Schistosomes Induce Regulatory Features in Human and Mouse CD1dhi B Cells: Inhibition of Allergic Inflammation by IL-10 and Regulatory T Cells

Chronic helminth infections, such as schistosomes, are negatively associated with allergic disorders. Here, using B cell IL-10-deficient mice, Schistosoma mansoni-mediated protection against experimental ovalbumin-induced allergic airway inflammation (AAI) was shown to be specifically dependent on IL-10-producing B cells. To study the organs involved, we transferred B cells from lungs, mesenteric lymph nodes or spleen of OVA-infected mice to recipient OVA-sensitized mice, and showed that both lung and splenic B cells reduced AAI, but only splenic B cells in an IL-10-dependent manner. Although splenic B cell protection was accompanied by elevated levels of pulmonary FoxP3+ regulatory T cells, in vivo ablation of FoxP3+ T cells only moderately restored AAI, indicating an important role for the direct suppressory effect of regulatory B cells. Splenic marginal zone CD1d+ B cells proved to be the responsible splenic B cell subset as they produced high levels of IL-10 and induced FoxP3+ T cells in vitro. Indeed, transfer of CD1d+ MZ-depleted splenic B cells from infected mice restored AAI. Markedly, we found a similarly elevated population of CD1dhi B cells in peripheral blood of Schistosoma haematobium-infected Gabonese children compared to uninfected children and these cells produced elevated levels of IL-10. Importantly, the number of IL-10-producing CD1dhi B cells was reduced after anti-schistosome treatment. This study points out that in both mice and men schistosomes have the capacity to drive the development of IL-10-producing regulatory CD1dhi B cells and furthermore, these are instrumental in reducing experimental allergic inflammation in mice

Problem Areas Reported by Substance Abusing Individuals and Their Concerned Significant Others

Substance use disorders (SUDs) have a serious impact on several life areas, including family functioning. This study examined problem areas that patients with SUDs and their family members experience in terms of quality of relations, psychological problems, physical distress, and quality of life. A sample of 32 dyadspersons with SUDs and a family memberwere recruited from a substance abuse treatment program, and completed the Maudsley Addiction Profile health symptoms section, EuroQol-5D, Relationship Happiness Scale, Dyadic Adjustment Scale, and the Dedication Scale. Family members reported that four significant others were directly affected by patients addiction-related problems, while patients reported that less than three family members were affected by their addiction. Consistently, family members indicated that they were less content with their relationship than patients and evaluated the consequences of patients SUDs as more negative and severe than the patients themselves. Furthermore, patients and their family members reported comparable levels of physical and psychological distress and quality of life scores. These systematically obtained findings support the notion that relationships of patients and family members are disrupted and both need help to improve their physical and psychological well-being. (Am J Addict 2011;21:3846

Problem areas reported by substance abusing individuals and their concerned significant others

Dvorac Opeka, smješten unutar značajnog arboretuma u mjestu Marčan u općini Vinica, sagradila je obitelj Keglević u 17. stoljeću te je isti poslužio kao dom još dvjema plemićkim obiteljima – Drašković i Bombelles – od kojih je svaka svojim graditeljskim intervencijama pridonijela konačnom izgledu dvorca kakav poznajemo danas. Svojom slojevitom stilskom građom dvorac nosi veliku arhitektonsku, povijesnu i ambijentalnu vrijednost. Pokušaji zaustavljanja propadanja, saniranja i adaptiranja devastiranog dvorca bili su višekratni, ali su redom bili neuspješni. Od 2011. godine, kad je tim Hrvatskog restauratorskog zavoda proveo temeljita istraživanja dvorca Opeka te ostalih objekata u arboretumu, radi se na obnovi. Istraživanja su pokazala da se konzervatorsko – restauratorskim zahvatima treba prezentirati najbolje sačuvani sloj građevine, a cijela znamenitost s perivojem prenamijeniti u funkciju koja bi obuhvaćala obrazovno-kulturno-gospodarsku vrijednost. Time bi projekt revitalizacije dvorca Opeka zasigurno pridonio gospodarskom rastu regije. Godine 2018. usvojen je projekt revitalizacije dvorca koji bi obuhvaćao sve navedene karakteristike. U sljedećim poglavljima dvorac Opeka smješten je u kontekst profane arhitekture 18. i 19. stoljeća u kontinentalnoj Hrvatskoj. Na kraju rada razrađen je projekt obnove dvorca iz 2018. godine. Kroz analizu projekta istaknut će se prednosti i nedostaci ovakvog pothvata s ciljem poticanja zahvata na preostalim zapuštenim dvorcima Hrvatskoga zagorja te stavljanja u primjerenu novu namjenu.Opeka Manor, located inside of a remarkable Garden in Marčan, a village of Vinica municipality, was built by the Keglević family in the 17th century and served as the home of two other noble families - Drašković and Bombelles - each of whom contributed to the final appearance of the manor as we know it today. With its layered style, the Opeka Manor has great architectural, historical and environmental value. There were many attempts to conserve and to rebuild the devastated castle, but all of them ended up unsuccessful. Ever since 2011, when the team of Croatian Restoration Institute did a complete research of the Castle and other objects inside the Garden, the creation of a plan for the restoration has been underway. The researches have shown that the aim of the restoration should be to present the most preserved layers of the Castle. Meanwhile, the entire monument, including the Garden, would be reused as a place that would include educational, cultural and economic values. The renovation project of the Opeka Manor would certainly contribute to the economic growth of the local area. In 2018, the project for the renovation of the Castle, which included all of the above characteristics, was accepted. In the following chapters, the Opeka Manor is presented in the context of the profane architecture of the 18th and 19th centuries in continental Croatia. At the end, the signed project for renovation and revitalisation of the Opeka Manor and Garden is elaborated. Through the analysis of the project, the advantages and disadvantages are highlighted with the aim of encouraging the reconstruction of the remaining abandoned castles and manors of Hrvatsko Zagorje

Problem areas reported by substance abusing individuals and their concerned significant others

Substance use disorders (SUDs) have a serious impact on several life areas, including family functioning. This study examined problem areas that patients with SUDs and their family members experience in terms of quality of relations, psychological problems, physical distress, and quality of life. A sample of 32 dyadspersons with SUDs and a family memberwere recruited from a substance abuse treatment program, and completed the Maudsley Addiction Profile health symptoms section, EuroQol-5D, Relationship Happiness Scale, Dyadic Adjustment Scale, and the Dedication Scale. Family members reported that four significant others were directly affected by patients addiction-related problems, while patients reported that less than three family members were affected by their addiction. Consistently, family members indicated that they were less content with their relationship than patients and evaluated the consequences of patients SUDs as more negative and severe than the patients themselves. Furthermore, patients and their family members reported comparable levels of physical and psychological distress and quality of life scores. These systematically obtained findings support the notion that relationships of patients and family members are disrupted and both need help to improve their physical and psychological well-being. (Am J Addict 2011;21:3846

Effects of prednisone on docetaxel pharmacokinetics in men with metastatic prostate cancer: A randomized drug-drug interaction study

Aims: Docetaxel has been approved for the treatment of metastatic prostate cancer in combination with prednisone. Since prednisone is known to induce the cytochrome P450 iso-enzyme CYP3A4, which is the main metabolizing enzyme of docetaxel in the liver, a potential drug–drug interaction may occur. In this prospective randomized pharmacokinetic cross-over study we investigated docetaxel exposure with concomitant prednisone, compared to docetaxel monotherapy in men with metastatic prostate cancer. Methods: Patients scheduled to receive at least 6 cycles of docetaxel (75 mg/m2) and who gave written informed consent were randomized to receive either the 1st 3 cycles, or the last 3 consecutive cycles with prednisone (twice daily 5 mg). Pharmacokinetic blood sampling was performed during cycle 3 and cycle 6. Primary endpoint was difference in docetaxel exposure, calculated as area under the curve (AUC0-inf) and analysed by means of a linear mixed model. Given the cross-over design the study was powered on 18 patients to answer the primary, pharmacokinetic, endpoint. Results: Eighteen evaluable patients were included in the trial. Docetaxel concentration with concomitant prednisone (AUC0-inf 2784 ng*h/mL, 95% confidence interval 2436–3183 ng*h/mL) was similar to the concentration of docetaxel monotherapy (AUC0-inf 2647 ng*h/mL, 95% confidence interval 2377–2949 ng*h/mL). Exploratory analysis showed no toxicity differences between docetaxel monotherapy and docetaxel cycles with prednisone. Conclusion: No significant difference in docetaxel concentrations was observed. In addition, we found similar toxicity profiles in absence and presence of prednisone. Therefore, from a pharmacokinetic point of view, docetaxel may be administrated with or without prednisone.</p

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified