Trypsin inhibition by macrocyclic and open-chain variants of the squash inhibitor MCoTI-II

MCoTl-I and MCoTl-II from the seeds of Momordica cochinchinensis are inhibitors of trypsin-like proteases and the only known members of the large family of squash inhibitors that are cyclic and contain an additional loop connecting the amino- and the carboxy-terminus. To investigate the contribution of macrocycle formation to biological activity, we synthesized a set of open-chain variants of MCoTl-II that lack the cyclization loop and contain various natural and non-natural amino acid substitutions in the reactive-site loop. Upon replacement of P1 lysine residue \#10 within the open-chain variant of MCoTl-II by the non-natural isosteric nucleo amino acid AlaG{[}beta-(guanin-9-yl)-L-alanine], a conformationally restricted arginine mimetic, residual inhibitory activity was detected, albeit reduced by four orders of magnitude. While the cyclic inhibitors MCoTl-I and MCoTl-II were found to be very potent trypsin inhibitors, with picomolar inhibition constants, the open-chain variants displayed an approximately 10-fold lower affinity. These data suggest that the formation of a circular backbone in the MCoTI squash inhibitors results in enhanced affinity and therefore is a determinant of biological activity

Monitoring food marketing to children: A joint Nordic monitoring protocol for marketing of foods and beverages high in fat, salt and sugar (HFSS) towards children and young people

The protocol describes methods for how to monitor marketing of foods and beverages high in fat, salt and sugar towards children and young people at a given time as cross-sectional studies, as well as allowing for monitoring of trends. The data provided could also be used for evaluation purposes, for instance providing relevant data for evaluating regulation practices and schemes in the respective countries; to study advertising and marketing practices, contents and forms over time. In addition to being a tool for monitoring purposes within each country, the protocol will also enable comparisons between the Nordic countries by establishing a joint understanding on how each marketing channel should be monitored. The protocol has been developed as a Nordic project between representatives and experts from Iceland, Finland, Sweden, Denmark and Norway together with international experts

Health impact assessment of agriculture and food policies: lessons learnt from the Republic of Slovenia.

The most important public health priority in agricultural policy-making is currently food safety, despite the relatively higher importance of food security, nutrition, and other agricultural-related health issues in terms of global burden of disease. There is limited experience worldwide of using health impact assessment (HIA) during the development of agriculture and food policies, which perhaps reflects the complex nature of this policy sector. This paper presents methods of HIA used in the Republic of Slovenia, which is conducting a HIA of proposed agricultural and food policies due to its accession to the European Union. It is the first time that any government has attempted to assess the health effects of agricultural policy at a national level. The HIA has basically followed a six-stage process: policy analysis; rapid appraisal workshops with stakeholders from a range of backgrounds; review of research evidence relevant to the agricultural policy; analysis of Slovenian data for key health-related indicators; a report on the findings to a key cross-government group; and evaluation. The experience in Slovenia shows that the HIA process has been a useful mechanism for raising broader public health issues on the agricultural policy agenda, and it has already had positive results for policy formation. HIA is one useful approach to more integrated policy-making across sectors, but clearly it is not the only mechanism to achieve this. A comparison of the approach used in Slovenia with HIA methods in other countries and policy contexts shows that there are still many limitations with HIA application at a government level. Lessons can be learnt from these case studies for future development and application of HIA that is more relevant to policy-makers, and assists them in making more healthy policy choices

High sugar content of European commercial baby foods and proposed updates to existing recommendations

The aim was to determine whether commercial baby foods marketed within Europe (up to 36 months of age) have inappropriate formulation and high sugar content and to provide suggestions to update European regulations and recommendations as part of a nutrient profile model developed for this age group. The latter was produced following recommended World Health Organization (WHO) steps, including undertaking a rapid literature review. Packaging information from countries across the WHO European region was used to determine mean energy from total sugar by food category. The percentage of products containing added sugar and the percentage of savoury meal‐type products containing pureed fruit were also calculated. A total of 2,634 baby foods from 10 countries were summarised: 768 sold in the United Kingdom, over 200 each from Denmark (319), Spain (241), Italy (430) and Malta (243) and between 99–200 from Hungary, Norway, Portugal, Estonia and Slovenia. On average, approximately a third of energy in baby foods in these European countries came from total sugar, and for most food categories, energy from sugar was higher than 10%. Use of added sugars was widespread across product categories, with concentrated fruit juice most commonly used. Savoury meal‐type purees did not contain added sugars except in United Kingdom and Malta; however, fruit as an ingredient was found in 7% of savoury meals, most frequently seen in UK products. Clear proposals for reducing the high sugar content seen in commercial baby foods were produced. These suggestions, relating to both content and labelling, should be used to update regulations and promote product reformulation

Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma

Asthma patients who continue to experience symptoms despite being on regular inhaled corticosteroids (ICS) represent a management challenge. Long-acting beta2-agonists (LABA) or anti-leukotrienes (LTRA) are two treatment options that could be considered as add-on therapy to ICS.ObjectivesWe compared the efficacy and safety profile of adding either daily LABA or LTRA in adults and children with asthma who remain symptomatic on ICS.Search strategyWe searched the Cochrane Airways Group Specialised Register (up to and including March 2010). We consulted reference lists of all included studies and contacted authors and pharmaceutical manufacturers for other published or unpublished studies.Selection criteriaWe included randomised controlled trials (RCTs) conducted in adults or children with recurrent asthma that was treated with ICS and where a fixed dose of a long-acting beta2-agonist or leukotriene agent was added for a minimum of 28 days.Data collection and analysisTwo authors independently assessed the risk of bias of included studies and extracted data. We sought unpublished data and further details of study design, where necessary.Main resultsWe included 17 RCTs (7032 participants), of which 16 recruited adults and adolescents (6850) and one recruited children aged 6 to 17 years (182). Participants demonstrated substantial reversibility to short-acting beta-agonist at baseline. The studies were at a low risk of bias. The risk of exacerbations requiring systemic corticosteroids was lower with the combination of LABA and ICS compared with LTRA and ICS, from 11% to 9% (RR 0.83, 95% CI 0.71 to 0.97; six studies, 5571 adults). The number needed to treat (NNT) with LABA compared to LTRA to prevent one exacerbation over 48 weeks was 38 (95% CI 22 to 244). The choice of LTRA did not significantly affect the results. The effect appeared stronger in the trials using a single device to administer ICS and LABA compared to those using two devices. In the absence of data from the paediatric trial and the clinical homogeneity of studies, we could not perform subgroup analyses. The addition to ICS of LABA compared to LTRA was associated with a statistically greater improvement from baseline in several of the secondary outcomes, including lung function, functional status measures and quality of life. Serious adverse events were more common with LABA than LTRA, although the estimate was imprecise (RR 1.35, 95% CI 1.00 to 1.82), and the NNT to harm for one additional patient to suffer a serious adverse event on LABA over 48 weeks was 78 (95% CI 33 to infinity). The risk of withdrawal for any reason in adults was significantly lower with LABA and ICS compared to LTRA and ICS (RR 0.84, 95% CI 0.74 to 0.96).Authors' conclusionsIn adults with asthma that is inadequately controlled on low doses of inhaled steroids and showing significant reversibility with beta2-agonists, LABA is superior to LTRA in reducing oral steroid treated exacerbations. Differences favouring LABA in lung function, functional status and quality of life scores are generally modest. There is some evidence of increased risk of SAEs with LABA. The findings support the use of a single inhaler for the delivery of LABA and inhaled corticosteroids. We are unable to draw conclusions about which treatment is better as add-on therapy for children.PLAIN LANGUAGE SUMMARYWhat are the effects of long-acting beta2-agonists compared with anti-leukotrienes when added to inhaled steroids?People who continue to experience asthma symptoms despite regularly taking inhaled corticosteroids are a challenge for management. It is not clear whether the addition of a long-acting beta2-agonist (LABA) such as formoterol or salmeterol would provide more benefit in comparison with an oral anti-leukotriene agent (LTRA), for example zafirlukast or montelukast.Seventeen trials (16 in adults and one in children) were included in this review and were of good quality. We found that the addition of a LABA provides significantly greater protection against exacerbations requiring oral steroids when compared with a LTRA for adults. Based on the results of our analyses, approximately 38 adults (with a range of between 22 and 244) would need to be treated with a LABA rather than a LTRA for 48 weeks to prevent one experiencing an exacerbation needing a course of oral steroids. The trial on children did not contribute data on the main outcome and therefore we could not draw any conclusions for children.LABAs also led to a greater improvement in lung function, improvement in symptoms, use of rescue medication, quality of life and symptoms compared to the use of LTRAs. The magnitude of the improvements was modest. Serious adverse events were more frequent with LABA than with LTRAs although this result was imprecise. Based on our analyses, around 78 people would need to be treated for 48 weeks with a LABA rather than a LTRA for one of them to experience a serious adverse event. However, due to the lack of precision around our result, the true number could be between 33 and infinity. There are currently insufficient data to draw any conclusions about the effects of these drugs in children

Cathepsins B, L and cystatin C in cyst fluid of ovarian tumors

Contains fulltext : 88032.pdf (publisher's version ) (Closed access)INTRODUCTION: In cancer, an extracellular and membrane bound localization of cathepsins contribute to the invasion of tumor cells at the basement membrane. METHODS: This is the first study that explored levels of cathepsins B (CatB), L (CatL) and their inhibitor cystatin C (CysC) in the cystic fluid (CF) of ovarian tumors (n = 110). RESULTS: CF contained considerable amounts of CatB, CatL and CysC. Remarkable differences in CatB and CatL and CysC CF levels were found between different histopathological tumor subtypes. Levels of CatB and CysC were significantly higher in CF of malignant serous tumors compared to those found in benign serous tumors (p = 0.010 and p = 0.001 respectively), whereas levels of CatL were significantly higher in CF of malignant mucinous tumors compared to those found in benign mucinous tumors (p = 0.035). CatB and CysC showed a strong correlation in the group of patients with malignant serous tumors (p < 0.001; R = 0.921) suggesting that the increase in CatB might be balanced by a corresponding increase in CysC. CONCLUSION: Further studies are warranted to investigate cathepsins as possible prognostic biomarkers for the aggressiveness of ovarian cancer.1 mei 201