Mineralocorticoid receptor (MR) activation is pro inflammatory and pro atherogenic. Antagonism of MR improves survival in humans with congestive heart failure caused by atherosclerotic disease. In animal models, activation of MR exacerbates atherosclerosis. The enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) prevents inappropriate activation of the mineralocorticoid receptor (MR) from inappropriate activation by glucocorticoids by inactivating glucocorticoids in mineralocorticoid-target tissues. To determine whether glucocorticoid-mediated activation of MR increases atheromatous plaque formation we generated Apoe−/−/11β-HSD2−/− double-knockout (E/b2) mice. On chow diet, E/b2 mice developed atherosclerotic lesions by 3 months of age, while Apoe−/− mice remained lesion-free. Brachiocephalic plaques in 3 month-old E/b2 mice showed increased macrophage and lipid content and reduced collagen content compared to similar sized brachiocephalic plaques in 6 month old Apoe−/− mice. Crucially, treatment of E/b2 mice with eplerenone, an MR antagonist, reduced plaque development and macrophage infiltration while increasing collagen and smooth muscle cell content without any effect on systolic blood pressure (SBP). In contrast, reduction of SBP in E/b2 mice using the epithelial sodium channel (ENaC) blocker amiloride produced a less profound atheroprotective effect. Vascular cell adhesion molecule 1 (VCAM-1) expression was increased in the endothelium of E/b2 mice compared to Apoe−/− mice. Similarly, aldosterone increased VCAM-1 expression in mouse aortic endothelial cells, an effect mimicked by corticosterone only in the presence of an 11β-HSD2 inhibitor. Thus, loss of 11β-HSD2 leads to striking atherogenesis associated with activation of MR stimulating pro-inflammatory processes in the endothelium of E/b2 mice.
atherosclerosis; mineralocorticoid receptor; 11β-hydroxysteroid dehydrogenase
This communication describes the synthesis of a new class of N-hydroxyguanidine (NHG) pro-drugs which release nitric oxide (NO), triggered by the action of γ-glutamyl transpeptidase (γ-GT), and have potential for the treatment of acute renal injury/failure (ARI/ARF).
Metabolic syndrome (MS) is common in patients with chronic kidney disease (CKD), but its contribution to arterial stiffness and endothelial dysfunction in CKD is not well defined. We hypothesized that risk factors for MS would independently predict arterial stiffness and endothelial dysfunction in CKD patients.
RESEARCH DESIGN AND METHODS
Risk factors for MS, carotid-femoral pulse wave velocity (CF-PWV) and flow-mediated dilation (FMD) as measures of arterial stiffness and endothelial dysfunction, respectively, were assessed in 113 minimally comorbid CKD patients and in 23 matched control subjects.
CF-PWV correlated with systolic blood pressure (SBP), waist circumference, and plasma glucose (r2 = 0.25, 0.09, and 0.09; P < 0.01 for all). FMD correlated with SBP (r2 = 0.09; P < 0.01) and waist circumference (r2 = 0.03; P < 0.05). CF-PWV increased progressively (r2 = 0.07; P < 0.01) with increasing number of risk factors for MS. In multiple linear regression, SBP and waist circumference were independent determinants of CF-PWV, whereas only SBP predicted FMD.
The number of MS risk factors is an important determinant of arterial stiffness in CKD patients irrespective of the degree of renal impairment. Although BP remains the major determinant of arterial stiffness and endothelial dysfunction, waist circumference independently predicts arterial stiffness. MS risk factors, particularly abdominal girth, are potential targets for future interventional studies in patients with CKD.
One year after the revelation by Dr. Furchgott in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr. Yanagisawa’s group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21-amino acid) peptide were quickly determined in humans, and it was reported that, in most cardiovascular diseases, circulating levels of ET-1 were increased, and ET-1 was then tagged as “a bad guy.” The discovery of two receptor subtypes in 1990, ETA and ETB, permitted optimization of the first dual ET-1 receptor antagonist in 1993 by Dr. Clozel’s team, who entered clinical development with bosentan, which was offered to patients with pulmonary arterial hypertension in 2001. The revelation of Dr. Furchgott opened a Pandora’s box with ET-1 as one of the actors. In this brief review, we will discuss the physiological and pathophysiological role of endothelium-derived ET-1 focusing on the regulation of the vascular tone, and as much as possible in humans. The coronary bed will be used as a running example in this review because it is the most susceptible to endothelial dysfunction, but references to the cerebral and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of nitric oxide and ET-1.
PMID: 19967386 CAMSID: cams3018
Vascular tone; Inflammation; Cardiovascular diseases
Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.
We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course.
This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk.
EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT01050270
Paracetamol; Acetylcysteine; Overdose; Antidotes; Hepatotoxicity
High doses of gabapentin were associated with pancreatic acinar cell tumors in male Wistar rats, but there is little published epidemiological data regarding gabapentin and carcinogenicity. We explored the association between gabapentin and cancer in a United States (US) medical care program, and followed up nominally significant associations in a United Kingdom (UK) primary care database.
In the US Kaiser Permanente Northern California (KPNC) health system, we performed nested case-control analyses of gabapentin and 55 cancer sites and all-cancer combined using conditional logistic regression. Up to ten controls were matched to each case on year of birth, sex, and year of cohort entry. No other covariates were included in models. Only dispensings for gabapentin 2 years or more prior to index date were considered. Nominally significant associations with an odds ratio > 1.00 and p < 0.05 for three or more dispensings versus no dispensings were followed up by similar nested-case control analyses in the UK General Practice Research Database (GPRD), adjusting for potential indications for gabapentin and risk factors for the specific cancers.
The following analyses had OR>1.00 and p<0.05 for three or more dispensings of gabapentin versus no dispensing (2-year lag) in KPNC, and were also examined in the GPRD: all-cancer, breast, lung and bronchus, urinary bladder, kidney/renal pelvis, stomach, anus/anal canal/anorectum, penis, and other nervous system. These cancers were not statistically significantly associated with gabapentin in the GPRD case-control studies (2-year lag). The GPRD and KPNC studies did not identify a statistically significant increased risk of pancreatic cancer with >2 prescriptions of gabapentin in 2-year lagged analyses.
The epidemiological data in a US cohort with up to 12 years of follow-up and a UK cohort with up to 15 years of follow up do not support a carcinogenic effect of gabapentin use. However, the confidence intervals for some analyses were wide, and an important effect cannot be confidently excluded.
Gabapentin; Cancer; Protopathic bias
Study objectives were to investigate the prevalence and causes of prescribing errors amongst foundation doctors (i.e. junior doctors in their first (F1) or second (F2) year of post-graduate training), describe their knowledge and experience of prescribing errors, and explore their self-efficacy (i.e. confidence) in prescribing.
A three-part mixed-methods design was used, comprising: prospective observational study; semi-structured interviews and cross-sectional survey. All doctors prescribing in eight purposively selected hospitals in Scotland participated. All foundation doctors throughout Scotland participated in the survey. The number of prescribing errors per patient, doctor, ward and hospital, perceived causes of errors and a measure of doctors' self-efficacy were established.
4710 patient charts and 44,726 prescribed medicines were reviewed. There were 3364 errors, affecting 1700 (36.1%) charts (overall error rate: 7.5%; F1:7.4%; F2:8.6%; consultants:6.3%). Higher error rates were associated with : teaching hospitals (p<0.001), surgical (p = <0.001) or mixed wards (0.008) rather thanmedical ward, higher patient turnover wards (p<0.001), a greater number of prescribed medicines (p<0.001) and the months December and June (p<0.001). One hundred errors were discussed in 40 interviews. Error causation was multi-factorial; work environment and team factors were particularly noted. Of 548 completed questionnaires (national response rate of 35.4%), 508 (92.7% of respondents) reported errors, most of which (328 (64.6%) did not reach the patient. Pressure from other staff, workload and interruptions were cited as the main causes of errors. Foundation year 2 doctors reported greater confidence than year 1 doctors in deciding the most appropriate medication regimen.
Prescribing errors are frequent and of complex causation. Foundation doctors made more errors than other doctors, but undertook the majority of prescribing, making them a key target for intervention. Contributing causes included work environment, team, task, individual and patient factors. Further work is needed to develop and assess interventions that address these.
This paper introduces a revolutionary way to interrogate optical fiber sensors based on fiber Bragg gratings (FBGs) and to integrate the necessary driving optoelectronic components with the sensor elements. Low-cost optoelectronic chips are used to interrogate the optical fibers, creating a portable dynamic sensing system as an alternative for the traditionally bulky and expensive fiber sensor interrogation units. The possibility to embed these laser and detector chips is demonstrated resulting in an ultra thin flexible optoelectronic package of only 40 μm, provided with an integrated planar fiber pigtail. The result is a fully embedded flexible sensing system with a thickness of only 1 mm, based on a single Vertical-Cavity Surface-Emitting Laser (VCSEL), fiber sensor and photodetector chip. Temperature, strain and electrodynamic shaking tests have been performed on our system, not limited to static read-out measurements but dynamically reconstructing full spectral information datasets.
dynamic read-out; fiber sensor; flexible; integration; low-cost; polymer embedding; ultra thin optoelectronic chip package; VCSEL
Calcitonin gene-related peptide (CGRP) is one of the most potent microvascular vasodilators identified to date. Vascular relaxation and vasodilation is mediated via activation of the CGRP receptor. This atypical receptor is made up of a G protein-coupled receptor called calcitonin receptor-like receptor (CLR), a single transmembrane protein called receptor activity-modifying protein (RAMP), and an additional protein that is required for Gas coupling, known as receptor component protein (RCP). Several mechanisms involved in CGRP-mediated relaxation have been identified. These include nitric oxide (NO)-dependent endothelium-dependent mechanisms or cAMP-mediated endothelium-independent pathways; the latter being more common. Subarachnoid hemorrhage (SAH) is associated with cerebral vasoconstriction that occurs several days after the hemorrhage and is often fatal. The vasospasm occurs in 30–40% of patients and is the major cause of death from this condition. The vasoconstriction is associated with a decrease in CGRP levels in nerves and an increase in CGRP levels in draining blood, suggesting that CGRP is released from nerves to oppose the vasoconstriction. This evidence has led to the concept that exogenous CGRP may be beneficial in a condition that has proven hard to treat. The present article reviews: (a) the pathophysiology of delayed ischemic neurologic deficit after SAH (b) the basics of the CGRP receptor structure, signal transduction, and vasodilatation mechanisms and (c) the studies that have been conducted so far using CGRP in both animals and humans with SAH.
GPCR; CGRP; subarachnoid hemorrhage; cerebral vasospasm; G proteins
Traditional methods for the analysis of vascular lesion formation are labour intensive to perform - restricting study to ‘snapshots’ within each vessel. This study was undertaken to determine the suitability of optical projection tomographic (OPT) imaging for the 3-dimensional representation and quantification of intimal lesions in mouse arteries.
Methods and Results
Vascular injury was induced by wire-insertion or ligation of the mouse femoral artery or administration of an atherogenic diet to apoE-deficient mice. Lesion formation was examined by OPT imaging of autofluorescent emission. Lesions could be clearly identified and distinguished from the underlying vascular wall. Planimetric measurements of lesion area correlated well with those made from histological sections subsequently produced from the same vessels (wire-injury: R2 = 0.92; ligation-injury: R2 = 0.89; atherosclerosis: R2 = 0.85), confirming both the accuracy of this methodology and its non-destructive nature. It was also possible to record volumetric measurements of lesion and lumen and these were highly reproducible between scans (coefficient of variation = 5.36%, 11.39% and 4.79% for wire- and ligation-injury and atherosclerosis, respectively).
These data demonstrate the eminent suitability of OPT for imaging of atherosclerotic and neointimal lesion formation, providing a much needed means for the routine 3-dimensional analysis of vascular morphology in studies of this type.
The Declaration of Helsinki, the World Medical Association's (WMA's) statement of ethical guidelines regarding medical research, is published in the three official languages of the WMA: English, French and Spanish.
A detailed comparison of the three official language versions was carried out to determine ways in which they differed and ways in which the wording of the three versions might illuminate the interpretation of the document.
There were many minor linguistic differences between the three versions. However, in paragraphs 1, 6, 29, 30 and in the note of clarification to paragraph 29, there were differences that could be considered potentially significant in their ethical relevance.
Given the global status of the Declaration of Helsinki and the fact that it is translated from its official versions into many other languages for application to the ethical conduct of research, the differences identified are of concern. It would be best if such differences could be eliminated but, at the very least, a commentary to explain any differences that are unavoidable on the basis of language or culture should accompany the Declaration of Helsinki. This evidence further strengthens the case for international surveillance of medical research ethics as has been proposed by the WMA.
Declaration of Helsinki; ethics; research; linguistics; international health problems; World Medical Association
Nitric oxide (NO) can be both pro- and anti-apoptotic in various cell types, including macrophages. This apparent paradox may result from the actions of NO-related species generated in the microenvironment of the cell, for example the formation of peroxynitrite (ONOO-). In this study we have examined the ability of NO and ONOO- to evoke apoptosis in human monocyte-derived macrophages (MDMϕ), and investigated whether preconditioning by cyclic guanosine monophosphate (cGMP) is able to limit apoptosis in this cell type.
Characterisation of the NO-related species generated by (Z)-1- [2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) and 1,2,3,4-oxatriazolium, 5-amino-3-(3,4-dichlorophenyl)-, chloride (GEA-3162) was performed by electrochemistry using an isolated NO electrode and electron paramagnetic resonance (EPR) spectrometry. Mononuclear cells were isolated from peripheral blood of healthy volunteers and cultured to allow differentiation into MDMϕ. Resultant MDMϕ were treated for 24 h with DETA/NO (100 – 1000 μM) or GEA-3162 (10 – 300 μM) in the presence or absence of BAY 41–2272 (1 μM), isobutylmethylxanthine (IBMX; 1 μM), 1H- [1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ; 20 μM) or 8-bromo-cGMP (1 mM). Apoptosis in MDMϕ was assessed by flow cytometric analysis of annexin V binding in combination with propidium iodide staining.
Electrochemistry and EPR revealed that DETA/NO liberated free NO radical, whilst GEA-3162 concomitantly released NO and O2-, and is therefore a ONOO- generator. NO (DETA/NO) had no effect on cell viability, but ONOO- (GEA-3162) caused a concentration-dependent induction of apoptosis in MDMϕ. Preconditioning of MDMϕ with NO in combination with the phosphodiesterase inhibitor, 3-Isobutyl-1-methylxanthine (IBMX), or the NO-independent stimulator of soluble guanylate cyclase, BAY 41–2272, significantly attenuated ONOO--induced apoptosis in a cGMP-dependent manner.
These results demonstrate disparities between the ability of NO and ONOO- to induce apoptosis in human MDMϕ. Furthermore, this study provides evidence for a novel cGMP-dependent pre-conditioning mechanism to limit ONOO--induced apoptosis in human MDMϕ.
Hypertension is generally poorly controlled in primary care. One possible intervention for improving control is the harnessing of patient expertise through education and encouragement to challenge their care.
To determine whether encouraging patients to manage their hypertension in an ‘expert’ manner, by providing them with information in a clear clinical guideline, coupled with an explicit exhortation to become involved in and to challenge their own care if appropriate, would improve their care.
Design of study
Single blind randomised controlled trial of detailed guideline versus standard information.
Single urban general practice over 1 year.
Patient-held guideline with written explicit exhortation to challenge care when appropriate. Two hundred and ninety-four of 536 eligible patients on the practice hypertension register were recruited, all of whom were randomised into one of two groups. Two hundred and thirty-six patients completed the study.
Primary outcome: average systolic blood pressure. Secondary outcomes: proportion of patients with blood pressure <150mmHg systolic and <90mmHg diastolic, average cholesterol, proportion of patients prescribed statins and aspirin according to guideline, hospital anxiety and depression score. No clinically, or statistically significant differences were found between intervention and control with respect to all parameters or in anxiety and depression levels. Statin and aspirin use improved throughout the course of the study in both groups. Statin use showed a trend (P = 0.02) in favour of control.
In this study there was no clinically significant perceived benefit to patients as a result of providing them with a hypertension guideline. Patient guidelines are currently planned for many chronic illnesses. It is important to determine the utility of such interventions before scarce resources are applied to them.
clinical trials; hypertension; physician–patient relations; primary health care; self-care
To examine whether augmentation index (AIx) is increased in Marfan syndrome (MFS) and associated with increased aortic root size, and whether a peripheral-to-central generalised transfer function (GTF) can be applied usefully in MFS.
10 MFS patients and 10 healthy controls (matched for sex, age and height) were studied before and after 400 μg sub-lingual GTN. Arterial waveforms were recorded using applanation tonometry. AIx and pulse pressure (PP) were determined for the radial and carotid arteries. Pulse wave velocity (PWV) was measured between carotid and femoral arteries. GTFs were generated to examine the relationship between radial and carotid waveforms.
AIx was greater in MFS compared to controls at radial (mean -31.4 (SD 14.3)% v -50.2(15.6)%, p = 0.003) and carotid (-7.6(11.2)% v -23.7(12.7)%, p = 0.004) sites. Baseline PP at all measurement sites, and PWV, did not differ between subject groups. Multivariate analysis demonstrated that PWV and carotid AIx were positively correlated with aortic root size (p < 0.001 and p = 0.012 respectively), independent of the presence of MFS. PP was not associated with aortic root size. GTN caused similar decreases in AIx in both controls and patients. Significant differences were found in GTFs between MFS and control subjects, which changed following GTN administration. However, when an independent GTF was used to derive carotid waves from radial waves, no differences were found in the degree of error between MFS and controls.
AIx is sensitive to the vascular abnormalities present in MFS, and may have a role as an adjunct to measurement of central PP and PWV. Differences between MFS and controls in the nature of the peripheral-to-central GTF are present, although have little effect on the pulse contour.
Many medical students are unprepared for skilled prescribing
How long someone has to live intuitively seems important in rationing decisions. Incorporating it into economic assessments, as described here, could make decisions fairer
Objective: To examine the possibility that low birth weight is a feature of the inherited predisposition to high blood pressure.
Design: Cross sectional study.
Setting: Primary care medical centre in Edinburgh.
Subjects: One offspring of 452 families (231 men and 221 women aged 16-26 years) in whom blood pressure, weight, and height were measured in 1986 and whose parents had blood pressure measured in 1979. Birth weights were obtained from case records (270 offspring) or by questionnaires sent to the mothers (182 offspring).
Main outcome measures: Birth weight and adult systolic blood pressure in offspring in relation to parental blood pressure.
Results: If parental blood pressures were not considered, a 1 kg decrease in birth weight was associated with a 2.24 mm Hg increase in systolic blood pressure of offspring (P=0.06) after correction for current weight and sex. However, parental blood pressures correlated positively with blood pressure of offspring, and higher maternal blood pressure was associated with lower birth weight (−3.03 g/mm Hg, P<0.01). After correction for parental blood pressures, a 1 kg decrease in birth weight was associated with only a 1.71 mm Hg increase in the systolic blood pressure of the offspring (P=0.15).
Conclusions: Low birth weight is a feature of the inherited predisposition to hypertension, perhaps because it is associated with higher maternal blood pressure during pregnancy. Parental blood pressure may be an important confounding factor in the relation between low birth weight and subsequent hypertension.
Key messages Hypertension has both inherited and environmental causes The relation between low birth weight and hypertension in later life may result from the mother’s nutritional environment during pregnancy This study found that mothers who have higher blood pressure in later life deliver babies with lower birth weight, who also develop higher blood pressure Hereditary factors therefore explain part of the relation between low birth weight and adult hypertension
Prescribing errors are a major source of morbidity and mortality and represent a significant patient safety concern. Evidence suggests that trainee doctors are responsible for most prescribing errors. Understanding the factors that influence prescribing behavior may lead to effective interventions to reduce errors. Existing investigations of prescribing errors have been based on Human Error Theory but not on other relevant behavioral theories. The aim of this study was to apply a broad theory-based approach using the Theoretical Domains Framework (TDF) to investigate prescribing in the hospital context among a sample of trainee doctors.
Semistructured interviews, based on 12 theoretical domains, were conducted with 22 trainee doctors to explore views, opinions, and experiences of prescribing and prescribing errors. Content analysis was conducted, followed by applying relevance criteria and a novel stage of critical appraisal, to identify which theoretical domains could be targeted in interventions to improve prescribing.
Seven theoretical domains met the criteria of relevance: “social professional role and identity,” “environmental context and resources,” “social influences,” “knowledge,” “skills,” “memory, attention, and decision making,” and “behavioral regulation.” From critical appraisal of the interview data, “beliefs about consequences” and “beliefs about capabilities” were also identified as potentially important domains. Interrelationships between domains were evident. Additionally, the data supported theoretical elaboration of the domain behavioral regulation.
In this investigation of hospital-based prescribing, participants’ attributions about causes of errors were used to identify domains that could be targeted in interventions to improve prescribing. In a departure from previous TDF practice, critical appraisal was used to identify additional domains that should also be targeted, despite participants’ perceptions that they were not relevant to prescribing errors. These were beliefs about consequences and beliefs about capabilities. Specifically, in the light of the documented high error rate, beliefs that prescribing errors were not likely to have consequences for patients and that trainee doctors are capable of prescribing without error should also be targeted in an intervention. This study is the first to suggest critical appraisal for domain identification and to use interview data to propose theoretical elaborations and interrelationships between domains.
Prescribing; Patient safety; Theoretical domains framework
Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies.