Publications by authors named "Basant K Puri"

109 Publications

Clinical Assessment of Autonomic Function in Fibromyalgia by the Refined and Abbreviated Composite Autonomic Symptom Score (COMPASS 31): A Case-Controlled Study.

Rev Recent Clin Trials 2021 Jun 11. Epub 2021 Jun 11.

University of Southampton. United Kingdom.

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: The study has the following 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 COMPASS 31.
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http://dx.doi.org/10.2174/1574887116666210612033002DOI Listing
June 2021

The endocannabinoidome in neuropsychiatry: Opportunities and potential risks.

Pharmacol Res 2021 Jun 11;170:105729. Epub 2021 Jun 11.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia. Electronic address:

The endocannabinoid system (ECS) comprises two cognate endocannabinoid receptors referred to as CB1R and CB2R ECS dysregulation is apparent in neurodegenerative/neuro-psychiatric disorders including but not limited to schizophrenia, major depressive disorder and potentially bipolar disorder. The aim of this paper is to review mechanisms whereby both receptors may interact with neuro-immune and neuro-oxidative pathways, which play a pathophysiological role in these disorders. CB1R is located in the presynaptic terminals of GABAergic, glutamatergic, cholinergic, noradrenergic and serotonergic neurons where it regulates the retrograde suppression of neurotransmission. CB1R plays a key role in long-term depression, and, to a lesser extent, long-term potentiation, thereby modulating synaptic transmission and mediating learning and memory. Optimal CB1R activity plays an essential neuroprotective role by providing a defense against the development of glutamate-mediated excitotoxicity, which is achieved, at least in part, by impeding AMPA-mediated increase in intracellular calcium overload and oxidative stress. Moreover, CB1R activity enables optimal neuron-glial communication and the function of the neurovascular unit. CB2R receptors are detected in peripheral immune cells and also in central nervous system regions including the striatum, basal ganglia, frontal cortex, hippocampus, amygdala as well as the ventral tegmental area. CB2R upregulation inhibits the presynaptic release of glutamate in several brain regions. CB2R activation also decreases neuroinflammation partly by mediating the transition from a predominantly neurotoxic "M1" microglial phenotype to a more neuroprotective "M2" phenotype. CB1R and CB2R are thus novel drug targets for the treatment of neuro-immune and neuro-oxidative disorders including schizophrenia and affective disorders.
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http://dx.doi.org/10.1016/j.phrs.2021.105729DOI Listing
June 2021

The lipid paradox in neuroprogressive disorders: Causes and consequences.

Neurosci Biobehav Rev 2021 Jun 9;128:35-57. Epub 2021 Jun 9.

C.A.R., Cambridge, UK. Electronic address:

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 A activation; cytosolic phospholipase A 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.
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http://dx.doi.org/10.1016/j.neubiorev.2021.06.017DOI Listing
June 2021

The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all?

Cytokine 2021 08 26;144:155593. Epub 2021 May 26.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria. Electronic address:

An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1β, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended.
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http://dx.doi.org/10.1016/j.cyto.2021.155593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149193PMC
August 2021

Polyphenols as adjunctive treatments in psychiatric and neurodegenerative disorders: Efficacy, mechanisms of action, and factors influencing inter-individual response.

Free Radic Biol Med 2021 May 29;172:101-122. Epub 2021 May 29.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.05.036DOI Listing
May 2021

The role of high-density lipoprotein cholesterol, apolipoprotein A and paraoxonase-1 in the pathophysiology of neuroprogressive disorders.

Neurosci Biobehav Rev 2021 06 28;125:244-263. Epub 2021 Feb 28.

Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.

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.
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http://dx.doi.org/10.1016/j.neubiorev.2021.02.037DOI Listing
June 2021

Estimates for Lyme borreliosis infections based on models using sentinel canine and human seroprevalence data.

Infect Dis Model 2020 16;5:871-888. Epub 2020 Oct 16.

CAR, Cambridge, UK.

Two models were developed to estimate Lyme borreliosis (LB) cases. One was based on the seroprevalence of 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 infections in sentinel dogs was used to quantify the prevalence of Lyme disease 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.
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http://dx.doi.org/10.1016/j.idm.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644786PMC
October 2020

Preventing the development of severe COVID-19 by modifying immunothrombosis.

Life Sci 2021 Jan 20;264:118617. Epub 2020 Oct 20.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.lfs.2020.118617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574725PMC
January 2021

Endothelial dysfunction in neuroprogressive disorders-causes and suggested treatments.

BMC Med 2020 10 19;18(1):305. Epub 2020 Oct 19.

IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia.

Background: Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined.

Main Text: Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial dynamics, loss of calcium ion homeostasis and inactivation of SIRT-1-mediated signalling pathways. Next, loss of cellular redox homeostasis is considered, including further aspects of the roles of hydrogen peroxide signalling, the pathological consequences of elevated NF-κB, compromised S-nitrosylation and the development of hypernitrosylation and increased transcription of atherogenic miRNAs. These molecular aspects are then applied to neuroprogressive disorders by considering the following potential generators of endothelial dysfunction and activation in major depressive disorder, bipolar disorder and schizophrenia: NF-κB; platelet activation; atherogenic miRs; myeloperoxidase; xanthene oxidase and uric acid; and inflammation, oxidative stress, nitrosative stress and mitochondrial dysfunction.

Conclusions: Finally, on the basis of the above molecular mechanisms, details are given of potential treatment options for mitigating endothelial cell dysfunction and activation in neuroprogressive disorders.
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http://dx.doi.org/10.1186/s12916-020-01749-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570030PMC
October 2020

Can endolysosomal deacidification and inhibition of autophagy prevent severe COVID-19?

Life Sci 2020 Dec 6;262:118541. Epub 2020 Oct 6.

C.A.R., Cambridge, UK. Electronic address:

The possibility is examined that immunomodulatory pharmacotherapy may be clinically useful in managing the pandemic coronavirus disease 2019 (COVID-19), known to result from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA virus. The dominant route of cell entry of the coronavirus is via phagocytosis, with ensconcement in endosomes thereafter proceeding via the endosomal pathway, involving transfer from early (EEs) to late endosomes (LEs) and ultimately into lysosomes via endolysosomal fusion. EE to LE transportation is a rate-limiting step for coronaviruses. Hence inhibition or dysregulation of endosomal trafficking could potentially inhibit SARS-CoV-2 replication. Furthermore, the acidic luminal pH of the endolysosomal system is critical for the activity of numerous pH-sensitive hydrolytic enzymes. Golgi sub-compartments and Golgi-derived secretory vesicles also depend on being mildly acidic for optimal function and structure. Activation of endosomal toll-like receptors by viral RNA can upregulate inflammatory mediators and contribute to a systemic inflammatory cytokine storm, associated with a worsened clinical outcome in COVID-19. Such endosomal toll-like receptors could be inhibited by the use of pharmacological agents which increase endosomal pH, thereby reducing the activity of acid-dependent endosomal proteases required for their activity and/or assembly, leading to suppression of antigen-presenting cell activity, decreased autoantibody secretion, decreased nuclear factor-kappa B activity and decreased pro-inflammatory cytokine production. It is also noteworthy that SARS-CoV-2 inhibits autophagy, predisposing infected cells to apoptosis. It is therefore also suggested that further pharmacological inhibition of autophagy might encourage the apoptotic clearance of SARS-CoV-2-infected cells.
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http://dx.doi.org/10.1016/j.lfs.2020.118541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537668PMC
December 2020

Trace Amine-Associated Receptor 1 (TAAR1): A new drug target for psychiatry?

Neurosci Biobehav Rev 2021 01 5;120:537-541. Epub 2020 Oct 5.

The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia; Centre for Youth Mental Health, University of Melbourne, Parkville, Australia; Department of Psychiatry, University of Melbourne, Parkville, Australia; University Hospital Geelong, Barwon Health, PO Box 281, Geelong, Victoria, 3220, Australia.

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 5HT 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.
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http://dx.doi.org/10.1016/j.neubiorev.2020.09.028DOI Listing
January 2021

Overactive Bladder Symptoms in Patients with Fibromyalgia: A Systematic Case-Controlled Study.

Rev Recent Clin Trials 2021 ;16(2):202-205

University of Southampton, Southampton, United Kingdom.

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.
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http://dx.doi.org/10.2174/1574887115999201006201328DOI Listing
January 2021

The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach.

Life Sci 2020 Oct 31;258:118166. Epub 2020 Jul 31.

Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia.

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.
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http://dx.doi.org/10.1016/j.lfs.2020.118166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392886PMC
October 2020

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders.

Eur Psychiatry 2020 01 31;63(1):e8. Epub 2020 Jan 31.

C.A.R., Cambridge, England, United Kingdom.

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 KATP channels, 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.
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http://dx.doi.org/10.1192/j.eurpsy.2019.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057392PMC
January 2020

Breastfeeding following Kangaroo Mother Care.

Authors:
Basant K Puri

Rev Recent Clin Trials 2020 ;15(1):3-4

CAR, Cambridge and Hammersmith Hospital, London, United Kingdom.

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http://dx.doi.org/10.2174/157488711501200116154916DOI Listing
March 2021

Is there a sex difference in adult salivary clearance of caffeine (1,3,7-trimethylpurine-2,6-dione)?

J Oral Biol Craniofac Res 2020 Apr-Jun;10(2):20-22. Epub 2020 Feb 6.

Medical Director, Breakspear Medical Group, Hemel Hempstead, UK.

Background: The salivary caffeine clearance is a non-invasive, safe, saliva-based method for assessing hepatic function and diagnosing chronic liver disease. The elimination of caffeine from the body follows first-order kinetics and principally involves catabolism by hepatic CYP1A2, with a half-life usually between three and 7 h. It is known that this process is affected by age and smoking tobacco. It has been suggested that sex might also be important, but there is scant evidence for this. The aim of this study was to assess whether there is a sex difference in salivary caffeine clearance in adults.

Methods: A cohort of 213 adults was studied. They were all non-smokers and none suffered from chronic liver disease. They consisted of 67 men (mean age 40.0 years) and 146 women (mean age 44.7 years). Following a period of dietary caffeine abstinence lasting at least 24 h, each subject ingested a single oral dose in the morning of caffeine, at a dose of 3 mg per kg body mass. Salivary samples were collected at 2 h and 14 h post-caffeine ingestion and were spectrophotometrically assayed for their caffeine concentrations.

Results: The two groups were matched for age. The mean (standard error) salivary caffeine clearance in the male subjects was 1.51 (0.10) mL min kg, while that in the female subjects was 1.60 (0.07) mL min kg ( = 0.495).

Conclusion: This relatively large study provides no evidence of a sex difference in salivary caffeine clearance.
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http://dx.doi.org/10.1016/j.jobcr.2020.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016269PMC
February 2020

Induced Ketosis as a Treatment for Neuroprogressive Disorders: Food for Thought?

Int J Neuropsychopharmacol 2020 06;23(6):366-384

The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Australia.

Induced ketosis (or ketone body ingestion) can ameliorate several changes associated with neuroprogressive disorders, including schizophrenia, bipolar disorder, and major depressive disorder. Thus, the effects of glucose hypometabolism can be bypassed through the entry of beta-hydroxybutyrate, providing an alternative source of energy to glucose. The weight of evidence suggests that induced ketosis reduces levels of oxidative stress, mitochondrial dysfunction, and inflammation-core features of the above disorders. There are also data to suggest that induced ketosis may be able to target other molecules and signaling pathways whose levels and/or activity are also known to be abnormal in at least some patients suffering from these illnesses such as peroxisome proliferator-activated receptors, increased activity of the Kelch-like ECH-associated protein/nuclear factor erythroid 2-related factor 2, Sirtuin-1 nuclear factor-κB p65, and nicotinamide adenine dinucleotide (NAD). This review explains the mechanisms by which induced ketosis might reduce mitochondrial dysfunction, inflammation, and oxidative stress in neuropsychiatric disorders and ameliorate abnormal levels of molecules and signaling pathways that also appear to contribute to the pathophysiology of these illnesses. This review also examines safety data relating to induced ketosis over the long term and discusses the design of future studies.
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http://dx.doi.org/10.1093/ijnp/pyaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311648PMC
June 2020

The role of microglia in neuroprogressive disorders: mechanisms and possible neurotherapeutic effects of induced ketosis.

Prog Neuropsychopharmacol Biol Psychiatry 2020 04 7;99:109858. Epub 2020 Jan 7.

Deakin University, IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Geelong, Victoria, Australia; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada. Electronic address:

A comprehensive review of molecular mechanisms involved in the promotion and maintenance of distinct microglia phenotypes is provided. The acquisition and perpetuation of predominantly pro-inflammatory microglial phenotypes have been implicated in the pathophysiology of several neuroprogressive diseases and is associated with reduced ATP production via oxidative phosphorylation, increased ATP generation by glycolysis, elevated oxidative and nitrosative stress and other metabolic, inflammatory and hormonal insults. Microglia can also adopt a predominantly anti-inflammatory phenotypes with neuroprotective properties. Strategies that promote and maintain a predominantly anti-inflammatory phenotype may hold promise as novel therapeutic opportunities for neuroprogressive illness. Induced ketosis may promote a transition towards predominantly anti-inflammatory microglial states/phenotypes by several mechanisms, including inhibition of glycolysis and increased NAD production; engagement of microglial GPR109A receptors; histone deacetylase inhibition; and elevated n-3 polyunsaturated fatty acids levels. Since microglia activation can now be assessed in vivo, these data provide a clear rationale for the design of transdiagnostic randomized controlled trials of the ketogenic diet and other ketosis-inducing strategies for neuroprogressive diseases, which may also provide mechanistic insights through the assessment of "target engagement".
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http://dx.doi.org/10.1016/j.pnpbp.2020.109858DOI Listing
April 2020

The Use of Thiopurine Derivatives in the Treatment of Inflammatory Bowel Disease.

Authors:
Basant K Puri

Rev Recent Clin Trials 2019 ;14(4):230-231

CAR, Cambridge and Hammersmith Hospital, London, United Kingdom.

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http://dx.doi.org/10.2174/157488711404191016121348DOI Listing
May 2020

Calcium Signaling and Gene Expression.

Authors:
Basant K Puri

Adv Exp Med Biol 2020 ;1131:537-545

CAR, Cambridge, UK.

Calcium signaling plays an important role in gene expression. At the transcriptional level, this may underpin mammalian neuronal synaptic plasticity. Calcium influx into the postsynaptic neuron via: N-methyl-D-aspartate (NMDA) receptors activates small GTPase Rac1 and other Rac guanine nucleotide exchange factors, and stimulates calmodulin-dependent kinase kinase (CaMKK) and CaMKI; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors that are not impermeable to calcium ions, that is, those lacking the glutamate receptor-2 subunits, leads to activation of Ras guanine nucleotide-releasing factor proteins, which is coupled with activation of the mitogen-activated protein kinases/extracellular signal-regulated kinases signaling cascade; L-type voltage-gated calcium channels activates signaling pathways involving CaMKII, downstream responsive element antagonist modulator and distinct microdomains. Key members of these signaling cascades then translocate into the nucleus, where they alter the expression of genes involved in neuronal synaptic plasticity. At the post-transcriptional level, intracellular calcium level changes can change alternative splicing patterns; in the mammalian brain, alterations in calcium signaling via NMDA receptors is associated with exon silencing of the CI cassette of the NMDA R1 receptor (GRIN1) transcript by UAGG motifs in response to neuronal excitation. Regulation also occurs at the translational level; transglutaminase-2 (TG2) mediates calcium ion-regulated crosslinking of Y-box binding protein-1 (YB-1) translation-regulatory protein in TGFβ1-activated myofibroblasts; YB-1 binds smooth muscle α-actin mRNA and regulates its translational activity. Calcium signaling is also important in epigenetic regulation, for example in respect of changes in cytosine bases. Targeting calcium signaling may provide therapeutically useful options, for example to induce epigenetic reactivation of tumor suppressor genes in cancer patients.
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http://dx.doi.org/10.1007/978-3-030-12457-1_22DOI Listing
October 2019

The effect of supplementation with Scutellaria baicalensis on hepatic function.

Med Hypotheses 2019 Dec 19;133:109402. Epub 2019 Sep 19.

Breakspear Medical Group, Hemel Hempstead, Hertfordshire, UK.

The dried root of the angiosperm Scutellaria baicalensis, also known as Chinese skullcap or Baikal skullcap, is widely used in traditional Chinese medicine, Korean traditional medicine and as a nutritional supplement; several studies have indicated that both the supplement and some of its ingredients may have clinically beneficial actions. However, the National Institutes of Health official guidance states that the use of Scutellaria "has been implicated in rare instances of clinically apparent liver injury" and that "the onset of symptoms and jaundice occurred within 6-24 weeks of starting skullcap, and the serum enzyme pattern was typically hepatocellular", with marked increases in serum alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin levels. Careful perusal of all such published case reports showed that in each case the patient was concurrently taking at least one other supplement which had an established association with hepatic dysfunction. The authors hypothesised that long-term supplementation with Scutellaria baicalensis does not lead to hepatic dysfunction. The aim of this study was to test this hypothesis by assessing liver function before and after starting supplementation with Scutellaria baicalensis. Pre- and post-supplementation serum assays of alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin were carried out in 17 patients (16 female) of average age 38.6 (standard error 4.4) years who had each taken 1335 mg dried root daily for an average of 444 (71) days. The mean baseline versus follow-up values for each liver function test were: alanine transaminase: 25.7 (2.6) IU/L v. 25.1 (1.7) IU/L; aspartate transaminase: 22.1 (1.1) IU/L v. 23.5 (1.3) IU/L; alkaline phosphatase: 63.7 (4.6) IU/L v. 63.3 (3.9) IU/L; and bilirubin: 6.1 (0.6) μM v. 6.0 (0.7) μM. None of these changes was statistically significant; indeed, three of the four parameters showed a non-significant decrease over time. Furthermore, none manifested clinical symptoms or signs of hepatic dysfunction during Scutellaria supplementation. These results suggest that daily intake of a relatively high level of Scutellaria baicalensis for over a year is not associated with any biochemical or clinical evidence of hepatic dysfunction. Indeed, Scutellaria baicalensis has been shown in murine experiments to have hepatoprotective actions.
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http://dx.doi.org/10.1016/j.mehy.2019.109402DOI Listing
December 2019

Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders.

Neurosci Biobehav Rev 2019 12 20;107:862-882. Epub 2019 Sep 20.

Deakin University, IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Geelong, Victoria, Australia; Deakin University, CMMR Strategic Research Centre, School of Medicine, Geelong, Victoria, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, the Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neubiorev.2019.09.025DOI Listing
December 2019

Myalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities.

Pharmacol Res 2019 10 8;148:104450. Epub 2019 Sep 8.

IMPACT Strategic Research Centre, School of Medicine, Deakin University, Barwon Health, Geelong, Australia; CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, Victoria, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, Australia.; The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Australia; Department of Psychiatry, University of Melbourne, Parkville, Australia.. Electronic address:

Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies, reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise. The presence of a multiplicity of pathophysiological abnormalities in at least the subgroup of people with ME/CFS diagnosed with the current international consensus "Fukuda" criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics. In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.
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http://dx.doi.org/10.1016/j.phrs.2019.104450DOI Listing
October 2019

Emerging role of innate B1 cells in the pathophysiology of autoimmune and neuroimmune diseases: Association with inflammation, oxidative and nitrosative stress and autoimmune responses.

Pharmacol Res 2019 10 24;148:104408. Epub 2019 Aug 24.

IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia; Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

B1 lymphocytes may be subdivided by CD5 and CD11b/Mac1 expression into B1a, with the CD5 and CD11b/Mac1 phenotype, and B1b, which present as CD19CD5CD11b. B1b cells share many surface and functional characteristics with marginal zone B cells but differ in distribution and B cell receptor (BCR) signalling pathways. They are normally concentrated in the peritoneum, pleural cavities, spleen and bone marrow and function as efficient phagocytes and antigen-presenting cells (APCs). While peritoneal B1b cells are relatively anergic, they may be activated by high cytokine levels, notably IL-10, IL-5 and IL-21, CD40 signalling and high doses of Toll-like receptor (TLR) ligands in the context of pathogen invasion; TLR ligation is also necessary. Their anti-inflammatory effects include: secretion of natural IgM by splenic and bone marrow B1b cell subsets as an early response to pathogen invasion; tissue homeostasis and enabling the immunologically silent clearance of neoplastic and apoptotic cells; inhibition of pro-inflammatory cytokines and increased production of TGF-β1, PGE and GcMAF by activated macrophages and dendritic cells; and, in the case of peritoneal B1 lymphocytes, acting as ultimate Breg precurors. Pro-inflammatory B1b properties may result from: abnormal trafficking; acting as APCs; and acting as a source of innate-response activator cells. Functional impairment or deficits in Bregs occur in multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis. Details are given of potential pathogenic roles of IgM and B1b lymphocytes in these autoimmune disorders and in deficit-schizophrenia, and how these changes relate to inflammatory and oxidative and nitrosative stress.
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http://dx.doi.org/10.1016/j.phrs.2019.104408DOI Listing
October 2019

The effect of successful low-dose immunotherapy ascertained by provocation neutralization on lymphocytic calcium ion influx following electric field exposure.

J Complement Integr Med 2019 Aug 15;17(1). Epub 2019 Aug 15.

Breakspear Medical Group Ltd, Hemel Hempstead, Hertfordshire, UK.

Background Low-dose immunotherapy affects baseline levels of intracellular calcium. However, the effect of background electric fields is yet to be ascertained. The aim of this study was to test the following hypotheses: desensitization by low-dose immunotherapy is associated with reduced calcium ion influx during electric field exposure; the effect of low-dose immunotherapy on intracellular calcium ion concentration does not depend on electric field exposure; and the intracellular calcium ion concentration is amplified by electric field exposure. Methods The experimental design was balanced and orthogonal. Intracellular lymphocytic calcium ion concentrations were assayed in 47 patients, following incubation with picogram amounts of 12 test allergens, using a cell-permeable calcium-sensing ratiometric fluorescent dye and fluorescence spectroscopy, both at baseline and following successful provocation neutralization treatment with low-dose immunotherapy. Duplicates were also exposed to an electric field which replicated the frequency spectrum measured in a non-Faraday shielded room. Results A significant or trend-level main effect was found for low-dose immunotherapy for: benzoate; formaldehyde; metabisulfite; natural gas; nitrosamines; organophosphates; salicylate; azo-dyes and precursors; nickel; and petrol (gasoline) exhaust. Significant or trend-level main effects for electric field exposure were observed for: formaldehyde; mercury (inorganic); natural gas; nickel; nitrosamines; petrol exhaust; salicylate; benzoate; and metabisulfite. There was no evidence of a statistical interaction between these two factors. Electric field exposure was associated with a higher intracellular calcium ion concentration. Conclusion There was support for all three hypotheses. The results suggest that patients may experience increased sensitivity to allergens as a result of exposure to everyday electric fields.
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http://dx.doi.org/10.1515/jcim-2017-0156DOI Listing
August 2019

The compensatory antioxidant response system with a focus on neuroprogressive disorders.

Prog Neuropsychopharmacol Biol Psychiatry 2019 12 24;95:109708. Epub 2019 Jul 24.

IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.

Major antioxidant responses to increased levels of inflammatory, oxidative and nitrosative stress (ONS) are detailed. In response to increasing levels of nitric oxide, S-nitrosylation of cysteine thiol groups leads to post-transcriptional modification of many cellular proteins and thereby regulates their activity and allows cellular adaptation to increased levels of ONS. S-nitrosylation inhibits the function of nuclear factor kappa-light-chain-enhancer of activated B cells, toll-like receptor-mediated signalling and the activity of several mitogen-activated protein kinases, while activating nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2); in turn, the redox-regulated activation of Nrf2 leads to increased levels and/or activity of key enzymes and transporter systems involved in the glutathione system. The Nrf2/Kelch-like ECH-associated protein-1 axis is associated with upregulation of NAD(P)H:quinone oxidoreductase 1, which in turn has anti-inflammatory effects. Increased Nrf2 transcriptional activity also leads to activation of haem oxygenase-1, which is associated with upregulation of bilirubin, biliverdin and biliverdin reductase as well as increased carbon monoxide signalling, anti-inflammatory and antioxidant activity. Associated transcriptional responses, which may be mediated by retrograde signalling owing to elevated hydrogen peroxide, include the unfolded protein response (UPR), mitohormesis and the mitochondrial UPR; the UPR also results from increasing levels of mitochondrial and cytosolic reactive oxygen species and reactive nitrogen species leading to nitrosylation, glutathionylation, oxidation and nitration of crucial cysteine and tyrosine causing protein misfolding and the development of endoplasmic reticulum stress. It is shown how these mechanisms co-operate in forming a co-ordinated rapid and prolonged compensatory antioxidant response system.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109708DOI Listing
December 2019

Parental Separation and Parental Mental Health in Childhood and Risk of Insomnia in Adulthood among Patients with Tinnitus.

J Am Acad Audiol 2020 03 5;31(3):217-223. Epub 2019 Jul 5.

Department of Experimental Psychology, University of Cambridge, Cambridge, UK.

Background: Many patients seeking help for tinnitus also suffer from insomnia. Adverse childhood experiences may affect the likelihood of insomnia in later life for such patients.

Purpose: To explore whether parental separation and parental mental health during childhood are related to the severity of insomnia among patients with tinnitus and/or hyperacusis seen in an Audiology clinic.

Research Design: This was a retrospective cross-sectional study.

Study Sample: One hundred seventy-four consecutive patients who attended a tinnitus/hyperacusis clinic in the United Kingdom were included.

Data Collection: Data were based on responses to questionnaires for people seeking help for tinnitus.

Results: Sixteen percent of patients (27/174) reported that during the first 18 years of life, their parents were separated or divorced and 41% (72/174) reported that their parent(s) suffered from a mental illness. The mean score for the insomnia severity index (ISI) was not significantly affected by parental separation or divorce. However, the mean ISI score was significantly worse for patients whose parents had a mental illness. A multinomial logistic regression model, adjusted for the presence of hyperacusis, hearing loss, age, and gender, indicated that for individuals experiencing tinnitus, a history of parental mental illness during their childhood increased the chance of severe insomnia by a factor of 3.4 (95% confidence interval: 1.1 to 10.8, p = 0.04). The risk of having severe insomnia was 3.8 times greater for patients with hyperacusis than for those without.

Conclusions: Among patients seeking help for tinnitus/hyperacusis, poor parental mental health was associated with severe insomnia.
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http://dx.doi.org/10.3766/jaaa.19023DOI Listing
March 2020

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

Metab Brain Dis 2019 04 13;34(2):385-415. Epub 2019 Feb 13.

Department of Medicine, Imperial College London, Hammersmith Hospital, London, England, W12 0HS, UK.

A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.
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http://dx.doi.org/10.1007/s11011-019-0388-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428797PMC
April 2019

Socioeconomic Deprivation, Adverse Childhood Experiences and Medical Disorders in Adulthood: Mechanisms and Associations.

Mol Neurobiol 2019 Aug 26;56(8):5866-5890. Epub 2019 Jan 26.

Department of Medicine, Hammersmith Hospital, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1007/s12035-019-1498-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614134PMC
August 2019

Early Life Trauma Predicts Affective Phenomenology and the Effects are Partly Mediated by Staging Coupled with Lowered Lipid-Associated Antioxidant Defences.

Biomol Concepts 2018 Nov 20;9(1):115-130. Epub 2018 Nov 20.

Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Av. Robert Koch 60; 86035-380, Londrina, PR, Brazil.

Background Early life trauma (ELT) may drive mood disorder phenomenology, nitro-oxidative pathways and impairments in semantic memory. There are no data regarding the impact of ELT on affective phenomenology and whether these pathways are mediated by staging or lowered lipid-associated antioxidant defences. Methods This study examined healthy controls (n=54) and patients with affective disorders including major depression, bipolar disorder and anxiety disorders (n=118). ELT was assessed using the Child Trauma Questionnaire. In addition, we measured affective phenomenology and assayed advanced oxidation protein products; malondialdehyde, paraoxonase 1 (CMPAase) activity, high-sensitivity C-reactive protein (hsCRP), and high-density lipoprotein (HDL) cholesterol. Results ELT was associated into with increased risk for mood and comorbid anxiety disorders and a more severe phenomenology, including staging characteristics, depression and anxiety severity, suicidal behaviours, type of treatments, disabilities, body mass index, smoking behaviour and hsCRP, as well as lowered health-related quality of life, antioxidant defences and semantic memory. The number of mood episodes and CMPAase/HDL-cholesterol levels could be reliably combined into a new vulnerability staging-biomarker index, which mediates in part the effects of ELT on affective phenomenology and oxidative stress. Moreover, the effects of female sex on mood disorders and affective phenomenology are mediated by ELT. Discussion The cumulative effects of different ELT drive many aspects of affective phenomenology either directly or indirectly through effects of staging and/or lipid-associated antioxidant defences. The results show that children, especially girls, with ELT are at great risk to develop mood disorders and more severe phenotypes of affective disorders.
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http://dx.doi.org/10.1515/bmc-2018-0010DOI Listing
November 2018
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