Cellular adhesion molecules in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders.

BACKGROUND: Endothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. METHODS: The study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. RESULTS: The total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. CONCLUSIONS: In our study, patients with schizophrenia - including the drug-naïve - have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation.

High dose statin treatment reduces circulating Dickkopf-1 following acute myocardial infarction.

BACKGROUND: Secreted glycoproteins of the Dickkopf (DKK) family modify Wnt signaling and may influence plaque destabilization but their modulation by statins in MI patients is not known. METHODS: We measured plasma DKK-1 and DKK-3 in patients with acute ST-segment elevation MI (STEMI) before percutaneous coronary intervention (PCI) and after 2 and 7 days and 2 months in patients receiving short-term high-dose (40 mg rosuvastatin, given before PCI; n = 25) and moderate dose (20 mg simvastatin, given the day after PCI; n = 34). In vitro modulation of DKK-1 in human umbilical vein endothelial cells (HUVECs) by statins were assessed. RESULTS: (i) Patients receiving high dose rosuvastatin had a marked decline in DKK-1 at day 2 which was maintained throughout the study period. However, a more prevalent use of ß-blockers in the simvastatin group, that could have contributed to higher DKK-1 levels in these patients. (ii) There was a strong correlation between baseline DKK-1 levels and change in DKK-1 from baseline to day 2 in patients receiving high dose rosuvastatin treatment. (iii) DKK-3 increased at day 2 but returned to baseline levels at 2 months in both treatment groups. (iv) Statin treatment dose-dependently decreased DKK-1 mRNA and protein levels in HUVEC. CONCLUSIONS: Our findings suggest that high dose statin treatment with 40 mg rosuvastatin could persistently down-regulate DKK-1 levels, even at 2 months after the initial event in STEMI patients.

Toxoplasma gondii infection associated with inflammasome activation and neuronal injury.

Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.

Canonical notch activation in patients with scrub typhus: association with organ dysfunction and poor outcome.

PURPOSE: The mechanisms that control inflammation in scrub typhus are not fully elucidated. The Notch pathways are important regulators of inflammation and infection, but have not been investigated in scrub typhus. METHODS: Plasma levels of the canonical Notch ligand Delta-like protein 1 (DLL1) were measured by enzyme immunoassay and RNA expression of the Notch receptors (NOTCH1, NOTCH2 and NOTCH4) in whole blood was analyzed by real-time PCR in patients with scrub typhus (n = 129), in patients with similar febrile illness without O. tsutsugamushi infection (n = 31) and in healthy controls (n = 31); all from the same area of South India. RESULTS: Our main results were: (i) plasma DLL1 was markedly increased in scrub typhus patients at hospital admission with a significant decrease during recovery. (ii) RNA expression of NOTCH4 was decreased at admission in whole blood. (iii) A similar pattern for DLL1 and NOTCH4 was seen in febrile disease controls. (iv) Admission DLL1 in plasma was associated with disease severity and short-term survival. (vi) Regulation of Notch pathways in O. tsutsugamushi-infected monocytes as evaluated by public repository data revealed enhanced canonical Notch activation with upregulation of DLL1 and downregulation of NOTCH4. CONCLUSION: Our findings suggest that scrub typhus patients are characterized by enhanced canonical Notch activation. Elevated plasma levels of DLL1 were associated with organ dysfunction and poor outcomes in these patients.

Long-term depot specific changes in adipose tissue after treatment of acromegaly.

CONTEXT: Patients with active acromegaly present a decreased adipose tissue (AT) mass, and short-term studies show that treatment leads to AT depot-specific gain. However, it remains unclear if the increase is persistent in the long-term perspective and/or is sex-dependent. DESIGN: To characterize the depot-specific changes of AT after treatment of acromegaly and identify contributing factors. METHODS: Adipose tissue, including visceral (VAT), subcutaneous (SAT), and total (TAT), and android to gynoid ratio (A/G ratio) were measured by dual energy X-ray absorptiometry at diagnosis (n = 62), and after treatment at short-term (median (IQR) 1.9 (1.5-2.3)) and long-term 5.5 (3.9-9.5) years, and correlated to clinical and biochemical measurements. Growth hormone (GH), insulin-like growth factor 1 (IGF-1), glucose and HbA1c levels, gonadal status, and the presence of diabetes mellitus were recorded. Remission status was assessed at the long-term visit (IGF-1/ULN ≤ 1.3). Differences in the temporal course of AT from baseline to short- and long-term follow-up according to sex, diabetes, gonadal, and remission status were evaluated by mixed model analysis, adjusted for age. RESULTS: Despite a stable body mass index, VAT and A/G ratio increased at both time points, whereas SAT mainly increased at short-term, plateauing afterwards (P < .05 for all). Visceral adipose tissue and A/G ratio were higher in men (P = .035 and P < .001), and the A/G ratio increased more than in women (P = .003). Glucose and HbA1c decreased short-term (P < .05) and remained stable at long-term. The increase in AT depots correlated with the decrease of disease activity at long-term. Remission status had no effect on changes in AT mass during follow-up. CONCLUSION: Treatment of acromegaly leads to an increase in AT mass in a depot- and sex-specific manner both at short-term and long-term follow-up. Glucose metabolism improves rapidly after disease control and persists.

Increased ferroptosis in leukocytes from preeclamptic women involving the long non-coding taurine upregulated gene 1 (TUG1).

BACKGROUND: Ferroptosis plays a key role in placental development and physiology, and abnormal ferroptosis has been implicated in trophoblast injury leading to preeclampsia (PE). We hypothesize that leukocytes isolated from PE exhibit increased ferroptosis and that extracellular vesicles contain long non-coding (lnc) RNA/mRNAs that modulate oxidative stress and iron toxicity in vascular endothelial cells. METHODS: We measured the expression of key regulators of ferroptosis in leukocytes and extracellular vesicles as well as circulating biomarkers of iron homeostasis and oxidative stress in plasma from women with/without PE at different timepoints during pregnancy. For markers that were dysregulated, we assessed their temporal correlation with established markers of disease activity and marker of endothelial activation. For markers dysregulated in early pregnancy, we assessed their ability to predict the development of PE. RESULTS: We found decreased lncRNA/mRNAs in leukocytes, but not extracellular vesicles, in PE that may modulate oxidative stress and iron toxicity. This decrease in anti-ferroptotic markers does not appear to be related to maternal disease activity or plasma oxidative stress status but rather to attenuated anti-inflammatory expression in these cells. Circulating ferritin was elevated in PE, supporting the hypothesis that PE represents a disbalance in iron homeostasis. Low lncRNA taurine upregulated gene 1 RNA levels in leukocytes at 22-24 weeks were strongly associated with the development of PE. CONCLUSIONS: Our findings suggest that maternal leukocytes in PE show decreased anti-ferroptotic activity that correlates with anti-inflammatory expression. Moreover, some of these changes in ferroptotic activity appear to precede the development of PE.

Maternal metabolic profiling across body mass index groups: An exploratory longitudinal study.

INTRODUCTION: Increased BMI has been identified as a risk factor for most pregnancy complications, but the underlying metabolic factors mediating the detrimental effects of BMI are largely unknown. We aimed to compare metabolic profiles in overweight/obese women (body mass index [BMI] ≥ 25 kg/m2 ) and normal weight/underweight women (BMI < 25 kg/m2 ) across gestation. We also explored how gestational weight gain (GWG) affected maternal metabolic profiles. MATERIAL AND METHODS: Exploratory nested case-control study based on a prospective longitudinal cohort of women who were healthy prior to pregnancy and gave birth at Oslo University Hospital from 2002 to 2008. The sample consisted of 48 women who were overweight/obese and 59 normal-weight/underweight women. Plasma samples from four time points in pregnancy (weeks 14-16, 22-24, 30-32 and 36-38) were analyzed by nuclear magnetic resonance spectroscopy and 91 metabolites were measured. Linear regression models were fitted for each of the metabolites at each time point. RESULTS: Overweight or obese women had higher levels of lipids in very-low-density lipoprotein (VLDL), total triglycerides, triglycerides in VLDL, total fatty acids, monounsaturated fatty acids, saturated fatty acids, leucine, valine, and total branched-chain amino acids in pregnancy weeks 14-16 compared to underweight and normal-weight women. Docosahexaenoic acid and degree of unsaturation were significantly lower in overweight/obese women in pregnancy weeks 36-38. In addition, overweight or obese women had higher particle concentration of XXL-VLDL and glycoprotein acetyls (GlycA) at weeks 14-16 and 30-32. GWG did not seem to affect the metabolic profile, regardless of BMI group when BMI was treated as a dichotomous variable, ≥25 kg/m2 (yes/no). CONCLUSIONS: Overweight or obese women had smaller pregnancy-related metabolic alterations than normal-weight/underweight women. There was a trend toward higher triglyceride and VLDL particle concentration in overweight/obese women. As this was a hypothesis-generating study, the similarities with late-onset pre-eclampsia warrant further investigation. The unfavorable development of fatty acid composition in overweight/obese women, with possible implication for the offspring, should also be studied further in the future.

Platelet and mitochondrial RNA is decreased in plasma-derived extracellular vesicles in women with preeclampsia-an exploratory study.

BACKGROUND: Circulating extracellular vesicles (EVs) are increased in preeclampsia (PE) and are associated with severity and progression. We examined in this exploratory cohort study if the mRNAs and long noncoding RNAs (lncRNAs) in plasma-derived EVs were dysregulated in PE compared to normal pregnancy and display different temporal patterns during gestation. METHODS: We isolated EVs from plasma at weeks 22-24 and 36-38 in women with and without PE (n=7 in each group) and performed RNA-seq, focusing on mRNAs and lncRNAs. We validated highly expressed mitochondrial and platelet-derived RNAs discovered from central pathways in 60 women with/without PE. We examined further one of the regulated RNAs, noncoding mitochondrially encoded tRNA alanine (MT-TA), in leukocytes and plasma to investigate its biomarker potential and association with clinical markers of PE. RESULTS: We found abundant levels of platelet-derived and mitochondrial RNAs in EVs. Expression of these RNAs were decreased and lncRNAs increased in EVs from PE compared to without PE. These findings were further validated by qPCR for mitochondrial RNAs MT-TA, MT-ND2, MT-CYB and platelet-derived RNAs PPBP, PF4, CLU in EVs. Decreased expression of mitochondrial tRNA MT-TA in leukocytes at 22-24 weeks was strongly associated with the subsequent development of PE. CONCLUSIONS: Platelet-derived and mitochondrial RNA were highly expressed in plasma EVs and were decreased in EVs isolated from women with PE compared to without PE. LncRNAs were mostly increased in PE. The MT-TA in leukocytes may be a useful biomarker for prediction and/or early detection of PE.

Endocortical Trabecularization in Acromegaly: The Cause for the Paradoxically Increased Vertebral Fracture Risk?

Growth hormone (GH) is nonphysiologically increased in acromegaly, stimulating target tissues directly and indirectly via insulin-like growth factor type 1 (IGF-1). Despite GH having anabolic effects on bone growth and renewal, the risk of vertebral fractures is paradoxically increased in acromegaly. We hypothesized that bone tissue compartments were differentially affected by hormonal alterations in active and controlled acromegaly. We aimed to study the effect of sex and gonadal status on long-term outcome of bone mass and structure to understand the biomechanical competence of bone. We followed 62 patients with newly diagnosed acromegaly longitudinally (median 4.8 years after pituitary surgery) to investigate changes assessed by dual X-ray absorptiometry (DXA), trabecular bone score (TBS), and hip structure analysis (HSA). At diagnosis, patients had increased bone mineral density (BMD) in most compartments compared with normative data (Z-scores). Conversely, TBS Z-score was decreased (Z = -0.64 (SD 1.73), p = 0.028). Following treatment of acromegaly, BMD increased further in compartments containing predominantly trabecular bone, such as the lumbar spine, in eugonadal and male subjects, while compartments with predominantly cortical bone, such as the hip and femoral neck, were unchanged. Total body measurements showed further increase in BMD independent of sex and gonadal status. TBS did not change. HSA revealed a significant decrease in cortical thickness in both sexes independent of gonadal status, whereas the overall size of bone (hip axis length and neck width) did not change over time. In conclusion, patients with acromegaly had increased bone mass and dimensions by DXA. Following normalization of disease activity, BMD increased mainly in compartments rich in trabecular bone, reflecting a closure of the remodeling space. However, HSA revealed a significant decrease in cortical thickness, implying endocortical trabecularization, potentially explaining the increased risk for incident vertebral fractures following treatment. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Metabolic profiling of pregnancies complicated by preeclampsia: A longitudinal study.

INTRODUCTION: Preeclampsia is associated with maternal metabolic disturbances, but longitudinal studies with comprehensive metabolic profiling are lacking. We aimed to determine metabolic profiles across gestation in women who developed preeclampsia compared with women with healthy pregnancies. We also explored the respective effects of body mass index (BMI) and preeclampsia on various metabolic measures. MATERIAL AND METHODS: We measured 91 metabolites by high-throughput nuclear magnetic resonance spectroscopy at four time points (visits) during pregnancy (weeks 14-16, 22-24, 30-32 and 36-38). Samples were taken from a Norwegian pregnancy cohort. We fitted a linear regression model for each metabolic measure to compare women who developed preeclampsia (n = 38) and healthy controls (n = 70). RESULTS: Among women who developed preeclampsia, 92% gave birth after 34 weeks of gestation. Compared to women with healthy pregnancies, women who developed preeclampsia had higher levels of several lipid-related metabolites at visit 1, whereas fewer differences were observed at visit 2. At visit 3, the pattern from visit 1 reappeared. At visit 4 the differences were larger in most subgroups of very-low-density lipoprotein particles, the smallest high-density lipoprotein, total lipids and triglycerides. Total fatty acids were also increased, of which monounsaturated fatty acids and saturated fatty acids showed more pronounced differences. Concentration of glycine tended to be lower in pregnancies with preeclampsia until visit 3, although this was not significant after correction for multiple testing. After adjustment for age, BMI, parity and gestational weight gain, all significant differences were attenuated at visits 1 and 2. The estimates were less affected by adjustment at visits 3 and 4. CONCLUSIONS: In early pregnancy, the metabolic differences between preeclamptic and healthy pregnancies were primarily driven by maternal BMI, probably representing the women's pre-pregnancy metabolic status. In early third trimester, several weeks before clinical manifestation, the differences were less influenced by BMI, indicating preeclampsia-specific changes. Near term, women with preeclampsia developed an atherogenic metabolic profile, including elevated total lipids, very-low-density lipoprotein, triglycerides, and total fatty acids.

Systemic Cell Adhesion Molecules in Severe Mental Illness: Potential Role of Intercellular CAM-1 in Linking Peripheral and Neuroinflammation.

BACKGROUND: Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells. METHODS: We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell-derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each). RESULTS: Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell-derived neurons from patients with SCZ. CONCLUSIONS: Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.

Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness.

BACKGROUND AND HYPOTHESIS: Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. STUDY DESIGN: We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. STUDY RESULTS: Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E-11), CCL25 (P = 9.6E-05) and LBP (P = 2.6E-04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E-04) were observed in SCZ and I-FABP (P = 2.5E-10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. CONCLUSIONS: Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

Serum amyloid A1 and pregnancy zone protein in pregnancy complications and correlation with markers of placental dysfunction.

BACKGROUND: Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, and chronic hypertension), diabetes mellitus, and placental dysfunction confer an increased risk of long-term maternal cardiovascular disease. Preeclampsia is also associated with acute atherosis that involves lesions of uteroplacental spiral arteries, resembling early stages of atherosclerosis. Serum amyloid A1 is involved in hypercoagulability and atherosclerosis and may aggregate into amyloid-aggregations of misfolded proteins. Pregnancy zone protein may inhibit amyloid aggregation. Amyloid is involved in Alzheimer's disease and cardiovascular disease; it has been identified in preeclampsia, but its role in preeclampsia pathophysiology is unclear. OBJECTIVE: We hypothesized that serum amyloid A1 would be increased and pregnancy zone protein decreased in hypertensive disorders of pregnancy and diabetic pregnancies and that serum amyloid A1 and pregnancy zone protein would correlate with placental dysfunction markers (fetal growth restriction and dysregulated angiogenic biomarkers) and acute atherosis. STUDY DESIGN: Serum amyloid A1 is measurable in both the serum and plasma. In our study, plasma from 549 pregnancies (normotensive, euglycemic controls: 258; early-onset preeclampsia: 71; late-onset preeclampsia: 98; gestational hypertension: 30; chronic hypertension: 9; diabetes mellitus: 83) was assayed for serum amyloid A1 and pregnancy zone protein. The serum levels of angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were available for 547 pregnancies, and the results of acute atherosis evaluation were available for 313 pregnancies. The clinical characteristics and circulating biomarkers were compared between the pregnancy groups using the Mann-Whitney U, chi-squared, or Fisher exact test as appropriate. Spearman's rho was calculated for assessing correlations. RESULTS: In early-onset preeclampsia, serum amyloid A1 was increased compared with controls (17.1 vs 5.1 µg/mL, P<.001), whereas pregnancy zone protein was decreased (590 vs 892 µg/mL, P=.002). Pregnancy zone protein was also decreased in diabetes compared with controls (683 vs 892 µg/mL, P=.01). Serum amyloid A1 was associated with placental dysfunction (fetal growth restriction, elevated soluble fms-like tyrosine kinase-1 to placental growth factor ratio). Pregnancy zone protein correlated negatively with soluble fms-like tyrosine kinase-1 to placental growth factor ratio in all study groups. Acute atherosis was not associated with serum amyloid A1 or pregnancy zone protein. CONCLUSION: Proteins involved in atherosclerosis, hypercoagulability, and protein misfolding are dysregulated in early-onset preeclampsia and placental dysfunction, which links them and potentially contributes to future maternal cardiovascular disease.

Markers of cellular senescence is associated with persistent pulmonary pathology after COVID-19 infection.

BACKGROUND: The lungs are the organ most likely to sustain serious injury from coronavirus disease 2019 (COVID-19). However, the mechanisms for long-term complications are not clear. Patients with severe COVID-19 have shorter telomere lengths and higher levels of cellular senescence, and we hypothesized that circulating levels of the telomere-associated senescence markers chitotriosidase, ß-galactosidase, cathelicidin antimicrobial peptide and stathmin 1 (STMN1) were elevated in hospitalized COVID-19 patients compared to controls and could be associated with pulmonary sequelae following hospitalization. METHODS: Ninety-seven hospitalized patients with COVID-19 who underwent assessment for pulmonary sequelae at three-month follow-up were included in the study. ß-Galactosidase and chitotriosidase were analysed by fluorescence; stathmin 1 and cathelicidin antimicrobial peptide were analysed by enzyme immuno-assay in plasma samples from the acute phase and after three-months. In addition, the classical senescence markers cyclin-dependent kinase inhibitor 1A and 2A were analysed by enzyme immuno-assay in peripheral blood mononuclear cell lysate after three months. RESULTS: We found elevated plasma levels of the senescence markers chitotriosidase and stathmin 1 in patients three months after hospitalization with COVID-19, and these markers in addition to protein levels of cyclin-dependent kinase inhibitor 2A in cell lysate, were associated with pulmonary pathology. The elevated levels of these markers seem to reflect both age-dependent (chitotriosidase) and age-independent (stathmin 1, cyclin-dependent kinase inhibitor 2A) processes. CONCLUSIONS: We suggest that accelerated ageing or senescence could be important for long-term pulmonary complications of COVID-19, and our findings may be relevant for future research exploring the pathophysiology and management of these patients.

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. METHODS: Plasma was collected during hospital admission and after 3 months from the NOR-Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene. RESULTS: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low-grade inflammation and respiratory dysfunction after 3 months. CONCLUSION: Respiratory dysfunction after COVID-19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID.

Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. METHODS: We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. RESULTS: We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. CONCLUSIONS: Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.

Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study.

BACKGROUND: Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. METHODS: We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. RESULTS: Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen's d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). CONCLUSIONS: These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

Dysregulated non-coding telomerase RNA component and associated exonuclease XRN1 in leucocytes from women developing preeclampsia-possible link to enhanced senescence.

Senescence in placenta/fetal membranes is a normal phenomenon linked to term parturition. However, excessive senescence which may be induced by telomere attrition, has been associated with preeclampsia (PE). We hypothesized that the telomerase complex in peripheral blood mononuclear cells (PBMC) and circulating telomere associated senescence markers would be dysregulated in women with PE. We measured long non-coding (nc) RNA telomerase RNA component (TERC) and RNAs involved in the maturation of TERC in PBMC, and the expression of TERC and 5'-3' Exoribonuclease 1 (XRN1) in extracellular vesicles at 22-24 weeks, 36-38 weeks and, 5-year follow-up in controls and PE. We also measured telomere length at 22-24 weeks and 5-year follow-up. The circulating senescence markers cathelicidin antimicrobial peptide (CAMP), ß-galactosidase, stathmin 1 (STMN1) and chitotriosidase/CHIT1 were measured at 14-16, 22-24, 36-38 weeks and at 5-year follow-up in the STORK study and before delivery and 6 months post-partum in the ACUTE PE study. We found decreased expression of TERC in PBMC early in pregnant women who subsequently developed PE. XRN1 involved in the maturation of TERC was also reduced in pregnancy and 5-year follow-up. Further, we found that the senescence markers CAMP and ß-galactosidase were increased in PE pregnancies, and CAMP remained higher at 5-year follow-up. ß-galactosidase was associated with atherogenic lipid ratios during pregnancy and at 5-year follow-up, in PE particularly. This study suggests a potential involvement of dysfunctional telomerase biology in the pathophysiology of PE, which is not restricted to the placenta.