P-glycoprotein, a membrane efflux pump encoded by the MDR1 gene, plays an important role in the development of multidrug resistance in human hepatoblastoma (HB). Chemosensitizers antagonize the efflux action of P-glycoprotein. This study investigates the effects of 3 chemosensitizers (the cyclosporin analogue SDZ PSC 833 (PSC 833), the acridone carboxamide derivative GG 918, and verapamil) on the chemotherapy of HB in vitro.

The doxorubicin (DOXO) concentration that produces 50% growth inhibition (IC50) in a HB cell line was determined and additional effects of PSC 833, GG 918, and verapamil were investigated in a cytotoxicity assay. The MDR1 gene expression after treatment was determined in a semiquantitative reverse transcription polymerase chain reaction approach.

The IC50 of DOXO is 2.5 microg/mL, 0.61 microg/mL for DOXO + PSC 833, 1.17 microg/mL for DOXO + verapamil, and 1.47 microg/mL for DOXO + GG 918. In combination with DOXO, cell growth was inhibited 4.1-fold by PSC 833, 2.1-fold by verapamil, and 1.9-fold by GG 918. The MDR1 gene expression was enhanced significantly in all treated cells, with and without modulator.

MDR1 modulators significantly improve the response of HB to DOXO in vitro. The combination of anticancer agents and MDR1 modulators might be a possible contribution to overcome multidrug resistance in HB.

MDR1 modulators improve the chemotherapy response of human hepatoblastoma to doxorubicin in vitro.

Journal of Pediatric Surgery

The administration of an anticoagulant in patients with liver disease (nonalcoholic steatohepatitis-NASH, nonalcoholic fatty liver disease-NAFLD, chronic hepatitis, or cirrhosis) who have an indication (atrial fibrillation, venous thrombosis, or pulmonary embolism) is challenging because there is an imbalance between thrombosis and bleeding. There is a need to focus our attention on preventing risk factors because diabetes, obesity, dyslipidemia, smoking, and sedentary behavior are risk factors for both NASH/NAFLD and AF, and these patients require anticoagulant treatment. Patients with advanced liver disease (Child-Pugh C) were excluded from studies, so vitamin K antagonists (VKAs) are still recommended. Currently, VKAs are recommended for other conditions (antiphospholipid syndrome, mitral valve stenosis, and mechanical valve prosthesis). Amongst the patients under chronic anticoagulant treatment, especially for the elderly, bleeding as a result of the improper use of warfarin is one of the important causes of emergency admissions due to adverse reactions. DOACs are considered to be efficient and safe, with apixaban offering superior protection against stroke and a good safety profile as far as major bleeding is concerned compared to warfarin. DOACs are safe in the Child-Pugh A and B classes (except rivaroxaban), and in the Child-Pugh C class are contraindicated. Given that there are certain and reliable data for chronic kidney disease regarding the recommendations, in liver function impairment more randomized studies must be carried out, as the current data are still uncertain. In particular, DOACs have a simple administration, minimal medication interactions, a high safety and effectiveness profile, and now a reversal agent is available (for dabigatran and idarucizumab). Patients are also statistically more compliant and do not require INR monitoring.

Oral Anticoagulation in Patients with Chronic Liver Disease.

Medicina

To describe the clinical manifestations of Hashimoto's encephalopathy (HE) and discuss its pathogenesis in light of recent research.

The pathogenesis of HE is uncertain. Available evidences point towards an autoimmune etiology due to vasculitis or other inflammatory process. Detection of thyroid antibodies - antithyroid peroxidase and anti-thyroglobulin are essential for diagnosis. Autoimmune encephalitis including Anti-IgLON5 disease needs to be excluded in suspected cases with appropriate tests for neuronal surface antibodies. Detection of thyroid autoantibodies is nonspecific, as these can be detected in some normal individuals and in other autoimmune diseases. In recent years, attention has turned to an aggressive form of Hashimoto's thyroiditis accompanied by elevated serum IgG4 levels in younger males with very high levels of thyroid antibodies. The role of the thyroid autoantibodies in the central nervous system (CNS) tissue damage remains unclear and these can act only as markers for diagnosis. Conversely, they have a role to play in determining the thyroid pathology - more glandular fibrosis associated with thyro-peroxidase antibody than with the thyroglobulin antibody. HE is a syndrome characterized by altered mental status, confusion, hallucinations, delusions, and sometimes seizures, in association with high serum anti-thyroid antibody concentration that is usually responsive to glucocorticoid therapy. Diagnosis requires the exclusion of other causes of encephalopathies and encephalitis including autoimmune encephalitis associated with neuronal surface antibodies and paraneoplastic ones. Diagnosis also is dependent on the demonstration of thyroid autoantibodies in serum. Since there is no direct pathophysiologic link between antithyroid antibodies, Hashimoto thyroiditis and the cerebral syndrome, the nomenclature HE could be misleading. The response to steroids led to a renaming of the syndrome to steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), though some cases do not respond to steroids. In recent years, attention has turned to an aggressive form of Hashimoto's thyroiditis accompanied by elevated serum IgG4 levels (IgG4-related disease). This is characterized by a higher incidence in men (5:1) than in women, onset at a younger age, more intense thyroid inflammation and higher antithyroid antibody titters. Such patients have excessive production of IgG4&#x2009;+&#x2009;plasmacytes, which infiltrate various organs leading to their fibrosis and sclerosis, sometimes resulting in inflammatory tumors. HE is treated with corticosteroids along with treatment of the dysthyroid condition, if any. There are yet no guidelines regarding steroid dose and/or duration.

Hashimoto's Encephalopathy: Case Series and Literature Review.

Current Neurology and Neuroscience Reports

Background Ventricular ectopy is observed in most of the population ranging from isolated premature ventricular contractions to rapid hemodynamically unstable ventricular tachyarrhythmias like ventricular tachycardia and ventricular fibrillation. Multiple mechanisms exist for ventricular arrhythmias such as triggered activity, reentry, and automaticity. Scar-based reentry forms the basis of most malignant VA that can lead to sudden cardiac death. Many antiarrhythmic drugs have been utilized for the suppression of ventricular arrhythmia. They are commonly classified using the Vaughan-Williams-Singh classification which distinguishes them based on the predominant action on different phases of the cardiac action potential. Class Ic agents are widely used in premature ventricular contraction suppression but are contraindicated in patients with prior myocardial infarction or ischemic scar, and heart failure. Beta-blockers continue to be a mainstay in the treatment of most symptomatic VA and are well tolerated, relatively safe, and have additional benefits in symptomatic coronary heart disease and left ventricular systolic dysfunction. Amiodarone continues to be used for the management of most cases of serious VA especially in the acute setting when accompanied by hemodynamic perturbations but has the disadvantage of having a poor toxicity profile for long-term use Summary Historically used for long-term ventricular arrhythmia suppression and prevention of sudden cardiac death, antiarrhythmics are now used to reduce implantable defibrillator shocks and symptoms. They still have a role in premature ventricular complex suppression in patients with failed catheter ablation or those who are not candidates for invasive therapy. Newer concepts in cardiac imaging and the use of artificial intelligence may help further delineate sudden cardiac risk and identify patients that may benefit from pharmacological management. Key Message Anti-arrhythmic agents continue to perform an important role in the suppression of ventricular arrhythmias especially channelopathies, polymorphic VT, and idiopathic ventricular fibrillation. Judicious use of these agents while recognizing side effects can help reduce the long-term effects of ventricular arrhythmias on cardiac function.

Pharmacotherapy in Ventricular Arrhythmias.

Cardiology

Cardiomyopathies are a heterogeneous group of structural, mechanical, and electrical heart muscle disorders which often correlate with life-threatening arrhythmias and progressive heart failure accounting for significant cardiovascular morbidity and mortality. Currently, cardiomyopathies still represent a leading reason for heart transplantation worldwide. The last years have brought remarkable advances in the field of cardiomyopathies especially in terms of understanding the molecular basis as well as the diagnostic evaluation and management. Although most cardiomyopathy treatments had long focused on symptom management, much of the current research efforts aim to identify and act on the disease-driving mechanisms. Regarding risk assessment and primary prevention of sudden cardiac death, additional data are still pending in order to pave the way for a more refined and early patient selection for defibrillator implantation. This review summarizes the current knowledge of hypertrophic, dilated and arrhythmogenic cardiomyopathy with a particular emphasis on their pathophysiology, clinical features, and diagnostic approach. Furthermore, the relevant ongoing studies investigating novel management approaches and main gaps in knowledge are highlighted.

Hypertrophic, Dilated, and Arrhythmogenic Cardiomyopathy: Where Are We?

Biomedicines

The current review is to describe the definition and prevalence of resistant arterial hypertension (RAH), the difference between refractory hypertension, patient characteristics and major risk factors for RAH, how RAH is diagnosed, prognosis and outcomes for patients.

According to the WHO, approximately 1.28 billion adults aged 30-79 worldwide have arterial hypertension, and over 80% of them do not have blood pressure (BP) under control. RAH is defined as above-goal elevated BP despite the concurrent use of 3 or more classes of antihypertensive drugs, commonly including a long-acting calcium channel blocker, an inhibitor of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a thiazide diuretic administered at maximum or maximally tolerated doses and at appropriate dosing frequency. RAH occurs in nearly 1 of 6 hypertensive patients. It often remains unrecognised mainly because patients are not prescribed &#x2265;3 drugs at maximal doses despite uncontrolled BP.

RAH distinctly increases the risk of developing coronary artery disease, heart failure, stroke and chronic kidney disease and confers higher rates of major adverse cardiovascular events as well as increased all-cause mortality. Timely diagnosis and treatment of RAH may mitigate the associated risks and improve short and long-term prognosis.

What is resistant arterial hypertension?

Blood Pressure

Sepsis-associated acute kidney injury (SA-AKI) is common in critically ill patients and is strongly associated with adverse outcomes, including an increased risk of chronic kidney disease, cardiovascular events and death. The pathophysiology of SA-AKI remains elusive, although microcirculatory dysfunction, cellular metabolic reprogramming and dysregulated inflammatory responses have been implicated in preclinical studies. SA-AKI is best defined as the occurrence of AKI within 7 days of sepsis onset (diagnosed according to Kidney Disease Improving Global Outcome criteria and Sepsis 3 criteria, respectively). Improving outcomes in SA-AKI is challenging, as patients can present with either clinical or subclinical AKI. Early identification of patients at risk of AKI, or at risk of progressing to severe and/or persistent AKI, is crucial to the timely initiation of adequate supportive measures, including limiting further insults to the kidney. Accordingly, the discovery of biomarkers associated with AKI that can aid in early diagnosis is an area of intensive investigation. Additionally, high-quality evidence on best-practice care of patients with AKI, sepsis and SA-AKI has continued to accrue. Although specific therapeutic options are limited, several clinical trials have evaluated the use of care bundles and extracorporeal techniques as potential therapeutic approaches. Here we provide graded recommendations for managing SA-AKI and highlight priorities for future research.

Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup.

Nature Reviews. Nephrology

BTS clinical statement on aspiration pneumonia.

Thorax

Heart failure with preserved ejection fraction (HFpEF), defined as HF with an EF of 50% or higher at diagnosis, affects approximately 3 million people in the US and up to 32 million people worldwide. Patients with HFpEF are hospitalized approximately 1.4 times per year and have an annual mortality rate of approximately 15%.

Risk factors for HFpEF include older age, hypertension, diabetes, dyslipidemia, and obesity. Approximately 65% of patients with HFpEF present with dyspnea and physical examination, chest radiographic, echocardiographic, or invasive hemodynamic evidence of HF with overt congestion (volume overload) at rest. Approximately 35% of patients with HFpEF present with "unexplained" dyspnea on exertion, meaning they do not have clear physical, radiographic, or echocardiographic signs of HF. These patients have elevated atrial pressures with exercise as measured with invasive hemodynamic stress testing or estimated with Doppler echocardiography stress testing. In unselected patients presenting with unexplained dyspnea, the H2FPEF score incorporating clinical (age, hypertension, obesity, atrial fibrillation status) and resting Doppler echocardiographic (estimated pulmonary artery systolic pressure or left atrial pressure) variables can assist with diagnosis (H2FPEF score range, 0-9; score &gt;5 indicates more than 95% probability of HFpEF). Specific causes of the clinical syndrome of HF with normal EF other than HFpEF should be identified and treated, such as valvular, infiltrative, or pericardial disease. First-line pharmacologic therapy consists of sodium-glucose cotransporter type 2 inhibitors, such as dapagliflozin or empagliflozin, which reduced HF hospitalization or cardiovascular death by approximately 20% compared with placebo in randomized clinical trials. Compared with usual care, exercise training and diet-induced weight loss produced clinically meaningful increases in functional capacity and quality of life in randomized clinical trials. Diuretics (typically loop diuretics, such as furosemide or torsemide) should be prescribed to patients with overt congestion to improve symptoms. Education in HF self-care (eg, adherence to medications and dietary restrictions, monitoring of symptoms and vital signs) can help avoid HF decompensation.

Approximately 3 million people in the US have HFpEF. First-line therapy consists of sodium-glucose cotransporter type 2 inhibitors, exercise, HF self-care, loop diuretics as needed to maintain euvolemia, and weight loss for patients with obesity and HFpEF.

Heart Failure With Preserved Ejection Fraction: A Review.

JAMA

The Coronavirus 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus, has resulted in unprecedented morbidity and mortality worldwide. While COVID-19 typically presents as viral pneumonia, cardiovascular manifestations such as acute coronary syndromes, arterial and venous thrombosis, acutely decompensated heart failure (HF), and arrhythmia are frequently observed. Many of these complications are associated with poorer outcomes, including death. Herein we review the relationship between cardiovascular risk factors and outcomes among patients with COVID-19, cardiovascular manifestations of COVID-19, and cardiovascular complications associated with COVID-19 vaccination.

MDR1 modulators improve the chemotherapy response of human hepatoblastoma to doxorubicin in vitro.

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MDR1 modulators improve the chemotherapy response of human hepatoblastoma to doxorubicin in vitro.

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