C1q nephropathy is a rare glomerular disease. Clinical presentation is diverse and ranges from asymptomatic hematuria or proteinuria to symptoms and signs of nephrotic/nephritic syndrome. On light microscopy, it can be classified into two subtypes: minimal change disease (MCD)/focal segmental glomerulosclerosis (FSGS) group and immune complex mediated proliferative glomerulonephritis group. A case of a 19-year-old male patient presenting nausea and decreased appetite will be reported. The labs showed severe nephrotic syndrome and a progressive kidney injury over a few months that were never diagnosed. The immune workup came back negative. The patient mentioned that he was taking protein shakes a few months earlier for bettering his physical fitness. A renal biopsy was done and showed a major reduction in renal mass and C1q nephropathy. He received steroids without any improvement. He was started on hemodialysis afterward then got transplanted 8 months later. In front of this rapid deterioration, FSGS might be the underlying etiology rather than MCD. Further studies are warranted to establish a connection between protein supplements, and progression of kidney disease.
Osteoporosis is a metabolic bone disorder that affects both sexes and is the most common cause of fractures. Osteoporosis therapies primarily inhibit osteoclast activity, and are seldom designed to trigger new bone growth thereby frequently causing severe systemic adverse effects. Physiologically, the intracellular redox state depends on the ratio of pro-oxidants, oxidizing agents (reactive oxygen species, ROS) and antioxidants. ROS is the key contributor to oxidative stress in osteoporosis as changes in redox state are responsible for dynamic bone remodeling and bone regeneration. Imbalances in ROS generation vs. antioxidant systems play a pivotal role in pathogenesis of osteoporosis, stimulating osteoblasts and osteocytes towards osteoclastogenesis. ROS prevents mineralization and osteogenesis, causing increased turnover of bone loss. Alternatively, antioxidants either directly or indirectly, contribute to activation of osteoblasts leading to differentiation and mineralization, thereby reducing osteoclastogenesis. Owing to the unpredictability of immune responsiveness and reported adverse effects, despite promising outcomes from drugs against oxidative stress, treatment in clinics targeting osteoclast has been limited. Nanotechnology-mediated interventions have gained remarkable superiority over other treatment modalities in regenerative medicine. Nanotherapeutic approaches exploit the antioxidant properties of nanoparticles for targeted drug delivery to trigger bone repair, by enhancing their osteogenic and anti-osteoclastogenic potentials to influence the biocompatibility, mechanical properties and osteoinductivity. Therefore, exploiting nanotherapeutics for maintaining the differentiation and proliferation of osteoblasts and osteoclasts is quintessential.
Psoriasis is a common chronic inflammatory skin disorder, which has adverse effects on patients’ quality of life. Natural products exhibit significant therapeutic capacities with small side effects and might be preferable alternative treatments for patients with psoriasis. This study summarizes the signaling pathways with the potential targets of natural products and their efficacy for psoriasis treatment.
The literature for this article was acquired from PubMed and Web of Science, from January 2010 to December 2020. The keywords for searching included “psoriasis” and “natural product”, “herbal medicine”, “herbal therapy”, “medicinal plant”, “medicinal herb” or “pharmaceutical plant”.
Herbal extracts, natural compounds, and herbal prescriptions could regulate the signaling pathways to alleviate psoriasis symptoms, such as T helper 17 (Th17) differentiation, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and other signaling pathways, which are involved in the inflammatory response and keratinocyte hyperproliferation. The anti-psoriatic effect of natural products in clinical trials was summarized.
Natural products exerted the anti-psoriatic effect by targeting multiple signaling pathways, providing evidence for the investigation of novel drugs. Further experimental research should be performed to screen and characterize the therapeutic targets of natural products for application in psoriasis treatment.
Lactate dehydrogenase (LDH) is an enzyme that acts as a catalyst in the conversion of lactate to pyruvate which is abundantly found in liver, kidney, heart and muscles. Previous studies have all shown a strong positive correlation between muscle fatigue and increased serum LDH levels with type 2 diabetes mellitus but no study has actually assessed the same for prediabetes. The basic objective of this study, thus, is to find out the correlation between muscle fatigue and serum LDH levels in prediabetic individuals.
A cross-sectional study was conducted in adults between 24–60 years old who were classified as prediabetic individuals as per norms established by American Diabetes Association. A total of 100 prediabetic individuals were selected for the study. Fatigability was calculated as a function of work done by the pleximeter finger of the dominant hand using Mosso’s ergograph. The study was conducted at Rajarshi Dashrath Autonomous State Medical College, Ayodhya.
Out of 100 prediabetic participants, 50% were males with a mean age of 44.14 ± 10.91 years and remaining 50% were females with a mean age of 41.12 ± 11.5 years. Overall, the average work done by the participants was 2.9 ± 1.2 weight lifted•total distance moved (kg•m) with an average serum LDH level of 323.84 ± 26.82 unit/litre (U/L).
This study aimed at assessing the correlation between muscle fatigue and serum LDH levels in prediabetic individuals so that further work can be initiated to improve the quality of life in prediabetics that maybe drastically hampered due to easy fatigability in prediabetic individuals.
Sexually transmitted diseases (STDs) need to be studied systematically to better understand their global spread. Transmission of Chlamydia trachomatis is a severe public health issue, with roughly 90 million new cases per year. Globally, Chlamydia trachomatis is the most frequent bacterial cause of STDs.
To better understand the dynamics and transmission of Chlamydia, the susceptible-exposed-infected-recovered-susceptible (SEIRS) model was constructed. Using a system of nonlinear ordinary differential equations, a basic reproduction number has been calculated at an equilibrium point, and the system is locally and globally asymptotically stable at both disease-free and endemic equilibrium points. Numerical simulations illustrate the behavior and flow of Chlamydia infections in different compartments.
Conclude from the proposed study that 25% of individuals have been exposed to Chlamydia, of which 20% of individuals get infections due to sexual activity and 55% of individuals get recovered. Twenty percent of individuals have been exposed to Chlamydia, of which 37% of individuals have been infected due to an unhygienic environment. Of those, 43% of individuals recovered. Also, it has been found that people are more likely to get infections because of an unhygienic environment than sexually active people. The recovery rate is also much better for people who have been infected because of an unhygienic environment.
Sexually transmitted infections can be reduced by up to 10%. While infection due to an unhygienic environment can be controlled up to a certain intensity. According to this research, public awareness campaigns and the improvement of personal hygiene will play a major role in reducing the spread of the epidemic in the future.
The brain and gut are connected both physically and biochemically. The gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems, the enteric nervous system and vagus nerve, and the gut microbiome. It can influence brain function and even behavior, suggesting that dietary interventions may help enhance and protect mental health and cognitive performance. This review focuses on the role of the microbiome and its metabolites in sleep regulation, neurodegenerative disorders, mechanisms of stress, and mood. It also provides examples of nutritional interventions which can restore healthy gut microbiota and aid with risk reduction and management of many disorders related to mental and cognitive health. Evidence suggests a shift in the gut microbiota towards a balanced composition could be a target to maintain brain health, reduce stress and improve quality of life.
The etiologies, presentation, and management of downhill varices in the era of modern medicine are relatively under-explored and mostly limited to case reports or case series.
Published case reports/series of patients ≥ 18 years old with proven/probable downhill esophageal varices were searched on Ovid MEDLINE and Ovid EMBASE for all published cases up to January 2021.
The mean age was 50.9 (standard deviation ± 17.6) years old for all downhill variceal cases. End-stage renal disease was the most common comorbidity (43.9%), followed by thyroid disease (12.2%), Behçet’s disease (9.8%), and pulmonary hypertension (7.3%). Dialysis catheters, central venous grafts, or additional catheters were additional risk factors (51.2%). Variceal bleeding presenting as hematemesis, melena, or both was the most common presenting symptom (80.5%).
Dialysis catheter-associated superior vena cava obstruction resulted in an increased risk of downhill varices. Other causes include thyroid malignancies, pulmonary hypertension, and Behçet’s disease.
Chronic kidney disease (CKD) is a major health problem but there are many modalities to prevent and manage CKD progression. Diet is one of these factors, which needs to be evaluated more. Adenine is a water-soluble nucleoprotein that exists in both vegetables and animal foods, which triggers and aggravates fibrosis process besides other metabolic derangements such as diabetes mellitus affection that accelerates glomerular filtration rate decline rapidly.
To screen differentially expressed genes related to gastric cancer based on The Cancer Genome Atlas (TCGA) database and construct a gastric cancer diagnosis model by machine learning.
Transcriptional data, genomic data, and clinical information of gastric cancer tissues and non-gastric cancer tissues were downloaded from the TCGA database, and differentially expressed genes of gastric cancer messenger RNA (mRNA) and long non-coding RNA (lncRNA) were screened out. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyzed the differentially expressed genes, and the protein-protein interaction (PPI) of differentially expressed genes was constructed. Core differentially expressed genes were screened by Cytoscape software’s molecular complex detection (MCODE) plug-in. The differential genes of lncRNA were analyzed by univariate Cox regression analysis and lasso regression for further dimension reduction to obtain the core genes. The core genes were screened by machine learning to construct the gastric cancer diagnosis model. The efficiency of the gastric cancer diagnosis model was verified externally by the Gene Expression Omnibus (GEO) database.
Finally, 10 genes including long intergenic non-protein coding RNA 1821 (LINC01821), AL138826.1, AC022164.1, adhesion G protein-coupled receptor D1-antisense RNA 1 (ADGRD1-AS1), cyclin B1 (CCNB1), kinesin family member 11 (KIF11), Aurora kinase B (AURKB), cyclin dependent kinase 1 (CDK1), nucleolar and spindle associated protein 1 (NUSAP1), and TTK protein kinase (TTK) were screened as gastric cancer diagnostic model genes. After efficiency analysis, it was found that the random forest algorithm model had the best comprehensive evaluation, with an accuracy of 92% and an area under the curve (AUC) of 0.9722, which was more suitable for building a gastric cancer diagnosis model. The GSE54129 data set was used to verify the gastric cancer diagnosis model with an AUC of 0.904, indicating that the gastric cancer diagnosis model had high accuracy.
Machine learning can simplify the bioinformatics analysis process and improve efficiency. The core gene discovered in this study is expected to become a gene chip for the diagnosis of gastric cancer.
The aim of this study is to propose a contrast-enhanced ultrasound (CEUS)-based morphologic classification of pyogenic liver abscess (PLA) reflecting different evolutive stages and to assess the added value of CEUS in the management of PLA.
Forty-four PLAs of different etiologies in 44 patients (male/female = 24/20; mean age 66 ± 14.7 years) were evaluated with ultrasound (US) B-mode and CEUS (using SonoVue). PLAs were mainly located in the right lobe (n = 28, 63.6%) with a mean diameter of 6.8 cm [standard deviation (SD) ± 3.2, range 1.7–15 cm]. Conventional US findings were categorized as the presence and extension of liquified areas, echogenicity and echostructure of the index lesion. Peripheral hyperenhancing rim, transient segmental enhancement, hyperenhancing septa and “honeycomb” aspect were considered PLA hallmarks in the arterial phase after contrast agent injection. CEUS results were judged as clinically relevant if they modified the approach to percutaneous treatment in comparison with pre-operative US B-mode findings.
CEUS was superior to US B-mode as to depiction of PLA internal echostructure and enabled identification of 4 evolutive stages of PLA: type I (tumor-like), type II (“honeycomb”), type III (multiloculated with incomplete septa), and type IV (cystic-like). In 22 cases (67.4%) out of 34 who underwent percutaneous treatment, the operator tailored percutaneous approach according to PLA internal echostructure observed during CEUS exam.
CEUS depicts the internal structure of PLA so allowing a morpho-evolutive classification of PLA and provides invaluable information for immediately tailoring the management to the single case. By showing the structure of PLA more precisely, CEUS allows a morpho-evolutive PLA classification and guides tailored management in the single case.
Retroelements are mobile genomic components requiring an RNA intermediate which is reverse-transcribed into complementary DNA for transposition. Human genome contains a vast amount of retroelements including retrotransposons and endogenous retroviruses. These elements are categorized according to presence or absence of long terminal repeats, LTRs or non-LTRs, as well as autonomous and non-autonomous according to involvement of reverse transcriptase. The retroelements have been accumulated in mammalian genomes over all evolutionary times through vertical transmission, and many of them were inactivated through accumulation of mutations. However, the retroelements entered into genome within the last 200,000 years are mostly functional. Some of the active retroelements are associated with varying autoimmune diseases because anti-retroelement antibodies might cross-react with other proteins in the human body. For instance, autoimmunity and inflammation could be stimulated by increased expression of long interspersed element 1 (LINE-1 or L1) or decreased L1 degradation. Different regulation of L1 expression might be related to the genetic and sex-related variations or environmental factors. Activation of retroelements is also controlled by epigenetic silencing mechanisms such as histone modification. Elevated levels of L1 retroelements could trigger the production of type I interferon, a crucial innate defense mechanism in mammals against viruses, and systemic autoimmune response is induced. Loss-of-function in some deoxyribonucleases (DNases) such as three prime repair exonuclease 1 that degrades reverse-transcribed DNA is also related to autoimmune diseases. Additionally, human endogenous retroviruses also play a role in autoimmune diseases. Involvement of retroelements in autoimmune disorders is exemplified with three diseases, i.e. systemic lupus erythematosus, Aicardi–Goutières syndrome, and multiple sclerosis.
Hyperuricemia as a putative risk factor for chronic kidney disease (CKD) progression remains controversial and debatable. This systematic review aims to explore the prevalence of hyperuricemia among CKD patients worldwide.
This study was conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines by using the existing literature from online databases such as MEDLINE/PubMed, ScienceDirect, Google Scholar, Cochrane library and grey literature. The effect size with corresponding 95% confidence interval (CI) was calculated to assess the pooled prevalence of hyperuricemia in chronic kidney patients. The subgroup analysis based on gender and geography was also carried out by utilizing comprehensive meta-analysis, version 2.0.
Twenty-three studies containing 212,740 participants were eligible for quantitative synthesis. The pooled prevalence of 43.6% (35.2–52.4%) hyperuricemia was reported in patients with CKD globally. In India, 38.4% of prevalence was observed. The gender specific prevalence (9 studies) was reported as 67.4% (60.9–73.3%) in case of male patients and 32.6% (26.7–39.1%) in female patients with 95% CI.
The prevalence of hyperuricemia was reported to be reasonably high among CKD patients worldwide. During the management of CKD, this high prevalence demands more prudent attention for this clinical complication which possibly can lead to positive renal outcomes.
Chronic kidney disease (CKD) is a worldwide public health issue and has ultimately progressed to an end-stage renal disease that requires life-long dialysis or renal transplantation. However, the underlying molecular mechanism of these pathological development and progression remains to be fully understood. The human gut microbiota is made up of approximately 100 trillion microbial cells including anaerobic and aerobic species. In recent years, more and more evidence has indicated a clear association between dysbiosis of gut microbiota and CKD including immunoglobulin A (IgA) nephropathy, diabetic kidney disease, membranous nephropathy, chronic renal failure and end-stage renal disease. The current review describes gut microbial dysbiosis and metabolites in patients with CKD thus helping to understand human disease. Treatment with prebiotics, probiotics and natural products can attenuate CKD through improving dysbiosis of gut microbiota, indicating a novel intervention strategy in patients with CKD. This review also discusses therapeutic options, such as prebiotics, probiotics and natural products, for targeting dysbiosis of gut microbiota in patients to provide more specific concept-driven therapy strategy for CKD treatment.
Around the world, more than 6.2 million individuals have died as a result of coronavirus disease 2019 (COVID-19). According to a recent survey conducted among immunologists, epidemiologists, and virologists, this disease is expected to become endemic. This implies that the disease could have a continuous presence and/or normal frequency in the population. Pharmacological interventions to prevent infection, as well as to treat the patients at an early phase of illness to avoid hospitalization are essential additions to the vaccines. Taurine is known to inhibit the generation of all inflammatory mediators linked to the cytokine storm. It can also protect against lung injury by suppressing increased oxidants production and promoting the resolution of the inflammatory process. Neutrophil lactoferrin degranulation stimulated by taurine may have antiviral effects against SARS-CoV-2, limiting viral replication. It is hypothesized that if taurine is administered early in the onset of COVID-19 disease, it may stop the cytokine storm from progressing, lowering morbidity and mortality.
The human body contains trillions of microbes which generally live in symbiosis with the host. The interaction of the gut microbiome with elements of the host immune system has far-reaching effects in the development of normal gut and systemic immune responses. Disturbances to this intricate relationship may be responsible for a multitude of gastrointestinal and systemic immune mediated diseases. This review describes the development of the gut microbiome and its interaction with host immune cells in both health and disease states.
Cardiovascular diseases are among the leading causes of death worldwide, imposing major health threats. Reactive oxygen species (ROS) are one of the most important products from the process of redox reactions. In the onset and progression of cardiovascular diseases, ROS are believed to heavily influence homeostasis of lipids, proteins, DNA, mitochondria, and energy metabolism. As ROS production increases, the heart is damaged, leading to further production of ROS. The vicious cycle continues on as additional ROS are generated. For example, recent evidence indicated that connexin 43 (Cx43) deficiency and pyruvate kinase M2 (PKM2) activation led to a loss of protection in cardiomyocytes. In this context, a better understanding of the mechanisms behind ROS production is vital in determining effective treatment and management strategies for cardiovascular diseases.
Chronic high salt (HS) intake causes minimal changes in blood pressure (BP) but it induces augmented hypertensive response to angiotensin II (AngII) administration in rodents. The mechanism of this augmentation is not clearly understood. As tumor necrosis factor-alpha (TNF-α) induces natriuresis by activating TNF-α receptor type 1 (TNFR1) but not type 2 (TNFR2), we hypothesize that TNFR1 activity is reduced when HS is given in combination of AngII that leads to enhanced sodium retention and thus, causing augmented hypertension. The aim of this study is to examine the responses to chronic HS intake and AngII administration on the renal tissue protein expressions of TNFR1 and TNFR2 in mice.
Different groups of mice (n = 6–7 in each group) chronically treated with or without AngII (25 ng/min; implanted minipump) for 4 weeks which were fed either normal salt (NS; 0.4% NaCl) or high salt (HS; 4% NaCl) diets. Systemic BP was measured by tail-cuff plethysmography. At the end of treatment period, kidneys were harvested after sacrificing the mice with euthanasia. Immuno-histochemical analysis of TNFR1 and TNFR2 proteins in renal tissues was performed by measuring the staining area and the intensity of receptors’ immunoreactivities using NIS-Elements software. The results were expressed in percent area of positive staining and the relative intensity.
HS intake alone did not alter mean BP (HS; 77 ± 1 vs. NS; 76 ± 3 vs. mmHg; tail-cuff plethysmography) but AngII induced increases in BP were augmented in HS group (104 ± 2 vs. 95 ± 2 mmHg; P < 0.05). The area of TNFR1 staining was higher in HS than NS group (6.0 ± 0.9% vs. 3.2 ± 0.7%; P < 0.05) but it was lower in AngII + HS than in AngII + NS group (5.0 ± 0.7% vs. 6.3 ± 0.7%; P = 0.068). TNFR2 immunoreactivity was minimal in NS and HS groups but it was high in AngII + NS and even higher in AngII + HS group.
These data suggest that the HS induced increased TNFR1 activity that facilitates enhanced sodium excretion is compromised in elevated AngII condition leading to salt retention and augmented hypertension.
A case of combined acute and chronic liver injury related to consumption of multi-ingredient nutritional oral supplements containing Aloe Vera gel and vitamin A among other vitamins, minerals and dietary elements such as fish and calamari oil in a 59-year-old female with unexplained hypertransaminasemia is reported. A unique complex liver injury was diagnosed on liver biopsy combining histological features of protracted acute hepatitis, mild manifestation of hypervitaminosis A and lipogranulomatous reaction attributed to Aloe Vera, vitamin A and lipids, respectively. Normalization of liver tests was achieved after discontinuation of all nutritional supplements. Updated Roussel Uclaf Causality Assessment Method (RUCAM) score (+8, probable) further supported herb-induced liver injury. The present case highlights the increasing incidence of complex histological liver injury linked to the constantly growing consumption of multi-ingredient dietary supplements and alternative medications.
Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) molecule approved for the treatment of both type 2 diabetes (T2D) and obesity. Semaglutide has a greater impact on glycated haemoglobin (HbA1c) reduction, compared to other GLP-1 RAs, and is the first molecule of this class available in oral formulation for T2D therapy, representing a useful option for subjects and physicians less prone to start an injective drug. Interestingly, due to its remarkable effects on weight reduction, higher than other GLP-1 RAs and very close to bariatric surgery, semaglutide is designated to change the approach to obesity therapy also in the subject not affected by diabetes. In addition to these favorable features, semaglutide, similarly to other GLP-1 RAs, offers beneficial effects on cardio-vascular (CV), renal, and liver protection, making this molecule an advantageous choice in the therapeutic management of “diabesity” (coexistence of both diabetes and obesity) and its co-morbidity.
While it is commonly thought that left ventricular (LV) systolic function may insidiously deteriorate in hypertensive patients, few prospective data are available to support this notion.
We evaluated 680 hypertensive patients (66 ± 7 years; 45% women) with electrocardiographic (ECG)-LV hypertrophy (ECG-LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echo-sub-study free of prevalent cardiovascular disease and with baseline ejection fraction (EF) ≥ 55%. Echocardiographic examinations were performed annually for 5 years during anti-hypertensive treatment. Development of reduced systolic function was defined as incident EF < 50%.
During a mean follow-up of 4.8 ± 1 years, 37 patients developed reduced EF without an inter-current myocardial infarction (5.4%). In analysis of covariance, patients who developed reduced EF were more often men, had greater baseline LV diameter and LV mass, lower mean EF (all P < 0.05), and similar diastolic function indices. At the last available examination before EF reduction, independently of covariates, patients with reduced EF showed a significant increase in left atrium (LA) size, LV diameter, end-systolic stress and mitral E/A ratio, as compared to those who did not develop reduced EF (all P < 0.05). In time-varying Cox regression analysis, also controlling for baseline EF, predictors of developing reduced EF were higher in-treatment LV diameter [hazard ratio (HR) = 5.19 per cm; 95% confidence interval (CI): 2.58–10.41] and higher in-treatment mitral E/A ratio (HR = 2.37 per unit; 95% CI: 1.58–3.56; both P < 0.0001).
In treated hypertensive patients with ECG-LVH at baseline, incident reduced EF is associated with the development of dilated LV chamber and signs of increased LV filling pressure (ClinicalTrials.gov identifier: NCT00338260).
Whether incident left bundle branch block (LBBB) is associated with increased cardiovascular (CV) morbidity and mortality in treated hypertensive patients with left ventricular hypertrophy (LVH) is unknown. Thus, the present study aimed to examine CV outcomes of incident LBBB in treated hypertensive patients with LVH.
In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, 9,193 hypertensive patients with LVH on screening electrocardiogram (ECG) were randomized to losartan or atenolol based treatment. Participants (n = 8,567) did not have LBBB (Minnesota code 7.1) on baseline ECG. Cox regression models controlling for significant covariates assessed independent associations of incident LBBB with CV events and all-cause mortality during 4.8 years mean follow-up.
Annual follow-up ECGs identified 295 patients (3.4%) with incident LBBB associated with male gender (P < 0.05), older age, higher Cornell voltage (both P < 0.005) and history of diabetes, isolated systolic hypertension and prevalent CV disease. When adjusted for the history of previous CV disease, diabetes, isolated systolic hypertension, the Framingham risk score, ECG-LVH and randomized study treatment, Cox regression models showed that incident LBBB predicted higher risk of the composite endpoint CV death, myocardial infarction and stroke [hazard ratio (HR) 1.9, 95% confidence intervals (CIs) 1.3–2.9, P < 0.001], CV death (HR 3.0, 95% CIs 1.84–5.0, P < 0.001), heart failure (HR 3.6, 95% CIs 1.9–6.6, P < 0.001) and all-cause mortality (HR 3.0, 95% CIs 2.0–4.3, P < 0.001).
These data suggest that among hypertensive patients with ECG-LVH receiving aggressive antihypertensive therapy, incident LBBB independently predicts increased risk of subsequent CV events including congestive heart failure and CV and all-cause mortality (ClinicalTrials.gov identifier: NCT00338260).
The present study investigated the appearance and severity of atrial fibrillation (AF) and heart failure (HF) in 8,702 hypertensive patients with left ventricular hypertrophy (LVH) receiving antihypertensive treatment in a prospective trial.
Patients who had a history of AF or HF were not included, and the participants had sinus rhythm when they were randomly allocated to blinded study medication. Endpoints were adjudicated.
Incident AF occurred in 679 patients (7.8%) and HF in 246 patients (2.8%) during 4.7 ± 1.1 years mean follow-up. Incident AF was associated with a > 4-fold increased risk of developing subsequent HF [hazards ratios (HRs) = 4.7; 95% confidence intervals (CIs), 3.1–7.0; P < 0.001] in multivariable Cox analyses adjusting for age, sex, race, randomized treatment, standard cardiovascular risk factors and incident myocardial infarction. The development of HF as a time-dependent variable was associated with a multivariable-adjusted 3-fold increase of the primary study endpoint (HRs = 3.11; 95% CIs, 1.52–6.39; P < 0.001) which was a composite of myocardial infarction, stroke or cardiovascular death. Incident HF was associated with a > 3-fold increased risk of developing subsequent AF (HRs = 3.3; 95% CIs, 2.3–4.9; P < 0.001). This development of AF was associated with a > 2-fold increase of the composite primary study endpoint in multivariable Cox analysis (HRs = 2.26; 95% CIs, 1.09–4.67; P = 0.028).
Incident atrial fibrillation and heart failure are associated with increased risk of the other in treated hypertensive patients with left ventricular hypertrophy. Such high-risk hypertensive patients who subsequently develop both atrial fibrillation and heart failure have particular high risk of composite myocardial infarction, stroke or cardiovascular death (ClinicalTrials.gov identifier: NCT00338260).
The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed less new-onset atrial fibrillation (AF) in hypertensive patients receiving losartan- vs. atenolol-based treatment. Because losartan reduces serum uric acid (SUA) levels, the aim of the present study was to investigate relations of SUA with new-onset AF in the study.
Hypertensive patients with electrocardiographic (ECG) left ventricular hypertrophy (LVH) and no prior AF (n = 8,243) were treated for 5.0 ± 0.4 years with losartan- or atenolol-based therapy. Associations of SUA with new-onset AF documented by Minnesota coding were assessed by Cox models using SUA and systolic blood pressure as time-varying covariates to take into account changes of SUA related to losartan or diuretic treatment, changes in renal function, and aging.
Time-varying SUA was associated with new AF defined by Minnesota code [hazard ratio (HR) = 1.19 per 16.8 μmol/L (1 mg/dL), (95% confidence intervals (CIs), 1.12–1.26), P < 0.0001], independent of losartan treatment [HR = 0.75 (95% CIs, 0.61–0.93), P = 0.007], older age [HR = 1.95 per 7.0 years (95% CIs, 1.73–2.20), P < 0.0001], male sex [HR = 1.46 (95% CIs, 1.09–1.94), P = 0.010] and higher Cornell voltage-duration product [HR = 1.10 per 1,023 ms·mm (95% CIs, 1.01–1.21), P = 0.034]. Similar results were obtained in Cox models with SUA levels partitioned according to baseline quartiles and in which AF was defined by physician reports or by both Minnesota coding and physician reports.
In-treatment SUA is a strong predictor for new-onset AF in hypertensive patients, independent of effects of antihypertensive treatment, age, sex, and ECG-LVH. Further research is needed to clarify how uric acid may provoke AF (ClinicalTrials.gov identifier: NCT00338260).
T cells play a central role in anti-tumor immunity, and reactive oxygen species (ROS) lie at the crossroad on the anti-tumor T cell responses. To activate efficient T cell immunity, a moderate level of ROS is needed, however, excessive ROS would cause toxicity to the T cells, because the improper level leads to the formation and maintenance of an immunosuppressive tumor microenvironment. Up to date, strategies that modulate ROS, either increasing or decreasing, have been widely investigated. Some of them are utilized in anti-tumor therapies, showing inevitable impacts on the anti-tumor T cell immunity with both obverse and reverse sides. Herein, the impacts of ROS-increasing and ROS-decreasing treatments on the T cell responses in the tumor microenvironment are reviewed and discussed. At the same time, outcomes of combination immunotherapies are introduced to put forward inspirations to unleash the potential of immunotherapies.
Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4+ T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously shown that CD4+ T cells isolated from women with PE cause hypertension, increased tumor necrosis factor alpha (TNF-α), endothelin-1, and soluble fms-like tyrosine kinase-1 (sFlt-1) when injected into pregnant nude-athymic rats compared to CD4+ T cells from normal pregnant (NP) women. However, the role of PE CD4+ T cells to cause AT1-AA as a mechanism of hypertension is not known. Our goal was to determine if PE CD4+ T cells stimulate AT1-AA in pregnant nude-athymic rats.
CD4+ T cells were isolated from human NP and PE placentasand injected into nude-athymic rats on gestational day (GD) 12. In order to examine the role of the PE CD4+ T cells to stimulate B cell secretion of AT1-AA, a subset of the rats receiving PE CD4+ T cells were treated with rituximab on GD 14 or anti-CD40 ligand (anti-CD40L) on GD 12. On GD 19, mean arterial pressure (MAP) and tissues were obtained.
MAP [114 ± 1 mmHg (n = 9)] and AT1-AA [19.8 ± 0.9 beats per minute (bpm, n = 4)] were increased in NP nude + PE CD4+ T cells compared to NP nude + NP CD4+ T cells [98 ± 2 mmHg (n = 7, P < 0.05) and 1.3 ± 0.9 bpm (n = 5, P < 0.05)]. Rituximab (103 ± 2 mmHg, n = 3, P < 0.05) and anti-CD40L (102 ± 1 mmHg, n = 3, P < 0.05) lowered MAP compared to NP nude + PE CD4+ T cells. Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4+ T cells.
These results show that placental CD4+ T cells play an important role in the pathophysiology of PE, by activating B cells secreting AT1-AA to cause hypertension during pregnancy.
Melatonin is the primary hormone of the pineal gland that is secreted at night. It regulates many physiological functions, including the sleep-wake cycle, gonadal activity, free radical scavenging, immunomodulation, neuro-protection, and cancer progression. The precise functions of melatonin are mediated by guanosine triphosphate (GTP)-binding protein (G-protein) coupled melatonin receptor 1 (MT1) and MT2 receptors. However, nuclear receptors are also associated with melatonin activity. Circadian rhythm disruption, shift work, and light exposure at night hamper melatonin production. Impaired melatonin level promotes various pathophysiological changes, including cancer. In our modern society, breast cancer is a serious problem throughout the world. Several studies have been indicated the link between low levels of melatonin and breast cancer development. Melatonin has oncostatic properties in breast cancer cells. This indolamine advances apoptosis, which arrests the cell cycle and regulates metabolic activity. Moreover, melatonin increases the treatment efficacy of cancer and can be used as an adjuvant with chemotherapeutic agents.
Since obesity is one of the main factors in the development of insulin resistance (IR) and is also associated with increased oxidative stress (OxS) rate, this study aims to review the published literature to collate and provide a comprehensive summary of the studies related to the status of the OxS in the pathogenesis of obesity and related IR. OxS represents an imbalance between the production of reactive oxygen and nitrogen species (RONS) and the capacity of the antioxidant defense system (AOS) to neutralize RONS. A steady-state of RONS level is maintained through endogenous enzymatic and non-enzymatic AOS components. Three crucial enzymes, which suppress the formation of free radicals, are superoxide dismutases, catalases, and glutathione peroxidases. The second line of AOS includes non-enzymatic components such as vitamins C and E, coenzyme Q, and glutathione which neutralizes free radicals by donating electrons to RONS. Emerging evidence suggests that high RONS levels contribute to the progression of OxS in obesity by activating inflammatory pathways and thus leading to the development of pathological states, including IR. In addition, decreased level of AOS components in obesity increases the susceptibility to oxidative tissue damage and further progression of its comorbidities. Increased OxS in accumulated adipose tissue should be an imperative target for developing new therapies in obesity-related IR.
The redox status in pathogenesis is critically regulated by careful balance between the generation of reactive oxygen species (ROS) and their elimination. Increased ROS level above the cellular tolerability threshold results in apoptotic or necrotic cell death. ROS belongs to a group of highly reactive compounds that have evolved to play key roles in cellular signaling pathways. It’s widely assumed that a reasonable amount of ROS is essential for a variety of biological processes. Elevated levels of ROS are known to cause various pathologic conditions like neurological disorders, cardiovascular conditions, inflammation, autoimmunity, and cancer. ROS is well known to initiate and assist in progression of tumor by promoting proliferation and survival of cancer cells and thus facilitates pro-tumorigenic signaling in tumor microenvironment. As cancer cells become more resilient to the effects of ROS manipulating drugs, increased antioxidant capacity attenuates their susceptibility to cancer treatment. Excessive environmental stress, on the other hand, can cause cancer cells to die. This review summarizes various molecular mechanisms including the role of checkpoint inhibitors that can be harnessed to develop effective therapeutic strategies for targeting ROS related signaling in cancer.
Cancer is the leading cause of mortality worldwide, which necessitates our consideration related to novel treatment approach. Tumor cells at the tumor microenvironment (TME), regulate a plethora of key mechanistic signaling pathways that obstruct antitumor immune responses by immune suppression, immune resistance or acquired immune tolerance. The present therapeutic regimes are provided independently or in combination, or as immunotherapies for cancer immune targeting. Immunotherapy has altered the arena of oncology and patient care. By using the host immune system, the immunostimulatory molecules can exert a robust, personalized response against the patient’s own tumors. Alternatively, tumors may exploit these strategies to escape immune recognition, and accordingly, such mechanisms represent chances for immunotherapy intervention. Nonetheless, despite promising outcomes from immunotherapies in recurrent and metastatic cancers, immune-therapeutics in clinics have been limited owing to unpredictability in the produced immune response and reported instances of immune-related adverse effects. The unrealized potential of immunotherapies in cancer management maybe due to the obstacles such as heterogeneous nature, multiple targets, patients’ immune response, specificity for cancer or variability in response generation in toxicity levels, delivery and cost related to therapeutics etc. Further revolutionary trends related to immunotherapies are noticeable with slower progress for cancer management. Recent advances in nanomedicine strategize to ameliorate the lacuna of immunotherapy as it relies on the inherent biophysical characteristics of nanocarriers: size, shape, surface charge and multifunctionality and exploiting them as first line therapy for delivery of biomolecules, single checkpoint inhibitors and for imaging of TME. Therefore, nano-assisted immunotherapies can boost the immunotherapeutic approach, overcoming factors that are with imminent potential risks related to it, thereby significantly improving the survival rate associated with it in cancer patients. Nanotechnology is anticipated to overcome the confines of existing cancer immunotherapy and to successfully combine various cancer treatment modes.
Isolated specific glycone–aglycone conjugated flavonoids which are investigated for their effect of bioavailability and molecular concentrations. The specific formula is then tested via in vitro and in vivo cytotoxicity tests.
Considering the higher affinity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), quercetin, quercetin 3-sambubioside-3’-glucoside, luteolin, apigenin-7-4’alloside, kaempferol-7-O-glucoside, epicatechin-epigallocatechin-3-O-gallate, and hesperetin were selected to investigate the effects of a new combination of the formula. Specific chemical analyses, such as high-performance liquid chromatography (HPLC), liquid chromatography–mass spectrometry (LC–MS), quadrupole time of flight mass spectrometry (QTOF–MS) analysis and ultraviolet–visible (UV–VIS) spectrophotometry, were performed for molecular qualification and quantification.
In silico molecular docking analyses have shown that flavonoids can bind strongly to the spike protein and main protease of the SARS-CoV-2 virus. Flavonoids also have anti-inflammatory and immune-modulating activity by inhibiting cytokines. Although flavonoids may be a treatment alternative for coronavirus disease 2019 (COVID-19), an effective flavonoid compound has yet to be developed. The main problem here is that the absorption rate of flavonoids is very low (2–10%) in the intestines, and these compounds are metabolized rapidly. In contrast, according to recent literature, a conjugated flavonoid mixture is better absorbed in the small intestine, and its toxic effects are relatively fewer.
It is found that the new formula has no cytotoxic or genotoxic effects. Furthermore, oral administrations of the new compound did not produce any toxicity symptoms or any mortality in male and female rats. The pre-clinical in vitro and in vivo toxicity test results indicated that the new flavonoid formula can be safely used for clinical trials.
Pseudoexfoliation (PXF) syndrome is an important public health concern requiring individual population level analysis. Disease prevalence differs by geographic location and ethnicity, and has environmental, demographic, genetic, and molecular risk factors have been demonstrated. Epidemiological factors that have been associated with PXF include age, sex, environmental factors, and diet. Genetic and molecular components have also been identified that are associated with PXF. Underserved populations are often understudied within scientific research, including research about eye disease such as PXF, contributing to the persistence of health disparities within these populations. In each population, PXF needs may be different, and by having research that identifies individual population needs about PXF, the resources in that population can be more efficiently utilized. Otherwise, PXF intervention and care management based only on the broadest level of understanding may continue to exacerbate health disparities in populations disproportionally burdened by PXF.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a fundamental role in regulating endothelial function and vascular tone in the physiological conditions of a vascular system. However, oxidative stress has detrimental effects on human health, and numerous studies confirmed that high ROS/RNS production contributes to the initiation and progression of cardiovascular diseases. The antioxidant defense has an essential role in the homeostatic functioning of the vascular endothelial system. Endogenous antioxidative defense includes various molecules and enzymes such as superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. Together all these antioxidative enzymes are essential for defense against harmful ROS features. ROS are mainly generated from redox-active compounds involved in the mitochondrial respiratory chain. Thus, targeting antioxidative enzymes and mitochondria oxidative balance may be a promising approach for vascular diseases occurrence and treatment. This review summarized the most recent research on the regulation of antioxidative enzymes in vascular diseases.
The processes of cancer and embryonic development have a partially overlapping effect. Several transcription factor families, which are highly conserved in the evolutionary history of biology, play a key role in the development of cancer and are often responsible for the pivotal developmental processes such as cell survival, expansion, senescence, and differentiation. As an evolutionary conserved and ubiquitously expression protein, CCCTC-binding factor (CTCF) has diverse regulatory functions, including gene regulation, imprinting, insulation, X chromosome inactivation, and the establishment of three-dimensional (3D) chromatin structure during human embryogenesis. In various cancers, CTCF is considered as a tumor suppressor gene and plays homeostatic roles in maintaining genome function and integrity. However, the mechanisms of CTCF in tumor development have not been fully elucidated. Here, this review will focus on the key roles of CTCF in cancer evolution and development (Cancer Evo-Dev) and embryogenesis.
Tissue-resident macrophages play critically important roles in host homeostasis and pathogenesis of diseases, with the functions of phagocytosis, metabolism, and immune modulation. Recently, two research studies accomplished by a collaborated group of researchers showed that there are two populations of liver resident Kupffer cells (KCs), including a major cluster of differentiation 206 low expression (CD206low)endothelial cell-selective adhesion molecule negative (ESAM−) population (KC1) and a minor CD206highESAM+ population (KC2). Both KC1 and KC2 express KC markers, such as C-type lectin domain family 4 member F (CLEC4F) and T-cell membrane protein 4 (Tim4). In fatty liver, the frequency of KC2 was increased, and those KC2 expressed some markers like liver sinusoidal endothelial cells (LSECs), such as CD31 and ESAM. In addition, KC2 population had a relatively higher expression of CD36, as fatty acid transporter, which was implicated in the production of reactive oxygen species (ROS) and lipid peroxidation. Furthermore, this collaborated group also showed that KC2 can cross-present hepatocellular antigens to prime antiviral function of CD8+ T cells by sensing interleukin-2 (IL-2) in hepatitis B virus (HBV) replication-competent transgenic mice. Increasing evidence shows that targeting hepatic macrophages can prevent and reverse non-alcoholic fatty liver disease (NAFLD), with a new suggested name metabolic dysfunction-associated fatty liver disease (MAFLD) to include metabolic dysfunction-associated fatty liver diseases, such as viruses and alcohol. In summary, differentiating specific populations of hepatic macrophages is critically important for the treatment of MAFLD or NAFLD, and their overlaps. Markers specifically expressed on sub-types of hepatic macrophages may be applied for liver disease diagnosis.
Non-alcoholic fatty liver disease (NAFLD) as the most common chronic liver disease poses a significant impact on public healthcare and economic risk worldwide. As a multifactorial disease, NAFLD is usually associated with many comorbidities such as obesity, insulin resistance, hypertension, hyperlipidemia, diabetes, and cardiovascular disease. Without effectively preventive intervention, the advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). However, there is no approved therapeutic treatment. Excessive fat accumulation in the liver is the hallmark of NAFLD, which can lead to mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Dysfunction of two organelles also induces the upregulation of reactive oxygen species (ROS), activation of the unfolded protein response (UPR), and disruption of calcium transport, which promote NAFLD progression. Herein, this review summarized the current understanding of the roles of mitochondrial dysfunction and ER stress in the pathogenesis of NAFLD. Specifically, this review focused on the key molecules associated with the ER-mitochondria communication and different treatment options by targeting ER stress and mitochondrial dysfunction to treat NAFLD or NASH. Clinical trials to evaluate the therapeutic efficacy of representative agents, such as natural products, metabolites, and modulators of stress, have been reviewed and analyzed. Overall, recent findings suggest that targeting ER stress and mitochondrial dysfunction holds a promise for NAFLD treatment.
The high heterogeneity in the definitions of low back pain encountered in the literature has led to the development of standardized definitions of this condition called “Delphi definitions of low back pain prevalence (Delphi DOLBaPP)” by a group of international researchers. In order to be widely used, these definitions need to be adapted according to the cultural and linguistic context. The aim of this work was to perform the cross-cultural adaptation of the Delphi DOLBaPP definitions in Quebec French and to pre-test them among French-speaking adults.
In order to enable practical use of the Delphi DOLBaPP definitions in different contexts, their presentation was adapted in the form of a questionnaire (referred to as the “Delphi DOLBaPP questionnaire”). The process of cross-cultural adaptation of the Delphi DOLBaPP questionnaire in French was conducted according to the most recognized recommendations for the cultural adaptation of measuring instruments. The resulting questionnaire and an evaluation form were then submitted to a sample of 82 adults.
A total of 41 participants (50.0%) reported low back pain. A high proportion of participants (89.0%) stated that it took them less than 5 minutes to complete the questionnaire. More than 62.0% of them did not find any question poorly worded or confusing. Nearly 80.0% of the participants found the questionnaire easy to understand. The cross-cultural adaptation process suggested minor modifications to the original Delphi DOLBaPP questionnaire.
This study has produced a cross-cultural adaptation of the Delphi DOLBaPP questionnaire in Quebec French that will enable French-speaking populations to share the benefits of using standardized definitions of low back pain in epidemiological studies.
Antenatal screening for hepatitis B surface antigen seropositivity is widely adopted to identify pregnant women with chronic hepatitis B virus (HBV) infection in order to target their newborn infants for combined passive-active neonatal immunization to prevent the maternal-to-child transmission of HBV. It is less certain whether the presence of chronic HBV infection in these largely asymptomatic women could impact their pregnancy outcome. There is now gathering information in the literature, though sometimes conflicting, on the obstetric implications of chronic HBV infection. The conflicting data is most probably related to confounding factors such as the immunological phase of chronic HBV infection, viral genotype and activity, presence of hepatic inflammation and other co-existing liver disorders such as non-alcoholic fatty liver disease, and coinfection with other virus such as hepatitis C virus and micro-organisms, which are usually not examined, but which could have made significant influence on the occurrence of many of the pregnancy complications and adverse fetal and neonatal outcome. For pregnancy complications, the evidence suggests association with increased gestational diabetes mellitus, preterm birth, intrahepatic cholestasis of pregnancy, caesarean delivery, and postpartum haemorrhage, probably increased placental abruption and prelabour rupture of the membranes, and no effect or a reduction in the hypertensive disorders of pregnancy, especially preeclampsia. For perinatal outcome, there may be increased miscarriage and fetal malformations, and increase in both low birthweight and large-for-gestational age/macrosomic infants, as well as increased intrauterine fetal demise/stillbirth and fetal distress. However, most studies have not elaborated on the mechanisms or explanations of many of the adverse outcomes. Taken together, maternal chronic HBV infection increases the risk of adverse obstetric outcome overall, but further prospective studies are warranted to elucidate the reasons and mechanisms of, and with a view to mitigating, these adverse obstetric outcomes.
According to the Global Cancer Observatory (GLOBOCAN) 2020, colorectal carcinoma (CRC) was the second leading cause of cancer death globally. Current literature utilizes reported databases such as Surveillance, Epidemiology, and End Results (SEER) to better understand the epidemiology of CRC. The global cancer observatory’s “Cancer Tomorrow” data visualization tools were used to predict the future incidence and mortality of colorectal cancers until 2030 as a guided tool to look over ways to reduce incidence by controlling risk factors of CRC. The total number of CRC is expected to rise by 2030, with a percent change of 17.3%. The expected percent change in colon cancer is more than rectal cancer (19.8% vs. 11.6%). The estimated number of deaths secondary to CRC is expected to increase in 2030, an estimated percent change of 22.2%. The incidence and mortality rate was higher in men vs. women; however, the gap seems to be closing on trend analysis. Major risk factors for CRC include familial syndromes, family history, race, gender, obesity, diet, alcohol, and smoking. Risk can be reduced by exercise and dietary changes, fiber intake, vitamin D, calcium, and minerals. Individualized screening based on age, gender, and additional risk factors could be an option that needs further comparative data to propose a definitive benefit over established screening guidelines.
Pregnancy increases the risk of common vascular events and also the rarer events like aortic dissection (AD)/aortic rupture and this is even more pronounced in patients with predisposing aortopathies. AD was found to occur in 0.0004% of all pregnancies, and it is more pronounced in patients with underlying connective tissue disorders. The normal hemodynamic changes on a weak aorta will lead to AD and/or rupture, more so with increase in the period of gestation. Hence the haemodynamic and hormonal changes during pregnancy make pregnancy itself a risk factor for AD. It is advised that women with Marfan syndrome who are planning pregnancy should go through prophylactic aortic repair if the diameter of the ascending aorta exceeds 4 cm. Pre-pregnancy counselling is very important in these patients and must include complete history taking, including family history, physical examination and advanced aortic imaging. There is a general consensus among various authors advising against surgery during pregnancy in stable patients due to increased maternal and fetal morbidity but it is justified if the condition is refractory to medical management or in life threatening stage like acute AD. Though the incidence of aortopathy in pregnancy is rare, there is a high maternal and fetal mortality associated with this condition.
Recently, Arrese and Colleagues have published a review article entitled, “Insights into Nonalcoholic Fatty-Liver Disease (NAFLD) Heterogeneity” (Semin Liver Dis. 2021;41:421–34. doi: 10.1055/s-0041-1730927). This milestone publication clearly and exhaustively explains the multitude of pathogenic pathways involved in the development and progression of disease eventually conducive to heterogeneous clinical phenotypes and different disease outcomes. The present commentary first briefly discusses the biological grounds of NAFLD heterogeneity and then illustrates the work by Arrese et al. In conclusion, the presently adopted nomenclatures appear inadequate in rendering the complexity of disease in the individual patient. In order to adopt the principles of personalized care, what remains to be done is to propose and validate a simple and accurate classification system. This should give full consideration to the principal disease modifiers and should shape a scheme to be adopted in both clinical practice and in the research arena. Care should be taken to not neglect the systemic nature of disease.
Excessive reactive oxygen species (ROS) may cause oxidative stress which is involved in aging and in the pathogenesis of various human diseases. Whereas unregulated levels of the ROS may be harmful, regulated basal level of ROS is even necessary to support cellular functions as a second messenger for homeostasis under physiological conditions. Therefore, redox medicine could develop as a new therapeutic concept for human health-benefits. Here, we introduce the involvement of ROS on the crossroads of stemness, senescence, and carcinogenesis in a stem cell and cancer cell biology. Amazingly, the anti-proliferative (APRO) family anti-proliferative proteins characterized by immediate early growth responsive genes may also be involved in the crossroads machinery. The biological functions of APRO proteins (APROs) seem to be quite intricate, however, which might be a key modulator of microRNAs (miRNAs). Given the crucial roles of ROS and APROs for pathophysiological functions, upcoming novel therapeutics should include vigilant modulation of the redox state. Next generation of medicine including regenerative medicine and/or cancer therapy will likely comprise strategies for altering the redox environment with the APROs via the modulation of miRNAs as well as with the regulation of ROS of cells in a sustainable manner.
As the novel coronavirus disease 2019 (COVID-19) pandemic impacts the global healthcare system, evolving data show increased frequency of arterial and venous thromboembolism among patients with COVID-19 infection. Aortic thrombus is a rare thrombotic event with a wide spectrum of clinical manifestations and potential catastrophic complications. This study aimed to elucidate the clinical manifestations, diagnosis and treatment dilemmas of aortic thrombus with COVID-19 infection and raise awareness among frontline medical providers. Aortic thrombosis is rare, but if not considered early in the course of COVID-19 infection, the data suggest that the diagnosis will probably not be made until potentially serious complications arise.
Literature review was conducted between November 1, 2019, and November 14, 2020, on PubMed and Embase to identify publications regarding aortic thrombosis among COVID-19 cases.
Most of the patients were male with a median age of 67 years, and had comorbidities (most commonly hypertension, dyslipidemia and diabetes mellitus). In our study, underlying atherosclerosis, a common risk factor for aortic thrombus, was identified among 56% of the patients. Aortic thrombus was symptomatic in 62% of these patients and most commonly manifested itself as acute limb ischemia (46%), whereas 30% of cases were found incidentally during the investigation of elevated inflammatory markers or increased oxygen requirement. Treatment was individualized given the lack of established guidelines for aortic thrombus, including anticoagulation, systemic and catheter directed thrombolysis, and surgical thrombectomy. Overall mortality was found to be 30% in our study.
Although rare, aortic thrombus has high morbidity and mortality, and can present without any symptoms or underlying aortic disease. Aortic thrombosis is rare, but if not considered early in the course of COVID-19 infection, the data suggest that the diagnosis will probably not be made until potentially serious complications arise.
With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.
Smartphone technology is increasingly used by the public to assess sleep. Specific features of some sleep-tracking applications are comparable to actigraphy in objectively monitoring sleep. The clinical utility of smartphone apps should be investigated further to increase access to convenient means of monitoring sleep.
Smartphone and subjective sleep measures were administered to 29 community-dwelling healthy adults [aged 20–67, Mean (M) = 26.8; 18 women, 11 men], and actigraphy to 19 of them. Total sleep time (TST) and sleep efficiency were measured with actigraphy and the Sleep Time App (Azumio Inc.). Sleep diaries captured subjective TST and sleep efficiency, and the Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index provided self-report data. An exit questionnaire was administered to examine App feasibility and likelihood of future use.
The App significantly overestimated TST when compared to actigraphy. There was no significant difference in sleep efficiency between methodologies. There was also no significant difference between TST recorded through the App and through sleep diaries. Participants’ self-reported ease of use of the smartphone App positively correlated with likelihood of future use.
Based on the current findings, future research is needed to investigate the utility and feasibility of multiple smartphone applications in monitoring sleep in healthy and clinical populations.
The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca2+, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca2+-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dysfunction during the progression of heart failure.
Monitoring the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) immunization in patients with autoimmune diseases is of particular concern to understand their response to the infection and to the vaccine. In fact, the immunological disorder and the immunosuppressive therapies could affect the serological response. SARS-CoV2 serological tests potentially provide this information, although they were rapidly commercialized with internal verifications. Here, we analysed the seroprevalence to SARS-CoV2 in a cohort of patients with liver autoimmune diseases.
From May to December 2020, a cohort of patients affected by primary biliary cholangitis (PBC), autoimmune hepatitis (AIH) and PBC/AIH overlap syndrome were screened with reverse transcription-polymerase chain reaction (RT-PCR) of nasopharyngeal swabs, rapid antigenic test and chemiluminescent serological test during routine follow-up.
The analysis of 42 patients was carried out: 18 (42.85%) PBC, 12 (28.57%) AIH and 12 (28.57%) PBC/AIH overlap syndromes. Only 2 patients (4.76%) resulted positive to the RNA, antigen and antibody detection tests, hence affected by SARS-CoV2 infection. 14 subjects out of 40 negative cases presented a positive serology for SARS-CoV2 antibodies, hence with a false positivity in the 35% of cases without infection. Notably, among these, 6 (42.86%) patients presented only immunoglobulin (Ig)M positivity, 6 (42.86%) patients presented positivity for only IgG and 2 (14.28%) patients were positive to both IgM and IgG. Notably, the presence of autoantibodies did not correlate with the serological false positivity, highlighting that there is no cross-reactivity with autoantibodies. Moreover, the presence of polyclonal hypergammaglobulinemia did not interfere with the serological test as its prevalence is not different between negative and false positive cases. Interestingly, the patients with false positive serology showed higher levels of gamma-glutamyltransferase (GGT) and C-reactive protein (CRP).
Patients with liver autoimmune diseases present a high rate of false positive SARS-CoV2 serology. Therefore, new strategies are needed to study the serological response in this patient category.
Acute aortic syndromes, including aortic dissection (AD), are rare. The AD detection risk score (ADDRS) and associated investigation pathway were developed to reduce missed diagnosis of AD. The methodology for its development was sub-optimal and it has not been robustly validated in the emergency department chest pain population. Recent research suggests that it will drive over-investigation and that the risks of missed diagnosis may not be in balance with the risks of the testing strategy. There are serious doubts about whether the score and investigation pathway are fit for purpose.
Submucosal esophageal hematoma is an uncommon clinical complication of anticoagulation. Current literature is scarce regarding presentation and management in acute submucosal hematomas in critically ill patients. Patients often present with retrosternal chest pain, making the diagnosis challenging due to overlap with common presentations of cardiopulmonary disorders. A high degree of suspicion is necessary in sedated patients. Several factors contribute to its etiology, and diagnosis often requires invasive techniques like endoscopy. However, management is usually supportive and aimed at its underlying cause. This is a case of a 68-year-old female who developed submucosal esophageal hematomas following anticoagulation for subarachnoid hemorrhage-related delayed neurological deficits in the intensive care unit.
Central pontine myelinolysis (CPM) is a rare manifestation of osmotic demyelination syndrome (ODS) which involves the pons and causes significant morbidity and mortality. CPM usually occurs in the setting of rapid correction of severe chronic hyponatremia. A rare case of CPM due to hyperglycemia in a 27-year-old man with type 1 diabetes is reported. During the patient’s hospitalization, his plasma glucose level showed a wide variability ranging from 38 mg/dL to 530 mg/dL; while plasma sodium level was constantly normal. At computed tomography (CT) scans, areas of hypodensity with a hyperdense ring were identified in the anterior part of the pons. At magnetic resonance imaging (MRI) scan, pontine abnormalities compatible with CPM were observed. According to laboratory tests, we concluded that CPM resulted from rapid and wide shifts in osmolar gradient owing to variability in plasma glucose levels. While universally recognized in several clinical settings, CPM is rarely observed in diabetic patients. Our report supports the notion that hyperosmolarity per se plays a key role in the pathogenesis of CPM, which may occur independently of sodium abnormalities.
The term non-alcoholic fatty liver disease (NAFLD) appears unfitting both in adults and in children. As obesity and metabolic syndrome play a relevant pathogenic role, an international group of adults’ liver disease experts has proposed to rename this condition metabolic (dysfunction)-associated fatty liver disease (MAFLD). While this new more appropriate and useful definition has mostly been met with good reactions in adults, it may present a tangled path in pediatrics. Here we further stress the recommendations of the North American and the European Societies for Pediatric Gastroenterology, Hepatology and Nutrition that a hyperechogenic liver in a child affected by obesity or overweight with chronically elevated liver enzymes should not be assumed to have NAFLD only. Especially in those patients who are not in the classic age range or who have particularly severe laboratory anomalies, other genetic, metabolic (inborn errors of metabolism, IEM), endocrine, intestinal and hepatic pediatric-onset conditions, should in fact be excluded, particularly when response to a weight loss trial is not available. The term pediatric fatty liver disease (PeFLD) with three subtypes [1. contextual diagnosis of an IEM; 2. metabolic (dysfunction)-associated fatty liver; 3. unknown cause of fatty liver] has recently been proposed aiming to separate true MAFLD from IEM and/or the other above mentioned conditions, which may be rare when considered individually but represent a large group when considered collectively. Although the cost-effectiveness ratio of this attitude is still indeterminate, it is likely that the advantage of the early identification of a specifically treatable pediatric-onset liver disease associated to/mimicking MAFLD would be rewarding.
Obesity and metabolic syndrome are conditions at high risk for the development of complications such as type 2 diabetes mellitus, atherosclerotic cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). The growing prevalence of NAFLD has recently raised attention in the clinical practice, due to the worsening prognosis observed in the affected patients. Sex hormones abnormalities, commonly found in subjects suffering from obesity and metabolic syndrome, have been recently hypothesized to be directly involved in the physiopathology of obesity-related comorbidites; however, their role in the pathogenesis of NAFLD remains unclear. In this review of the available literature, a summary of the knowledge about the role of sex steroids abnormalities in the risk of developing NAFLD was performed, mentioning the possible clinical implications for therapy.
Some have said that it is inappropriate and perhaps impossible to consider wave and Windkessel phenomena simultaneously. For 50 years, arterial hemodynamics has been dominated by the frequency-domain “impedance analysis” in which it was assumed that all variations in aortic pressure and flow were caused only by forward- and backward-going waves. This paper is a review of the results of incorporating the effects of Frank’s Windkessel. We have taken the view that measured aortic pressure is the sum of a Windkessel component and forward-going and backward-going wave components. When the Windkessel component is initially subtracted out, the pattern of propagation and reflection of wave components becomes clear. Furthermore, this analysis obviates the implications of impedance analysis that have not been explained satisfactorily.
Immunotherapy is a unique approach to treat cancer that targets tumours besides triggering the immune cells. It attempts to harness the supremacy and specificity of immune cells for the regression of malignancy. The key strategy of immunotherapy is that it boosts the natural defence and manipulates the immune system at both cellular and molecular levels. Long-lasting anti-tumour response, reduced metastasis, and recurrence can be achieved with immunotherapy than conventional treatments. For example, targeting cytotoxic T-lymphocyte antigen-4 (CTLA4) by monoclonal antibody is reported as an effective strategy against cancer progression in vivo and chimeric antigen receptor (CAR) modified T-cells are known to express a stronger anti-tumour activity. CTLA4 and CAR are, therefore, beneficial in cancer immunotherapy; however, in clinical settings, both are expensive and cause adverse side effects. Nanomaterials have augmented advantages in cancer immunotherapy, besides their utility in effective delivery and diagnostics. In particular, materials based on lipids, polymers, and metals have been sought-after for delivery technologies. Moreover, the surface of nanomaterials can be engineered using ligands, antigens, and antibodies to target immune cells. In this sense, checkpoint inhibitors, cytokines, agonistic antibodies, surface receptors, and engineered T-cells are promising to regulate the immune system against tumours. Therefore, emerging nanomaterials that can be used for the treatment of cancer is the prime focus of this review. The correlation of mode of administration and biodistribution of various nanomaterials is reviewed here. Besides, the acute and chronic side effects and outcome of clinical trials in the context of cancer immunotherapy are discussed.
Although clinicians primarily diagnose dementia based on a combination of metrics such as medical history and formal neuropsychological tests, recent work using linguistic analysis of narrative speech to identify dementia has shown promising results. We aim to build upon research by Thomas JA & Burkardt HA et al. (J Alzheimers Dis. 2020;76:905–2) and Alhanai et al. (arXiv:1710.07551v1. 2020) on the Framingham Heart Study (FHS) Cognitive Aging Cohort by 1) demonstrating the predictive capability of linguistic analysis in differentiating cognitively normal from cognitively impaired participants and 2) comparing the performance of the original linguistic features with the performance of expanded features.
Data were derived from a subset of the FHS Cognitive Aging Cohort. We analyzed a sub-selection of 98 participants, which provided 127 unique audio files and clinical observations (n = 127, female = 47%, cognitively impaired = 43%). We built on previous work which extracted original linguistic features from transcribed audio files by extracting expanded features. We used both feature sets to train logistic regression classifiers to distinguish cognitively normal from cognitively impaired participants and compared the predictive power of the original and expanded linguistic feature sets, and participants’ Mini-Mental State Examination (MMSE) scores.
Based on the area under the receiver-operator characteristic curve (AUC) of the models, both the original (AUC = 0.882) and expanded (AUC = 0.883) feature sets outperformed MMSE (AUC = 0.870) in classifying cognitively impaired and cognitively normal participants. Although the original and expanded feature sets had similar AUC, the expanded feature set showed better positive and negative predictive value [expanded: positive predictive value (PPV) = 0.738, negative predictive value (NPV) = 0.889; original: PPV = 0.701, NPV = 0.869].
Linguistic analysis has been shown to be a potentially powerful tool for clinical use in classifying cognitive impairment. This study expands the work of several others, but further studies into the plausibility of speech analysis in clinical use are vital to ensure the validity of speech analysis for clinical classification of cognitive impairment.
Impaired sleep quality and sleep oxygenation are common sleep pathologies. This study assessed the impact of these abnormalities on white matter (WM) integrity in an epidemiological cohort.
The target population was the Framingham Heart Study Generation-2/Omni-1 Cohorts. Magnetic resonance imaging (diffusion tensor imaging) was used to assess WM integrity. Wearable digital devices were used to assess sleep quality: the (M1-SleepImageTM system) and the Nonin WristOx for nocturnal oxygenation. The M1 device collects trunk actigraphy and the electrocardiogram (ECG); sleep stability indices were computed using cardiopulmonary coupling using the ECG. Two nights of recording were averaged.
Stable sleep was positively associated with WM health. Actigraphic periods of wake during the sleep period were associated with increased mean diffusivity. One marker of sleep fragmentation which covaries with respiratory chemoreflex activation was associated with reduced fractional anisotropy and increased mean diffusivity. Both oxygen desaturation index and oxygen saturation time under 90% were associated with pathological directions of diffusion tensor imaging signals. Gender differences were noted across most variables, with female sex showing the larger and significant impact.
Sleep quality assessed by a novel digital analysis and sleep hypoxia was associated with WM injury, especially in women.
The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. Besides its importance as regulator of the cardiovascular function, the RAS has also been associated to the modulation of higher brain functions, including cognition, memory, depression and anxiety. For many years, angiotensin II (Ang II) has been considered the major bioactive component of the RAS. However, the existence of many other biologically active RAS components has currently been recognized, with similar, opposite, or distinct effects to those exerted by Ang II. Today, it is considered that the RAS is primarily constituted by two opposite arms. The pressor arm is composed by Ang II and the Ang II type 1 (AT1) receptor (AT1R), which mediates the vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory effects of the RAS. The depressor arm is mainly composed by Ang-(1-7), its Mas receptor (MasR) which mediates the depressor, vasodilatory, antiproliferative, antioxidant and anti-inflammatory effects of Ang-(1-7) and the AT2 receptor (AT2R), which opposes to the effects mediated by AT1R activation. Central Ang-(1-7) is implicated in the control of the cardiovascular function, thus participating in the regulation of blood pressure. Ang-(1-7) also exerts neuroprotective actions through MasR activation by opposing to the harmful effects of the Ang II/AT1R axis. This review is focused on the expression and regulation of the Ang-(1-7)/MasR axis in the brain, its main neuroprotective effects and the evidence regarding its involvement in the pathophysiology of several diseases at cardiovascular and neurological level.
The adrenal cortex plays a key role in the regulation of metabolism, salt and water homeostasis and sex differentiation by synthesizing glucocorticoid, mineralocorticoid and androgen hormones. Evidence exists that angiotensin II regulates adrenocortical function and it has been contended that angiotensin peptides of the non-canonical branch of the renin angiotensin system (RAS) might also modulate steroidogenesis in adrenals. Thus, the aim of this review is to examine the role of the RAS, and particularly of the angiotensin peptides and their receptors, in the regulation of adrenocortical hormones with particular focus on aldosterone production.
Vascular aging, aortic stiffness and hypertension are mechanistically interrelated. The perspective presented here will focus mainly on the molecular mechanisms of age-associated increases in the stiffness of the vascular smooth muscle cell (VSMC). This review will highlight the mechanisms by which the VSMC contributes to disorders of vascular aging. Distinct functional sub-components of the vascular cell and the molecular mechanisms of the protein-protein interactions, signaling mechanisms and intracellular trafficking processes in the setting of the aging aorta will be detailed.
Nucleolin (NCL) is a multifunctional nucleolar phosphoprotein harboring critical roles in cells such as cell proliferation, survival, and growth. The dysregulation and overexpression of NCL are related to various pathologic and oncological indications. These characteristics of NCL make it an ideal target for the treatment of various cancers. AS1411 is a synthetic quadruplex-forming nuclease-resistant DNA oligonucleotide aptamer which shows a considerably high affinity for NCL, therefore, being capable of inducing growth inhibition in a variety of tumor cells. The high affinity and specificity of AS1411 towards NCL make it a suitable targeting tool, which can be used for the functionalization of therapeutic payload-delivery nanosystems to selectively target tumor cells. This review explores the advances in NCL-targeting cancer therapy through AS1411-functionalized delivery nanosystems for the selective delivery of a broad spectrum of therapeutic agents.
The limitations of current cancer treatments have stimulated the application of nanotechnology to develop more effective and safer cancer therapies. Remarkable progress has been made in the development of nanomedicine to overcome issues associated with conventional cancer treatment, including low drug solubility, insufficient targeting, and drug resistance. The modulation of nanoparticles allows the improvement of drug pharmacokinetics, leading to improved targeting and reduced side effects. In addition, nanoparticles can be conjugated to ligands that specifically target cancer cells. Furthermore, strategies that exploit tumor characteristics to locally trigger drug release have shown to increase targeted drug delivery. However, although some clinical successes have been achieved, most nanomedicines fail to reach the clinic. Factors that hinder clinical translation vary from the complexity of design, incomplete understanding of biological mechanisms, and high demands during the manufacturing process. Clinical translation might be improved by combining knowledge from different disciplines such as cell biology, chemistry, and tumor pathophysiology. An increased understanding on how nanoparticle modifications affect biological systems is pivotal to improve design, eventually aiding development of more effective nanomedicines. This review summarizes the key successes that have been made in nanomedicine, including improved drug delivery and release by polymeric nanoparticles as well as the introduction of strategies that overcome drug resistance. In addition, the application of nanomedicine in immunotherapy is discussed, and several remaining challenges addressed.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening drug reaction, which can affect multiple organs. Patients with DRESS syndrome and hepatic manifestations may present alterations ranging from mild hepatitis to acute liver failure. The diagnosis might be difficult, and the management of these patients is challenging. This report analyzes a series of five cases reporting the clinical presentation, which ranged from acute hepatitis to liver failure, and discussed their treatment.
The renal lesions–including severe acute kidney injury–are severe outcomes in severe acute respiratory syndrome coronavirus 2 infections. There are no reports regarding the influence of the nutritional status on the severity and progress of these lesions. Ageing is also an important risk factor.
In the present study we compared the influence of overweight and undernutrition on the levels of renal angiotensin converting enzymes 1 and 2 (ACE and ACE2), which were evaluated by Western blotting. Since the renin-angiotensin-aldosterone system (RAAS) has been implicated in the progress of kidney failure during coronavirus disease 2019, the influence of Angiotensin-(3-4) [Ang-(3-4)] was investigated. Ang-(3-4) is the shortest angiotensin-derived peptide, which is considered the physiological antagonist of several Ang II effects.
Both overweight and undernutrition downregulate the levels of ACE2 without influence on the levels of ACE in proximal tubules from kidney rats. Administration of Ang-(3-4) upregulates ACE2 to levels above the control in overweight but not in undernourished rats.
Chronic undernourishment and overnourishment conditions play a central role in the renal ACE/ACE2 balance, and that the role of RAAS is also different in overweight and undernutrition.
Reduced pre-operative cognitive functioning in older adults is a risk factor for postoperative complications, but it is unknown if preoperative digitally-acquired clock drawing test (CDT) cognitive screening variables, which allow for more nuanced examination of patient performance, may predict lengthier hospital stay and greater cost of hospital care. This issue is particularly relevant for older adults undergoing transcatheter aortic valve replacement (TAVR), as this surgical procedure is chosen for intermediate-risk older adults needing aortic replacement. This proof of concept research explored if specific latency and graphomotor variables indicative of planning from digitally-acquired command and copy clock drawing would predict post-TAVR duration and cost of hospitalization, over and above age, education, American Society of Anesthesiologists (ASA) physical status classification score, and frailty.
Form January 2018 to December 2019, 162 out of 190 individuals electing TAVR completed digital clock drawing as part of a hospital wide cognitive screening program. Separate hierarchical regressions were computed for the command and copy conditions of the CDT and assessed how a-priori selected clock drawing metrics (total time to completion, ideal digit placement difference, and hour hand distance from center; included within the same block) incrementally predicted outcome, as measured by R2 change significance values.
Above and beyond age, education, ASA physical status classification score, and frailty, only digitally-acquired CDT copy performance explained significant variance for length of hospital stay (9.5%) and cost of care (8.9%).
Digital variables from clock copy condition provided predictive value over common demographic and comorbidity variables. We hypothesize this is due to the sensitivity of the copy condition to executive dysfunction, as has been shown in previous studies for subtypes of cognitive impairment. Individuals undergoing TAVR procedures are often frail and executively compromised due to their cerebrovascular disease. We encourage additional research on the value of digitally-acquired clock drawing within different surgery types. Type of cognitive impairment and the value of digitally-acquired CDT command and copy parameters in other surgeries remain unknown.
In recent years, cancer immunotherapy has received unprecedented attention due to the clinical achievements. The applications of biomedical engineering and materials science to cancer immunotherapy have solved the challenges caused by immunotherapy to a certain extent. Among them, cell-derived vesicles are natural biomaterials chosen as carriers or immune-engineering in view of their many unique advantages. This review will briefly introduce the recent applications of cell-derived vesicles for cancer immunotherapy.
Substance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively). A genome-wide association study of OD and CD related phenotypes reflecting the time between first self-reported use of these substances and a first DSM-IV dependence diagnosis was conducted.
Cox proportional hazards regression in a discovery sample of 6,188 African-Americans (AAs) and 6,835 European-Americans (EAs) participants in a genetic study of multiple substance dependence phenotypes were used to test for association between genetic variants and these outcomes. The top findings were tested for replication in two independent cohorts.
In the discovery sample, three independent regions containing variants associated with time to dependence at P < 5 × 10−8 were identified, one (rs61835088 = 1.03 × 10−8) for cocaine in the combined EA-AA meta-analysis in the gene FAM78B on chromosome 1, and two for opioids in the AA portion of the sample in intergenic regions of chromosomes 4 (rs4860439, P = 1.37 × 10−8) and 9 (rs7032521, P = 3.30 × 10−8). After meta-analysis with data from the replication cohorts, the signal at rs61835088 improved (HR = 0.87, P = 3.71 × 10−9 and an intergenic SNP on chromosome 21 (rs2825295, HR = 1.14, P = 2.57 × 10−8) that missed the significance threshold in the AA discovery sample became genome-wide significant (GWS) for CD.
Although the two GWS variants are not in genes with obvious links to SUD biology and have modest effect sizes, they are statistically robust and show evidence for association in independent samples. These results may point to novel pathways contributing to disease progression and highlight the utility of related phenotypes to better understand the genetics of SUDs.
Popularity of electronic cigarettes (i.e. e-cigarettes) is soaring in Canada. Understanding person-level correlates of current e-cigarette use (vaping) is crucial to guide tobacco policy, but prior studies have not fully identified these correlates due to model overfitting caused by multicollinearity. This study addressed this issue by using classification tree, a machine learning algorithm.
This population-based cross-sectional study used the Canadian Tobacco, Alcohol, and Drugs Survey (CTADS) from 2017 that targeted residents aged 15 or older. Forty-six person-level characteristics were first screened in a logistic mixed-effects regression procedure for their strength in predicting vaper type (current vs. former vaper) among people who reported to have ever vaped. A 9:1 ratio was used to randomly split the data into a training set and a validation set. A classification tree model was developed using the cross-validation method on the training set using the selected predictors and assessed on the validation set using sensitivity, specificity and accuracy.
Of the 3,059 people with an experience of vaping, the average age was 24.4 years (standard deviation = 11.0), with 41.9% of them being female and 8.5% of them being aboriginal. There were 556 (18.2%) current vapers. The classification tree model performed relatively well and suggested attraction to e-cigarette flavors was the most important correlate of current vaping, followed by young age (< 18) and believing vaping to be less harmful to oneself than cigarette smoking.
People who vape due to flavors are associated with very high risk of becoming current vapers. The findings of this study provide evidence that supports the ongoing ban on flavored vaping products in the US and suggests a similar regulatory intervention may be effective in Canada.
Prior research employing a standard backward digit span test has been successful in operationally defining neurocognitive constructs associated with the Fuster’s model of executive attention. The current research sought to test if similar behavior could be obtained using a cross-modal mental manipulation test.
Memory clinic patients were studied. Using Jak-Bondi criteria, 24 patients were classified with mild cognitive impairment (MCI), and 33 memory clinic patients did not meet criteria for MCI (i.e. non-MCI). All patients were assessed with the digital version of the WRAML-2 Symbolic Working Memory Test-Part 1, a cross-modal mental manipulation task where patients hear digits, but respond by touching digits from lowest to highest on an answer key. Only 4 and 5-span trials were analyzed. Using an iPad, all test stimuli were played; and, all responses were obtained with a touch key. Only correct trials were analyzed. Average time to complete trials and latency for each digit was recorded.
Groups did not differ when average time to complete 4-span trials was calculated. MCI patients displayed slower latency, or required more time to re-order the 1st and 3rd digits. Regression analyses, primarily involving initial and latter response latencies, were associated with better, but different underlying neuropsychological abilities. Almost no 5-span analyses were significant.
This cross-modal test paradigm found no difference for total average time. MCI patients generated slower 1st and 3rd response latency, suggesting differences in time allocation to achieve correct serial order recall. Moreover, different neuropsychological abilities were associated with different time-based test components. These data extend prior findings using a standard backward digit span test. Differences in time epochs are consistent with constructs underlying the model of executive attention and help explain mental manipulation deficits in MCI. These latency measures could constitute neurocognitive biomarkers that track emergent disease.
Diabetic foot syndrome (DFS) is a complication of diabetes in which the presence of infections, ulceration and/or destruction of deep tissue associated with neuropathy, peripheral atherosclerosis and comorbidity affect the prognosis, the need for limb amputation and quality of life. Purpose of the present study is to report the features of patients with acute DFS admitted to our Diabetic Foot Unit tertiary Center in 2019.
In all patients admitted, the approach was performed through a multidisciplinary team (Diabetic Foot Care Team) and described in a specific diagnostic-therapeutic-assistance program. Criteria of inclusion were presence of sepsis and/or suspected osteomyelitis and/or critical limb ischemia. Clinical features and interventions performed were registered. Primary endpoints were mortality and amputation (major, minor). Secondary endpoints were length of hospitalization, type of revascularization and duration of antibiotic therapy.
Among 75 consecutive patients (mean age 70.9 years) enrolled, prevalence of acute DFS was higher among men (M/F 3:1). Poor glycemic control [mean hemoglobin A1c (HbA1c) 67.9 ± 22.3 mmol/mol], long duration of diabetes (mean 19 ± 16.3 years), high low-density lipoprotein-cholesterol (mean 89.5 ± 45.1 mg/ dL) and obesity (mean Body Mass Index 30.2 ± 7.6 kg/m2) were common. Diabetes-related complications as peripheral arterial disease (PAD) (76%), ischemic heart disease (48%), retinopathy (40.5%), hepatic steatosis (50%), heart failure (17.8%) were present. During hospitalization, 21 subjects (28.4%) underwent lower limb amputations (overall rate of major amputation 4%), and 41.3% underwent percutaneous angioplasty. Long period of hospitalization (18.4 ± 7.9 days) and prolonged antibiotic therapy (23.9 ± 15.9 days) were observed. Major amputation was associated with C-reactive protein > 6.5 mg/dL (P = 0.03), osteomyelitis (P = 0.001), prior insulin therapy (P = 0.015).
Male sex, co-morbidity, PAD, systemic inflammation and poor glycemic control are major features of acute hospitalized DFS. An approach through a multidisciplinary team is recommended in order to treat vascular and extra-vascular complications aimed at reducing mortality and at improving quality of life.
Patients submitted to liver transplantation (LT) are exposed to high risk of cardiovascular (CV) complications which are the main determinants of both short-term and long-term morbidity and mortality in LT. Non-alcoholic fatty liver disease (NAFLD) is a very frequent condition in general population and is associated with a high risk of cardiovascular disease (CVD) which represents the first cause of death of these patients. NAFLD is predicted to become the first indication to LT and nowadays is also frequently detected in patients submitted to LT for other indications. Thus, the risk of CVD in patients submitted to LT is forecasted to increase in the next years. In this review the extent of CV involvement in patients submitted to LT and the role of NAFLD, either recurring after transplantation or as de novo presentation, in increasing CV risk is analysed. The risk of developing metabolic alterations, including diabetes, hypertension, dyslipidemia and weight gain, all manifestations of metabolic syndrome, occurring in the first months after LT, is depicted. The different presentations of cardiac involvement, represented by early atherosclerosis, coronary artery disease, heart failure and arrhythmias in patients with NAFLD submitted to LT is described. In addition, the tools to detect cardiac alterations either before or after LT is reported providing the possibility for an early diagnosis of CVD and an early therapy able to reduce morbidity and mortality for these diseases. The need for long-term concerted multidisciplinary activity with dietary counseling and exercise combined with drug treatment of all manifestations of metabolic syndrome is emphasized.
Silent coronary artery disease (CAD) is one of the manifestations of heart disease that particularly affects subjects with type 2 diabetes mellitus (T2DM). From a clinical point of view, silent CAD represents a constant challenge for the diabetologist, who has to decide whether a patient could or could not be screened for this disease. In the present narrative review, several aspects of silent CAD are considered: the epidemiology of the disease, the associated risk factors, and main studies conducted, in the last 20 years, especially aimed to demonstrate the usefulness of the screening of silent CAD, to improve cardiovascular outcomes in type 2 diabetes.
Despite its high frequency of occurrence, mild traumatic brain injury (mTBI), or concussion, is difficult to recognize and diagnose, particularly in pediatric populations. Conventional methods to diagnose mTBI primarily rely on clinical questionnaires and sometimes include neuroimaging or pencil and paper neuropsychological testing. However, these methods are time consuming, require administration/interpretation from health professionals, and lack adequate test sensitivity and specificity. This study explores the use of BrainCheck Sport, a computerized neurocognitive test that is available on iPad, iPhone, or computer desktop, for mTBI assessment. The BrainCheck Sport Battery consists of 6 gamified traditional neurocognitive tests that assess areas of cognition vulnerable to mTBI such as attention, processing speed, executing functioning, and coordination.
We administered BrainCheck Sport to 10 participants diagnosed with mTBI at the emergency department of Children’s hospital or local high school within 96 h of injury, and 115 normal controls at a local high school. Statistical analysis included Mann-Whitney U test, chi-square tests, and Hochberg tests to examine differences between the mTBI group and control group on each assessment in the battery. Significant metrics from these assessments were used to build a logistic regression model that distinguishes mTBI from control participants.
BrainCheck Sport was able to detect significant differences in Coordination, Stroop, Immediate/Delayed Recognition between normal controls and mTBI patients. Receiver operating characteristic (ROC) analysis of our logistic regression model found a sensitivity of 84% and specificity of 81%, with an area under the curve of 0.884.
BrainCheck Sport has potential in distinguishing mTBI from control participants, by providing a shorter, gamified test battery to assess cognitive function after brain injury, while also providing a method for tracking recovery with the opportunity to do so remotely from a patient’s home.
Human voice contains rich information. Few longitudinal studies have been conducted to investigate the potential of voice to monitor cognitive health. The objective of this study is to identify voice biomarkers that are predictive of future dementia.
Participants were recruited from the Framingham Heart Study. The vocal responses to neuropsychological tests were recorded, which were then diarized to identify participant voice segments. Acoustic features were extracted with the OpenSMILE toolkit (v2.1). The association of each acoustic feature with incident dementia was assessed by Cox proportional hazards models.
Our study included 6, 528 voice recordings from 4, 849 participants (mean age 63 ± 15 years old, 54.6% women). The majority of participants (71.2%) had one voice recording, 23.9% had two voice recordings, and the remaining participants (4.9%) had three or more voice recordings. Although all asymptomatic at the time of examination, participants who developed dementia tended to have shorter segments than those who were dementia free (P < 0.001). Additionally, 14 acoustic features were significantly associated with dementia after adjusting for multiple testing (P < 0.05 / 48 = 1 × 10–3). The most significant acoustic feature was jitterDDP_sma_de (P = 7.9 × 10–7), which represents the differential frame-to-frame Jitter. A voice based linear classifier was also built that was capable of predicting incident dementia with area under curve of 0.812.
Multiple acoustic and linguistic features are identified that are associated with incident dementia among asymptomatic participants, which could be used to build better prediction models for passive cognitive health monitoring.
Research suggests that Alzheimer’s disease (AD) is heterogeneous with numerous subtypes. Through a proprietary interactive ML system, several underlying biological mechanisms associated with AD pathology were uncovered. This paper is an introduction to emerging analytic efforts that can more precisely elucidate the heterogeneity of AD.
A public AD data set (GSE84422) consisting of transcriptomic data of postmortem brain samples from healthy controls (n = 121) and AD (n = 380) subjects was analyzed. Data were processed by an artificial intelligence platform designed to discover potential drug repurposing candidates, followed by an interactive augmented intelligence program.
Using perspective analytics, six perspective classes were identified: Class I is defined by TUBB1, ASB4, and PDE5A; Class II by NRG2 and ZNF3; Class III by IGF1, ASB4, and GTSE1; Class IV is defined by cDNA FLJ39269, ITGA1, and CPM; Class V is defined by PDE5A, PSEN1, and NDUFS8; and Class VI is defined by DCAF17, cDNA FLJ75819, and SLC33A1. It is hypothesized that these classes represent biological mechanisms that may act alone or in any combination to manifest an Alzheimer’s pathology.
Using a limited transcriptomic public database, six different classes that drive AD were uncovered, supporting the premise that AD is a heterogeneously complex disorder. The perspective classes highlighted genetic pathways associated with vasculogenesis, cellular signaling and differentiation, metabolic function, mitochondrial function, nitric oxide, and metal ion metabolism. The interplay among these genetic factors reveals a more profound underlying complexity of AD that may be responsible for the confluence of several biological factors. These results are not exhaustive; instead, they demonstrate that even within a relatively small study sample, next-generation machine intelligence can uncover multiple genetically driven subtypes. The models and the underlying hypotheses generated using novel analytic methods may translate into potential treatment pathways.
Glycemic homeostasis is an essential mechanism for the proper working of an organism. However, balance in blood lipid and protein levels also plays an important role. The discovery of the hormone insulin and the description of its function for glycemic control made fundamental scientific progress in this field. However, since then our view of the problem has been deeply influenced only in terms of glucose and insulin (in an insulin-centric and glucose-centric way). Based on recent scientific discoveries, a fine and sophisticated network of hormonal and metabolic interactions, involving almost every apparatus and tissue of the human body, has been theorized. Efficient metabolic homeostasis is founded on these intricate interactions. Although it is still not fully defined, this complex network can undergo alterations that lead to metabolic disorders such as diabetes mellitus (DM). The endocrine pancreas plays a crucial role in the metabolic balance of an organism, but insulin is just one of the elements involved and each single pancreatic islet hormone is worthy of our concern. Moreover, pancreatic hormones need to be considered in a general view, concerning both their systemic function as direct mediators and as hormones, which, in turn, are regulated by other hormones or other substances. This more complex scenario should be taken into account for a better understanding of the pathophysiology and the therapeutic algorithms of DM. As a consequence, improvements in modern medicine could help to contemplate this new perspective. This review is focused on some aspects of gut-pancreas interaction, aiming to integrate this synergy into a wider context involving other organs and tissues.
This commentary is the product of a concerted effort to understand the needs, barriers, and gaps in the field of speech and language biomarkers for Alzheimer’s disease (AD). It distills interviews, surveys, and extensive correspondence with global leaders in the areas of dementia research, clinical trials, linguistics, and data analytics into an idealized clinical-study design for the harmonized collection of voice recordings. The ultimate goal of the effort is to democratize the ongoing speech and language analytics efforts by making such rich datasets available to the wider research ecosystem.
Technology in diabetes is rapidly evolving, with the aim of helping affected people to safely optimize their blood glucose control. New technologies are now considered as an essential tool for managing glycemia predominantly in people with type 1 diabetes, and clinical trials have demonstrated that in these subjects the use of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems are associated with improved glycemic control along with a better quality of life. Literature regarding technologies and type 2 diabetes is relatively lacking, but innovations may have an important role also in the management of these patients. Some studies in adults with type 2 diabetes have shown benefits with the use of CGM in terms of glycemic variability and improved therapeutic adjustments. Clinical trials about CSII and CGM use in type 2 diabetes may have some pitfalls and future studies are needed to assess how these advanced systems could improve clinical outcomes and also ensure cost-effectiveness in this population. In this narrative review, we aim to highlight the most relevant studies on this topic and to focus on the potential role of new technological devices in type 2 diabetes management.
Quantitative analysis of brain single photon emission computed tomography (SPECT) perfusion imaging is dependent on normative datasets that are challenging to produce. This study investigated the combination of SPECT neuroimaging from a large clinical population rather than small numbers of controls. The authors hypothesized this “population template” would demonstrate noninferiority to a control dataset, providing a viable alternative for quantifying perfusion abnormalities in SPECT neuroimaging.
A total of 2, 068 clinical SPECT scans were averaged to form the “population template”. Validation was three-fold. First, the template was imported into SPECT brain analysis software, MIMneuro®, and compared against its control dataset of 90 individuals through its region and cluster analysis tools. Second, a cohort of 100 cognitively impaired subjects was evaluated against both the population template and MIMneuro®’s normative dataset to compute region-based metrics. Concordance and intraclass correlation coefficients, mean square deviations, total deviation indices, and limits of agreement were derived from these data to measure agreement and test for noninferiority. Finally, the same patients were clinically read in CereMetrix® to confirm that expected perfusion patterns appeared after comparison to the template.
MIMneuro®’s default threshold for normality is ± 1.65 z-score and this served as our noninferiority margin. Direct comparison of the template to controls produced no regions that exceeded this threshold and all clusters identified were far from statistically significant. Agreement measures revealed consistency between the softwares and that CereMetrix® results were noninferior to MIMneuro®, albeit with proportional bias. Visual analysis also confirmed that expected perfusion patterns appeared when individual scans were compared to the population template within CereMetrix®.
The authors demonstrated a population template was noninferior to a smaller control dataset despite inclusion of abnormal scans. This suggests that our patient-based population template can serve as an alternative for identifying and quantifying perfusion abnormalities in brain SPECT.
Non-alcoholic fatty liver disease (NAFLD) has become the most common liver alteration worldwide. It encompasses a spectrum of disorders that range from simple steatosis to a progressive form, defined non-alcoholic steatohepatitis (NASH), that can lead to advanced fibrosis and eventually cirrhosis and hepatocellular carcinoma. On liver histology, NASH is characterized by the concomitant presence of significant fat accumulation and inflammatory reaction with hepatocellular injury. Until now, liver biopsy is still required to differentiate simple steatosis from NASH and evaluate the degree of liver fibrosis. Unfortunately, this technique has well-known limitations, including invasiveness and expensiveness. Moreover, it may be biased by sampling error and intra- or inter-observed variability. Furthermore, due to the increasing prevalence of NAFLD worldwide, to program a systematic screening with liver biopsy is not imaginable. In recent years, different techniques were developed and validated with the aim of non-invasively identifying NASH and assess liver fibrosis degrees. The non-invasive tests range from simple blood-tests analyses to composite scores and complex imaging techniques. Nevertheless, even if they could represent cost-effective strategies for diagnosing NASH, advanced fibrosis and cirrhosis, their accuracy and consequent usefulness are to be discussed. With this aim, in this review the authors summarize the current state of non-invasive assessment of NAFLD. In particular, in addition to the well-established tests, the authors describe the future perspectives in this field, reporting the latest tests based on OMICS, gut-miocrobioma and micro-RNAs. Finally, the authors provide an accurate assessment of how these non-invasive tools perform in clinical practice depending on the clinical context, with the aim of giving the clinicians a useful tool to try to resolve the diagnostic conundrum of NAFLD.
The pathophysiological mechanisms underlying the close relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and only partially known. The purpose of this paper was to review the current knowledge of these mechanisms in a unified manner. Subjects with NAFLD and T2DM have established insulin resistance (IR), which exacerbates the two comorbidities. IR worsens NAFLD by increasing the accumulation of free fatty acids (FFAs) in the liver. This occurs due to an increase in the influx of FFAs from peripheral adipose tissue by the activation of hormone-sensitive lipase. In addition, there is de novo increased lipogenesis, a transcription factor, the sterols regulatory element-binding transcription factor 1c (SREBP-1c), which activates the expression of several genes strongly promotes lipogenesis by the liver and facilitate storage of triglycerides. Lipids accumulation in the liver induces a chronic stress in the endoplasmic reticulum of the hepatocytes. Genome-wide association studies have identified genetic variants associated with NAFLD severity, but unrelated to IR. In particular, the alteration of patatin-like phospholipase domain-containing protein 3 contributes to the susceptibility to NAFLD. Furthermore, the lipotoxicity of ceramides and diacylglycerol, well known in T2DM, triggers a chronic inflammatory process favoring the progression from hepatic steatosis to steatohepatitis. Reactive oxygen species produced by mitochondrial dysfunction trigger both liver inflammation and beta-cells damage, promoting the progression of both NAFLD and T2DM. The close association between NAFLD and T2DM is bidirectional, as T2DM may trigger both NAFLD onset and its progression, but NAFLD itself may contribute to the development of IR and T2DM. Future studies on the mechanisms will have to deepen the knowledge of the interaction between the two pathologies and should allow the identification of new therapeutic targets for the treatment of NAFLD, currently substantially absent.
Nonalcoholic fatty liver disease (NAFLD) is a serious condition that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is associated with metabolic syndrome (MetS) and all of its components. According to data, around 25–30% of population has NAFLD. Giving the growing incidence of MetS, obesity and diabetes mellitus type 2, NAFLD related terminal-stage liver disease is becoming prevailing indication for liver transplantation. In order to prevent terminal stage of this disease, it is crucial to determine those that are in risk group, to modify their risk factors and monitor their potential progression. In the absence of other causes of chronic liver disease, the prime diagnosis of NAFLD in daily clinical practice includes anamnesis, laboratory results (increased levels of aminotransferases and gammaglutamil transferases) and imaging methods. The biggest challenge with NAFLD patients is to differentiate simple steatosis from nonalcoholic steatohepatitis, and detection of fibrosis, that is the main driver in NAFLD progression. The gold standard for NAFLD diagnosis still remains the liver biopsy (LB). However, in recent years many noninvasive methods were invented, such as transient elastography (TE). TE (FibroScan®, Echosens, Paris, France) is used for diagnosis of pathological differences of liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). Investigations in the last years have confirmed that elastographic parameters of steatsis (CAP) and fibrosis (LSM) are reliable biomarkers to non-invasively assess liver steatosis and fibrosis respectively in NAFLD patients. A quick, straightforward and non-invasive method for NAFLD screening in patients with MetS components is TE-CAP. Once diagnosed, the next step is to determine the presence of fibrosis by LSM which should point out high risk patients. Those patients should be referred to hepatologists. LB may be avoided in a substantial number of patients if TE with CAP is used for screening.
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver chronic disease worldwide. The pathogenesis of NAFLD is complex and involves many metabolic enzymes and multiple pathways. Posttranslational modifications of proteins (PMPs) added another layer of complexity to the pathogenesis of NAFLD. PMPs change protein properties and regulate many biological functions, including cellular localization, stability, intracellular signaling, and protein function. Lysine acetylation is a common reversible PMP that consists of the transfer of an acetyl group from acetyl-coenzyme A (CoA) to a lysine residue on targeted proteins. The deacetylation reaction is catalyzed by deacetylases called sirtuins. This review summarizes the role of acetylation in NAFLD with a focus on sirtuins 1 and 3.
Diabetes and cancer are widespread worldwide and the number of subjects presenting both diseases increased over the years. The management of cancer patients having diabetes represents a challenge not only because of the complexity and heterogeneity of these pathologies but also for the lack of standardised clinical guidelines. The diagnosis of cancer is traumatizing and monopolizes the attention of both patients and caregivers. Thus, pre-existent or new-onset diabetes can be overshadowed thus increasing the risk for short- and long-term adverse events. Moreover, drugs used for each disease can interfere with the clinical course of the concomitant disease, making challenging the management of these patients. Over the years, this issue has become more relevant because of the increased patients’ life expectancy due to the improved efficacy of diabetes and cancer therapies.
The purpose of this review is to highlight what is known and what should be taken into consideration to optimise the clinical management of patients with diabetes and cancer. Due to the complexity of these diseases, a multidisciplinary, shared approach, including all the protagonists involved, is necessary to improve patients’ quality of life and lifespan.
The prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating the genetic variants mostly associated with MAFLD in polygenic risk scores. These scores might be used in combination with metabolic factors to identify those patients at higher risk to develop more severe liver disease and to schedule an individual therapeutic approach.
The currently ongoing coronavirus disease 19 (COVID-19) pandemic has affected globally human health and economy. Research in progress has shown facts associated with this disease and raised questions relevant for disease control and prevention. In this perspective, the collaboration between science and art in visual communication using the artwork “Enseñanza” (“Teaching”) contributes to the representation of the lessons learned from COVID-19 and the way forward. To advance preparedness for current and future pandemics, the authors propose to address international collaborations, support to science, access to food supplies and health services, sustainable development and a “One Health” approach searching a balanced interaction of humanity with nature and a more holistic approach to disease prevention and control.
Pooled prevalence of nonalcoholic fatty liver disease (NAFLD) globally is about 25%. Nonalcoholic steatohepatitis (NASH) with advanced fibrosis has been linked with substantial morbidity and mortality, without having to-date any licensed treatment. C-C chemokine receptor (CCR) antagonists have been investigated as candidates for the treatment of NASH. Inhibition of CCR2 is expected to mitigate hepatic inflammation, through reducing the activation of Kupffer cells, as well as the infiltration of monocytes and macrophages into the liver. Inhibition of CCR5 is expected to mitigate hepatic fibrogenesis, through impairing the activation of hepatic stellate cells, as well as to mitigate hepatic inflammation, through impairing the activation of Kupffer cells and macrophages. Cenicriviroc (CVC) is the first in class, dual inhibitor of CCR2 and CCR5. After exhibiting favorable results in animal models, CVC was shown to be beneficial in NASH patients with more severe fibrosis at a phase 2b trial (CENTAUR) and is currently at a phase 3 clinical trial (AURORA). Apart from CVC, other CCR5 mono-antagonists, such as maraviroc, are under evaluation in clinical trials with human immunodeficiency virus patients with NAFLD. The aim of this review was to summarize existing evidence on CVC and other CCR antagonists in NASH patients, primarily focusing on their clinical efficacy and safety.
Rational government of patient fluxes from primary care to hepatology clinic is a priority of nonalcoholic fatty liver disease (NAFLD) research. Estimating pre-test probability of disease, risk of fibrosis progression, and exclusion of competing causes of liver disease must be addressed. Here we propose a novel taxonomic classification of NAFLD based on hepatic, pathogenic and systemic features of disease in the individual patient. The variable course of disease in any given patient remains a clinical enigma. Therefore, future studies will have to better characterize the role of genetic polymorphisms, family and personal history, diet, alcohol, physical activity and drugs as modifiers of the course of disease and clues to the early diagnosis of hepatocellular carcinoma. A better understanding of these, together with a taxonomic diagnosis, may prompt a more accurate personalization of care. For example, understanding the putative role of psycho-depression in NAFLD promises to revolutionize disease management in a proportion of cases. Similarly, sex differences in outcome and response to treatment are insufficiently characterized. More studies are awaited regarding those forms of NAFLD which occur secondary to endocrine derangements. The intersections between NAFLD and the lung must better be defined. These include the bi-directional associations of NAFLD and chronic obstructive pulmonary disease and sleep apnoea syndrome, as well as the totally unexplored chapter of NAFLD and coronavirus disease 2019 (COVID-19). Finally, the therapeutic roles of intermittent fasting and anticoagulation must be assessed. In conclusion, over the last 20 years, NAFLD has taught us a lot regarding the pathogenic importance of insulin resistance, the limitations of correcting this in the treatment of NAFLD, the root causes of diabetes and the metabolic syndrome, sex differences in disease and the role of nuclear receptors. However, the overwhelming COVID-19 pandemic is now expected to reset the priorities of public health.
To test if the impairment of mononuclear cell (MNC) migration in patients with hereditary hemorrhagic telangiectasia (HHT) is due to the reduction of the endoglin (ENG) receptor on the cell surface and oxidative stress.
MNCs of HHT patients and normal controls were subjected to migration assay. Fractions of MNCs were pre-incubated with antibodies specific to HHT causative genes ENG [hereditary hemorrhagic telangiectasia type 1 (HHT1)] or activin receptor-like kinase 1 [ALK1, hereditary hemorrhagic telangiectasia type 2 (HHT2)], AMD3100 or Diprotin-A to block ENG, ALK1 C-X-C chemokine receptor 4 (CXCR4) or CD26 (increased in HHT1 MNCs) before migration assay. The MNCs were allowed to migrate toward stromal cell-derived factor-1α (SDF-1α) for 18 h. The expression of CXCR4, CD26, superoxide dismutase 1 (SOD1) and glutathione peroxidase 1 (GPX1) in MNCs and nitric oxide levels in the plasma were analyzed.
Compared to the controls, fewer HHT1 MNCs and similar number of HHT2 MNCs migrated toward SDF-1α. Diprotin-A pre-treatment improved HHT1 MNC-migration, but had no effect on normal and HHT2 MNCs. Pre-incubation with an anti-ENG antibody reduced the migration of normal MNCs. Diprotin-A did not improve the migration of ENG antibody pre-treated MNCs. Anti-ALK1 antibody had no effect on MNC-migration. AMD3100 treatment reduced normal and HHT MNC-migration. ENG mRNA level was reduced in HHT1 and HHT2 MNCs. ALK1 mRNA was reduced in HHT2 MNCs only. CD26 expression was higher in HHT1 MNCs. Pre-treatment of MNCs with anti-ENG or anti-ALK1 antibody had no effect on CD26 and CXCR4 expression. The expression of antioxidant enzymes, SOD1, was reduced in HHT1 MNCs, which was accompanied with an increase of ROS in HHT MNCs and nitric oxide in HHT1 plasma.
Reduction of ENG receptor on MNC surface reduced monocyte migration toward SDF-1α independent of CD26 expression. Increased oxidative stress could alter HHT MNC migration behavior.
Epigenetic variation of DNA methylation of the mu-opioid receptor gene (OPRM1) has been identified in the blood and saliva of individuals with opioid use disorder (OUD) and infants with neonatal opioid withdrawal syndrome (NOWS). It is unknown whether epigenetic variation in OPRM1 exists within placental tissue in women with OUD and whether it is associated with NOWS outcomes. In this pilot study, the authors aimed to 1) examine the association between placental OPRM1 DNA methylation levels and NOWS outcomes, and 2) compare OPRM1 methylation levels in opioid-exposed versus non-exposed control placentas.
Placental tissue was collected from eligible opioid (n = 64) and control (n = 29) women after delivery. Placental DNA was isolated and methylation levels at six cytosine-phosphate-guanine (CpG) sites within the OPRM1 promoter were quantified. Methylation levels were evaluated for associations with infant NOWS outcome measures: need for pharmacologic treatment, length of hospital stay (LOS), morphine treatment days, and treatment with two medications. Regression models were created and adjusted for clinical co-variates. Methylation levels between opioid and controls placentas were also compared.
The primary opioid exposures were methadone and buprenorphine. Forty-nine (76.6%) of the opioid-exposed infants required pharmacologic treatment, 10 (15.6%) two medications, and average LOS for all opioid-exposed infants was 16.5 (standard deviation 9.7) days. There were no significant associations between OPRM1 DNA methylation levels in the six CpG sites and any NOWS outcome measures. No significant differences were found in methylation levels between the opioid and control samples.
No significant associations were found between OPRM1 placental DNA methylation levels and NOWS severity in this pilot cohort. In addition, no significant differences were seen in OPRM1 methylation in opioid versus control placentas. Future association studies examining methylation levels on a genome-wide level are warranted.
Recent randomized controlled trials (RCTs) have tested the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RA) to specifically treat non-alcoholic fatty liver disease (NAFLD). We performed a meta-analysis of RCTs to investigate the efficacy of GLP-1 RAs for treatment of NAFLD or non-alcoholic steatohepatitis (NASH).
We systematically searched PubMed and ClinicalTrials.Gov databases utilizing specific terms to identify placebo-controlled or head-to-head RCTs (last research on March 1, 2020) involving NAFLD patients with the aim of evaluating the efficacy of GLP-1 RAs to treat NAFLD/NASH. Primary outcomes were changes in serum liver enzymes, liver fat content, or histologic resolution of NASH. Weighted mean differences (WMD) were used to test the differences between the treatment arms.
Overall, we found 7 placebo-controlled or head-to-head RCTs involving 472 middle-aged individuals (66% men; 77% with established diabetes) followed for a median of 16 weeks that have used liraglutide or exenatide to treat NAFLD on imaging (n = 6) or biopsy (n = 1). Compared to placebo or reference therapy, treatment with GLP-1 RAs decreased serum alanine aminotransferase [n = 7 studies; WMD: –8.77 IU/L, 95% confidence intervals (CI) –17.69 to 0.14 IU/L; I2 = 87.3%], gamma-glutamyltransferase levels (n = 4 studies; WMD: –10.17 IU/L, 95% CI –14.27 IU/L to –6.07 IU/L; I2 = 0%) and imaging-defined liver fat content (n = 4 studies; WMD: –6.23%, 95% CI –8.95% to –3.51%; I2 = 85.9%). In one RCT involving 55 patients with biopsy-proven NASH, a 48-week treatment with liraglutide also led to a greater histological resolution of NASH than placebo.
GLP-1 RAs (mostly liraglutide) seem to be a promising treatment option for NAFLD or NASH.
Nonalcoholic fatty liver disease (NAFLD) is a substantial and growing problem worldwide and has become the second most common indication for liver transplantation as it may progress to cirrhosis and develop complications from portal hypertension primarily caused by advanced fibrosis and erratic tissue remodeling. However, elevated portal venous pressure has also been detected in experimental models of fatty liver and in human NAFLD when fibrosis is far less advanced and cirrhosis is absent. Early increases in intrahepatic vascular resistance may contribute to the progression of liver disease. Specific pathophenotypes linked to the development of portal hypertension in NAFLD include hepatocellular lipid accumulation and ballooning injury, capillarization of liver sinusoidal endothelial cells, enhanced contractility of hepatic stellate cells, activation of Kupffer cells and pro-inflammatory pathways, adhesion and entrapment of recruited leukocytes, microthrombosis, angiogenesis and perisinusoidal fibrosis. These pathological events are amplified in NAFLD by concomitant visceral obesity, insulin resistance, type 2 diabetes and dysbiosis, promoting aberrant interactions with adipose tissue, skeletal muscle and gut microbiota. Measurement of the hepatic venous pressure gradient by retrograde insertion of a balloon-tipped central vein catheter is the current reference method for predicting outcomes of cirrhosis associated with clinically significant portal hypertension and guiding interventions. This invasive technique is rarely considered in the absence of cirrhosis where currently available clinical, imaging and laboratory correlates of portal hypertension may not reflect early changes in liver hemodynamics. Availability of less invasive but sufficiently sensitive methods for the assessment of portal venous pressure in NAFLD remains therefore an unmet need. Recent efforts to develop new biomarkers and endoscopy-based approaches such as endoscopic ultrasound-guided measurement of portal pressure gradient may help achieve this goal. In addition, cellular and molecular targets are being identified to guide emerging therapies in the prevention and management of portal hypertension.
Non-alcoholic fatty liver disease (NAFLD) remains a major cause of chronic liver disease worldwide. Despite extensive studies, the heterogeneity of the risk factors as well as different disease mechanisms complicate the goals toward effective diagnosis and management. Recently, it has been shown that sex differences play a role in the prevalence and progression of NAFLD. In vitro, in vivo, and clinical studies revealed that the lower prevalence of NAFLD in premenopausal as compared to postmenopausal women and men is mainly due to the protective effects of estrogen and body fat distribution. It has been also described that males and females present differential pathogenic features in terms of biochemical profiles and histological characteristics. However, the exact molecular mechanisms for the gender differences that exist in the pathogenesis of NAFLD are still elusive. Lipogenesis, oxidative stress, and inflammation play a key role in the progression of NAFLD. For NAFLD, only a few studies characterized these mechanisms at the molecular level. Therefore, we aim to review the reported differential molecular mechanisms that trigger such different pathogenesis in both sexes. Differences in lipid metabolism, glucose homeostasis, oxidative stress, inflammation, and fibrosis were discussed based on the evidence reported in recent publications. In conclusion, with this review, we hope to provide a new perspective for the development of future practice guidelines as well as a new avenue for the management of the disease.
Left ventricular ejection fraction is the critical parameter used for heart failure classification, decision making and assessing prognosis. It is defined as a volumetric ratio and is essentially a composite of arterial and ventricular elastances, but not intrinsic contractility. The clinician should be aware of its numerous limitations when measuring and reporting it. And make a step toward more insightful understanding of hemodynamics.
Retinopathy of prematurity (ROP) is a blinding morbidity of preterm infants, which represents a significant clinical problem, accounting for up to 40% of all childhood blindness. ROP displays a range of severity, though even mild disease may result in life-long visual impairment. This is complicated by the fact that our current treatments have significant ocular and potentially systemic effects. Therefore, disease prevention is desperately needed to mitigate the life-long deleterious effects of ROP for preterm infants. Although ROP demonstrates a delayed onset of retinal disease following preterm birth, representing a potential window for prevention, we have been unable to sufficiently alter the natural disease course and meaningfully prevent ROP. Prevention therapeutics requires knowledge of early ROP molecular changes and risk, occurring prior to clinical retinal disease. While we still have an incomplete understanding of these disease mechanisms, emerging data integrating contributions of maternal/placental pathobiology with ROP are poised to inform novel approaches to prevention. Herein, we review the molecular basis for current prevention strategies and the clinical outcomes of these interventions. We also discuss how insights into early ROP pathophysiology may be gained by a better understanding of maternal and placental factors playing a role in preterm birth.
Racial disparities in opioid use disorder (OUD) management exist, however, and there is limited research on factors that influence opioid cessation in different population groups.
We employed multiple machine learning prediction algorithms least absolute shrinkage and selection operator, random forest, deep neural network, and support vector machine to assess factors associated with ceasing opioid use in a sample of 1,192 African Americans (AAs) and 2,557 individuals of European ancestry (EAs) who met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for OUD. Values for nearly 4,000 variables reflecting demographics, alcohol and other drug use, general health, non-drug use behaviors, and diagnoses for other psychiatric disorders, were obtained for each participant from the Semi-Structured Assessment for Drug Dependence and Alcoholism, a detailed semi-structured interview.
Support vector machine models performed marginally better on average than other machine learning methods with maximum prediction accuracies of 75.4% in AAs and 79.4% in EAs. Subsequent stepwise regression considered the 83 most highly ranked variables across all methods and models and identified less recent cocaine use (AAs: odds ratio (OR) = 1.82, P = 9.19 × 10−5; EAs: OR = 1.91, P = 3.30 × 10−15), shorter duration of opioid use (AAs: OR = 0.55, P = 5.78 × 10−6; EAs: OR = 0.69, P = 3.01 × 10−7), and older age (AAs: OR = 2.44, P = 1.41 × 10−12; EAs: OR = 2.00, P = 5.74 × 10−9) as the strongest independent predictors of opioid cessation in both AAs and EAs. Attending self-help groups for OUD was also an independent predictor (P < 0.05) in both population groups, while less gambling severity (OR = 0.80, P = 3.32 × 10−2) was specific to AAs and post-traumatic stress disorder recovery (OR = 1.93, P = 7.88 × 10−5), recent antisocial behaviors (OR = 0.64, P = 2.69 × 10−3), and atheism (OR = 1.45, P = 1.34 × 10−2) were specific to EAs. Factors related to drug use comprised about half of the significant independent predictors in both AAs and EAs, with other predictors related to non-drug use behaviors, psychiatric disorders, overall health, and demographics.
These proof-of-concept findings provide avenues for hypothesis-driven analysis, and will lead to further research on strategies to improve OUD management in EAs and AAs.
Chronic kidney disease (CKD) is a disease regularly seen in clinical practice. At present, CKD is described as a change of kidney structure and/or function and it is classified in relation to cause, values of glomerular filtration rate and albuminuria category. Seeing that CKD is closely linked to the development of end-stage renal disease and other comorbidities, the determination of additional independent predictors for CKD is clinically necessary. At present, there is evidence associating non-alcoholic fatty liver disease (NAFLD) with CKD, thereby suggesting that NAFLD patients may require intensive surveillance to reduce their risk of CKD. In 2008, genome-wide association studies documented an association between the variant rs738409 (C > G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene (mainly implicated in the lipid regulation) and the entire spectrum of NAFLD (i.e., liver steatosis, non-alcoholic steatohepatitis, fibrosis, and hepatocellular carcinoma). In the last years, accumulating epidemiological evidence suggests the existence of a relationship between PNPLA3 rs738409 and risk of CKD, indicating that rs738409 may also contribute to the kidney injury. This is of particular scientific interest, as such association may explain, at least in part, the epidemiological association between liver and kidney disease. In this narrative review, we will discuss the accumulating evidence regarding the association between PNPLA3 rs738409 and risk of CKD, the putative biological mechanisms underpinning such relationship, and the possible future perspective.