These immunological tests were performed blind to group status. RESULTS: There were no significant differences between the patient and control groups in respect of positive results for coxsackievirus A7 IgG (p=0.467), coxsackievirus B1 IgG (p=0.491), coxsackievirus A7 IgA (p=0.586), coxsackievirus B1 IgA (p=0.467), echovirus IgG (p=0.236), and echovirus IgA (p=1). CONCLUSIONS: The results of this systematic study do not support the hypothesis that fibromyalgia is associated with infection by a human enterovirus.

Background/objectives: Diagnosis of human infection by various species of the bacterial genus Borrelia is mainly reliant on serological testing, polymerase chain reaction (PCR) or culture but such serological tests have been reported to have heterogeneous sensitivities, while Borrelia PCR and culture have been reported as being of modest diagnostic value. It has been suggested that the adjunctive use of the lymphocyte transformation test-memory lymphocyte immunostimulation assay (LTT-MELISA) may be helpful in this regard; however, the clinical usefulness of this assay has been questioned. The Borrelia immunodominant 41-kDa flagellin protein almost always gives rise to a marked human antibody response following infection. It was therefore decided to determine whether the LTT-MELISA detects the human antibody response to this antigen. Methods: Blood samples from consecutive patients with possible borreliosis attending a clinic were independently tested by both Western blots and LTT-MELISA. Results: After omitting cases with indeterminate Western blot results and equivocal LTT-MELISA results, multiple linear regression modelling demonstrated that the 41-kDa flagellin immunoglobulin (Ig) M level was predictable from two LTT-MELISA variables (F (2,51) = 5.981, P = 0.005). Similarly, the corresponding 41-kDa IgG model also contained two LTT-MELISA variables (F (2,57) = 3.700, P = 0.031). Conclusion: It is concluded that the LTT-MELISA appears to be able to detect the response to this antigen.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by NFE2L2. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of N-acetylcysteine, coenzyme Q10 and melatonin is accompanied by increased Nrf2 activity. N-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q10, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.

There are nine subfamilies of TAARs. They are predominantly intracellular, located in the central nervous system and peripherally. They have a role in homeostasis and rheostasis, and also in olfaction. They demonstrate significant cross-talk with the monoamine system and are involved in the regulation of cAMP signalling and K+ channels. There is evidence to suggest that TAAR1 may be a promising therapeutic target for the treatment of schizophrenia, psychosis in Parkinson's disease, substance use disorders, and the metabolic syndrome and obesity. TAAR1 expression may also be a prognostic biomarker for cancers. A number of TAAR modulators have been identified, including endogenous ligands and new chemical entities. Some of these agents have shown efficacy in animal models of addiction behaviours, depression and anxiety. Only one agent, SEP-363856, has progressed to randomised clinical trials in humans; however further, larger studies with SEP-363856 are required to clarify its suitability as a new treatment for schizophrenia spectrum disorders. SEP-363856 is an agonist of TAAR1 and 5HT1A and it is not clear to what extent its efficacy can be attributed to TAAR1 rather than to other drug targets. However, current research suggests that TAAR1 has an important role in human physiology and pathophysiology. TAAR1 modulators may become an important new drug class for the management of a wide array of mental disorders in the future.

Two models were developed to estimate Lyme borreliosis (LB) cases. One was based on the seroprevalence of Borrelia infections in human samples. This model used corrections for false negative and false positive results from published test sensitivity and specificity measures. A second model based on Borrelia infections in sentinel dogs was used to quantify the prevalence of Lyme disease Borrelia infections in humans; the reference baseline for this model was human and canine infections in Germany. A comparison of the two models is shown and differences discussed. The relationships between incidence, prevalence and total infection burden for LB were derived from published data and these were used in both models to calculate annual incidence, prevalence and total LB infections. The modelling was conservative and based on medical insurance records coded for erythema migrans. Linear model growth rates were used in place of the commonly adopted exponential growth. The mean of the two models was used to create estimates for various countries and continents. Examples from the analyses for LB estimated for 2018 include: incidence - USA 473,000/year, Germany 471,000/year, France 434,000/year and UK 132,000/year; prevalence - USA 2.4 million, Germany 2.4 million, France 2.2 million and UK 667,000; total infections - USA 10.1 million, Germany 10.0 million, France 9.3 million and UK 2.8 million. Estimates for the world for 2018 are: incidence 12.3 million/year; prevalence 62.1 million; and total infection burden 262.0 million. These figures are far higher than officially published data and reflect not only the underestimation of diagnosed cases, which is acknowledged by health agencies, but also undiagnosed and misdiagnosed cases.

Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.

To assess the impact of tinnitus in fibromyalgia.A quantitative controlled study was carried out. The 25-item Tinnitus Handicap Inventory (THI) and the Revised Fibromyalgia Impact Questionnaire (FIQR) were administered to 27 patients who fulfilled the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology and to 26 healthy controls who had no history of suffering from fibromyalgia or any other rheumatological or neurological illness.The two groups were matched for age, sex and ethnicity. The fibromyalgia patients were significantly more likely to suffer from tinnitus than the controls: 16 (59.3%) of the patients suffered from tinnitus, compared with two (7.7%) of the controls (p0.001). The median (interquartile range) total THI score for the fibromyalgia group was 6 (44), which was significantly higher than that of 0 (0) for the control group (p0.001). The fibromyalgia group scored significantly higher than the control group for 24 of the 25 THI items. The total THI score across all subjects was positively correlated with the FIQR scores (rs = 0.408, p = 0.002).Fibromyalgia is associated with a relatively high prevalence of tinnitus.

Low back pain is a relatively common health problem which afflicts many adults, and its prevalence increases with age. Several studies have indicated that psychosocial factors are of importance in low back pain. The aim of this study was to carry out a systematic review of the efficacy of psychoeducation in managing low back pain from evidence provided by randomised controlled trials. The inclusion criteria for studies included in this systematic review were randomised controlled trials; patients with low back pain, with or without sciatica; the inclusion of a psychoeducation (treatment) arm; and age of patients ≥ 17 years. Data extraction revealed the heterogeneous nature of the psychoeducational interventions. Accordingly, it was deemed inappropriate to carry out a formal meta-analysis. Ultimately, nine studies, corresponding to 10 publications, were included in the systematic review. When possible, group contrast mean difference effect sizes were calculated for the studies. Overall, favourable outcomes associated with personalised telephone coaching, while unfavourable outcomes were associated with both Transtheoretical Model-based counselling and motivational enhancement treatment. Other forms of one-to-one counselling were associated with intermediate outcomes. Psychoeducation via personalised telephone coaching was particularly associated with reduced low back pain, reduced daily living disability, improved function and improved recovery expectation. On the basis of this review, the following suggestions are made relating to the design and publication of future studies of the efficacy of psychoeducation in the management of low back pain. First, it would be good to use an experimental design which blinds both the patients and the assessors to group status. Second, it is recommended that all the relevant outcome data from a study are published, either in the corresponding paper or in an on-line supplement. Third, it is important to ensure that the intervention and control groups are matched at baseline. Clearly, baseline group differences can emerge following random allocation of patients into two groups. It may be useful, therefore, to carry out all baseline assessments immediately prior to the randomisation process; an independent assessor could then examine the degree of matching at baseline before the rest of the study proceeds. It is also important that sufficiently large sample sizes be recruited.

Preliminary evidence has pointed an association of the gene HLA-DRB1 with fibromyalgia. HLA-DRB1 alleles carrying the shared or susceptibility epitope encoding the five-amino acid motif QKRAA, QRRAA or RRRAA in positions 70 to 74 of the major histocompatibility complex class II DRβ chain are associated with several autoimmune diseases.The objective of this study was to test the hypothesis that susceptibility epitope-encoding HLA-DRB1 alleles are associated with fibromyalgia.Using a case-control design, the prevalence of susceptibility epitope-encoding HLADRB1 alleles in 27 white Caucasian patients fulfilling the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology was compared with that in 27 white Caucasian ageand sex-matched healthy controls.13 (48%) of the fibromyalgia patients had susceptibility epitope-coding HLA-DRB1 alleles compared with 15 (56%) of the controls (P = 0.785). The DRB1*01 allele encoding the protective epitope 70-DERAA-74 motif was found in one of the control subjects; none of the fibromyalgia patients had such a protective epitope.While the present study does not provide evidence supporting the potential role of HLA-DRB1 in the etiology of fibromyalgia, it does not exclude the possibility that there is a polygenic component to a putative genetic causative role.

Activated immune-inflammatory, oxidative and nitrosative stress (IO&NS) pathways and consequent mitochondrial aberrations are involved in the pathophysiology of psychiatric disorders including major depression, bipolar disorder and schizophrenia. They offer independent and shared contributions to pathways underpinning medical comorbidities including insulin resistance, metabolic syndrome, obesity and cardiovascular disease - herein conceptualized as somatoprogression. This narrative review of human studies aims to summarize relationships between IO&NS pathways, neuroprogression and somatoprogression. Activated IO&NS pathways, implicated in the neuroprogression of psychiatric disorders, affect the pathogenesis of comorbidities including insulin resistance, dyslipidaemia, obesity and hypertension, and by inference, metabolic syndrome. These conditions activate IO&NS pathways, exacerbating neuroprogression in psychiatric disorders. The processes whereby proinflammatory cytokines, nitrosative and endoplasmic reticulum stress, NADPH oxidase isoforms, PPARγ inactivation, SIRT1 deficiency and intracellular signalling pathways impact lipid metabolism and storage are considered. Through associations between body mass index, chronic neuroinflammation and FTO expression, activation of IO&NS pathways arising from somatoprogression may contribute to neuroprogression. Early evidence highlights the potential of adjuvants targeting IO&NS pathways for treating somatoprogression and neuroprogression.

DNA adducts are associated with a number of diseases, including cancer. Based on a recent report by our group, the aim of this study was to test the hypothesis that DNA adducts can be removed by means of one or more of the following three intervention programmes: intermittent whole-body hyperthermia; detoxification; and cell repair. The number of DNA adducts and total DNA adduct concentrations were measured in 104 patients who underwent one or more of the three intervention programmes. DNA adduct assessments were carried out on extracted genomic DNA by gas-liquid chromatography, with any DNA adducts found being localised using DNA microarrays. The baseline median number of DNA adducts was 2. The follow-up median number of adducts was highly significantly lower at 0 (p 0.000000000000003). The mean total DNA adduct concentration at baseline was 9.308 ng/mL, and highly significantly lower at follow-up at 1.553 ng/mL (p 0.000000000000006). Of the three intervention programmes, only the intermittent whole-body hyperthermia was associated with a significant reduction in DNA adducts. This study offers support for the hypothesis that DNA adducts can be removed by intermittent whole-body hyperthermia. The intermittent hyperthermia used involved infrared-A (wavelength 700-1400 nm, or, equivalently, a frequency of 215-430 THz) being preferentially delivered to the whole body, apart from the head, for up to one hour per session, with gradual core body temperature elevation usually occurring during the first 20-30 min. These results may offer an explanation at the molecular level for other reported clinical benefits of intermittent whole-body hyperthermia.

The endocannabinoid system (ECS) appears to regulate metabolic, cardiovascular, immune, gastrointestinal, lung, and reproductive system functions, as well as the central nervous system. There is also evidence that neuropsychiatric disorders are associated with ECS abnormalities as well as oxidative and nitrosative stress pathways. The goal of this mechanistic review is to investigate the mechanisms underlying the ECS's regulation of redox signalling, as well as the mechanisms by which activated oxidative and nitrosative stress pathways may impair ECS-mediated signalling. Cannabinoid receptor (CB)1 activation and upregulation of brain CB2 receptors reduce oxidative stress in the brain, resulting in less tissue damage and less neuroinflammation. Chronically high levels of oxidative stress may impair CB1 and CB2 receptor activity. CB1 activation in peripheral cells increases nitrosative stress and inducible nitric oxide (iNOS) activity, reducing mitochondrial activity. Upregulation of CB2 in the peripheral and central nervous systems may reduce iNOS, nitrosative stress, and neuroinflammation. Nitrosative stress may have an impact on CB1 and CB2-mediated signalling. Peripheral immune activation, which frequently occurs in response to nitro-oxidative stress, may result in increased expression of CB2 receptors on T and B lymphocytes, dendritic cells, and macrophages, reducing the production of inflammatory products and limiting the duration and intensity of the immune and oxidative stress response. In conclusion, high levels of oxidative and nitrosative stress may compromise or even abolish ECS-mediated redox pathway regulation. Future research in neuropsychiatric disorders like mood disorders and deficit schizophrenia should explore abnormalities in these intertwined signalling pathways.

The endocannabinoid system (ECS) is composed of the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylgycerol (2-AG), their target cannabinoid receptors (CB

Background COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS. Main body The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of neutrophil extracellular traps (NETs) producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID-19 are discussed in detail., Graphical abstract Unlabelled Image

Background: Although fibromyalgia is a common cause of chronic musculoskeletal pain, its aetiology and pathophysiology are uncertain. It has recently been suggested that fibromyalgia symptomatology represents a T lymphocyte-mediated immune response to pathogens, which are known risk factors for autoimmune diseases. One major suggested candidate pathogen is the bacterial genus Borrelia. However, to date, this hypothesis has not been tested. Objective: The aim was to carry out the first test of this hypothesis by comparing Borrelia-specific T lymphocyte reactivity in fibromyalgia patients and matched controls. Methods: The enzyme-linked immunospot assay was used to detect T-lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen), outer surface protein (Osp) A from Borrelia burgdorferi sensu stricto, Borrelia afzelii and Borrelia garinii, native OspC plus decorin binding protein A recombinant and lymphocyte function antigen-1 (shared epitope) in 27 patients who fulfilled the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology and in 26 control subjects. The assays were carried out blind to the group status of the participants. Results: The two groups did not differ by age, sex or ethnicity. They did not differ significantly in respect of T lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen) (p = 0.847), Osp mix (p = 0.709) or lymphocyte function antigen-1 (p = 0.367). Conclusion: This novel controlled study provides no evidence of an association between fibromyalgia and Borrelia-specific T lymphocytes.

Background: It has been shown that autonomic dysfunction in fibromyalgia can be assessed by the Composite Autonomic Symptom Score (COMPASS) questionnaire. More recently, a refined and much abbreviated 31-item version of the questionnaire has been developed, the COMPASS 31. Objectives: First, to determine whether the COMPASS 31 can assess changes in autonomic function in fibromyalgia. Second, to assess whether the COMPASS 31 values in fibromyalgia patients are positively correlated with scores on the Revised Fibromyalgia Impact Questionnaire (FIQR). Method: A cross-sectional, case-controlled study was carried out with 25 fibromyalgia patients and 26 healthy controls. Results: The two groups were matched for age, sex and ethnicity, but not for body mass index (BMI). The total mean (standard error) COMPASS 31 for the fibromyalgia patients, 37.2 (1.8), differentiated the patients from the controls (9.5 (1.4); p < 0.00000001). The scores were greater in the fibromyalgia patients across all COMPASS 31 autonomic domains, namely orthostatic intolerance (p < 0.00000001), and vasomotor (p < 0.0001), secretomotor (p < 0.000001), gastrointestinal (p < 0.000001), bladder (p < 0.00001) and pupillomotor functions (p < 0.00000001). The total COMPASS 31 values were positively correlated with FIQR scores (rs = 0.45, p < 0.05). General linear modelling of the COMPASS 31 scores showed that only group status (fibromyalgia or control) was significant (p = 3.4 × 10-16), with age, sex and BMI being non-significant. Conclusion: This study confirms that non-pain autonomic dysfunction symptoms occur in fibromyalgia and can be assessed with the COMPASS 31.

This book explores the historical background to, and present-day understanding of, a number of unusual psychiatric disorders. This fully revised new edition contains a new chapter on a range of recently emerging conditions as well as updated literature and a collection of new and updated cases. Since the publication of the fourth edition, there have been many developments in the field of psychiatry, including changes in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the advancement of neuroimaging and related research, which have been incorporated into the fifth edition. In this now classic text, each chapter covers an individual disorder in detail, using several case studies gathered by the authors themselves to illustrate and exemplify the disorders discussed. The clear and easy-to-understand writing style ensures that this text is accessible for the wide range of studies and professions who will find it useful. Uncommon Psychiatric Syndromes, Fifth Edition, is essential reading for psychiatrists, clinical psychologists, psychiatric nurses, psychiatric social workers, social workers and other mental health professionals. It will also be of interest to graduate students in the fields of psychiatry and psychology as well as those enrolled in psychiatry resident courses.

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed., Graphical abstract Unlabelled Image

Chronic systemic inflammation is associated with an increased risk of cardiovascular disease in an environment of low low-density lipoprotein (LDL) and low total cholesterol and with the pathophysiology of neuroprogressive disorders. The causes and consequences of this lipid paradox are explored. Circulating activated neutrophils can release inflammatory molecules such as myeloperoxidase and the pro-inflammatory cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha. Since activated neutrophils are associated with atherosclerosis and cardiovascular disease and with major depressive disorder, bipolar disorder and schizophrenia, it seems reasonable to hypothesise that the inflammatory molecules released by them may act as mediators of the link between systemic inflammation and the development of atherosclerosis in neuroprogressive disorders. This hypothesis is tested by considering the association at a molecular level of systemic inflammation with increased LDL oxidation; increased small dense LDL levels; increased lipoprotein (a) concentration; secretory phospholipase A2 activation; cytosolic phospholipase A2 activation; increased platelet activation; decreased apolipoprotein A1 levels and function; decreased paroxonase-1 activity; hyperhomocysteinaemia; and metabolic endotoxaemia. These molecular mechanisms suggest potential therapeutic targets.

Severe socioeconomic deprivation (SED) and adverse childhood experiences (ACE) are significantly associated with the development in adulthood of (i) enhanced inflammatory status and/or hypothalamic-pituitary-adrenal (HPA) axis dysfunction and (ii) neurological, neuroprogressive, inflammatory and autoimmune diseases. The mechanisms by which these associations take place are detailed. The two sets of consequences are themselves strongly associated, with the first set likely contributing to the second. Mechanisms enabling bidirectional communication between the immune system and the brain are described, including complex signalling pathways facilitated by factors at the level of immune cells. Also detailed are mechanisms underpinning the association between SED, ACE and the genesis of peripheral inflammation, including epigenetic changes to immune system-related gene expression. The duration and magnitude of inflammatory responses can be influenced by genetic factors, including single nucleotide polymorphisms, and by epigenetic factors, whereby pro-inflammatory cytokines, reactive oxygen species, reactive nitrogen species and nuclear factor-κB affect gene DNA methylation and histone acetylation and also induce several microRNAs including miR-155, miR-181b-1 and miR-146a. Adult HPA axis activity is regulated by (i) genetic factors, such as glucocorticoid receptor polymorphisms; (ii) epigenetic factors affecting glucocorticoid receptor function or expression, including the methylation status of alternative promoter regions of NR3C1 and the methylation of FKBP5 and HSD11β2; (iii) chronic inflammation and chronic nitrosative and oxidative stress. Finally, it is shown how severe psychological stress adversely affects mitochondrial structure and functioning and is associated with changes in brain mitochondrial DNA copy number and transcription; mitochondria can act as couriers of childhood stress into adulthood.

Lowered high-density lipoprotein (HDL) cholesterol has been reported in major depressive disorder, bipolar disorder, first episode of psychosis, and schizophrenia. HDL, its major apolipoprotein component, ApoA1, and the antioxidant enzyme paraoxonase (PON)1 (which is normally bound to ApoA1) all have anti-atherogenic, antioxidant, anti-inflammatory, and immunomodulatory roles, which are discussed in this paper. The paper details the pathways mediating the anti-inflammatory effects of HDL, ApoA1 and PON1 and describes the mechanisms leading to compromised HDL and PON1 levels and function in an environment of chronic inflammation. The molecular mechanisms by which changes in HDL, ApoA1 and PON1 might contribute to the pathophysiology of the neuroprogressive disorders are explained. Moreover, the anti-inflammatory actions of ApoM-mediated sphingosine 1-phosphate (S1P) signalling are reviewed as well as the deleterious effects of chronic inflammation and oxidative stress on ApoM/S1P signalling. Finally, therapeutic interventions specifically aimed at improving the levels and function of HDL and PON1 while reducing levels of inflammation and oxidative stress are considered. These include the so-called Mediterranean diet, extra virgin olive oil, polyphenols, flavonoids, isoflavones, pomegranate juice, melatonin and the Mediterranean diet combined with the ketogenic diet.

Background:: A recent survey reported an association between fibromyalgia and overactive bladder. Objective:: To carry out the first systematic case-controlled study to compare the level of overactive bladder symptoms in a group of fibromyalgia patients and a group of matched controls. Methods:: The symptom-bother OAB-q8 questionnaire and Revised Fibromyalgia Impact Questionnaire (FIQR) were administered to 27 patients who fulfilled the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology and to 26 healthy controls who had no history of suffering from fibromyalgia or any other rheumatological or neurological illness. Results:: The groups were matched in respect of age, sex and ethnicity. None of the 53 subjects was taking medication which might cause urinary urgency, none was suffering from, or had recently suffered from, a urinary tract infection and none had undergone a previous operative procedure on the lower urinary tract. Twenty-five (93%) patients had evidence of an overactive bladder during the previous four weeks, compared with five (19%) of the control group (p < 0.001). In terms of symptom severity, the mean (standard error) OAB-q8 score was 24.4 (1.5) in the fibromyalgia patients and 10.8 (4.5) in the controls (p < 0.001). Furthermore, the total OAB-q8 and FIQR scores were positively correlated (rs = 0.727, p < 0.001). Conclusion:: This systematic controlled study confirms that fibromyalgia is associated with overactive bladder symptoms. The relatively high prevalence of 93% indicates that overactive bladder is an important urological association of fibromyalgia and should be routinely assessed in these patients.

Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATPchannels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

AIM To investigate the repeatability of proton magnetic resonance spectroscopy in the in vivo measurement of human cerebral levels of choline-containing compounds (Cho). METHODS Two consecutive scans were carried out in six healthy resting subjects at a magnetic field strength of 1.5 T. On each occasion, neurospectroscopy data were collected from 64 voxels using the same 2D chemical shift imaging (CSI) sequence. The data were analyzed in the same way, using the same software, to obtain the values for each voxel of the ratio of Cho to creatine. The Wilcoxon related-samples signed-rank test, coefficient of variation (CV), repeatability coefficient (RC), and intraclass correlation coefficient (ICC) were used to assess the repeatability. RESULTS The CV ranged from 2.75% to 33.99%, while the minimum RC was 5.68%. There was excellent reproducibility, as judged by significant ICC values, in 26 voxels. Just three voxels showed significant differences according to the Wilcoxon related-samples signed-rank test. CONCLUSION It is therefore concluded that when CSI multivoxel proton neurospectroscopy is used to measure cerebral choline-containing compounds at 1.5 T, the reproducibility is highly acceptable.