Tumor Invasion of Salmonella enterica Serovar Typhimurium Is Accompanied by Strong Hemorrhage Promoted by TNF-α

BACKGROUND:Several facultative anaerobic bacteria with potential therapeutic abilities are known to preferentially colonize solid tumors after systemic administration. How they efficiently find and invade the tumors is still unclear. However, this is an important issue to be clarified when bacteria should be tailored for application in cancer therapy. METHODOLOGY/PRINCIPAL FINDINGS:We describe the initial events of colonization of an ectopic transplantable tumor by Salmonella enterica serovar Typhimurium. Initially, after intravenous administration, bacteria were found in blood, spleen, and liver. Low numbers were also detected in tumors associated with blood vessels as could be observed by immunohistochemistry. A rapid increase of TNF-alpha in blood was observed at that time, in addition to other pro-inflammatory cytokines. This induced a tremendous influx of blood into the tumors by vascular disruption that could be visualized in H&E stainings and quantified by hemoglobin measurements of tumor homogenate. Most likely, together with the blood, bacteria were flushed into the tumor. In addition, blood influx was followed by necrosis formation, bacterial growth, and infiltration of neutrophilic granulocytes. Depletion of TNF-alpha retarded blood influx and delayed bacterial tumor-colonization. CONCLUSION:Our findings emphasize similarities between Gram-negative tumor-colonizing bacteria and tumor vascular disrupting agents and show the involvement of TNF-alpha in the initial phase of tumor-colonization by bacteria

Women’s beliefs about medicines and adherence to pharmacotherapy in pregnancy: Opportunities for community pharmacists?

Background During pregnancy women might weigh benefits of treatment against potential risks to the unborn child. However, non-adherence to necessary treatment can adversely affect both mother and child. To optimize pregnant women’s beliefs and medication adherence, community pharmacists are ideally positioned to play an important role in primary care. Objective This narrative review aimed to summarize the evidence on 1) pregnant women’s beliefs, 2) medication adherence in pregnancy, and 3) community pharmacists’ counselling during pregnancy. Method Three search strategies were used in Medline and Embase to find original studies evaluating women’s beliefs, medication adherence and community pharmacists’ counselling during pregnancy. All original descriptive and analytic epidemiological studies performed in Europe, North America and Australia, written in English and published from 2000 onwards were included. Results We included 14 studies reporting on women’s beliefs, 11 studies on medication adherence and 9 on community pharmacists’ counselling during pregnancy. Women are more reluctant to use medicines during pregnancy and tend to overestimate the teratogenic risk of medicines. Risk perception varies with type of medicine, level of health literacy, education level and occupation. Furthermore, low medication adherence during pregnancy is common. Finally, limited evidence showed current community pharmacists’ counselling is insufficient. Barriers hindering pharmacists are insufficient knowledge and limited access to reliable information. Conclusion Concerns about medication use and non-adherence are widespread among pregnant women. Community pharmacists’ counselling during pregnancy is insufficient. Further education, training and research are required to support community pharmacists in fulfilling all the opportunities they have when counselling pregnant women

Wpływ erozji entropogenicznej na zasoby glebowej materii organicznej w winnicach Kotliny Fordońskiej

The aim of this paper has been to define the influence of accelerated erosion on basic properties and the SOM stocks of soils within vineyards located on western slopes of the Lower Vistula Valley. The study was conducted within four vineyards situated 30 km north-east from Bydgoszcz. During the field work 44 auger holes were made. On the basis of results of drilling, eight places for soil pits were selected. The study sites were characterised by considerable diversity of soil cover. The SOM stocks in studied profiles ranged from 2,98 to 63,9 kg m⁻². The upper parts of the Lower Vistula Valley slopes were dominated by Luvisols developed from glacial tills. Pedons located in toe and foot slope positions represented Chernozems and Phaeozems developed from layered fluvial sediments. The translocation of soil was caused by accelerated erosion that heightened differentiation in the primeval SOM stocks. Although, the Luvisols were truncated in result of accelerated erosion, they were not significantly depleted in organic matter stocks. Most Chernozems and Phaeozems located in toe and foot slope positions were enhanced in SOM stocks due to accumulation of humus colluvial material on their surface. The short period of existence of vineyards makes it impossible to determine the impact of grass roots decay on carbon content in surface soil horizons between rows of vine.Celem badań było określenie wpływu erozji antropogenicznej na podstawowe właściwości i zasoby materii organicznej w glebach winnic położonych na zachodnich zboczach Doliny Dolnej Wisły. Badaniami objęto cztery winnice położone 30 km na północny-wschód od Bydgoszczy. W ramach prac terenowych wykonano 44 wiercenia, na podstawie których wybrano 8 miejsc, w których wykopano odkrywki glebowe. Stanowiska badawcze odznaczały się znacznym zróżnicowaniem pokrywy glebowej. Zasoby glebowej materii organicznej w poszczególnych pedonach mieściły się w szerokim przedziale między 2,98 a 63,9 kg m⁻². W górnych odcinkach zbocza Doliny Dolnej Wisły dominowały Luvisole rozwinięte z glin lodowcowych. W dolnej części zboczy występowały gleby z dobrze rozwiniętymi poziomami próchnicznymi zaklasyfikowane jako Phaeozemy i Chernozemy. Skałami macierzystymi tych gleb były warstwowane osady wodnego pochodzenia. Erozyjne przemieszczenie materiału glebowego doprowadziło do powiększenia naturalnego zróżnicowania zasobów glebowej materii organicznej. Pomimo iż, Luvisole odznaczały się znacznym zerodowaniem, nie odnotowano w nich znacznego spadku zasobów węgla organicznego w porównaniu z analogicznymi naturalnymi glebami leśnymi. Akumulacja próchnicznych deluwiów u podnóża zboczy doprowadziła jednak do znacznego wzrostu zasobów próchnicy w większości Phaeozemów i Chernozemów. Stosunkowo krótki okres funkcjonowania winnic uniemożliwia określenie wpływu roślinności trawiastej porastającej międzyrzędzia na zawartość węgla w poziomach powierzchniowych badanych gleb

CC chemokine receptor 7 and 9 double-deficient hematopoietic progenitors are severely impaired in seeding the adult thymus.

T-cell development depends on recruitment of bone marrow-derived precursor cells to the thymus via a multistep adhesion cascade involving the chemokine receptor CCR9. However, CCR9 deficiency does not result in complete abrogation of progenitor entry into the adult thymus. Therefore, we tested the hypothesis that additional chemokine/chemokine receptor systems might play a role in this process. To this end, we generated mice deficient in both CCR9 and CCR7. Deficiency in both chemokine receptors resulted in severely reduced numbers of early T-cell progenitors and in near-complete abrogation of thymus reconstitution. Progenitors in bone marrow and peripheral blood remained largely unaffected in CCR7(-/-)CCR9(-/-) mice, and direct intrathymic transfer of precursors from CCR7(-/-)CCR9(-/-) mice as well as single-mutant mice showed that intrathymic differentiation of these precursors remained functional. Thus, our data reveal a previously unrecognized role of CCR7 in progenitor seeding of the adult thymus, which is largely masked by compensatory effects of CCR9 signals. In turn, CCR7 signals can partially compensate for CCR9 signals, thus explaining the rather mild phenotype of CCR9(-/-) mice with respect to progenitor seeding

Immunoglobulins drive terminal maturation of splenic dendritic cells

Nature and physiological status of antigen-presenting cells, such as dendritic cells DCs, are decisive for the immune reactions elicited. Multiple factors and cell interactions have been described that affect maturation of DCs. Here, we show that DCs arising in the absence of immunoglobulins (Ig) in vivo are impaired in cross-presentation of soluble antigen. This deficiency was due to aberrant cellular targeting of antigen to lysosomes and its rapid degradation. Function of DCs could be restored by transfer of Ig irrespective of antigen specificity and isotype. Modulation of cross-presentation by Ig was inhibited by coapplication of mannan and, thus, likely to be mediated by C-type lectin receptors. This unexpected dependency of splenic DCs on Ig to cross-present antigen provides insights into the interplay between cellular and humoral immunity and the immunomodulatory capacity of I

Mammalian VPS45 orchestrates trafficking through the endosomal system.

Vacuolar protein sorting 45 homolog (VPS45), a member of the Sec1/Munc18 (SM) family, has been implicated in the regulation of endosomal trafficking. VPS45 deficiency in human patients results in congenital neutropenia, bone marrow fibrosis, and extramedullary renal hematopoiesis. Detailed mechanisms of the VPS45 function are unknown. Here, we show an essential role of mammalian VPS45 in maintaining the intracellular organization of endolysosomal vesicles and promoting recycling of cell-surface receptors. Loss of VPS45 causes defective Rab5-to-Rab7 conversion resulting in trapping of cargos in early endosomes and impaired delivery to lysosomes. In this context, we demonstrate aberrant trafficking of the G-CSF receptor (G-CSFR) in the absence of VPS45. Furthermore, we find that lack of VPS45 in mice is not compatible with embryonic development. Thus, we identify mammalian VPS45 as a critical regulator of trafficking through the endosomal system and early embryogenesis of mice

Konvolúciós hálózat fejlesztése online játékokhoz

T-cell receptor (TCR) signal strength determines selection and lineage fate at the CD4(+)CD8(+) double-positive stage of intrathymic T-cell development. Members of the miR-181 family constitute the most abundantly expressed microRNA at this stage of T-cell development. Here we show that deletion of miR-181a/b-1 reduced the responsiveness of double-positive thymocytes to TCR signals and virtually abrogated early invariant natural killer T (iNKT) cell development, resulting in a dramatic reduction in iNKT cell numbers in thymus as well as in the periphery. Increased concentrations of agonist ligand rescued iNKT cell development in miR-181a/b-1(-/-) mice. Our results define a critical role of miR-181a/b-1 in early iNKT cell development and show that miR-181a/b-1 sets a TCR signaling threshold for agonist selection