Elevated Plasma Concentrations Research Articles

Plasma concentrations of neurofilament light, p-Tau231 and glial fibrillary acidic protein are elevated in patients with chronic kidney disease and correlate with measured glomerular filtration rate

BackgroundPatients with chronic kidney disease (CKD) have a high prevalence of cerebrovascular disease and cognitive impairment. The objective was to analyse whether plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated Tau231 (p-Tau231) are elevated in patients with CKD and to identify independent predictors of these biomarkers, with an emphasis on the role of measured glomerular filtration rate (mGFR).MethodsIn this cross-sectional cohort study, we included 110 patients with CKD stages 3 and 4 (estimated GFR 15–59 ml/min/1.73 m2) without manifest cerebrovascular disease or dementia, and 55 healthy controls. Biomarkers of neurological disorders were measured with ultrasensitive single molecule array methods.ResultsPlasma concentrations (median [IQR]) of NfL (37.5 [22.1–47.5] vs. 13.4 [10.5–16.7] ng/L, p < 0.001), p-Tau231 (25.7 [19.1–38.7] vs. 13.9 [10.5–16.3] ng/L, p < 0.001) and GFAP (190 [140–281] vs. 153 [116–211] ng/L, p < 0.001) were elevated in patients with CKD vs. controls. Measured GFR was negatively correlated with NfL (r = − 0.706, p < 0.001), p-Tau231 (r = − 0.561, p < 0.001), and GFAP (r = − 0.385, p < 0.001). In multivariable linear regression models, mGFR was an independent predictor of log-transformed plasma concentrations of NfL (standardized beta coefficient [β] = − 0.439, p < 0.001) and GFAP (β = − 0.321, p < 0.001).ConclusionPatients with CKD had elevated plasma concentrations of NfL, p-Tau231 and GFAP compared with controls, and these biomarkers were inversely correlated with mGFR. Measured GFR was a significant, independent predictor of plasma concentrations of NfL and GFAP in patients with CKD. The mechanisms underlying this association need further investigation. Plasma levels of NfL and GFAP should be interpreted cautiously in patients with marked reductions in GFR.

Acid sphingomyelinase deficiency: Laboratory diagnosis, genetic and epidemiologic aspects of a 50-year French cohort.

Acid sphingomyelinase deficiency: Laboratory diagnosis, genetic and epidemiologic aspects of a 50-year French cohort.

Elevated plasma concentrations of lipoprotein (a) are associated with cardiovascular diseases in patients with early-onset type 2 diabetes mellitus.

To ascertain whether vascular complications and high lipoprotein (a) [Lp(a)] concentrations are related in individuals with early-onset type 2 diabetes mellitus (T2DM). This observational cross-sectional study included 591 individuals with early-onset T2DM who were divided into four groups based on Lp(a) values which was measured using immunoturbidimetry and presented as mg/dL: high, >50; intermediate, 30≤Lp(a)<50; low, 10≤Lp(a)<30; and very low, <10. The relationship between the risk of vascular complications and Lp(a) level was examined using a logistic regression model. The median age of onset for individuals with early-onset T2DM (n=591) was 37 years, duration of diabetes was 12 years, and glycated hemoglobin (HbA1c) level was 8.8%. The median Lp(a) was 10.40 (4.80-21.80) mg/dL, and Lp(a) concentration did not correlate with age, sex, or glycemic control (P>0.05). Individuals in the low Lp(a) (OR=2.12, 95% CI 1.17-3.84, P<0.05), intermediate Lp(a) (OR=2.76, 95% CI 1.10-6.98, P<0.05) and high Lp(a) (OR=4.79, 95% CI 2.03-11.31, P<0.01) groups had an increased risk of coronary heart disease (CHD) compared with those in the very low Lp(a) group after adjustment. Nevertheless, among individuals with early-onset T2DM, there was no correlation between Lp(a) concentration and the risk of cerebrovascular disease (CVL) and microvascular complications (P>0.05). In patients with early-onset T2DM, Lp(a) concentration was independently associated with CHD. Lp(a) testing is essential to determine who has a latent high risk of CHD among patients with early-onset T2DM.

Genetic Determinants of the Familial Hypercholesterolaemia Phenotype.

Individuals with familial hypercholesterolaemia (FH) have severely elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) from birth and as a consequence have an elevated morbidity and mortality due to the development of coronary heart disease (CHD). Monogenic FH can be caused by carrying a single copy of a pathogenic variant in any of four genes (LDLR/APOB/PCSK9/APOE), which are all involved in the clearance of LDL-C from the blood by the liver. FH is one of the most common inherited disorders, with an estimated prevalence of carriers of around 1/280 individuals in most populations and ancestry groups. However, such variants can be found usually only in 20%-30% of clinically FH subjects, and in the majority of the no-variant individuals, the phenotype is most likely explained by the inheritance of a greater-than-average number of common variants of small effect, with such individuals better given the diagnosis of 'polygenic hypercholesterolaemia'. Also, in a proportion of no-variant subjects who meet the clinical criteria, the most likely explanation is due to overproduction of Lp(a) which is an LDL-C particle with a bound copy of the 'little-a' protein. Here, we review the research that has elucidated the genetic architecture of the FH phenotype and discuss recent studies and future prospects of finding additional genes where variants can cause FH.

The effect of highly bioavailable forms of curcumin on lipoprotein(a) plasma levels: A systematic review and meta-analysis of randomized clinical studies.

The effect of highly bioavailable forms of curcumin on lipoprotein(a) plasma levels: A systematic review and meta-analysis of randomized clinical studies.

The role of glutathione S-transferase mu 2 in mitigating fatty acid-induced hepatic inflammation in dairy cows.

Fatty liver is a major metabolic disorder in perinatal dairy cows, characterized by elevated plasma concentrations of nonesterified fatty acids (NEFA) and hepatic inflammation. Glutathione S-transferase mu 2 (GSTM2), a phase II detoxification enzyme, regulates cellular antioxidant and detoxification processes in nonruminants. However, its involvement in NEFA-induced hepatic inflammation in dairy cows with fatty liver remains unclear. This study aimed to elucidate the role of GSTM2 in mediating hepatic inflammation caused by elevated NEFA levels in dairy cows with severe fatty liver. An in vivo study was conducted using 10 healthy cows (hepatic triacylglycerol [TG] content <1%) and 10 cows with severe fatty liver (hepatic TG content >10%), matched for the number of lactations (median = 3, range = 2-4) and DIM (median = 9 d, range = 3-15 d). Liver tissue and blood samples were collected before feeding. Compared with healthy cows, cows with severe fatty liver had higher plasma concentrations of NEFA, BHB, haptoglobin (HP), plasma amyloid A (SAA), and lower plasma concentration of glucose. These cows also showed significantly lower abundance of hepatic GSTM2 and overactivated hepatic inflammatory pathways, as indicated by increased abundance of phosphorylated inhibitor of κB (IκB)α and nuclear factor κB (NF-κB) p65, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 (CASP1), as well as mRNA levels of tumor necrosis factor α (TNFA), IL6, and IL1B. In vitro, hepatocytes isolated from 5 healthy calves (1 d old, fasted female, 30-40 kg of BW) were used to determine the effects of GSTM2 on hepatic inflammation. First, hepatocytes were treated with NEFA (1.2 mM) for varying durations (0.5, 1, 3, 6, 9, 12, 15, or 18 h). The NEFA treatment significantly increased the phosphorylation of IκBα and NF-κB p65, protein abundance of NLRP3, ASC and CASP1, and mRNA levels of TNFA, IL6 and IL1B, peaking at 9 and 12 h. Second, hepatocytes were treated with different concentrations of NEFA (0, 0.6, 1.2, or 2.4 mM) for 9 h, which decreased GSTM2 protein and mRNA abundance. Meanwhile, GSTM2 was silenced using small interfering RNA or overexpressed using adenovirus for 48 h in hepatocytes, followed by NEFA treatment. Silencing GSTM2 augmented the NEFA-induced increase in phosphorylation of IκBα and NF-κB p65, as well as protein abundance of NLRP3, ASC and CASP1, and mRNA levels of TNFA, IL6 and IL1B. Conversely, overexpression of GSTM2 mitigated these inflammatory signals upon NEFA treatment. In summary, these findings indicate that GSTM2 plays a crucial role in modulating NEFA-induced hepatic inflammation. Targeting GSTM2 may offer new strategies to treat or prevent fatty liver disease in dairy cows.

Pharmacokinetics and Safety of Oral Pyrophosphate in Systemic Sclerosis Patients-A Pilot Study.

Calcinosis is a manifestation of systemic sclerosis with a severe negative impact on quality of life. Efforts to find a treatment for calcinosis have been hindered by our limited understanding of the underlying pathomechanism. We propose that extracellular pyrophosphate deficiency may have a causal role in the formation of these mineralized deposits, because pyrophosphate inhibits the deposition of hydroxyapatite-the major constituent of calcinosis-and supplementing pyrophosphate may have therapeutic potential in the treatment of calcinosis. Systemic sclerosis patients were treated with a single dose of 50 mg/kg disodium pyrophosphate (cohort 1, n = 10), or a daily dose of 25 mg/kg disodium pyrophosphate for seven consecutive days (cohort 2, n = 10). Safety of oral pyrophosphate treatment was assessed with special focus on gastrointestinal tolerance, serum phosphate and calcium levels, and potential electrocardiography abnormalities. Absorption kinetics and peak plasma pyrophosphate concentrations were measured by the adenosine triphosphate sulfurylase method. Gastrointestinal adverse effects associated with oral pyrophosphate treatment were rare and mild. The only consistent abnormality among the serum parameters studied was a transient elevation of serum phosphate levels (change: 0.2 to 0.62 and 0.15 to 0.44 mmol/L in cohorts 1 and 2, respectively). Based on electrocardiography results, both doses can be regarded as safe in terms of corrected QT interval prolongation in short-term treatment. Serum pyrophosphate levels increased significantly in both cohorts. Oral pyrophosphate treatment was found to be safe in patients with systemic sclerosis and resulted in elevated plasma concentrations comparable to results obtained in healthy volunteers. This provides rationale to test the therapeutic potential of pyrophosphate against calcinosis.

Metabolite Changes Associated with Resectable Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is insidious, with only 15-20% of those diagnosed suitable for surgical resection as it is either too advanced and has invaded local structures or has already spread to distant sites. The associated tumor microenvironment provides a protective shield which limits the efficacy of chemotherapeutic agents, but also impairs the delivery of nutrients required for the PDAC cells. To compensate for this, metabolic adaptions occur to provide alternative sources of fuel. The aim of this study is to explore metabolomic differences between participants with resectable PDAC compared to healthy volunteers (HV). The objectives were to use nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) to determine if resectable PDAC induces sufficient metabolic adaptations and variations which could be used to discriminate between the two groups. Plasma samples were collected from fasted individuals with resectable PDAC (n = 23, median age 68 [IQR 56-75], 69.6% male) and HV (n = 24, median age 63 [IQR 58-71], 54.2% male). Samples were analyzed using NMR and the Biocrates MxP Quant 500 kit at University Hospital Southampton. NMR spectroscopy identified six independent metabolites that significantly discriminated between the PDAC and HV groups, including elevated plasma concentrations of 3-hydroxybutyrate and citrate, with decreased amounts of glutamine and histidine. MS analysis identified 84 metabolites with a significant difference between the PDAC and HV cohorts. The metabolites with a fold change (FC) > 1.5 in the PDAC population were conjugated bile acids (taurocholic acid, glycocholic acid, and glycochenodexoycholic acid). In conclusion, using metabolomics, biochemical differences between resectable PDAC and HV were detected. These differences indicate metabolic plasticity and utilization of alternative fuel sources.

FATP1-mediated fatty acid uptake in renal tubular cells as a countermeasure for hypothermia

Hypothermia is a condition in which body temperature falls below 35 °C, resulting from exposure to low environmental temperatures or underlying medical conditions. Postmortem examinations have revealed increased levels of fatty acids in blood and lipid droplet formation in renal tubules during hypothermia. However, the causes and implications of these findings are unclear. This study aimed to analyze the biological significance of these phenomena through lipidomics and transcriptomics analyses of specimens from emergency hypothermia patients and mouse hypothermia models. Both human hypothermia patients and murine models exhibited elevated plasma concentrations of fatty acids and their derivatives compared with controls. Hypothermic mouse kidneys displayed lipid droplet formation, with gene expression analysis revealing enhanced fatty acid uptake and β-oxidation in renal tubular cells. In primary cultured mouse renal proximal tubular cells, low temperatures increased the expression levels of Fatty acid transport protein 1 (FATP1), a fatty acid transporter, and boosted oxygen consumption via β-oxidation. Mice treated with FATP1 inhibitors showed a more rapid decrease in body temperature upon exposure to low temperatures compared with untreated mice. In conclusion, increased fatty acid uptake mediated by FATP1 in renal tubular cells plays a protective role during hypothermia.Key messagesLow temperatures increase FATP1 expression and fatty acid uptake in renal proximal tubular cells, resulting in enhanced β-oxidation.Renal proximal tubular cells play an important role in the resistance to hypothermia via lipid uptake.Maintaining renal lipid metabolism is essential for cold stress adaptation.

Concurrent Diabetic Mellitus with Cushing Syndrome in a Dog

Cortisol is the principal glucocorticoid released by the adrenals in dogs and cats. Prolonged exposure to inappropriately elevated plasma concentrations of free cortisol leads to devolpment of Cushing’s syndrome or hyperadrenocorticism (HAC) (Rijnberk et al., 2010). HAC is typically a chronic and progressive disease, encountered in middle aged to older dogs. These dogs are usually in a good condition with excellent appetite. The clinical manifestations include polyuria, polydipsia, increased appetite, weight gain, abdominal enlargement, and cutaneous lesion. Laboratory findings include neutrophilia, monocytosis, increased alanine aminotransferase and alkaline phosphatase, increased triglycerides and cholestrol. Screening tests for HAC includes ACTH stimulation test, Low dose dexamethasone suppression test and Urinary cortisol : creatinine ratio. Diagnosis of HAC is confirmed by ultrasonography, Computed Tomography, Magnetic Resonance Imaging (Rijnberk et al., 2010). Laproscopic adrenalectomy is surgical procedure of choice in veterinary medicine or by the use of adrenocorticolytic and adrenocorticostatic drugs (Rijnberk et al., 2010). HAC is occasionally associated with fasting hyperglycemia, overt diabetes mellitus and ketoacidosis. The incidence of DM with HAC in dogs is approximately 16.6-22.0 % (Poppl et al., 2016). The clinical signs for DM are almost common to those of HAC (Polyuria, polydipsia, weight gain, hepatomegaly) (Hess et al., 2000). This communication puts on record a case of concurrent diabetic mellitus with Cushing syndrome in a dog.

In vitro study of size-dependent inhibition of human cytochrome P450 (P450) P450-1A2, P450-2A6, P450-2B6, P450-2C8, P450-2E1, P450-2J2, and P450-3A5 by zinc oxide nanoparticles (ZnONPs)

Zinc oxide nanoparticles (ZnONPs) are employed widely in various fields. However, these ZnONPs may potentially inhibit enzyme activities. Cytochrome P450 (P450-) isozymes, which play a crucial function in human bio-transforming drugs, can be inhibited by ZnONPs, leading to slower clearance of co-administrated drugs and elevated drug plasma concentrations. This study aimed to reveal the inhibitory effects of the ZnO nano-sized particles, (&lt;50 nm ZnONP50), (&lt;100nm ZnONP100), and bulk particles (ZnOBP) on human recombinant P450-1A2, P450-2A6, P450-2B6, P450-2C8, P450-2E1, P450-2J2, and P450-3A5 under a size-dependent context. Fluorescence enzymatic assays were carried out to quantify enzyme activities in vitro. The results indicated that ZnO particles inhibited the tested P450 isozymes with varying potencies. ZnONP50 inhibited P450-2B6 and P450-2E1 with Ki values of 20.3 μg/mL and 16.6 μg/mL following a mixed mode; inhibited P450-2C8 with Ki value of 43.3 μg/mL competitively; inhibited P450-2J2 with Ki values of 8.2 μg/mL and 2. 5 μg/mL non-competitively. ZnONP100 inhibited P450-2B6 and P450-2E1 with Ki values of 6.7 μg/mL and 40.1 μg/mL following mixed mode; inhibited P450-2J2 with Ki value of 20.0 μg/mL following mixed or non-competitive mode; inhibited P450-3A5 with Ki value of 0.5 μg/mL non-competitively. ZnOBP competitively inhibited the enzymatic activity of P450-2E1 with Ki value of 28.3 μg/mL. The inhibition potency observed for P450-2B6, P450-2J2, and P450-2E1 depended on the size of the ZnO particle. In conclusion, the interactions between ZnONP products and co-administered drugs metabolized by these inhibited P450-isozymes should be further investigated using in vivo models. Additionally, in silico studies are recommended to characterize these interactions at the molecular level.

C-Reactive Protein, International Normalized Ratio, and Fibrinogen in Diagnostic Scale of Complicated Acute Appendicitis.

Background/Objectives: Differentiating complicated acute appendicitis (CA) and uncomplicated acute appendicitis (UC) is essential to guide clinical management. While CA requires urgent surgical management, UC can be treated with antibiotic therapy in selected cases. However, accurate identification of CA remains a clinical challenge. This study aimed to identify factors associated with CA and to develop a diagnostic severity scale. Methods: In this retrospective study, we included 132 adult patients (>16 years) with a confirmed postsurgical diagnosis of appendicitis, of whom 52 had CA and 80 had UA. Signs, symptoms, comorbidities, laboratory values, and ultrasonographic findings were evaluated to determine predictive factors and construct a diagnostic scale. Results: The factors most significantly associated with CA were elevated plasma concentrations of C-reactive protein (>7.150 mg/dL), fibrinogen (481.5 mg/dL), International Normalized Ratio (INR) (>1.150), and the presence of free fluid periappendicular. The combination of these factors within one scale showed an area under the curve (AUC) of 0.84, with a sensitivity of 78.75% and a specificity of 82.69%. Conclusions: Serum C-reactive protein concentration, fibrinogen, and INR can be employed individually or as part of a scale as important indicators in diagnosing CA.

Elevated Lipid Concentrations in Seminal Plasma Can Reduce Sperm Motility in Simmental Bulls.

Sperm motility is a key factor influencing male fertility and is associated with metabolic and lipid profiles across species. The aim of this study was to investigate the relationship between sperm motility and the seminal plasma lipid profile in Simmental bulls, and to identify key lipids potentially influencing sperm motility. Semen samples were collected from 26 healthy Simmental bulls with an average age of 4.9 years. Sperm quality was evaluated using computer-assisted sperm analysis (CASA). Based on motility, the samples were divided into two groups: high sperm motility (HSM > 65%) and low sperm motility (LSM < 65%). Compared to the LSM group, the HSM group exhibited significantly higher sperm viability, motility, straight-line velocity, beat-cross frequency, and sperm acrosome integrity, while the sperm malformation rate was lower (p < 0.05). Lipid profiles were determined using LC-MS/MS, and 40 differential lipids were identified by multivariate statistical analysis. Among them, 39 lipids were upregulated in the LSM group compared to the HSM group. They were primarily triglycerides and carnitines, mainly involved in four metabolic pathways related to glycerophospholipid and linoleic acid metabolism. Notably, PC (16:0/20:4; 14:0/18:3), LPC (22:4/0:0; 22:6/0:0), and PE (14:0/18:1; 18:1/20:3) were diagnosed with great accuracy (AUC > 0.7), which means they may serve as potential biomarkers for sperm motility.

Cognitive impairment caused by compromised hepatic ketogenesis is prevented by endurance exercise.

Extensive research has demonstrated endurance exercise to be neuroprotective. Whether these neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. To investigate the role of hepatic ketone production on brain health during exercise, healthy 6-month-old female rats underwent viral knockdown of the rate-limiting enzyme in the liver that catalyses the first reaction in ketogenesis: 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2). Rats were then subjected to either a bout of acute exercise or 4weeks of chronic treadmill running (5days/week) and cognitive behavioural testing. Acute exercise elevated ketone plasma concentration 1h following exercise. Hepatic HMGCS2 knockdown, verified by protein expression, reduced ketone plasma concentration 1h after acute exercise and 48h after chronic exercise. Proteomic analysis and enrichment of the frontal cortex revealed hepatic HMGCS2 knockdown reduced markers of mitochondrial function 1h after acute exercise. HMGCS2 knockdown significantly reduced state 3 complex I+II respiration in isolated mitochondria from the frontal cortex after chronic exercise. Spatial memory and protein markers of synaptic plasticity were significantly reduced by HMGCS2 knockdown. These deficiencies were prevented by chronic endurance exercise training. In summary, these are the first data to propose that hepatic ketogenesis is required to maintain cognition and mitochondrial function, irrespective of training status, and that endurance exercise can overcome neuropathology caused by insufficient hepatic ketogenesis. These results establish a mechanistic link between liver and brain health that enhance our understanding of how peripheral tissue metabolism influences brain health. KEY POINTS: Decades of literature demonstrate endurance exercise to be neuroprotective. Whether neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. This study provides the first set of data that suggest hepatic ketogenesis is required to maintain cognition, synaptic plasticity and mitochondrial function. These data indicate endurance exercise can protect against cognitive decline caused by compromised hepatic ketogenesis. These results establish a mechanistic link between liver and brain function, prompting further investigation of how hepatic metabolism influences brain health.

Elevated plasma molybdenum level increases the risk of premature ovarian insufficiency through vascular endothelial injury

Abstract STUDY QUESTION Is elevated plasma molybdenum level associated with increased risk for idiopathic premature ovarian insufficiency (POI)? SUMMARY ANSWER Elevated plasma molybdenum level is associated with an increased risk of idiopathic POI through vascular endothelial injury and inhibition of granulosa cell proliferation. WHAT IS KNOWN ALREADY Excessive molybdenum exposure has been associated with ovarian oxidative stress in animals but its role in the development of POI remains unknown. STUDY DESIGN, SIZE, DURATION Case-control study of 30 women with idiopathic POI and 31 controls enrolled from August 2018 to May 2019. In vitro experimentation. Animal studies using distilled water containing sodium molybdate. PARTICIPANTS/MATERIALS, SETTING, METHODS Logistic regression analysis of the association between plasma concentrations of molybdenum and calcium and POI odds ratio. Plasma samples were from 30 patients with idiopathic POI and 31 controls. Both groups were comparable in terms of age and body mass index. Proliferation assay, flow cytometry analyses for cell cycle, nitric oxide and calcium, gene expression, and protein analysis using human umbilical vein endothelial cells and KGN (human ovarian granulosa-like tumor cell line) cells. Sexual hormones, ovarian function, vascular injury, and platelet activation were evaluated in mice exposed to excessive molybdenum. MAIN RESULTS AND THE ROLE OF CHANCE Case-control study showed that the elevation of plasma concentrations of molybdenum and calcium was positively associated with the POI odds ratio. In vitro study showed that molybdenum treatment increased the permeability of human umbilical vein endothelial cells through enhancing nitric oxide generation and cytosolic calcium influx. In vivo study showed that increased vascular permeability induced by molybdenum resulted in platelet activation and serotonin release within mouse ovaries. Serotonin decreased granulosa cell proliferation by inducing cellular quiescence. Molybdenum also directly inhibited granulosa cell proliferation by downregulating isocitrate dehydrogenase (IDH1). Inhibition of granulosa cell proliferation ultimately led to ovarian dysfunction in mice, including altered estrus cycles, serum sex hormone concentrations, ovarian morphology, and ovarian reserve. LIMITATIONS, REASONS FOR CAUTION There are two limitations in the current study. First, it remains unclear whether the elevation of plasma molybdenum content is due to environmental exposure or altered metabolism. Second, rigorous and multicenter studies, with a larger sample size, should be carried out to confirm the elevation of plasma molybdenum and calcium concentrations in patients with idiopathic POI. WIDER IMPLICATIONS OF THE FINDINGS Our findings highlight an association between elevated plasma concentrations of molybdenum and calcium and increased risk of idiopathic POI. This discovery offers crucial insights into the pathogenesis of idiopathic POI and the search for effective preventive measures. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Natural Science Foundation of China (82271664), the interdisciplinary program of Shanghai Jiao Tong University (YG2022ZD028), the Research Projects of Shanghai Municipal Health Committee (202240343), and Shanghai Clinical Research Center for Cell Therapy (23J41900100). None of the authors has any conflict of interest to disclose. TRIAL REGISTRATION NUMBER N/A.

Enhanced prediction of thrombotic events in hospitalized COVID-19 patients with soluble thrombomodulin.

We aimed to determine the predictive accuracy of elevated soluble thrombomodulin (sTM) and angiopoietin-2 (Ang2) for thrombotic events (TE) in hospitalized COVID-19 patients. We conducted a nested case-control study within a cohort of people admitted to hospital with COVID-19 from March 2020 to August 2022. The cases (people with TE within 28 days after hospital admission) were matched by propensity score to comparable patients without TE. We determined plasma levels of sTM and Ang2 in all available frozen samples, prioritizing the earliest post-admission samples, using an automated immunoassay technique. Among 2,524 hospitalized COVID-19 patients (43% females; median age 67 years), 73 had TE (incidence 1.15 events per 1000 patient-days of follow-up). Frozen plasma samples were available for 43 cases and 176 controls. Elevated plasma concentration of sTM was significantly associated with TE (2.8 [1.8, 4] vs. 1.52 [1.1, 2.65] ng/mL; p = 0.001) and mortality (median [Q1, Q3], 3.32 [2.16, 4.65] vs. 1.58 [1.11, 2.73] ng/mL; p = 0.001), while D-dimer showed a specific association with TE (2.3 [0.8, 7.4] vs. 0.75 [0.4, 1.6] mcg/mL; p = 0.001). In contrast, Ang2 was not associated with any of these events. The association with thrombotic events remained in adjusted models (HR [95%CI] per unit increase, 1.24 [1.04-1.47] for sTM; 1.07 [1.03-1.10] for D-dimer). The adjusted regression model that included both biomarkers, sTM and D-dimer, improved (AUC 73%, sensitivity 77% and specificity 65% for TE diagnosis; p = 0.007) the predictive capacity of the same model without sTM. In conclusion, determination of soluble thrombomodulin along with D-dimer enhances thrombotic risk assessment in hospitalized COVID-19 patients.

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

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

Impact of direct oral anticoagulants on ROTEM® variables; a sample size-calculated experimental study

Direct oral anticoagulants (DOAC) are increasingly common, with bleeding events associated with elevated plasma concentrations. Rotational thromboelastometry (ROTEM), a point-of-care tool for assessing secondary hemostasis, has demonstrated a correlation with increasing concentrations of DOAC. However, previous studies have only partially explored this relationship. The primary aim in the current study was to investigate the impact of increasing rivaroxaban concentrations on clotting time (CT) in the EXTEM assay. The secondary aims were to investigate the impact of increasing rivaroxaban concentrations on clot formation time (CFT) and α-angle (AA) and to investigate the impact of increasing concentrations of dabigatran and apixaban on CT, CFT and AA. Blood from 12 healthy volunteers was spiked to anticipated concentrations of rivaroxaban, dabigatran and apixaban at 0, 50, 100, 200, 500 and 1000 µg/L each. Blood with these varying concentrations was analyzed in four different ROTEM assays and CT, CFT and AA were extracted. CT increased linearly with increasing concentrations of all three DOACs. Rivaroxaban and dabigatran spiked blood showed an increase in CT-EXTEM for the 200–1000µg/L concentrations, compared to baseline, and apixaban for the 500–1000 µg/L concentrations. CFT and AA were affected only in supratherapeutic concentrations for all tested DOACs and primarily in the INTEM assay. Among the tested DOACs, apixaban demonstrated the least impact on CT across all assays. In conclusion, ROTEM-derived CT measurements can serve as surrogate markers for DOAC concentrations.

Comparative Pharmacokinetic Assessment of Curcumin in Rats Following Intratracheal Instillation Versus Oral Administration: Concurrent Detection of Curcumin and Its Conjugates in Plasma by LC-MS/MS.

To establish and validate an LC-MS/MS method for the simultaneous determination of curcumin (CUR) as well as its glucuronide conjugate (COG) and sulfate conjugate (COS) in rat plasma. The method was employed to evaluate and compare the pharmacokinetic behaviors of curcumin following oral and intratracheal administration in rats. Rat plasma samples were separated by chromatography on a C18 column after protein precipitation with acetonitrile. Gradient elution with a mobile phase of 0.5 mM ammonium acetate in acetonitrile was utilized. Mass spectrometry detection incorporated an electrospray ionization (ESI) source, multiple reaction monitoring (MRM), and dual-mode (positive and negative) scanning for quantitative analysis. A total of 12 SD rats were randomly divided into two groups and were orally (20 mg/kg) or intratracheally (10 mg/kg) administrated curcumin, respectively. CUR, COG, and COS concentrations in plasma were measured to assess pharmacokinetic disparities. The method demonstrated linearity within the ranges of 2-400 ng/mL for CUR and COS and 5-1000 ng/mL for COG. Intratracheal administration significantly elevated CUR plasma concentrations compared to oral administration. The exposure of COG was higher than COS following oral administration. Conversely, intratracheal administration resulted in markedly higher COS exposure, with no significant difference in COG exposure after dose normalization between oral and inhalation routes. The established LC-MS/MS method provides a reliable tool for the simultaneous measurement of CUR, COG, and COS in rat plasma, facilitating preclinical pharmacokinetic investigations. The study reveals distinct pharmacokinetic profiles for CUR following oral versus intratracheal administration, suggesting that inhalation may offer superior therapeutic efficacy.

Th1 polarization in Bordetella pertussis vaccine responses is maintained through a positive feedback loop.

Outbreaks of Bordetella pertussis (BP), the causative agent of whooping cough, continue despite broad vaccination coverage and have been increasing since vaccination switched from whole-BP (wP) to acellular BP (aP) vaccines. wP vaccination has been associated with more durable protective immunity and an induced Th1 polarized memory T cell response. Here, a multi-omics approach was applied to profile the immune response of 30 wP and 31 aP-primed individuals and identify correlates of T cell polarization before and after Tdap booster vaccination. We found that transcriptional changes indicating an interferon response on day 1 post-booster along with elevated plasma concentrations of IFN-γ and interferon-induced chemokines that peaked at day 1-3 post-booster correlated best with the Th1 polarization of the vaccine-induced memory T cell response on day 28. Our studies suggest that wP-primed individuals maintain their Th1 polarization through this early memory interferon response. This suggests that stimulating the interferon pathway during vaccination could be an effective strategy to elicit a predominant Th1 response in aP-primed individuals that protects better against infection.