Pathophysiology Of Disease Research Articles

Epidemiology and Impact of Social Hardships in Children With Multiple Sclerosis in the United States.

Social determinants of health (SDOH) affect patient health outcomes, but the impact on patients with pediatric-onset multiple sclerosis (POMS) has not been well studied. Study objectives were to (1) describe the frequency of adverse SDOH, (2) evaluate social hardships as a potential barrier to the initiation of disease-modifying therapy (DMT), and (3) explore the association between adverse SDOH and disease outcomes in POMS, as well as study attrition. This was a retrospective multicenter observational study conducted through the United States Network of Pediatric MS Centers database. Participants were patients diagnosed with POMS (excluding primary progressive MS). The primary outcome was time to initiation of DMT. Secondary outcomes included most recent Expanded Disability Status Scale (EDSS) score, steroid treatment for the first event, time to second event, and study attrition. Demographic variables and clinical outcomes were compared between patients with and without hardships (maternal education of high school or less, public insurance/no insurance, or single/no-income household). Multivariable regression models were used to assess the impact of social hardship on study outcomes. There were 996 total participants (69% female, mean age at symptom onset and EDSS score [±SD] were 14.2 ± 3 and 1.2 ± 1.1, respectively). Of 768 patients with complete demographic information, 66% reported a hardship. Hardship was associated with younger age at symptom onset and diagnosis. While there was no difference in time to DMT initiation, patients with hardship were more likely to receive steroids for the first event (odds ratio [OR] 1.66, 95% CI 1.21-2.26, p = 0.002). Lack of private insurance was associated with increased risk of study attrition (OR 1.85, 95% CI 1.14-3.00, p = 0.012) and higher EDSS score (β = 0.15, 95% CI 0.01, 0.28). Living in a no-income household (vs dual-income) was associated with a shorter time to second event (hazard ratio 1.33, 95% CI 1.02-1.74, p = 0.034). The experience of hardships is common and associated with younger age at symptom onset and diagnosis, as well as shorter time to second event. Lack of private insurance is associated with study attrition and a higher EDSS score despite no difference in time to initiating DMT. There may be differences in early disease pathophysiology related to social hardship, and future studies are needed to better understand this complex relationship.

PACS2/CPT1A/DHODH signaling promotes cardiomyocyte ferroptosis in diabetic cardiomyopathy

ObjectivesThe pathophysiology of diabetic cardiomyopathy (DCM) is a phenomenon of great interest, but its clinical problems have not yet been effectively addressed. Recently, the mechanism of ferroptosis in the pathophysiology of various diseases, including DCM, has attracted widespread attention. Here, we explored the role of PACS2 in ferroptosis in DCM through its downregulation of PACS2 expression.Methods and resultsCardiomyocytes were treated with high glucose and palmitic acid (HGPA), and the detection of cardiomyocyte iron ions, lipid peroxides, and reactive oxygen species (ROS) revealed clear ferroptosis during these treatments. Silencing PACS2 downregulated CPT1A expression and upregulated DHODH expression significantly, reversing HGPA-induced ferroptosis. Further silencing of PACS2 with a CPT1A agonist exacerbated cardiomyocyte ferroptosis while promoting mitochondrial damage in cardiomyocytes. Using a mouse model of type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), we found that PACS2 deletion reversed these treatment-induced increases in cellular iron ions, impaired cardiac function, mitochondrial damage and ferroptosis in cardiac muscle tissues.ConclusionsThe PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in DCM by regulating cardiomyocyte mitochondrial function.

Protective effect of Apelin-13 on oxygen and glucose deprivation induced-damage in retinal ganglion cells cultured in vitro.

Ischemic-anoxic injury plays an important role in the pathophysiology of diabetes retinopathy, optic neuropathy, even glaucoma and other ocular diseases. It may ultimately cause damage to neuronal death like retinal ganglion cells (RGCs) and subsequent visual loss. RGCs are essential elements of the retina and optic nerve that are crucial to visual formation. Ischemic-anoxic injury, inflammation, and oxidative stress are vital causes of RGC death. Thus, neuroprotection is essential for the treatment of these ocular diseases. Recent studies have shown the neuroprotective property of apelin-13 in many disease models. In this study, we isolated RGCs and found that apelin-13 promoted the viability of RGCs and increased the phosphorylation of Protein kinase B (PKB, Akt) in an in vitro oxygen-glucose deprivation model. Moreover, apelin-13 increased the expressions of glucose-6-phosphate dehydrogenase (G6PD) and nicotinamide adenine dinucleotide phosphate (NADPH) and reduced the level of reactive oxygen species (ROS). And, we also found that apelin-13 could promote the expressions of glucose transporter-1 (GLUT1) and adenosine triphosphate (ATP). These results indicated that apelin-13 could delay or stop RGC death, which might be as potential therapeutic targets for treatment of diseases mediated by ischemic-anoxic damage like diabetes retinopathy, optic neuropathy, even glaucoma.

Quantitative Systems Pharmacology-Based Digital Twins Approach Supplements Clinical Trial Data for Enzyme Replacement Therapies in Pompe Disease.

Pompe disease is a rare, progressive neuromuscular disease caused by deficient lysosomal glycogen degradation, and includes both late-onset (LOPD) and severe infantile-onset (IOPD) phenotypes. Due to very small patient numbers in IOPD and the high phenotypic heterogeneity observed in this population, a quantitative systems pharmacology (QSP)-based "digital twin" approach was developed to perform an in silico comparison of the efficacy of avalglucosidase alfa vs. the standard of care, in a virtual population of IOPD patients. A QSP model was developed that represents key elements of Pompe disease pathophysiology, including tissue glycogen accumulation and the elevation of the biomarker urine Hex4 in both LOPD and IOPD patients. In this approach, the QSP model was used to generate digital twins of each IOPD patient enrolled in the avalglucosidase alfa clinical program, considering their respective disease burden, demographics, and treatment history. This virtual cohort supplemented clinical observations by simulating and comparing tissue glycogen and urine Hex4 following avalglucosidase alfa treatment vs. the standard of care. The digital twin analysis supports the interpretation that the enhanced reduction in urine Hex4 observed following avalglucosidase alfa treatment is attributable to greater tissue glycogen clearance. Overall, this study provides mechanism-based insight into avalglucosidase alfa efficacy across the phenotypic spectrum of Pompe disease and demonstrates the value of applying a QSP-based digital twin analysis to support rare disease drug development.

High glucose potentiates Zika virus induced-astroglial dysfunctions.

Zika virus (ZIKV) is a neurotropic flavivirus that induces congenital Zika syndrome and neurodevelopmental disorders. Given that ZIKV can infect and replicate in neural cells, neurological complications in adult brain are also observed. Glial cells may emerge to delay and/or prevent the development of ZIKV-induced neurodegeneration. These cells actively participate in metabolic, inflammatory and redox processes, and consequently, in the pathophysiology of neurodegenerative diseases, including diabetic encephalopathy. In this sense, changes in glucose metabolism can support the inflammatory activity of astroglial cells; however, the effects of increased glucose concentration during ZIKV infection have not yet been explored in astroglial cells. Here, we evaluated functional parameters of astroglial cells exposed to ZIKV upon normal and high glucose concentrations, focusing on inflammatory profile, oxidative stress, and expression of critical genes for astroglial functions. High glucose potentiated the pro-inflammatory and oxidative effects of ZIKV, as well as potentiated the downregulation of signaling pathways, such as Nrf-2 (nuclear factor erythroid derived 2 like 2), sirtuin 1 (SIRT1), peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α), and poly (ADP-ribose) polymerase (PARP). In summary, our results suggest that high glucose can favor the activation of inflammatory signaling while impairing cytoprotective pathways in astroglial cells exposed to ZIKV and reinforce the hypothesis that this virus is highly neurotrophic, with significant impact in glial cells.

MicroRNAs as Biomarkers and Therapeutic Targets in Female Infertility

The study of microRNAs (miRNAs) has emerged in recent decades as a key approach to understanding the pathophysiology of many diseases, exploring their potential role as biomarkers, and testing their use as future treatments. Not only have neurological, cardiovascular diseases, or cancer benefited from this research but also infertility. Female infertility, as a disease, involves alterations at multiple levels, such as ovarian and uterine alterations. This review compiles the latest studies published in humans that link female disorders that affect fertility with altered miRNA profiles. Studies on ovarian alterations, including diminished ovarian reserve (DOR), poor ovarian response to stimulation (POR), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS), are summarized and classified based on the expression and type of sample analyzed. Regarding uterine disorders, this review highlights upregulated and downregulated miRNAs primarily identified as biomarkers for endometriosis, adenomyosis, decreased endometrial receptivity, and implantation failure. However, despite the large number of studies in this field, the same limitations that reduce reproducibility are often observed. Therefore, at the end of this review, the main limitations of this type of study are described, as well as specific precautions or safety measures that should be considered when handling miRNAs.

Defective Atg16l1 in intestinal epithelial cells links to altered fecal microbiota and metabolic shifts during pregnancy in mice

ABSTRACT Throughout gestation, the female body undergoes a series of transformations, including profound alterations in intestinal microbial communities. Changes gradually increase toward the end of pregnancy and comprise reduced α-diversity of microbial communities and an increased propensity for energy harvest. Despite the importance of the intestinal microbiota for the pathophysiology of inflammatory bowel diseases, very little is known about the relationship between these microbiota shifts and pregnancy-associated complications of the disease. Here, we explored the longitudinal dynamics of gut microbiota composition and functional potential during pregnancy and after lactation in Atg16l1 ∆IEC mice carrying an intestinal epithelial deletion of the Crohn’s disease risk gene Atg16l1. Using 16S rRNA amplicon and shotgun metagenomic sequencing, we demonstrated divergent temporal shifts in microbial composition between Atg16l1 wildtype and Atg16l1 ∆IEC pregnant mice in trimester 3, which was validated in an independent experiment. Observed differences included microbial genera implicated in IBD such as Lachnospiraceae, Roseburia, Ruminococcus, and Turicibacter. Changes partially recovered after lactation. Additionally, metagenomic and metabolomic analyses suggest an increased capacity for chitin degradation, resulting in higher levels of free N-acetyl-glucosamine products in feces, alongside reduced glucose and myo-inositol levels in serum around the time of delivery. On the host side, we found that the immunological response of Atg16l1 ∆IEC mice is characterized by higher colonic mRNA levels of TNFα and CXCL1 in trimester 3 and a lower weight of offspring at birth. Understanding pregnancy-dependent microbiome changes in the context of IBD may constitute the first step in the identification of fecal microbial biomarkers and microbiota-directed therapies that could help improve precision care for managing pregnancies in IBD patients.

EVALUATION OF GLUTATHIONE PEROXIDASE ACTIVITY, MALONYLALDEHYDE AND SELENIUM LEVELS IN SICKLE CELL ANAEMIA INDIVIDUALS ATTENDING NAUTH, NNEWI IN SOUTH-EASTERN NIGERIA.

Background: Oxidative stress is an imbalance between the production and clearance of toxic free radicals known as reactive oxygen species (ROS). It is associated with hemolysis, a hallmark of SCD. SCD has long been recognized as an inflammatory condition and oxidative stress play important role in pathophysiology of SCA. Imbalance between production and elimination of reactive oxygen species (ROS) damages cell structures, including lipids, membranes, proteins and nucleic acids resulting in cell death or altered cell function. Aim: The aim of this study was to measure the serum level of Glutathione peroxidase, Malonaldehyde and Selenium in SCA (HbSS) in their steady state, AA (Healthy adult) and AS (sickle cell carriers) Methods: This is a cross- sectional study. A total of one hundred and fifty aged matched participants were recruited for this study.50 SCA subjects with sickle cell anemia (SS). Glutathione peroxidase and Malonyaldehyde were measured using turbidometry and colorimetric methods respectively while Selenium was analysed using Atomic Absorption Spectrophotometry (AAS) Results: The result of analysis of variance (ANOVA) showed that the mean serum level of MDA concentration (2.97±0.29) was higher in the SS group and was statistically significant (p< 0.05). MDA concentration was lower in the AS group. In the post hoc analysis MDA was statistically significant between SS vs AS and AA vs AA. The glutathione peroxidase activity was significantly lower in the SS group (0.85±0.12) compare with the mean values obtained in the AA and AS group. The GPx activity among the three groups was statistically significant while the post hoc analysis among the three groups showed statistical difference and was significant (p < 0.005) The Selenium levels in the SS group is lower compared with the values observed between the AA and AS group. The Se levels in the SS group was statistically lower (5.73±1.34) (p < 0.05) and showed significant difference. The comparison study between AS vs SS and AA vs AA were statistically significant. Conclusion: The decrease in selenium level potentiates low and weakened antioxidant activity and capacity which also is a reflection of low level of glutathione peroxidase observed which is supposed to attack free radicals to prevent oxidative stress. The findings from this study are in tandem with other researches suggesting that the pathophysiology of sickle cell disease is associated with oxidative stress

A critique of measurement of defective insulin secretion and insulin sensitivity as a precision approach to gestational diabetes.

Precision medicine approaches to gestational diabetes mellitus (GDM) have categorised patients according to disease pathophysiology (insulin resistance, insulin insufficiency or both), and demonstrated associations with clinical outcomes. We aimed to assess whether using enhanced processing to determine indices of insulin secretion and sensitivity is analytically robust, reproducible in a different population, and useful diagnostically and prognostically in clinical practice. A total of 1308 pregnant women with one or more risk factors for GDM who underwent a 75 g OGTT at one of nine hospital sites were recruited to this observational study. Specimens were collected for determination of glucose levels using standard and enhanced procedures, HbA1c and insulin analysis. GDM diagnosis and management followed National Institute for Health and Care Excellence guidance. We categorised women into pathophysiological subtypes: insulin-resistant GDM (HOMA2-S < 25th centile of the population with normal glucose tolerance [NGT]), insulin-insufficient GDM (HOMA2-B < 25th centile), both or neither. We assessed associations with pregnancy outcomes using logistic regression. Using enhanced specimen handling, 1027/1308 (78.5%) women had NGT, with 281/1308 (21.5%) being classified as having GDM. Of this group, 135/281 (48.0%) had insulin-resistant GDM, 73/281 (26.0%) had insulin-insufficient GDM and 2/281 (0.7%) had both insulin-resistant and insulin-insufficient GDM. Unexpectedly, 71 patients (25.3%) had GDM with both HOMA2-S and HOMA2-B ≥25th centile (GDM-neither). This novel subgroup appeared to be relatively insulin-sensitive in the fasting state but developed marked post-load hyperglycaemia and hyperinsulinaemia, suggesting an isolated postprandial defect in insulin sensitivity that was not captured by HOMA2-B or HOMA2-S. Women within most GDM subgroups had comparable pregnancy outcomes to those of normoglycaemic women, and HOMA2-B and HOMA2-S were weak predictors of pregnancy outcomes. Maternal BMI predicted a similar number of outcomes to HOMA2-S, suggesting that there was no additional predictive value in adding HOMA2-S. Similar findings were obtained when using different indices and standard specimen handling techniques. Precision categorisation of GDM using HOMA2-S and HOMA2-B does not provide useful diagnostic or prognostic information, but did distinguish a novel subgroup of patients with GDM, characterised by an isolated postprandial defect in insulin sensitivity.

Ruxolitinib Treatment Ameliorates Clinical, Immunological, and Transcriptomic Aberrations in Patients with STAT3 Gain-of-Function Disease

BackgroundSTAT3 gain-of-function (GOF) disease presents with lymphoproliferation, autoimmunity, and failure to thrive. While JAK inhibitors have alleviated symptoms, their effects on disease pathogenesis remain unclear. ObjectiveWe prospectively investigated the clinical, immunological, and transcriptomic responses of four STAT3 GOF patients under long-term ruxolitinib treatment. MethodsWe conducted clinical and immunological evaluations at baseline and after ruxolitinib treatment at 3, 8, 12, and over 12 months. Our assessments included circulating T follicular helper cells (cTFH), regulatory T (Treg) cells, cytokine levels, and proliferation assays. Furthermore, we investigated the transcriptomic changes with treatment and conducted T-cell receptor sequencing. ResultsRuxolitinib achieved substantial control over the clinical manifestations. Post-treatment evaluations demonstrated a notable increase in naive CD4+ and CD8+ T cell populations, alongside a significant reduction in effector memory T cells. Additionally, there was a decrease in cTFH cells and double-negative T cells. Treg cell percentages and their canonical markers, already reduced before treatment, further declined with ruxolitinib. The treatment did not alter IFN-γ, IL-17A, IL-10, IL-4 cytokine productions of CD4+ T cells. Importantly, ruxolitinib effectively normalized the previously dysregulated transcriptome profile in peripheral blood mononuclear cells, bringing it closer to that of healthy controls. This normalization was most striking in the downregulation of STAT3-targeted genes, interferon-related genes, myeloid cell activation, and cytotoxic effector CD8+ T-cell genes, with effects persisting for up to 12 months. Self-reactive T-cell indices based on TCR repertoire analysis revealed potential auto-reactive cell clones in the patient samples. ConclusionRuxolitinib reversed cellular and transcriptomic signatures, enhancing our understanding of the disease's pathophysiology and highlighting essential immunological markers for precise monitoring.

Ferroptosis: mechanisms and therapeutic targets.

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation in membrane phospholipids. Since its identification in 2012, extensive research has unveiled its involvement in the pathophysiology of numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious diseases, autoimmune conditions, metabolic disorders, and skin diseases. Oxidizable lipids, overload iron, and compromised antioxidant systems are known as critical prerequisites for driving overwhelming lipid peroxidation, ultimately leading to plasma membrane rupture and ferroptotic cell death. However, the precise regulatory networks governing ferroptosis and ferroptosis-targeted therapy in these diseases remain largely undefined, hindering the development of pharmacological agonists and antagonists. In this review, we first elucidate core mechanisms of ferroptosis and summarize its epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, and N6-methyladenosine modification) and nonepigenetic modifications (e.g., genetic mutations, transcriptional regulation, and posttranslational modifications). We then discuss the association between ferroptosis and disease pathogenesis and explore therapeutic approaches for targeting ferroptosis. We also introduce potential clinical monitoring strategies for ferroptosis. Finally, we put forward several unresolved issues in which progress is needed to better understand ferroptosis. We hope this review will offer promise for the clinical application of ferroptosis-targeted therapies in the context of human health and disease.

Research Progress of Pyroptosis in Renal Diseases.

Kidney diseases, particularly Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD), are identified as global public health issues affecting millions of individuals. In addition, the frequency of renal diseases in the population has increased dramatically and rapidly in recent years. Renal disorders have become a significant public health burden. The pathophysiology of renal diseases is significantly connected with renal cell death, including apoptosis, necrosis, necroptosis, ferroptosis, pyroptosis, and autophagy, as is now recognized. Unlike other forms of cell death, pyroptosis is a unique planned cell death (PCD). Scientists have proven that pyroptosis is crucial in developing various disorders, and this phenomenon is gaining increasing attention. It is considered a novel method of inflammatory cell death. Intriguingly, inflammation is among the most significant pathological characteristics of renal disease. This study investigates the effects of pyroptosis on Acute Kidney Injury (AKI), Chronic Kidney Disease (CKD), Diabetic Nephropathy (DN), Immunoglobulin A (IgA) Nephropathy, and Lupus Nephritis (LN) to identify novel therapeutic targets for kidney diseases.

Molecular dynamics studies reveal the structural impacts of LRRK2 R1441C and LRRK2 D1994A mutations in Parkinson's disease

Parkinson's Disease (PD) is a continuingly deteriorating neurological ailment affecting over 8.5 million patients globally as of 2019, and the numbers are expected to keep rising. To aid in identifying therapeutic targets, molecular dynamics simulations are convenient and cost-effective methods for enriching our knowledge of the molecular pathophysiology of diseases. Many proteins and their corresponding mutations have been identified to contribute to this disease, of which Leucine-rich repeat kinase 2 (LRRK2) is accountable for a significant percentage. Several mutations involving the domains in LRRK2 have been studied, which are known to interfere with various enzymatic processes, ultimately leading to trademark features of PD like aggregation of protein inclusions called Lewy Bodies (LBs), mitochondrial dysfunctions, etc. The precise molecular mechanism of the mutations' pathophysiology is still unclear. This research article looks at the structural effects of mutations, namely the R1441C and D1994A mutations, on the surrounding residues in the protein, offering novel insights into pathophysiological changes at an atomistic level. Our results indicate a gain of electrostatic interactions with a stable αβ motif within the LRR-Roc linker, amongst other changes. This article also highlights the potential involvement and importance of the αβ motif in LRRK2 associated PD.

Single-cell analysis combined with transcriptome sequencing identifies autophagy hub genes in macrophages after spinal cord injury

Spinal cord injury (SCI) is a neurological disease characterized by the loss of motor and sensory function below the injury level. The pathogenesis of SCI is complex, involving the recruitment of various cells that play key roles in the injury area. Single-cell RNA sequencing (scRNA-seq) can analyze cell heterogeneity and inter-cell communication. Bulk RNA-seq offers advantages such as low cost, mature technology and high throughput. Joint analysis of bulk RNA-seq and scRNA-seqis more complementary for exploring the pathophysiology of diseases. In this study, we revealed changes in cell clusters and intercellular signaling after SCI through the scRNA-seq analysis. Bioinformatics analyses and experimental verification showed that macrophages increase rapidly and become the dominant cell type after SCI. The mTOR gene is the key molecule of M1 macrophage autophagy blockade and the PI3K-AKT-mTOR signaling pathway plays an important role in blockings macrophage autophagy.

Ex vivo functional whole organ in biomedical research: a review.

Model systems are critical in biomedical and preclinical research. Animal and in vitro models serve an important role in our current understanding of human physiology, disease pathophysiology, and therapy development. However, if the system is between cell culture and animal models, it may be able to overcome the knowledge gap that exists in the current system. Studies employing ex vivo organs as models have not been thoroughly investigated. Though the integration of other organs and systems has an impact on many biological mechanisms and disorders, it can add a new dimension to modeling and aid in the identification of new possible therapeutic targets. Here, we have discussed why the ex vivo organ model is desirable and the importance of the inclusion of organs from diverse species, described its historical aspects, studied organs as models in scientific research, and its ex vivo stability. Wealso discussed,how an ex vivo organ model might help researchers better understand organ physiology, as well as organ-specific diseases and therapeutic targets. We emphasized how this ex vivo organ dynamics will be more competent than existing models, as well as what tissues or organs would have potentially viable longevity for ex vivo modeling including human tissues, organs, and/or at least biopsies and its possible advantage in clinical medicine including organ transplantation procedure and precision medicine.

The role of NLRP3 and NLRP12 inflammasomes in glioblastoma.

Glioblastoma (GBM) is the deadliest malignant brain tumor, with a survival of less than 14 months after diagnosis. The highly invasive nature of GBM makes total surgical resection challenging, leading to tumor recurrence and declined survival. The heterocellular composition of the GBM reprograms its microenvironment, favoring tumor growth, proliferation, and migration. The innate immune cells in the GBM tumor microenvironment, including microglia, astrocytes, and macrophages, express pattern recognition receptors such as NLRs (Nucleotide-binding domain and leucine-rich repeat-containing) that sense pathogen- and damage-associated molecular patterns initiating inflammation. Upon activation, NLRP3 promotes inflammation by NLRP3 inflammasome formation. Auto-proteolytic cleavage and activation of Caspase-1 within the inflammasome leads to caspase-1-mediated cleavage, activation, and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. In contrast, NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-κB pathway. NLRP3 and NLRP12 have been implicated in the disease pathophysiology of several cancers with cell-context-dependent, pro- or anti-tumorigenic roles. In this review, we discuss the current literature on the mechanistic roles of NLRP3 and NLRP12 in GBM and the gaps in the scientific literature in the context of GBM pathophysiology with potential for targeted therapeutics.

Immunological Approaches in the Diagnosis and Treatment of Psychiatric Disorders - a Historical Overview.

Background For over 130 years, scientists have been suggesting that infection and inflammation may play a role in psychosis and other psychiatric disorders. First attempts to treat psychosis by immune-modulating therapies were made early in the last century; however, after the development of antipsychotics in the 1950s, scientific interest shifted away from immunological aspects of psychiatric disorders to the involvement of catecholamines, in particular dopamine, in psychosis. Summary Antipsychotic treatment was not as successful as expected, so the 1990s saw renewed interest in inflammation and psychoneuroimmunological research in schizophrenia and beyond. In parallel, advances in immunological research methods allowed immunological and inflammatory mechanisms to be studied in more detail. Key Messages Clinical studies and meta-analyses have demonstrated the positive effects of anti-inflammatory treatment in psychiatric disorders. More research is needed to elucidate exactly how immunological mechanisms result in disease pathophysiology, with the aim to improve anti-inflammatory treatments and personalized treatment.

Urinary metabolomics provide insights into coronary artery disease in individuals with type 1 diabetes.

Type 1 diabetes increases the risk of coronary artery disease (CAD). High-throughput metabolomics may be utilized to identify metabolites associated with disease, thus, providing insight into disease pathophysiology, and serving as predictive markers in clinical practice. Urine is less tightly regulated than blood, and therefore, may enable earlier discovery of disease-associated markers. We studied urine metabolomics in relation to incident CAD in individuals with type 1 diabetes. We prospectively studied CAD in 2501 adults with type 1 diabetes from the Finnish Diabetic Nephropathy Study. 209 participants experienced incident CAD within the 10-year follow-up. We analyzed the baseline urine samples with a high-throughput targeted urine metabolomics platform, which yielded 54 metabolites. With the data, we performed metabolome-wide survival analyses, correlation network analyses, and metabolomic state profiling for prediction of incident CAD. Urinary 3-hydroxyisobutyrate was associated with decreased 10-year incident CAD, which according to the network analysis, likely reflects younger age and improved kidney function. Urinary xanthosine was associated with 10-year incident CAD. In the network analysis, xanthosine correlated with baseline urinary allantoin, which is a marker of oxidative stress. In addition, urinary trans-aconitate and 4-deoxythreonate were associated with decreased 5-year incident CAD. Metabolomic state profiling supported the usage of CAD-associated urinary metabolites to improve prediction accuracy, especially during shorter follow-up. Furthermore, urinary trans-aconitate and 4-deoxythreonate were associated with decreased 5-year incident CAD. The network analysis further suggested glomerular filtration rate to influence the urinary metabolome differently between individuals with and without future CAD. We have performed the first high-throughput urinary metabolomics analysis on CAD in individuals with type 1 diabetes and found xanthosine, 3-hydroxyisobutyrate, trans-aconitate, and 4-deoxythreonate to be associated with incident CAD. In addition, metabolomic state profiling improved prediction of incident CAD.

Autoantibodies immuno-mechanically modulate platelet contractile force and bleeding risk

Altered mechanotransduction has been proposed as a putative mechanism for disease pathophysiology, yet evidence remains scarce. Here we introduce a concept we call single cell immuno-mechanical modulation, which links immunology, integrin biology, cellular mechanics, and disease pathophysiology and symptomology. Using a micropatterned hydrogel-laden coverslip compatible with standard fluorescence microscopy, we conduct a clinical mechanobiology study, specifically focusing on immune thrombocytopenia (ITP), an autoantibody-mediated platelet disorder that currently lacks a reliable biomarker for bleeding risk. We discover that in pediatric ITP patients (n = 53), low single platelet contraction force alone is a “physics-based” biomarker of bleeding (92.3% sensitivity, 90% specificity). Mechanistically, autoantibodies and monoclonal antibodies drive increases and decreases of cell force by stabilizing integrins in different conformations depending on the targeted epitope. Hence, immuno-mechanical modulation demonstrates how antibodies may pathologically alter mechanotransduction to cause clinical symptoms and this phenomenon can be leveraged to control cellular mechanics for research, diagnostic, and therapeutic purposes.

Pathophysiology, Diagnosis, and Management of Coronary Artery Disease inthe Setting of Atrial Fibrillation.

Atrial fibrillation (AF) and coronary artery disease are frequently associated and, when so, lead to a grim prognosis. Recent studies suggest the presence of interconnected pathophysiological pathways between the 2 conditions that can promote and aggravate each other, igniting a vicious cycle. Notwithstanding, in contrast with the attention dedicated to the management of antithrombotic treatment, research on other aspects of coronary artery disease in AF is only recently gaining traction. The clinical impact of correct assessment of coronary artery stenosis in AF is especially high, due to the antithrombotic therapy imposed by both AF and coronary stenting. Until recently, an in-depth characterization of coronary microcirculation in AF was lacking. However, contemporary studies indicate that coronary microvascular dysfunction is a frequent encounter in AF, possibly explaining the ischemic symptoms even in the absence of obstructive coronary artery disease and interfering with the use of pressure-based indices to evaluate the hemodynamic significance of coronary artery stenosis. This comprehensive review addresses our current knowledge on coronary physiology in AF and its repercussion on the invasive management of coronary artery disease in this setting.