Silymarin protects liver against toxic effects of anti-tuberculosis drugs in experimental animals

<p>Abstract</p> <p>Background</p> <p>The first line anti-tuberculosis drugs isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) continues to be the effective drugs in the treatment of tuberculosis, however, the use of these drugs is associated with toxic reactions in tissues, particularly in the liver, leading to hepatitis. Silymarin, a standard plant extract with strong antioxidant activity obtained from <it>S. marianum</it>, is known to be an effective agent for liver protection and liver regeneration. The aim of this study was to investigate the protective actions of silymarin against hepatotoxicity caused by different combinations of anti-tuberculosis drugs.</p> <p>Methods</p> <p>Male Wistar albino rats weighing 250–300 g were used to form 6 study groups, each group consisting of 10 rats. Animals were treated with intra-peritoneal injection of isoniazid (50 mg/kg) and rifampicin (100 mg/kg); and intra-gastric administration of pyrazinamid (350 mg/kg) and silymarin (200 mg/kg). Hepatotoxicity was induced by a combination of drugs with INH+RIF and INH+RIF+PZA. Hepatoprotective effect of silymarin was investigated by co-administration of silymarin together with the drugs. Serum biochemical tests for liver functions and histopathological examination of livers were carried out to demonstrate the protection of liver against anti-tuberculosis drugs by silymarin.</p> <p>Results</p> <p>Treatment of rats with INH+RIF or INH+RIF+PZA induced hepatotoxicity as evidenced by biochemical measurements: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities and the levels of total bilirubin were elevated, and the levels of albumin and total protein were decreased in drugs-treated animals. Histopathological changes were also observed in livers of animals that received drugs. Simultaneous administration of silymarin significantly decreased the biochemical and histological changes induced by the drugs.</p> <p>Conclusion</p> <p>The active components of silymarin had protective effects against hepatotoxic actions of drugs used in the chemotherapy of tuberculosis in animal models. Since no significant toxicity of silymarin is reported in human studies, this plant extract can be used as a dietary supplement by patients taking anti-tuberculosis medications.</p

How well do blood folate concentrations predict dietary folate intakes in a sample of Canadian lactating women exposed to high levels of folate? An observational study

<p>Abstract</p> <p>Background</p> <p>In 1998, mandatory folic acid fortification of white flour and select cereal grain products was implemented in Canada with the intention to increase dietary folate intakes of reproducing women. Folic acid fortification has produced a dramatic increase in blood folate concentrations among reproductive age women, and a reduction in neural tube defect (NTD)-affected pregnancies. In response to improved blood folate concentrations, many health care professionals are asking whether a folic acid supplement is necessary for NTD prevention among women with high blood folate values, and how reliably high RBC folate concentrations predict folate intakes shown in randomized controlled trials to be protective against NTDs. The objective of this study was to determine how predictive blood folate concentrations and folate intakes are of each other in a sample of well-educated lactating Canadian women exposed to high levels of synthetic folate.</p> <p>Methods</p> <p>The relationship between blood folate concentrations and dietary folate intakes, determined by weighed food records, were assessed in a sample of predominantly university-educated lactating women (32 ± 4 yr) at 4-(n = 53) and 16-wk postpartum (n = 55).</p> <p>Results</p> <p>Median blood folate concentrations of all participants were well above plasma and RBC folate cut-off levels indicative of deficiency (6.7 and 317 nmol/L, respectively) and all, except for 2 subjects, were above the cut-off for NTD-risk reduction (>906 nmol/L). Only modest associations existed between total folate intakes and plasma (r = 0.46, <it>P </it>< 0.001) and RBC (r = 0.36, <it>P </it>< 0.01) folate concentrations at 16-wk postpartum. Plasma and RBC folate values at 16-wk postpartum correctly identified the quartile of folate intake of only 26 of 55 (47%) and 18 of 55 (33%) of subjects, respectively. The mean RBC folate concentration of women consuming 151–410 μg/d of synthetic folate (2^ndquartile of intake) did not differ from that of women consuming >410 μg/d (3^rdand 4^thquartile).</p> <p>Conclusion</p> <p>Folate intakes, estimated by food composition tables, and blood folate concentrations are not predictive of each other in Canadian lactating women exposed to high levels of folate. Synthetic intakes > 151–410 μg/d in these women produced little additional benefit in terms of maximizing RBC content. More studies are needed to examine the relationship between blood folate concentration and NTD risk. Until data from such studies are available, women planning a pregnancy should continue to consume a daily folic acid supplement of 400 μg.</p

Beneficial Endocrine but Adverse Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide Transgenic Rat Model of Type 2 Diabetes: Interactions With Metformin

ObjectiveWe sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes.Research design and methodsHIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and beta-cell mass, function, and turnover were measured in each group.ResultsSitagliptin plus metformin had synergistic effects to preserve beta-cell mass in HIP rats. Metformin more than sitagliptin inhibited beta-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. beta-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis.ConclusionsThe combination of metformin and sitagliptin had synergistic actions to preserve beta-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation

Countering the Australian 'ndrangheta: The criminalisation of mafia behaviour in Australia between national and comparative criminal law

Mafia-type criminal groups belonging to, or originated from, the Calabrian ‘ndrangheta from Southern Italy, have been object of recent academic research and media attention in Australia. The Australian ‘ndrangheta, as qualified form of organised crime, poses new challenges for law enforcement in the country. This paper briefly looks at the strategies to fight organised crime in Australia, with specific focus on anti-association laws. By using a comparative approach, the paper will look at the criminalisation of mafias as qualified forms of organised crime in other two jurisdictions, Italy and the USA, to advocate for an effective mafia criminalisation in Australia. In conclusion, this paper will argue that, in order to also fight mafia phenomena, criminal law in Australia should focus on behaviours of organised crime groups rather than only on the criminalisation of proscribed associations and their illegal activities

Youth social behaviour and network therapy (Y-SBNT) : adaptation of a family and social network intervention for young people who misuse alcohol and drugs – a randomised controlled feasibility trial

Background: Family interventions appear to be effective at treating young people’s substance misuse. However, implementation of family approaches in UK services is low. This study aimed to demonstrate the feasibility of recruiting young people to an intervention based on an adaptation of adult social behaviour and network therapy. It also sought to involve young people with experience of using substance misuse services in the research process. Objectives: To demonstrate the feasibility of recruiting young people to family and social network therapy and to explore ways in which young people with experience of using substance misuse services could be involved in a study of this nature. Design: A pragmatic, two-armed, randomised controlled open feasibility trial. Setting: Two UK-based treatment services for young people with substance use problems, with recruitment taking place from May to November 2014. Participants: Young people aged 12–18 years, newly referred and accepted for structured interventions for drug and/or alcohol problems. Interventions: A remote, web-based computer randomisation system allocated young people to adapted youth social behaviour and network therapy (Y-SBNT) or treatment as usual (TAU). Y-SBNT participants were intended to receive up to six 50-minute sessions over a maximum of 12 weeks. TAU participants continued to receive usual care delivered by their service. Main outcome measures: Feasibility was measured by recruitment rates, retention in treatment and follow-up completion rates. The main clinical outcome was the proportion of days on which the main problem substance was used in the preceding 90-day period as captured by the Timeline Follow-Back interview at 3 and 12 months. Results: In total, 53 young people were randomised (Y-SBNT, n = 26; TAU, n = 27) against a target of 60 (88.3%). Forty-two young people attended at least one treatment session [Y-SBNT 22/26 (84.6%); TAU 20/27 (74.1%)]; follow-up rates were 77.4% at month 3 and 73.6% at month 12. Data for nine young people were missing at both months 3 and 12, so the main clinical outcome analysis was based on 24 young people (92.3%) in the Y-SBNT group and 20 young people (74.1%) in the TAU group. At month 12, the average proportion of days that the main problem substance was used in the preceding 90 days was higher in the Y-SBNT group than in the TAU group (0.54 vs. 0.41; adjusted mean difference 0.13, 95% confidence interval –0.12 to 0.39; p = 0.30). No adverse events were reported. Seventeen young people with experience of substance misuse services were actively involved throughout the study. They informed key elements of the intervention and research process, ensuring that the intervention was acceptable and relevant to our target groups; contributing to the design of key trial documents, ideas for a new model of public involvement and this report. Two parents were also involved. Conclusions: The adapted intervention could be delivered in young people’s services, and qualitative interviews found that Y-SBNT was acceptable to young people, family members and staff. Engagement of family and network members proved difficult within the intervention and research aspects. The study proved the feasibility of this work in routine services but outcome measurement based on narrow substance use variables may be limited and may fail to capture other important changes in wider areas of functioning for young people. Validation of the EuroQol-5 Dimensions for young people aged 12–18 years should be considered and flexible models for involvement of young people in research are required to achieve inclusive representation throughout all aspects of the research process. Although recommendation of a full trial of the Y-SBNT intervention compared with TAU is not supported, this study can inform future intervention development and UK research within routine addiction services. Trial registration: Current Controlled Trials ISRCTN93446265. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 15. See the NIHR Journals Library website for further project information

Can user testing of a clinical trial patient information sheet make it fit-for-purpose? - a randomized controlled trial

Background: The participant information sheet (PIS) provided to potential trial participants is a critical part of the process of valid consent. However, there is long-standing concern that these lengthy and complex documents are not fit-for-purpose. This has been supported recently through the application of a performance-based approach to testing and improving readability called user testing. This method is now widely used to improve patient medicine leaflets - determining whether people can find and understand key facts. This study applied for the first time a controlled design to determine whether a PIS developed through user testing had improved readability over the original, using a sheet from a UK trial in acute myeloid leukemia (AML16). Methods: In the first phase the performance of the original PIS was tested on people in the target group for the trial. There were three rounds of testing including 50 people in total - with the information revised according to its performance after each of the first 2 rounds. In the second phase, the revised PIS was compared with the original in a parallel groups randomised controlled trial (RCT) A total of 123 participants were recruited and randomly allocated to read one version of the PIS to find and show understanding of 21 key facts. Results: The first, developmental phase produced a revised PIS significantly altered in its wording and layout. In the second, trial phase 66% of participants who read the revised PIS were able to show understanding of all aspects of the trial, compared with 15% of those reading the original version (Odds Ratio 11.2; Chi-square = 31.5 p < .001). When asked to state a preference, 87.1% participants chose the revised PIS (Sign test p < .001). Conclusions: The original PIS for the AML16 trial may not have enabled valid consent. Combining performance-based user testing with expertise in writing for patients and information design led to a significantly improved and preferred information sheet. User testing is an efficient method for indicating strengths and weaknesses in trial information, and Research Ethics Committees and Institutional Review Boards should consider requesting such testing, to ensure that PIS are fit-for-purpose

Predicting invasions of North American basses in Japan using native range data and a genetic algorithm

Largemouth bass Micropterus salmoides and smallmouth bass M. dolomieu have been introduced into freshwater habitats in Japan, with potentially serious consequences for native fish populations. In this paper we apply the technique of ecological niche modeling using the genetic algorithm for rule-set prediction (GARP) to predict the potential distributions of these two species in Japan. This algorithm constructs a niche model based on point occurrence records and ecological coverages. The model can be visualized in geographic space, yielding a prediction of potential geographic range. The model can then be tested by determining how well independent point occurrence data are predicted according to the criteria of sensitivity and specificity provided by receiver–operator curve analysis. We ground-truthed GARP’s ability to forecast the geographic occurrence of each species in its native range. The predictions were statistically significant for both species (P , 0.001). We projected the niche models onto the Japanese landscape to visualize the potential geographic ranges of both species in Japan. We tested these predictions using known occurrences from introduced populations of largemouth bass, both in the aggregate and by habitat type. All analyses robustly predicted known Japanese occurrences (P , 0.001). The number of smallmouth bass in Japan was too small for statistical tests, but the 10 known occurrences were predicted by the majority of models

Alleviating health risks associated with rainwater harvesting

Perceived and real public health risks associated with the quality of water from alternative water sources and supply systems, such as rainwater harvesting (RWH) and grey water reuse, continue to restrict their uptake in many countries. One option to alleviate these health risks is to treat alternative water to potable standard at the point of use (POU) as opposed to the point of supply, as undertaken in centralised systems. This paper presents the results of three international empirical field trials of a novel POU RWH treatment device. The results indicate that where the harvested rainwater did not contain elevated levels of pesticides or physico-chemical determinands, the POU device was able to reduce levels in outlet water to meet UK, EU and World Health Organization potable standards. Regarding microbiological determinands, such as total viable counts and coliforms, and microbial pathogens, such as Pseudomonas aeruginosa and Legionella spp., the device achieved reduction to potable standard and full pathogen removal, respectively. Thus, while it is possible to treat harvested rainwater to potable standard with a POU device, whether it is desirable to do so to alleviate risks for all end uses remains a question for further debate

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants.

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS