Maternal recognition of the (semi) allogeneic fetus during implantation and pregnancy

The recognition of __self__ and __none-self__ is one of the most important mechanisms for the human immune system whether or not to mediate a response. Cells identified as __self__ are tolerated whereas __non-self__ cells induce a cytotoxic reaction. However, during pregnancy the maternal immune system has to tolerate the presence of __non-self__ cells in maternal tissue, as the fetus is semi-allogeneic expressing both maternal and paternal antigens. This immunological acceptance of the __non-self__ fetus for the duration of pregnancy is called the immunological paradox. In this thesis we focused on the maternal immune recognition during implantation, pregnancy and pregnancy complications. Though pregnancy is sometimes considered as an immune deficient condition, both the innate as the adaptive immunity are activated and several aspects of these immune systems are studied in this thesis.Afdeling Verloskunde LUMC, BMA BV (Mosos), Chipsoft BV, Greiner Bio-One, Memidis Pharma BV, Nationaal Referentie Centrum voor Histocompatibiliteit , Stichting HELLP Syndroom , ZonMWUBL - phd migration 201

Opportunities and perspectives for utilisation of co-products in the meat industry

peer-reviewedMeat co-products are the non-meat components arising from meat processing/fabrication and are generated in large quantities on a daily basis. Co-products are considered as low added-value products, and in general it is difficult for industries to divert efforts into increasing their value. While many of these products can be edible those not used for human consumption or pet food is usually processed to be used as animal feed, fertilizer or fuel. However, to a large extent meat co-products are an excellent source of high nutritive value protein, minerals and vitamins and hence may be better diverted to contribute to alleviate the increasing global demand for protein. In this review the current uses, legislation and potential techniques for meat co-products processing are reviewed with the aim of showing a route to improve meat industry sustainability, profitability and better usage of available resources

Optimization of protein recovery from bovine lung by pH shift process using response surface methodology

peer-reviewedBACKGROUND Response surface methodology (RSM) was used in a sequential manner to optimize solubilization and precipitation conditions in the recovery of protein from bovine lung using pH shift. RESULTS Separate D‐optimal designs were employed for protein solubilization and precipitation. Independent variables investigated for protein solubilization were time (10–120 min), temperature (4–20 °C), pH (8.0–11.0) and solvent/sample ratio (2.5–10). Variables for protein precipitation were time (0–60 min) and pH (4.25–6.00). Soluble protein yields ranged from 323 to 649 g kg−1 and the quadratic model for protein solubilization revealed a coefficient of determination R2 of 0.9958. Optimal conditions for maximum protein solubility were extraction time 140 min, temperature 19 °C, pH 10.8 and solvent/sample ratio 13.02. Protein precipitation yields varied from 407 to 667 g kg−1, giving a coefficient of determination R2 of 0.9335. Optimal conditions for maximum protein precipitation were pH 5.03 and 60 min. Based on the RSM model, solubilization conditions were manipulated to maximize protein solubilization under reduced water and alkaline usage. These conditions were also validated. CONCLUSION Models for solubilization and precipitation using bovine and porcine lung were validated; predicted and actual yields were in good agreement, showing cross‐species applicability of the results. © 2017 Society of Chemical Industr

Co-products of beef processing enhance non-haem iron absorption in an in vitro digestion/caco-2 cell model

Beef processing produces high volumes of protein rich, low value, ‘waste’ co‐products such as offal. Beef improves uptake of low bioavailable non‐haem iron (found in vegetables, fortificants, supplements) and this effect is dubbed the ‘meat‐factor’, although the underlying mechanism is not fully understood. Here, we investigate whether bovine co‐products (kidney, lung, heart) not previously studied share this enhancing potential. This was determined by coupled in vitro digestion of co‐products and subsequent caco‐2 cell ferritin formation (an intracellular iron storage protein). In this study we show that bovine co‐products significantly increase caco‐2 cells’ response to non‐haem iron from infant rice cereal. The presence of these co‐products, (kidney, lung and heart), increased relative uptake (by 207.13%, 171.21%, 265.28%, respectively), to a greater extent than beef (30.23%). Our findings present a novel function for co‐products of beef processing that may have potential as food ingredients to improve non‐haem iron bioavailability, thus adding value

Does cannabis use predict psychometric schizotypy via aberrant salience?

Cannabis can induce acute psychotic symptoms in healthy individuals and exacerbate pre-existing psychotic symptoms in patients with schizophrenia. Inappropriate salience allocation is hypothesised to be central to the association between dopamine dysregulation and psychotic symptoms. This study examined whether cannabis use is associated with self-reported salience dysfunction and schizotypal symptoms in a non-clinical population. 910 University students completed the following questionnaire battery: the cannabis experience questionnaire modified version (CEQmv); schizotypal personality questionnaire (SPQ); community assessment of psychic experience (CAPE); aberrant salience inventory (ASI). Mediation analysis was used to test whether aberrant salience mediated the relationship between cannabis use and schizotypal traits. Both frequent cannabis consumption during the previous year and ASI score predicted variation across selected positive and disorganised SPQ subscales. However, for the SPQ subscales ‘ideas of reference’ and ‘odd beliefs’, mediation analysis revealed that with the addition of ASI score as a mediating variable, current cannabis use no longer predicted scores on these subscales. Similarly, cannabis use frequency predicted higher total SPQ as well as specific Positive and Disorganised subscale scores, but ASI score as a mediating variable removed the significant predictive relationship between frequent cannabis use and ‘odd beliefs’, ‘ideas of reference’, ‘unusual perceptual experiences’, ‘odd speech’, and total SPQ scores. In summary, cannabis use was associated with increased psychometric schizotypy and aberrant salience. Using self-report measures in a non-clinical population, the cannabis-related increase in selected positive and disorganised SPQ subscale scores was shown to be, at least in part, mediated by disturbance in salience processing mechanisms

A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes

Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties

Functional protein rich extracts from bovine and porcine hearts using acid or alkali solubilisation and isoelectric precipitation

Alkali solubilisation (ALS) was compared with acid solubilisation (ACS) for preparation of protein rich extracts from bovine and porcine hearts. ACS and ALS recovered 51.53%–55.74% of the total protein from bovine and porcine hearts. All extracts were rich in myofibrillar proteins with both treatments resulting in reductions in fat, collagen and cholesterol contents compared with starting materials. At 0% NaCl, ACS and ALS extracts had good gelling properties with the ALS gels having lower % cook loss. While treatments did not affect gel hardness, ACS extracts formed gel networks with higher storage modulus after heating and cooling. At 2% NaCl gel hardness, % cook loss and storage modulus values increased, with greater increases occurring for ACS extracts. The results show that ALS‐ and ACS‐based processes have potential to produce functional ingredients for processed meat products

Assay strategies for the discovery and validation of therapeutics targeting <i>Brugia pahangi</i> Hsp90

The chemotherapy of lymphatic filariasis relies upon drugs such as diethylcarbamazine and ivermectin that largely target the microfilarial stages of the parasite, necessitating continued treatment over the long reproductive life span of the adult worm. The identification of compounds that target adult worms has been a long-term goal of WHO. Here we describe a fluorescence polarization assay for the identification of compounds that target Hsp90 in adult filarial worms. The assay was originally developed to identify inhibitors of Hsp90 in tumor cells, and relies upon the ability of small molecules to inhibit the binding of fluorescently labelled geldanamycin to Hsp90. We demonstrate that the assay works well with soluble extracts of Brugia, while extracts of the free-living nematode C. elegans fail to bind the probe, in agreement with data from other experiments. The assay was validated using known inhibitors of Hsp90 that compete with geldanamycin for binding to Hsp90, including members of the synthetic purine-scaffold series of compounds. The efficacy of some of these compounds against adult worms was confirmed in vitro. Moreover, the assay is sufficiently sensitive to differentiate between binding of purine-scaffold compounds to human and Brugia Hsp90. The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target

Adjunctive Medication Management and Contingency Management to enhance adherence to acamprosate for alcohol dependence: the ADAM trial RCT

BACKGROUND: Acamprosate is an effective and cost-effective medication for alcohol relapse prevention but poor adherence can limit its full benefit. Effective interventions to support adherence to acamprosate are therefore needed. OBJECTIVES: To determine the effectiveness of Medication Management, with and without Contingency Management, compared to Standard Support alone in enhancing adherence to acamprosate and the impact of adherence to acamprosate on abstinence and reduced alcohol consumption. DESIGN: Multicentre, three-arm, parallel-group, randomised controlled clinical trial. SETTING: Specialist alcohol treatment services in five regions of England (South East London, Central and North West London, Wessex, Yorkshire and Humber and West Midlands). PARTICIPANTS: Adults (aged 18 years or more), an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of alcohol dependence, abstinent from alcohol at baseline assessment, in receipt of a prescription for acamprosate. INTERVENTIONS: (1) Standard Support, (2) Standard Support with adjunctive Medication Management provided by pharmacists via a clinical contact centre (12 sessions over 6 months), (3) Standard Support with adjunctive Medication Management plus Contingency Management that consisted of vouchers (up to £120) to reinforce participation in Medication Management. Consenting participants were randomised in a 2 : 1 : 1 ratio to one of the three groups using a stratified random permuted block method using a remote system. Participants and researchers were not blind to treatment allocation. MAIN OUTCOME MEASURES: Primary outcome: self-reported percentage of medication taken in the previous 28 days at 6 months post randomisation. Economic outcome: EuroQol-5 Dimensions, a five-level version, used to calculate quality-adjusted life-years, with costs estimated using the Adult Service Use Schedule. RESULTS: Of the 1459 potential participants approached, 1019 (70%) were assessed and 739 (73 consented to participate in the study, 372 (50%) were allocated to Standard Support, 182 (25%) to Standard Support with Medication Management and 185 (25%) to Standard Support and Medication Management with Contingency Management. Data were available for 518 (70%) of participants at 6-month follow-up, 255 (68.5%) allocated to Standard Support, 122 (67.0%) to Standard Support and Medication Management and 141 (76.2%) to Standard Support and Medication Management with Contingency Management. The mean difference of per cent adherence to acamprosate was higher for those who received Standard Support and Medication Management with Contingency Management (10.6%, 95% confidence interval 19.6% to 1.6%) compared to Standard Support alone, at the primary end point (6-month follow-up). There was no significant difference in per cent days adherent when comparing Standard Support and Medication Management with Standard Support alone 3.1% (95% confidence interval 12.8% to -6.5%) or comparing Standard Support and Medication Management with Standard Support and Medication Management with Contingency Management 7.9% (95% confidence interval 18.7% to -2.8%). The primary economic analysis at 6 months found that Standard Support and Medication Management with Contingency Management was cost-effective compared to Standard Support alone, achieving small gains in quality-adjusted life-years at a lower cost per participant. Cost-effectiveness was not observed for adjunctive Medication Management compared to Standard Support alone. There were no serious adverse events related to the trial interventions reported. LIMITATIONS: The trial's primary outcome measure changed substantially due to data collection difficulties and therefore relied on a measure of self-reported adherence. A lower than anticipated follow-up rate at 12 months may have lowered the statistical power to detect differences in the secondary analyses, although the primary analysis was not impacted. CONCLUSIONS: Medication Management enhanced with Contingency Management is beneficial to patients for supporting them to take acamprosate. FUTURE WORK: Given our findings in relation to Contingency Management enhancing Medication Management adherence, future trials should be developed to explore its effectiveness and cost-effectiveness with other alcohol interventions where there is evidence of poor adherence. TRIAL REGISTRATION: This trial is registered as ISRCTN17083622 https://doi.org/10.1186/ISRCTN17083622. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 22. See the NIHR Journals Library website for further project information

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives