Gut Dysbiosis and Hemodynamic Changes as Links of the Pathogenesis of Complications of Cirrhosis.

The aim was to evaluate the relationship between gut dysbiosis and hemodynamic changes (hyperdynamic circulation) in cirrhosis, and between hemodynamic changes and complications of this disease. This study included 47 patients with cirrhosis. Stool microbiome was assessed using 16S rRNA gene sequencing. Echocardiography with a simultaneous assessment of blood pressure and heart rate was performed to assess systemic hemodynamics. Patients with hyperdynamic circulation had more severe cirrhosis, lower albumin, sodium and prothrombin levels, higher C-reactive protein, aspartate aminotransferase and total bilirubin levels, and higher incidences of portopulmonary hypertension, ascites, overt hepatic encephalopathy, hypoalbuminemia, hypoprothrombinemia, systemic inflammation, and severe hyperbilirubinemia than patients with normodynamic circulation. Patients with hyperdynamic circulation compared with those with normodynamic circulation had increased abundance of Proteobacteria, Enterobacteriaceae, Bacilli, Streptococcaceae, Lactobacillaceae, Fusobacteria, Micrococcaceae, Intestinobacter, Clostridium sensu stricto, Proteus and Rumicoccus, and decreased abundance of Bacteroidetes, Bacteroidaceae, Holdemanella, and Butyrivibrio. The systemic vascular resistance and cardiac output values correlated with the abundance of Proteobacteria, Enterobacteriaceae, Bacilli, Streptococcaceae, Lactobacillaceae, Micrococcaceae, and Fusobacteria. Heart rate and cardiac output value were negatively correlated with the abundance of Bacteroidetes. The mean pulmonary artery pressure value was positively correlated with the abundance of Proteobacteria and Micrococcaceae, and negatively with the abundance of Holdemanella.

Sarcopenia in cirrhosis: Prospects for therapy targeted to gut microbiota.

Decreased muscle mass and function, also known as sarcopenia, is common in patients with cirrhosis and is associated with a poor prognosis. Although the pathogenesis of this disorder has not been fully elucidated, a disordered gut-muscle axis probably plays an important role. Decreased barrier function of the gut and liver, gut dysbiosis, and small intestinal bacterial overgrowth (SIBO) can lead to increased blood levels of ammonia, lipopolysaccharides, pro-inflammatory mediators, and myostatin. These factors have complex negative effects on muscle mass and function. Drug interventions that target the gut microbiota (long-term use of rifaximin, lactulose, lactitol, or probiotics) positively affect most links of the compromised gut-muscle axis in patients with cirrhosis by decreasing the levels of hyperammonemia, bacterial translocation, and systemic inflammation and correcting gut dysbiosis and SIBO. However, although these drugs are promising, they have not yet been investigated in randomized controlled trials specifically for the treatment and prevention of sarcopenia in patients with cirrhosis. No data exist on the effects of fecal transplantation on most links of gut-muscle axis in cirrhosis; however, the results of animal experimental studies are promising.

Epidemiology of small intestinal bacterial overgrowth.

Small intestinal bacterial overgrowth (SIBO) is defined as an increase in the bacterial content of the small intestine above normal values. The presence of SIBO is detected in 33.8% of patients with gastroenterological complaints who underwent a breath test, and is significantly associated with smoking, bloating, abdominal pain, and anemia. Proton pump inhibitor therapy is a significant risk factor for SIBO. The risk of SIBO increases with age and does not depend on gender or race. SIBO complicates the course of a number of diseases and may be of pathogenetic significance in the development of their symptoms. SIBO is significantly associated with functional dyspepsia, irritable bowel syndrome, functional abdominal bloating, functional constipation, functional diarrhea, short bowel syndrome, chronic intestinal pseudo-obstruction, lactase deficiency, diverticular and celiac diseases, ulcerative colitis, Crohn's disease, cirrhosis, metabolic-associated fatty liver disease (MAFLD), primary biliary cholangitis, gastroparesis, pancreatitis, cystic fibrosis, gallstone disease, diabetes, hypothyroidism, hyperlipidemia, acromegaly, multiple sclerosis, autism, Parkinson's disease, systemic sclerosis, spondylarthropathy, fibromyalgia, asthma, heart failure, and other diseases. The development of SIBO is often associated with a slowdown in orocecal transit time that decreases the normal clearance of bacteria from the small intestine. The slowdown of this transit may be due to motor dysfunction of the intestine in diseases of the gut, autonomic diabetic polyneuropathy, and portal hypertension, or a decrease in the motor-stimulating influence of thyroid hormones. In a number of diseases, including cirrhosis, MAFLD, diabetes, and pancreatitis, an association was found between disease severity and the presence of SIBO. Further work on the effect of SIBO eradication on the condition and prognosis of patients with various diseases is required.

Impact of vaccination against the novel coronavirus infection (COVID-19) with Sputnik V on mortality during the delta variant surge.

OBJECTIVES: The aim is to study impact of vaccination against the novel coronavirus disease (COVID-19) with Sputnik V on mortality during the period of predominance of the delta variant of SARS-CoV-2. METHODS: This was a retrospective cohort study of individuals with state health insurance at the Moscow Ambulatory Center. The cohorts included 41,444 persons vaccinated with Sputnik V, 15,566 survivors of COVID-19, and 71,377 non-immune persons. The deaths of patients that occurred from June 1, 2021, to August 31, 2021, were analyzed. RESULTS: Overall (0.39 % vs. 1.92 %; p < 0.001), COVID-19-related (0.06 % vs. 0.83 %; p < 0.001), and non-COVID mortality (0.33 % vs. 1.09 %; p < 0.001) was lower among vaccinated individuals than among non-immune individuals. The efficacy of vaccination against death from COVID-19 was 96 % [95 % CI 91-98 %] in the general population, 100 % among those aged 18-50 years, 97 % [95 % CI 76-100 %] among those aged 51-70 years, 98 % [95 % CI 90-100 %] among those aged 71-85 years, and 88 % [95 % CI 49-97 %] among those aged > 85 years. CONCLUSION: COVID-19 vaccination with Sputnik V is associated with a decrease in overall and COVID-19-related mortality and is not with increased non-COVID mortality.

Clinical significance of molecular subtypes of gastrointestinal tract adenocarcinoma.

Adenocarcinomas of the gastrointestinal tract (esophagus, stomach, and colon) represent a heterogeneous group of diseases with distinct etiology, clinical features, treatment approaches, and prognosis. Studies are ongoing to isolate molecular genetic subtypes, perform complete biological characterization of the tumor, determine prognostic groups, and find predictive markers to the effectiveness of therapy. Separate molecular genetic classifications were created for esophageal adenocarcinoma [The Cancer Genome Atlas (TCGA)], stomach cancer (TCGA, Asian Cancer Research Group), and colon cancer (Colorectal Cancer Subtyping Consortium). In 2018, isolation of TCGA molecular genetic subtypes for adenocarcinomas of the gastrointestinal tract (esophagus, stomach, and colon) highlighted the need for further studies and clinical validation of subtyping of gastrointestinal adenocarcinomas. However, this approach has limitations. The aim of our work was to critically analyze integration of molecular genetic subtyping of gastrointestinal adenocarcinomas in clinical practice.

Involvement of Oxidative Stress and the Innate Immune System in SARS-CoV-2 Infection.

The emergence of the novel coronavirus in December 2019 in China marked the beginning of a pandemic that impacted healthcare systems and economic life all over the world. The virus primarily targets the respiratory system causing severe acute respiratory syndrome (SARS) in some patients, and therefore received the name of SARS-CoV-2. The pathogen stands out among other coronaviruses by its rapid transmission from human to human, with the majority of infected individuals being asymptomatic or presenting with only minor illness, therefore facilitating the pathogen spread. At the same time, people from the risk groups, such as the elderly, patients suffering from chronic diseases, or obese individuals, have increased chances of developing a severe or even fatal disease. The search for risk factors explaining this phenomenon continues. In this review, we focus on the known mechanisms of SARS-CoV-2 infection affecting the functioning of the immune system and discuss potential risk factors responsible for the severe disease course. Oxidative stress is one of such factors, which plays a prominent role in innate immunity activity, and recent research has revealed its tight involvement in SARS-CoV-2 infection. We discuss these recent findings and the development of excessive inflammation and cytokine storm observed during SARS-CoV-2 infection. Finally, we consider potential use of antioxidant drugs for alleviating the severe symptoms in affected patients.

Contribution of Neurotrophins to the Immune System Regulation and Possible Connection to Alcohol Addiction.

The first references to neurotrophic factors date back to the middle of the 20th century when the nerve growth factor (NGF) was first discovered. Later studies delivered a large amount of data on neurotrophic factors. However, many questions regarding neurotrophin signaling still remain unanswered. One of the principal topics in neurotrophin research is their role in the immune system regulation. Another important research question is the possible involvement of neurotrophin signaling in the pathological processes associated with alcoholism. Among known neurotrophins, NT-4 remains the least studied and appears to be involved in alcoholism and chronic stress pathogenesis. In this review we discuss known neurotrophin signaling cascades mediated by different neurotrophin receptors, as well as provide a generalization of the data regarding the influence of neurotrophins NGF, BDNF, and NT-4 on the immune system and their potential contribution to the pathogenesis of alcoholism.

Water-based nanoparticulate polymeric system for protein delivery: permeability control and vaccine application.

The idea of using polymeric nanoparticles as drug carriers is receiving an increasing amount of attention both in academia and industry, Nanoparticles have a number of potential applications in protein, drug and vaccine delivery, as well as gene therapy applications. In this article, we focus on this unique drug delivery technology as a method to control the release rate of substances, not only for protein delivery but also for delivering an experimental vaccine immunogen. Nanoparticles were assembled on the basis of ionic interaction between water-soluble polymers so that the resulting particles were stable in physiologic media. Among the typical polymers used to assemble nanoparticles, different polysaccharides, natural amines, and poly-amines were investigated. The entrapped substances tested included a protein and antigens. Polydextran aldehyde was incorporated into the particle core, to enable physiologic cross-linking as a method to control permeability. This resulted in long-term retention of substances that would otherwise rapidly leak out of the nanoparticles. Results of cross-linking experiments clearly demonstrated that the release rate could be substantially reduced, depending on the degree of cross-linking. For vaccine antigen delivery tests, we measured an antibody production after subcutaneous and oral administration. The data indicated that only the cross-linked antigen was immunogenic when the oral route of administration was used. The data presented in this article address primarily the utility of nanoparticulates for oral delivery of vaccine antigen.

Maximizing the in vivo efficiency of gene transfer by means of nonviral polymeric gene delivery vehicles.

We have screened many synthetic and natural polymers for their ability to facilitate gene delivery in vivo into subcutaneous tissue. We postulated that gene delivery polymeric vehicles could control the chemical and biological stability of plasmid as well as their colloidal and surface properties, and this may lead to enhanced gene delivery in vivo. The screening was based on reporter gene (luciferase) expression using a plasmid containing the cytomegalovirus promoter. The control of charge density of resulting particles was achieved by selecting different ratios of polymer to plasmid mass as well as polymer chemistry. As opposed to in vitro observations, only polymers that lead to negatively charged particles exhibited an in vivo activity, in opposite to in vitro case. Such polymers exhibited relatively low positive charge chemistry (or neutral charge). The most potent polymeric vehicles were members of a Tetronic polymer series (synthetic polyethylene-polypropylene block copolymers; BASF, Mount Olive, NJ) or from a noncharged polyvinylpyrrolidine formulation. Plasmid dose response and time relationships were established for some polymers. Results were applied to the redesign of particles for biolistic (gene gun) plasmid gene delivery.