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71.
Elderly, psychiatric patients admitted to a long-stay ward become physically ill and die. Which care can be offered on the ward and which cases require transferring a patient to specialized psychiatric-medical wards or a hospice? We studied 40 cases of death by malignancy in a clinic for elderly, long-term admitted psychiatric patients. Transferring the patient to such a ward was never indicated. Our population appeared to have a lack of awareness of their illness and expressed very few physical complaints. The possibilities of curative treatment of the malignancy were limited; the emphasis of the treatment was on palliative care. Because of the intensive support given on the patients ward the patients were able to die in peace. Deep sedation was never required. 相似文献
72.
de Gouw D Diavatopoulos DA Bootsma HJ Hermans PW Mooi FR 《FEMS microbiology reviews》2011,35(3):441-474
Pertussis, or whooping cough, is a highly contagious, acute respiratory disease of humans that is caused by the Gram-negative bacterial pathogen Bordetella pertussis. In the face of extensive global vaccination, this extremely monomorphic pathogen has persisted and re-emerged, causing approximately 300,000 deaths each year. In this review, we discuss the interaction of B. pertussis with the host mucosal epithelium and immune system. Using a large number of virulence factors, B. pertussis is able to create a niche for colonization in the human respiratory tract. The successful persistence of this pathogen is mainly due to its ability to interfere with almost every aspect of the immune system, from the inhibition of complement- and phagocyte-mediated killing to the suppression of T- and B-cell responses. Based on these insights, we delineate ideas for the rational design of improved vaccines that can target the 'weak spots' in the pathogenesis of this highly successful pathogen. 相似文献
73.
Fredrick M Mobegi Sacha AFT van Hijum Peter Burghout Hester J Bootsma Stefan PW de Vries Christa E van der Gaast-de Jongh Elles Simonetti Jeroen D Langereis Peter WM Hermans Marien I de Jonge Aldert Zomer 《BMC genomics》2014,15(1)
Background
Bacterial respiratory tract infections, mainly caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are among the leading causes of global mortality and morbidity. Increased resistance of these pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials.Result
Here, we report a proof of concept study for the reliable identification of potential drug targets in these human respiratory pathogens by combining high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics. Approximately 20% of all genes in these three species were essential for growth and viability, including 128 essential and conserved genes, part of 47 metabolic pathways. By comparing these essential genes to the human genome, and a database of genes from commensal human gut microbiota, we identified and excluded potential drug targets in respiratory tract pathogens that will have off-target effects in the host, or disrupt the natural host microbiota. We propose 249 potential drug targets, 67 of which are targets for 75 FDA-approved antimicrobials and 35 other researched small molecule inhibitors. Two out of four selected novel targets were experimentally validated, proofing the concept.Conclusion
Here we have pioneered an attempt in systematically combining the power of high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics to discover potential drug targets at genome-scale. By circumventing the time-consuming and expensive laboratory screens traditionally used to select potential drug targets, our approach provides an attractive alternative that could accelerate the much needed discovery of novel antimicrobials.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-958) contains supplementary material, which is available to authorized users. 相似文献74.
RhoA exerts a permissive effect on volume-regulated anion channels in vascular endothelial cells 总被引:2,自引:0,他引:2
Carton I Trouet D Hermans D Barth H Aktories K Droogmans G Jorgensen NK Hoffmann EK Nilius B Eggermont J 《American journal of physiology. Cell physiology》2002,283(1):C115-C125
Cell swelling triggers in most cell typesan outwardly rectifying anion current,ICl,swell, via volume-regulated anion channels (VRACs). We have previously demonstrated in calf pulmonary artery endothelial (CPAE) cells that inhibition of the Rho/Rho kinase/myosin light chain phosphorylation pathway reduces the swelling-dependent activation of ICl,swell. However, theseexperiments did not allow us to discriminate between a direct activatorrole or a permissive effect. We now show that the Rho pathway did notaffect VRAC activity if this pathway was activated by transfecting CPAEcells with constitutively active isoforms of G (a Rho activatingheterotrimeric G protein subunit), Rho, or Rho kinase. Furthermore,biochemical and morphological analysis failed to demonstrate activationof the Rho pathway during hypotonic cell swelling. Finally,manipulating the Rho pathway with either guanosine5'-O-(3-thiotriphosphate) or C3 exoenzyme had no effect onVRACs in caveolin-1-expressing Caco-2 cells. We conclude that the Rhopathway exerts a permissive effect on VRACs in CPAE cells, i.e.,swelling-induced opening of VRACs requires a functional Rho pathway,but not an activation of the Rho pathway. 相似文献
75.
Alex F. de Vos Mark C. Dessing Adriana J. J. Lammers Alexander P. N. A. de Porto Sandrine Florquin Onno J. de Boer Regina de Beer Sanne Terpstra Hester J. Bootsma Peter W. Hermans Cornelis van ‘t Veer Tom van der Poll 《PloS one》2015,10(2)
Toll-like receptors (TLR) and the downstream adaptor protein MyD88 are considered crucial for protective immunity during bacterial infections. Streptococcus (S.) pneumoniae is a human respiratory pathogen and a large majority of clinical pneumococcal isolates expresses an external polysaccharide capsule. We here sought to determine the role of pneumococcal capsule in MyD88-mediated antibacterial defense during S. pneumonia pneumonia. Wild type (WT) and Myd88-/- mice were inoculated intranasally with serotype 2 S. pneumoniae D39 or with an isogenic capsule locus deletion mutant (D39∆cps), and analysed for bacterial outgrowth and inflammatory responses in the lung. As compared to WT mice, Myd88-/- mice infected with D39 demonstrated a modestly impaired bacterial clearance accompanied by decreased inflammatory responses in the lung. Strikingly, while WT mice rapidly cleared D39∆cps, Myd88-/- mice showed 105-fold higher bacterial burdens in their lungs and dissemination to blood 24 hours after infection. These data suggest that the pneumococcal capsule impairs recognition of TLR ligands expressed by S. pneumoniae and thereby partially impedes MyD88-mediated antibacterial defense. 相似文献
76.
Techniques for genetic engineering in mycobacteria 总被引:3,自引:0,他引:3
The study of mycobacterial genetics has experienced quick technical developments in the past ten years, despite a relatively slow start, caused by difficulties in accessing these recalcitrant species. The study of mycobacterial pathogenesis is important in the development of new ways of treating tuberculosis and leprosy, now that the emergence of antibiotic-resistant strains has reduced the effectiveness of current therapies. The tuberculosis vaccine strain M. bovis BCG might be used as a vector for multivalent vaccination. Also, non-pathogenic mycobacterial strains have many possible biotechnological applications. After giving a historical overview of methods and techniques, we will discuss recent developments in the search for alternative host strains and DNA transfer systems. Special attention will be given to the development of vectors and techniques for stabilizing foreign DNA in mycobacteria. 相似文献
77.
Rutger L. van Bezooijen H. Goey Gerrit Stoter J. Hermans G. J. Fleuren 《Cancer immunology, immunotherapy : CII》1997,43(5):293-298
Interleukin-2 (IL-2)-based immunotherapy can induce antitumor responses in about 25% of patients with metastatic renal cell
carcinoma (RCC). The limited effect and the severe side-effects of IL-2 have led us to perform a prognostic factor analysis.
Twenty-four patients with metastatic RCC were treated with IL-2. Flow cytometry and immunohistology were used to determine
DNA ploidy, HLA-II expression on tumor cells, and the presence of macrophages in the primary tumor. These variables were examined
in relation to survival. The 4-year overall survival rate was 38%. Forty-six percent of the primary tumors were aneuploid.
All tumors, except one, showed HLA-II expression and macrophage presence. A statistically significant correlation (r = 0.66, P = 0.002) was found between HLA-II expression and macrophage presence. Patients with high HLA-II expression had a lower 4-year
survival (22% compared to 50%), as had patients with high macrophage presence (20% compared to 42%). Of note, patients characterized
by both high HLA-II and high macrophage expression had the worst survival (13% compared to 50%). We concluded that DNA ploidy
was not predictive for survival, whereas HLA-II expression and macrophage presence may represent valuable prognostic factors
related to survival. The present data suggest that more of the patients with no or moderate HLA-II expression and/or no or
moderate macrophage presence in the primary tumor could survive with persistance of their malignant disease after having received
IL-2 immunotherapy, as compared to patients with both high HLA-II and high macrophage expression.
Received: 2 April 1996 / Accepted: 15 October 1996 相似文献
78.
J. J. A. van Bruggen K. B. Zwart J. G. F. Hermans E. M. van Hove C. K. Stumm G. D. Vogels 《Archives of microbiology》1986,144(4):367-374
Epifluorescence microscopy revealed the presence of a methanogenic bacterium as an endosymbiont in the sapropelic marine ciliate Metopus contortus. The in situ methanogenic activity of the symbiont could be demonstrated. The isolated endosymbiont was an irregular, disc-shaped bacterium with a diameter of 1.6–3.4 m. It had a generation time of 7 or 12 hours on growth on H2/CO2 or formate, respectively. The temperature range for growth was between 16 and 36°C with an optimum at 32°C. The optimal pH range for growth was 6.8 to 7.3. Salts, with an optimum concentration of 0.25 M, and tungsten were required for growth. The mol% G+C was 38.7%. The cell envelope consisted of proteins and a glycoprotein with an apparent molecular weight of 110,000. Morphology, antigenic relationship and the G+C content established the isolate MC1 as a new species of the genus Methanoplanus, and the name Methanoplanus endosymbiosus is proposed.Abbreviations G+C
Guanine+cytosine
- SDS
sodium dodecylsulfate
- PIPES
piperazine-N,N-bis (2-ethane) sulfonic acid 相似文献
79.
Replacement of extracellular Cl- by isethionate or sulfate during stimulation with glucose or tolbutamide reversibly inhibited insulin release by perifused mouse islets. The concentration of ionized Ca2+ was decreased by 30 and 55% in isethionate and sulfate solutions, respectively. If this fall was prevented, the inhibition of release was only slightly affected (isethionate) or substantially attenuated (sulfate). In conclusion, the inhibition of insulin release occurring in Cl(-)-free solutions cannot be completely ascribed to a decrease in ionized Ca2+ in the medium. The contribution of this latter depends on the Cl- substitute. 相似文献
80.