Influence of Physiological Variables and Comorbidities on Plasma Aß40, Aß42, and p-tau181 Levels in Cognitively Unimpaired Individuals.

Plasma biomarkers for Alzheimer's disease (AD) are a promising tool that may help in early diagnosis. However, their levels may be influenced by physiological parameters and comorbidities that should be considered before they can be used at the population level. For this purpose, we assessed the influences of different comorbidities on AD plasma markers in 208 cognitively unimpaired subjects. We analyzed both plasma and cerebrospinal fluid levels of Aß40, Aß42, and p-tau181 using the fully automated Lumipulse platform. The relationships between the different plasma markers and physiological variables were studied using linear regression models. The mean differences in plasma markers according to comorbidity groups were also studied. The glomerular filtration rate showed an influence on plasma Aß40 and Aß42 levels but not on the Aß42/Aß40 ratio. The amyloid ratio was significantly lower in diabetic and hypertensive subjects, and the mean p-tau181 levels were higher in hypertensive subjects. The glomerular filtration rate may have an inverse relationship on plasma Aß40 and Aß42 levels but not on the amyloid ratio, suggesting that the latter is a more stable marker to use in the general population. Cardiovascular risk factors might have a long-term effect on the amyloid ratio and plasma levels of p-tau181.

Sex hormones and the total testosterone:estradiol ratio as predictors of severe acute respiratory syndrome coronavirus 2 infection in hospitalized men.

BACKGROUND: The predictive ability of the early determination of sex steroids and the total testosterone:estradiol ratio for the risk of severe coronavirus disease 2019 or the potential existence of a biological gradient in this relationship has not been evaluated. OBJECTIVES: To assess the relationship of sex steroid levels and the total testosterone:estradiol ratio with the risk of severe acute respiratory syndrome coronavirus 2 infection in men, defined as the need for intensive care unit admission or death, and the predictive ability of each biomarker. MATERIALS AND METHODS: This was a prospective observational study. We included all consecutive adult men with severe acute respiratory syndrome coronavirus 2 infections in a single center admitted to a general hospital ward or to the intensive care unit. Sex steroids were evaluated at the centralized laboratory of our hospital. RESULTS: We recruited 98 patients, 54 (55.1%) of whom developed severe coronavirus disease in 2019. Compared to patients with nonsevere coronavirus disease 2019, patients with severe coronavirus disease 2019 had significantly lower serum levels of total testosterone (111 ± 89 vs. 191 ± 143 ng/dL; p < 0.001), dehydroepiandrosterone (1.69 ± 1.26 vs. 2.96 ± 2.64 ng/mL; p < 0.001), and dehydroepiandrosterone sulfate (91.72 ± 76.20 vs. 134.28 ± 98.261 µg/dL; p = 0.009), significantly higher levels of estradiol (64.61 ± 59.35 vs. 33.78 ± 13.78 pg/mL; p = 0.001), and significantly lower total testosterone:estradiol ratio (0.28 ± 0.31 vs. 0.70 ± 0.75; p < 0.001). The lower the serum level of androgen and the lower the total testosterone:estradiol ratio values, the higher the likelihood of developing severe coronavirus disease 2019, with the linear trend in the adjusted analyses being statistically significant for all parameters except for androstenedione (p = 0.064). In the receiver operating characteristic analysis, better predictive performance was shown by the total testosterone:estradiol ratio, with an area under the curve of 0.77 (95% confidence interval 0.68-0.87; p < 0.001). DISCUSSION AND CONCLUSION: Our results suggest that men with severe acute respiratory syndrome coronavirus 2 infection, decreased androgen levels and increased estradiol levels have a higher likelihood of developing an unfavorable outcome. The total testosterone:estradiol ratio showed the best predictive ability.

Accuracy of plasma Aß40, Aß42, and p-tau181 to detect CSF Alzheimer's pathological changes in cognitively unimpaired subjects using the Lumipulse automated platform.

BACKGROUND: The arrival of new disease-modifying treatments for Alzheimer's disease (AD) requires the identification of subjects at risk in a simple, inexpensive, and non-invasive way. With tools allowing an adequate screening, it would be possible to optimize the use of these treatments. Plasma markers of AD are very promising, but it is necessary to prove that alterations in their levels are related to alterations in gold standard markers such as cerebrospinal fluid or PET imaging. With this research, we want to evaluate the performance of plasma Aß40, Aß42, and p-tau181 to detect the pathological changes in CSF using the automated Lumipulse platform. METHODS: Both plasma and CSF Aß40, Aß42, and p-tau181 have been evaluated in a group of 208 cognitively unimpaired subjects with a 30.3% of ApoE4 carriers. We have correlated plasma and CSF values of each biomarker. Then, we have also assessed the differences in plasma marker values according to amyloid status (A - / +), AD status (considering AD + subjects to those A + plus Tau +), and ATN group defined by CSF. Finally, ROC curves have been performed, and the area under the curve has been measured using amyloid status and AD status as an outcome and different combinations of plasma markers as predictors. RESULTS: Aß42, amyloid ratio, p-tau181, and p-tau181/Aß42 ratio correlated significantly between plasma and CSF. For these markers, the levels were significantly different in the A + / - , AD + / - , and ATN groups. Amyloid ratio predicts amyloid and AD pathology in CSF with an AUC of 0.89. CONCLUSIONS: Plasma biomarkers of AD using the automated Lumipulse platform show good diagnostic performance in detecting Alzheimer's pathology in cognitively unimpaired subjects.

TNF Inhibitors Exert a "Hidden" Beneficial Effect in the Cardiovascular Lipoprotein Profile of RA Patients.

Purpose: A high cardiovascular risk has been described in patients with rheumatoid arthritis (RA); the effects of different biological agents have also been described in these patients. The aim of the present study is to examine the effects of tumor necrosis factor inhibitors (TNFi) in the lipoprotein profile of RA patients using a broad laboratory assessment including a large number of non-routine tests. Patients and Methods: RA patients treated with and without TNFi (70 patients in each group) were cross-sectionally compared regarding a broad spectrum of lipoprotein parameters including serum levels of total and HDL, LDL and VLDL cholesterol triglycerides, lipoprotein A (LpA), apolipoprotein A1 (Apo A), B100 (Apo B) and paroxonase. For each lipoprotein subfraction (HDL, LDL and VLDL), we assess specific concentrations of cholesterol, triglycerides, phospholipids and proteins and total mass of each one. Additionally, HDL Apo A, LDL and VLDL Apo B concentrations and number of particles of LDL and VLDL were also determined. Exploratory univariate and multivariate analyses of the different variables were performed. Results: Seventy patients in each subset were enrolled. Patients on treatment with TNFi showed a trend to be younger and to have a longer disease duration. Regarding the lipoprotein analyses, borderline significant higher levels of serum Apo A were detected and an independent association with lower HDL mass, LDL triglyceride, VLDL cholesterol, VLDL Apo B, VLDL mass, number of VLDL cholesterol molecules and number of particles of VLDL was clearly observed. Conclusion: TNFi treatment was associated with beneficial atherogenic effects at the lipoprotein level especially centered in the VLDL-related parameters consistent with a reduction of the atherogenic risk.

Impact of SARS-CoV-2 infection on liver disease.

Introduction: Abnormal liver biochemistry is not a rare finding in the context of SARS-CoV-2 infection, regardless of patients having pre-existing chronic disease or not. Content: This review examines the current body of knowledge on the relationship between COVID-19 and liver injury, which is frequently found in this setting. Summary: Although the pathogenesis of liver injury is not fully understood, it has been suggested to be the result of a combination of multiple factors. These include direct injury caused by the virus, immune system hyperactivation, ischemic and drug-induced injury. The prognostic valor of these alterations is also the subject of intense research. Due to their potential impact, these alterations require proper management and treatment, especially in patients with chronic liver disease or liver transplant recipients. Outlook: Some aspects associated with liver injury during COVID-19, especially in severe presentations, are not well understood. Studies assessing the clinical impact of COVID-19 on the healthy or diseased liver may help adjust treatment and immunization guidelines to the profile of the patient.

Control of occult hepatitis B virus infection.

Background: The diagnosis of hepatitis B virus (HBV) infection requires HBV DNA testing and serologic testing for detection of the surface antigen (HBsAg) and the hepatitis B core antibody (anti-HBc). There is a population of patients with occult HBV infection (OBI), which is not detected by HBsAg or HBV DNA quantification in blood, despite the presence of active replication in the liver. Scope: This document provides a definition of OBI and describes the diagnostic techniques currently used. It also addresses the detection of patients with risk factors and the need for screening for OBI in these patients. Summary: Correct diagnosis of OBI prevents HBV reactivation and transmission. Diagnosis of OBI is based on the detection of HBV DNA in patients with undetectable HBsAg in blood. Perspectives: A high number of patients with OBI may remain undiagnosed; therefore, screening for OBI in patients with factor risks is essential. For a correct diagnosis of OBI, it is necessary that new markers such as ultrasensitive HBsAg are incorporated, and a more comprehensive marker study is performed by including markers such as cccDNA.

Measurement and clinical usefulness of bilirubin in liver disease.

Elevated plasma bilirubin levels are a frequent clinical finding. It can be secondary to alterations in any stage of its metabolism: (a) excess bilirubin production (i.e., pathologic hemolysis); (b) impaired liver uptake, with elevation of indirect bilirubin; (c) impaired conjugation, prompted by a defect in the UDP-glucuronosyltransferase; and (d) bile clearance defect, with elevation of direct bilirubin secondary to defects in clearance proteins, or inability of the bile to reach the small bowel through bile ducts. A liver lesion of any cause reduces hepatocyte cell number and may impair the uptake of indirect bilirubin from plasma and diminish direct bilirubin transport and clearance through the bile ducts. Various analytical methods are currently available for measuring bilirubin and its metabolites in serum, urine and feces. Serum bilirubin is determined by (1) diazo transfer reaction, currently, the gold-standard; (2) high-performance liquid chromatography (HPLC); (3) oxidative, enzymatic, and chemical methods; (4) direct spectrophotometry; and (5) transcutaneous methods. Although bilirubin is a well-established marker of liver function, it does not always identify a lesion in this organ. Therefore, for accurate diagnosis, alterations in bilirubin concentrations should be assessed in relation to patient anamnesis, the degree of the alteration, and the pattern of concurrent biochemical alterations.

Biochemical assessment of metabolic associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) is defined as fat accumulation in the liver in the presence of metabolic alterations. This disorder is generally asymptomatic and may progress to severe liver disease, which are linked to inflammation and/or fibrosis. MAFLD has a high prevalence (26%) and therefore a considerable number of patients are at high risk of having advanced liver disease. This document provides an overview of the most relevant serological markers in the characterization and diagnosis of MAFLD. An example is provided of a routine diagnostic algorithm that incorporates serological testing. A range of useful serological scores are currently available for the management of MAFLD patients, especially for the stratification of patients at risk of fibrosis. A large proportion of the population is at risk of developing severe liver disease. The integration of non-invasive serological markers in the stratification of patients at risk for liver fibrosis may contribute to improve the control and management of MAFLD patients.

Influence of aquaporin-1 gene polymorphism on water retention in liver cirrhosis.

UNLABELLED: Water retention is a major clinical problem in patients with liver cirrhosis. The factors that predispose to water retention are poorly understood but may involve genetic factors. Recent research suggests that renal aquaporins may be a pathophysiological factor involved in this condition. Aquaporin-1 (AQP1) is expressed in the proximal tubule and aquaporin-2 (AQP2) in the renal collecting duct cells. The aim of our study was to investigate the distribution of single nucleotide polymorphisms (SNPs) of AQP1: rs1049305 (C/G) and AQP2: rs3741559 (A/G) and rs467323 (C/T) in 100 cirrhotic patients with ascites and to analyze their relationship with dilutional hyponatremia. METHODS: Genomic DNA was extracted from peripheral blood. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman SNP Genotyping Assays. The possible influence of rs1049305 (C/G) in AQP1 gene expression was evaluated by luciferase assays in vitro. RESULTS: The allelic frequencies of the AQP1 gene were the following: CC = 15%; CG = 49%; GG = 36%. Patients with CC genotype had significantly lower plasma sodium concentration than those with CG or GG genotype. Luciferase assays showed that the rs1049305 (C/G) in the AQP1 gene functionally affected the expression level in vitro. In addition, we did not find any relationship between AQP2 SNPs observed and plasma sodium concentration. CONCLUSIONS: Our results suggest that the rs1049305 (C/G, UTR3) AQP1 polymorphism could be involved in the genetic susceptibility to develop water retention in patients with liver cirrhosis.

Endothelial dysfunction, measured by reactive hyperaemia using strain-gauge plethysmography, is an independent predictor of adverse outcome in heart failure.

AIMS: In congestive heart failure (CHF), arterial response is regulated by endothelial molecules. The aim of this study was to evaluate whether endothelial dysfunction (ED) was a predictor of outcome in a cohort of patients with heart failure. METHODS AND RESULTS: Endothelial function was assessed in 242 patients with CHF by forearm reactive hyperaemia measured with intermittent venous occlusion plethysmography using a mercury strain gauge. The main endpoints were: 'total events' (death, heart attack, angina, stroke, NYHA class IV, or hospitalization due to heart failure) analysed using Cox regression for repeated events and 'death'. Patients were followed-up for 5 years. Post-hyperaemia forearm blood flow (PHFABF) was an independent predictor of total events [P = 0.01; hazard ratio [Exp(B)] 0.665, standard error (SE) 0.182]. Risk stratification by basal forearm blood flow (BFABF) showed that patients with basal blood flow above the median (3.03 mL min(-1) 100 mL(-1)) benefited from an increase in PHFABF, whereas in patients with a BFABF below the median, the increase in PHFABF did not diminish the risk of events. There was no relation between variations in PHFABF and death. CONCLUSION: Post-hyperaemia forearm blood flow, as a measure of ED, is an independent predictor of major events in patients with CHF. A BFABF below the median is more predictive of an increased risk of complications.

Increased bactericidal/permeability increasing protein in patients with cirrhosis.

BACKGROUND: High levels of endotoxin in patients with cirrhosis are thought to be responsible for the activation of tumour necrosis factor-alpha (TNF)-alpha-mediated pro-inflammatory pathways involved in haemodynamic alterations. Bactericidal/permeability increasing protein (BPI) is a protein found in neutrophils with endotoxin-binding and neutralization capacity. It is not known whether defective BPI production or release is present in cirrhosis. AIMS: We investigated the levels of BPI in cirrhotic patients and its relation to other endotoxin-binding proteins and inflammatory markers. METHODS: Plasmatic levels of BPI, lipopolysaccharide-binding protein, soluble CD14, TNF-alpha and BPI mRNA expression in neutrophils were determined in 130 patients and 30 healthy controls. The capacity of patients' plasma to inhibit lipopolysaccharide (LPS)-mediated TNF-alpha production by monocytes from healthy donors was assessed in vitro. RESULTS: Patients with cirrhosis exhibited an increase in BPI mRNA and plasma level of BPI when compared with healthy controls (P<0.05). Child C group displayed the highest frequency of patients with a high concentration of BPI. A positive correlation was found between TNF-alpha and plasma levels of BPI (P<0.01). High levels of BPI in plasma were able to significantly reduce in vitro TNF-alpha release by monocytes after a challenge with LPS (8.54 +/- 1.04 vs. 10.44 +/- 0.85 pg/ml, P=0.028). CONCLUSION: BPI is increased in cirrhotic patients, especially in those with more severe liver disease. The amount of BPI in the plasma correlated with the TNF-alpha level and was able to reduce LPS-mediated TNF production by monocytes. BPI possibly plays a regulatory role by antagonizing the pro-inflammatory mechanisms mediated by TNF-alpha.