An assay approach, designed to allow accurate measurement of the rate of thrombin inhibition by antithrombin III in the presence of heparin, is described. In essence the approach takes advantage of the fact that synthetic substrates, e.g. N-alpha-p-tosyl-L-glycyl-L-prolyl-L-arginine-p-nitroanilide, bind to the active site of thrombin, which slows the rate of reaction with antithrombin III. The rate of thrombin inhibition can be monitored continuously by change in absorbance at 400 nm or measured by end point determination. In either case, reproducible rate measurements can be made under a variety of experimental conditions not easily examined with conventional assay approaches.

Measurement of the heparin enhanced-antithrombin III/thrombin reaction rate in the presence of synthetic substrate.

Thrombosis Research

Heart failure (HF) is a major contributor to hospitalisations and accounts for 7% of cardiovascular-related deaths, with patients who have chronic kidney disease and type 2 diabetes at heightened risk. Existing treatment guidelines inadequately address these comorbidities. Steroidal mineralocorticoid receptor antagonists (MRAs) are commonly used in HF with reduced ejection fraction but pose risks, such as hyperkalaemia and acute kidney injury. Finerenone, a non-steroidal MRA, offers a safer alternative, with higher selectivity, reduced electrolyte disturbances and beneficial effects on heart and kidney tissues. Preclinical studies show anti-inflammatory and anti-fibrotic effects, while phase III trials (ARTS and ARTS-HF) demonstrated fewer hyperkalaemia incidents compared with spironolactone. In phase III trials (FIDELIO-DKD and FIGARO-DKD), finerenone reduced HF hospitalisations by 22% in patients with chronic kidney disease and type 2 diabetes. The FINEARTS-HF trial found that finerenone significantly reduced the risk of worsening HF events or CV death in patients with HF with mildly reduced or preserved ejection fraction. Its combination with therapies, such as sodium-glucose cotransporter 2 inhibitors, shows promise and ongoing trials, such as REDEFINE-HF, FINALITY-HF and CONFIRMATION-HF, are investigating its efficacy in other HF phenotypes. These studies will further establish the role of finerenone in managing cardio-renal-metabolic diseases.

Finerenone: Will It Be a Game-changer?

Cardiac Failure Review

Insomnia is a common and challenging complaint in older adults (&gt; 65 years) because of age-related alterations in sleep physiology. Cognitive behavioral therapy for insomnia is the gold standard for treatment of insomnia in young as well as older patients. Both clinicians and patients often prefer the simplicity of medication, but risks associated with some hypnotics increase with age. Pharmacologic options for older adults include low-dose doxepin, melatonin, ramelteon, and the dual orexin receptor antagonists. A well-informed clinician can help patients navigate the risks and benefits of both pharmacologic and behavioral options.

Insomnia in older adults: A review of treatment options.

Cleveland Clinic Journal of Medicine

Recent progress has notably improved outcomes for patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), namely granulomatosis with polyangiitis and microscopic polyangiitis. Since 2021, several international scientific societies have recommended rituximab (RTX) as the preferred primary treatment for maintaining remission in AAV patients. Decisions regarding retreatment with RTX are based on individual patient risk factors for disease flare-ups and the potential consequences of such flares. In reviewing available evidence and reporting our experiences at G. Bosco Hub Hospital in Turin, Italy, we explore various trials focusing on the maintenance therapy in AAV and discuss areas of unmet need.

How We Treat ANCA-Associated Vasculitis: A Focus on the Maintenance Therapy.

Journal of Clinical Medicine

Allergic rhinitis (AR) is a common disorder that is strongly linked to asthma and conjunctivitis. Classic symptoms include nasal congestion, nasal itch, rhinorrhea and sneezing. A thorough history, physical examination and assessment of allergen sensitization are important for establishing the diagnosis of AR. Intranasal corticosteroids and second-generation antihistamines are the mainstay of treatment. Allergen immunotherapy is an effective immune-modulating treatment for use in addition to or as an alternative to pharmacologic therapy. This article provides an overview on the pathophysiology, diagnosis, and appropriate management of AR.

Allergic rhinitis.

Allergy, Asthma, and Clinical Immunology

Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia. It typically occurs in older patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and apoptosis in clonal B-cells.

The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as typical B-cell markers.

Two clinical staging systems, Rai and Binet, provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the TP53 gene predict a shorter time to progression with most targeted therapies. The CLL international prognostic index (CLL-IPI) integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL. The CLL-IPI retains its significance in the era of targeted agents, but the overall prognosis of CLL patients with high-risk stages has improved.

Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: combinations of the BCL2 inhibitor venetoclax with obinutuzumab, or venetoclax with ibrutinib, or monotherapy with one of the inhibitors of Bruton tyrosine kinase (BTK). At relapse, the initial treatment may be repeated if the treatment-free interval exceeds 3&#x2009;years. If the leukemia relapses earlier, therapy should be changed using an alternative regimen.

Combinations of targeted agents now provide efficient therapies with a fixed duration that generate deep and durable remissions. These fixed-duration therapies have gained territory in the management of CLL, as they are cost-effective, avoid the emergence of resistance, and offer treatment free time to the patient. The cure rate of these novel combination regimens is unknown. Moreover, the optimal sequencing of targeted therapies remains to be determined. A medical challenge is to treat patients who are double-refractory to both BTK and BCL2 inhibitors. These patients need to be treated within experimental protocols using novel drugs.

Chronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy.

American Journal of Hematology

Sepsis often leads to vasoplegia and a hyperdynamic cardiac state, with treatment focused on restoring vascular tone. However, sepsis can also cause reversible myocardial dysfunction, particularly in the elderly with pre-existing heart conditions. The Surviving Sepsis Campaign Guidelines recommend using dobutamine with norepinephrine or epinephrine alone for patients with septic shock with cardiac dysfunction and persistent hypoperfusion despite adequate fluid resuscitation and stable blood pressure. However, the definition of cardiac dysfunction and hypoperfusion in these guidelines remains controversial, leading to varied clinical interpretations. Cardiac dysfunction with persistent hypoperfusion despite restoring adequate preload and afterload is often considered a cardiogenic shock. Therefore, sepsis complicated by new-onset myocardial dysfunction or worsening of underlying myocardial dysfunction due to sepsis-induced cardiomyopathy, resulting in cardiogenic shock, can be defined as "Sepsis-induced cardiogenic shock (SICS)". SICS is known to be associated with significantly higher mortality. A history of cardiac dysfunction is a strong predictor of SICS, highlighting the need for precise diagnosis and management given the aging population and rising cardiovascular disease prevalence. Therefore, SICS might benefit from early invasive hemodynamic monitoring with a pulmonary artery catheter (PAC), unlike those with septic shock alone. While routine PAC monitoring for all septic patients is impractical, echocardiography could be a useful screening tool for high-risk individuals. If echocardiography indicates cardiogenic shock, PAC might be warranted for continuous monitoring. The role of inotropes in SICS remains uncertain. Mechanical circulatory support (MCS) might be considered for severe cases, as high-dose vasopressors and inotropes are associated with worse outcomes. Correct patient selection is the key to improving outcomes with MCS. Engaging a cardiogenic shock team for a multidisciplinary approach can be beneficial. In summary, addressing the evidence gaps in SICS diagnosis and management is crucial. Echocardiography for screening, advanced monitoring with PAC, and careful patient selection for MCS are important for optimal patient care.

Sepsis-induced cardiogenic shock: controversies and evidence gaps in diagnosis and management.

Journal of Intensive Care

Hepatic encephalopathy - when lactulose and rifaximin are not working.

Gastroenterology

Obesity has emerged as a global epidemic with far-reaching health complications, including its role as an independent risk factor for chronic kidney disease (CKD). Increasing evidence suggests that obesity contributes to CKD through multiple mechanisms, including chronic inflammation, hemodynamic alterations, insulin resistance, and lipid accumulation. These processes can culminate in histopathological changes collectively referred to as obesity-related glomerulopathy (ORG). This review aims to provide a comprehensive overview of the current knowledge regarding the prevalence, clinical manifestations, and pathophysiology of ORG. Furthermore, we emphasize the importance of identifying key biomarkers that facilitate the early detection of ORG. Finally, we explore emerging therapeutic strategies that offer promise in mitigating this growing global health crisis.

Obesity-Related Chronic Kidney Disease: From Diagnosis to Treatment.

Diagnostics

Marathon training and running have many beneficial effects on human health and physical fitness; however, they also pose risks. To date, no comprehensive review regarding both the benefits and risks of marathon running on different organ systems has been published.

The aim of this review was to provide a comprehensive review of the benefits and risks of marathon training and racing on different organ systems. A predefined search strategy including keywords (e.g., marathon, cardiovascular system, etc.) and free text search was used. Articles covering running regardless of sex, age, performance level, and event type (e.g., road races, mountain marathons) were considered, whereas articles examining only cycling, triathlon, stress-tests or other sports were excluded. In total, we found 1021 articles in PubMed, Scopus, and Google Scholar, of which 329 studies were included in this review. Overall, marathon training offers several benefits for different organ systems and reduces all-cause mortality. As such, it improves cardiovascular risk factors, leads to favorable cardiac adaptations, enhances lung function, and improves quality of life in chronic kidney disease patients. It also enhances gastrointestinal mobility and reduces the risk of specific tumors such as colorectal cancer and hepatocellular carcinoma. Marathon training enhances bone health and skeletal muscle metabolism. It further positively affects hematopoiesis and cytotoxic abilities of natural killer cells, and may act neuroprotective on a long-term basis. After a marathon, changes in biomarkers suggesting pathological events in certain organ systems such as cardiovascular, renal, gastrointestinal, liver, hematological, immune, musculoskeletal, central nervous, and endocrine systems can often be observed. Mostly, these changes are limited to 1-3 days post-race and usually normalize within a week. Moreover, marathon running poses the risk of serious adverse events such as sudden cardiac death or acute liver failure. Concerning lung function, a decrease after a marathon race was observed. Acute kidney injury, as well as electrolyte imbalances, are relatively common amongst marathon finishers. Many runners complain of gastrointestinal symptoms during or after long-distance running. Many runners suffer from running-related musculoskeletal injuries often impairing performance. A marathon is often accompanied by an acute inflammatory response with transient immunosuppression, making runners susceptible to infections. Also, hormonal alterations such as increased cortisol levels or decreased testosterone levels immediately after a race are observed. Disturbances in sleep patterns are commonly found in marathon runners leading up to or directly after the race.

All in all, marathon training is generally safe for human health and individual organ systems. Considering the high popularity of marathon running, these findings supply athletes, coaches, sports scientists, and sports medicine practitioners with practical applications. Further large-scale studies examining long-term effects on the cardiovascular, renal, and other system are needed.

Measurement of the heparin enhanced-antithrombin III/thrombin reaction rate in the presence of synthetic substrate.

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