Local Treatment of Driveline Infection with Bacteriophages.

Drive line infections (DLI) are common infectious complications after left ventricular assist devices (LVAD) implantation. In case of severe or persistent infections, when conservative management fails, the exchange of the total LVAD may become necessary. We present a case of successful treatment of DL infection with a combination of antibiotics, debridement and local bacteriophage treatment.

Vascular Response Toward an Absorbable Sirolimus-eluting Polymeric Scaffold for Vascular Application in a Model of Normal Porcine Carotid Arteries.

BACKGROUND: Fully absorbable polymeric scaffolds, as a potential alternative to permanent metallic stents, are entering the clinical field. The aim of this study is to assess the in vivo biocompatibility of a novel Sirolimus-eluting (SIR) absorbable scaffold based on poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P4HB) for interventional application. METHODS: Absorbable PLLA/P4HB scaffolds either loaded with SIR coating or unloaded scaffolds were implanted interventionally into common carotid arteries of 14 female. Bare metal stents (BMS) served as control. Peroral dual anti-platelet therapy was administered throughout the study. Stented common carotid arteries segments were explanted after 4 weeks, and assessed histomorphometrically. RESULTS: The absorbable scaffolds showed a decreased residual lumen area and higher stenosis after 4 weeks (PLLA/P4HB: 6.56 ± 0.41 mm² and 37.56 ± 4.67%; SIR-PLLA/P4HB: 6.90 ± 0.58 mm² and 35.60 ± 3.15%) as compared to BMS (15.29 ± 1.86 mm² and 7.65 ± 2.27%). Incorporation of SIR reduced the significantly higher inflammation of unloaded scaffolds however not to a level compared to bare metal stent (PLLA/P4HB: 1.20 ± 0.19; SIR-PLLA/P4HB: 0.96 ± 0.24; BMS: 0.54 ± 0.12). In contrast, the BMS showed a slightly elevated vascular injury score (0.74 ± 0.15), as compared to the PLLA/P4HB (0.54 ± 0.20) and the SIR-PLLA/P4HB (0.48 ± 0.15) groups. CONCLUSION: In this preclinical model, the new absorbable polymeric (SIR-) scaffolds showed similar technical feasability and safety for vascular application as the permanent metal stents. The higher inflammatory propensity of the polymeric scaffolds was slightly reduced by SIR-coating. A smaller strut thickness of the polymeric scaffolds might have been a positive effect on tissue ingrowth between the struts and needs to be addressed in future work on the stent design.

Bacteriophages for the Treatment of Graft Infections in Cardiovascular Medicine.

Bacterial infections of vascular grafts represent a major burden in cardiovascular medicine, which is related to an increase in morbidity and mortality. Different factors that are associated with this medical field such as patient frailty, biofilm formation, or immunosuppression negatively influence antibiotic treatment, inhibiting therapy success. Thus, further treatment strategies are required. Bacteriophage antibacterial properties were discovered 100 years ago, but the focus on antibiotics in Western medicine since the mid-20th century slowed the further development of bacteriophage therapy. Therefore, the experience and knowledge gained until then in bacteriophage mechanisms of action, handling, clinical uses, and limitations were largely lost. However, the parallel emergence of antimicrobial resistance and individualized medicine has provoked a radical reassessment of this approach and cardiovascular surgery is one area in which phages may play an important role to cope with this new scenario. In this context, bacteriophages might be applicable for both prophylactic and therapeutic use, serving as a stand-alone therapy or in combination with antibiotics. From another perspective, standardization of phage application is also required. The ideal surgical bacteriophage application method should be less invasive, enabling highly localized concentrations, and limiting bacteriophage distribution to the infection site during a prolonged time lapse. This review describes the latest reports of phage therapy in cardiovascular surgery and discusses options for their use in implant and vascular graft infections.

[The Importance of Anatomy in the Training of the Vascular Surgeon]. / Der Stellenwert der Anatomie in der Weiterbildung des Gefäßchirurgen.

Vascular surgery has developed very dynamically in recent years, especially with the introduction of endovascular techniques. However, this has also changed surgeons' requirements. Classical surgical procedures have been almost completely displaced by endovascular techniques; new hybrid interventions have emerged while complex operations are concentrated in few centres. Therefore, developing expertise in open aortic surgery is increasingly challenging in vascular surgical training programs.Cadaver models provide an opportunity for exposure and repetitive training of individual surgical steps without endangering patients.As part of the training of highly complex vascular surgery operations, we carried out and evaluated the thoracoabdominal aortic replacement with 13 participants in 6 ethanol-preserved corpses.A simulation of surgical procedures on human cadaveric models cannot fully replace real experiences, but allows surgeons in training to practice and achieve dexterity in performing procedures in a safe and reproducible way.

Can Recognition of Spinal Ischemia Be Improved? Application of Motor-Evoked Potentials, Serum Markers, and Breath Gas Analysis in an Acutely Instrumented Pig Model.

BACKGROUND: Paraplegia due to spinal cord ischemia (SCI) is a serious complication after repair of thoracoabdominal aortic aneurysms. For prevention and early treatment of spinal ischemia, intraoperative monitoring of spinal cord integrity is essential. This study was intended to improve recognition of SCI through a combination of transcranial motor-evoked potentials (tc-MEPs), serum markers, and innovative breath analysis. METHODS: In 9 female German Landrace pigs, tc-MEPs were captured, markers of neuronal damage were determined in blood, and volatile organic compounds (VOCs) were analyzed in exhaled air. After thoraco-phrenico-laparotomy, SCI was initiated through sequential clamping (n = 4) or permanently ligating (n = 5) SAs of the abdominal and thoracic aorta in caudocranial orientation until a drop in the tc-MEPs to at least 25% of the baseline was recorded. VOCs in breath were determined by means of solid-phase microextraction coupled with gas chromatography-mass spectrometry. After waking up, clinical and neurological status was evaluated (Tarlov score). Spinal cord histology was obtained in postmortem. RESULTS: Permanent vessel ligature induced a worse neurological outcome and a higher number of necrotic motor neurons compared to clamping. Changes of serum markers remained unspecific. After laparotomy, exhaled acetone and isopropanol showed highest concentrations, and pentane and hexane increased during ischemia-reperfusion injury. CONCLUSIONS: To mimic spinal ischemia occurring in humans during aortic aneurysm repair, animal models have to be meticulously evaluated concerning vascular anatomy and function. Volatiles from breath indicated metabolic stress during surgery and oxidative damage through ischemia reperfusion. Breath VOCs may provide complimentary information to conventional monitoring methods.

Immunosuppressants accelerate microvascular thrombus formation in vivo: role of endothelial cell activation.

BACKGROUND: In the early postoperative period after pancreas-kidney transplantation, pancreatic venous thrombosis is a major complication that leads to allograft dysfunction and graft loss. Beside ischemia and reperfusion injury, immunosuppressive drugs have been accused of supporting thrombogenicity. The aim of this study was to evaluate the effect of commonly applied immunosuppressants on microvascular thrombus formation in normal and postischemic tissue in vivo. METHODS: In the skin fold chambers of tacrolimus-, cyclosporine A-, antithymocyte globulin-, rapamycine-, or saline-treated mice, light/dye-induced microvascular thrombus formation was studied. Additional mice underwent ischemia and reperfusion of the skin fold chamber tissue and received tacrolimus, antithymocyte globulin, or saline before reperfusion. Additionally, the effect of prednisolone was tested in animals with ischemia and reperfusion. Concentrations of sP-selectin, soluble vascular cell adhesion molecule-1, and asymmetric dimethylarginine were assessed by enzyme-linked immunosorbent assay. Immunohistochemistry of the skin fold chamber tissue served for analysis of vascular endothelial nitric oxide synthase and inducible nitric oxide synthase expression. RESULTS: In normal tissue, tacrolimus, cyclosporine A, antithymocyte globulin, and rapamycine accelerated microvascular thrombus formation significantly when compared with saline. Whereas ischemia and reperfusion in saline-treated mice enhanced thrombus formation, thrombogenicity was not further increased by ischemia and reperfusion in tacrolimus- or antithymocyte globulin-treated animals. Application of prednisolone reversed the tacrolimus- and antithymocyte globulin-induced prothrombotic effect. Antithymocyte globulin increased sP-selectin and soluble vascular cell adhesion molecule-1, whereas tacrolimus induced asymmetric dimethylarginine production significantly. While tacrolimus and antithymocyte globulin additionally induced endothelial nitric oxide synthase and inducible nitric oxide synthase expression, cyclosporine A influenced only endothelial inducible nitric oxide synthase expression. CONCLUSION: Immunosuppressants enhance thrombus formation in vivo. Although antithymocyte globulin activates the microvascular endothelium, we show for the first time that tacrolimus increases asymmetric dimethylarginine plasma levels. Thus, impaired nitric oxide availability might be the underlying mechanism for the tacrolimus-associated increased thrombogenicity. The efficacy of prednisolone to reverse the tacrolimus-associated and antithymocyte globulin-associated acceleration of thrombus formation underlines the application of this anti-inflammatory drug prior to reperfusion in immunosuppressive regimens.

Listeria monocytogenes activated p38 MAPK and induced IL-8 secretion in a nucleotide-binding oligomerization domain 1-dependent manner in endothelial cells.

Nucleotide-binding oligomerization domain (Nod) proteins serve as intracellular pattern recognition molecules recognizing peptidoglycans. To further examine intracellular immune recognition, we used Listeria monocytogenes as an organism particularly amenable for studying innate immunity to intracellular pathogens. In contrast to wild-type L. monocytogenes, the nonpathogenic Listeria innocua, or L. monocytogenes mutants lacking internalin B or listeriolysin O, poorly invaded host cells and escaped into host cell cytoplasm, respectively, and were therefore used as controls. In this study, we show that only the invasive wild-type L. monocytogenes, but not the listeriolysin O- or internalin B-negative L. monocytogenes mutants or L. innocua, substantially induced IL-8 production in HUVEC. RNA interference and Nod1-overexpression experiments demonstrated that Nod1 is critically involved in chemokine secretion and NF-kappaB activation initiated by L. monocytogenes in human endothelial cells. Moreover, we show for the first time that Nod1 mediated activation of p38 MAPK signaling induced by L. monocytogenes. Finally, L. monocytogenes- and Nod1-induced IL-8 production was blocked by a specific p38 inhibitor. In conclusion, L. monocytogenes induced a Nod1-dependent activation of p38 MAPK signaling and NF-kappaB which resulted in IL-8 production in endothelial cells. Thus, Nod1 is an important component of a cytoplasmic surveillance pathway.

Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae.

Streptococcus pneumoniae, the major cause of community-acquired pneumonia and bacterial meningitis, has been shown to transiently invade epithelial and endothelial cells. Innate immune receptors including Toll-like receptors recognize various pathogens, such as S. pneumoniae, by identifying conserved pathogen-associated molecular patterns. Recently, two members of a novel class of pattern recognition receptors, the cytosolic proteins nucleotide-binding oligomerization domain 1 (Nod1)/CARD4 and Nod2/CARD15, have been found to detect cell wall peptidoglycans. Here we tested the hypothesis that Nod proteins are involved in the intracellular recognition of pneumococci. Data indicate that pneumococci invade HEK293 cells. Genetic complementation studies in these cells demonstrate that NF-kappaB activation induced by S. pneumoniae depends on Nod2. Moreover, intracellular transfection of inactivated pneumococci yielded similar effects, confirming the Nod2 dependence of NF-kappaB activation by pneumococci in HEK293 cells. By dominant negative overexpression and small interfering RNA experiments, we show for the first time that interleukin-1 receptor-associated kinase participates in Nod2-dependent NF-kappaB activation. Additionally, dominant negative interleukin-1 receptor-associated kinase 2, tumor necrosis factor receptor-associated factor 6, NF-kappaB-inducing kinase, transforming growth factor-beta-activated kinase-binding protein 2, and transforming growth factor-beta-activated kinase 1 also inhibited Nod2-dependent NF-kappaB activation. We finally demonstrate that in C57BL/6 mouse lung tissue in vivo as well as in the bronchial epithelial cell line BEAS-2B, Nod1 and Nod2 mRNA expressions were up-regulated after pneumococcal infection. Data presented suggest that Nod proteins contribute to innate immune recognition of S. pneumoniae. Furthermore, Rip-2 and members of the Toll-like receptor-signaling cascade are involved in the Nod2-dependent activation of NF-kappaB induced by pneumococci.