Acetaminophen (APAP) is the most commonly used drug for the treatment of pain and fever around the world. At the same time, APAP can cause dose-related hepatocellular necrosis, responsible for nearly ...500 deaths annually in the United States (US) alone, as well as 100,000 calls to US Poison Control Centers, 50,000 emergency room visits and 10,000 hospitalisations per year. As an over-the-counter and prescription product (with opioids), APAP toxicity dwarfs all other prescription drugs as a cause of acute liver failure in the US and Europe, but it is not regulated in any significant way. In this review the ongoing controversy surrounding the proper role for this ubiquitous pain reliever: its history, pathogenesis, clinical challenges in recognition and management, and current regulatory status are highlighted. A new solution to a 50-year-old problem is proposed.
Acute liver failure Stravitz, R Todd; Lee, William M
The Lancet (British edition),
09/2019, Letnik:
394, Številka:
10201
Journal Article
Recenzirano
Acute liver failure is a rare and severe consequence of abrupt hepatocyte injury, and can evolve over days or weeks to a lethal outcome. A variety of insults to liver cells result in a consistent ...pattern of rapid-onset elevation of aminotransferases, altered mentation, and disturbed coagulation. The absence of existing liver disease distinguishes acute liver failure from decompensated cirrhosis or acute-on-chronic liver failure. Causes of acute liver failure include paracetamol toxicity, hepatic ischaemia, viral and autoimmune hepatitis, and drug-induced liver injury from prescription drugs, and herbal and dietary supplements. Diagnosis requires careful review of medications taken, and serological testing for possible viral exposure. Because of its rarity, acute liver failure has not been studied in large, randomised trials, and most treatment recommendations represent expert opinion. Improvements in management have resulted in lower mortality, although liver transplantation, used in nearly 30% of patients with acute liver failure, still provides a life-saving alternative to medical management.
This study was conducted to characterize metabolic features of the breast muscle (pectoralis major) in chickens affected with the Wooden Breast myopathy. Live birds from two purebred chicken lines ...and one crossbred commercial broiler population were clinically examined by manual palpation of the breast muscle (pectoralis major) at 47-48 days of age. Metabolite abundance was determined by gas chromatography/mass spectrometry (GC/MS) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) using breast muscle tissue samples from 16 affected and 16 unaffected chickens. Muscle glycogen content was also quantified in breast muscle tissue samples from affected and unaffected chickens. In total, levels of 140 biochemicals were significantly different (FDR<0.1 and fold-change A/U>1.3 or <0.77) between affected and unaffected chickens. Glycogen content measurements were considerably lower (1.7-fold) in samples taken from Wooden Breast affected birds when compared with samples from unaffected birds. Affected tissues exhibited biomarkers related to increased oxidative stress, elevated protein levels, muscle degradation, and altered glucose utilization. Affected muscle also showed elevated levels of hypoxanthine, xanthine, and urate molecules, the generation of which can contribute to altered redox homeostasis. In conclusion, our findings show that Wooden Breast affected tissues possess a unique metabolic signature. This unique profile may identify candidate biomarkers for diagnostic utilization and provide mechanistic insight into altered biochemical processes contributing to tissue hardening associated with the Wooden Breast myopathy in commercial chickens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute Liver Failure Lee, William M.
Seminars in respiratory and critical care medicine,
02/2012, Letnik:
33, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
Acute liver failure (ALF) (sometimes referred to as fulminant hepatic failure) is a clinical syndrome from a variety of causes resulting from rapid loss in hepatocyte function, typically ...associated with coagulopathy and encephalopathy in a patient without preexisting liver disease or cirrhosis. Cerebral edema is a cardinal feature and may produce uncal herniation, yielding brain stem compression and death. The typical interval from onset of symptoms to onset of encephalopathy is 1 to 2 weeks, but cases evolving more slowly, up to 6 months, may still be included in the definition. ALF is rare, affecting 2000 patients annually in the United States, and comprises ∼7% of liver transplants annually. Currently, in the United States, acetaminophen accounts for ∼50% of all cases of ALF, but other etiologies include hepatitis, drug-induced liver injury, autoimmune hepatitis. Prior to the availability of liver transplantation (LT), mortality of ALF was extremely high, often exceeding 90%; most common causes of death were multiorgan failure, hemorrhage, infection, and cerebral edema. Fortunately, survival has improved considerably in the last 3 decades (overall survival now exceeds 60%). In large part, this improved survival reflects the option of LT but also reflects the high frequency of acetaminophen toxicity as a cause of ALF. In fact, most patients with ALF are not candidates for LT. Critical care of patients with ALF is key to their survival, and decisions must sometimes be made with inadequate information. We review standard practices (medical, pharmacological, and LT) and new research initiatives and findings for this interesting but vexing orphan disease. Particular attention will be paid to practical matters for clinicians to consider in approaching the ALF patient.
Background and Aims
Acute liver failure (ALF) is characterized by significant changes in the hemostatic system and by systemic inflammation. The formation of neutrophil extracellular traps (NETs), in ...which an activated neutrophil expels its DNA, histones, and granular enzymes, such as myeloperoxidase (MPO), has been associated with immune‐mediated and thrombotic diseases. We hypothesized that formation of NETs in patients with ALF contributes to progression of disease.
Approach and Results
A total of 676 patients with ALF (international normalized ratio INR, ≥1.5) or severe acute liver injury (ALI; INR, ≥2.0) were recruited from the U.S. ALF Study Group Registry between 2011 and 2018, of whom 308 patients (45.6%) had acetaminophen‐induced ALF. Up to 21 days after admission, 483 patients (71.5%) survived without liver transplantation (LT). Levels of cell‐free DNA (cfDNA) and the specific NET marker MPO‐DNA complexes were measured in plasma samples obtained on admission and compared to levels in healthy controls. In addition, liver tissue obtained at transplantation of 20 ALF patients was stained for NETs. Levels of cfDNA were 7.1‐fold, and MPO‐DNA complexes 2.5‐fold, higher in patients with ALF compared to healthy controls. cfDNA levels were not associated with 21‐day transplant‐free survival, but were higher in those patients with more‐severe disease on admission, as reflected by various laboratory and clinical parameters. MPO‐DNA levels were 30% higher in patients with ALF who died or required urgent LT. Liver tissue of ALF patients stained positive for NETs in 12 of 18 evaluable patients.
Conclusions
Here, we provide evidence for NET formation in patients with ALF. Elevated plasma levels of MPO‐DNA complexes in patients with ALF were associated with poor outcome, which suggests that NET formation contributes to disease progression.
Although acute liver failure caused by drug-induced liver injury comprises a small fraction of overall drug-induced liver injury, these patients require high resource use and have relatively poor ...outcomes. Drug-induced liver injury caused by idiosyncrasy more often leads to death or transplantation than does acetaminophen acute liver failure, but the number of patients in each category receiving a graft is roughly the same. Efforts in the future to improve outcomes should focus on more effective treatments and better methods to identify those that might experience poor outcomes.
Drawing on the authors' extensive experience in the processing and disposal of waste, An Introduction to Nuclear Waste Immobilisation, Second Edition examines the gamut of nuclear waste issues from ...the natural level of radionuclides in the environment to geological disposal of waste-forms and their long-term behavior. It covers all-important aspects of processing and immobilization, including nuclear decay, regulations, new technologies and methods. Significant focus is given to the analysis of the various matrices used, especially cement and glass, with further discussion of other matrices such as bitumen. The final chapter concentrates on the performance assessment of immobilizing materials and safety of disposal, providing a full range of the resources needed to understand and correctly immobilize nuclear waste. * The fully revised second edition focuses on core technologies and has an integrated approach to immobilization and hazards * Each chapter focuses on a different matrix used in nuclear waste immobilization: cement, bitumen, glass and new materials * Keeps the most important issues surrounding nuclear waste - such as treatment schemes and technologies and disposal - at the forefront
Summary Over the last three decades acute liver failure (ALF) has been transformed from a rare and poorly understood condition with a near universally fatal outcome, to one with a well characterized ...phenotype and disease course. Complex critical care protocols are now applied and emergency liver transplantation (ELT) is an established treatment option. These improvements in care are such that the majority of patients may now be expected to survive ( Fig. 1 ). Key features of the condition have changed dramatically over time, with a remarkable fall in the incidence of cerebral edema and intracranial hypertension, a much feared complication. In this review, we summarize the current understanding of key aspects of the classification, pathophysiology and management of ALF, and discuss the foreseeable challenges that will need to be addressed for further improvements to be achieved.
Cancer primarily develops because of somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing the discovery of ...alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here we analyze the complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify noncoding regions that are recurrently mutated in cancer. We use new frequency- and sequence-based approaches to comprehensively scan the genome for noncoding mutations with potential regulatory impact. These methods identify recurrent mutations in regulatory elements upstream of PLEKHS1, WDR74 and SDHD, as well as previously identified mutations in the TERT promoter. SDHD promoter mutations are frequent in melanoma and are associated with reduced gene expression and poor prognosis. The non-protein-coding cancer genome remains widely unexplored, and our findings represent a step toward targeting the entire genome for clinical purposes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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