Colchicine in patients with heart failure and preserved left ventricular ejection fraction: rationale and design of a prospective, randomised, open-label, crossover clinical trial.

INTRODUCTION: Systemic low-grade inflammation is a fundamental pathophysiological mechanism of heart failure with preserved left ventricular ejection fraction (HFpEF). The efficacy of anti-inflammatory therapy in HFpEF is largely understudied. The aim of the study is to assess the anti-inflammatory effect of colchicine in HFpEF by looking at inflammatory biomarkers: high-sensitivity C reactive protein (hsCRP) and soluble suppression of tumorigenicity 2 (sST2). METHODS AND ANALYSIS: This is a single-centre, prospective, randomised controlled, open-label, blinded-endpoint crossover clinical trial of stable but symptomatic patients with HFpEF. Patients will be randomised to either colchicine treatment 0.5 mg two times per day or usual care for 12 weeks followed by a 2-week washout period and crossover to 12 weeks of treatment with the alternate therapy. The primary objective is to investigate if administration of colchicine compared with usual care reduces inflammation in patients with HFpEF measured by primary endpoint sST2 and co-primary endpoint hsCRP at baseline and 12-week follow-up. Secondary objective is to determine if treatment with colchicine influences N-terminal pro-B-type natriuretic peptide levels, left ventricular diastolic function and remodelling, right ventricular systolic function and left atrial volumetric characteristics. We are aiming to enrol a total of 40 participants. This trial will answer the question if colchicine treatment reduces systemic low-grade inflammation and influences left ventricular diastolic function and remodelling with patients with HFpEF. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ethics Committee of Sechenov University (reference: 03-22). TRIAL REGISTRATION NUMBER: NCT05637398.

Case of benralizumab-induced exacerbations of chronic spontaneous urticaria.

The role of IL-5 in chronic spontaneous urticarial (CSU) is unclear. It may be that benralizumab is an important bidirectional modifier of CSU; that is, blocking IL-5 may improve CSU in some patients, but it is possible that it may worsen CSU in others.

Unexpected clinical case of Pasteurella multocida infectious endocarditis in a patient with iv drug abuse: why epidemiological history matters.

Introduction: Right-sided lesions caused by staphylococci are the most common clinical entity of infectious endocarditis (IE) among iv drug abusers. But some aspects of the epidemiological history are critical in terms of early detection of uncommon pathogens. Case report: We describe a clinical observation of native aortic valve IE caused by Pasteurella multocida in a 37-year-old female with a history of heroin addiction, alcohol abuse and liver cirrhosis.She presented herself at our hospital with acute fever, chills, subconjunctival petechial hemorrhages, traces of scratches on the hands, splenomegaly, peripheral edema, elevated WBC and inflammatory serum markers. Initial transthoracic echocardiography was negative, but the patient was put on oxacillin for suspected right-sided IE. The transesophageal echocardiography revealed vegetation on noncoronary leaflet of aortic valve. Blood culture was positive with the growth of P. multocida in 4/4 samples.On detailed questioning, a close domestic contact with cats was revealed. Oxacillin was switched to meropenem and tigecycline with a prompt clinical response. The P. multocida isolate was found to be susceptible to penicillins, so the patient was discharged after 3 weeks with recommendations to take amoxicillin for up to 4 weeks. At 3 and 6 months follow-up there were no signs of IE relapse revealed. Conclusions: P. multocida is a rare causative agent of IE. In our case, this pathogen was identified in a patient with injection drug use, where such etiology is not usually assumed. The close contact with cats was not taken into account, which caused late diagnosis and delayed therapy.

Salmonella sepsis in a patient with TLR4 gene polymorphisms.

Non-typhoid Salmonella gastroenteritis is one of the most common forms of intestinal infections among the population of developed countries and generalized forms of infection are rare. We present a case of 67-year-old woman with salmonaella sepsis, deep venous thrombosis, and septic thromboembolism of pulmonary artery complicated with development of necrotizing pneumonia. Generalization of the infectious process was mediated by the presence of polymorphisms in the TLR4 gene. Development of pulmonary infarction is infrequent. Even rarer is a formation of cavities in infarcted lung tissue, usually in the background of the infectious disease. A combination of 2 rare conditions in 1 patient demonstrates the need of multidisciplinary approach in treatment of severe and atypical forms of infectious diseases to evaluate the primary etiology of such state. The article will discuss various aspects of lung tissue damage caused by Salmonella and give a brief overview of the literature on this topic.

Dysbiosis, gut barrier dysfunction and inflammation in dementia: a pilot study.

BACKGROUND: Dementia is an increasing public health threat worldwide. The pathogenesis of dementia has not been fully elucidated yet. Inflammatory processes are hypothesized to play an important role as a driver for cognitive decline but the origin of inflammation is not clear. We hypothesize that disturbances in gut microbiome composition, gut barrier dysfunction, bacterial translocation and resulting inflammation are associated with cognitive dysfunction in dementia. METHODS: To test this hypothesis, a cohort of 23 patients with dementia and 18 age and sex matched controls without cognitive impairments were studied. Gut microbiome composition, gut barrier dysfunction, bacterial translocation and inflammation were assessed from stool and serum samples. Malnutrition was assessed by Mini Nutritional Assessment Short Form (MNA-SF), detailed information on drug use was collected. Microbiome composition was assessed by 16S rRNA sequencing, QIIME 2 and Calypso 7.14 tools. RESULTS: Dementia was associated with dysbiosis characterized by differences in beta diversity and changes in taxonomic composition. Gut permeability was increased as evidenced by increased serum diamine oxidase (DAO) levels and systemic inflammation was confirmed by increased soluble cluster of differentiation 14 levels (sCD14). BMI and statin use had the strongest impact on microbiome composition. CONCLUSION: Dementia is associated with changes in gut microbiome composition and increased biomarkers of gut permeability and inflammation. Lachnospiraceae NK4A136 group as potential butyrate producer was reduced in dementia. Malnutrition and drug intake were factors, that impact on microbiome composition. Increasing butyrate producing bacteria and targeting malnutrition may be promising therapeutic targets in dementia. TRIAL REGISTRATION: NCT03167983 .

The effects of a multispecies synbiotic on microbiome-related side effects of long-term proton pump inhibitor use: A pilot study.

Side effects of proton pump inhibitors (PPI) can be linked to the changes in the intestinal microbiome that occur during therapy, especially in long-term users. Therefore, the microbiome might also be a key player in the reduction of PPI side effects. We tested the effects of a three-month intervention with a multispecies synbiotic on intestinal inflammation, gut barrier function, microbiome composition, routine laboratory parameters and quality of life in patients with long-term PPI therapy. Thirty-six patients received a daily dose of a multispecies synbiotic for three months and were clinically observed without intervention for another three months. After intervention 17% of patients reached normal calprotectin levels; the overall reduction did not reach statistical significance (-18.8 ng/mg; 95%CI: -50.5; 12.9, p = 0.2). Elevated zonulin levels could be significantly reduced (-46.3 ng/mg; 95%CI: -71.4; -21.2; p < 0.001). The abundance of Stomatobaculum in the microbiome was reduced and Bacillus increased during the intervention. Furthermore, albumin, alkaline phosphatase and thrombocyte count were significantly increased and aspartate transaminase was significantly decreased during intervention. Gastrointestinal quality of life showed significant improvements. In conclusion, microbiome-related side effects of long-term PPI use can be substantially reduced by synbiotic intervention. Further studies are warranted to optimize dosage and duration of the intervention.

Disease severity and proton pump inhibitor use impact strongest on faecal microbiome composition in liver cirrhosis.

BACKGROUND & AIMS: Compositional changes of the faecal microbiome in cirrhosis are well described and have been associated with complications and prognosis. However, it is less well known, which disease or treatment-related factors affect microbiome composition most distinctively. METHODS: 16S rDNA sequencing data of 88 cirrhotic outpatients were investigated. Factors influencing microbiome composition were analysed by univariate and multivariate redundancy analysis. The association of the identified factors with changes in diversity and taxonomic composition was studied in depth using analysis of composition of microbiome, LDA-effect size and least absolute shrinkage and selection operator regularized regression. RESULTS: Disease severity and aetiology, proton pump inhibitor (PPI) use, nutritional status, age and C-reactive protein are significant explanatory variables for faecal microbiome composition in liver cirrhosis. Despite some taxonomic overlaps especially between disease severity and PPI use, we could show that the effects of disease severity, aetiology, PPI use and age are independent factors influencing microbiome composition also in subgroup analyses. CONCLUSION: Our cross sectional system biology study identifies disease severity, aetiology, PPI use and age as independent factors that influence microbiome composition in liver cirrhosis. In chronic diseases with high morbidity, such as liver cirrhosis, precise patient metadata documentation is of utmost importance in microbiome analysis. Further studies with a higher sample size are necessary to validate this finding. TRIAL REGISTRATION NUMBER: NCT01607528.

A single alcohol binge impacts on neutrophil function without changes in gut barrier function and gut microbiome composition in healthy volunteers.

Alcohol binge drinking is a dangerous drinking habit, associated with neurological problems and inflammation. The impact of a single alcohol binge on innate immunity, gut barrier and gut microbiome was studied. In this cohort study 15 healthy volunteers received 2 ml vodka 40% v/v ethanol/kg body weight. Neutrophil function was studied by flow cytometry; markers of gut permeability and inflammation (lactulose/mannitol/sucrose test, zonulin, calprotectin, diamino-oxidase) were studied with NMR spectroscopy and enzyme-linked immunosorbent assay in urine, stool and serum respectively. Bacterial products in serum were quantified using different reporter cell lines. Gut microbiome composition was studied by 16S rDNA sequencing and bioinformatics analysis. After a single alcohol binge, neutrophils were transiently primed and the response to E.coli stimulation with reactive oxygen species (ROS) production was transiently increased, on the other hand the percentage of neutrophils that did not perform phagocytosis increased. No changes in gut permeability, inflammatory biomarker, bacterial translocation and microbiome composition could be detected up to 4 hours after a single alcohol binge or on the next day. A single alcohol binge in young, healthy volunteers transiently impacts on neutrophil function. Although the exact biological consequence of this finding is not clear yet, we believe that this strengthens the importance to avoid any alcohol binge drinking, even in young, otherwise healthy persons.

Licorice abuse: time to send a warning message.

Licorice extract has always been recognized as a sweetener and a thirst quencher. Its nutritive value is overrated by many who consume significant amounts and are prone to complications. Glycyrrhetic acid, the active metabolite in licorice, inhibits the enzyme 11-ß-hydroxysteroid dehydrogenase enzyme type 2 with a resultant cortisol-induced mineralocorticoid effect and the tendency towards the elevation of sodium and reduction of potassium levels. This aldosterone-like action is the fundamental basis for understanding its health benefits and the wide spectrum of adverse effects. Herein, we present a comprehensive review of licorice along with the reported complications related to excess intake. Despite its apparent use in a few clinical scenarios, the daily consumption of licorice is never justified because its benefits are minor compared to the adverse outcomes of chronic consumption. The review highlights the importance of investigating the dietary habits and herbal remedies which are being used worldwide on cultural and habitual bases rather than reliable scientific evidence. Licorice is a US Food and Drug Administration (FDA) approved food supplement used in many products without precise regulations to prevent toxicity. Increased awareness among the public is required through TV commercials, newspapers, internet sites, magazines and product labels regarding the upper limit of ingestion and health hazards associated with excess intake. We hope that this review will serve as a warning message that should be transmitted from physicians to patients to avoid excessive licorice intake as well as a message to the FDA to start regulating the use of this substance.