Exploring S100A8/A9, Neopterin, and MMP3 in Familial Mediterranean Fever.

Familial mediterranean fever (FMF) is characterized by inflammatory attacks due to overactivation of pyrin inflammasome. This study aimed to investigate the reliability of S100A8/A9, neopterin, and matrix metalloproteinase 3 (MMP3) at monitoring subclinical inflammation and disease activity, and at differentiating FMF attacks from appendicitis, the most common misdiagnosis among FMF patients. Blood samples (n=75), comprising from FMF patients during an attack (n=20), the same FMF patients during the attack-free period (n=14), patients with appendicitis (n=24), and healthy volunteers (n=17) were obtained. Duplicate determinations of S100A8/A9, neopterin, and MMP-3 levels were conducted using the enzyme-linked immunosorbent assay (ELISA). FMF patients with and without attack and patients with appendicitis had significantly elevated S100A8/A9 levels compared to healthy volunteers (p-values: <0.001, 0.036, 0.002, respectively). Patients with appendicitis and FMF patients with and without attack had significantly increased serum neopterin levels compared to healthy volunteers (p-value: <0.001). MMP3 levels were significantly higher among patients with appendicitis and FMF patients during attack compared to healthy controls (p-values: <0.001, 0.001). Serum levels of S100A8/A9, neopterin, and MMP3 were increased significantly during attacks compared to attack-free periods among FMF patients (p-values: 0.03, 0.047, 0.007). S100A8/A9 emerges as a valuable marker for monitoring disease activity. Neopterin and S100A8/A9 might help physicians to monitor subclinical inflammation during the attack-free periods of FMF patients. MMP3 might aid in diagnosing FMF attacks when distinguishing between attack and attack-free periods is challenging.

Quantification of Enteric Dysfunction in Cystic Fibrosis: Inter- and Intraindividual Variability.

OBJECTIVES: To test the utility of various biomarkers as indicators of gut dysfunction in cystic fibrosis (CF) and determine whether intraindividual variations in these measures are repeatable over short intervals and whether interindividual variations correlate with clinical outcomes. STUDY DESIGN: We performed a cross-sectional, limited longitudinal study of children with CF aged 1-21 years who provided blood and stool samples at 2 or 3 visits, 2 weeks and 3 months apart, which were assayed for markers of intestinal inflammation (fecal calprotectin [fCal], lipocalin-2 [fLcn2], neopterin), and permeability (plasma lipopolysaccharide [LPS] antibodies, LPS-binding protein) by enzyme immunoassays. Control specimens were obtained from children without CF who had undergone esophagogastroduodenoscopy and had no evidence of gut inflammation. RESULTS: Twenty-six of 29 participants with CF completed the study. Sixty-nine stools (57 case/12 control) and 76 plasmas (60 case/16 control) were analyzed. LPS antibody had reliable intraindividual stability. fCal, fLcn2, and neopterin were significantly greater in CF than in control samples. fCal was negatively correlated with 3-month interval change (Δ) in weight-for-age z-score, body mass index/weight-for-length z-score, and forced expiratory volume in 1 second. fLcn2 was negatively correlated with FEV1 but not with anthropometrics. No marker correlated with Δbody mass index/weight-for-length z-score or ΔFEV1. CONCLUSIONS: fLcn2 is elevated in people with CF and might predict worse interval pulmonary function. Expanded studies are warranted to test if fLcn2 correlates with changes in additional outcomes.

Neopterin in patients with COPD, asthma, and ACO: association with endothelial and lung functions.

BACKGROUND AND OBJECTIVE: Endothelial dysfunction has been widely recognized in chronic airway diseases, including chronic obstructive pulmonary disease (COPD) and asthma; however, it remains unclear in asthma-COPD overlap (ACO). Neopterin (NP), a metabolite of guanosine triphosphate, is a novel biomarker for identifying the increased risk of adverse cardiovascular events. This study aims to investigate the association of NP with endothelial dysfunction and impaired lung function in COPD, asthma, and ACO patients. METHODS: A total of 77 subjects were prospectively recruited. All the participants underwent lung function test, endothelial function evaluation, including pulse wave velocity (PWV) and flow-mediated dilation (FMD), and blood sample detection. Moreover, the effect of NP on endothelial cells (ECs) in anoxic environments was assessed in vitro. RESULTS: Endothelial function was significantly decreased in the COPD and ACO patients compared with that in the healthy controls (P < 0.05). Forced expiratory volume in 1 s (FEV1) was negatively correlated with PWV and positively correlated with FMD (P < 0.05). NP was significantly increased in patients with chronic respiratory diseases compared with that in the control group, with COPD being the highest, followed by asthma, and ACO as the last (P < 0.05). The plasma level of NP exhibited negative correlations with FEV1 and positive correlations with PWV (P < 0.05). In vitro, a high level of NP increased the reactive oxygen species (ROS) and decreased the mitochondrial membrane potential (ΔΨm) of ECs dose-dependently in a hypoxic environment (P < 0.05). CONCLUSION: NP was related to disease severity of chronic airway diseases and involved in the pathogenesis of endothelial dysfunction. A high NP level may contribute to endothelial dysfunction by increasing the oxidative stress of ECs dose-dependently in a hypoxic environment. Our findings may provide a novel evaluation and therapeutic target for endothelial dysfunction related to chronic airway diseases.

Neopterin, kynurenine metabolites, and indexes related to vitamin B6 are associated with post-stroke cognitive impairment: The Nor-COAST study.

BACKGROUND AND AIMS: We have previously shown that systemic inflammation was associated with post-stroke cognitive impairment (PSCI). Because neopterin, kynurenine pathway (KP) metabolites, and B6 vitamers are linked to inflammation, in our study we investigated whether those biomarkers were associated with PSCI. MATERIAL AND METHODS: The Norwegian Cognitive Impairment After Stroke study is a prospective multicenter cohort study of patients with acute stroke recruited from May 2015 through March 2017. Plasma samples of 422 participants (59 % male) with ischemic stroke from the index hospital stay and 3 months post-stroke were available for analyses of neopterin, KP metabolites, and B6 vitamers using liquid chromatography-tandem mass spectrometry. Mixed linear regression analyses adjusted for age, sex, and creatinine, were used to assess whether there were associations between those biomarkers and cognitive outcomes, measured by the Montreal Cognitive Assessment scale (MoCA) at 3-, 18-, and 36-month follow-up. RESULTS: Participants had a mean (SD) age of 72 (12) years, with a mean (SD) National Institutes of HealthStroke Scale score of 2.7 (3.6) at Day 1. Higher baseline values of quinolinic acid, PAr (i.e., an inflammatory marker based on vitamin B6 metabolites), and HKr (i.e., a marker of functional vitamin B6 status based on selected KP metabolites) were associated with lower MoCA score at 3, 18, and 36 months post-stroke (p < 0.01). Higher baseline concentrations of neopterin and 3-hydroxykynurenine were associated with lower MoCA scores at 18 and 36 months, and higher concentrations of xanthurenic acid were associated with higher MoCA score at 36 months (p < 0.01). At 3 months post-stroke, higher concentrations of neopterin and lower values of pyridoxal 5́-phosphate were associated with lower MoCA scores at 18- and 36-month follow-up, while lower concentrations of picolinic acid were associated with a lower MoCA score at 36 months (p < 0.01). CONCLUSION: Biomarkers and metabolites of systemic inflammation, including biomarkers of cellular immune activation, indexes of vitamin B6 homeostasis, and several neuroactive metabolites of the KP pathway, were associated with PSCI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02650531.

Modulation of cell-mediated immunity during pregnancy in wild bonobos.

During pregnancy, the mammalian immune system must simultaneously protect against pathogens while being accommodating to the foreign fetal tissues. Our current understanding of this immune modulation derives predominantly from industrialized human populations and laboratory animals. However, their environments differ considerably from the pathogen-rich, resource-scarce environments in which pregnancy and the immune system co-evolved. For a better understanding of immune modulation during pregnancy in challenging environments, we measured urinary neopterin, a biomarker of cell-mediated immune responses, in 10 wild female bonobos (Pan paniscus) before, during and after pregnancy. Bonobos, sharing evolutionary roots and pregnancy characteristics with humans, serve as an ideal model for such investigation. Despite distinct environments, we hypothesized that cell-mediated immune modulation during pregnancy is similar between bonobos and humans. As predicted, neopterin levels were higher during than outside of pregnancy, and highest in the third trimester, with a significant decline post-partum. Our findings suggest shared mechanisms of cell-mediated immune modulation during pregnancy in bonobos and humans that are robust despite distinct environmental conditions. We propose that these patterns indicate shared immunological processes during pregnancy among hominins, and possibly other primates. This finding enhances our understanding of reproductive immunology.

Neopterin production in relation to COVID-19 in the Haut-Ogooué Province, Gabon.

BACKGROUND: In sub-Saharan Africa, understanding of the immune process associated with the COVID-19 pandemic remains scarce. This study aimed to investigate the relationship between plasma neopterin concentrations and COVID-19 infection, focusing on changes over time and age-related changes in immune response. METHODS: A retrospective case study was conducted during the first wave of COVID-19 from March to August 2020. Whole blood and associated symptoms and comorbidities were collected from patients of all ages and sexes. Concentrations of plasma neopterin were measured using a commercial competitive neopterin ELISA (Neopterin ELISA, IBL International GmbH, Germany). RESULTS: We analyzed data for 325 patients: 38% (n = 124) with COVID-19, and 62% (n = 201) without COVID-19, as a control group. We found that plasma neopterin concentrations were significantly higher in the COVID-19 group (mean value 45.1 nmol/L (SD 19)) than in the control group (mean value 33.8 nmol/L (SD 13)) (p = 0.004). In addition, neopterin levels decreased gradually over time in patients with COVID-19 (p < 0.001). Moreover, ROC analysis found that the best cut-off value for diagnosing COVID-19 patients based on plasma neopterin levels was 38.85 nmol/L with 70% sensitivity and 82% specificity (AUC, 0.74 [0.69-0.82], p < 0.05). We also found an increase in neopterin production with increasing age (p < 0.001). CONCLUSION: Our findings contribute to our growing understanding of neopterin levels as a promising biomarker for the detection of COVID-19 cases in sub-Saharan Africa.

Biological variation of serum neopterin concentrations in apparently healthy individuals.

OBJECTIVES: The aims of this study were to determine the biological variation (BV), reference change value (RCV), index of individuality (II), and quality specifications for serum neopterin concentrations; a measurand provided by clinical laboratories as an indicator of cellular immunity. METHODS: The study delivered serum samples collected for 10 consecutive weeks from 12 apparently healthy individuals (3 male, 9 female). Serum neopterin concentrations were measured using high-performance liquid chromatography with fluorometric detection. The data analysis was performed using an online statistical tool and addressed published criteria for estimation of biological variation. RESULTS: The mean neopterin concentration was 5.26 nmol/L. The within-subject biological variation (CVI) with 95 % confidence interval (CI) of neopterin serum concentrations was 11.54 % (9.98-13.59), and the between-subject biological variation (CVG) with 95 % CI was 43.27 % (30.52-73.67). The neopterin asymmetrical RCV was -24.9 %/+33.1 %, and the II was 0.27. The desirable quality specifications for neopterin were <5.77 % for precision, <11.20 % for bias, and <20.72 % for total allowable error (TEa). When analytical variation was used instead of CVI to calculate TEa, the desirable TEa was <18.39. CONCLUSIONS: This study determined BV data for neopterin, an indicator of cell-mediated immune response. Asymmetric RCV values, of 24.9 % decrease or a 33.1 % increase between consecutive measurements indicate significant change. The II of 0.27 indicates a high degree of individuality, therefore that it is appropriate to consider the use of personal reference data and significance of change rather than the reference interval as points of reference for the evaluation of neopterin serum concentrations.

Evaluation of inflammatory biomarkers and vitamins in hospitalized patients with SARS-CoV-2 infection and post-COVID syndrome.

OBJECTIVES: Concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios predict prognosis and the need for oxygen therapy in patients hospitalized for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The aims of the present study were to evaluate the changes of these biomarkers early in the course of infection, the association with the prior coronavirus disease (COVID-19) vaccination and therapeutic administration of Anti-SARS-CoV-2 monoclonal antibodies, investigation of other potential biomarkers including neuropilin, 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanosine in patients hospitalized with SARS-CoV-2 infection and an assessment of these biomarkers and vitamins A, E and D in patients with post-COVID syndrome. METHODS: Urine and blood samples were obtained on the 1st to the 4th day and 4th to 7th day from 108 patients hospitalized with COVID-19. Chromatography tandem mass spectrometry methods were used to analyse neopterin, kynurenine, tryptophan, liposoluble vitamins, and DNA damage biomarkers. RESULTS: A statistically significant decrease of neopterin, kynurenine and kynurenine/tryptophan ratios was observed on after 4th to 7th day of hospitalization, and concentrations of these biomarkers were increased in patients with poor prognosis and subsequent post-COVID syndrome. The concentrations of remaining biomarker and vitamins were not associated with outcomes, although markedly decreased concentrations of vitamin A, E and D were noted. CONCLUSIONS: The concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios decrease during the course of infection SARS-CoV-2 and are associated with the post-COVID syndrome. No other prognostic biomarkers were identified.

Adjunctive silymarin supplementation and its effects on disease severity, oxidative stress, and inflammation in patients with Alzheimer's disease.

BACKGROUND: Brain tissue in Alzheimer's patients is exposed to oxidative stress. Silymarin is an adjunct drug that has anti-inflammatory and antioxidant properties. OBJECTIVE: This study aimed to evaluate the effect of silymarin on biomarkers of oxidative stress, inflammation, and disease severity in Alzheimer's patients. METHODS: This randomized, single-blind clinical trial study was performed on 33 patients with Alzheimer's disease (AD) whose disease was confirmed by DSM-5 criteria and by brain imaging. Patients in the case group received three 250 mg silymarin capsules daily (each containing 150 mg silymarin), as an adjunctive medication in addition to the routine medication regimen. In the placebo group (control), patients received the same amount of placebo. All patients underwent Mini Mental State Exam (MMSE) and a panel of blood tests including malondialdehyde, neopterin, catalase, paraoxonase-1, total oxidative status, and total antioxidant capacity to reevaluate the changes pre/postintervention at the end of the trimester. RESULTS: The catalase and MDA serum levels after the adjunctive silymarin treatment decreased significantly (Catalasebefore silymarin = 9.29 ± 7.02 vs Catalaseafter silymarin = 5.32 ± 2.97, p = 0.007 and MDAbefore silymarin = 4.29 ± 1.90 vs MDAafter silymarin = 1.66 ± 0.84, p < 0.001) while MMSE increased notably (MMSEbefore silymarin = 10.39 ± 6.42 vs MMSEafter silymarin = 13.37 ± 6.81, p < 0.001). CONCLUSION: Silymarin can be effective as an adjunct drug and a powerful antioxidant in reducing oxidative stress and improving the course of AD.

Neopterin, 7,8-dihydroneopterin, total neopterin levels and their ratio in periodontitis: New dilemma.

OBJECTIVE: Determine the saliva and serum levels of neopterin (NP) and 7,8-dihydroneopterin (7,8NP) in periodontitis patients and to reveal the relationship of these data with clinical periodontal parameters. MATERIALS AND METHODS: Twenty-three patients with stage III/grade B periodontitis and 23 periodontally healthy individuals were included. Clinical periodontal measurements were recorded (plaque index, pocket depth, clinical attachment loss & bleeding on probing). Saliva and serum levels of NP and 7,8NP were analyzed by high-performance liquid chromatography. RESULTS: Saliva NP, 7,8NP and Total Neopterin (TNP) levels were significantly elevated in the periodontitis than the control group (p < 0.001).ROC analyses of saliva NP, 7,8NP and TNP yielded areas under the curves of 0.873-0.938 for discriminating periodontitis from health, and saliva TNP was found the most accurate biomarker (AUC = 0.938).There was no significant difference among the periodontitis and control groups for saliva TNP/NP and TNP/7,8NP ratios and serum NP, 7,8NP and TNP levels (p > 0.05). CONCLUSION: Increased saliva TNP, NP and 7,8NP levels in periodontitis may suggest these biomarkers are regulating immune activation and oxidative stress mechanism in periodontal inflammation. Additionally, together with these results, equivalence of the TNP/NP ratio in intergroups may suggest that the effects of immune activation and oxidative stress mechanisms are equal in the periodontitis.

Verification studies of tryptophan and kynurenine determination using HPLC and evaluation of the kynurenine pathway and neopterin levels in human colostrum samples.

Colostrum, the first breast fluid produced by mammals after giving birth, is followed by breast milk, which serves as the sole source of nutrients for breastfed newborns and infants. Tryptophan, an essential amino acid, plays a crucial role in the development and maturation of the central nervous system in infants. Tryptophan is primarily degraded through the kynurenine pathway. Owing to its sensitivity to dietary intake, immune-mediated tryptophan degradation is assessed by the kynurenine-to-tryptophan ratio, with a focus on one of the rate-limiting enzymes in the pathway. This study involved the validation of the simultaneous determination of tryptophan and kynurenine using HPLC. The validated method was then used to detect levels of tryptophan and kynurenine, as well as to calculate the kynurenine-to-tryptophan ratio in colostrum samples. Simultaneously, these results were compared with colostrum neopterin levels measured using commercial enzyme-linked immunosorbent assay kits. The mean levels for tryptophan, kynurenine, and neopterin were 17.3 ± 62.4 µM, 0.45 ± 0.03 µM, and 28.9 ± 2.6 nM, respectively. This study is among the few that have evaluated these parameters in colostrum samples. Neopterin levels secreted by the mammary gland were found not to be correlated with tryptophan degradation, a process influenced by the mother's nutritional status.

Exploring oxidative stress, immunological and metabolic biomarkers in dairy cows with postpartum pyometra.

Pyometra is a prevalent and severe infectious disease that affects the reproductive systems of cattle worldwide. This study's main goal was to investigate the biomarkers for oxidative stress (OS), adiponectin, leptin and neopterin (NPT) in cows suffering from postpartum pyometra. The study also aimed to determine which bacteria were most commonly implicated in the development of the disease. A total of 74 cows with pyometra were examined and compared to a control group of healthy cows (n = 20). In comparison to the healthy control and post-treatment groups, the pyometra group showed higher mean values of leptin, adiponectin and malondialdehyde (MDA). In contrast, the glutathione (GSH) and superoxide dismutase (SOD) mean values were lower in the pyometra group as compared to the post-treatment and control groups. NPT levels in the post-treatment groups were lower than those in cows with pyometra but comparable to the healthy control group (p > .05). When compared to the other biomarkers, NPT, leptin and adiponectin showed higher sensitivity and specificity in identifying pyometra cases (AUC ≥0.99). The predominant bacterial isolates from the ptomtra-affected cows consisted of Escherichia coli (N = 29; 39.2%), Arcanobacterium pyogenes (N = 27; 36.5%) and Fusobacterium necrophorum (N = 13; 17.6%). Mixed infection was determined in nine samples (12.2%). Conclusively, OS, adiponectin, leptin and NPT play crucial roles in comprehending the development of postpartum pyometra in cows and have the potential to serve as biomarkers for the disease.

Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers.

INTRODUCTION: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. OBJECTIVES: To identify central nervous system (CNS) disease biomarkers of j-NPSLE. METHODS: A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. RESULTS: Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (Rs = 0.832, p < 0.0001, n = 23 paired samples). CONCLUSION: CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE.

Increased neopterin in cerebrospinal fluid in active adult neurohistiocytosis.

Diagnosis of neuro-histiocytosis is challenging and relies on clinical presentation, imaging, and cerebrospinal fluid (CSF) analysis to exclude differential diagnoses. Brain biopsy remains the gold standard for accurate diagnosis, but it is rarely performed because of the risk of the procedure and the low rentability in neurodegenerative presentation. Therefore, there is an unmet need to identify a specific biomarker for diagnosing neurohistiocytosis in adults. Because microglia (brain macrophages) is involved in the pathogenesis of neurohistiocytosis and produces neopterin secondary to aggression, the purpose of our study was to evaluate the value of the CSF neopterin levels for the diagnosis of active neurohistiocytosis. Of the 21 adult patients with histiocytosis, four patients had clinical symptoms compatible with neurohistiocytosis. In the two patients with a confirmed diagnosis of neurohistiocytosis, CSF neopterin levels were elevated as well as IL-6 and IL-10 levels. In contrast, the two other patients in whom the diagnosis of neurohistiocytosis was infirmed and all other patients with histiocytosis without active neurological disease involvement had normal CSF neopterin levels. In summary, increased CSF neopterin concentration represented a valuable tool for diagnosing active neuro-histiocytosis in adults with histiocytic neoplasms in this preliminary study.

Pre-analytical long-term stability of neopterin and neurofilament light in stored cerebrospinal fluid samples.

OBJECTIVES: The aim of this study was to evaluate the impact of long-term sample storage on the concentrations of neopterin and neurofilament light (Nfl) in cerebrospinal fluid (CSF) samples. These are useful markers of neuroinflammation and neuronal damage and have been applied as biomarkers for several neurological diseases. However, different pre-analytical variables have potential to influence results. METHODS: Twenty-one CSF samples donated by patients with HTLV-1-associated myelopathy (HAM) and stored for up to 11 years at -80 °C were retested after three-years for neopterin (n=10) and Nfl (n=11) by ELISA. RESULTS: There was a strong correlation between the paired results (r>0.98, p<0.0001). Neopterin concentrations (nmol/L) ranged from 12.4 to 64 initially and from 11.5 to 64.4 when retested, with means (SD) of 30 (18.4) 1st test and 33 (19.1) 2nd test. Nfl concentrations (pg/mL) ranged from 79.9 to 3,733 initially and from 86.3 to 3,332, when retested with means (SD) of 1,138 (1,272) 1st test and 1,009 (1,114) at re-test. CONCLUSIONS: Storing CSF samples at -80 °C appears not to impact the quantification of neopterin and Nfl allowing confidence in the reporting of archived samples.

Neopterin and kynurenine in serum and urine as prognostic biomarkers in hospitalized patients with delta and omicron variant SARS-CoV-2 infection.

OBJECTIVES: Currently, no biomarker or scoring system could clearly identify patients at risk of progression to a severe coronavirus disease (COVID)-19. Even in patients with known risk factors, the fulminant course cannot be predicted with certainty. Analysis of commonly determined clinical parameters (frailty score, age, or body mass index) together with routine biomarkers of host response (C-reactive protein and viral nucleocapsid protein) in combination with new biomarkers neopterin, kynurenine, and tryptophan, could aid in predicting the patient outcome. METHODS: In 2021 and 2022, urine and serum samples were prospectively collected on 1st to 4th day after hospital admission in 108 consecutive COVID-19 patients hospitalized at the University Hospital Hradec Králové, Czech Republic. Delta and omicron virus variants were studied. Neopterin, kynurenine and tryptophan were determined by liquid chromatography. RESULTS: A significant correlation was observed between urinary and serum biomarker concentrations. Urinary and serum neopterin, kynurenine and kynurenine/tryptophan ratio were significantly (p≤0.05) higher in patients who subsequently needed oxygen therapy vs. patients without oxygen therapy. These parameters were also significantly increased in patients who died during the hospitalization compared to survivors. Complex equations have been derived using the investigated biomarkers and other clinical or laboratory parameters to predict the risk of subsequent oxygen therapy or death during hospitalization. CONCLUSIONS: Present data demonstrate that neopterin, kynurenine and kynurenine/tryptophan ratio in the serum or in the urine represent promising biomarkers in the management of COVID-19 that may help to guide important therapeutic decisions.

Urinary neopterin and biopterin indicate that inflammation has a role in autism spectrum disorder.

Inflammation is thought to be involved in the pathogenesis of autism spectrum disorder (ASD). Pteridine metabolites are biomarkers of inflammation that increase on immune system activation. In this study, we investigated the urinary pteridine metabolites in ASD patients as a possible biomarker for immune activation and inflammation. This observational, cross-sectional, prospective study collected urine samples from 212 patients with ASD and 68 age- and sex-matched healthy individuals. Urine neopterin (NE) and biopterin (BIO) levels were measured. Patients who had chronic disorders, active infection at the time of sampling, or high C-reactive protein levels were excluded. The urine NE and BIO concentrations were determined by high-performance liquid chromatography. The ratios of both NE and BIO to creatinine (CRE) were used to standardise the measurements. The NE/CRE and NE/BIO levels were significantly higher in ASD patients than controls. Univariate and multivariate models revealed a significant increase in NE/CRE and NE/BIO in ASD patients. There was a significant relationship between the NE/BIO [average area under the curve (AUC) = 0.717; range: 0.637-0.797] and NE/CRE (average AUC = 0.756; range: 0.684-0.828) ratios, which distinguished individuals with ASD from controls. The elevated NE/CRE and NE/BIO ratios suggest that inflammation and T cell-mediated immunity are involved in the pathophysiology of autism. NE/BIO could serve as a diagnostic inflammatory marker in the pathogenesis of ASD.

Early assessment of extremity compartment syndrome by biochemical markers in a rat model.

BACKGROUND: This experimental study aimed to define a biochemical marker that will enable early diagnosis of acute compartment syndrome (ACS) of extremities, a mortal condition that occurs due to trauma. METHODS: A total of 15 Wistar rats were included in the study in which saline infusion technique, a clinically compatible ACS model, was applied. After the rats were anesthetized with ketamine-xylazine, the in-compartment pressure of the hind limb was slowly increased with saline delivered through the angiocatheter, and after reaching the target compartment pressure, the pressure level was kept with a rubber tourniquet. The in-compartment pressure level was continuously monitored with a pressure transducer. The rats were divided into three groups. No intervention was applied to the control group (CG) (n = 3). In study group 1 (SG1) (n = 6), ACS was created using the saline infusion technique, keeping the in-compartment pressure between 30 and 40 mmHg for 45 min. In study group 2 (SG2) (n = 6), ACS was created using the saline infusion technique, keeping the in-compartment pressure between 30 and 40 mmHg for 90 min. Fasciotomy was performed on all rats. Tissue samples were obtained for histopathological examination and blood samples for biochemical analysis. RESULTS: Total oxidant status (TOS) (p = 0.004), ischemia-modified albumin (IMA) (p = 0.030), aspartate transferase (AST) (p = 0.003) and neopterin (p = 0.012) levels differed significantly between groups in the early period of muscle ischemia. In fact, TOS levels differed significantly between the groups even in the cellular phase where signs of ischemia were not observed (p = 0.048, p = 0.024). According to histopathological evaluation, there was no significant difference between the groups. DISCUSSION: TOS can be detected in the early reversible stage of ischemia, when the histopathological findings of ACS do not occur.

Cellular immunity in subacute thyroiditis: a new perspective through neopterin.

Subacute thyroiditis (SAT) is an inflammatory disorder of the thyroid gland. Although its etiology is not fully understood, it is believed to occur shortly after viral infections and is mostly associated with human leukocyte antigen (HLA)-B*35. Cellular immunity is prominent in SAT. Neopterin is produced by activated monocytes/macrophages and is a marker of cellular immunity. Its production is stimulated by interferon gamma (IFN-γ), provided mainly by activated helper T lymphocytes type 1 (Th1) in the adaptive immune system. Therefore, with these cells' activation, an increase in serum neopterin levels is expected. We aimed to evaluate neopterin levels in demonstrating cellular immunity in SAT and compared 15 SAT patients with 16 healthy controls. Since all SAT patients were in the active thyrotoxic phase, we found a significant difference in thyroid functions. Classical inflammatory markers, erythrocyte sedimentation rate, and C-reactive protein were markedly elevated in the patient group. Although we expected to find an increase considering that cellular immunity is at the forefront in the pathogenesis of SAT, we found serum neopterin levels significantly lower in the patient group than in the control group. There is an increase in CD8+ T cells in the thyroid tissue in SAT. The possible relationship with HLA-B*35- major histocompatibility complex class I in SAT, and the antigen presentation to CD8+ T cells may be the reason why we observed low serum neopterin levels in patients due to the cytokine imbalance. Neopterin provides unique and independent data from classical acute phase response indicators.

Correlations between cerebrospinal fluid biomarkers, neurocognitive tests, and resting-state electroencephalography (rsEEG) in patients with HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorders (HAND) are highly prevalent in people living with HIV (PLWH) despite successful treatment with combination antiretroviral therapy (cART). HAND pathogenesis is complex and definitive surrogate biomarkers are not clearly defined. Brain function has been assessed through the evaluation of cortical source rhythms with delta waves associated with neurological impairment. The aim of this study was to assess the correlation between EEG cortical sources, cerebrospinal fluid (CSF) biomarkers, and neurocognitive tests in PLWH with HAND. PLWH with HAND without significant comorbidities were enrolled. Baseline rsEEG-LORETA waves, CSF biomarkers (t-tau, p-tau, ß-amiloid42, neopterin, S100ß), and neurocognitive tests were correlated and compared through non-parametric tests (Spearman's rho and Mann-Whitney); data are presented as medians (interquartile ranges). Fifty-four patients were enrolled. Median time of suppressed HIV-RNA and CD4+ T-lymphocyte were 10 years (5.5-15) and 691/uL (477-929). Thirty-nine participants (72%) underwent CSF collection: abnormal biomarkers were found in a small percentage. Only neopterin showed a statistically significant correlation with delta activity [parietal (rho 0.579; p < 0.001), occipital (rho 0.493; p = 0.007), and global sources (rho 0.464 p = 0.011)]. Seven patients (12.9%) showed an abnormal neopterin level (> 1.5 ng/mL) with significantly higher delta source activity compared to the ones with in-range concentrations. We observed a statistically significant correlation between working memory test Trail Making B with both CSF neopterin levels and delta waves (p values < 0.05). In a small sample of PLWH with HAND, we observed that higher CSF neopterin levels were associated with higher EEG delta waves and worse working memory tests.