FIB-4 liver fibrosis index correlates with aortic valve sclerosis in non-alcoholic population.

AIM: Hepatic fibrosis, a progressive scarring of liver tissue, is commonly caused by non-alcoholic fatty liver disease (NAFLD), which increases the risk of cardiovascular disease. The Fibrosis-4 (FIB-4) index is a non-invasive tool used to assess liver fibrosis in patients with NAFLD. Aortic valve sclerosis (AVS), a degenerative disorder characterized by thickening and calcification of valve leaflets, is prevalent in the elderly and associated with increased cardiovascular morbidity and mortality. Recent studies have suggested that AVS may also be linked to other systemic diseases such as liver fibrosis. This study aimed to investigate the relationship between the FIB-4 index and AVS in a non-alcoholic population, with the hypothesis that the FIB-4 index could serve as a potential marker for AVS. METHOD: A total of 92 patients were included in this study. AVS was detected using transthoracic echocardiography, and patients were divided into groups according to the presence of AVS. The FIB-4 index was calculated for all patients and compared between the groups. RESULTS: A total of 17 (18.4%) patients were diagnosed AVS. Patients with AVS had higher rates of diabetes mellitus, older age, hypertension, angiotensin-converting enzyme inhibitor use, higher systolic blood pressure (BP) and diastolic BP in the office, coronary artery disease prevalence, left atrial volume index (LAVI), left ventricular mass index (LVMI), and late diastolic peak flow velocity (A) compared to those without AVS. Moreover, AVS patients had significantly higher creatinine levels and lower estimated glomerular filtration rate. Remarkably, the FIB-4 index was significantly higher in patients with AVS. In univariate and multivariate analyses, higher systolic BP in the office (OR, 1.044; 95% CI 1.002-1.080, p = .024) and higher FIB-4 index (1.46 ± .6 vs. .91 ± .46, p < .001) were independently associated with AVS. CONCLUSION: Our findings suggest that the FIB-4 index is associated with AVS in non-alcoholic individuals. Our results highlight the potential utility of the FIB-4 index as a non-invasive tool for identifying individuals at an increased risk of developing AVS.

Causal ALS genes impact the MHC class II antigen presentation pathway.

Mutations in RNA/DNA-binding proteins cause amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain unclear. Here, we report that a set of ALS-associated proteins, namely FUS, EWSR1, TAF15, and MATR3, impact the expression of genes encoding the major histocompatibility complex II (MHC II) antigen presentation pathway. Both subunits of the MHC II heterodimer, HLA-DR, are down-regulated in ALS gene knockouts/knockdown in HeLa and human microglial cells, due to loss of the MHC II transcription factor CIITA. Importantly, hematopoietic progenitor cells (HPCs) derived from human embryonic stem cells bearing the FUSR495X mutation and HPCs derived from C9ORF72 ALS patient induced pluripotent stem cells also exhibit disrupted MHC II expression. Given that HPCs give rise to numerous immune cells, our data raise the possibility that loss of the MHC II pathway results in global failure of the immune system to protect motor neurons from damage that leads to ALS.

A comparative analysis of prolotherapy efficacy in patients with knee osteoarthritis across varied dextrose concentrations.

OBJECTIVE: To compare the effectiveness of prolotherapy with dextrose concentrations of 5%, 10%, and 20% in patients diagnosed with knee osteoarthritis. METHODS: This study was planned as a prospective, randomized controlled interventional trial. Prolotherapy at 5% dextrose concentration in group 1, 10% in group 2, and 20% in group 3 was applied to the knee intra-articularly and periarticularly at 0, 3, and 6 weeks, and a home exercise program was given. Group 4 received a home exercise program. All groups received hotpack therapy at weeks 0, 3, and 6. Outcome measures included the visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), knee range of motion, timed up and go test, and Short Form-36. RESULTS: A total of 128 patients were divided into 4 groups. At the 6th and 12th weeks, VAS scores were significantly lower in groups 2 and 3 than in group 4 (p < 0.05). At the 12th week, the WOMAC pain score was significantly lower in group 3 than in group 4, and WOMAC physical function and WOMAC total scores were significantly lower in groups 1, 2, and 3 than in group 4 (p < 0.05). Week 6 active and passive knee flexion and week 12 passive knee flexion were significantly higher in group 3 than in group 4 (p < 0.05). CONCLUSIONS: Although no significant difference was observed among the dextrose prolotherapy groups, higher dextrose concentrations demonstrated a greater improvement compared to the control group. Therefore, the use of 20% dextrose is recommended due to its significant superiority. Long-term follow-up and placebo-controlled studies are needed. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT05537077, registration date: 09.03.2022, retrospectively registered. Key Points • The utilization of dextrose prolotherapy has gained popularity in the management of osteoarthritis, aiming to harness its regenerative and proliferative properties. However, the comparative efficacy of various concentrations of dextrose prolotherapy in treating knee osteoarthritis remains unexplored in the literature. This study aimed to address this gap by comparing different concentrations of dextrose prolotherapy in the treatment of knee osteoarthritis. The findings revealed no statistically significant difference among the various concentrations of dextrose prolotherapy for knee osteoarthritis treatment.

Non-alcoholic faty liver disease and liver fibrosis score have an independent relationship with the presence of mitral annular calcification.

Non-alcoholic faty liver disease (NAFLD) and liver fibrosis score (FIB 4) are associated with increased mortality from cardiovascular causes. NAFLD and cardiac diseases are different manifestations of systemic metabolic syndrome. In this study, we aimed to reveal the relationship between NAFLD and FIB 4 liver fibrosis scores and mitral annular calcification (MAC). One hundred patients were included in the study. Blood samples and echocardiography measurements were obtained from each subject. The two groups were compared in terms of demographic and echocardiographic characteristics. Thirty-one men and 69 women with a mean age of 48.6 ± 13.1 years were included in the analysis. The patients were divided into two groups as those with MAC (n = 26) and those without (n = 74). The baseline demographic and laboratory data for the two groups were compared. In the group with MAC (+) age, serum creatinine levels, FIB4 and NAFLD Scores; HL, DM rates, angiotensin converting enzyme (ACE) inhibitor and statin usage rates were higher, with statistical significance. NAFLD and FIB 4 liver fibrosis scores have an independent relationship with MAC.

Erratum: Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.

[This corrects the article DOI: 10.1016/j.isci.2021.103463.].

TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau.

Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities.

Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.

Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context.