Serum Aminotransferase Concentrations Research Articles

Evaluation of Vicarious Somatosensory Experience in Diabetes Mellitus: Bases for Empathy and Social Cognition.

Diabetes Mellitus (DM) is a common metabolic disorder with negative impacts on brain functions. Social cognition and vicarious experience impairments are features of DM. This research aimed to estimate the social cognition and vicarious experience among Jordanian people with diabetes. Cognitive abilities were assessed using the Vicarious Pain Questionnaire (VPQ) and the Mirror Touch Questionnaire (MTQ). Data on disease history, medications, routine laboratory measurements, and anthropometric indices. Patients had lower pain responses and intensity scores, and higher unpleasantness scores than the control group (p < 0.05). Most of the VPQ and MTQ measures were mainly impaired among study participants who had higher education, were not practicing exercises, and were not consuming healthy diets (p < 0.05). The number of responses to the VPQ and average pain intensity were negatively correlated with age and positively correlated with both the serum aminotransferase (AST) concentration and the serum urea concentration (p < 0.05). The average unpleasantness score was positively correlated with the duration of therapy, serum creatinine, and albumin concentrations (p < 0.05). The final regression models for the number of pain responses and localized-generalized included group, practicing exercise, and AST, while the model for the average pain intensity included only the grouping variable. The model for average unpleasantness included grouping, AST, Albumin, consuming a healthy diet, and duration of therapy. The Jordanian diabetic patients who participated in the study had impaired social cognition and vicarious experience. A healthy lifestyle had a significant effect on the scores of the vicarious experience in addition to the level of education. Despite being the first study in Jordan to assess vicarious experience in DM, further studies are needed considering imaging and electrophysiological workup. Besides, further prospective studies are needed to determine the significance of the current study.

CD73 mediates the therapeutic effects of endometrial regenerative cells in concanavalin A-induced hepatitis by regulating CD4+ T cells

BackgroundAs a kind of mesenchymal-like stromal cells, endometrial regenerative cells (ERCs) have been demonstrated effective in the treatment of Concanavalin A (Con A)-induced hepatitis. However, the therapeutic mechanism of ERCs is not fully understood. Ecto-5`-nucleotidase (CD73), an enzyme that could convert immune-stimulative adenosine monophosphate (AMP) to immune-suppressive adenosine (ADO), was identified highly expressed on ERCs. The present study was conducted to investigate whether the expression of CD73 on ERCs is critical for its therapeutic effects in Con A-induced hepatitis.MethodsERCs knocking out CD73 were generated with lentivirus-mediated CRISPR-Cas9 technology and identified by flow cytometry, western blot and AMPase activity assay. CD73-mediated immunomodulatory effects of ERCs were investigated by CD4+ T cell co-culture assay in vitro. Besides, Con A-induced hepatitis mice were randomly assigned to the phosphate-buffered saline treated (untreated), ERC-treated, negative lentiviral control ERC (NC-ERC)-treated, and CD73-knockout-ERC (CD73-KO-ERC)-treated groups, and used to assess the CD73-mediated therapeutic efficiency of ERCs. Hepatic histopathological analysis, serum transaminase concentrations, and the proportion of CD4+ T cell subsets in the liver and spleen were performed to assess the progression degree of hepatitis.ResultsExpression of CD73 on ERCs could effectively metabolize AMP to ADO, thereby inhibiting the activation and function of conventional CD4+ T cells was identified in vitro. In addition, ERCs could markedly reduce levels of serum and liver transaminase and attenuate liver damage, while the deletion of CD73 on ERCs dampens these effects. Furthermore, ERC-based treatment achieved less infiltration of CD4+ T and Th1 cells in the liver and reduced the population of systemic Th1 and Th17 cells and the levels of pro-inflammatory cytokines such as IFN-γ and TNF-α, while promoting the generation of Tregs in the liver and spleen, while deletion of CD73 on ERCs significantly impaired their immunomodulatory effects locally and systemically.ConclusionTaken together, it is concluded that CD73 is critical for the therapeutic efficiency of ERCs in the treatment of Con A-induced hepatitis.

Using a decision tree algorithm to distinguish between repeated supra-therapeutic and acute acetaminophen exposures

BackgroundThis study aimed to compare clinical and laboratory characteristics of supra-therapeutic (RSTI) and acute acetaminophen exposures using a predictive decision tree (DT) algorithm.MethodsWe conducted a retrospective cohort study using the National Poison Data System (NPDS). All patients with RSTI acetaminophen exposure (n = 4,522) between January 2012 and December 2017 were included. Additionally, 4,522 randomly selected acute acetaminophen ingestion cases were included. After that, the DT machine learning algorithm was applied to differentiate acute acetaminophen exposure from supratherapeutic exposures.ResultsThe DT model had accuracy, precision, recall, and F1-scores of 0.75, respectively. Age was the most relevant variable in predicting the type of acetaminophen exposure, whether RSTI or acute. Serum aminotransferase concentrations, abdominal pain, drowsiness/lethargy, and nausea/vomiting were the other most important factors distinguishing between RST and acute acetaminophen exposure.ConclusionDT models can potentially aid in distinguishing between acute and RSTI of acetaminophen. Further validation is needed to assess the clinical utility of this model.

Liver transaminase concentrations in children with acute SARS-CoV-2 infection

ObjectiveTo evaluate the relationship between SARS-CoV-2 infection and liver injury by comparing transaminase concentrations among children tested for SARS-CoV-2 and other respiratory viruses in pediatric emergency departments. Design & methodsEligible children were <18 years with suspected SARS-CoV-2, tested using molecular approaches in emergency departments between March 7, 2020, and June 15, 2021 (Pediatric Emergency Research Network), and between August 6, 2020, and February 22, 2022 (Pediatric Emergency Research Canada). We compared aspartate (AST) and alanine aminotransferase (ALT) concentrations at presentation for SARS-CoV-2 and other respiratory viruses through a multivariate linear regression model, with the natural log of serum transaminase concentrations as dependent variables. ResultsOf 16,892 enrolled children, 2,462 (14.6%) had transaminase concentrations measured; 4318 (25.6%) were SARS-CoV-2 positive, and 3932 (23.3%) were tested for additional respiratory viruses. Among study participants who had additional respiratory virus testing performed, the most frequently identified viruses were enterovirus/rhinovirus [8.7% (343/3,932)], respiratory syncytial virus [4.6% (181/3,932)], and adenovirus [2.6% (103/3,932)]. Transaminase concentrations were elevated in 25.6% (54/211) of children with isolated SARS-CoV-2 detection and 21.6% (117/541) of those with no virus isolated; P = 0.25. In the multivariable model, isolated SARS-CoV-2 detection was not associated with elevated ALT (adjusted geometric mean ratio (IU/L): 0.96; 95%Confidence Interval (CI): 0.84, 1.08) or AST (adjusted geometric mean ratio (IU/L): 1.03; 95%CI: 0.92, 1.16) concentrations, with negative respiratory panel as the referent group. Ninety-day follow-up was completed in 82.2% (3,550/4,318) of SARS-CoV-2 positive children; no cases of new-onset liver disease were reported. ConclusionAmong those tested, transaminase concentrations did not vary between SARS-CoV-2-positive children and those with a negative respiratory viral panel. In multivariate analysis, SARS-CoV-2 infection was not associated with increased initial transaminase concentrations compared to other respiratory viruses.

Dimethyl fumarate protects against hepatic ischemia-reperfusion injury by alleviating ferroptosis via the NRF2/SLC7A11/HO-1 axis

ABSTRACT Dimethyl fumarate (DMF), a therapeutic agent for relapsing-remitting multiple sclerosis, has cytoprotective and antioxidant effects. Ferroptosis, a pathological cell death process, is recently shown to play a vital part in ischemia-reperfusion injury (IRI). This study aimed to unveil the suppressive role of DMF on ferroptosis in liver IRI. The anti-ferroptosis effect of DMF on hepatic IRI was investigated using a liver IRI mouse model and a hypoxia-reoxygenation injury (HRI) model in alpha mouse liver (AML12) cells. Serum transaminase concentrations reflected liver function. Hematoxylin and eosin staining was used to assess liver damage. Cell viability was evaluated utilizing the CCK-8 assay. Malondialdehyde (MDA), the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, and BODIPY 581/591C11 were measured to estimate the injury caused by lipid peroxidation. Western blotting and real-time polymerase chain reaction (RT-PCR) were performed to explore the underlying molecular mechanisms. We demonstrated the anti-ferroptosis effects of DMF both in vivo and in vitro. DMF treatment ameliorated hepatic IRI. KEGG enrichment analysis and transmission electron microscopy revealed a close relationship between ferroptosis and liver IRI. Furthermore, DMF protected against HRI by inhibiting ferroptosis via activating the nuclear factor E2-related factor 2 (NRF2) pathway. Interestingly, NRF2 knockdown notably decreased the expression of SLC7A11 and HO-1 and blocked the anti-ferroptosis effects of DMF. DMF inhibits ferroptosis by activating the NRF2/SLC7A11/HO-1 axis and exerts a protective effect against hepatic IRI.

Low cardiopulmonary fitness is associated with higher liver fat content and higher gamma-glutamyltransferase concentrations in the general population - "The Sedentary's Liver".

We investigated the association between low cardiorespiratory fitness and liver fat content (LFC) in the general population. We evaluated data from 2151 adults (51.1% women) from two population-based cohorts of the Study of Health in Pomerania (SHIP-2 and SHIP-TREND-0). We analysed the cross-sectional associations of peak oxygen uptake (VO2peak ) with LFC, assessed by magnetic resonance imaging proton density fat fraction, as well as serum gamma-glutamyltransferase (GGT) and aminotransferase concentrations by multivariable regression models. We observed significant inverse associations of VO2peak with LFC and serum GGT, but not with serum aminotransferase levels. Specifically, a 1L/min lower VO2peak was associated with a 1.09% (95% confidence interval [CI]: 0.45-1.73; P=.002) higher LFC and a 0.18μkatal/L (95% CI: 0.09-0.26; P<.001) higher GGT levels. The adjusted odds ratio (OR) for the risk of prevalent hepatic steatosis (HS) by a 1L/min decrease in VO2peak was 1.61 (95% CI: 1.22-2.13; P=.001). Compared to subjects with high VO2peak , obese and overweight individuals with low VO2peak had 1.78% (95% CI: 0.32-3.25; P=.017) and 0.94% (95% CI: 0.15-1.74; P=.021) higher mean LFC, respectively. Compared to those with high VO2peak , low VO2peak was independently associated with a higher risk of prevalent HS in the obese (adjusted-OR 2.29, 95% CI=1.48-3.56; P<.001) and overweight (adjusted OR 1.57, 95% CI=1.16-2.14; P=.04) groups. Lower VO2peak was significantly associated with greater LFC and higher serum GGT levels in a population-based cohort of adult individuals. Our results suggest that low VO2peak might be a risk factor for HS.

Methyl eugenol attenuates liver ischemia reperfusion injury via activating PI3K/Akt signaling

BackgroundLiver ischemia reperfusion injury (LIRI) often occurs during liver transplantation, resection, and various circulatory shock procedures, leading to severe metabolic disorders, inflammatory immune responses, oxidative stress injury, and cell apoptosis. Methyl eugenol (ME) is structurally similar to eugenol and has anti-inflammatory and apoptotic pharmacological effects. However, whether ME protects the liver from LIRI damage requires further investigation. MethodsWe established a partially warm LIRI model by subjecting C57BL/6J mice to 60 min of ischemia, followed by reperfusion for 6 h. We also established a hypoxia-reoxygenation injury (H/R) cell model by subjecting AML12 (a mouse liver cell line) cells to 24 h hypoxia, followed by 18 h normoxia. The extent of liver injury was assessed by serum transaminase concentrations, hematoxylin and eosin staining, quantitative real-time PCR, myeloperoxidase activity, and TUNEL analysis. Apoptosis was detected using flow cytometry. The protein levels of p-PI3K, PI3K, p-Akt, Akt, p-Bad, Bad, Bcl-2, Bax, and cleaved caspase-3 were detected by western blotting. LY294002, an inhibitor of PI3K/Akt signaling, was used to elucidate the relationship between ME and PI3K/Akt signaling. ResultsME successfully alleviated LIRI-induced liver injury, inflammatory response, and apoptosis induced, as well as liver cell injury induced by hypoxia reoxygenation. ME is known to activate the PI3K/Akt signaling pathway in hepatocyte injury in vivo and in vitro, and when this signaling pathway is inhibited, the protective effect of ME is abrogated. ConclusionsThe use of ME is a potential therapeutic approach for regulating LIRI by activating PI3K/Akt signaling.

From the Editor's Desk...

From the Editor's Desk...

Changes in blood and physio-clinical indices of West African Dwarf goat during road transport

The study was carried out to determine the effect of road transportation on some blood and physioclinical indices in West African Dwarf (WAD) goats. Nineteen (19) WAD goats aged between 6 and 8 months weighing between 4.16Kg and 5.90Kg were transported in a wagon for 3 hours 18 minutes. Collection of data on rectal temperature (RT) and heart rate (HR), and blood sampling were carried out just before loading the animals into the wagon and repeated immediately on arrival at the destination. The blood samples were analyzed for packed cell volume (PCV), haemoglobin concentration (HB), red blood cell (RBC), white blood cell (WBC), neutrophil (NEU), lymphocyte (LYM), eosinophil (EOS), corpuscular haemoglobin concentration (MCHC), mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV). Serum alkaline phosphatase (ALP), aminotransferase (AST) and alanine transaminase (ALT) concentrations were also determined. Except the reduced (P&lt;0.05) haemoglobin (Hb) after transportation, the results showed that haematological parameters and pulse rate were comparable before departure and on arrival(P&gt;0.05). Rectal temperature was however slightly higher(P&lt;0.05) on arrival compared to departure in mixed sex and male goats. Serum AST, ALT and ALP were higher (P&lt;0.05) before transportation compared to the values obtained on arrival. The findings showed no remarkable influence of transport by road on the haematological parameters and pulse rate of WAD goats except reduced HB, serum AST, ALT and ALP and increasedrectal temperature observed after transportation.

Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA's root cause. In pivotal mouse toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury. Data from 325 patients with SMA who had received OA through 31 December 2019, in 5 clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events, laboratory data, concomitant medications, and prednisolone use were analyzed. Based on adverse events and laboratory data, 90 of 100 patients had elevated liver function test results (alanine aminotransferase, and/or aspartate aminotransferase, and/or bilirubin concentrations). Of these, liver-associated adverse events were reported for 34 of 100 (34%) and 10 of 43 (23%) patients in clinical trials and MAP/RESTORE, respectively. Two patients in MAP had serious acute liver injury, which resolved completely. While all events in the overall population resolved, prednisolone treatment duration varied (range: 33-229 days), with a majority receiving prednisolone for 60-120 days. More than 60% had elevations in either alanine aminotransferase, aspartate aminotransferase, or bilirubin concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications. Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention. Onasemnogene abeparvovec is a type of medicine called a "gene therapy," which is used to treat babies and young children who have a rare, serious inherited condition called "spinal muscular atrophy" (SMA). It works by supplying a fully functioning copy of the survival motor neuron or SMN gene, which then helps the body produce enough SMN protein. However, it can cause an immune response that could lead to an increase in enzymes produced by the liver. This article provides information about the liver injury and how to prevent and recognize if it happens, so that it may be treated properly.

Characterization of anti-plasmodial, analgesic and anti-inflammatory fraction of Maytenus senegalensis (lam.) Exell leaf extract in mice

BackgroundThe treatment inadequacy and toxicity associated with conventional anti-malarial, anti-inflammatory and analgesic drugs has called for the search of alternatives from medicinal plants, particularly, their phytochemicals with inherent pharmacological properties. In the present study, purified fraction of M. senegalensis leaf was evaluated for antimalarial, anti-inflammatory and analgesic properties.MethodAntimalarial study was conducted against Plasmodium chabaudi and Plasmodium berghei using 4 days suppressive test, while anti-inflammatory and analgesic studies were conducted using egg albumin induced paw oedema and acetic acid induced pain model respectively. Sub-acute toxicity was assessed using serum biochemical parameters following 3 weeks administrations of the purified fraction.ResultsThe purified fraction of M. senegalensis leaf shows dose dependent antiplasmodial activity with percentage curative effects of 15.24 ± 0.89, 45.70 ± 3.43 and 48.50 ± 4.56 at 75, 150 and 300 mg/kg bw against Plasmodium chabaudi and % curative effects of 44.25 ± 3.21, 72.74 ± 6.54 and 76.30 ± 8.32 respectively against Plasmodium berghei. The purified fraction exhibited 53.16 ± 4.09 and 60.76 ± 7.54 anti-inflammatory effect, 43.35 ± 4.98% and 44.83 ± 3.86% analgesic effect at 75 and 150 mg/kg bw respectively. GC-MS analysis confirmed the presence of 20α)-3-hydroxy-2-oxo-24-nor-friedela-1(10),3,5,7-tetraen-carboxylic acid-(29)-methylester, 2(4H)-Benzofuranone, 5,6,7,7a-tetrahydro- and 3-hydroxy-20(29)-lupen-28-ol and a terpenes (phytol) as the major antimalarial compounds in the fraction. The purified fraction increases the serum total proteins and transaminases concentrations but had no effect on serum levels of sodium, potassium, chloride, alkaline phosphatase, triglyceride and glucose in the mice.ConclusionThe purified fraction of M. senegalensis leaf exhibited promising antimalarial, analgesic and anti-inflammatory activities. Thus, could serve as a template for the synthesis of new drug.

Natural History of Serum Enzyme Levels in Duchenne Muscular Dystrophy and Implications for Clinical Practice.

In Duchenne muscular dystrophy, creatine kinase and transaminases are released into the circulation, indicating muscle injury. Their usefulness in monitoring muscle injury or disease progression has not yet been fully evaluated. Thus, this study examined serum creatine kinase and transaminase concentrations at different ages in patients with Duchenne muscular dystrophy and evaluated their association with muscle injury. This is a prospective cohort study that included 110 patients with Duchenne muscular dystrophy categorized by age groups. Creatine kinase and transaminases were quantified in the serum; the Vignos scale evaluated the muscle function. Creatine kinase and transaminase levels were higher in ambulatory than that in nonambulatory patients, which significantly decreased as age increased. Serum creatine kinase and transaminase concentrations were elevated in all ages, and those aged 3-4 yrs had the highest concentrations. Age and Vignos Scale were significantly correlated with creatine kinase and transaminase concentrations. Age, creatine kinase, and transaminases explained the 42.5% of loss of muscle function. This study added the knowledge on the natural history of Duchenne muscular dystrophy at different ages and confirmed that creatine kinase and transaminases decrease with age and loss of muscle function, making them generally inappropriate for monitoring response to therapy, although they are useful for the clinical diagnosis.

Weight Regain in Formerly Obese Mice Hastens Development of Hepatic Steatosis Due to Impaired Adipose Tissue Function.

Weight regain after weight loss is common, and there is evidence to suggest negative effects on health because of weight cycling. This study sought to investigate the impact of weight regain in formerly obese mice on adipose tissue architecture and stromal cell function. A diet-switch model was employed for obesity induction, weight loss, and weight regain in mice. Flow cytometry quantified adipose tissue leukocytes in adipose tissue. Liver and adipose tissue depots were compared to determine tissue-specific effects of weight cycling. Epididymal white adipose tissue of formerly obese mice failed to expand in response to repeat exposure to high-fat diet and retained elevated numbers of macrophages and T cells. Weight regain was associated with disproportionally elevated liver mass, hepatic triglyceride content, serum insulin concentration, and serum transaminase concentration. These effects occurred despite an extended 6-month weightloss cycle and theydemonstrate that formerly obese mice maintain durable alterations in their physiological response to weight regain. Conditioned media from epididymal adipose tissue of formerly obese mice inhibited adipogenesis of 3T3-L1 preadipocytes, suggesting a potential mechanism to explain failed epididymal adipose tissue expansion during weight regain. Metabolic abnormalities related to defects in adipose tissue expansion and ongoing dysfunction manifest in formerly obese mice during weight regain.

Agmatine Attenuates Liver Ischemia Reperfusion Injury by Activating Wnt/β-catenin Signaling in Mice

Liver ischemia reperfusion injury (LIRI) is a common problem during surgical procedures of the liver. It causes severe inflammatory responses and cell death, eventually leading to serious liver damage. Agmatine (AGM) is an endogenous polyamine with analgesic, anti-inflammatory, and antiapoptotic effects. However, it is still unknown whether AGM can protect the liver from damage caused by LIRI. For the in vivo experiments, a mouse model of partial warm hepatic ischemia reperfusion was established using C57BL/6J mice and then serum transaminase concentrations were analyzed. Histopathology was used to evaluate the degree of liver injury and quantitative real-time PCR was used to measure the amount of inflammatory cytokines. For the in vitro experiments, a cellular model of cobalt chloride (CoCl2)-induced hypoxia was established using AML12 cells. Flow cytometry was performed to measure the apoptosis levels. Western blotting analysis was conducted to measure the levels of proteins involved in apoptosis and Wnt/β-catenin signaling. We also chose 2 inhibitors of the Wnt/β-catenin signaling to elucidate the relationship between AGM and the Wnt/β-catenin signaling. AGM showed protective effects against LIRI-induced liver damage, inflammatory responses, and cell apoptosis along with alleviation of CoCl2-induced hepatocyte injury. AGM activated the Wnt/β-catenin signaling pathway during LIRI and CoCl2-induced hepatocyte injury; however, when the Wnt/β-catenin pathway was inhibited, the protective effects of AGM declined. AGM showed protective effects against LIRI by activating the Wnt/β-catenin signaling pathway.

Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2–5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study

The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years. In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight <14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132. The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24. Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of disease. Vertex Pharmaceuticals Incorporated.

Serum Transaminase Concentrations and the Presence of Irritable Bowel Syndrome Are Associated with Serum 25-Hydroxy Vitamin D Concentrations in Adolescent Girls Who Are Overweight and Obese

Background/Aims: Vitamin D deficiency has become endemic globally and its etiology is complex. Few studies have investigated the determinants of serum 25-hydroxy vitamin D (25-OH D). The aim of this study was to investigate the association between lifestyle patterns, liver functional tests (LFTs), and the presence of irritable bowel syndrome (IBS) with serum 25-OH D in apparently healthy girls. Methods: This cross-sectional study was undertaken in 965 adolescent girls aged 12–18 years. IBS was diagnosed using the Rome III questionnaire. An electrochemiluminescence method was used to measure serum 25-OH D. LFTs were measured using commercial kits and an auto analyzer. Linear regression and univariate analyses were performed to determine the association between continuous and categorical variables with serum 25-OH D respectively. Results: Serum 25-OH D was significantly higher in normal weight subjects compared to either overweight or obese subjects (9.5 ± 7.02 vs. 7.9 ± 5.7 ng/mL, p = 0.03). Physical activity level was positively associated with serum 25-OH D in overweight and obese subjects (β = 0.15, p < 0.05). An inverse relationship was found between the presence of IBS and 25-OH D in both normal (β = –1.95, p < 0.05), overweight and obese subjects (β = –1.83, p < 0.05). Serum alanine transaminase (ALT; β = –0.19, p < 0.05) and aspartate transaminase (β = –0.17, p < 0.05) were inversely associated with serum 25-OH in overweight and obese subjects. Conclusions: Individuals with IBS had significantly lower serum 25-OH D concentrations. In addition, there was an inverse association between serum ALT and 25-OH D. Prospective studies, and perhaps interventional trials, will be required to clarify these associations.

MicroRNA-155 Deficiency in Kupffer Cells Ameliorates Liver Ischemia-Reperfusion Injury in Mice.

MicroRNA-155 (miR-155) is known to be involved in autoimmune diseases, inflammation, and transplantation. However, its role in a warm hepatic ischemia-reperfusion (IR) model has not been fully elucidated. Partial hepatic IR was performed in wild-type and miR-155-deficient mice treated with or without GdCl3, and then the serum transaminase concentration and histology were analyzed. Kupffer cells (KCs) were isolated from the liver after IR, and immunohistochemistry was used to evaluate activation and polarization. In addition, the mRNA concentrations of various inflammatory cytokines were measured. Macrophages were obtained from the abdominal cavity and challenged with or without lipopolysaccharide to determine the influence of miR-155 deficiency on macrophage polarization in vitro. Furthermore, we used in vitro coculture assays to determine the effect of miR-155 deficiency on hepatocyte apoptosis induced directly by KCs. miR-155 deficiency ameliorated liver IR injury, and inhibition of KCs by GdCl3 abolished this protective effect. miR-155 deficiency decreased CD80, CD86, and major histocompatibility complex class II expression in KCs after IR and tipped the M1/M2 balance toward an anti-inflammatory profile, where proinflammatory cytokine secretion was suppressed and IL-10 was enhanced. In addition, hepatocyte apoptosis was reduced in coculture with miR-155-deficient KCs in vitro. miR-155 deficiency plays an effective role in attenuating liver IR injury likely by regulating the activation and inflammatory response, as well as modifying the polarization of KCs.

Effects of shortening the close-up period length coupled with increased supply of metabolizable protein on performance and metabolic status of multiparous Holstein cows.

This experiment was conducted to compare conventional (CON; 21 d) and shortened (SH; 10 d) close-up period, and evaluate the effect of shortened close-up period combined with feeding different metabolizable protein (MP) levels on dry matter (DM) intake, metabolic status, and performance of dairy cows. Forty-eight multiparous Holstein cows with similar parity, body weight (BW), and previous lactation milk yield were divided into 2 groups. The first group (n = 24) received the far-off diet from -60 to -21 d (CON), and the second group (n = 24) received same far-off diet from -60 to -10 d (SH) relative to expected parturition. Cows were then moved to individual stalls and randomly allocated to 1 of 3 close-up diets: low MP diet (LMP; MP = 79 g/kg of DM), medium MP diet (MMP; MP = 101 g/kg of DM), or high MP diet (HMP; MP = 118 g/kg of DM). Treatments were used in a 2 × 3 factorial arrangement with 2 lengths of close-up period (CON and SH) and 3 levels of MP (LMP, MMP, and HMP). All diets were fed for ad libitum intake during the close-up period. After calving, all cows received the same fresh cow diet. We found no interaction between close-up period length and MP levels for traits, except for postpartum serum fatty acids and β-hydroxybutyrate (BHB). The concentrations of postpartum serum fatty acids and BHB were higher on LMP than MMP and HMP diets in SH group. The cows of the SH group tended to produce less colostrum in the first milking than cows in CON group. The length of close-up period did not affect pre- and postpartum DM intake or energy balance of cows during the last week of prepartum, but cows of the CON group had greater BW changes during the last 3 wk before parturition than cows in SH group. Cows fed MMP and HMP diets consumed 1.2 and 1 kg more DM than for those fed LMP prepartum, respectively. The concentrations of prepartum BHB and Ca were higher for SH cows than CON group cows. Except for blood urea N concentration, no other blood metabolite in prepartum was affected by dietary MP. We found no effects of close-up period length or MP levels in the close-up diet on urinary pH, purine derivative excretion, and microbial N flow. Postpartum, milk yield was not affected by close-up period length, but cows in CON group tended to have higher 4% fat-corrected milk yield, had higher milk fat content and yield, had greater BW and body condition score loss, and higher energy negative balance than cows in the SH group. Cows fed MMP diet ate 1.8 kg more DM and yielded 3.37 kg more milk than those fed the LMP diet. Milk fat, protein, and lactose content, milk urea N, and somatic cell count were not affected by MP levels, but the yield of milk protein and lactose were higher on MMP diet than on LMP diet. Concentrations of postpartum serum fatty acids and BHB were decreased by shortening the close-up period length, but glucose, cholesterol, and triglyceride were similar between close-up groups. During the postpartum period, serum fatty acids, BHB, aminotransferase, and Ca concentrations were decreased by increasing the MP levels in the close-up diet. It appears from this data set that multiparous cows will benefit from a shortened close-up period, and feeding a moderate MP diet could improve DM intake, milk yield, and metabolic status of periparturient dairy cows.

Thrombospondin‐1 Contributes to Hepatic Pathology and Systemic Complications in the Acetaminophen and Azoxymethane Mouse Models of Acute Liver Failure

IntroductionAcute liver failure results from a significant loss of liver function and has few effective treatments and poor clinical outcomes. Numerous systemic complications can occur following acute liver failure though the development of neurological complications, a disease state called hepatic encephalopathy, greatly increases mortality. Previously we have demonstrated that transforming growth factor beta 1 (TGFβ1) is upregulated during acute liver failure and promotes disease progression. TGFβ1 requires interactions with other proteins, such as thrombospondin‐1 (TSP‐1), to become activated and be capable of binding its receptors. Therefore, we hypothesize that TSP‐1 contributes to acute liver failure disease progression through its activation of TGFβ1.MethodsMale C57Bl/6 mice or TSP‐1 knockout mice were injected with acetaminophen (APAP; 300 and 600 mg/kg) to generate acute liver injury or azoxymethane, (AOM; 100 mg/kg) to induce acute liver failure and hepatic encephalopathy. APAP‐treated mice had serum and liver collected at 6 hours and 24 hours post injection while AOM‐treated mice had serum, liver and brain collected once at coma. Liver pathology was assessed in both models by H&amp;E staining, cytokine ELISAs and reactive oxygen species (ROS), reactive nitrogen species (RNS), nitrotyrosine and transaminase assessments. Hepatic glutathione concentrations were assessed in APAP‐treated mice using a fluorometic assay. TGFβ1 and TSP‐1 expression was assessed by immunoblotting, immunohistochemistry, ELISA and/or real‐time PCR in both models. In AOM‐treated mice, cognitive impairment was monitored by assessment of reflex responses and ataxia and cerebral edema, microglia activation and neuroinflammation via cytokine ELISAs.ResultsMice injected with AOM or APAP had elevated hepatic TGFβ1 and TSP‐1 levels, which colocalized primarily to hepatocytes. AOM and APAP‐treated mice with genetic knockout of TSP‐1 had reduced hepatocyte necrosis, injury and oxidative stress compared to wildtype controls as assessed by H&amp;E staining, ROS, RNS and serum transaminase concentrations. Levels of hepatic and circulating proinflammatory cytokines were also reduced in both models in TSP‐1 knockout mice compared to wildtype controls. APAP‐treated mice had reduced glutathione concentrations that were increased in TSP‐1 knockout mice. AOM‐treated TSP‐1 knockout mice also had delayed development of hepatic encephalopathy as indicated by a delay in the time to coma, a reduction in cerebral edema, attenuated microglia activation, and reduced neuroinflammation compared to wildtype controls.ConclusionsStrategies employed to reduce TSP‐1 signaling in APAP‐treated mice reduced liver damage and pathology while AOM‐treated mice had reduced liver damage, neuroinflammation and improved neurological outcomes. Therefore, targeting TSP‐1 signaling may be a novel therapeutic target for the management of acute liver failure and/or hepatic encephalopathy.Support or Funding InformationThe study was funded by a VA Career Development Award‐2 (BX003486‐01) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (BLR&amp;D) to Dr. McMillin, an NIH R01 award (DK082435) to Dr. DeMorrow and a VA Merit award (BX002638‐01) from the United States Department of Veterans Affairs BLR&amp;D to Dr. DeMorrow. This material is the result of work supported with resources and the use of facilities at the Central Texas Veterans Health Care System, Temple, Texas. The views are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.

Outcomes from massive paracetamol overdose: a retrospective observational study.

This article is commented on by Bateman DN and Dear JW. Should we treat very large paracetamol overdose differently? Br J Clin Pharmacol 2017; 83: 1163-5. https://doi.org/10.1111/bcp.13279 AIMS: Treatment of paracetamol (acetaminophen) overdose with acetylcysteine is standardized, with dose determined only by patient weight. The validity of this approach for massive overdoses has been questioned. We systematically compared outcomes in massive and non-massive overdoses, to guide whether alternative treatment strategies should be considered, and whether the ratio between measured timed paracetamol concentrations (APAPpl ) and treatment nomogram thresholds at those time points (APAPt ) provides a useful assessment tool. This is a retrospective observational study of all patients (n=545) between 2005 and 2013 admitted to a tertiary care toxicology service with acute non-staggered paracetamol overdose. Massive overdoses were defined as extrapolated 4-h plasma paracetamol concentrations >250mgl-1 , or reported ingestions ≥30g. Outcomes (liver injury, coagulopathy and kidney injury) were assessed in relation to reported dose and APAPpl :APAPt ratio (based on a treatment line through 100mgl-1 at 4h), and time to acetylcysteine. Ingestions of ≥30g paracetamol correlated with higher peak serum aminotransferase (r=0.212, P<0.0001) and creatinine (r=0.138, P=0.002) concentrations. Acute liver injury, hepatotoxicity and coagulopathy were more frequent with APAPpl :APAPt ≥3 with odds ratios (OR) and 95% confidence intervals (CI) of 9.19 (5.04-16.68), 35.95 (8.80-158.1) and 8.34 (4.43-15.84), respectively (P<0.0001). Heightened risk persisted in patients receiving acetylcysteine within 8h of overdose. Patients presenting following massive paracetamol overdose are at higher risk of organ injury, even when acetylcysteine is administered early. Enhanced therapeutic strategies should be considered in those who have an APAPpl :APAPt ≥3. Novel biomarkers of incipient liver injury and abbreviated acetylcysteine regimens require validation in this patient cohort.