Composition of Bacteriophages for Therapeutic and Prophylactic Use in Monkeys.

Keeping rhesus monkeys as laboratory animals requires timely prevention and treatment of infections, including diseases of bacterial etiology. Based on our own studies of the microflora of healthy and sick monkeys, as well as analysis of published reports, we identified clinically significant representatives of pathogenic and opportunistic bacteria: E. coli, Staphylococcus aureus, Klebsiella spp., Proteus spp. The isolates of these bacterial species and genera circulating in monkeys kept in the enclosure were isolated, four virulent bacteriophage strains with a wide spectrum of lytic activity against these isolates were selected and newly isolated. The composition based on virulent bacteriophage strains was tested on monkeys with assessment of its safety and its dynamics of detection of phage-specific DNA.

[Heart failure: ventricular assist devices and cardiac transplantation : A review of current surgical innovations]. / Kardiales Pumpversagen: Herzunterstützungssysteme und Herztransplantation : Eine Übersicht aktueller chirurgischer Innovationen.

BACKGROUND: End-stage heart failure is one of the leading causes of death in Germany. Cardiac transplantation is still considered the gold standard for the treatment of terminal heart failure; however, there is a discrepancy between patients on the waiting list and yearly performed transplantations. As an alternative, ventricular assist devices have achieved a high level of importance but treatment is still associated with challenges. Novel systems as well as innovative surgical techniques contribute to improving the safety and effectiveness of the treatment. OBJECTIVE: To generate an overview of current surgical innovations in cardiac transplantation and mechanical circulatory support. MATERIAL AND METHODS: A Medline search was conducted regarding innovations in cardiac transplantation and mechanical circulatory support. RESULTS AND CONCLUSION: Not only the number of yearly performed cardiac transplantations has changed but also recipient profiles. While in the pioneering era of transplantation the typical candidate was young, not previously operated on and with lower levels of comorbidities, today's patients are significantly older, have been fitted with ventricular assist devices and have increased operative risk profiles. Modern methods of organ preservation enable longer transportation and operation times as well as an improved assessment of graft function and perspectives for graft optimization in the future. In the area of ventricular assist devices, advances in the reduction of the stroke rate seem to have been achieved by the latest generation devices. From a surgical perspective, less invasive surgical techniques with promising initial results have been established at numerous centers.

Lobe-wise assessment of lung volume and density distribution in lung transplant patients and value for early detection of bronchiolitis obliterans syndrome.

PURPOSE: To evaluate quantitative computed tomography (CT) measurements of the lung parenchyma in lung transplant (LTx) patients for early detection of the bronchiolitis obliterans syndrome (BOS). MATERIALS AND METHODS: 359 CT scans of 122 lung transplant patients were evaluated. Measurements of lung volume and density were performed for the whole lung and separately for each lobe. For longitudinal analysis the difference between the baseline at 6 months after LTx and follow-up examinations was calculated. Patients with and without BOS (matched 1:2) were compared at two different time points, the last examination before the BOS onset and the first examination within one year after BOS onset. RESULTS: 30 patients developed BOS during the follow-up period. Longitudinal changes in the lung volume and lung density measured on CT differed significantly between those patients with and without early BOS, in particular the difference of the inspiratory and expiratory lung volume (p < 0.001), the ratio of the expiratory and inspiratory lung volume (p < 0.001-p = 0.001) and MLD (p < 0.001-p = 0.001), the volume on expiration (p < 0.001-p = 0.007), the MLD on expiration (p < 0.001-p = 0.007), and the percentiles on expiration (p < 0.001-p = 0.002) with an increase of lung volume and a decrease of lung density. Changes were pronounced in the lower lobes. Before BOS onset, patients with and without future development of BOS showed no significant differences. CONCLUSION: Longitudinal changes of lung volume and lung density measured on CT start markedly at BOS onset with increased lung volume and decreased lung density indicating increased inflation levels. Even though this method may help to diagnose BOS at onset it is not useful as a predictor for BOS before disease onset.

Preoperative serum uric acid predicts incident acute kidney injury following cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) following cardiac surgery is a frequent complication and several risk factors increasing its incidence have already been characterized. This study evaluates the influence of preoperative increased serum uric acid (SUA) levels in comparison with other known risk factors on the incidence of AKI following cardiac surgery. METHODS: During a period of 5 month, 247 patients underwent elective coronary artery bypass grafting, valve replacement/ repair or combined bypass and valve surgery. Datas were prospectively analyzed. Primary endpoint was the incidence of AKI as defined by the AKI criteria comparing patients with preoperative serum uric acid (SUA) levels below versus above the median. Multivariate logistic regression analysis was used to identify independent predictors of postoperative AKI. RESULTS: Thirty (12.1%) of the 247 patients developed postoperative AKI, 24 of 30 (80%) had preoperative SUA- levels above the median (≥373 µmol/l) (OR: 4.680, CI 95% 1.840; 11.904, p = 0.001). In the multivariate analysis SUA levels above the median (OR: 5.497, CI 95% 1.772; 17.054, p = 0.003), cardiopulmonary bypass (CPB) time > 90 min (OR: 4.595, CI 95% 1.587; 13.305, p = 0.005), cardiopulmonary bypass (CPB) > 30 kg/m2 (OR: 3.208, CI 95% 1.202; 8.562; p = 0.02), and preoperative elevated serum-creatinine levels (OR: 1.015, CI 95% 1.001; 1.029, p = 0.04) were independently associated with postoperative AKI. CONCLUSIONS: Serum uric acid is an independent risk marker for AKI after cardiac surgery. From all evaluated factors it showed the highest odds ratio.

Single lung transplantation from a donor 8 months after double lung transplantation.

Scarcity of donors leads transplant surgeons to consider extended-criteria lungs and occasionally to accept the unlikely. Here we report a case of successful single lung transplantation from a donor 8 months after double lung transplantation.

Guidelines versus reality: is coronary stent application in three-vessel disease standard or the exception?

The national guidelines for treatment of chronic coronary heart disease (CHD) recommend surgical coronary aortic bypass grafting (CABG) rather than percutaneous coronary intervention (PCI) for patients with a coronary three-vessel disease. The epidemiology of three-vessel CHD and data about the application of different revascularisation strategies raise suspicion of deviation from the guidelines in the treatment of those patients. Claims data containing records of almost 10 million patients of the largest German statutory health insurance fund (Techniker Krankenkasse) were utilised to measure adherence to the guidelines for treatment of groups of patients with one-, two-, and three-vessel CHD, respectively. The impact of age, sex, and comorbidity on each patient's revascularisation procedure was investigated as well. There was no significant difference in the rate of PCI between the groups. In conclusion, the hypothesis that patients with a coronary three-vessel disease are not always treated according to the recommendations of the national guidelines could not be disproved by this study. Finally, the results of this study suggest that the best revascularisation strategy for each patient with two- and three-vessel disease should be decided upon by an interdisciplinary discussion between both cardiologists and cardiac surgeons.

TIMP3 is Regulated by Pericytes upon Shear Stress Detection Leading to a Modified Endothelial Cell Response.

OBJECTIVES: Atherosclerosis is a hallmark of cardiovascular disease. Shear stress on endothelial cells has been linked to atherogenesis and to fibrous cap thinning and rupture. Pericytes reside in the sub-endothelial space of vessels and have vasoprotective effects. They are subjected to shear stress when endothelial cell integrity is disrupted. The aim was to investigate the susceptibility and response of pericytes to shear stress. METHODS: Endothelial cells and pericytes were seeded in two dimensional monocultures and co-cultures, and in a novel three dimensional co-culture system and were subjected to no, low and high shear stress (0, 10, 30 dyne/cm2) for 48 h. The morphological response to flow was assessed by histology and the expression of extracellular matrix proteins was analysed using quantitative polymerase chain reaction, immunoblotting, and ELISA. RESULTS: While endothelial cells aligned into flow direction, pericytes aligned perpendicularly (p < .001), indicating that they must be capable of sensing flow. When pericytes were embedded into a 3D matrix they showed similar alignment and pericytes built long processes towards the lumen. Under shear stress endothelial cells upregulated "a disintegrin and metalloproteinase with thrombospondin motif 1" (ADAMTS-1) (p < .01) and pericytes upregulated "tissue inhibitor of matrix metalloproteinase" (TIMP) 3 (p < .05), an inhibitor of ADAMTS-1, meanwhile differential expression of extracellular matrix (ECM) proteins could be detected in co-cultures of both cells. For TIMP3 expression direct cell-cell contact between endothelial cells and pericytes was required. CONCLUSION: The experiments highlight that pericytes are able to sense direct flow thereby regulating ECM proteins known to be involved in vascular remodelling. Furthermore, pericytes counter-regulate endothelial ADAMTS-1 by protective TIMP3 expression to prevent matrix degradation and maintain vascular stability. For this protective effect direct cell contact was necessary. This observation might represent an adaptive, protective mechanism of pericytes to counteract endothelial damage in the onset of atherosclerosis.

Development and Characterization of a Porcine Mitral Valve Scaffold for Tissue Engineering.

Decellularized scaffolds represent a promising alternative for mitral valve (MV) replacement. This work developed and characterized a protocol for the decellularization of whole MVs. Porcine MVs were decellularized with 0.5% (w/v) SDS and 0.5% (w/v) SD and sterilized with 0.1% (v/v) PAA. Decellularized samples were seeded with human foreskin fibroblasts and human adipose-derived stem cells to investigate cellular repopulation and infiltration, and with human colony-forming endothelial cells to investigate collagen IV formation. Histology revealed an acellular scaffold with a generally conserved histoarchitecture, but collagen IV loss. Following decellularization, no significant changes were observed in the hydroxyproline content, but there was a significant reduction in the glycosaminoglycan content. SEM/TEM analysis confirmed cellular removal and loss of some extracellular matrix components. Collagen and elastin were generally preserved. The endothelial cells produced newly formed collagen IV on the non-cytotoxic scaffold. The protocol produced acellular scaffolds with generally preserved histoarchitecture, biochemistry, and biomechanics.

[Cardiac surgery in the elderly]. / Herzchirurgie im Alter.

Due to the increasing demographic changes and the fact that cardiovascular diseases are still the leading cause of death, the mean chronological age of patients undergoing cardiac surgery is steadily increasing. In 2015, 14.8% of these patients were aged 80 years and older. This meta-analysis reviewed if and under what circumstances elderly patients benefit from cardiac surgical procedures without running the risk of limitations in the quality of life and high rates of morbidity and mortality. Generally, the chronological age was not a risk factor for higher perioperative and postoperative morbidity and mortality but the biological age was the critical factor, in particular the associated comorbidities of patients and the timing of the surgical procedure in the course of the disease. The result is that elective operations resulted in a better outcome than operations in a symptomatic or decompensated stage of a disease. Compared to patients receiving conventional medicinal therapy, elderly patients undergoing cardiac surgery had an improved life expectancy. A significant increase in the quality of life could also be identified and was ultimately comparable to those of younger patients after cardiac surgery; therefore, elderly patients even those over 80 years old benefit in all aspects of cardiac surgery, as long as individually adapted operative techniques are considered.

Association of Higher CD4+ CD25high CD127low , FoxP3+ , and IL-2+ T Cell Frequencies Early After Lung Transplantation With Less Chronic Lung Allograft Dysfunction at Two Years.

Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLAD at 2 years. Among lung-transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+ CD25high T cells and further analyzed for CTLA4, CD127, FoxP3, and IL-2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLAD within 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+ CD25high CD127low , CD4+ CD25high FoxP3+ and CD4+ CD25high IL-2+ T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLAD at 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLAD development.

Streptococcus mitis and Gemella haemolysans were simultaneously found in atherosclerotic and oral plaques of elderly without periodontitis-a pilot study.

OBJECTIVES: Local infections may contribute to the initiation and progression of several clinical diseases in humans. Atherosclerotic plaques of subjects suffering from periodontitis are colonized by periopathogens; however, the presence of bacteria in atherosclerotic plaques in patients without severe forms of periodontitis is of high relevance for the general population. MATERIALS AND METHODS: Patients who were electively treated for atherosclerotic lesions of the carotid artery and without clinical signs of periodontitis were eligible for the study. Oral and atherosclerotic plaques were sampled, processed, and analyzed for their microbial composition by 454-sequencing. RESULTS: Seventeen patients were included in the analyses, and 76 % of all atherosclerotic plaque specimens were positive for bacterial DNA. In the oral plaques, 76,532 sequences were identified representing 1 phylum, 17 classes, 112 families, and 263 genera. In atherosclerotic plaques, 6112 sequences representing 1 phylum, 4 classes, 8 families, and 36 genera were found. The bacterial DNAs of the species Gemella haemolysans and Streptococcus mitis were simultaneously found in atherosclerotic as well as oral plaque samples of 3 patients. CONCLUSIONS: These results indicated that in subjects without periodontitis, the transmission of oral bacteria to atherosclerotic plaques of the carotid artery is a feasible event. CLINICAL RELEVANCE: The prevention of transient bacteremia from the oral cavity requires high levels of oral health.

Pulmonary metastasectomy - A retrospective comparison of surgical outcomes after laser-assisted and conventional resection.

INTRODUCTION: Indications and surgical techniques for pulmonary metastasectomy (PME) are controversially discussed issues. Laser-assisted surgery (LAS) is a recent innovation that has been advocated especially in patients with multiple pulmonary metastases (PM). However, there are hardly any studies comparing surgical outcomes after laser-assisted and conventional resection. The aim of the current study was to evaluate the value of LAS in a larger study population. MATERIALS & METHODS: A retrospective analysis was completed on 178 consecutive patients undergoing 236 PMEs at a single center between 2010 and 2015. The main endpoint was survival. Statistical analysis was performed using the Kaplan-Meier method and survival rates were compared with the log rank test. Follow-up was done with special attention to the development of recurrent PM. Local relapse was defined as a recurrent metastasis in direct relation to the previously resected area according to CT scan comparisons. RESULTS: LAS was performed on 256 metastases in 99 patients, non-laser-assisted surgery (NLAS) on 127 metastases in 79 patients. 5-year-survival rates were 69.3% in all patients, 65.7% after LAS and 73.6% after NLAS. There was no statistically significant survival difference after LAS or NLAS (p = 0.41). The rate of local relapse was 0.8% after LAS vs 3.1% after NLAS (p = 0.073). CONCLUSION: Despite a larger number of negative predictors for survival in LAS patients, overall survival (OS) was similar in the compared groups. There was also a trend for a lower risk of local relapses after LAS. Therefore, LAS should be considered a promising method for PME.

In Vivo Development of Transplant Arteriosclerosis in Humanized Mice Reflects Alloantigen Recognition and Peripheral Treg Phenotype of Lung Transplant Recipients.

Experimentally, regulatory T cells inhibit rejection. In clinical transplantations, however, it is not known whether T cell regulation is the cause for, or an epiphenomenon of, long-term allograft survival. Here, we study naïve and alloantigen-primed T cell responses of clinical lung transplant recipients in humanized mice. The pericardiophrenic artery procured from human lung grafts was implanted into the aorta of NODrag-/- /IL-2rγc-/- mice reconstituted with peripheral blood mononuclear cells (PBMCs) from the respective lung recipient. Naïve or primed allogeneic PBMCs procured 21 days post-lung transplantation with or without enriching for CD4+ CD25high T cells were used. Transplant arteriosclerosis was assessed 28 days later by histology. Mice reconstituted with alloantigen-primed PBMCs showed significantly more severe transplant arteriosclerosis than did mice with naïve PBMCs (p = 0.005). Transplant arteriosclerosis was equally suppressed by enriching for autologous naïve (p = 0.012) or alloantigen-primed regulatory T cells (Tregs) (p = 0.009). Alloantigen priming in clinical lung recipients can be adoptively transferred into a humanized mouse model. Transplant arteriosclerosis elicited by naïve or alloantigen-primed PBMCs can be similarly controlled by potent autologous Tregs. Cellular therapy with expanded autologous Tregs in lung transplantation might be a promising future strategy.

A new era of thoracic oncology? Ex-vivo stereotactic ablative radiosurgery within Ex-vivo Lung Treatment System as a hybrid therapy for unresectable locally advanced pulmonary malignancies.

The concept of oligometastases is the medical rationale for a local treatment of a limited number of metastatic tumor manifestations. Patients with pulmonary oligometastases are candidates for surgery or radiotherapy, however there are a number of technical issues that limit treatment. Technical issues relating to radiotherapy include organs at risk of irradiation, chest wall toxicity and decreased precision of tumor targeting because of breathing movements. Technical issues relating to surgery include loss of lung parenchyma and unresectability. We propose the hypothesis that ex-vivo radiosurgery as new hybrid technique in thoracic oncology has the capability to overcome these technical issues and will expand the medical spectrum in thoracic oncology. The proposed - highly complex - technique consists of surgical lung explantation, followed by stereotactic radiotherapy during ex-vivo perfusion followed by surgical re-implantation.

[Pioneering surgical innovations in Germany : Part 2: public funding and origins of surgical innovations]. / Bahnbrechende chirurgische Innovationen in Deutschland : Teil 2: Öffentliche Finanzierung und Ursprünge chirurgischer Innovationen.

BACKGROUND: In recent years research that conforms with evidence-based medicine (EBM) has been demanded even in surgery. Uniform studies were carried out to prove the benefits of new procedures; however, compared to other research sectors, public third party funding for surgical research was significantly cut back. OBJECTIVE: Collation of special features in surgery with respect to external funding of surgical top level research. Examination of the benefits of a continuous promotion and of organizations involved in research. MATERIAL AND METHODS: Part one of this investigation presented the methods used to identify and analyze pioneering research in surgery. RESULTS: Out of a total of 15 revolutionary innovations only 3 projects were financed by external funding and 2 projects received indirect financial support as a result of a cooperation with the medical industry. This demonstrates that the majority of projects were neither directly nor indirectly subsidized. Apart from one instance the majority of innovations were generated by university hospitals highly active in research. DISCUSSION: In effect, the non-existing external funding for outstanding surgical innovations and hospitals suggests that a reformation of surgical research is required. To strengthen the quality of innovations in surgery a concentration of funding to institutions that are highly active in research makes sense. Institutional funding directly linked to a project should form a key component of support particularly in the early stages of development.

Phenotyping Chronic Lung Allograft Dysfunction Using Body Plethysmography and Computed Tomography.

Restrictive subtype of chronic lung allograft dysfunction (CLAD) was recently described after lung transplantation. This study compares different definitions of a restrictive phenotype in CLAD patients and impact on survival. Eighty-nine CLAD patients out of 1191 screened patients (September 1987 to July 2012) were included as complete longitudinal lung volume measurements and chest computed tomography (CT) after CLAD onset was available. CT findings and lung volumes were quantified and survival was calculated for distinctive groups and predictive factors for worse survival were investigated. Graft survival in patients with total lung capacity (TLC) between 90% and 81% of baseline (BL) (n = 13, 15%) in CLAD course was similar to those with TLC >90% BL (n = 64, 56%; log-rank test p = 0.9). Twelve patients (13%) developed a TLC ≤80% BL and 10 (11%) had significant parenchymal changes on CT, of whom 6 (46%) also had TLC ≤80% BL. CT changes correlated with TLC ≤80% BL (Φ-coefficient = 0.48, p = 0.001). Patients with either TLC ≤80% or significant CT changes (n = 16, 18%) had a significantly reduced survival (log-rank p < 0.001). Forced vital capacity loss at CLAD onset was associated with poorer survival but did not correlate with the TLC or CT changes. A restrictive subtype of CLAD may be defined by either TLC ≤80% BL or severe parenchymal changes on chest CT.

Suitability and Usability of Claims Data for Review of Guidelines for the Treatment of Chronic Heart Failure.

Background: Guidelines have special importance in medicine, however, it is questionable to what extent these recommendations are applied in daily care, and under which conditions claims data can be used for verification of guideline adherence. Method: Advantages and limitations of claims data for verification of guidelines compliance in the therapeutic area as well as the guidelines themselves were analysed and critically assessed. To substantiate these results, claims data of a major German health insurance fund (Techniker Krankenkasse) were analysed. Results: 104 236 patients were identified. With certain limitations, claims data are useful for verifying guideline adherence; it could be shown that in pharmacotherapy the beta-adrenergic receptor blocker was used to the highest extent (70.5%). In contrast, only 56.4% of patients were treated with pure ACE inhibitors and ACE combined preparation. Conclusion: In order to validate guideline adherence by means of claims data analyses, a number of conditions relating to the database, the therapeutic area and the guidelines themselves have to be considered. Guideline recommendations, which, for example, are based on clinical data, cannot be reviewed by using claims data. Despite these limitations, claims data provide a suitable tool for reviewing selected guideline recommendations. They show that the current use of pharmacotherapy as well as clinical and diagnostic interventions might be increased in accordance with the guideline recommendations.