Flynnweeks1352

Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces cytochrome (CYP) 2B6 and possibly CYP3A4. So far, it is unknown whether metamizole induces additional CYPs and by which mechanism. Therefore, we assessed the activity of 6 different CYPs in 12 healthy male subjects before and after treatment with 3 g of metamizole per day for 1 week using a phenotyping cocktail approach. In addition, we investigated whether metamizole induces CYPs by an interaction with the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR) in HepaRG cells. In the clinical study, we confirmed a moderate induction of CYP2B6 (decrease in the efavirenz area under the plasma concentration time curve (AUC) by 79%) and 3A4 (decrease in the midazolam AUC by 68%) by metamizole. SGD-1010 In addition, metamizole weakly induced CYP2C9 (decrease in the flurbiprofen AUC by 22%) and moderately CYP2C19 (decrease in the omeprazole AUC by 66%) but did not alter CYP2D6 activity. In addition, metamizole weakly inhibited CYP1A2 activity (1.79-fold increase in the caffeine AUC). We confirmed these results in HepaRG cells, where 4-MAA, the principal metabolite of metamizole, induced the mRNA expression of CYP2B6, 2C9, 2C19, and 3A4. In HepaRG cells with a stable knockout of PXR or CAR, we could demonstrate that CYP induction by 4-MAA depends on CAR and not on PXR. In conclusion, metamizole is a broad CYP inducer by an interaction with CAR and an inhibitor of CYP1A2. link2 Regarding the widespread use of metamizole, these findings are of substantial clinical relevance.

Bumetanide, a diuretic agent, that reduces intracellular chloride-thereby reinforcing GABAergic inhibition-has been reported to improve core symptoms of autism in children. Given the positive results reported from French trials of bumetanide in children with autism, we decided to evaluate its effects in a small-scale pilot study, in advance of a larger randomised controlled study (RCT).

This was an open-label three-month trial of bumetanide on six children (five boys), aged 3-14years with autism. Ratings according to the Parental Satisfaction Survey (PASS) were used after four and twelve weeks to assess symptom change. Blood electrolyte status was monitored.

Improvement in the PASS domain "Communicative and cognitive abilities" was marked or very marked in four children, and two had some improvements. Few negative side effects were reported.

Our small cohort responded well to bumetanide, particularly with regard to "Communicative and cognitive abilities". Taken with the evidence from larger-scale RCTs, we suggest that bumetanide should be considered for inclusion in ethically approved treatment/management trials for children with autism, subject to rigorous follow-up in large-scale RCTs.

Our small cohort responded well to bumetanide, particularly with regard to "Communicative and cognitive abilities". Taken with the evidence from larger-scale RCTs, we suggest that bumetanide should be considered for inclusion in ethically approved treatment/management trials for children with autism, subject to rigorous follow-up in large-scale RCTs.To improve our understanding of underlying toxic mechanisms, it is important to evaluate differences in effects that a variety of metals exert at concentrations representing the same toxic level to the organism. Therefore, the main goal of the present study was to compare the effects of waterborne copper (Cu(II)), zinc (Zn(II)) and cadmium (Cd (II)) on a freshwater fish, the common carp (Cyprinus carpio), at concentrations being 0%, 25%, 50% and 100% of the 96 h LC50 (the concentration which is lethal to 50% of the population in 96 h). All the exposures were performed for a period of 1 week at 20°C. Our results show a rapid increase in the amount of copper and cadmium accumulated in the gills, while zinc only started to increase by the end of the experiment. All three metal ions increased metallothionein gene expression in both gills and liver. However, clear adverse effects were mainly observed for the Cu exposed group. Cu caused a decrease in Na level in gill tissue; it altered the expression of genes involved in ionoregulation such as Na+ /K+ -ATPase and H+ -ATPase as well as the expression of oxidative stress-related genes, such as catalase, glutathione reductase and glutathione S-transferase. Zinc and cadmium exposure did not alter the ion levels in the gills. In addition, no obvious effect of oxidative stress was observed, except for a transient increase in glutathione reductase at the highest cadmium concentration.

To develop a high-resolution three-dimensional (3D) magnetic resonance imaging (MRI)-based treatment planning approach for uveal melanomas (UM) in proton therapy.

For eight patients with UM, a segmentation of the gross tumor volume (GTV) and organs-at-risk (OARs) was performed on T1- and T2-weighted 7 Tesla MRI image data to reconstruct the patient MR-eye. An extended contour was defined with a 2.5-mm isotropic margin derived from the GTV. A broad beam algorithm, which we have called πDose, was implemented to calculate relative proton absorbed doses to the ipsilateral OARs. Clinically favorable gazing angles of the treated eye were assessed by calculating a global weighted-sum objective function, which set penalties for OARs and extreme gazing angles. An optimizer, which we have named OPT'im-Eye-Tool, was developed to tune the parameters of the functions for sparing critical-OARs.

In total, 441 gazing angles were simulated for every patient. Target coverage including margins was achieved in all the caseeloped. Further validation of the whole treatment process is the next step in the goal to achieve both a non-invasive and a personalized proton therapy treatment.

The feasibility and suitability of a 3D MRI-based treatment planning approach have been successfully tested on a cohort of eight patients diagnosed with UM. Moreover, a gaze-angle trade-off dose optimization with respect to OARs sparing has been developed. Further validation of the whole treatment process is the next step in the goal to achieve both a non-invasive and a personalized proton therapy treatment.Predicted heart mass (PHM) equations have been proposed as an alternative method for size matching in heart transplantation. We assessed association between donor-recipient size mismatch, defined using PHM equations, and survival post-heart transplant in the United Kingdom. Data from all adult patients who received a heart transplant between 1995 and 2017 were obtained from the United Kingdom Transplant Registry. PHM was calculated using published equations. Primary outcome was 1-year survival post-heart transplantation. Recipients of undersized organs had reduced 1-year survival (HR 1.31, 95% CI 1.03-1.67, p = .03). Oversizing had no impact on survival (HR 0.99, 95% CI 0.78-1.26, p = .96). Gender mismatching had no impact on survival in the cohort matched by PHM (HR 1.12, 95% CI 0.86-1.47, p = .4). In recipients without pulmonary hypertension, undersizing by PHM had no impact on 1-year survival (HR 0.95, 95% CI 0.61-1.49, p = .83). In recipients with pulmonary hypertension, oversizing donor RV by using PHM RV equation (PHMRV ) results in improved survival at 1 year (HR 0.65, 95% CI 0.5-0.83, p = .001). In conclusion, receiving an organ undersized by PHM was associated with decreased 1-year survival. Subgroup analyses demonstrated that undersizing only impacted survival in recipients with pulmonary hypertension and that these recipients had improved outcomes if they received an organ with an RV oversized by >10% by PHMRV .Currently, there has been a surge of interest in revealing the interactions between plasma and food matrices. In this study, we investigated the impacts of atmospheric cold plasma (ACP) treatment on the structural, physicochemical and allergenic characteristics of soybean protein isolate (SPI). SPI dispersions were subjected to ACP treatments at different frequencies (80 to 100 Hz) and durations (1 to 10 min) to investigate the effects of exposing conditions. Results showed that ACP induced reactive oxygen species-mediated oxidation of soy proteins, resulting in modifications in the secondary and ternary structures of SPI. As a consequence, functional properties of SPI, such as emulsifying (56 to 168%, compared with control) and foaming properties (60 to 194%) were influenced by varying degrees. In addition, under certain circumstance (120 Hz, 5 min), the IgE-binding level of SPI was decreased by up to 75%, when compared to the control. Moderate treatment yielded products with improved functionality and reduced allergenicity, while extensive exposure induced a loss of vendibility due to protein aggregation. PRACTICAL APPLICATION In this study, we demonstrated for the first time, that plasma species reacted with soybean proteins, resulting in spatial structural changes which are closely related with protein functionality and allergenicity. ACP interacts with macromolecules in aqueous systems and thus can be an alternative and promising nonthermal approach in modifying soybean proteins, whereas the exact role of different processing parameters needs to be well-elaborated.

Cutaneous ulcers of Behçet disease (BD) are rare but have high morbidity and resistance to conventional therapies. An important and essential aspect of ulcer management is debridement. Regarding maggot therapy (MT), excretions of the green bottle fly, Lucilia sericata, have been shown to have the ability to remove necrotic debris and promote healing.

To evaluate the efficacy of MT for cutaneous ulcers of BD.

In this open-label trial, patients with BD with refractory leg ulcers suitable for MT were enrolled. Maggot application was performed until complete debridement was achieved, and all patients were followed up for 12months afterwards to assess the total healing of ulcers.

In total, 24 patients with 32 ulcers were enrolled. Using MT, 91.6% of all ulcers were completely debrided. Mean time to debridement was 14.9days and mean number of cycles required was 5.3. Mean ulcer size was decreased by 23% with treatment. Time to debridement was positively correlated with pretreatment ulcer size and ulcer duration (P=0.01 and P<0.01) but not with ulcer depth, comorbidities, smoking, age or sex (P>0.05 for all). During follow-up, 79.1% of all ulcers healed completely. Mean time required for total healing was positively correlated with ulcer duration, pretreatment and post-treatment ulcer area, ulcer depth and mean time to total debridement (P<0.03, P=0.00, P=0.04 and P<0.01, respectively).

To our knowledge, the findings presented in this first and unique study may provide key answers about factors affecting success rate of MT in BD cutaneous ulcers.

To our knowledge, the findings presented in this first and unique study may provide key answers about factors affecting success rate of MT in BD cutaneous ulcers.Lampreys are extant members of the agnathan (jawless) vertebrates that diverged ~500 million years ago, during a critical stage of vertebrate evolution when image-forming eyes first emerged. Among lamprey species assessed thus far, the retina of the southern hemisphere pouched lamprey, Geotria australis, is unique, in that it possesses morphologically distinct photoreceptors and expresses five visual photopigments. This study focused on determining the number of different photoreceptors present in the retina of G. australis and whether each cell type expresses a single opsin class. Five photoreceptor subtypes were identified based on ultrastructure and differential expression of one of each of the five different visual opsin classes (lws, sws1, sws2, rh1, and rh2) known to be expressed in the retina. link3 This suggests, therefore, that the retina of G. australis possesses five spectrally and morphologically distinct photoreceptors, with the potential for complex color vision. Each photoreceptor subtype was shown to have a specific spatial distribution in the retina, which is potentially associated with changes in spectral radiance across different lines of sight.