Determinants of oral bioavailability of soil-borne contaminants

Children ingest soil, either accidentally via hand-to-mouth behavior or deliberately. In this manner, a child ingests on average between 50 and 200 mg soil/day, although amounts of as much as 60 g/day have also been observed. Hence, soil ingestion can be a main route of exposure to soil-borne contaminants to children. To estimate the health risk associated to this exposure route, and to assess intervention values for contaminants in soils, one needs to know the oral bioavailability of the soil-borne contaminant. The objective of this thesis was to gain insight into the determinants of oral bioavailability of soil-borne polychlorinated biphenyls (PCBs), lindane and lead. Oral bioavailability of soil-borne contaminants is defined as the contaminant fraction that reaches the systemic circulation. Before a soil-borne contaminant becomes bioavailable it has to go through four steps: 1) soil ingestion, 2) mobilization from soil during digestion, i.e. bioaccessibility, 3) intestinal absorption of the bioaccessible contaminant, and 4) first-pass effect. In the present thesis, mobilization from soil, distribution among different physicochemical contaminant forms in small intestinal fluid, i.e. chyme, and intestinal absorption, have been studied. To that end, we employed a physiologically based in vitro digestion model that mimicked the gastro-intestinal digestion. In vitro differentiated intestinal cells were employed to similate intestinal absorption. After ingestion of soil-borne PCBs, lindane and lead, the freely dissolved concentration in chyme can assumed to be small. The freely dissolved fraction is the contaminant fraction that is at least available for intestinal absorption. Expected main fractions for the hydrophobic organic compounds (HOCs) are PCBs and lindane sorbed to bile salt micelles, digestive proteins and soil, whereas lead phosphate, lead bile and lead soil complexes are main fractions for lead. The distribution of the presently used HOCs among sorbing constituents in chyme was based on partitioning. The in vitro experiments indicate that not all ingested and soil-borne PCBs, lindane and lead are mobilized from soil during digestion, i.e. become bioaccessible, and therefore do not reach the systemic circulation and become bioavailable. Furthermore, not all bioaccessible lead is expected to be absorbed, causing a further reduction of the lead fraction that becomes bioavailable relative to the ingested amount. Nevertheless, a considerable fraction of the contaminants (several tens of %) appears to be able to become bioavailable, stressing the importance of exposure to contaminants via soil ingestion. Physicochemical conditions in the gastro-intestinal tract are expected to affect the bioaccessibility and thereby the oral bioavailability of the soil-borne contaminants. The physiological worst case situation for the PCBs and lindane is most likely the fed state, since that results in high concentrations of sorbing constituents in the gastro-intestinal tract. The worst case situation for lead is most likely the fasted state so that the gastric pH is low, inducing a high mobilization from soil. The PCBs, lindane and lead have in common that more than the freely dissolved fraction is transported across the intestinal membrane. The freely dissolved concentration can be considered the driving force for the contaminant flux towards the intestinal cells, while the labile contaminants represent the pool of contaminants that may dissociate and contribute to the flux and thus to oral bioavailability. Chemical sampling techniques such as Solid Phase Microextraction (SPME) and voltammetric techniques offer possibilities to investigate mass transfer of contaminants in a complex medium towards biological phases like Caco-2 cells

HTS pulse-stretcher and second order modulator: design and first results

One of the remaining challenges in the application of superconducting electronics is the interfacing between superconducting and semiconducting environments. The voltage and speed mismatch between RSFQ pulses and semiconducting read-out electronics makes it necessary to amplify as well as stretch the RSFQ pulses. Moreover, circuits based on HTS (High Temperature Superconductor) technology are very attractive since they can operate under considerably relaxed cooling effort, which is one of the main problems with LTS (Low Temperature Superconductor) circuits. Within the European project SuperADC, a HTS second order sigma delta modulator and a pulse stretcher, used as an interface between the modulator and the first semi-conducting amplifier stage, have been designed at Twente University and will be presented here

Blood clearance and tissue distribution of PEGylated and non-PEGylated gold nanorods after intravenous administration in rats\ud

Aims: To develop and determine the safety of gold nanorods, whose aspect ratios can be tuned to obtain plasmon peaks between 650 and 850 nm, as contrast enhancing agents for diagnostic and therapeutic applications. Materials & methods: In this study we compared the blood clearance and tissue distribution of cetyl trimethyl ammonium bromide (CTAB)-capped and polyethylene glycol (PEG)-coated gold nanorods after intravenous injection in the tail vein of rats. The gold content in blood and various organs was measured quantitatively with inductively coupled plasma mass spectrometry. Results & discussion: The CTAB-capped gold nanorods were almost immediately (<15 min) cleared from the blood circulation whereas the PEGylation of gold nanorods resulted in a prolonged blood circulation with a half-life time of 19 h and more wide spread tissue distribution. While for the CTAB-capped gold nanorods the tissue distribution was limited to liver, spleen and lung, the PEGylated gold nanorods also distributed to kidney, heart, thymus, brain and testes. PEGylation of the gold nanorods resulted in the spleen being the organ with the highest exposure, whereas for the non-PEGylated CTAB-capped gold nanorods the liver was the organ with the highest exposure, per gram of organ. Conclusion: The PEGylation of gold nanorods resulted in a prolongation of the blood clearance and the highest organ exposure in the spleen. In view of the time frame (up to 48 h) of the observed presence in blood circulation, PEGylated gold nanorods can be considered to be promising candidates for therapeutic and diagnostic imaging purpose

A review of trials investigating ctDNA-guided adjuvant treatment of solid tumors:The importance of trial design

Circulating tumor DNA (ctDNA) holds promise as a biomarker for guiding adjuvant treatment decisions in solid tumors. This review systematically assembles ongoing and published trials investigating ctDNA-directed adjuvant treatment strategies. A total of 57 phase II/III trials focusing on ctDNA in minimal residual disease (MRD) detection were identified, with a notable increase in initiation over recent years. Most trials target stage II or III colon/colorectal cancer, followed by breast cancer and non-small cell lung cancer. Trial methodologies vary, with some randomizing ctDNA-positive patients between standard-of-care (SoC) treatment and intensified regimens, while others aim to de-escalate therapy in ctDNA-negative patients. Challenges in trial design include the need for randomized controlled trials to establish clinical utility for ctDNA, ensuring adherence to standard treatment in control arms, and addressing the ethical dilemma of withholding treatment in high-risk ctDNA-positive patients. Longitudinal ctDNA surveillance emerges as a strategy to improve sensitivity for recurrence, particularly in less proliferative tumor types. However, ctDNA as longitudinal marker is often not validated yet. Ultimately, designing effective ctDNA interventional trials requires careful consideration of feasibility, meaningful outcomes, and potential impact on patient care.</p

Structure and the Physico-Mechanical Properties of the Ceramic Coatings Obtained by the Cumulative -Detonation Device

Dense, with good adhesion to the substrate, hard, wear-resistant coatings from the powder of Al2O3 were obtained on the surface of the steel (STE255) by using the cumulative-detonation device. The results of investigations of the structure and physico-mechanical properties of the coatings by using scanning, optical microscopy, X-ray phase analysis, microhardness and tribological tests are presented. It was found that optimization of plasma spraying to helps reduce the porosity of coatings of Al2O3 less than 1 % and to increase the hardness of them to 1250 HV0.3. The tribological investigations have shown that the coatings of Al2O3 significantly increase the wear resistance of the sample STE255 and provide a low ability to wear out the coating. When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/3546

Concern-Driven Integrated Toxicity Testing Strategies for Nanomaterials - Report of the NanoSafety Cluster Working Group 10

Bringing together topic-related European Union-(EU)-funded projects, the so-called “NanoSafety Cluster” aims at identifying key areas for further research on risk assessment procedures for nanomaterials (NM). The outcome of NanoSafety Cluster Working Group 10, this commentary presents a vision for concern-driven integrated approaches for the (eco-)toxicological testing and assessment (IATA) of NM. Such approaches should start out by determining concerns, i.e. specific information needs for a given NM based on realistic exposure scenarios. Recognized concerns can be addressed in a set of tiers using standardized protocols for NM preparation and testing. Tier 1 includes determining physico-chemical properties, non-testing (e.g. structure activity relationships) and evaluating existing data. In tier 2, a limited set of in vitro and in vivo tests are performed that can either indicate that the risk of the specific concern is sufficiently known or indicate the need for further testing, including details for such testing. Ecotoxicological testing begins with representative test organisms followed by complex test systems. After each tier, it is evaluated whether the information gained permits assessing the safety of the NM so that further testing can be waived. By effectively exploiting all available information, IATA allow accelerating the risk assessment process and reducing testing costs and animal use (in line with the 3Rs principle implemented in EU Directive 2010/63/EU). Combining material properties, exposure, biokinetics, and hazard data, information gained with IATA can be used to recognize groups of NM based upon similar modes-of-action. Grouping of substances in return should form integral part of the IATA themselves

The added value of H-2 antagonists in premedication regimens during paclitaxel treatment

BACKGROUND: Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine. METHODS: This prospective, pre-post interventional, non-inferiority study compared the standard premedication regimen (N = 183) with dexamethasone, clemastine and ranitidine with a premedication regimen without ranitidine (N = 183). The primary outcome was the incidence of HSR grade >= 3. Non-inferiority was determined by checking whether the upper bound of the twosided 90% confidence interval (CI) for the difference in HSR rates excluded the +6% non-inferiority margin. RESULTS: In both the pre-intervention (with ranitidine) and post-intervention (without ranitidine) group 183 patients were included. The incidence of HSR grade >= 3 was 4.4% (N = 8) in the pre-intervention group and 1.6% (N = 3) in the post-intervention group: difference -2.7% (90% CI: -6.2 to 0.1). CONCLUSIONS: As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine

Scopolaminebutyl given prophylactically for death rattle: Study protocol of a randomized double-blind placebo-controlled trial in a frail patient population (the SILENCE study)

Background: Death rattle (DR), caused by mucus in the respiratory tract, occurs in about half of patients who are in the dying phase. Relatives often experience DR as distressing. Anticholinergics are recommended to treat DR, although there is no evidence for the effect of these drugs. Anticholinergic drugs decrease the production of mucus but do not affect existing mucus. We therefore hypothesize that these drugs are more effective when given prophylactically. Methods: We set up a randomized double-blind, placebo-controlled, multi-center study evaluating the efficacy of prophylactically given subcutaneous scopolaminebutyl for the prevention of DR in the dying phase. The primary outcome is the occurrence of DR defined as grade ≥ 2 according to the scale of Back measured by a nurse at 2 consecutive time points with an interval of 4 h. Secondary outcomes include adverse effects, quality of dying, quality of life in the last three days and bereavement. A sub-study will explore the experience of participating in a clinical trial in the dying phase from the perspective of relatives. Four hospices will include 200 patients. Discussion: This is the first double-blind placebo-controlled study to prevent DR in patients in the hospice setting. Research in dying patients is challenging. We will apply ethical and organizational strategies as suggested in the literature

The interplay between tamoxifen and endoxifen plasma concentrations and coagulation parameters in patients with primary breast cancer

Background: Tamoxifen is an effective treatment for primary breast cancer but increases the risk for venous thromboembolism. Tamoxifen decreases anticoagulant proteins, including antithrombin (AT), protein C (PC) and tissue factor (TF) pathway inhibitor, and enhances thrombin generation (TG). However, the relation between plasma concentrations of both tamoxifen and its active metabolite endoxifen and coagulation remains unknown. Methods: Tamoxifen and endoxifen were measured in 141 patients from the prospective open-label intervention TOTAM-study after 3 months (m) and 6 m of tamoxifen treatment. Levels of AT and PC, the procoagulant TF, and TG parameters were determined at both timepoints if samples were available (n = 53–135 per analysis). Levels of coagulation proteins and TG parameters were correlated and compared between: 1) quartiles of tamoxifen and endoxifen levels, and 2) 3 m and 6 m of treatment. Results: At 3 m, levels of AT, PC, TF and TG parameters were not associated with tamoxifen nor endoxifen levels. At 6 m, median TF levels were lower in patients in the 3rd (56.6 [33] pg/mL), and 4th (50.1 [19] pg/mL) endoxifen quartiles compared to the 1st (lowest) quartile (76 [69] pg/mL) (P=0.027 and P=0.018, respectively), but no differences in anticoagulant proteins or TG parameters were observed. An increase in circulating TF levels (3 m: 46.0 [15] versus 6 m: 54.4 [39] pg/mL, P &lt; 0.001) and TG parameters was observed at the 6 m treatment timepoint, while AT and PC levels remained stable.Conclusions: Our results indicate that higher tamoxifen and endoxifen levels are not correlated with an increased procoagulant state, suggesting tamoxifen dose escalation does not further promote hypercoagulability.</p