The therapy of complicated Kaposiform hemangioendothelioma (KHE) is still difficult. We present the first case of laryngomalacia with simultaneous mammalian target of Rapamycin (mTOR)-positive KHE of ...the neck and thoracic inlet and concurrent Kasabach-Meritt Phenomenon (KMP) in an 11-month-old boy suffering life-threatening progress despite intravenous vincristine, corticosteroids, propranolol and local interstitial laser-application. The laryngomalacia restored after laser-supraglottoplasty. Successfully treatment of the prior fatal course of the KHE with KMP was initiated not till adding the mTOR inhibitor sirolimus to therapy. After 16 months single therapy of KHE with oral sirolimus the boy presented free of symptoms with minimal residual disease and excellent functional long-term results. Thus we stopped sirolimus therapy. The results are stable for 9 months without therapy. The special features including full report of histopathologic findings of this utmost complicated case are demonstrated in detail underlining the effectiveness of sirolimus for KHE.
The extracellular matrix of articular cartilage is the primary target of osteoarthritic cartilage degradation. However, cartilage cells have a pivotal role during osteoarthritis, as they are mainly ...responsible for the anabolic-catabolic balance required for matrix maintenance and tissue function. In addition to the severe changes in the extracellular matrix, the cells also display abnormalities during osteoarthritic cartilage degeneration, such as inappropriate activation of anabolic and catabolic activities, and alterations in cell number through processes like proliferation and (apoptotic) cell death. The cells are exposed to additional stimuli such as nonphysiologic loading conditions and byproducts of matrix destruction, as well as abnormal levels of cytokines and growth factors. This exposure can lead to a structured cellular response pattern that may be either beneficial or detrimental to the cartilage tissue. Potentially even more problematic for preserving tissue homeostasis, neighboring osteoarthritic chondrocytes display strong heterogeneity in their phenotype, gene expression patterns, and cellular responses. As the disease progresses, osteoarthritic chondrocytes can no longer maintain tissue integrity. Evidence suggests that cell aging is important in the pathogenesis of osteoarthritis. Thus, anti-aging strategies might complement existing therapeutic targets related to anabolism, catabolism, inflammation, and apoptosis-processes that are integral to the pathogenesis of osteoarthritis.
A side-by-side comparison of bioaugmentation, biostimulation, and a recirculation-only control was implemented in a chloroethene-contaminated aquifer. The objective was to develop a contaminant mass ...balance based on the analysis of groundwater and aquifer solids and to quantify key dechlorinating populations during treatment to determine their relation to the rate of chloroethenes removed. The bioaugmentation strategy, using a Dehalococcoides-containing PCE-to-ethene dechlorinating inoculum enriched from the same aquifer, resulted in a near-stoichiometric dechlorination of both sorbed and dissolved chloroethenes to ethene within 6 weeks. In the biostimulation plot, continuous lactate and nutrient injection resulted in dechlorination but only following a 3-month lag period. Molecular tools targeting the 16S rRNA genes of Dehalococcoides and Desulfuromonas spp. were used to qualitatively monitor the distribution and quantitatively (Real-Time PCR) measure the abundance of the dechlorinating populations during the test. In the bioaugmentation plot, Dehalococcoides populations increased 3−4 orders of magnitude throughout the test area. Dehalococcoides populations also increased in the biostimulation plot but at a slower rate and immediately before the onset of rapid dechlorination. Terminal Restriction Fragment Length Polymorphism analysis indicated that the inoculum only impacted the bioaugmentation plot. This work extends the knowledge gained from previous field studies which reported qualitative relationships between the occurrence of Dehalococcoides populations and ethene production. Furthermore, the results demonstrate that bioreactive barriers capitalizing on reductively dechlorinating populations to control the migration of chloroethene plumes can be effectively designed once hydrologic information is incorporated.
Eco-agriculture is the trend of rural development in this age. This research uses the moringa tree as an example to build up the eco-agricultural and renewable framework for a typical village in ...Ghana. An energy balance is analyzed using an urbs tool, while business and financial models are built up following MVP (minimum viable product).
Objective In risk stratification of aortic diseases such as aneurysm and aortic dissection, diameter is one parameter whose influence on the average aortic wall stress is directly described by the ...Laplace law. More advanced mechanical models can be used and may yield additional information, such as transmural stress distributions. The question then arises of how refined models need to be to provide clinicians with practical help. Methods Two sets of finite element models were used. The relative roles of diameter, material stiffness, longitudinal stretch, blood pressure, wall thickness, and vessel curvature were explored using simplified aortic models for comparison with the Laplace law. The influences of the material properties nonlinearity and residual stress on the transmural stress distribution were investigated using an advanced aortic model including recent experimental findings in older humans. Results The Laplace law was confirmed as one effective, basic tool to assess the average wall stress in the aortic wall, both in the circumferential and longitudinal directions. However, the simplified models were sufficient to show that, as already reported in the literature, longitudinal stretch and vessel curvature have potentially equally strong or even stronger contributions to wall stress than the parameters included in the Laplace law. When the advanced model was used, and residual stress induced by large opening angles such as found in older subjects was introduced, the transmural stress gradient was found inverted compared with expectations, with the largest stresses now toward the adventitia. The results suggested that the intima may be increasingly shielded from higher stresses as one gets older, which might be protective against the initiation of dissection tears in the thoracic aorta. Conclusion Biomechanical analysis of the aorta may be refined by using increasingly detailed computational models. Simplified models can readily improve on the Laplace law in the assessment of aortic wall stress, and as such, may already contribute to better risk stratification of aortic disease. Advanced models may also enhance our understanding of the mechanistic aspects in the pathogenesis of aortic disease. However, their applicability in a patient-specific context may be limited by the large number of input data they require, some of which might stay out of the clinicians' reach.
Summary Background Composite tissue allotransplantation (CTA) is a newly emerging field of transplantation. Immunological research in CTA has been intensified due to the recent clinical success of ...hand and face transplantation. Establishing immunological tolerance by adoptive transfer of ex vivo cultured tolerance-inducing cell types is of growing interest. Transplant acceptance-inducing cells (TAICs) are a type of deactivated immunoregulatory macrophages. Methods A total of 36 allogeneic hind limb transplantations in the rat were performed in six groups. Group A (Lewis (LW) → Brown-Norway (BN)) received Lewis-donor-derived TAICs locally (i.m.). Group B (LW → BN) received Lewis-donor-derived TAICs systemically (i.v.) and group C (Sprague Dawley (Sp-D) → BN) served as a control group receiving Lewis-donor-derived TAICs systemically (i.v.). Groups D (LW → BN), E (LW → BN), and F (BN → BN) also served as control groups with group D receiving no immunosuppression, group E receiving FK506 and prednisolone and group F receiving no immunosuppression with isograft transplantations (BN → BN). The timing of rejection was assessed by clinical observation and histological findings. Results Rejection of the allogeneic hind limb occurred on average 7.7 days after transplantation in group A and 7.4 days in group B. Rejection was significantly delayed (Log-rank test, p < 0.01) compared to groups C and D, where rejection of the allogeneic hind limb occurred on average 5.8 days and 5.6 days after transplantation. No rejection was seen in groups E and F. Conclusion For the first time, TAICs have been applied in a CTA model and demonstrated a significant immunosuppressive effect. Even though the immunomodulatory effect is relatively modest, the results of this study justify subsequent research on TAIC therapy to improve experimental and clinical outcome after CTA.
Summary Background/Objective Currently, due to lack of optimal donors, more marginal organs are transplanted. Therefore, there is a high interest to ameliorate preischemic organ preservation, ...especially for critical donor organs. In this regard, a new histidine-tryptophane ketoglutarate (HTK-N) solution has been designed and its protective efficacy was compared with the standard preservation solutions—University of Wisconsin solution and standard HTK or Custodiol (Bretschneider's solution). Methods Seventy-two landrace pigs were included into the study, as donors and recipients. The donor kidneys were perfused during explantation with cold University of Wisconsin solution ( n = 12), standard HTK ( n = 12), or HTK-N solutions ( n = 12), kept in the respective preservation solution at 4°C for 30 hours, implanted in the recipient pigs, and reperfused. The pigs survived in daily control for 7 days. The serum creatinine and blood urea nitrogen were assessed in pre- and postreperfusion phase on the 3rd day and 7th day posttransplantation. Additionally, tissue samples were taken to analyze the histopathological degree of tubular injury and regeneration before and after reperfusion. Results The three preservation groups were comparable in age, body weight, and hemodynamic parameters. According to statistical proof, they differed in none of the control parameters. Conclusion Although the new preservation HTK solution is in several points a well-thought-out modification of the standard HTK solution, its preservation efficacy, at least for kidney preservation in a pig model for 30 hours, seems to be comparable to the current used solutions. A real advantage, however, could be confirmed in clinical settings, where marginal organs may influence the clinical outcome.
Background Trypsinogen activation, oxygen radicals, cytokines, leukocyte infiltration, and pancreatic ischemia are important steps in the pathogenesis of necrotizing pancreatitis and associated ...systemic complications. Several drugs that inhibit those pathogenetic steps attenuated biochemical and histologic changes, while survival remained low. The aim of the present study was to evaluate the benefit of multidrug approaches compared to monotherapies on organ injury and survival in acute experimental pancreatitis in the rat model of retrograde bile injection combined with intravenous cerulein. Methods Necrotizing pancreatitis was induced in rats. After a therapy-free interval of 6 hours, 10 treatment regimens were evaluated: multidrug regimen 1, which contained the protease inhibitor gabexate mesilate, oxygen-free radical scavengers, nitric oxide donor L-arginine, a platelet-activating factor antagonist, and antibodies against intracellular adhesion molecule-1 (ICAM-1) dissolved in dextran, was compared to multidrug regimen 2 (dextran, acetylcysteine, L-arginine, and anti–ICAM-1), monotherapies of each of the drugs, and standard intravascular volume replacement. Results Both multidrug regimens significantly reduced pancreatic and systemic injury and microcirculatory disturbances compared to any of the monotherapies. Treatment with regimen 1 decreased 24-hour mortality to 0% and increased long-term survival to 85% (standard therapy, 70% and 15%, respectively). Multidrug regimen 2 was as effective as regimen 1. Conclusion Treatment of acute necrotizing pancreatitis with multidrug regimens significantly decreases short-term mortality compared to monotherapies. Moreover, multidrug strategies are still effective after a wide therapeutic window. Key to this effective therapy is the inhibition of microcirculatory disturbances and of the systemic inflammatory response. The experimental superiority of the multidrug approach should be confirmed in a clinical trial.
Summary Objective The initiation/progression factors of osteoarthritic (OA) cartilage degeneration and the involved biological mechanisms remain rather enigmatic. One core reason for this might be a ...cellular senescence-like phenotype of OA chondrocytes, which might show a fundamentally different behavior pattern unexpected from the biological mechanism established in young cells. Design This study was designed to investigate one core property of senescent cells, the heterogeneity of gene expression, in OA chondrocytes by double-labeling immunolocalization using two genes (vimentin, S-100 protein) as surrogates, which are constitutively expressed by (normal) chondrocytes. The level of genomic DNA damage in OA chondrocytes was compared to normal chondrocytes and in vitro experiments designed to demonstrate that stochastic genomic DNA damage is able to induce heterogeneity of gene expression in chondrocytes. Results We show a significantly increased heterogeneity of gene expression for vimentin and S-100 protein as well as a significantly increased genomic DNA damage in the OA compared to normal chondrocytes, whereas no evidence of critical telomere shortening was found. In vitro experiments demonstrated that stochastic genomic DNA damage induced by increased oxidative or genotoxic stress is able to induce the heterogeneity in gene expression found in the OA cells in situ. Conclusions Our results suggest that OA chondrocytes show a special form of age-related cell degeneration, “progressive/stress-induced senescence”, progressing over time due to accumulated DNA damage and subsequent chaotic gene activation pattern. This promotes increased malfunctioning of the cells and finally the loss of their capacity to keep up cell and tissue homeostasis, i.e., prevent OA.
Background and purpose
This study investigated the prognostic role of tumor cell expression of erythropoietin (EPO) and its receptor (EPO-R) in patients with locally advanced squamous cell carcinoma ...of the head and neck (SCCHN) treated with surgery plus radiotherapy.
Patients and methods
The impact of EPO, EPO-R, and 11 additional factors on locoregional control (LRC), metastases-free survival (MFS), and overall survival (OS) was retrospectively evaluated in 144 patients. Additional factors were age, gender, performance status, preradiotherapy (pre-RT) hemoglobin levels, tumor site, histologic grade, T category, N category, human papillomavirus (HPV) status, extent of resection, and chemotherapy. Univariate analyses were performed with the Kaplan–Meier method and the log-rank test, multivariate analyses with the Cox proportional hazard model.
Results
On multivariate analysis, improved LRC was significantly associated with no EPO expression (risk ratio RR 3.72; 95 % confidence interval CI 1.35–15.42; p = 0.008), lower T category (RR 1.60; 95 %CI 1.14–2.32; p = 0.005), and oropharynx or larynx cancer (RR 1.23; 95 %CI 1.02–1.49; p = 0.033). Improved MFS was significantly associated with no EPO expression (RR 5.45; 95 %CI 1.13–97.81; p = 0.031), lower T category (RR 1.66; 95 %CI 1.11–2.65; p = 0.013), lower N category (RR 2.44; 95 %CI 1.04–6.66; p = 0.039), HPV positivity (RR 3.14; 95 %CI not available; p = 0.034), and oropharynx or larynx cancer (RR 1.28; 95 %CI 1.01–1.61; p = 0.041). Improved OS was significantly associated with no EPO expression (RR 4.77; 95 %CI 1.63–20.68; p = 0.003), no EPO-R expression (RR 2.36; 95 %CI 1.22–4.92; p = 0.010), lower T category (RR 1.44; 95 %CI 1.04–2.04; p = 0.027), oropharynx or larynx cancer (RR 1.30; 95 %CI 1.08–1.57; p = 0.007), and pre-RT hemoglobin ≥ 12 g/dl (RR 1.94; 95 %CI 1.03–3.65; p = 0.042).
Conclusion
EPO expression of tumor cells was an independent prognostic factor for LRC, MFS, and OS. EPO-R expression was an independent prognostic factor for OS.
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