Marker Of Disease Research Articles

Quality of life, fatigue and markers in sarcoidosis: A section from Turkey.

Sarcoidosis can affect every organ with varying frequency based on ethnicity, gender and age. We aimed to evaluate the health-related quality of life (HRQoL) and fatigue levels of our sarcoidosis patients. However, our second aim is to determine whether patient or disease markers correlate with quality of life assessment questionnaires. Pulmonary sarcoidosis patients who were followed up in the chest diseases outpatient clinic of our hospital were included in this prospective study. In the follow-up of 2023, routine blood tests, angiotensin-converting enzyme (ACE), posteroanterior lung (thorax computed tomography in patients with parenchymal involvement) were requested from the patients. Participants were asked to fill out the short-form 36-item questionnaire (SF-36), fatigue assessment scale (FAS) and fatigue severity scale (FSS) under the control of the outpatient clinic. A total of 189 patients, 139 (73.5%) female and 50 (26.5%) male, diagnosed with Sarcoidosis were included. The mean age of our patients was 53.1±13.6. ACE (IU/L) 68.5±44.5. Of the patients we followed up for pulmonary sarcoidosis, 111 (58.7%) had single organ involvement and 78 (41.3%) had additional organ involvement. FAS; It was high in 103 (64.3%) patients and 29 (15.3%) were very tired. FSS value was 4.45±0.7 (3-5.88). All SF-36 parameters were lower than expected; MH and SF was minimally lower, PF, RP, BP, GH, RE and VT were significantly lower. SF-36 scores were found to be lower in the women and additional organ involvement participating. We found a significant decrease in HRQoL and an increase in fatigue scores of our patients. These changes were more pronounced in women participating in the study than in men. In addition, the involvement of additional organs with the lung negatively affected the quality of life.

Heterogeneity and Penumbra of White Matter Hyperintensities in Small Vessel Diseases Determined by Quantitative MRI.

White matter hyperintensities (WMHs) are established structural imaging markers of cerebral small vessel disease. The pathophysiologic condition of brain tissue varies over the core, the vicinity, and the subtypes of WMH and cannot be interpreted from conventional magnetic resonance imaging. We aim to improve our pathophysiologic understanding of WMHs and the adjacently injured normal-appearing white matter in terms of microstructural and microvascular alterations using quantitative magnetic resonance imaging in patients with sporadic and genetic cerebral small vessel disease. Structural T2-weighted imaging, multishell diffusion imaging, and dynamic contrast-enhanced magnetic resonance imaging were performed at 3T in 44 participants with sporadic cerebral small vessel disease and 32 participants with monogenic cerebral small vessel disease (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; 59±12 years, 41 males) between June 2017 and May 2020 as part of the prospective, multicenter (Edinburgh, the United Kingdom; Maastricht, the Netherlands; and Munich, Germany), observational INVESTIGATE-SVDs study (Imaging Neurovascular, Endothelial and Structural Integrity in Preparation to Treat Small Vessel Diseases). The mean diffusivity, free water content, and perfusion (all derived from multishell diffusion imaging), as well as the blood-brain barrier leakage and plasma volume fraction (derived from dynamic contrast-enhanced magnetic resonance imaging), were compared between deep and periventricular WMH types using paired t tests. Additional spatial analyses were performed inside and outside the WMH types to determine the internal heterogeneity and the extent of the penumbras, that is, adjacent white matter at risk for conversion to WMH. Periventricular WMH had higher mean diffusivity, higher free water content, and more plasma volume compared with deep WMH (P<0.001, P=0.01, and P<0.001, respectively). No differences were observed in perfusion (P=0.94) and blood-brain barrier leakage (P=0.65) between periventricular and deep WMHs. The spatial analyses inside WMH and the adjacent white matter revealed a gradual gradient in white matter microstructure, free water content, perfusion, and plasma volume but not in blood-brain barrier leakage. We showed different pathophysiological heterogeneity of the 2 WMH types. Periventricular WMHs display more severe damage and fluid accumulation compared with deep WMH, whereas deep WMHs reflect stronger hypoperfusion in the lesion's core. URL: https://www.isrctn.com; Unique identifier: ISRCTN10514229.

Longitudinal changes in white matter free water in cerebral small vessel disease: Relationship to cerebral blood flow and white matter fiber alterations.

White matter (WM) free water (FW) is a potential imaging marker for cerebral small vessel disease (CSVD). This study aimed to characterize longitudinal changes in WM FW and investigate factors contributing to its elevation in CSVD. We included 80 CSVD patients and 40 normal controls (NCs) with multi-modality MRI data. Cerebral blood flow (CBF) was measured, and fiber alterations were assessed using total apparent fiber density (AFDt). FW were extracted from whole WM, white matter hyperintensities (WMH) and normal-appearing WM (NAWM). Baseline and longitudinal FW elevation were compared between patients and NCs, and between WMH and NAWM. We investigated whether baseline vascular risk factor score, CBF, and AFDt could predict longitudinal FW elevation. Association between cognition and WM FW in CSVD was also assessed. Results shown that FW was higher and increased faster in CSVD compared to NCs and in WMH compared to NAWM. Baseline AFDt predicted longitudinal FW elevation in CSVD patients, while CBF predicted FW changes only in controls. WM FW was associated with cognitive impairment. These findings suggest that CSVD is associated with a faster increase in WM FW. Hypoperfusion and WM fiber alterations might accelerate FW elevation, which is associated with cognitive decline.

NOTCH3 variants of unknown significance underpin vascular dysfunction in neurodegenerative disease: a case series of three nfvPPA-FTD patients.

The NOTCH3 gene encodes for an evolutionarily conserved protein, whose functions encompass both embryonic cell proliferation and adult tissue-specific differentiation. Among others, a pivotal role in maintaining functional integrity of neurovascular unit (NVU) is supported by the association of several NOTCH3 gene mutations with neuroimaging markers of cerebral small vessel disease (SVD). Indeed, a pathogenic role of NOTCH3 is recognised in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, an increasing number of NOTCH3 variants with unclear pathogenic role have been identified in patients suspected of having CADASIL. The following case series describes three patients under the age of 65 with clinical diagnosis of nonfluent-variant of primary progressive aphasia (nfvPPA), whose genetic analysis revealed the presence of three distinct novel variants of unknown significance (VUS) in NOTCH3 gene. The diagnostic work-up revealed common features among the patients: clinical presentation -nfvPPA at neuropsychological evaluation with consistent extrapyramidal symptoms; neuroimaging -low brain MR burden of SVD and FDG-PET impairment of cortical areas involved in speech production network; and biomarkers -Cerebrospinal fluid (CSF) analysis negative for Alzheimer's Disease (AD), corroborating suspicion of underlying Frontotemporal Lobe Degeneration (FTLD). The retrieved VUS in NOTCH3 suggest that the involvement of Notch signalling in pathophysiology of neurodegenerative disease is more complex and needs to be fully explored. Rare variants in SVD-associated genes may influence progression of neurodegeneration via the dysfunction of several vascular pathways.

Evaluating Biomarkers for Diagnosis and Treatment Monitoring in Gaucher Disease

Aim/Objective: The primary goal of this study is to explore the impact of consistent treatment on key disease marker, Lyso-Gb1. Additionally, this research aims to evaluate the influence of splenectomy on Lyso-gb1 concentrations within the patient group. Materials and Methods: 37 patients diagnosed with GD were categorized based on treatment compliance into three groups: 28 in the regular treatment group, who consistently followed their treatment; 6 in the irregular treatment group, with inconsistent treatment adherence; and 3 in the untreated group. A control group of 33 healthy individuals without GD was also included. Enzyme replacement therapy was utilized as the treatment regimen. The analysis of Lyso-Gb1 levels was performed using liquid chromatography coupled with tandem mass spectrometry, ensuring high precision in measurement. Results: Lyso-Gb1 levels were significantly higher in GD patients compared to the healthy control group (p

Serum thioredoxin and lactoferrin in rheumatoid arthritis and their association with rheumatoid factor

Background: Thioredoxin (Trx) and lactoferrin (Lf) are multifunctional proteins part of the body anti-oxidant defence and counteract the oxidative tissue damage. The purpose of our study is to investigate Trx and Lf levels in serum of rheumatoid arthritis (RA) patients and establish the association of these proteins with the rheumatoid factor (RF) and other disease markers. Methods: The study included 114 patients with RA and 42 healthy subjects. Serum concentrations of Trx, Lf, RF, anti-cyclic citrullinated peptide (anti-CCP) antibodies, CRP, and IL-6 were determined using commercially available ELISA kits. Results: Serum thioredoxin levels in RA were significantly higher compared to the control group, 36.4 (29.6-40.2), ng/mL versus 19.0 (16.3-26.8), ng/mL, p &lt; 0.0001. Serum lactoferrin levels were elevated in RA compared to the control group but the difference was not statistically significant, 579.6 (312.8-947.5), ng/mL versus 519.0 (262.5-928.0), ng/mL. We found significant negative correlations of Trx and Lf with rheumatoid factor in RA (r= -0.254, p=0.05 and r= -0.238, p=0.014, respectively). The correlations of thioredoxin and lactoferrin with other disease markers such as anti-CCP antibodies, DAS28, ESR, CRP, and IL-6 were not statistically significant. A strong positive correlation between Trx and Lf was observed in the study group of RA patients (r=0.519, p&lt;0.0001), but not in the control group. Conclusions: Thioredoxin and lactoferrin were associated with rheumatoid factor, but not with anti-CCP antibodies and systemic disease activity, therefore the two proteins may serve as new biomarkers for assessment of pathological changes and monitoring of disease severity and progression in RA.

The Application of Salivary Exosomes in the Diagnosis of Oral Disease.

Oral diseases not only greatly impact patients' daily lives, but also pose a severe threat to their overall health. Due to the constant exposure of saliva to oral diseases, the former plays a vital role in their diagnosis and monitoring. Exosomes, nanosized bilayer lipid encapsulated nanovesicles, are widely present in saliva and can be released by any type of cell. Exosomes inherit features from their mother cells in both physiological and pathological conditions. The molecular characteristics and expression levels of exosomes depend on their cellular origin, and they can directly reflect the physiological state of the body and cells. This makes salivary exosomes a promising source for early detection and monitoring of oral diseases. As a result, researchers have been exploring the potential use of exosomes as biomarkers for diagnosing and predicting various oral diseases. This review provides an overview of the composition, separation and function of salivary exosomes. It also discusses their potential as diagnostic and prognostic markers for several oral diseases, including periodontitis, primary Sjögren's syndrome, oral mucosal diseases, hand-foot-mouth disease and oral squamous cell carcinoma. By studying salivary exosomes, researchers hope to improve the early detection and monitoring of oral diseases, leading to better outcomes for patients.

Peak width of skeletonized mean diffusivity as a marker of small vessel disease in patients with temporal lobe epilepsy with hippocampal sclerosis.

White matter abnormalities in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) are well known. Peak width of skeletonized mean diffusivity (PSMD) is a novel marker for quantifying white matter integrity that may reflect small vessel disease. In this study, we aimed to quantify the extent of white matter damage in patients with TLE and HS by using PSMD. We enrolled 52 patients with TLE with HS and 54 age- and sex-matched healthy controls. Diffusion tensor imaging (DTI) was performed using a 3-T magnetic resonance imaging scanner. We measured PSMD using DTI findings and compared PSMD between patients with TLE with HS and healthy controls. We also evaluated the correlation between PSMD and clinical factors in patients with TLE and HS. PSMD differed significantly between healthy controls and patients with TLE and HS, and it was higher in the patients (2.375 × 10-4 mm2/s vs. 2.108 × 10-4 mm2/s, p < .001). Furthermore, PSMD in the ipsilateral hemisphere of the HS was higher than in the contralateral hemisphere of the HS (2.472 × 10-4 mm2/s vs. 2.258 × 10-4 mm2/s, p = .040). PSMD was positively correlated with age (r = .512, p < .001) and age at seizure onset (r = .423, p = .002) in patients with TLE and HS. Patients with TLE and HS had higher PSMD values than healthy controls, and PSMD was positively correlated with age. These findings provide evidence of white matter damage probably due to small vessel disease in patients with TLE and HS and support the feasibility of PSMD as a promising imaging marker for epileptic disorders.

Advantages of a genomic DNA-based NGS assay for detection of mutant NPM1 measurable residual disease in AML.

Mutations in the Nucleophosmin-1 (NPM1) gene are among the most common molecular aberrations in acute myeloid leukemia (AML). Various studies have established mutant NPM1 (mNPM1) as a faithful molecular measurable residual disease (MRD) marker with prognostic significance. Assessment of prognostic mNPM1 is included in the European LeukemiaNet (ELN) recommendations on MRD detection in AML. Due to recent advancements of promising drugs targeting mNPM1 AML, monitoring of mNPM1 MRD has gained interest, and is generally done by reverse transcriptase quantitative PCR (RT-qPCR). However, these RT-qPCR assays use cDNA as input, are based on gene expression levels of mNPM1, and are generally limited to specific mNPM1 gene variants. The main advantages of next-generation sequencing (NGS) using genomic DNA as input are stability, independence of gene expression levels, and the ability to detect any NPM1 variant in a single assay. Here we comprehensively investigated the applicability of NGS on DNA to detect mNPM1 MRD in a cohort of 119 (cDNA) and 310 (DNA) mNPM1 AML patients in complete remission after two cycles of induction chemotherapy. We demonstrate high correlations in levels and prognostic value between RT-qPCR/cDNA and NGS/DNA approaches, postulating NGS/DNA as an attractive alternative to RT-qPCR. We report that the 2% mNPM1/ABL1 threshold by RT-qPCR/cDNA corresponds to a NGS/DNA variant allele frequency (VAF) of 0.01%. The NGS/DNA threshold of >0.01% after two cycles of induction chemotherapy identifies significantly more AML patients with an increased relapse risk than current RT-qPCR/cDNA assays. The prognostic significance of mNPM1 MRD appears greatest in FLT3-ITD AML patients.

Quantifying the Corneal Nerve Whorl Pattern.

The corneal nerves within the sub-basal nerve plexus (SBNP) display a distinctive whorl-like pattern, a highly dynamic structure that could be a marker of diseases. Previous studies have reported a decrease in whorl nerve density in patients with diabetes, indicating an avenue for noninvasive monitoring of diabetic neuropathy. However, conflicting results have since been reported, highlighting the need for improved quantitative analysis of the corneal whorl. We present an automated algorithm to characterize the whorl shape and test the hypothesis that the whorl organization is affected by diabetic neuropathy. The SBNP whorl was analyzed as a vector field, from which seven whorl metrics were calculated. The efficacy of these whorl metrics was demonstrated in synthetic images, ex vivo mouse corneas, and in a publicly available dataset of wide-field in vivo confocal microscopy (IVCM) images of diabetic and control subjects. Linear discriminant analysis and the Peacock test were used to test for statistical differences. Our analysis code is made freely available. Using our whorl metrics, we were able to quantify different whorl patterns in our patient population and statistically compare cohorts. We determined that whorl patterns tend to present bilaterally in patients (P < 0.001), but there were no significant differences between whorl patterns in patients with diabetes and control subjects, nor between patients with or without neuropathy symptoms. We present a generalizable framework to statistically compare corneal nerve patterns in cohorts of patients. SBNP whorl patterns could serve as a noninvasive marker for ocular diseases, whereas few quantitative IVCM endpoints have been identified to date.

ATP2A3 in Primary Aldosteronism: Machine Learning-Based Discovery and Functional Validation.

Aldosterone-producing adenomas (APAs) are a common cause of primary aldosteronism that can lead to cardiovascular complications if left untreated. Machine learning-based bioinformatics approaches have emerged as powerful tools for identifying potential disease markers, gaining widespread recognition in biomedical research. We aimed to use machine learning to discover novel biomarkers of APAs to identify new pathophysiological mechanisms. We applied 2 machine learning algorithms to published RNA sequencing data to identify APA feature genes. Validation was performed using APA tissue samples, spatial transcriptomics, pig adrenal glands, and in vitro assays in a human adrenocortical cell line. Machine learning identified ATP2A3 as a key feature gene in APA, and its upregulation in APAs compared with the adjacent cortex was confirmed by spatial transcriptomics. In human adrenocortical cells, angiotensin II treatment increased ATP2A3 gene expression 9.15-fold. Silencing ATP2A3 decreased basal CYP11B2 expression and aldosterone secretion by 3.51-fold and 1.46-fold, respectively, and by 1.77-fold and 1.94-fold under angiotensin II stimulation. Dietary sodium restriction in pigs significantly increased ATP2A3 mRNA and protein levels. Spatial transcriptomics showed that APA cells exhibited higher ATP2A3 gene expression compared with all other adrenal cell types. The suppressive effect of ATP2A3 silencing on CYP11B2 expression was further enhanced by Ca2+ inhibitors. The ATP2A3 gene is highly expressed in APA and is a key regulator of CYP11B2 expression and aldosterone production.

Body mass index and the prevalence of high-risk colorectal adenomas in a population undergoing screening colonoscopy in Alberta, Canada.

There is limited evidence regarding body mass index (BMI) as an early marker of high-risk adenoma (HRA) at the time of screening colonoscopy. Because high-risk adenomas (HRA) can develop into colorectal cancer (CRC), BMI could serve as an important clinical predictor of future risk of CRC. We examined data from 1831 adults undergoing screening colonoscopy at the Forzani & MacPhail Colon Cancer Screening Center in Alberta, Canada. We fit multivariable logistic regression models to examine the association between BMI and HRA. Non-linear relationships for BMI on HRA were also evaluated using restricted cubic splines. The mean BMI in patients with HRA was 28.2kg/m2 compared to 27.4kg/m2 in patients without adenomas (t test: p=0.003). In the adjusted models, those with a BMI over 30kg/m2 had 1.45 (95% CI 1.05-2.00) times the odds of HRA detected during colonoscopy compared to those with a BMI below 25kg/m2. Examining BMI as continuous, the odds of HRA were 1.20 (95% CI 1.04-1.37) times higher for every 5kg/m2 increase in BMI. The findings of this study suggest that excess body mass is associated with higher risk of HRA among a screening population and may be useful an early marker of future disease.

The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome21. We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n=357); and a legacy study (n=468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ40 and Aβ42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia. Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted. National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).

Small vessel disease in patients with restless legs syndrome evidenced by elevated peak width of skeletonized mean diffusivity

Peak width of skeletonized mean diffusivity (PSMD) is a novel marker of small vessel disease. This study aimed to investigate small vessel disease in patients with restless legs syndrome (RLS) using PSMD. We prospectively enrolled 65 patients with primary RLS and 59 age- and sex-matched healthy controls. Diffusion tensor imaging (DTI) was performed using a 3-T magnetic resonance imaging scanner in patients with RLS and healthy controls. We obtained PSMD by DTI in several steps, including preprocessing, skeletonization, application of a custom mask, and histogram analysis. We compared the PSMD between patients with RLS and healthy controls and performed a correlation analysis between the PSMD and clinical characteristics in patients with RLS. The PSMD significantly differed between patients with RLS and healthy controls; it was higher in patients with RLS than that in healthy controls (2.423 vs. 2.298 × 10−4 mm2/s, p = 0.017). The PSMD significantly differed according to the RLS severity (2.305 × 10−4 mm2/s, moderate RLS; 2.368 × 10−4 mm2/s, severe RLS; 2.477 × 10−4 mm2/s, very severe RLS; p = 0.003). Additionally, the PSMD was positively correlated with age (r = 0.522, p < 0.001) and RLS severity (r = 0.263, p = 0.033). Patients with RLS exhibited a higher PSMD than that in healthy controls, indicating the evidence of small-vessel disease in RLS and that the severity increased as RLS severity increased. These findings provide crucial information for clinical management and treatment strategies, highlighting the importance of addressing small vessel disease in patients with RLS.

Impact of Short-Term Diesel Exhaust Exposure on Prothrombotic Markers in Chronic Obstructive Pulmonary Disease: A Randomized, Double-Blind, Crossover Study.

Rationale: Growing evidence suggests that air pollution exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) that is associated with an increased prothrombotic state and adverse cardiovascular outcomes. However, much of this work is based on observational data or human exposure studies involving younger participants. The biological causality and mechanism of air pollution-induced prothrombotic response in patients with COPD remain to be explored. Objectives: The main aim of this work was to investigate the impact of short-term diesel exhaust (DE) exposure on circulating prothrombotic markers-fibrinogen and plasminogen activator inhibitor-1 (PAI-1)-and urinary eicosanoids in patients with COPD. Methods: Twenty-nine research participants were recruited in this randomized, double-blind, crossover, controlled human exposure study to DE. Participants included former smokers with and without mild or moderate COPD (ex-smokers [ES] and COPD group) and healthy never-smokers without COPD (nonsmoker [NS] group). Each participant was exposed to DE (300 μg/m3 of particulate matter with an aerodynamic diameter ≤2.5 μm) and filtered air for 2 hours on different occasions, in randomized order, separated by a 4-week washout. Blood and urine samples were collected before and 24 hours after each exposure. Plasma fibrinogen and serum PAI-1 concentrations were quantified using enzyme-linked immunosorbent assays. Urinary eicosanoid concentrations were quantified using ultraperformance liquid chromatography coupled to tandem mass spectrometry. Linear mixed-effects models were used for statistical comparisons. Results: Participants with COPD showed an increase in plasma fibrinogen (effect estimate, 1.27 [1.06-1.53]; P = 0.01) after DE relative to filtered air, but no significant DE-associated change in serum PAI-1 (0.95 [0.87-1.04]; P = 0.26). In never-smokers and ex-smokers without COPD, fibrinogen (NS group, 1.10 [0.99-1.23]; P = 0.08; ES group, 0.86 [0.68-1.09]; P = 0.08] and PAI-1 (NS group, 1.12 [0.96-1.32]; P = 0.15; ES group, 0.90 [0.79-1.03]; P = 0.13) were not changed after DE exposure. Participants with COPD showed a DE-attributable increase in urinary thromboxane B2 (TXB2) metabolite concentrations as follows: 11-dehydro-TXB2 (1.45 [1.02-2.08]; P = 0.04) and 2,3-dinor-TXB2 (1.45 [1.05-2.00]; P = 0.03). Conclusions: Participants with COPD had increased plasma fibrinogen and urinary TXB2 metabolites after short-term DE exposure, suggesting they may be more susceptible to a pollution-attributable prothrombotic response than healthy control subjects or ex-smokers without COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02236039).

Thoracic Aortic Calcification and Complex Large Aortic Arch Plaque in Patients with Chronic Coronary Syndrome.

Aortic arch plaque (AAP) morphology and complexity can serve as markers of atherosclerotic cardiovascular disease. This study investigated 1) the diagnostic value of the thoracic aortic calcification (TAC) score for detecting AAP and large complex AAP and 2) the prognostic significance of TAC in patients with chronic coronary syndrome (CCS). The predictors of AAPs with large (≥ 4 mm in thickness) and complex (ulcerated or protruded) morphologies were evaluated in 412 symptomatic patients with CCS who underwent coronary computed tomography angiography and simultaneous assessment of the aortic arch. Receiver operating curve analysis was performed to determine whether the TAC score can improve the diagnostic value of complex large AAP compared with clinical parameters. Multivariate logistic regression analyses revealed that the TAC score was an independent predictor of complex large AAP (odds ratio, 1.46; P = 0.0074). The area under the curve (AUC) for the base model comprising clinical parameters (age ≥ 70 years + current smoking status + systolic blood pressure) was 0.707 (P = 0.0177). The addition of a TAC score of ≥ 978 Agatston units (AUC, 0.744) significantly improved the AUC (AUC, 0.751, P < 0.001) for patients aged ≥ 70 years (AUC, 0.638). The multivariable Cox hazard model revealed that TAC of ≥ 432.4 (hazard ratio [HR], 4.312; P = 0.01) and large complex AAP are independently associated with the incidence of major adverse cardiovascular events (HR, 3.108; P = 0.011). This study demonstrated that TAC and AAP morphology serve as markers of major adverse cardiovascular events. The combination of advanced age, TAC score, and obstructive CAD exhibited robust diagnostic accuracy in detecting complex large AAP.

Clinical Utility of Bone Turnover Markers in Chronic Kidney Disease

Chronic kidney disease (CKD) often leads to mineral and bone disorders (CKD-MBDs), which are nearly universal in patients undergoing dialysis. CKD-MBD includes abnormal calcium-phosphate metabolism, vascular and soft tissue calcification, and bone abnormalities (renal osteodystrophy [ROD]). Bone fragility in CKD occurs due to low bone mass and poor bone quality, and patients with CKD have higher fracture and mortality rates. Bone histomorphometry is the gold standard for ROD diagnosis; however, it is labor-intensive and expensive. The Kidney Disease Improving Global Outcomes clinical practice guidelines on CKD-MBD suggest serum parathyroid hormone (PTH) and bone-specific alkaline phosphatase (bone ALP) for predicting bone turnover in ROD. In this review, we focus on the role of PTH and bone turnover markers, intact procollagen type N-terminal propeptide of type I collagen, bone ALP, and tartrate-resistant acid phosphatase 5b in diagnosing ROD, predicting fractures, and guiding treatment in patients with CKD.

The association between small vessel disease and obstructive sleep apnea: a peak width of skeletonized mean diffusivity-based study.

Peak width of skeletonized mean diffusivity (PSMD) is a novel marker of small vessel disease in the brain. This study aimed to investigate the association between small vessel disease and obstructive sleep apnea (OSA) using PSMD. We enrolled patients with OSA and age- and sex-matched healthy controls, and performed diffusion tensor imaging (DTI) using a 3-tesla MRI scanner in them. We calculated the PSMD based on DTI in several steps, including preprocessing, skeletonization, application of a custom mask, and histogram analysis using the FSL program. We compared the PSMD between patients with OSA and healthy controls and investigated the correlation between PSMD and clinical factors. Thirty-nine patients with OSA (apnea-hypopnea index > 5; mean = 20.5) and 48 healthy controls were enrolled. The PSMD was significantly higher in patients with OSA than that in the healthy controls (2.521 vs. 2.320 × 10- 4 mm2/s, p = 0.013). In addition, PSMD positively correlated with age (r = 0.512, p < 0.001) and body mass index (r = 0.472, p = 0.002). However, PSMD was not associated with polysomnographic measurements. The mean PSMD is higher in patients with OSA than that in healthy controls, indicating a white matter injury due to small-vessel disease in patients with OSA. Our study highlights the importance of actively diagnosing and treating OSA. In addition, PSMD can be used to determine the relationship between sleep disorders and small vessel disease.

Serum of Interferon Lambda-1 level as a protein biomarker for the diagnosis of COVID-19 severity

Abstract SARS-CoV-2, which mostly affects the respiratory system, is the agent that causes COVID-19. The virus enters human cells through the ACE2 receptor, which is expressed on the surface of many different types of cells in the body. Once inside the cell, the virus begins to replicate and spread throughout the body. Interferon Lambda-1, also known as IFN-λ1, is a type of cytokine that is secreted by the immune system of the body in response to viral infections. Objective to evaluate if serum levels of Interferon Lambda-1 are associated with how severe the COVID-19 infection is, so as to determine if this cytokine may be considered as a disease marker. This study was undertaken as a case control, using a study population of one hundred and twenty COVID-19 patients (79 males, 41 females). The COVID-19 patients were divided into three groups based on the severity of the illness: critical disease (n=30), severe disease (n=30), and mild/moderate disease (n=60), with (n=60) healthy volunteers as the control group (35 males, 25 females). Between January 2022 and May 2022, the patients were collected from Al-Amal hospitals and the AL-Shefaa center in AL- Najaf City, Iraq. Basic patient clinical and demographic data was obtained, along with blood samples. Enzyme-linked immunosorbent tests (ELISA) were used to measure the blood’s concentration of interferon lambda-1. Total cholesterol, triglycerides and high density lipoprotein content were measured by colorimetric methods. Ichroma was tested for serum ferritin and D-dimer, while CBC was obtained via Swelab to ascertain if interferon Lambda-1 levels are related to the severity of the disease. Interferon Lambda-1 levels in the patient group were determined to be higher, particularly in cases with mild to moderate (64.19±18.77) pg/mL (P=0.0001), severe (236.51±63.65) pg/mL (P=0.0001), and critical (465.61±62.16) pg/mL (P=0.0001) cases, as compared to healthy controls (41.72±12.92) pg/mL groups, respectively. Our results showed a significant negative correlation between SPO2%, Lymphocyte, HDL, TC and Hb (p.value=0.001) levels in the group of COVID-19 patients. TG, VLDL-C, neutrophils, WBCs, platelets, the N/L ratio, D-dimer, CRP and ferritin all have a significant positive correlation (p.value=0.001) with Interferon Lambda-1 in the COVID-19 patients group. A cutoff value of 50.50 (ng/mL) with a sensitivity of 82.5% and a specificity of 80.9% (AUC: 0.910, 95% CI 0.870-0.950; p&lt;0.0001) for Interferon Lambda-1 predicted severe COVID-19. In comparison to the mild/moderate patient group and healthy controls, we found that severe and critical COVID-19 patients had considerably greater serum Interferon Lambda-1 concentrations. This could be a useful sign of the disease’s severity. In order to prevent the onset of pulmonary inflammation, high blood Interferon Lambda-1 concentrations in the early stages of COVID-19 should be continuously monitored. Our work also revealed that Interferon Lambda-1 was highly associated with COVID-19 severity. We believe that Interferon Lambda-1 may be a valuable biomarker in determining the severity of the disease in COVID-19 patients.

Exogenous α-Synuclein Induces Oxidative Damage to Dopaminergic Neurons Through p-NMDAR2B/Nur77.

Alpha-synuclein (α-syn) is a major pathological marker of Parkinson's disease (PD), and its abnormal expression and aggregation lead to dopaminergic neuron degeneration, in which oxidative stress plays an important role. However, the exact molecular mechanism by which α-syn causes PD remains unclear. In this study, exogenous α-syn, also known as α-syn preformed fibrils (α-syn PFFs), was used to construct in vivo and in vitro models of PD. Behavioral, Western blotting, biochemical, immunofluorescence, flow cytometry, electron microscopy, etc. were used to investigate the pathological mechanism of PD induced by α-syn. We found that 6months after striatum injection of α-syn PFFs, mice exhibited motor deficits. Meanwhile, the protein expression of pS129-α-syn (p-α-syn) and α-syn oligomer significantly increased, while the expression of TH significantly decreased, and the oxidative stress in the substantia nigra was aggravated. In addition, we found an increase in the protein expression of NMDAR2B and p-Tyr1472-NMDAR2B (p-NMDAR2B) and a decrease in the protein expression of Nur77. However, in α-syn PFFs-induced SH-SY5Y cells, we found that inhibiting p-NMDAR2B increased the protein expression of Nur77, while overexpression of Nur77 did not affect the expression of p-NMDAR2B. Inhibition of p-NMDAR2B and overexpression of Nur77 reversed α-syn PFF-induced oxidative stress, thus reducing mitochondrial damage and cytotoxicity. Therefore, we speculate that α-syn PFF-induced oxidative stress in dopaminergic neurons may be mediated by p-NMDAR2B/Nur77. Our study provides novel insights into the pathology mechanism underlying α-syn-induced PD.