Pathophysiology Of Disturbances Research Articles

Plasma levels of matrix metalloproteinases in early psychosis, anxiety and depression: Evidence from the ALSPAC cohort

BackgroundConverging evidence supports the role of Matrix Metalloproteinases (MMPs) in psychiatric disorders. Originally identified as regulators of the extracellular matrix (ECM), MMPs’ functions span multiple processes, including inflammation, synaptic plasticity, neuronal migration, and blood–brain barrier maintenance. Tissue Inhibitors of Metalloproteinases (TIMPs) are major regulators of MMPs. In the present study we examined the associations of plasma MMPs and TIMPs with mental disorders in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). MethodsThe present study was a nested case control study within the Avon Longitudinal Study of Parents and Children and comprised 374 participants who met criteria for psychiatric disorders (35 met the criteria for psychotic disorder, 201 for mild/moderate depressive disorder, and 266 for generalised anxiety disorder) and 401 controls. All cases and controls had were selected from the group of 4019 participants who had attended at age 24 years, completed psychiatric assessments and provided plasma samples. Plasma concentrations of MMP2, MMP3, MMP9 and TIMP-4 were quantified using proximity extension assays available on Olink® Cardiovascular Panel III. Logistic regression analysis compared standardised MMPs and TIMPs levels in cases and controls. Models were adjusted for sex, body mass index, and cigarette smoking. ResultsThere was evidence for an association between MMP3 and depressive disorder (Odds ratio [OR] 1.35, 95 % confidence interval [CI] 1.06–1.73). There was evidence for an association between TIMP4 and depressive disorder (OR 1.51, 95 % CI 1.22–1.88) and generalised anxiety disorder (OR 1.43, 95 % CI 1.19–1.72). There was no evidence for an association between MMPs and psychotic disorders. ConclusionsThe study revealed that 24-year-olds with depressive and anxiety disorders exhibited elevated plasma concentrations of TIMP-4 compared to controls. There was evidence for an association between MMP3 and depressive disorder. These findings provide further support for the involvement of metalloproteinases as biomarkers in the pathophysiology of mental disorders during early adulthood.

Symposium Highlight: PULMONARY LYMPHATICS HISTORY, ANATOMY, AND PATHOPHYSIOLOGY: EMERGING KNOWLEDGE AND A LOOK TO THE FUTURE

Central lymphatic disorders of the lung have not received intense investigation. Lymphatic system physiology is presented in the context of historical developments and basic lung lymphatic anatomy is reviewed followed by emerging characteristics of primary and secondary pathophysiological disturbances of lymphatic involvement in a number of pulmonary diseases including Gorham-Stout disease, pulmonary edema and infections and inflammatory conditions including lymphangioleiomyomatosis (LAM). The future includes potential molecular targeting of lymphangiogenesis or lymphatic vessels for interventional occlusion. This article is an amalgamation of presentations at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease and as part of a Special Symposium on the Lymphatic system of the Heart and Lung in Health and Disease at the 26th International Congress of Lymphology meeting held in Barcelona, Spain, September 2017, which has been updated to 2024.

Extracellular DNA from the blood plasma of patients with schizophrenia stimulates the TLR9-NF-kB signaling pathway in cultured human lymphocytes

Schizophrenia is a mental illness of complex etiology. Recently, there has been increased interest in the role of the immune system in the pathophysiology of mental disorders. The concept of neuroinflammation in neurodevelopmental disorders is gaining widespread interest, including the role of Toll-like receptors.Schizophrenia is associated with an increase in the concentration of cfDNA in human blood, and the composition of cfDNA fragments changes significantly compared to cellular DNA: GC-rich fragments of the ribosomal repeat accumulate and base oxidation occurs. Similar changes, but less pronounced, also occur for cfDNA from healthy donors.To confirm the hypothesis about the possible participation of cfDNA in the inflammation induction, we studied the effect of cfDNA samples on cultured mononuclear cells.Unlike cellular DNA, cfDNA(SZ) and cfDNA(K) stimulate transcription of the TLR9 gene in mononuclear cells. After 1 hour the amount of TLR9 RNA increases by 2.9 and 3.3 times compared to the control. After 24 hours, the TLR9 RNA level decreases slightly, but is still 2-3 times higher than the control level. After 1 hour, TLR9 protein increases by 1.5 and 1.7 times, respectively, and further increased after 24h of culture.An increase TLR9 protein expression correlates with an increase of the transcription factor NF-kB in lymphocytes and is accompanied by an increase in proinflammatory cytokine IL8 RNA, the transcription of IL8 is controlled by the NF-kB factor.Thus, cfDNA(SZ) and cfDNA(K) stimulate the TLR9-NF-kB-proinflammatory cytokine signaling pathway in lymphocytes. The effect of cfDNA also depends on the concentration of these fragments in the extracellular environment. Since the concentrations of cfDNA in the blood of patients with schizophrenia are significantly increased compared to healthy donors, we should expect a much higher level of activation of the TLR9-NF-kB signaling pathway in the body cells of sick people.Samples of cfDNA from patients with schizophrenia have a pronounced biological effect on cells of the immune system, stimulating the synthesis of pro-inflammatory cytokines by activating the TLR9-NF-kB-proinflammatory cytokines signaling pathway. High levels of cfDNA in blood plasma may be one of the reasons for the induction and maintenance of low-level inflammation in schizophrenia.

The role of quantitative electroencephalography in diagnostic workup of mental disorders.

Electroencephalography (EEG) is a non-invasive diagnostic tool, enabling us to assess the electrical activity of the brain and its disturbance in a great number of psychiatric conditions. This paper provides a narrative overview of the most recent advantages of EEG use in various psychiatric disorders that are associated. This article analyses selected psychiatric disorders. We discussed anxiety disorders characterized by chronic fear, dementia leading to cognitive decline, schizophrenia disrupting logical thinking, bipolar affective disorder with alternating episodes of mania and depression, and depression manifested by gradual loss of vital energy. We have shown that EEG testing, by monitoring the electrical activity of the brain, is a helpful tool in identifying specific brain wave patterns associated with these disorders. In the study of mental illness the EEG variant called quantitative EEG (QEEG) is of particular avail as to the spatial discrimination. QEEG is based on digital coding and transformation according to Fourier algorithm. Recently, even more complex methods of EEG data analysis have been implemented, including artificial intelligence (AI), deep learning (DL) and its branch: machine learning (ML). The use of sophisticated EEG postprocessing adds important information about the pathophysiology of mental disorders. More so, EEG/QEEG recording (in particular spectral analysis), if repeated over time may help to follow up the treatment results and to establish a prognosis as to the course of the given condition. Reliability, safety and availability of EEG makes it to be an indispensable tool in modern psychiatry. Use of EEG, QEEG may lead to faster and more precise differential diagnostic workup. Use of EEG/QEEG changes as an objective outcome measure in clinical trials may support the development of personalized pharmacotherapy or psychotherapy.

Inflammation, Oxidative Stress, and Endothelial Dysfunction in the Pathogenesis of Vascular Damage: Unraveling Novel Cardiovascular Risk Factors in Fabry Disease.

Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A (GLA) gene, disrupts lysosomal function, leading to vascular complications. The accumulation of globotriaosylceramide (Gb3) in arterial walls triggers upregulation of adhesion molecules, decreases endothelial nitric oxide synthesis, and induces reactive oxygen species production. This cascade results in fibrotic thickening, endothelial dysfunction, hypercontractility, vasospasm, and a pro-thrombotic phenotype. AFD patients display increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating heightened cardiovascular risk. Nailfold capillaroscopy (NFC) shows promise in diagnosing and monitoring microcirculatory disorders in AFD, though it remains underexplored. Morphological evidence of AFD as a storage disorder can be demonstrated through electron microscopy and immunodetection of Gb3. Secondary pathophysiological disturbances at cellular, tissue, and organ levels contribute to the clinical manifestations, with prominent lysosomal inclusions observed in vascular, cardiac, renal, and neuronal cells. Chronic accumulation of Gb3 represents a state of ongoing toxicity, leading to increased cell turnover, particularly in vascular endothelial cells. AFD-related vascular pathology includes increased renin-angiotensin system activation, endothelial dysfunction, and smooth muscle cell proliferation, resulting in IMT increase. Furthermore, microvascular alterations, such as atypical capillaries observed through NFC, suggest early microvascular involvement. This review aims to unravel the complex interplay between inflammation, oxidative stress, and endothelial dysfunction in AFD, highlighting the potential connections between metabolic disturbances, oxidative stress, inflammation, and fibrosis in vascular and cardiac complications. By exploring novel cardiovascular risk factors and potential diagnostic tools, we can advance our understanding of these mechanisms, which extend beyond sphingolipid accumulation to include other significant contributors to disease pathogenesis. This comprehensive approach can pave the way for innovative therapeutic strategies and improved patient outcomes.

Azoxystrobin Induced Changes in the Gill Histoarchitecture, Brain Acetylcholinesterase Activity and the Behavior of the Fish <i>Pethia conchonius</i> from the River Teesta

Azoxystrobin is a globally used strobilurin fungicide, which contaminates waterbodies through surface run-off. Its bioaccumulation in aquatic animals via food chains can induce serious pathophysiological disturbances. Therefore, histopathological and neuronal effects of azoxystrobin have been assessed in the fish, Pethia conchonius in the laboratory condition. Azoxystrobin-treated fish showed slow movement, crowding at the bottom, loss of equilibrium, and excess mucus secretion at all concentrations (0.025mg/L, 0.0514 mg/L, and 0.103mg/L) at 48 hours of exposure compared to the control. A significant dose and time-dependent inhibition in acetylcholinesterase activity was observed (p<0.05). The highest acetylcholinesterase inhibition (45.45 ± 1.07) was noted for the highest concentration at 96 hours of exposure than the control groups (88.35 ± 0.71). In contrast to the control, different histopathological changes in gill tissues have been observed like, epithelial lifting, lamellar fusion, epithelial hyperplasia, and the curling of secondary lamellae in the azoxystrobin-exposed groups after 24 hours of treatment. The results of this study indicated that azoxystrobin is neurotoxic as well as damaging to gills.

Cytosolic Escape of Mitochondrial DNA Triggers cGAS-STING Pathway-Dependent Neuronal PANoptosis in Response to Intermittent Hypoxia.

Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), characterized by neuronal cell death and neurocognitive impairment. We focus on the accumulated mitochondrial DNA (mtDNA) in the cytosol, which acts as a damage-associated molecular pattern (DAMP) and activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a known trigger for immune responses and neuronal death in degenerative diseases. However, the specific role and mechanism of the mtDNA-cGAS-STING axis in IH-induced neural damage remain largely unexplored. Here, we investigated the involvement of PANoptosis, a novel type of programmed cell death linked to cytosolic mtDNA accumulation and the cGAS-STING pathway activation, in neuronal cell death induced by IH. Our study found that PANoptosis occurred in primary cultures of hippocampal neurons and HT22 cell lines exposed to IH. In addition, we discovered that during IH, mtDNA released into the cytoplasm via the mitochondrial permeability transition pore (mPTP) activates the cGAS-STING pathway, exacerbating PANoptosis-associated neuronal death. Pharmacologically inhibiting mPTP opening or depleting mtDNA significantly reduced cGAS-STING pathway activation and PANoptosis in HT22 cells under IH. Moreover, our findings indicated that the cGAS-STING pathway primarily promotes PANoptosis by modulating endoplasmic reticulum (ER) stress. Inhibiting or silencing the cGAS-STING pathway substantially reduced ER stress-mediated neuronal death and PANoptosis, while lentivirus-mediated STING overexpression exacerbated these effects. In summary, our study elucidates that cytosolic escape of mtDNA triggers cGAS-STING pathway-dependent neuronal PANoptosis in response to IH, mainly through regulating ER stress. The discovery of the novel mechanism provides theoretical support for the prevention and treatment of neuronal damage and cognitive impairment in patients with OSA.

Obesity to Type 2 Diabetes Mellitus: Importance of Longitudinal Characterization of the Progressive Phases as Identified in Rhesus Monkeys Maintained Under Constant Diet and Environmental Conditions

The complex physiological mechanisms that underlie the links between obesity and T2DM involve “adiposity-induced” alterations in beta cell function —not yet mechanistically understood. Clearly the changes in beta cell function are greatly increased during the progression of obesity, --not reduced!! AND multiorgan insulin resistance whose mechanisms are unknown (although likely reduced by weight loss). Rhesus monkeys have shown these and have provided an amazing look at the Phases that lead to T2DM. We have previously summarized, in a table of 49 variables, the many ways that the nonhuman primate rhesus monkey offers exciting opportunities for insight into these extraordinary conditions compared to the human with T2DM. The Importance of longitudinal characterization, with a number of measurements that are regularly and periodically carried out to assess longitudinally some of the pathophysiological processes that develop spontaneously and naturally in these monkeys as they progress from normal, lean, young animals to obese animals with or without various physiological disturbances undergo the aging process. Usually these disturbances develop at varying rates in different monkeys and include hypertension, hyperlipidemia, hyperinsulinemia, hyperglycemia, impaired glucose tolerance, insulin resistance, peripheral neuropathy, impaired renal clearance, and cardiovascular disease—in short, the entire syndrome that becomes manifest in aged and diabetic humans. The longitudinal studies depend specifically on regular assessment of each animal and determination of the rate at which that animal is or is not progressing in the development of pathophysiological disturbances. Identification of phases allows one to estimate where a given monkey is in regard to the progression to overt diabetes. Application to humans will greatly increase our predictive ability to understand the mechanisms underlying both obesity and T2DM. NIA NO1AG3 1012. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Are Advanced Oxidation Protein Products (AOPPs) Levels Altered in Neuropsychiatric Disorders? An Integrative Review.

Neuropsychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are considered a public health problem since it interferes in personal relationships and at work. The pathophysiological mechanisms of these mental disorders are still not completely understood. The variety and heterogeneity of symptoms, as well as the absence of biomarkers, make the diagnosis, prognosis, and treatment of these disorders difficult. However, oxidative stress appears to play a role in the pathophysiology of these diseases. In this context, advanced oxidation protein products (AOPPs) are considered a biomarker of protein oxidative damage and have been associated with neuroinflammatory diseases. In patients with neuropsychiatric disorders, increased levels of AOPPs were associated with the severity of symptoms and decreased quality of life. Thus, the objective of this integrative review is to investigate and discuss the relationship between AOPPs levels and MDD, BD, and SZ. Different databases were consulted and approximately 112 scientific articles were found relating AOPPs and psychiatric disorders. In the majority of studies, the blood levels of AOPPs were increased in MDD, BD, and SZ and associated with the severity of the disorders. Although the association of this marker with the risk of developing one of these mental disorders is more uncertain, some studies have suggested this relationship. Of the twenty-four studies highlighted, only four did not find significant differences in AOPPs levels in patients with the disorders mentioned. In summary, it may be suggested that the assessment of AOPPs levels can be a useful tool in the evaluation of neuropsychiatric disorders, at least for prognostic evaluation. However, the role of this biomarker in the pathophysiology of mental disorders is still unclear, as well as whether reducing its levels represents a potential therapeutic strategy.

Should Glucokinase be Given a Chance in Diabetes Therapeutics? A Clinical-Pharmacological Review of Dorzagliatin and Lessons Learned So Far.

Despite advances in the management of type 2 diabetes mellitus (T2DM), one-third of patients with diabetes do not achieve the desired glycemic goal. Considering this inadequacy, many agents that activate glucokinase have been investigated over the last two decades but were withdrawn before submission for marketing permission. Dorzagliatin is the first glucokinase activator that has been granted approval for T2DM, only in China. As overstimulation of glucokinase is linked with pathophysiological disturbances such as fatty liver and cardiovascular issues and a loss of therapeutic efficacy with time. This review aims to highlight the benefits of glucokinase activators vis-à-vis the risks associated with chronic enzymatic activation. We discuss the multisystem disturbances expected with chronic activation of the enzyme, the lessons learned with glucokinase activators of the past, the major efficacy and safety findings with dorzagliatin and its pharmacological properties, and the status of other glucokinase activators in the pipeline. The approval of dorzagliatin in China was based on the SEED and the DAWN trials, the major pivotal phase III trials that enrolled patients with T2DM with a mean glycosylated hemoglobin of 8.3-8.4%, and a mean age of 53-54.5years from multiple sites in China. Patients with uncontrolled diabetes, cardiac diseases, organ dysfunction, and a history of severe hypoglycemia were excluded. Both trials had a randomized double-blind placebo-controlled phase of 24weeks followed by an open-label phase of 28weeks with dorzagliatin. Drug-naïve patients with T2DM with a disease duration of 11.7months were enrolled in the SEED trial while the DAWN trial involved patients with T2DM with a mean duration of 71.5months and receiving background metformin therapy. Compared with placebo, the decline in glycosylated hemoglobin at 24weeks was more with dorzagliatin with an estimated treatment difference of -0.57% in the SEED trial and -0.66% in the DAWN trial. The desired glycosylated hemoglobin (<7%) was also attained at more than two times higher rates with dorzagliatin. The glycemic improvement was sustained in the SEED trial but decreased over 52weeks in the DAWN trial. Hyperlipidemia was observed in 12-14% of patients taking dorzagliatin versus 9-11% of patients receiving a placebo. Additional adverse effects noticed over 52weeks with dorzagliatin included an elevation in liver enzymes, hyperuricemia, hyperlacticacidemia, renal dysfunction, and cardiovascular disturbances. Considering the statistically significant improvement in glycosylated hemoglobin with dorzagliatin in patients with T2DM, the drug may be given a chance in treatment-naïve patients with a shorter disease history. However, with the waning therapeutic efficacy witnessed in patients with long-standing diabetes, which was also one of the potential concerns with previously tested molecules, extended studies involving patients with chronic and uncontrolled diabetes are needed to comment upon the long-term therapeutic performance of dorzagliatin. Likewise, evidence needs to be generated from other countries, patients with organ dysfunction, a history of severe hypoglycemia, cardiac diseases, and elderly patients before extending the use of dorzagliatin. Apart from monitoring lipid profiles, long-term safety studies of dorzagliatin should involve the assessment of serum uric acid, lactate, renal function, liver function, and cardiovascular parameters.

The pathophysiology and management of depression in cardiac surgery patients

BackgroundDepression is common in the cardiac surgery population. This contemporary narrative review aims to explore the main pathophysiological disturbances underpinning depression specifically within the cardiac surgery population. The common non-pharmacological and pharmacological management strategies used to manage depression within the cardiac surgery patient population are also explored.MethodsA total of 1291 articles were identified through Ovid Medline and Embase. The findings from 39 studies were included for qualitative analysis in this narrative review.ResultsDepression is associated with several pathophysiological and behavioral factors which increase the likelihood of developing coronary heart disease which may ultimately require surgical intervention. The main pathophysiological factors contributing to depression are well characterized and include autonomic nervous system dysregulation, excessive inflammation and disruption of the hypothalamic–pituitary–adrenal axis. There are also several behavioral factors in depressed patients associated with the development of coronary heart disease including poor diet, insufficient exercise, poor compliance with medications and reduced adherence to cardiac rehabilitation. The common preventative and management modalities used for depression following cardiac surgery include preoperative and peri-operative education, cardiac rehabilitation, cognitive behavioral therapy, religion/prayer/spirituality, biobehavioral feedback, anti-depressant medications, and statins.ConclusionThis contemporary review explores the pathophysiological mechanisms leading to depression following cardiac surgery and the current management modalities. Further studies on the preventative and management strategies for postoperative depression in the cardiac surgery patient population are warranted.

Transcription factor EB: A potential integrated network regulator in metabolic-associated cardiac injury.

With the worldwide pandemic of metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD), cardiometabolic disease (CMD) has become a significant cause of death in humans. However, the pathophysiology of metabolic-associated cardiac injury is complex and not completely clear, and it is important to explore new strategies and targets for the treatment of CMD. A series of pathophysiological disturbances caused by metabolic disorders, such as insulin resistance (IR), hyperglycemia, hyperlipidemia, mitochondrial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress (ERS), autophagy dysfunction, calcium homeostasis imbalance, and endothelial dysfunction, may be related to the incidence and development of CMD. Transcription Factor EB (TFEB), as a transcription factor, has been extensively studied for its role in regulating lysosomal biogenesis and autophagy. Recently, the regulatory role of TFEB in other biological processes, including the regulation of glucose homeostasis, lipid metabolism, etc. has been gradually revealed. In this review, we will focus on the relationship between TFEB and IR, lipid metabolism, endothelial dysfunction, oxidative stress, inflammation, ERS, calcium homeostasis, autophagy, and mitochondrial quality control (MQC) and the potential regulatory mechanisms among them, to provide a comprehensive summary for TFEB as a potential new therapeutic target for CMD.

The interplay between sexual abuse and inflammation, oxidative stress, and DNA damage in drug-naïve panic disorder patients.

Although accumulating evidence suggests an interplay between child abuse and inflammatory processes and the pathophysiology of mental disorders, few studies have investigated the cellular mechanisms related to this matter. Furthermore, no studies to date have evaluated cytokine, oxidative stress, and DNA damage levels in drug-naïve panic disorder (PD) patients and their possible association with childhood trauma. The aim of the present study was to determine the levels of the proinflammatory interleukin (IL)-1B, the oxidative stress marker TBARS, and8-hydroxy-2' -deoxyguanosine (8-OHdG; representing DNA damage) in drug-naïve PD patients compared to controls. Furthermore, this investigation aimed to determine whether early-life trauma could predict peripheral levels of the previously mentioned markers in unmedicated PD patients. This work showed that drug-naïve PD patients presented elevated levels of TBARS and IL-1B but not 8-OHdG compared to healthy controls. In addition, sexual abuse during childhood was associated with increased levels of IL-1B in PD patients. Our findings suggest that the microglial NLRP3 inflammasome complex might be activated in drug-naïve PD patients. This study is the first to associated sexual abuse with increased levels of IL-1B in drug-naïve PD patients and to demonstrate that this population presents high concentrations of oxidative stress and inflammation markers but not DNA damage markers when compared to healthy controls. Independent replication of these findings would support further clinical trials of inflammasome inhibitory drugs in PD patients, which could lead to effective novel treatments for people with PD and contribute to elucidating pathophysiological differences depending on trauma exposure in the immune disturbances accompanying PD.

An Interdisciplinary Reappraisal of Delirium and Proposed Subtypes.

An interdisciplinary plenary session entitled "Rethinking and Rehashing Delirium" was held during the 2021 Annual Meeting of the Academy of Consultation-Liaison Psychiatry to facilitate dialog on the prevalent approach to delirium. Panel members included a psychiatrist, neurointensivist, and critical care specialist, and attendee comments were solicited with the goal of developing a statement. Discussion was focused on a reappraisal of delirium and, in particular, its disparate terminology and history in relation to acute encephalopathy. The authors endorse a recent joint position statement that describes acute encephalopathy as a rapidly evolving (<4 weeks) pathobiological brain process that presents as subsyndromal delirium, delirium, or coma and suggest the following points of refinement: (1) to suggest that "delirium disorder" describe the diagnostic construct including its syndrome, precipitant(s), and unique pathophysiology; (2) to restrict the term "delirium" to describing the clinical syndrome encountered at the bedside; (3) to clarify that the disfavored term "altered mental status" may occasionally be an appropriate preliminary designation where the diagnosis cannot yet be specified further; and (4) to provide rationale for rejecting the terms acute brain injury, failure, or dysfunction. The final common pathway of delirium appears to involve higher-level brain network dysfunction, but there are many insults that can disrupt functional connectivity. We propose that future delirium classification systems should seek to characterize the unique pathophysiological disturbances ("endotypes") that underlie delirium and delirium's individual neuropsychiatric symptoms. We provide provisional means of classification in hopes that novel subtypes might lead to specific intervention to improve patient experience and outcomes. This paper concludes by considering future directions for the field. Key areas of opportunity include interdisciplinary initiatives to harmonize efforts across specialties and settings, enhance underrepresented groups in research, integration of delirium and encephalopathy in coding, development of relevant quality and safety measures, and exploration of opportunities for translational science.

On the origins of sleep disordered breathing, cardiorespiratory and metabolic dysfunction: which came first, the chicken or the egg?

Sleep disordered breathing (SDB) is a complex, sex specific and highly heterogeneous group of respiratory disorders. Nevertheless, sleep fragmentation and repeated fluctuations of arterial blood gases for several hours per night are at the core of the problem; together, they impose significant stress to the organism with deleterious consequences on physical and mental health. SDB increases the risk of obesity, diabetes, depression and anxiety disorders; however, the same health issues are risk factors for SDB. So, which came first, the chicken or the egg? What causes the appearance of the first significant apnoeic events during sleep? These are important questions because although moderate to severe SDB affects ∼500million adults globally, we still have a poor understanding of the origins of the disease, and the main treatments (and animal models) focus on the symptoms rather than the cause. Because obesity, metabolic dysfunction and stress-related neurological disorders generally appear progressively, we discuss how the development of these diseases can lead to specific anatomical and non-anatomical traits of SDB in males and females while considering the impacts of sex steroids. In light of the growing evidence indicating that the carotid bodies are important sensors of key metabolic and endocrine signals associated with stress and dysmetabolism, we propose that these organs play a key role in the process.

Risk factors and consequences of post-esophagectomy delirium: a systematic review and meta-analysis.

Post-operative delirium (POD) is a state of mental and neurocognitive impairment characterized by disorientation and fluctuating levels of consciousness. POD in the context of esophageal surgery may herald serious and potentially life-threatening post-operative complications, or conversely be a symptom of severe underlying pathophysiologic disturbances. The aim of the present systematic review and meta-analysis is to explore risk factors associated with the development of POD and assess its impact on post-operative outcomes. A systematic literature search of the MedLine, Web of Science, Embase and Cochrane CENTRAL databases and the clinicaltrials.gov registry was undertaken. A random-effects model was used for data synthesis with pooled outcomes expressed as Odds Ratios (OR), or standardized mean differences (WMD) with corresponding 95% Confidence Intervals. Seven studies incorporating 2449 patients (556 with POD and 1893 without POD) were identified. Patients experiencing POD were older (WMD 0.29 ± 0.13years, P < 0.001), with higher Charlson's Comorbidity Index (CCI; WMD 0.31 ± 0.23, P = 0.007) and were significantly more likely to be smokers (OR 1.38, 95% CI 1.07-1.77, P = 0.01). Additionally, POD was associated with blood transfusions (OR 2.08, 95% CI 1.56-2.77, P < 0.001), and a significantly increased likelihood to develop anastomotic leak (OR 2.03, 95% CI 1.25-3.29, P = 0.004). Finally, POD was associated with increased mortality (OR 2.71, 95% CI 1.24-5.93, P = 0.01) and longer hospital stay (WMD 0.4 ± 0.24, P = 0.001). These findings highlight the clinical relevance and possible economic impact of POD after esophagectomy for malignant disease and emphasize the need of developing effective preventive strategies.

Characterization of female reproductive disturbances post-traumatic injury in Drosophila melanogaster.

Traumatic injuries (TIs) from intimate partner violence, vehicular collisions, high-impact sports, and even mundane activities can be fatal. However, survivors of TIs can have pathophysiological disturbances post-injury, including neurodegenerative diseases, mental illness, and metabolic disorders.Reproductive issues are a known consequence of TI especially in women, however this has remained poorly understood. Drosophila melanogaster has recently emerged as a stellar model of TI, however reproductive consequences have not been reported. Using the Drosophila model, we find reproductive consequences in the form of decreased egg laying and the retention of mature egg chambers mimicking issues in ovulation. These findings indicate that reproductive consequences of TI are conserved between Drosophila and humans.

Relationship between thyroid function and Major Depressive Disorder (MDD): an integrative literature review

Thyroid function is closely associated with neuropsychological functions, including mental status and cognitive functions. Subclinical hypothyroidism (HSC) is defined as a condition with elevated levels of thyroid stimulating hormone (TSH) and normal levels of free thyroxine (T4). Although the role played by thyroid hormones in the pathophysiology of mental disorders is unclear, it has been suggested that small changes in thyroid hormone levels, even within the normal range, may be related to altered brain function in depression. Currently, there are 2 explanatory hypotheses: serotonin deficit and noradrenaline deficit in the central nervous system caused by hormonal disorders. It is important to emphasize that the thyroid-psychic pathway is bidirectional, therefore, both thyroid alterations can cause depressive symptoms or exacerbate a previous psychiatric pathology, and depression can promote thyroid disorders, the latter being less frequent. Thus, the role of thyroid function in depressive illness is unclear. Although there is some evidence that mild thyroid alterations predispose to cases of depression, the specific abnormalities involving the thyroid and depressive conditions remain poorly understood. However, there is a causal link.

Integration of real-world clinical data into the Munich Mental Health Biobank – clinical and scientific potential and challenges

Introduction New insights into the pathophysiology of mental disorders and innovations in psychiatric care depend on the availability of representative, longitudinal and multidimensional datasets across diverse, transdiagnostic populations. Biobanks usually attempt to collect such data in parallel to clinical routine, which is resource-intensive, puts additional burden on health-care providers, and may reduce the generalizability of the results. Despite containing rich phenotypic and biological information, data generated in routine clinical care is seldomly used for research purposes, because it is usually unstructured and locked in data silos. To truly link clinical practice and research, solutions that optimize the generation and scientific utilization of real-world clinical data are needed.ObjectivesEvaluation of a new digital infrastructure which warrants the efficient, automatized, and structured collection of real-world data in psychiatric care, and integrates the generated data into existing biobanking efforts.MethodsWe have developed a new documentation system which augments the existing IT-structures, enables the collection of routine clinical data in a structured format and involves patients in the data generation process. In an implementation science approach, to replicate and extend the findings of Blitz et al. (JMIR Ment Health 2021), we are investigating the acceptance, efficacy, and safety of the system in our outpatient clinic for affective disorders.ResultsFirst results describing the technical safety, usage metrics, and acceptance of the system, and the quality of the collected data will be presented.ConclusionsChallenges of collecting real-world data for biobanking and research purposes and perspectives on future digital solutions will be discussed.DisclosureNo significant relationships.

Effects of Risperidone and Prenatal Poly I:C Exposure on GABAA Receptors and AKT-GSK3β Pathway in the Ventral Tegmental Area of Female Juvenile Rats.

The ventral tegmental area (VTA) in the ventral midbrain is the origin of the dopaminergic neurotransmission pathways. Although GABAA receptors and AKT-GSK3β signaling are involved in the pathophysiology of mental disorders and are modulated by antipsychotics, an unmet task is to reveal the pathological changes in these biomarkers and antipsychotic modulations in the VTA. Using a juvenile polyriboinosinic-polyribocytidylic acid (Poly I:C) psychiatric rat model, this study investigated the effects of adolescent risperidone treatment on GABAA receptors and AKT/GSK3β in the VTA. Pregnant female Sprague–Dawley rats were administered Poly I:C (5mg/kg; i.p) or saline at gestational day 15. Juvenile female offspring received risperidone (0.9 mg/kg, twice per day) or a vehicle from postnatal day 35 for 25 days. Poly I:C offspring had significantly decreased mRNA expression of GABAA receptor β3 subunits and glutamic acid decarboxylase (GAD2) in the VTA, while risperidone partially reversed the decreased GAD2 expression. Prenatal Poly I:C exposure led to increased expression of AKT2 and GSK3β. Risperidone decreased GABAA receptor β2/3, but increased AKT2 mRNA expression in the VTA of healthy rats. This study suggests that Poly I:C-elicited maternal immune activation and risperidone differentially modulate GABAergic neurotransmission and AKT-GSK3β signaling in the VTA of adolescent rats.