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The microbial cell wall is essential for maintenance of cell shape and resistance to external stressors1. The primary structural component of the cell wall is peptidoglycan, a glycopolymer with peptide crosslinks located outside of the cell membrane1. Peptidoglycan biosynthesis and structure are responsive to shifting environmental conditions such as pH and salinity2-6, but the mechanisms underlying such adaptations are incompletely understood. Precursors of peptidoglycan and other cell surface glycopolymers are synthesized in the cytoplasm and then delivered across the cell membrane bound to the recyclable lipid carrier undecaprenyl phosphate7 (C55-P, also known as UndP). Here we identify the DUF368-containing and DedA transmembrane protein families as candidate C55-P translocases, filling a critical gap in knowledge of the proteins required for the biogenesis of microbial cell surface polymers. Gram-negative and Gram-positive bacteria lacking their cognate DUF368-containing protein exhibited alkaline-dependent cell wall and viability defects, along with increased cell surface C55-P levels. pH-dependent synthetic genetic interactions between DUF368-containing proteins and DedA family members suggest that C55-P transporter usage is dynamic and modulated by environmental inputs. C55-P transporter activity was required by the cholera pathogen for growth and cell shape maintenance in the intestine. We propose that conditional transporter reliance provides resilience in lipid carrier recycling, bolstering microbial fitness both inside and outside the host.
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Proteínas Bacterianas , Proteínas Portadoras , Aptitud Genética , Bacterias Gramnegativas , Bacterias Grampositivas , Fosfatos de Poliisoprenilo , Proteínas Bacterianas/metabolismo , Proteínas Portadoras/metabolismo , Membrana Celular/metabolismo , Pared Celular/química , Pared Celular/metabolismo , Lípidos/análisis , Peptidoglicano/metabolismo , Fosfatos de Poliisoprenilo/metabolismo , Bacterias Gramnegativas/química , Bacterias Gramnegativas/citología , Bacterias Gramnegativas/metabolismo , Bacterias Grampositivas/química , Bacterias Grampositivas/citología , Bacterias Grampositivas/metabolismo , Viabilidad MicrobianaRESUMEN
The emergence of multidrug-resistant bacterial pathogens is a growing threat to global public health. Here, we report the development and characterization of a panel of nine-amino acid residue synthetic peptides that display potent antibacterial activity and the ability to disrupt preestablished microbial biofilms. The lead peptide (Peptide K6) showed bactericidal activity against Pseudomonas aeruginosa and Staphylococcus aureus in culture and in monocultures and mixed biofilms in vitro. Biophysical analysis revealed that Peptide K6 self-assembled into nanostructured micelles that correlated with its strong antibiofilm activity. When surface displayed on the outer membrane protein LamB, two copies of the Peptide K6 were highly bactericidal to Escherichia coli. Peptide K6 rapidly increased the permeability of bacterial cells, and resistance to this toxic peptide occurred less quickly than that to the potent antibiotic gentamicin. Furthermore, we found that Peptide K6 was safe and effective in clearing mixed P. aeruginosa-S. aureus biofilms in a mouse model of persistent infection. Taken together, the properties of Peptide K6 suggest that it is a promising antibiotic candidate and that design of additional short peptides that form micelles represents a worthwhile approach for the development of antimicrobial agents.
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Antibacterianos , Coinfección , Animales , Ratones , Antibacterianos/farmacología , Micelas , Staphylococcus aureus , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Catiónicos Antimicrobianos/química , Biopelículas , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosaRESUMEN
Background. The impact of vascular cooling effects in hepatic microwave ablation (MWA) is controversially discussed. The objective of this study was a systematic assessment of vascular cooling effects in hepatic MWA ex vivo. Methods. Microwave ablations were performed in fresh porcine liver ex vivo with a temperature-controlled MWA generator (902-928 MHz) and a non-cooled 14-G-antenna. Energy input was set to 9.0 kJ. Hepatic vessels were simulated by glass tubes. Three different vessel diameters (3.0, 5.0, 8.0 mm) and vessel to antenna distances (5, 10, 20 mm) were examined. Vessels were perfused with saline solution at nine different flow rates (0-500 mL/min). Vascular cooling effects were assessed at the largest cross-sectional ablation area. A quantitative and semi-quantitative/morphologic analysis was carried out. Results. 228 ablations were performed. Vascular cooling effects were observed at close (5 mm) and medium (10 mm) antenna to vessel distances (P < .05). Vascular cooling effects occurred around vessels with flow rates ≥1.0 mL/min (P < .05) and a vessel diameter ≥3 mm (P < .05). Higher flow rates did not result in more distinct cooling effects (P > .05). No cooling effects were measured at large (20 mm) antenna to vessel distances (P > .05). Conclusion. Vascular cooling effects occur in hepatic MWA and should be considered in treatment planning. The vascular cooling effect was mainly affected by antenna to vessel distance. Vessel diameter and vascular flow rate played a minor role in vascular cooling effects.
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Técnicas de Ablación , Ablación por Catéter , Porcinos , Animales , Microondas/uso terapéutico , Estudios Transversales , Hígado/cirugía , Hígado/irrigación sanguínea , Técnicas de Ablación/métodos , Frío , Ablación por Catéter/métodosRESUMEN
The facultative human pathogen Vibrio cholerae changes its transcriptional profile upon oral ingestion by the host to facilitate survival and colonization fitness. Here, we used a modified version of recombination-based in vivo expression technology to investigate gene silencing during the in vivo passage, which has been understudied. Using a murine model of cholera, we screened a V. cholerae transposon library composed of 10,000 randomly generated reporter fusions and identified 101 in vivo repressed (ivr) genes. Our data indicate that constitutive expression of ivr genes reduces colonization fitness, highlighting the necessity to down-regulate these genes in vivo. For example, the ivr gene clcA, encoding an H+/Cl- transporter, could be linked to the acid tolerance response against hydrochloric acid. In a chloride-dependent manner, ClcA facilitates survival under low pH (e.g., the stomach), but its presence becomes detrimental under alkaline conditions (e.g., lower gastrointestinal tract). This pH-dependent clcA expression is controlled by the LysR-type activator AphB, which acts in concert with AphA to initiate the virulence cascade in V. cholerae after oral ingestion. Thus, transcriptional networks dictating induction of virulence factors and the repression of ivr genes overlap to regulate in vivo colonization dynamics. Overall, the results presented herein highlight the impact of spatiotemporal gene silencing in vivo. The molecular characterization of the underlying mechanisms can provide important insights into in vivo physiology and virulence network regulation.
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Antiportadores/metabolismo , Proteínas Bacterianas/metabolismo , Cólera/microbiología , Tracto Gastrointestinal/microbiología , Vibrio cholerae/metabolismo , Ácidos/metabolismo , Animales , Antiportadores/genética , Proteínas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica , Humanos , Ratones , Regiones Promotoras Genéticas , Vibrio cholerae/genéticaRESUMEN
We lay the foundation for determining the microscopic spin interactions in two-dimensional (2D) ferromagnets by combining angle-dependent ferromagnetic resonance (FMR) experiments on high quality CrI_{3} single crystals with theoretical modeling based on symmetries. We discover that the Kitaev interaction is the strongest in this material with Kâ¼-5.2 meV, 25 times larger than the Heisenberg exchange Jâ¼-0.2 meV, and responsible for opening the â¼5 meV gap at the Dirac points in the spin-wave dispersion. Furthermore, we find that the symmetric off-diagonal anisotropy Γâ¼-67.5 µeV, though small, is crucial for opening a â¼0.3 meV gap in the magnon spectrum at the zone center and stabilizing ferromagnetism in the 2D limit. The high resolution of the FMR data further reveals a µeV-scale quadrupolar contribution to the S=3/2 magnetism. Our identification of the underlying exchange anisotropies opens paths toward 2D ferromagnets with higher T_{C} as well as magnetically frustrated quantum spin liquids based on Kitaev physics.
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BACKGROUND: This analysis aims at evaluating the impact of multidisciplinary tumor boards on clinical outcome of multiple tumor entities, the effect of the specific number of multidisciplinary tumor boards and potential differences between the tumor entities. METHODS: By a matched-pair analysis we compared the response to treatment, overall survival, relapse or disease free survival and progression free survival of patients whose cases were discussed in a tumor board meeting with patients whose cases were not. It was performed with patients registered in the cancer registry of the University of Bonn and diagnosed between 2010 and 2016. After the matching process with a pool of 7262 patients a total of 454 patients with 66 different tumor types were included in this study. RESULTS: First, patients with three or more multidisciplinary tumor board meetings in their history show a significantly better overall survival than patients with no tumor board meeting. Second, response to treatment, relapse free survival and time to progression were not found to be significantly different. Third, there was no significant difference for a specific tumor entity. CONCLUSION: This study revealed a positive impact of a higher number of multidisciplinary tumor boards on the clinical outcome. Also, our analysis hints towards a positive effect of multidisciplinary tumor boards on overall survival.
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Comunicación Interdisciplinaria , Recurrencia Local de Neoplasia/mortalidad , Neoplasias/mortalidad , Grupo de Atención al Paciente/organización & administración , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Neoplasias/patología , Neoplasias/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Objectives: Contrast-enhanced computed tomography (CECT) is used to monitor technical success immediately after hepatic microwave ablation (MWA). However, it remains unclear, if CECT shows the exact extend of the thermal destruction zone, or if tissue changes such as peri-lesionary edema are depicted as well. The objective of this study was to correlate immediate post-interventional CECT with histological and macroscopic findings in hepatic MWA in porcine liver in vivo.Methods: Eleven MWA were performed in porcine liver in vivo with a microwave generator (928 MHz; energy input 24 kJ). CECT was performed post-interventionally. Livers were explanted and ablations were bisected immediately after ablation. Samples were histologically analyzed after vital staining (NADH-diaphorase). Ablation zones were histologically and macroscopically outlined. We correlated histologic findings, macroscopic images and CECT.Results: Three ablation zones were identified in histological and macroscopic findings. Only one ablation zone could be depicted in CECT. Close conformity was observed between histological and macroscopic findings. The ablation zone depicted in CECT overestimated the histological avital central zone and inner red zone (p < = .01). No differences were found between CECT and the histological outer red zone (p > .05).Conclusions: Immediate post-interventional CECT overestimated the clinically relevant zone of complete cell ablation after MWA in porcine liver in vivo. This entails the risk of incomplete tumor ablation and could lead to tumor recurrence.
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Técnicas de Ablación/métodos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Ablación por Radiofrecuencia/métodos , Tomografía Computarizada por Rayos X/métodos , Animales , Modelos Animales de Enfermedad , Masculino , PorcinosRESUMEN
BACKGROUND: Modern, individualised therapies can improve the survival of patients with colorectal cancer. However, not all patients are referred for treatment to a certified colorectal cancer centre, where a tumor board supports the implementation of their therapy in accordance to guidelines. This study examines the feasibility and demand of a structured, online-based, qualified second opinion for patients with colorectal cancer. METHOD: A 15-month pilot study between 2009 and 2011, offered patients with colorectal cancer to obtain a qualified second opinion of a tumour board based on an electronic patient record completed online with the assistance of a case manager. Life-satisfaction levels and quality of life (EORCT QLQ-C30) of the participants has been monitored for a year. RESULTS: In 95â% of the cases, a complete electronic patient record and a second opinion could be generated. Less than half of the participants received their first therapy recommendation from a clinic with a tumour board. The second opinion confirmed the initial medical opinion in 40â% of the cases - 33â% showed a partial and 27â% showed a significant deviation. In case of a deviation, the implementation of the second opinion improved the patients' quality of life. CONCLUSION: Generating an online-based, qualified second opinion by an interdisciplinary tumour board is technically and logistically well feasible. The online-based second opinion could significantly improve the quality of treatment for patients with colorectal cancer in the future and thus improve their quality of life.
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Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Proyectos Piloto , Calidad de Vida , Derivación y ConsultaRESUMEN
BACKGROUND: The arguments for applying minimally invasive techniques are, besides cosmetic results, reduced access trauma and less postoperative pain. In thyroid surgery, cosmetic aspects are gaining importance. Whether minimally invasive endoscopic thyroid surgery is less painful has not been shown yet. METHOD: In this study, we analyse the outcome of 246 patients who underwent cervical endoscopic video-assisted thyroid surgery (CEViTS) regarding the surgery itself, their postoperative pain and satisfaction with the procedure. RESULTS: CEViTS is routinely performed in our hospital. In this study, no postoperative bleedings that would have made a reoperation necessary occurred. All lobectomies could be completed endoscopically. In two cases, conversions (enlargement of the 5-mm incision to 25 mm) were necessary. Transient nerve palsy was registered in three patients (1.22%). One patient (0.41%) had a permanent palsy of the recurrent laryngeal nerve. In comparison to open surgery (n = 173 patients), the 246 CEViTS patients had a significantly lower pain level (p = 0.047). CONCLUSIONS: Cervical endoscopic video-assisted thyroid surgery (CEViTS) can be considered a safe, less traumatizing and useful minimally invasive procedure in endoscopic thyroid surgery.
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Endoscopía/efectos adversos , Endoscopía/métodos , Dolor Postoperatorio , Satisfacción del Paciente , Tiroidectomía/efectos adversos , Tiroidectomía/métodos , Cirugía Asistida por Video , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Parálisis/diagnóstico , Hemorragia Posoperatoria , Nervio Laríngeo Recurrente , Glándula Tiroides/cirugía , Adulto JovenRESUMEN
BACKGROUND: Polyploidy and apomixis are important factors influencing plant distributions often resulting in range shifts, expansions and geographical parthenogenesis. We used the Ranunculus auricomus complex as a model to asses if the past and present distribution and climatic preferences were determined by these phenomena. RESULTS: Ecological differentiation among diploids and polyploids was tested by comparing the sets of climatic variables and distribution modelling using 191 novel ploidy estimations and 561 literature data. Significant differences in relative genome size on the diploid level were recorded between the "auricomus" and "cassubicus" groups and several new diploid occurrences were found in Slovenia and Hungary. The current distribution of diploids overlapped with the modelled paleodistribution (22 kyr BP), except Austria and the Carpathians, which are proposed to be colonized later on from refugia in the Balkans. Current and historical presence of diploids from the R. auricomus complex is suggested also for the foothills of the Caucasus. Based on comparisons of the climatic preferences polyploids from the R. auricomus complex occupy slightly drier and colder habitats than the diploids. CONCLUSIONS: The change of reproductive mode and selection due to competition with the diploid ancestors may have facilitated the establishment of polyploids within the R. auricomus complex in environments slightly cooler and drier, than those tolerated by diploid ancestors. Much broader distribution of polyploid apomicts may have been achieved due to faster colonization mediated by uniparental reproductive system.
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Apomixis , Clima , Dispersión de las Plantas , Poliploidía , Ranunculus/fisiología , Europa (Continente) , Ranunculus/genéticaRESUMEN
As it became evident recently, extracellular DNA could be a versatile nutrient source of the facultative pathogen Vibrio cholerae along the different stages of its life cycle. By the use of two extracellular nucleases and periplasmic phosphatases, V. cholerae degrades extracellular DNA to nucleosides. In this study, we investigated the nucleoside uptake via identification and characterization of VCA0179, VC1953 and VC2352 representing the three nucleoside transport systems in V. cholerae. Based on our results VC2352 seems to be the dominant nucleoside transporter. Nevertheless, all three transporters are functional and can contribute to the utilization of nucleosides as a sole source of carbon or nitrogen. We found that the transcriptional activity of these three distal genes is equally promoted or antagonized by CRP or CytR respectively. Finally, mutants impaired for nucleoside uptake exhibit decreased transition fitness from the host into low carbon environments along the life cycle of V. cholerae.
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Cólera/microbiología , Nucleósidos/metabolismo , Vibrio cholerae/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Transporte Biológico , Cólera/metabolismo , Regulación Bacteriana de la Expresión Génica , Humanos , Proteínas de Transporte de Nucleósidos/genética , Proteínas de Transporte de Nucleósidos/metabolismo , Vibrio cholerae/genéticaRESUMEN
PURPOSE: Radiofrequency ablation (RFA) for primary liver tumors and liver metastases is restricted by a limited ablation size. Multipolar RFA is a technical advancement of RFA, which is able to achieve larger ablations. The aim of this ex vivo study was to determine optimal ablation parameters for multipolar RFA depending on applicator distance and energy input. METHODS: RFA was carried out ex vivo in porcine livers with three internally cooled, bipolar applicators in multipolar ablation mode. Three different applicator distances were used and five different energy inputs were examined. Ablation zones were sliced along the cross-sectional area at the largest ablation diameter, orthogonally to the applicators. These slices were digitally measured and analyzed. RESULTS: Sixty RFA were carried out. A limited growth of ablation area was seen in all test series. This increase was dependent on ablation time, but not on applicator distance. A steady state between energy input and energy loss was not observed. A saturation of the minimum radius of the ablation zone was reached. Differences in ablation radius between the three test series were seen for lowest and highest energy input ( P < .05). No differences were seen for medium amounts of energy ( P > .05). CONCLUSIONS: The ablation parameters applicator distance and energy input can be chosen in such a way, that minor deviations of the preplanned ablation parameters have no influence on the size of the ablation area.
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Ablación por Catéter , Hígado/cirugía , Animales , Neoplasias Hepáticas , Porcinos , TemperaturaRESUMEN
The facultative human pathogen Vibrio cholerae has to adapt to different environmental conditions along its lifecycle by means of transcriptional, translational and post-translational regulation. This study provides a first comprehensive analysis regarding the contribution of the cytoplasmic AAA+ proteases Lon, ClpP and HslV to distinct features of V. cholerae behaviour, including biofilm formation, motility, cholera toxin expression and colonization fitness in the mouse model. While absence of HslV did not yield to any altered phenotype compared to wildtype, absence of Lon or ClpP resulted in significantly reduced colonization in vivo. In addition, a Δlon deletion mutant showed altered biofilm formation and increased motility, which could be correlated with higher expression of V. cholerae flagella gene class IV. Concordantly, we could show by immunoblot analysis, that Lon is the main protease responsible for proteolytic control of FliA, which is required for class IV flagella gene transcription, but also downregulates virulence gene expression. FliA becomes highly sensitive to proteolytic degradation in absence of its anti-sigma factor FlgM, a scenario reported to occur during mucosal penetration due to FlgM secretion through the broken flagellum. Our results confirm that the high stability of FliA in the absence of Lon results in less cholera toxin and toxin corgulated pilus production under virulence gene inducing conditions and in the presence of a damaged flagellum. Thus, the data presented herein provide a molecular explanation on how V. cholerae can achieve full expression of virulence genes during early stages of colonization, despite FliA getting liberated from the anti-sigma factor FlgM.
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Endopeptidasa Clp/metabolismo , Péptido Hidrolasas/metabolismo , Mapas de Interacción de Proteínas , Vibrio cholerae/enzimología , Vibrio cholerae/fisiología , Animales , Biopelículas/crecimiento & desarrollo , Toxina del Cólera/metabolismo , Humanos , Mucosa Intestinal/microbiología , Locomoción , Ratones , Vibrio cholerae/crecimiento & desarrollo , Vibrio cholerae/metabolismoRESUMEN
The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1alpha/beta-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.
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Aterosclerosis/metabolismo , Aterosclerosis/patología , Proteínas Portadoras/metabolismo , Colesterol/química , Colesterol/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis , Aterosclerosis/inducido químicamente , Trasplante de Médula Ósea , Proteínas Adaptadoras de Señalización CARD , Proteínas Portadoras/genética , Catepsina B/metabolismo , Catepsina L/metabolismo , Colesterol/farmacología , Cristalización , Proteínas del Citoesqueleto/deficiencia , Dieta Aterogénica , Femenino , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Interleucina-1/deficiencia , Interleucina-18/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/patología , Ratones , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Cavidad Peritoneal/patología , Fagocitos/efectos de los fármacos , Fagocitos/patología , Fagocitos/fisiología , Receptores de LDL/deficiencia , Factores de TiempoRESUMEN
PURPOSE: Major limitations of conventional RFA are vascular cooling effects. However, vascular cooling effects are supposed to be less pronounced in multipolar RFA. The objective of this ex vivo study was a systematic evaluation of the vascular cooling effects in multipolar RFA. MATERIALS AND METHODS: Multipolar RFA with three bipolar RFA applicators was performed ex vivo in porcine liver (applicator distance 20 mm, energy input 40 kJ). A saline-perfused glass tube ('vessel') was placed parallel to the applicators in order to simulate a natural liver vessel. Five applicator-to-vessel geometries were tested. A liquid-filled glass tube without perfusion was used as a dry run. Ablations were orthogonally cut to the applicators at a defined height. Cooling effects were analysed qualitatively and quantitatively along these cross sectional areas. RESULTS: Thirty-six ablations were performed. A cooling effect could be seen in all ablations with perfused vessels compared to the dry run. While this cooling effect did not have any influence on the ablation areas (859-1072 mm(2) versus 958 mm(2) in the dry run, p > 0.05), it had a distinctive impact on ablation shape. A vascular cooling effect could be observed in all ablations with perfusion directly around the vessel independent of the applicator position compared to the dry run (p < 0.01). CONCLUSIONS: A vascular cooling effect occurred in all multipolar RFA with simulated liver vessels ex vivo independent of the applicator-to-vessel geometry. While the cooling effect did not influence the total ablation area, it had a distinctive impact on the ablation shape.
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Ablación por Catéter/métodos , Hígado/efectos de la radiación , Animales , Humanos , Perfusión , PorcinosRESUMEN
BACKGROUND/AIMS: Recent data suggest that tumors of the right and left colon should be distinguished as they differ in clinical and molecular characteristics. METHODS: A total of 1,319 patients who underwent surgical resection for colon cancer (CC) were investigated. Tumors between the ileocecal valve and the hepatic flexure were classified as right CC (RCC), tumors between the splenic flexure and the rectum as left CC (LCC). RESULTS: RCC revealed a higher cause-specific mortality risk (hazard ratio 1.36, 95% CI 1.10-1.68, p = 0.005) and lower 5-year cause-specific (RCC 64.9%, 95% CI 60.4-69.4, LCC 70.7%, 95% CI 67.2-74.2, p = 0.032) and disease-free (RCC 56.0%, 95% CI 51.5-60.5, LCC 59.9%, 95% CI 56.2-63.6, p = 0.025) survival rates. RCCs were more often microsatellite instable (RCC 37.2%, LCC 13.0%, p < 0.001) and more often showed KRAS (RCC 42.5%, LCC 18.9%, p = 0.001) and BRAF mutations (RCC 26.6%, LCC 3.2%, p < 0.001). CONCLUSION: RCC and LCC differ significantly regarding clinical, histopathological and molecular genetic features and can be considered as distinct entities. The reduced prognosis of RCC may be caused by higher rates of microsatellite instability, KRAS and BRAF mutations.
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Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Colectomía , Colon/patología , Neoplasias del Colon/mortalidad , Neoplasias del Colon/cirugía , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Colon/cirugía , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , Pronóstico , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Vibrio cholerae and enterotoxic Escherichia coli (ETEC) remain two dominant bacterial causes of severe secretory diarrhea and still a significant cause of death, especially in developing countries. In order to investigate new effective and inexpensive therapeutic approaches, we analyzed nanoparticles synthesized by a green approach using corresponding salt (silver or zinc nitrate) with aqueous extract of Caltropis procera fruit or leaves. We characterized the quantity and quality of nanoparticles by UV-visible wavelength scans and nanoparticle tracking analysis. Nanoparticles could be synthesized in reproducible yields of approximately 10(8) particles/ml with mode particles sizes of approx. 90-100 nm. Antibacterial activity against two pathogens was assessed by minimal inhibitory concentration assays and survival curves. Both pathogens exhibited similar resistance profiles with minimal inhibitory concentrations ranging between 5×10(5) and 10(7) particles/ml. Interestingly, zinc nanoparticles showed a slightly higher efficacy, but sublethal concentrations caused adverse effects and resulted in increased biofilm formation of V. cholerae. Using the expression levels of the outer membrane porin OmpT as an indicator for cAMP levels, our results suggest that zinc nanoparticles inhibit adenylyl cyclase activity. This consequently deceases the levels of this second messenger, which is a known inhibitor of biofilm formation. Finally, we demonstrated that a single oral administration of silver nanoparticles to infant mice colonized with V. cholerae or ETEC significantly reduces the colonization rates of the pathogens by 75- or 100-fold, respectively.
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Antibacterianos/farmacología , Escherichia coli Enterotoxigénica/efectos de los fármacos , Nanopartículas/metabolismo , Plata/farmacología , Vibrio cholerae/efectos de los fármacos , Zinc/farmacología , Animales , Antibacterianos/uso terapéutico , Calotropis/química , Cólera/prevención & control , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/prevención & control , Ratones , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Nanopartículas/uso terapéutico , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Plata/aislamiento & purificación , Plata/uso terapéutico , Resultado del Tratamiento , Zinc/aislamiento & purificación , Zinc/uso terapéuticoRESUMEN
Thin metal films deposited on polymer substrates are used in flexible electronic devices such as flexible displays or printed memories. They are often fabricated as complicated multilayer structures. Understanding the mechanical behavior of the interface between the metal film and the substrate as well as the process of crack formation under global tension is important for producing reliable devices. In the present work, the deformation behavior of copper films (50-200 nm thick), bonded to polyimide directly or via a 10 nm chromium interlayer, is investigated by experimental analysis and computational simulations. The influence of the various copper film thicknesses and the usage of a brittle interlayer on the crack density as well as on the stress magnitude in the copper after saturation of the cracking process are studied with in situ tensile tests in a synchrotron and under an atomic force microscope. From the computational point of view, the evolution of the crack pattern is modeled as a stochastic process via finite element based cohesive zone simulations. Both, experiments and simulations show that the chromium interlayer dominates the deformation behavior. The interlayer forms cracks that induce a stress concentration in the overlying copper film. This behavior is more pronounced in the 50 nm than in the 200 nm copper films.
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PURPOSE: Surgical site infection (SSI) remains to be one of the most frequent infectious complications following abdominal surgery. Prophylactic intra-operative wound irrigation (IOWI) before skin closure has been proposed to reduce bacterial wound contamination and the risk of SSI. However, current recommendations on its use are conflicting especially concerning antibiotic and antiseptic solutions because of their potential tissue toxicity and enhancement of bacterial drug resistances. METHODS: To analyze the existing evidence for the effect of IOWI with topical antibiotics, povidone-iodine (PVP-I) solutions or saline on the incidence of SSI following open abdominal surgery, a systematic review and meta-analysis of randomized controlled trials (RCTs) was carried out according to the recommendations of the Cochrane Collaboration. RESULTS: Forty-one RCTs reporting primary data of over 9000 patients were analyzed. Meta-analysis on the effect of IOWI with any solution compared to no irrigation revealed a significant benefit in the reduction of SSI rates (OR = 0.54, 95 % confidence Interval (CI) [0.42; 0.69], p < 0.0001). Subgroup analyses showed that this effect was strongest in colorectal surgery and that IOWI with antibiotic solutions had a stronger effect than irrigation with PVP-I or saline. However, all of the included trials were at considerable risk of bias according to the quality assessment. CONCLUSION: These results suggest that IOWI before skin closure represents a pragmatic and economical approach to reduce postoperative SSI after abdominal surgery and that antibiotic solutions seem to be more effective than PVP-I solutions or simple saline, and it might be worth to re-evaluate their use for specific indications.