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Reuter, Kerstin C. ; Loitsch, Stefan Marcel ; Dignaß, Axel Uwe ; Steinhilber, Dieter ; Stein, Jürgen
Introduction: Despite the excellent anti-inflammatory and immunosuppressive action of glucocorticoids (GCs), their use for the treatment of inflammatory bowel disease (IBD) still carries significant risks in terms of frequently occurring severe side effects, such as the impairment of intestinal tissue repair. The recently-introduced selective glucocorticoid receptor (GR) agonists (SEGRAs) offer anti-inflammatory action comparable to that of common GCs, but with a reduced side effect profile.
Methods: The in vitro effects of the non-steroidal SEGRAs Compound A (CpdA) and ZK216348, were investigated in intestinal epithelial cells and compared to those of Dexamethasone (Dex). GR translocation was shown by immunfluorescence and Western blot analysis. Trans-repressive effects were studied by means of NF-κB/p65 activity and IL-8 levels, trans-activation potency by reporter gene assay. Flow cytometry was used to assess apoptosis of cells exposed to SEGRAs. The effects on IEC-6 and HaCaT cell restitution were determined using an in vitro wound healing model, cell proliferation by BrdU assay. In addition, influences on the TGF-β- or EGF/ERK1/2/MAPK-pathway were evaluated by reporter gene assay, Western blot and qPCR analysis.
Results: Dex, CpdA and ZK216348 were found to be functional GR agonists. In terms of trans-repression, CpdA and ZK216348 effectively inhibited NF-κB activity and IL-8 secretion, but showed less trans-activation potency. Furthermore, unlike SEGRAs, Dex caused a dose-dependent inhibition of cell restitution with no effect on cell proliferation. These differences in epithelial restitution were TGF-β-independent but Dex inhibited the EGF/ERK1/2/MAPK-pathway important for intestinal epithelial wound healing by induction of MKP-1 and Annexin-1 which was not affected by CpdA or ZK216348.
Conclusion: Collectively, our results indicate that, while their anti-inflammatory activity is comparable to Dex, SEGRAs show fewer side effects with respect to wound healing. The fact that SEGRAs did not have a similar effect on cell restitution might be due to a different modulation of EGF/ERK1/2 MAPK signalling.
Foocharoen, Chingching ; Tyndall, Alan ; Hachulla, Eric ; Rosato, Edoardo ; Allanore, Yannick ; Farge-Bancel, Dominique ; Caramaschi, Paola ; Airó, Paolo ; Nikolaevna, Starovojtova M. ; Pereira da Silva, José A. ; Stamenkovic, Bojana ; Riemekasten, Gabriela ; Rednic, Simona ; Sibilia, Jean ; Wiland, Piotr ; Tarner, Ingo ; Smith, Vanessa ; Onken, Anna Theresa ; Abdel Atty Mohamed, Walid A. ; Distler, Oliver ; Morović-Vergles, Jadranka ; Himsel, Andrea ; de la Peña Lefebvre, Paloma G. ; Hügle, Thomas ; Walker, Ulrich A.
Introduction: Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known.
Method: This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively.
Results: Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients.
Conclusions: Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed.
Fusco, Francesco Maria ; Schilling, Stefan ; De Iaco, Giuseppina ; Brodt, Hans-Reinhard ; Brouqui, Philippe ; Maltezou, Helena C. ; Bannister, Barbara ; Gottschalk, René ; Thomson, Gail ; Puro, Vincenzo ; Ippolito, Giuseppe
Background: In Emergency and Medical Admission Departments (EDs and MADs), prompt recognition and appropriate infection control management of patients with Highly Infectious Diseases (HIDs, e.g. Viral Hemorrhagic Fevers and SARS) are fundamental for avoiding nosocomial outbreaks.
Methods: The EuroNHID (European Network for Highly Infectious Diseases) project collected data from 41 EDs and MADs in 14 European countries, located in the same facility as a national/regional referral centre for HIDs, using specifically developed checklists, during on-site visits from February to November 2009.
Results: Isolation rooms were available in 34 facilities (82,9%): these rooms had anteroom in 19, dedicated entrance in 15, negative pressure in 17, and HEPA filtration of exhausting air in 12. Only 6 centres (14,6%) had isolation rooms with all characteristics. Personnel trained for the recognition of HIDs was available in 24 facilities; management protocols for HIDs were available in 35.
Conclusions: Preparedness level for the safe and appropriate management of HIDs is partially adequate in the surveyed EDs and MADs.
Bezemer, Geert ; van Gool, Arthur R. ; Verheij-Hart, Elke ; Hansen, Bettina E. ; Lurie, Yoav ; Esteban, Juan I. ; Lagging, Martin ; Negro, Francesco ; Zeuzem, Stefan ; Ferrari, Carlo ; Pawlotsky, Jean-Michel ; Neumann, Avidan U. ; Schalm, Solko Walle ; Knegt, Robert Jacobus de
Background: Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study).
Methods: The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128).
Results: At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL.
Conclusions: Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females.
Background: Europe was certified to be polio-free in 2002 by the WHO. However, wild polioviruses remain endemic in India, Pakistan, Afghanistan, and Nigeria, occasionally causing polio outbreaks, as in Tajikistan in 2010. Therefore, effective surveillance measures and vaccination campaigns remain important. To determine the poliovirus immune status of a German study population, we retrospectively evaluated the seroprevalence of neutralizing antibodies (NA) to the poliovirus types 1, 2 and 3 (PV1, 2, 3) in serum samples collected from 1,632 patients admitted the University Hospital of Frankfurt am Main, Germany, in 2001, 2005 and 2010.
Methods: Testing was done by using a standardized microneutralization assay.
Results: Level of immunity to PV1 ranged between 84.2% (95%CI: 80.3-87.5), 90.4% (88.3-92.3) and 87.5% (85.4-88.8) in 2001, 2005 and 2010. For PV2, we found 90.8% (87.5-90.6), 91.3% (89.3-93.1) and 89.8% (88.7-90.9), in the same period. Seroprevalence to PV3 was 76.6% (72.2-80.6), 69.8% (66.6-72.8) and 72.9% (67.8-77.5) in 2001 and 2005 and 2010, respectively. In 2005 and 2010 significant lower levels of immunity to PV3 in comparison to PV1 and 2 were observed. Since 2001, immunity to PV3 is gradually, but not significantly decreasing.
Conclusion: Immunity to PV3 is insufficient in our cohort. Due to increasing globalization and worldwide tourism, the danger of polio-outbreaks is not averted - even not in developed countries, such as Germany. Therefore, vaccination remains necessary.
Berghuis, Dagmar ; Schilham, Marco Willem ; Vos, Hanneke I. ; Santos, Susy J. ; Klöß, Stephan ; Buddingh', Emilie P. ; Maarten Egeler, R. ; Hogendoorn, Pancras Cornelis Wilhelmus ; Lankester, Arjan C.
Background: Ewing sarcoma patients have a poor prognosis despite multimodal therapy. Integration of combination immunotherapeutic strategies into first-/second-line regimens represents promising treatment options, particularly for patients with intrinsic or acquired resistance to conventional therapies. We evaluated the susceptibility of Ewing sarcoma to natural killer cell-based combination immunotherapy, by assessing the capacity of histone deacetylase inhibitors to improve immune recognition and sensitize for natural killer cell cytotoxicity.
Methods: Using flow cytometry, ELISA and immunohistochemistry, expression of natural killer cell receptor ligands was assessed in chemotherapy-sensitive/-resistant Ewing sarcoma cell lines, plasma and tumours. Natural killer cell cytotoxicity was evaluated in Chromium release assays. Using ATM/ATR inhibitor caffeine, the contribution of the DNA damage response pathway to histone deacetylase inhibitor-induced ligand expression was assessed.
Results: Despite comparable expression of natural killer cell receptor ligands, chemotherapy-resistant Ewing sarcoma exhibited reduced susceptibility to resting natural killer cells. Interleukin-15-activation of natural killer cells overcame this reduced sensitivity. Histone deacetylase inhibitor-pretreatment induced NKG2D-ligand expression in an ATM/ATR-dependent manner and sensitized for NKG2D-dependent cytotoxicity (2/4 cell lines). NKG2D-ligands were expressed in vivo, regardless of chemotherapy-response and disease stage. Soluble NKG2D-ligand plasma concentrations did not differ between patients and controls.
Conclusion: Our data provide a rationale for combination immunotherapy involving immune effector and target cell manipulation in first-/second-line treatment regimens for Ewing sarcoma.
Much is known about the computation in individual neurons in the cortical column. Also, the selective connectivity between many cortical neuron types has been studied in great detail. However, due to the complexity of this microcircuitry its functional role within the cortical column remains a mystery. Some of the wiring behavior between neurons can be interpreted directly from their particular dendritic and axonal shapes. Here, I describe the dendritic density field (DDF) as one key element that remains to be better understood. I sketch an approach to relate DDFs in general to their underlying potential connectivity schemes. As an example, I show how the characteristic shape of a cortical pyramidal cell appears as a direct consequence of connecting inputs arranged in two separate parallel layers.
The small bowel is essential to sustain alimentation and small bowel Crohn's disease (CD) may severely limit its function. Small bowel imaging is a crucial element in diagnosing small
bowel CD, and treatment control with imaging is increasingly used to optimize the patients outcome. Thereby, capsule endoscopy, Balloon-assisted enteroscopy, and Magnetic resonance imaging have become key players to manage CD patients. In this review, role of small bowel imaging is detailed discussed for use in diagnosing and managing Crohn's disease patients.
Lipid-laden alveolar macrophages and pH monitoring have been used in the diagnosis of chronic aspiration in children with gastroesophageal reflux (GER). This study was conducted to prove a correlation between the detection of alimentary pulmonary fat phagocytosis and an increasing amount of proximal gastroesophageal reflux. It was assumed that proximal gastroesophageal reflux better correlates with aspiration than distal GER. Patients from 6 months to 16 years with unexplained recurrent wheezy bronchitis and bronchial hyperreactivity, or recurrent pneumonia with chronic cough underwent 24-hour double-channel pH monitoring and bronchoscopy with bronchoalveolar lavage (BAL). Aspiration of gastric content was determined by counting lipid laden alveolar macrophages from BAL specimens. There were no correlations between any pH-monitoring parameters and counts of lipid-laden macrophages in the whole study population, even when restricting analysis to those with abnormal reflux index expressing clinically significant GER. Quantifying lipid-laden alveolar macrophages from BAL in children with gastroesophageal-related respiratory disorders does not have an acceptable specificity to prove chronic aspiration as an underlying etiology. Therefore, research for other markers of pulmonary aspiration is needed.
Niyazi, Karim-Maximilian ; Maihoefer, Cornelius ; Krause, Mechthild ; Rödel, Claus ; Budach, Wilfried ; Belka, Claus
Background and Purpose: Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments.
Material and methods: Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab / trastuzumab / panitumumab / nimotuzumab, bevacizumab, sunitinib / sorafenib / lapatinib / gefitinib / erlotinib / sirolimus, thalidomide / lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms.
Results: Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported.
Conclusions: The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard to efficacy, early and late toxicity.