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We conducted an analytical review of 194 full papers on interferon (IFN) therapy for chronic hepatitis C to evaluate current methodology (i.e. study design, criteria for evaluating the efficacy of therapy and predictors of response). Of the papers evaluated, 64 were randomized controlled trials (RCT), 40 were non-randomized controlled trials (NRCT) and 90 were observational studies (OS). The methodological analysis was focused mainly on clinical trials. The number of patients enrolled in RCT was higher compared with the number enrolled in NRCT. Uniform enrolment criteria were used in less than 50% of the trials. Only 20% of RCT and 2.5% of NRCT used criteria for defining sample size. The response rate was calculated on an intention-to-treat basis in 36 of the RCT and in 14 of the NRCT. The outcome of treatment and the criteria employed to define the response to treatment were found to be far from standardized. In 51.5% of the RCT and 42.5% of the NRCT, normalization of alanine aminotransferase (ALT) level at the end of follow-up was the only marker of response studied. Only 57.6% of the trials considered histological evidence as an important outcome. Among the clinical trials, 71.1% evaluated predictors of good response to IFN therapy. In 51% of the OS, ALT normalization by the end of follow-up was the only criterion for defining response. In conclusion, to ensure a high level of reliability in comparing or combining the results of different studies, some basic general requirements must be followed when planning trials on antiviral therapy. [ABSTRACT FROM AUTHOR]

Background Persons with HIV and tuberculosis (TB) co-infection require transaminase monitoring while on hepatotoxic medications. A novel paper-based, point-of-care transaminase test is in development at an anticipated cost of $1 per test. Methods To project long-term clinical outcomes and estimate the cost-effectiveness of using a paper-based fingerstick test to monitor for drug-induced liver injury (DILI), as compared with automated testing and with no laboratory monitoring. The design was a decision analytic model, including deterministic and probabilistic sensitivity analyses. Data sources were observational cohorts and a validation study of the paper-based test. The target population was HIV/TB co-infected persons in South Africa on antiretroviral therapy who were initiating TB therapy. Interventions: (1) clinical (no laboratory) monitoring; (2) monitoring using the paper-based test with a ≥120 IU/mL threshold for positivity; (3) monitoring using the paper-based test with a ≥200 IU/mL threshold for positivity; (4) monitoring using the paper-based test using 1 of 3 categories: <120 IU/mL, 120 to 200 IU/mL, and >200 IU/mL (“bin placement”); (5) monitoring using automated ALT testing using the same 3 categories (“automated testing”). The outcome measures were discounted quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Results The ICER of automated testing was $5180/QALY. Use of the paper-based test with the bin placement strategy was cost-effective compared with clinical monitoring alone. Conclusion At its current performance, monthly DILI monitoring by bin placement using the paper-based test was cost-effective, compared with clinical monitoring, in HIV/TB co-infected persons in South Africa. [ABSTRACT FROM AUTHOR]

Branched-chain amino acid aminotransferases, widely present in natural organisms, catalyze bidirectional amino transfer between branched-chain amino acids and branched-chain a-ketoacids in cells. Branched-chain amino acid aminotransferases play an important role in the metabolism of branchedchain amino acids. In this paper, the interspecific evolution and biological characteristics of branched-chain amino acid aminotransferases are introduced, the related research of branched-chain amino acid aminotransferases in animals, plants, microorganisms and humans is summarized and the molecular mechanism of branched-chain amino acid aminotransferase is analyzed. It has been found that branched-chain amino acid metabolism disorders are closely related to various diseases in humans and animals and plants, such as diabetes, cardiovascular diseases, brain diseases, neurological diseases and cancer. In particular, branched-chain amino acid aminotransferases play an important role in the development of various tumors. Branched-chain amino acid aminotransferases have been used as potential targets for various cancers. This article reviews the research on branched-chain amino acid aminotransferases, aiming to provide a reference for clinical research on targeted therapy for various diseases and different cancers. [ABSTRACT FROM AUTHOR]

N‐acetylcysteine (NAC) is regarded as an effective treatment of paracetamol overdoses. However, in cases of "massive" paracetamol overdoses, recent studies indicate that patients may not be sufficiently treated with the standard dose of NAC (300 mg/kg over 20–21 h). The subject is further complicated because "massive overdoses" and "high‐risk" are defined differently; some studies use the ingested amount (e.g., >40 g), and some studies use blood concentrations of paracetamol and transaminases. This narrative review investigates whether high‐dose NAC significantly decreases the risk of hepatotoxicity in patients with massive paracetamol overdoses. Three observational studies were analysed; one study with 373 patients found no significant difference (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.49–3.29). One study with 79 patients found a significant difference (OR: 0.27, 95% CI: 0.08–0.94). The third study with 89 patients found a significant difference in hepatoxicity between the groups (p = 0.043). There are no solid evidence to support that treatment with high‐dose NAC significantly reduces the rate of hepatotoxicity in patients presenting with massive paracetamol overdoses. Differences in inclusion criteria in the included studies make the studies incomparable. This paper shows that standardized inclusion is needed to determine whether a high‐dose NAC regimen should be included in clinical practice. [ABSTRACT FROM AUTHOR]

Presents articles to be published in the "European Journal of Biochemistry." "Characterization of a cDNA Clone Encoding Mollusc Insulin-Related Peptide II of Lymnaea Stagnalis," by A. B. Smith, W. P. M. Geraerts, I. Meester, H. van Heerikhuizen and J. Joosse; "Effects of Dexamethasone and cAMP on Tyrosine Aminotransferase Expression in Cultured Fetal Rat Hepatocytes," by L. L. Shelly and G. C. T. Yeoh; "Transient Kinetics of Flavin-Photosensitized Oxidation of Reduced Redox Proteins--Comparison of c-type Cytochromosomes and Plastocyanins," by J. A. Navarro, M. A. De la Rosa and G. Tollin; "Membrane-Bound Cytochromes in Chloroflexus Aurantiacus Studied by EPR," by P. van Vliet, D. Zannoni, W. Nitschke and A. W. Rutherford; Others.

The present investigation was designed to assess the effects of strips made of different materials on the recovery of enzymes in gingival crevicular fluid (GCF) (Experiment 1), and to examine a possible relationship between lysosomal enzyme activities and number of crevicular polymorphonuclear leukocytes (PMNs) (Experiment 2). In Experiment 1, GCF was collected with capillaries from 14 patients with periodontal disease, and applied on various test strips in microcentrifuge tubes or directly into tubes (controls). Strips were then shaken and centrifuged to elute GCF enzymes. The supernate was used for determinations of alkaline phosphatase (ALP), β-glucuronidase (BG) and aspartate aminotransferase (AST) activities. The % recoveries were calculated as relative percentages to controls. When using saline as eluent, 90% or more ALP, BG and AST were found to be recovered from strips of durapore and papers. More than 35% of ALP and BG was found to remain on paper points. However, the % recoveries from paper points were improved using eluent with 0.1% (w/v) cetyl pyridinium chloride. In Experiment 2, 54 GCF samples were collected from 3 periodontitis patients by using durapore strips, in order to measure both PMN numbers and BG activities in the same samples. The 2 parameters showed strong and positive correlation with 0.847 (p<0.001) of the Pearson's correlation coefficient. These findings suggest that durapore is a useful material not only for counting PMNs but also for measuring activities of GCF enzymes. Elevation of BG activities in GCF can be due to increasing numbers of PMNs. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper presents a paradigm-shifted approach for adverse event (AE) analysis from classic descriptive summary into modern informative statistics to fulfill precision medicine. It defines early AE and derives a series of innovative AE biomarkers to assess grade, treatment relatedness, occurrence, frequency, and duration. Comprehensive data analysis generates opportunities for global discovery of predictive early AE-derived biomarkers. A proof of concept in two lung cancer studies demonstrates the potential clinical utility of early AE-derived biomarkers in patients with advanced non-small cell lung cancer treated with immunotherapy. The methodology also provides a useful tool to help discover predictive AE biomarkers for treatment response and survival outcomes. Rationale: Adverse events (AEs) have been shown to have clinical associations, in addition to patient safety assessments of drugs of interest. However, due to their complex content and associated data structure, AE evaluation has been restricted to descriptive statistics and small AE subset for efficacy analysis, limiting the opportunity for global discovery. This study takes a unique approach to utilize AE-associated parameters to derive a set of innovative AE metrics. Comprehensive analysis of the AE-derived biomarkers enhances the chance of discovering new predictive AE biomarkers of clinical outcomes. Methods. We utilized a set of AE-associated parameters (grade, treatment relatedness, occurrence, frequency, and duration) to derive 24 AE biomarkers. We further innovatively defined early AE biomarkers by landmark analysis at an early time point to assess the predictive value. Statistical methods included the Cox proportional hazards model for progression-free survival (PFS) and overall survival (OS), two-sample t-test for mean difference of AE frequency and duration between disease control (DC: complete response (CR) + partial response (PR) + stable disease (SD)) versus progressive disease (PD), and Pearson correlation analysis for relationship of AE frequency and duration versus treatment duration. Two study cohorts (Cohort A: vorinostat + pembrolizumab, and B: Taminadenant) from two immunotherapy trials in late-stage non-small cell lung cancer were used to test the potential predictiveness of AE-derived biomarkers. Data from over 800 AEs were collected per standard operating procedure in a clinical trial using the Common Terminology Criteria for Adverse Events v5 (CTCAE). Clinical outcomes for statistical analysis included PFS, OS, and DC. Results: An early AE was defined as event occurrence at or prior to day 30 from initial treatment date. The early AEs were then used to calculate the 24 early AE biomarkers to assess overall AE, each toxicity category, and each individual AE. These early AE-derived biomarkers were evaluated for global discovery of clinical association. Both cohorts showed that early AE biomarkers were associated with clinical outcomes. Patients previously experienced with low-grade AEs (including treatment related AEs (TrAE)) had improved PFS, OS, and were associated with DC. The significant early AEs included low-grade TrAE in overall AE, endocrine disorders, hypothyroidism (pembrolizumab's immune-related adverse event (irAE)), and platelet count decreased (vorinostat related TrAE) for Cohort A and low-grade AE in overall AE, gastrointestinal disorders, and nausea for Cohort B. In contrast, patients with early development of high-grade AEs tended to have poorer PFS, OS, and correlated with PD. The associated early AEs included high-grade TrAE in overall AE, gastrointestinal disorders with two members, diarrhea and vomiting, for Cohort A and high-grade AE in overall AE, three toxicity categories, and five related individual AEs for Cohort B. One low-grade TrAE, alanine aminotransferase increased (vorinostat + pembrolizumab related), was an irAE and correlated with worse OS in Cohort A. Conclusions: The study demonstrated the potential clinical utility of early AE-derived biomarkers in predicting positive and negative clinical outcomes. It could be TrAEs or combination of TrAEs and nonTrAEs from overall AEs, toxicity category AEs, to individual AEs with low-grade event leaning to encouraging effect and high-grade event to undesirable impact. Moreover, the methodology of the AE-derived biomarkers could change current AE analysis practice from a descriptive summary into modern informative statistics. It modernizes AE data analysis by helping clinicians discover novel AE biomarkers to predict clinical outcomes and facilitate the generation of vast clinically meaningful research hypotheses in a new AE content to fulfill the demands of precision medicine. [ABSTRACT FROM AUTHOR]

Protein engineering is a powerful and widely applied tool for tailoring enzyme properties to meet application-specific requirements. An attractive group of biocatalysts are PLP-dependent amine transaminases which are capable of converting prochiral ketones to the corresponding chiral amines by asymmetric catalysis. The enzymes often display high enantioselectivity and accept various amine donors. Practical applications of these amine transaminases can be hampered by enzyme instability and by their limited substrate scope. Various strategies to improve robustness of amine transaminases and to redirect their substrate specificity have been explored, including directed evolution, rational design and computation-supported engineering. The approaches used and results obtained are reviewed in this paper, showing that different strategies can be used in a complementary manner and can expand the applicability of amine transaminases in biocatalysis. [ABSTRACT FROM AUTHOR]

Food safety is a global public health issue, which often arises from asymmetric information between consumers and suppliers. With the development of information technology in human life, building a food traceability information sharing platform is viewed as one of the best ways to overcome the trust crisis and resolve the problem of information asymmetry in China. However, among the myriad information available from the food supply chain, there is a lack of knowledge on consumer preference. Based on the best-worst scaling approach, this paper investigated consumer preferences for vegetable, pork, and dairy product traceability information. Specifically, this paper measured the relative importance that consumers place on the traceable information. The results indicate that consumers have varying priorities for information in different cases. “Pesticide/veterinary use,” “picking/slaughtering date,” and “fertilizer/feed use” are the most preferred traceable information for Chinese consumers in the case of vegetables, while “picking/slaughtering date” and “history of illness and taking protective measures” are the most preferred information in the case of pork. In the case of dairy products, consumers prefer “processing information,” “environmental information of the origin,” and “traceable tag certification information” most. The results of this study call for the direct involvement of the Chinese government in the food safety information sharing system as following. First, given consumers’ diverse preferences, different types of traceable information should be recorded into the information sharing platform depending on food types. Second, the government could promote the step-by-step construction of such a platform based on the priority of consumers’ preferences. Third, new technology should be applied to guarantee the reliability of traceable information. Finally, local preferences in terms of the way consumers receive and understand information should be taken into consideration. [ABSTRACT FROM AUTHOR]

Artificial intelligence technologies such as machine learning have been applied to protein engineering, with unique advantages in protein structure, function prediction, catalytic activity, and other issues in recent years. Screening better mutants is still a bottleneck in protein engineering. In this paper, a new sequence-activity relationship method was analyzed for its application in improving the thermal stability of Aspergillus terreus (R)-ω-selective amine transaminase. The experimental data from 6 single-point mutated enzymes were used as a learning dataset to build models and predict the thermostability of 26 mutants. Based on digital signal processing (DSP), this method digitized the amino acid sequence of proteins by fast Fourier transform (FFT) and then established the best model applying partial least squares regression (PLSR) to screen out all possible mutants, especially those with high performance. In protein engineering, the innovative sequence activity relationship (ISAR) method can make a reasonable prediction using limited experimental data and significantly reduce the experimental cost. The half-life ( T 1 / 2 ) of (R)-ω-transaminase was fitted with the amino acid sequence by the ISAR algorithm, resulting in an R 2 of 0.8929 and a cvRMSE of 4.89. At the same time, the mutants with higher T 1 / 2 than the existing ones were predicted, laying the groundwork for better (R)-ω-transaminase in the later stage. The ISAR algorithm is expected to provide a new technique for protein evolution and screening. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The COVID-19 pandemic is progressing rapidly, sending the world into a great panic. Healthcare professionals have responded by embarking on a concerted search for therapies to cure and prevent COVID-19. Recently, interferon (IFN) has emerged as a potential therapy as it is associated with reducing lung inflammation and suppressing viral replication. This research paper assessed the efficacy of high-dose nebulized IFN α 2b in severe COVID-19 pneumonia. METHODS: This is a retrospective study. It commenced on April 9 and ended on June 17, 2020. Researchers selected participants from hospitalized patients aged 18 years and above who were diagnosed with severe COVID-19 pneumonia. Other inclusion criteria were bilateral pneumonia on lung or chest X-ray scan and severe respiratory distress. SMART-COP, which is a risk stratification scoring tool, and radiologic severity index (RSI) were used to assess pneumonia severity. Patients in the treatment cohort received nebulized IFN α 2b at a dose of 10 million IU every 12 hours for 5 days, in addition to standard treatment. Patients in the control cohort received standard treatment only. RESULTS: Seventy-three patients met the inclusion criteria; 37 were included in the treatment cohort and 36 in the control cohort. Mechanical ventilation was needed in 14 of 36 (38.9%) patients in the control cohort, compared with 6 of 37 (27.4%) patients in the treatment cohort (HR 5.62 [95% CI 1.81-17.48]; P = .003). For pneumonia severity, there was a hazard ratio (HR) of 3.72 [95% CI 1.74-7.98]; P = ·.01. After 5 days of treatment, chest X-rays indicated significant beneficial changes in the treatment group (HR 2.24 [CI 1.05-4.79]; P = .036). Multivariate analysis revealed that pneumonia severity and RSI remained higher in the control group. The HR was 3.44 [95% CI 1.49-7.94]; P = .004 and 2.26 [95% CI 0.99-5.16]; P = .05, respectively. There was an increase in liver aminotransferases in 5 (14%) participants in the control cohort and 3 (8%) participants in the treatment cohort. CONCLUSION: High-dose nebulized IFN α 2b has potential efficacy in mitigating severe COVID-19 pneumonia. This study established that administering high-dose nebulized IFN α 2b significantly reduces pneumonia severity in COVID-19 patients. We also found a strong relationship between using nebulized IFN α 2b and reduced need for mechanical ventilation among patients with severe COVID-19 pneumonia. However, a well-designed control trial is needed to confirm the drug's efficacy in reducing the COVID-19 pneumonia severity. [ABSTRACT FROM AUTHOR]

Simple Summary: The degree of liver damage after liver resection is generally assessed by serum ALT levels. Postoperative ALT levels may have a multifactorial cause correlated with the extent of resection, duration of surgery and of vascular clamping. Extensive and prolonged manipulation of the liver during open hepatectomy could also be correlated with hepatocyte injury. The aim of our study was to assess if a minimally invasive approach for liver resection, with less manipulation of the liver, may be associated with less transient hepatic damage and with consequent lower postoperative ALT levels than those detected after open hepatectomy. The results showed that liver resections performed using a minimally invasive approach were associated with significantly lower postoperative ALT values when compared with those performed by open approach. Moreover, the duration of hepatic pedicle clamping and multiple liver resections were independent predictors for high postoperative peak ALT levels on POD 1 and the minimally invasive approach showed a protective effect. Background: Postoperative serum ALT levels are one of the most frequently used marker to detect liver tissue damage following liver resection. The aim of this study was to evaluate if minimally invasive liver surgery (MILS) may result in less hepatic injury than open hepatectomy by assessing the differences of postoperative ALT levels. Methods: Patients who underwent MILS between 2009 and 2019 at our unit were included and compared with open liver resections. Median ALT levels was measured on postoperative day (POD) 1, 3 and 5. Postoperative peak transaminase (PPT) of ALT was determined on POD 1. The stabilized inverse probability treatment weighing (SIPTW) process was used to balance the two groups. A multivariable logistic regression analysis was used to analyze factors associated with high PPT. Results: After SIPTW, 292 MILS were compared with 159 open resections. Median ALT levels on POD 1, 3 and 5 were significantly higher in the open group than in the MILS group (301 vs. 187, p = 0.002; 180 vs. 121, p < 0.0001; 104 vs. 60, p < 0.0001; respectively). At the multivariable logistic regression analysis, MILS showed a protective effect for high PPT. Conclusions: MILS was associated with significantly lower postoperative ALT levels compared with open liver resections. MILS showed a protective effect for high PPT. [ABSTRACT FROM AUTHOR]

Background: There are contradictory effects regarding the effect of NAD + precursor on glucose metabolism and liver enzymes. In order to obtain a better viewpoint from them, this study aimed to comprehensively investigate the effects of NAD + precursor supplementation on glucose metabolism, C-reactive protein (CRP), and liver enzymes. Methods: PubMed/MEDLINE, Web of Science, SCOPUS, and Embase databases were searched using standard keywords to identify all controlled trials investigating the glucose metabolism, CRP, and liver enzymes effects of NAD + precursor. Pooled weighted mean difference (WMD) and 95% confidence intervals (95% CI) were achieved by random-effects model analysis for the best estimation of outcomes. Results: Forty-five articles with 9256 participants' were included in this article. The pooled findings showed that NAD + precursor supplementation had a significant increase in glucose (WMD: 2.17 mg/dL, 95% CI: 0.68, 3.66, P = 0.004) and HbA1c (WMD: 0.11, 95% CI: 0.06, 0.16, P < 0.001) as well as a significant decrease in CRP (WMD: -0.93 mg/l, 95% CI -1.47 to -0.40, P < 0.001) compared with control group, and was not statistically significant with respect to insulin and homeostasis model assessment of insulin resistance (HOMA-IR). However, we found no systemic changes in aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase (ALP) levels after NAD + precursor supplementation. The results of the subgroup analysis showed that the intake of NAD + precursor during the intervention of more than 12 weeks caused a greater increase in the glucose level. Furthermore, Nicotinic acid supplementation (NA) causes a greater increase in glucose and HbA1c levels than nicotinamide (NE) supplementation. Conclusions: Overall, these findings suggest that NAD + precursor supplementation might have an increase effect on glucose metabolism as well as a decrease in CRP. [ABSTRACT FROM AUTHOR]

Aminotransferases (ATs) are an ancient enzyme family that play central roles in core nitrogen metabolism, essential to all organisms. However, many of the AT enzyme functions remain poorly defined, limiting our fundamental understanding of the nitrogen metabolic networks that exist in different organisms. Here, we traced the deep evolutionary history of the AT family by analyzing AT enzymes from 90 species spanning the tree of life (ToL). We found that each organism has maintained a relatively small and constant number of ATs. Mapping the distribution of ATs across the ToL uncovered that many essential AT reactions are carried out by taxon-specific AT enzymes due to wide-spread nonorthologous gene displacements. This complex evolutionary history explains the difficulty of homology-based AT functional prediction. Biochemical characterization of diverse aromatic ATs further revealed their broad substrate specificity, unlike other core metabolic enzymes that evolved to catalyze specific reactions today. Interestingly, however, we found that these AT enzymes that diverged over billion years share common signatures of multisubstrate specificity by employing different nonconserved active site residues. These findings illustrate that AT family enzymes had leveraged their inherent substrate promiscuity to maintain a small yet distinct set of multifunctional AT enzymes in different taxa. This evolutionary history of versatile ATs likely contributed to the establishment of robust and diverse nitrogen metabolic networks that exist throughout the ToL. The study provides a critical foundation to systematically determine diverse AT functions and underlying nitrogen metabolic networks across the ToL. [ABSTRACT FROM AUTHOR]

Background: Platelets were shown to be relevant for liver regeneration. In particular, platelet-stored serotonin (5-HT) proved to be a pro-regenerative factor in this process. The present study aimed to investigate the perioperative course of 5-HT and evaluate associations with patient and graft outcomes after othotopic liver transplantation (OLT). Methods: 5-HT was quantified in plasma and serum of 44 OLT recipients perioperatively, and in their respective donors. Olthoff's criteria for early allograft dysfunction (EAD) were used to evaluate postoperative outcomes. Results: Patients with higher donor intra-platelet 5-HT per platelet (IP 5-HT PP) values had significantly lower postoperative transaminases (ASAT POD1: p = 0.006, ASAT POD5: p = 0.006, ASAT POD10: p = 0.02, ALAT POD1: p = 0.034, ALAT POD5: p = 0.017, ALAT POD10: p = 0.04). No significant differences were seen between postoperative 5-HT values and the occurrence of EAD. A tendency was measured that donor IP 5-HT PP is lower in donor-recipient pairs that developed EAD (p = 0.07). Conclusions: Donor IP 5-HT PP might be linked to the postoperative development of EAD after OLT, as higher donor levels are correlated with a more favorable postoperative course of transaminases. Further studies with larger cohorts are needed to validate these findings. [ABSTRACT FROM AUTHOR]

An efficient synthesis of [5,6-3H] (+/−) gamma vinyl GABA 5 from 4-aminohex-5-ynoic acid 3 is described. [ABSTRACT FROM AUTHOR]

Background: Aspartate aminotransferase (AST) is an enzyme normally confined to the cytoplasm of cells, but released to the extracellular environment upon cell death. Its levels are associated with the severity of experimental gingivitis and the loss of periodontal attachment. The aim of the present study was to investigate the presence and activity levels of AST in peri-implant crevicular fluid (PCF) from healthy and diseased endosseous implants in order to assess if AST in PCF can be further studied as a possible objective diagnostic aid in oral implantology. Methods: Eighty-one fixtures from 81 systemically healthy subjects were divided into 3 groups. 27 healthy implants (HI), 27 implants with mucositis (MI) and 27 implants affected by peri-implantitis (PI) according to well-defined clinical and radiographic criteria. PCF was collected by the insertion of a # 40 standardized endodontic paper point to the base of the crevice or packet for 30 seconds. AST activity was determined spectrophotometrically at 25°C. The results were expressed as AST Units/ml in PCF. Results: An AST activity was detected in each sample from HI, MI and PI. The mean AST activity in HI was 0.26 ± 0.16 U/ml; in MI, 0.38 ± 0.27 U/ml; in PI, 0.62 ± 0.29 U/ml. ANOVA showed that the difference among HI, MI, and PI was statistically significant at P<0.01 level. Post-hoc tests demonstrated that a significant difference in AST activity existed between HI/PI (t = 5.14; P<0.01) and MI/PI (t = 3.09: P<0.01). No statistically significant difference was found between HI/MI (t = 1.07; P>0.1) AST activity was significantly (P<0.01) associated with probing depth (r = 0.55), the amount of bone loss (r = 0.60) and bleeding on probing (r = 0.67). When the threshold for a positive AST test was set ≤4 U/ml, a sensitivity = 0,81 and a specificity = 0.74 were found in the detection of peri-implantitis; the positive predictive value was 61% and the negative predictive value was 88%. Conclusions: Within the limits of this study, our results may suggest that PCF analysis could be further investigated in longitudinal studies as a suitable diagnostic strategy in the evaluation of dental implants. [ABSTRACT FROM AUTHOR]

Gallbladder small cell carcinoma (SCC) comprises only 0.5 % of all gallbladder cancer and consists of aggressive tumors with poor survival outcomes against current treatments. These tumors are most common in elderly females, particularly those with cholecystolithiasis. We report the case of a 79-year-old woman with gallbladder small cell carcinoma. The patient had intermittent right upper quadrant abdominal pain and was admitted to our hospital due to suspected acute cholecystitis. She regularly received medical treatment for diabetes, hypertension, and dyslipidemia. On initial laboratory evaluation, the levels of aspartate aminotransferase (AST), total bilirubin, and C-reactive protein (CRP) were markedly elevated. She underwent computed tomography (CT) for screening. CT images showed a thick-walled gallbladder containing multiple stones and multiple 3-cm-sized round nodular lesions, which were suggestive of metastatic lymph nodes. After percutaneous transhepatic gallbladder drainage was performed, endoscopic ultrasound-guided fine needle aspiration of enlarged lymph nodes resulted in a diagnosis of small cell carcinoma or adenocarcinoma. However, we could not identify the primary lesion before the surgery because of no decisive factors. We performed cholecystectomy because there was a possibility of cholecystitis recurrence risk and also partial liver resection because we suspected tumor invasion. The final pathological diagnosis was neuroendocrine carcinoma of the gallbladder, small cell type. The tumor stage was IVb, T3aN1M1. The patient died 13 weeks after the surgery. In the present paper, we review the current available English-language literature of gallbladder SCC. [ABSTRACT FROM AUTHOR]

Background Many deceased liver donors with a history of alcohol abuse are excluded based upon medical history alone. This paper summarizes the transplant outcomes for a large number of deceased liver donors with a documented history of alcohol abuse. Methods The records for 1478 consecutive deceased liver donors were reviewed (2001-2012). As per the United Network for Organ Sharing criteria, heavy alcohol use by an organ donor is defined as chronic intake of two or more drinks per day. Donors with a documented history of alcohol abuse were divided into three groups according to duration of abuse (<10 years, 10-24 years and 25 + years). Reperfusion biopsies are reported. Outcomes include biopsy appearance, early graft function and early and late graft survival. Results There were 161 donors with alcohol abuse: <10 years (29%); 10-24 years (42%); and ≥25 years (29%). Risk of 90-day graft loss for these three groups was: 0%, 3% and 2%, compared to 3% for all other donors ( P = 0.62). Graft survival at 1 year for donor grafts with and without alcohol abuse was 89% and 87% ( P = 0.52). There was no difference in early graft function. Cox proportional hazards modelling for graft survival demonstrates no statistically significant difference in survival up to 10 years post-transplant. Conclusions This study demonstrates successful transplantation of a large number of deceased donor liver grafts from donors with a documented history of alcohol abuse ( n = 161; 11% of all grafts). These extended criteria donor allografts may, therefore, be utilized successfully with similar outcomes. [ABSTRACT FROM AUTHOR]

Effect of cobalt manganese ferrite nanoparticles (M-NPs) (Co0.5Mn0.5Fe2O4) on vanadium hazards was assessment in the present study. Four groups of adult male albino rats [control group and three variably treated groups with ammonium metavanadate accompanied with or without cobalt M-NPs] were studied. The oral administration of ammonium metavanadate (Am.V) (20 mg/kg b.wt.) demonstrated the facility of vanadium to distribute and accumulate in the distinctive body organs and ordered as kidney > liver > lung > brain > spleen. Also, Am.V administration induce a significant disturbance in many physiological parameters (RBS, cholesterol, triglyceride, aspartate transaminase, alanine transaminase, Alb., bilirubin, Alk.Ph., urea, creat., Hb%, red blood cell count and packed cell volume) which might be expected to the liberation of free radicals according to the vanadium intoxication or its ability to disturb many body metabolisms. On the other hand, the intraperitoneal administration of 5% M-NPs in parallel with Am.V orally administration showed the ability of M-NPs to reduce Am.V dangerous impacts, which might be resulted from the essentiality of M-NPs metals to the body metabolism and to its free radicals scavenging properties. So, M-NPs could reduce Am.V hazardous effects. [ABSTRACT FROM AUTHOR]

Introduction and aim: Methamphetamine-use disorder is a pressing global public health issue. In Sudan, the escalating methamphetamine (METH) consumption has become a significant social and health problem. This study aims to evaluate liver and kidney biomarkers in methamphetamine addicts in Khartoum state Material and methods: The study was an analytical prospective cross-sectional hospital-based study. One hundred participants were enrolled in this study, fifty were cases (methamphetamine addicts), and others were healthy non-METH users as a comparative group. Results: METH users had a mean age of (27±7) years and had been using METH for an average of (14±9) months. Urea and creatinine levels were also significantly elevated in METH users compared to non-users, with p<0.001 and p=0.044, respectively. Their aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly higher compared to non-users, with p<0.001. Concusion: There was significant increases in creatinine, urea, and aminotransferases levels in the case group. ALT showed a moderate positive correlation with abuse duration, while AST showed no significant correlation. Urea and creatinine levels had strong and moderate positive correlations with abuse duration, respectively. [ABSTRACT FROM AUTHOR]

40-week-old Lohman Brown layers were used in this study. Three diets with different levels of crude protein allowed the consumption of 15.38, 13.58 and 11.78 g/d/cap., respectively. The experimental feeding lasted four weeks. Laboratory determinations were performed at the end of the experimental period. Triglycerides, total cholesterol, GOT, GPT and γ-GT transaminases, HDL-cholesterol, protein, albumin, γ-globulins and uric acid were determined in the blood serum. Nitrogen intake, nitrogen excretion in manure, nitrogen retention in the body and in the egg were also determined. Thus, following four weeks of experimental feeding, serum transaminases and HDL-cholesterol remained within normal limits. Triclycerides and uric acid presented an increase of their serum values. As a consequence of the decrease in daily nitrogen intake, nitrogen excretion and nitrogen retention as total in the body decreased while nitrogen excretion as total in the egg remained unmodified. [ABSTRACT FROM AUTHOR]

In all reported cases of foreign body migration or impaction in the biliary tree, there is no mention of the presence of hypereosinophilia among the laboratory findings. This could possibly be attributed to the local tissue reaction caused by the impacted foreign body. Here, we present our experience with the removal of a screw from a surgical retractor that became lodged in the common bile duct (CBD) and migrated in a patient who had previously undergone a left lateral hepatectomy for hepatic hydatidosis. The imaging was not sufficient to make a diagnosis, and the interpretation of hypereosinophilia in such a case could pose a challenge. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the addition of liquid cellulose, produced by Humicola grisea, in 21-day-old broiler chickens' diets. The treatments comprised control rations of corn and soybean meal and rations to which 500 mL/t and 1000 mL/t of cellulase were added. A total of 180 male broiler chickens were used, distributed in a completely randomized design, with three treatments and six replicates. Broiler chicken performance was monitored during the period from 1 to 21 days old. Significant effects were detected for digestibility only between four and seven days old, when a reduced dry matter nitrogen intake was recorded, and for nitrogen digestibility in the broilers fed cellulase-supplemented rations at a dose of 1000 m/L. Among the analyzed digestive organs, only the biometrics of the large intestine were affected significantly at seven days old. The absolute weights of the liver and pancreas and the activities of amylase, alkaline phosphatase, and transaminases were not affected significantly, indicating that cellulase did not affect the metabolism of these organs. No significant effect was detected in the serum for electrolytes, total protein, or alkaline phosphatase. So, the addition of liquid cellulase produced by Humicola grisea did not affect performance and metabolism in 21-day-old broiler chickens. [ABSTRACT FROM AUTHOR]

Our genetic background has not changed over the past century, but chronic diseases are on the rise globally. In addition to the genetic component, among the critical factors for many diseases are inhabitants of our intestines (gut microbiota) as a crucial environmental factor. Dysbiosis has been described in liver diseases with different etiologies like non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD), viral hepatitis, autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cirrhosis, hepatocellular carcinoma (HCC). On the other hand, new technologies have increased our understanding of liver disease genetics and treatment options. Genome-wide association studies (GWAS) identify unknown genetic risk factors, positional cloning of unknown genes associated with different diseases, gene tests for single nucleotide variations (SNVs), and next-generation sequencing (NGS) of selected genes or the complete genome. NGS also allowed studying the microbiome and its role in various liver diseases has begun. These genes have proven their effect on microbiome composition in host genome–microbiome association studies. We focus on altering the intestinal microbiota, and supplementing some bacterial metabolites could be considered a potential therapeutic strategy. The literature data promote probiotics/synbiotics role in reducing proinflammatory cytokines such as TNF-α and the interleukins (IL-1, IL-6, IL-8), therefore improving transaminase levels, hepatic steatosis, and NAFLD activity score. However, even though microbial therapy appears to be risk-free, evaluating side effects related to probiotics or synbiotics is imperative. In addition, safety profiles for long-term usage should be researched. Thus, this review focuses on the human microbiome and liver diseases, recent GWASs on liver disease, the gut-liver axis, and the associations with the microbiome and microbiome during/after liver disease therapy. [ABSTRACT FROM AUTHOR]

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid deriving from 7β epimerization of primary bile compound chenodeoxycholic acid. It may have antioxidant, immunomodulatory, antifibrotic and cytoprotective effects, therefore it has been extensively used in the treatment of cholestatic chronic liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis of pregnancy, etc.). Due to the effectiveness of UDCA in decreasing serum liver enzyme levels also in non-cholestatic patients with chronic liver damage of various etiologies, this bile acid is now extensively used in clinical practice in combination with standard therapies, or as alternative treatment. In this paper, after a review of the biochemistry and physiology of UDCA, we have analyzed available data from the international literature on the efficacy and safety of UDCA in patients with hypertransaminasemia due to non-cholestatic chronic liver diseases, such as chronic viral hepatitis B and C and liver steatosis, the three main causes of aminotransferase elevation in western countries. [ABSTRACT FROM AUTHOR]

Objective:Herbal medicine and medical plants such as Ziziphus Jujuba are widely used in the treatment of diseases such as diabetes mellitus. We investigated the effects of ethanol extracts of Ziziphus Jujuba fruit on serum glucose, triglycerides, LDL-cholesterol, HDL-cholesterol, cholesterol and activities of aminotransferase enzymes in streptozocin-induced diabetic adult male rats. Materials and Methods: Adult Wistar rats were rendered hyperglycemic. Animals were divided into four equal groups (7 per group). Animals in all groups were treated for 14 days. Blood samples were collected from the heart of the animals. Results: Continuous supplementation of ethanol extract in drinkable water of diabetic rats resulted to a significant decrease of fasting blood glucose, cholesterol and increase in high density lipoprotein levels after 14 days (P<0.05), but the levels of triglycerides, LDL-cholestrol, activities of alanine aminotransferase and aspartate aminotransferase did not changed significantly in treatment group compared to control group(P>0.05). Conclusion: This paper discussed the antidiabetic effect of an alcoholic extract of Ziziphus Jujuba on streptozocin-induced diabetes in rats. Researchers showed that Streptozocin injection led to diabetes mellitus, which may be due to destruction of β cells of the islets of Langerhans. [ABSTRACT FROM AUTHOR]

Thioacetamide (C2H5NS; TAA), an organosulfur compound is formally used in leather processing, laboratories, textile and paper industries. TAA is a model hepatotoxicant, consumed to induce acute and chronic liver injury due to its effects on protein synthesis, RNA, DNA and Gamma-glutamyl transpeptidase activity. TAA undergoes a two-step bioactivation to sulfine, and afterward to sulfene, a reactive metabolite. Sulfine is accountable for the enlargement of nucleoli, increase in nuclear volume and intracellular concentration of Ca++, change in cell permeability, and inhibit mitochondrial activity. At the same time Sulfene is responsible for the release of nitric oxide synthase and NF-jB directing to centrilobular necrosis, protein denaturation and lipid peroxidation. Furthermore, it impairs the urea cycle and the activity of ornithine aminotransferase. Prolonged oral intake of this compound directs to macro liver nodules, liver cell adenomas, cholangiomas and hepatocarcinomas, histologically similar to that caused due to viral hepatitis infection. [ABSTRACT FROM AUTHOR]

The high in vivo flux of the glutamate/glutamine cycle puts a strong demand on the return of ammonia released by phosphate activated glutaminase from the neurons to the astrocytes in order to maintain nitrogen balance. In this paper we review several amino acid shuttles that have been proposed for balancing the nitrogen flows between neurons and astrocytes in the glutamate/glutamine cycle. All of these cycles depend on the directionality of glutamate dehydrogenase, catalyzing reductive glutamate synthesis (forward reaction) in the neuron in order to capture the ammonia released by phosphate activated glutaminase, while catalyzing oxidative deamination of glutamate (reverse reaction) in the astrocytes to release ammonia for glutamine synthesis. Reanalysis of results from in vivo experiments using N and N labeled ammonia and N leucine in rats suggests that the maximum flux of the alanine/lactate or branched chain amino acid/branched chain amino acid transaminase shuttles between neurons and astrocytes are approximately 3-5 times lower than would be required to account for the ammonia transfer from neurons to astrocytes needed for glutamine synthesis (amide nitrogen) to sustain the glutamate/glutamine cycle. However, in the rat brain both the total ammonia fixation rate by glutamate dehydrogenase and the total branched chain amino acid transaminase activity are sufficient to support a branched chain amino acid/branched chain keto acid shuttle, as proposed by Hutson and coworkers, which would support the de novo synthesis of glutamine in the astrocyte to replace the ~20 % of neurotransmitter glutamate that is oxidized. A higher fraction of the nitrogen needs of total glutamate neurotransmitter cycling could be supported by hybrid cycles in which glutamate and tricarboxylic acid cycle intermediates act as a nitrogen shuttle. A limitation of all in vivo studies in animals conducted to date is that none have shown transfer of nitrogen for glutamine amide synthesis, either as free ammonia or via an amino acid from the neurons to the astrocytes. Future work will be needed, perhaps using methods for selectively labeling nitrogen in neurons, to conclusively establish the rate of amino acid nitrogen shuttles in vivo and their coupling to the glutamate/glutamine cycle. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Papic et al. (2011) Liver involvement during influenza infection: perspective on the 2009 influenza pandemic. Influenza and Other Respiratory Viruses 6(3), e2-e5. Elevation of liver transaminase levels is a frequent observation during systemic infections. The aim of our study was to investigate liver damage during pandemic 2009 influenza A/H1N1 infection in comparison with seasonal influenza. Serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase (GGT) were significantly higher in patients with pandemic influenza compared to seasonal influenza, which was strongly correlated with hypoxia. Moreover, a positive correlation between C-reactive protein and serum GGT, alkaline phosphatase, and lactate dehydrogenase was noticed. Our findings support the hypothesis that the pandemic 2009 influenza A/H1N1 is an illness with a significant immune response to infection leading to hepatocellular injury. [ABSTRACT FROM AUTHOR]

The objective of this study is to describe the clinical and laboratory features of macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SOJIA) at a tertiary care center in northwest India. Review of medical records of all children with SOJIA admitted during the period January 1995-December 2008 in Pediatric Allergy and Immunology Unit, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, was done. Six patients (5 boys and 1 girl) with SOJIA and MAS were identified. Mean age at time of disease onset was 6.5 years. MAS was the presenting manifestation of SOJIA in 4 patients. Clinical manifestations included fever (6/6), clinical shock (6/6), encephalopathy (5/6), generalized lymphadenopathy (4/6), hepatosplenomegaly (3/6), jaundice and abdominal tenderness (3/6), cardiac involvement (3/6), and meningeal irritation (2/6). Laboratory findings at onset of MAS included decreasing total leukocyte and platelet counts, coagulopathy, elevated transaminases, hyponatremia, and lipid abnormalities. Hemophagocytosis was demonstrable in the bone marrow in 4 patients and in the lymph node in 1. For treatment, we used intravenous methylprednisolone (4/6), oral prednisolone (2/6), and intravenous immunoglobulin (2/6). Outcome was favorable in all patients except one who died of rapidly progressive disease. This paper describes the experience of JIA-related macrophage activation syndrome in a tertiary Indian center. We have shown that MAS can be the early presenting manifestation of evolving SOJIA. Early diagnosis and aggressive management can have a significant impact on the mortality associated with this syndrome. We stress on the role of glucocorticoids in the management of this condition and believe that glucocorticoids have a far more important role in the management of this condition than what has been previously reported. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease encompasses a spectrum of disease from asymptomatic steatosis, with or without elevated aminotransferases, to cirrhosis with relative complications and hepatocellular carcinoma. Owing to the increasing prevalence of nonalcoholic fatty liver disease and the potential for nonalcoholic steatohepatitis to progress to cirrhosis and liver-related mortality, more research has been focused on therapy of this important liver disease over the last two decades. To date, weight loss and physical activity represent the cornerstone of treatment, with interventions being limited to subjects at risk of disease progression, but the type of treatment remains a matter of debate. A few medications have shown promising results in preliminary pilot studies, but few agents have been tested rigorously. Today, multiple therapeutic approaches are considered the way to go in treating nonalcoholic steatohepatitis patients. In this paper we review the status of current and emerging therapeutic strategies for children and adult patients with nonalcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]

Transaminases remain one of the most promising biocatalysts for use in chiral amine synthesis, however their industrial implementation has been hampered by their general instability towards, for example, high amine donor concentrations and organic solvent content. Herein we describe the identification, cloning and screening of 29 novel transaminases from a household drain metagenome. The most promising enzymes were fully characterised and the effects of pH, temperature, amine donor concentration and co-solvent determined. Several enzymes demonstrated good substrate tolerance as well as an unprecedented robustness for a wild-type transaminase. One enzyme in particular readily accepted IPA as an amine donor giving the same conversion with 2–50 equivalents, as well as being tolerant to a number of co-solvents, and operational in up to 50% DMSO – a characteristic as yet unobserved in a wild-type transaminase. This work highlights the value of using metagenomics for biocatalyst discovery from niche environments, and here has led to the identification of one of the most robust native transaminases described to date, with respect to IPA and DMSO tolerance. [ABSTRACT FROM AUTHOR]

Auxin is an essential hormone, but its biosynthetic routes in plants have not been fully defined. In this paper, we show that the TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS (TAA) family of amino transferases converts tryptophan to indole-3-pyruvate (IPA) and that the YUCCA (YUC) family of flavin monooxygenases participates in converting IPA to indole-3-acetic acid, the main auxin in plants. Both the YUCs and the TAAs have been shown to play essential roles in auxin biosynthesis, but it has been suggested that they participate in two independent pathways. Here, we show that all of the taa mutant phenotypes, including defects in shade avoidance, root resistance to ethylene and N-1-naphthylphthalamic acid (NPA), are phenocopied by inactivating YUC genes. On the other hand, we show that the taa mutants in several known auxin mutant backgrounds, including pid and npy1, mimic all of the well-characterized developmental defects caused by combining yuc mutants with the auxin mutants. Furthermore, we show that overexpression of YUC1 partially suppresses the shade avoidance defects of taa1 and the sterile phenotypes of the weak but not the strong taa mutants. In addition, we discovered that the auxin overproduction phenotypes of YUC overexpression lines are dependent on active TAA genes. Our genetic data show that YUC and TAA work in the same pathway and that YUC is downstream of TAA. The yuc mutants accumulate IPA, and the taa mutants are partially IPA-deficient, indicating that TAAs are responsible for converting tryptophan to IPA, whereas YUCs play an important role in converting IPA to indole-3-acetic acid. [ABSTRACT FROM AUTHOR]

Coagulopathy is an important complication associated with hepatitis E virus (HEV) infection in pregnant women. Postpartum haemorrhage (PPH) remains a serious risk while managing the labour of these women. The aim of this paper is to study the factors influencing the occurrence of PPH in pregnant women with hepatitis E infection with coagulopathy. The labours of 38 pregnant women with hepatitis E and deranged coagulation profile were followed. Factors that may predict postpartum bleeding complications in women with HEV infection and deranged coagulation profile were statistically analysed. Of 38 pregnant women with acute viral hepatitis due to HEV, 13 (34%) suffered a PPH while 25 (66%) did not. On univariate analysis low alanine aminotransferase (P = 0.016), high international normalized ratio (P = 0.003), high levels of D-dimer (P = 0.008), presence of hepatic encephalopathy (P = 0.028), intrauterine fetal death (P = 0.001) and gastrointestinal bleeding (P = 0.004) were found to predict PPH. However, on multivariate analysis the only independent variable that predicted PPH was the presence gastrointestinal (GI) bleeding (odds ratio [OR] 11.363; 95% CI: 1.003, 125; P = 0.050). Women with GI bleeding have 11 times higher risk of PPH than those without a GI bleed; however, the confidence interval is very wide. Administration of fresh frozen plasma in the peripartum period reduces the risk of PPH. In conclusion, early recognition of factors which predict the risk of PPH and timely intervention with judicious use of blood and blood components in the peripartum period can improve the outcome of pregnant women with HEV infection with deranged coagulation. [ABSTRACT FROM AUTHOR]

Objectives The aim of this research paper was to investigate the hepatoprotective and antioxidant effects of gallic acid in paracetamol-induced liver damage in mice. Methods In the present study, the hepatoprotective and antioxidant effects of gallic acid were evaluated against paracetamol-induced hepatotoxicity in mice and compared with the silymarin, a standard hepatoprotective drug. The mice received a single dose of paracetamol (900 mg/kg body weight i.p.). Gallic acid (100 mg/kg body weight i.p.) and silymarin (25 mg/kg body weight i.p.) were administered 30 min after the injection of paracetamol. After 4 h, liver marker enzymes (aspartate transaminase, alanine transaminase and alkaline phosphatase) and inflammatory mediator tumour necrosis factor-alpha (TNF-α) were estimated in serum, while the lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione- S-transferase and glutathione) were determined in liver homogenate of the control and experimental mice. Key findings Increased activities of liver marker enzymes and elevated TNF-α and lipid peroxidation levels were observed in mice exposed to paracetamol ( P < 0.05), whereas the antioxidant status was found to be depleted ( P < 0.05) when compared with the control group. However gallic acid treatment (100 mg/kg body weight i.p.) significantly reverses ( P < 0.05) the above changes by its antioxidant action compared to the control group as observed in the paracetamol-challenged mice. Conclusions The results clearly demonstrate that gallic acid possesses promising hepatoprotective effects. [ABSTRACT FROM AUTHOR]

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Aim: Paediatric overweight has a high incidence and has serious consequences for health, including non-alcoholic fatty liver disease (NAFLD). However, very little is known about NAFLD among young people, particularly from a population perspective. This paper reports the prevalence of elevated concentrations of four liver enzymes and their associations with adiposity in a representative population sample of Australian adolescents. Methods: Overnight fasting blood samples were collected from a representative population sample of 500 Grade 10 students (15-years-old) attending schools in Sydney, Australia, between February and May, 2004. Weight, height and waist girth were measured. The prevalence of adverse concentrations of the enzymes alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were described for all boys and girls and by body mass index (BMI) categories. The nature of the associations between the enzyme concentrations and indices of adiposity were characterised, and regression equations for estimating enzyme concentrations from BMI were prepared. Results: The prevalence of adverse concentrations of ALT (most likely as a result of NAFLD) and GGT were approximately 10%, while the prevalence of adverse concentrations of AST and ALP were approximately 7% and 5% respectively. The prevalence of adverse concentrations of ALT, GGT and AST increased across BMI categories, while the prevalence of adverse concentrations of ALP declined across BMI categories. Conclusions: The high prevalence of NAFLD in a population sample of healthy Australian adolescents represents a significant burden of disease. [ABSTRACT FROM AUTHOR]

Acetaminophen overdoses are the number one cause of acute liver failure (ALF) in the United States; they account for 50% of all cases of ALF and carry a 30% mortality. Nevertheless, acetaminophen is a highly successful product with sales easily exceeding a billion dollars annually. A narcotic-containing acetaminophen preparation is the number one generic drug sold in the United States. Historically, a strong association was claimed with alcohol as a co-factor and the accidental nature of ingestions was emphasized but the association with alcohol remains a matter of debate. Recently, a very reliable assay has been developed which detects a byproduct of the toxic reaction, acetaminophen-CYS adducts, protein-acetaminophen compounds that are released from damaged hepatocytes in similar fashion to aminotransferases. The US Acute Liver Failure Study Group is a multi-center network established to gather data prospectively on all forms of acute liver failure, a rare but often fatal condition. The group has data on more than 500 acetaminophen cases and described 275 of them in detail in a recent paper. The clinical pattern of presentation is somewhat different in the US compared with the UK, since nearly half are considered to be unintentional, the result of overuse of acetaminophen-containing compounds for pain relief, without suicidal intent. Despite the relatively good prognosis for acetaminophen overdoses, 30% die once acute liver failure occurs and this is the largest cause of death in the entire ALF registry. [ABSTRACT FROM AUTHOR]

One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case–control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1*07 and DQA1*02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.The Pharmacogenomics Journal (2008) 8, 186–195; doi:10.1038/sj.tpj.6500458; published online 15 May 2007 [ABSTRACT FROM AUTHOR]

The most attractive, as well as challenging, multistep organic syntheses would preferably be carried out in a single reactor, as a one-pot synthesis. For biocatalytic syntheses, multistep reactions in one-pot mode bring a number of advantages, while at the same time raising unique challenges such as the compatibility of different biocatalysts. In this paper, we have developed a transketolase–transaminase (TK-TAm) two-step one-pot aminotriol synthesis reaction model, which integrates reaction kinetic models with process characterization (consisting of component degradation as a function of pH and concentration, aldehyde toxicity towards the enzyme, and ketol donor and acceptor side-reactions with TAm). Based on the analysis of the effect of the TAm/TK activity ratio on product yield, simulations provided guidance for further process and biocatalyst development. [ABSTRACT FROM AUTHOR]

The safety of paracetamol when given in the recommended dosage is well documented. However, in recent years there have been many reports of liver failure associated with repeated exposure to supratherapeutic doses of paracetamol. This paper reviews the literature on chronic supratherapeutic paracetamol exposure in children and the different dosing guidelines. Based on which, we suggest the following approach: liver injury secondary to repeated dosing of paracetamol should be considered when a child has received more than 75 mg/kg/d for at least 2 d, or if risk factors for paracetamol toxicity have been identified. Liver transaminases, coagulation factors, and paracetamol serum concentrations should be measured in these children and in symptomatic children with vomiting, right upper quadrant abdominal pain, and jaundice who have taken paracetamol. Treatment with N-acetyl cysteine should be started regardless of paracetamol concentrations if transaminases or INR are elevated. Conclusion: Liver injury secondary to repeated dosing of paracetamol is rare but may result in severe morbidity and mortality. The cumulative dose of paracetamol should not exceed 75 mg/kg/d. Children treated with higher doses for more than 2 d should be evaluated for possible liver injury and treated with N-acetyl cysteine if evidence of liver injury is found. [ABSTRACT FROM AUTHOR]

This paper is the eighth in a series dealing with reference procedures for the measurement of catalytic activity concentrations of enzymes at 37°C and the certification of reference preparations. Other parts deal with: Part 1. The concept of reference procedures for the measurement of catalytic activity concentrations of enzymes; Part 2. Reference procedure for the measurement of catalytic concentration of creatine kinase; Part 3. Reference procedure for the measurement of catalytic concentration of lactate dehydrogenase; Part 4. Reference procedure for the measurement of catalytic concentration of alanine aminotransferase Part 5. Reference procedure for the measurement of catalytic concentration of aspartate aminotransferase Part 6. Reference procedure for the measurement of catalytic concentration of γ-glutamyltransferase; Part 7. Certification of four reference materials for the determination of enzymatic activity of γ-glutamyltransferase, lactate dehydrogenase, alanine aminotransferase and creatine kinase at 37°C. The procedure described here is deduced from the previously described 30°C IFCC reference method. Differences are tabulated and commented on. Clin Chem Lab Med 2006;44:1146–55. [ABSTRACT FROM AUTHOR]

Liu GT, Li Y, Wei HL, Zhang H, Xu JY, Yu LH. Mechanism of protective action of bicyclol against CCl4-induced liver injury in mice. Liver International 2005: 25: 872–279. © Blackwell Munksgaard 2005 Bicyclol is a novel synthetic drug for the treatment of chronic viral hepatitis in China. This paper reports the protective action of bicyclol against experimental liver injury in mice and its mechanism of action. Oral administration of bicyclol markedly reduced the elevated serum transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) and the hepatic morphologic changes induced by CCl4 in mice. Mechanistic studies demonstrated that bicyclol significantly inhibited CCl4-induced lipid peroxidation of liver microsomes and 14CCl4 covalent binding to microsomal lipids and proteins in vitro, and decreased the level of the trichloromethyl free radical (•CCl3) generated from CCl4 metabolism by NADPH-reduced liver microsomes. On the other hand, bicyclol neither directly inhibited the activity of ALT or AST in vitro nor affected hepatic ALT protein content in mice. These results suggest that bicyclol has remarkable hepatoprotective effects and its mechanism of action may be related to a decrease in free radical-induced damage to hepatocytes. [ABSTRACT FROM AUTHOR]

The article discusses several notes by clinicians related to liver. Non-alcoholic fatty liver diseases (NAFLD) are a new growth area in hepatology research, and are being increasingly diagnosed. In the USA, a survey has shown that 80 percent of patients with abnormal transaminase values have NAFLD. It has been associated with the insulin resistance syndrome, obesity; diabetes and hyperdyslipidaemia. This syndrome has recently been defined as metabolic syndrome, using five variable factors, central obesity, hypertension, hypertriglyceridaernia low high density lipoprotein cholesterol and hyperglycaemia. The authors of the first paper evaluated the presence of metabolic syndrome using the above criteria in a cohort of 304 consecutive NAFLD Italian patients.

Background: Metabolic syndrome (MetS) is a group of metabolic abnormalities characterised by hypertension, central obesity, dyslipidaemia and dysregulation of blood glucose, associated with the risk of diabetes, cardiovascular disease and overall mortality. The presence of elevated liver enzymes may precede the development of MetS, with alterations of the liver being observed that are directly related to metabolic problems. The study aims to provide the best evidence on the association between liver enzymes (ALT, AST, GGT) and MetS by determining the effect size of these biomarkers. Methods: A systematic review and meta-analysis of studies indexed in PubMed and Scopus databases were performed. Study quality was assessed using the STROBE tool. The Grade Pro tool was used to evaluate the evidence, and the quantitative synthesis was performed using RevMan (Cochrane Collaboration). Results: Seventeen articles comparing liver enzyme concentrations between 76,686 with MetS (MetS+) and 201,855 without MetS (MetS-) subjects were included. The concentration of ALT, AST and GGT in the MetS + subjects was significantly higher than in the control group 7.13 IU/L (CI95% 5.73–8.54; p < 0.00001; I2 = 96%), 2.68 IU/L (CI95% 1.82–3.54; p < 0.00001; I2 = 96%) and 11.20 IU/L (CI95% 7.11–15.29; p < 0.00001; I2 = 96%), respectively. Conclusions: The evaluation of the relationship of liver enzymes in the pathophysiological process of MetS could lead to new insights into early diagnosis. [ABSTRACT FROM AUTHOR]

Diterpenoid alkaloids (DAs) have been often utilized in clinical practice due to their analgesic and anti‐inflammatory properties. Natural DAs are prevalent in the family Ranunculaceae, notably in the Aconitum genus. Nevertheless, the evolutionary origin of the biosynthesis pathway responsible for DA production remains unknown. In this study, we successfully assembled a high‐quality, pseudochromosome‐level genome of the DA‐rich species Aconitum vilmorinianum (A. vilmorinianum) (5.76 Gb). An A. vilmorinianum‐specific whole‐genome duplication event was discovered using comparative genomic analysis, which may aid in the evolution of the DA biosynthesis pathway. We identified several genes involved in DA biosynthesis via integrated genomic, transcriptomic, and metabolomic analyses. These genes included enzymes encoding target ent‐kaurene oxidases and aminotransferases, which facilitated the activation of diterpenes and insertion of nitrogen atoms into diterpene skeletons, thereby mediating the transformation of diterpenes into DAs. The divergence periods of these genes in A. vilmorinianum were further assessed, and it was shown that two major types of genes were involved in the establishment of the DA biosynthesis pathway. Our integrated analysis offers fresh insights into the evolutionary origin of DAs in A. vilmorinianum as well as suggestions for engineering the biosynthetic pathways to obtain desired DAs. [ABSTRACT FROM AUTHOR]

The assessment of the nutritional and inflammatory status of paediatric patients with coeliac disease is an interesting approach to early diagnosis and functional follow-up. Most authors agree that the normalisation of symptoms takes about one year. The aim of the study was to evaluate the clinical manifestation and normalisation of routine analytics in Spanish children diagnosed with celiac disease. Methods: We performed a retrospective case–control study in Spanish paediatric patients, including 21 celiac patients and 20 healthy controls. The 21 patients selected in the case–control study were followed for 5 years after starting a gluten-free diet (GFD). All patients had type 3 villous atrophy according to the Marsh–Oberhuber classification. A total of 39 blood samples were taken before the start of the GFD, and 109 were taken after. Twenty control sera from healthy donors were used for comparison. Results: We found that patients had a subclinical but statistically significant increase in blood calcium, transaminases, and white blood cells, and a decrease in serum iron, at the time of diagnosis. Our study also shows that analytical values normalise within five years on a gluten-free diet. Conclusions: The use of a combination of subclinical changes, including low iron, high calcium, elevated leukocytes, lymphocytes, and ALT levels in blood samples, together with a low growth percentile, is pertinent in detecting coeliac disease. This set of parameters could help in the diagnosis of patients without clinical symptoms. We can also show that the levels of Fe, Ca, transaminases, and leucocytes remain subclinically altered after 3 years, despite the gluten-free diet. [ABSTRACT FROM AUTHOR]

This paper presents the first purification of the mitochondrial branched‐chain amino acid aminotransferase (BCATm) from sheep placenta. It is a homodimer with an apparent subunit molecular mass of 41 kDa. The enzyme differs from those of the rat and human as it appears to form at least one intermolecular disulfide bond. The sheep BCATm cDNA (1.4 kb) encodes a mature polypeptide of 366 amino acids with a calculated molecular mass of 41 329 Da and a partial mitochondrial targeting sequence of seven amino acids. The sheep BCATm sequence shares higher identity with other mammalian BCATm isoenzymes (82–85%) than with the cytosolic isoenzymes (60%). By Northern blot analysis, a message of 1.7 kb was detected in sheep placenta and skeletal muscle. Measurements of BCAT activity, mRNA and BCATm protein in sheep placenta and skeletal muscle revealed that BCATm is the sole BCAT isoenzyme expressed in placenta, whereas it contributes 57 and 71% of the BCAT activity in tensor fascia latae and masseter muscles from weaned lambs respectively. Skeletal muscle, the main site of branched‐chain amino acid transamination, exhibits significantly lower BCAT activity in sheep than in rat. Our results suggest that the low BCATm mRNA level probably accounts for the low BCAT activity in sheep skeletal muscle, and that the metabolic scheme for branched‐chain amino acid catabolism is specific to each species. [ABSTRACT FROM AUTHOR]