An experimental model of scalp expansion: a method of optimizing flap size and shape

An experimental model has been developed for testing and comparing the placement and characteristics of expanders for soft-tissue advancement. Expanders are fixed to model heads and covered with a stockinet sleeve, and the sleeve is impregnated with prevulcanized latex. The resulting stockinet-latex has many of the physical properties of skin and can be manipulated to ensure optimal covering and suture length prior to surgery. The system is rapid and reliable. Several types of scalp flaps were tested using the model. The models can be used in teaching and prior to surgery. Their use ensures an à la carte expansion that minimizes the risk of expansion failure.     

Prevention of in-stent restenosis: towards an in situ treatment?

The use of intracoronary stents represent a major breakthrough in the armamentarium of interventional cardiology. Stents reduce significantly the incidence of recurrent stenosis (in-stent restenosis) via an improved post-procedure luminal diameter and an abrogation of the constrictive remodeling of the arterial wall. However, stent-related arterial injury results in intense proliferative and inflammatory responses and severe intimal hyperplasia, which, in 20% to 40% of the patients, may end up with clinically significant in-stent restenosis. Efficient prevention of in-stent restenosis has yet to be found. Systemic treatments have failed because they don't take into account the specific physiopathology and, most importantly, the focal nature of in-stent intimal hyperplasia. Hence, local prevention appears to be a straightforward approach to the unsolved issue of in-stent restenosis. In situ beta- or gamma-irradiation (brachytherapy) has received much attention as a curative treatment of in-stent restenosis but is not indicated for prevention. In contrast, drug-releasing stents have been tested in experimental models and have already provided very promising results in randomized clinical trials. Most of clinical studies have been performed with the antiproliferative agents sirolimus and paclitaxel, but other agents are under scrutiny. In addition, important research is carried out, in which the efficacy of antiproliferative genes is investigated. Clearly, drug-releasing stents are on the verge of profoundly modifying our practice of interventional cardiology. However, several questions remain unanswered as regard to the long term efficacy/toxicity and the cost-effectiveness of this new approach.     

Comparison of artificial neural network and logistic regression models for predicting in-hospital mortality after primary liver cancer surgery

Background

Since most published articles comparing the performance of artificial neural network (ANN) models and logistic regression (LR) models for predicting hepatocellular carcinoma (HCC) outcomes used only a single dataset, the essential issue of internal validity (reproducibility) of the models has not been addressed. The study purposes to validate the use of ANN model for predicting in-hospital mortality in HCC surgery patients in Taiwan and to compare the predictive accuracy of ANN with that of LR model.

Methodology/Principal Findings

Patients who underwent a HCC surgery during the period from 1998 to 2009 were included in the study. This study retrospectively compared 1,000 pairs of LR and ANN models based on initial clinical data for 22,926 HCC surgery patients. For each pair of ANN and LR models, the area under the receiver operating characteristic (AUROC) curves, Hosmer-Lemeshow (H-L) statistics and accuracy rate were calculated and compared using paired T-tests. A global sensitivity analysis was also performed to assess the relative significance of input parameters in the system model and the relative importance of variables. Compared to the LR models, the ANN models had a better accuracy rate in 97.28% of cases, a better H-L statistic in 41.18% of cases, and a better AUROC curve in 84.67% of cases. Surgeon volume was the most influential (sensitive) parameter affecting in-hospital mortality followed by age and lengths of stay.

Conclusions/Significance

In comparison with the conventional LR model, the ANN model in the study was more accurate in predicting in-hospital mortality and had higher overall performance indices. Further studies of this model may consider the effect of a more detailed database that includes complications and clinical examination findings as well as more detailed outcome data.     

Promoting blood vessel growth in ischemic diseases: challenges in translating preclinical potential into clinical success

Angiogenic therapy, which involves the use of an exogenous stimulus to promote blood vessel growth, is an attractive approach for the treatment of ischemic diseases. It has been shown in animal models that the stimulation of blood vessel growth leads to the growth of the whole vascular tree, improvement of ischemic tissue perfusion and improved muscle aerobic energy metabolism. However, very few positive results have been gained from Phase 2 and 3 clinical angiogenesis trials. Many reasons have been given for the failures of clinical trials, including poor transgene expression (in gene-therapy trials) and instability of the vessels induced by therapy. In this Review, we discuss the selection of preclinical models as one of the main reasons why clinical translation has been unsuccessful thus far. This issue has received little attention, but could have had dramatic implications on the expectations of clinical trials. We highlight crucial differences between human patients and animal models with regards to blood flow and pressure, as well as issues concerning the chronic nature of ischemic diseases in humans. We use these as examples to demonstrate why the results from preclinical trials might have overestimated the efficacy of angiogenic therapies developed to date. We also suggest ways in which currently available animal models of ischemic disease could be improved to better mimic human disease conditions, and offer advice on how to work with existing models to avoid overestimating the efficacy of new angiogenic therapies.     

Dendritic cells: limited potential in immunotherapy

Dendritic cells (DC) represent the most potent antigen-presenting cells (APC) of the immune system for their unique capability of presenting antigen to T-cells. Their use as cellular vaccines after charging with antigen ex vivo has been shown to induce protective and therapeutic anti-tumor immunity with regression of tumor manifestations in animal models of experimental cancer therapy. Human monocyte-derived DC (MoDC) generated in vitro in the presence of GM-CSF and IL-4 are regarded equivalent to immature DC. They can be induced to mature under various experimental conditions. MoDC, in their immature as well as mature state have been widely used for experimental as well as for clinical purposes. However, unequivocal proof for the clinical efficiency of MoDC-based anti-tumor vaccinations is still missing. There is now increasing experimental evidence demonstrating that MoDC may be hampered in their ability to migrate in response to inflammatory as well as homeostatic chemataxins. We therefore suggest that MoDC may not represent the equivalent of migratory DC in vivo limiting their use as magic bullets in tumor immunotherapy.     

An Approach Based on Mutually Informed Neural Networks to Optimize the Generalization Capabilities of Decision Support Systems Developed for Heart Failure Prediction

Available clinical methods for heart failure (HF) diagnosis are expensive and require a high-level of experts intervention. Recently, various machine learning models have been developed for the prediction of HF where most of them have an issue of over-fitting. Over-fitting occurs when machine learning based predictive models show better performance on the training data yet demonstrate a poor performance on the testing data and the other way around. Developing a machine learning model which is able to produce generalization capabilities (such that the model exhibits better performance on both the training and the testing data sets) could overall minimize the prediction errors. Hence, such prediction models could potentially be helpful to cardiologists for the effective diagnose of HF. This paper proposes a two-stage decision support system to overcome the over-fitting issue and to optimize the generalization factor. The first stage uses a mutual information based statistical model while the second stage uses a neural network. We applied our approach to the HF subset of publicly available Cleveland heart disease database. Our experimental results show that the proposed decision support system has optimized the generalization capabilities and has reduced the mean percent error (MPE) to 8.8% which is significantly less than the recently published studies. In addition, our model exhibits a 93.33% accuracy rate which is higher than twenty eight recently developed HF risk prediction models that achieved accuracy in the range of 57.85% to 92.31%. We can hope that our decision support system will be helpful to cardiologists if deployed in clinical setup.     

Stereoscopically observed deformations of a compliant abdominal aortic aneurysm model

A new experimental setup has been implemented to precisely measure the deformations of an entire model abdominal aortic aneurysm (AAA). This setup addresses a gap between the computational and experimental models of AAA that have aimed at improving the limited understanding of aneurysm development and rupture. The experimental validation of the deformations from computational approaches has been limited by a lack of consideration of the large and varied deformations that AAAs undergo in response to physiologic flow and pressure. To address the issue of experimentally validating these calculated deformations, a stereoscopic imaging system utilizing two cameras was constructed to measure model aneurysm displacement in response to pressurization. The three model shapes, consisting of a healthy aorta, an AAA with bifurcation, and an AAA without bifurcation, were also evaluated with computational solid mechanical modeling using finite elements to assess the impact of differences between material properties and for comparison against the experimental inflations. The device demonstrated adequate accuracy (surface points were located to within 0.07?mm) for capturing local variation while allowing the full length of the aneurysm sac to be observed at once. The experimental model AAA demonstrated realistic aneurysm behavior by having cyclic strains consistent with reported clinical observations between pressures 80 and 120?mm Hg. These strains are 1-2%, and the local spatial variations in experimental strain were less than predicted by the computational models. The three different models demonstrated that the asymmetric bifurcation creates displacement differences but not cyclic strain differences within the aneurysm sac. The technique and device captured regional variations of strain that are unobservable with diameter measures alone. It also allowed the calculation of local strain and removed rigid body motion effects on the strain calculation. The results of the computations show that an asymmetric aortic bifurcation created displacement differences but not cyclic strain differences within the aneurysm sac.     

Impact of hyperoxia on cardiac pathophysiology

Mechanical ventilation with high oxygen therapy (hyperoxia) is widely implemented in critical care and ICU settings. Although supplemental oxygen is beneficial to treat hypoxia, its use is also associated with poor outcomes and high mortality in patients. Lung injury due to hyperoxia exposure has been well-documented in patients, including in adults and neonates. Thus, lung injury due to hyperoxia has been extensively researched in both preclinical and clinical studies. However, hyperoxia has also been shown to be associated with hemodynamic changes in patients in ICU, including reductions in heart rate, stroke volume, and cardiac output. In addition, certain experimental studies report that hyperoxia exposure in neonates results in cardiac dysfunction in later adult life. Despite this, until recently, the impact of hyperoxia within the heart has not been well studied, or reported, specifically in adult experimental models. To close this significant gap, our lab has sought to clarify hyperoxia-induced cardiac pathophysiology in adult murine models. This review discusses the current findings regarding the cardiovascular impact of hyperoxia exposure.     

Myocardial ischemia, reperfusion, and infarction in chronically instrumented, intact, conscious, and unrestrained mice

In the United States alone, the National Heart, Lung, and Blood Institute (NHLBI) has invested several hundred million dollars in pursuit of myocardial infarct-sparing therapies. However, due largely to methodological limitations, this investment has not produced any notable clinical application or cardioprotective therapy. Among the major methodological limitations is the reliance on animal models that do not mimic the clinical situation. In this context, the limited use of conscious animal models is of major concern. In fact, whenever possible, studies of cardiovascular physiology and pathophysiology should be conducted in conscious, complex models to avoid the complications associated with the use of anesthesia and surgical trauma. The mouse has significant advantages over other experimental models for the investigation of infarct-sparing therapies. The mouse is inexpensive, has a high throughput, and presents the ability of one to create genetically modified models. However, successful infarct-sparing therapies in anesthetized mice or isolated mouse hearts may not be successful in more complex models, including conscious mice. Accordingly, a conscious mouse model of myocardial ischemia and reperfusion has the potential to be of major importance for advancing the concepts and methods that drive the development of infarct-sparing therapies. Therefore, we describe, for the first time, the use of an intact, conscious, and unrestrained mouse model of myocardial ischemia-reperfusion and infarction. The conscious mouse model permits occlusion and reperfusion of the left anterior descending coronary artery in an intact, complex model free of the confounding influences of anesthetics and surgical trauma. This methodology may be adopted for advancing the concepts and ideas that drive cardiovascular research.     

低温在脊髓损伤治疗中应用的研究进展

脊髓损伤多由高空坠落、车祸、运动冲击等原因引起,是脊柱外科的一种常见疾病,至今仍是一个治疗难题。低温疗法是一种重要的物理治疗手段,以多种机制减少脊髓损伤后有害因素的产生,是一种有效的脊髓保护途径。其在脊髓损伤的研究中表现出很好的效果,为脊髓损伤的治疗提供了新的思路,然而也发现一些低温治疗导致的全身性或某些系统为主的不良影响,需要我们进一步研究和解决,以期达到更好的治疗效果。本文就低温治疗用于脊髓损伤应用中的研究进展进行综述。     

Regional intravascular sympathetic blockade for better results in flap surgery: an experimental study of free flaps, island flaps, and pedicle flaps in the rabbit ear

Flap survival is still a major problem in reconstructive surgery. Increased flap survival after systemic administration of drugs inhibiting the adrenergic system has been reported in experimental studies. The clinical use, however, is restricted by systemic side effects. It has been demonstrated that, using guanethidine, an effective regional intravascular sympathetic (RIS) block can be obtained without systemic effects. Using this type of block, an experimental study was made on the survival and quality of different types of flaps in the rabbit ear. The results obtained in 72 flaps created in the ears of 36 rabbits were assessed by the extent of flap edema, peripheral neovascularization, flap temperature, and flap surviving area. The RIS block reduced edema and scab formation, caused higher flap temperatures, better neovascularization, and increased surviving flap area, as compared with equal flaps in the untreated contralateral ear of the same animal. The effect of RIS block may be considered as a "pharmacological delay" procedure. From the experiments as well as clinical experience, it may be concluded that this technique is a safe and effective procedure. Therefore, the RIS block method is recommended for clinical use in flap techniques in extremities of man.     

Dying T lymphocytes call for the death of tumor cells

Immunotherapy that specifically targets tumor cells is the preferred approach to induce tumor regression.Over the pastdecade,significant progress has been made in devising various methods to direct the immune system to respond to tumorcells.The major hurdle for successful immunotherapy is to overcome immune tolerance in the tumor microenvironment.Recent clinical trials with dendritic cell-based vaccination[1,2]and CTLA4 blocking antibodies[3]have shown greatpromise,though complete cancer regression is not always achieved[4].Currently,alternative strategies potentially leadingto cancer eradication or regression in animal or clinical models are being enthusiastically pursued.In this issue of CellResearch,Wang et al.report a novel way to induce tumor immunity by the use of irradiated autologous T cells[5].     

CD36: A multi-modal target for acute stroke therapy

A role for CD36 in the pathogenesis of atherosclerosis, inflammation and lipid metabolism has been well-documented. However, little is known about the role of CD36 in cerebral ischemia. The intent of this review is to develop the concept that CD36, whose functions have been implicated in other pathological events, is a prototypic inflammatory receptor that contributes to the pathogenesis of cerebral ischemia. The importance of CD36 as a treatment target is indicated by the fact that many treatment strategies that are effective in experimental models of stroke exhibit little or no efficacy in clinical trials. The failure of clinical trials may be due to the use of animal models of stroke that do not reflect traditional risk factors for stroke in humans. The discussion will be focused on two risk factors, hyperlipidemia and diabetes, that modulate CD36 responses. Blocking the expression and function of CD36 by pharmacological or genetic means will provide insight not only toward identifying CD36 as a novel molecular target but also for developing effective therapeutic strategies to treat stroke victims. More importantly, coupling clinically relevant conditions with CD36-mediated ischemic injury may provide an appropriate animal model paradigm and develop a scientific understanding that could lead to clinical translational studies involving human subjects.     

Human adipose stem cells: current clinical applications

Adipose-derived stem cells are multipotent cells that can easily be extracted from adipose tissue, are capable of expansion in vitro, and have the capacity to differentiate into multiple cell lineages, which have the potential for use in regenerative medicine. However, several issues need to be studied to determine safe human use. For example, there are questions related to isolation and purification of adipose-derived stem cells, their effect on tumor growth, and the enforcement of U.S. Food and Drug Administration regulations. Numerous studies have been published, with the interest in the potential for regenerative medicine continually growing. Several clinical trials using human adipose stem cell therapy are currently being performed around the world, and there has been a rapid evolution and expansion of their number. The purpose of this article was to review the current published basic science evidence and ongoing clinical trials involving the use of adipose-derived stem cells in plastic surgery and in regenerative medicine in general. The results of the studies and clinical trials using adipose-derived stem cells reported in this review seem to be promising not only in plastic surgery but also in a wide variety of other specialties. Nevertheless, those reported showed disparity in the way adipose-derived stem cells were used. Further basic science experimental studies with standardized protocols and larger randomized trials need to be performed to ensure safety and efficacy of adipose-derived stem cells use in accordance with U.S. Food and Drug Administration guidelines.     

Objectives and Methods of Iron Chelation Therapy

Recent developments in the understanding of the molecular control of iron homeostasis provided novel insights into the mechanisms responsible for normal iron balance. However in chronic anemias associated with iron overload, such mechanisms are no longer sufficient to offer protection from iron toxicity, and iron chelating therapy is the only method available for preventing early death caused mainly by myocardial and hepatic damage. Today, long-term deferoxamine (DFO) therapy is an integral part of the management of thalassemia and other transfusion-dependent anemias, with a major impact on well-being and survival. However, the high cost and rigorous requirements of DFO therapy, and the significant toxicity of deferiprone underline the need for the continued development of new and improved orally effective iron chelators. Within recent years more than one thousand candidate compounds have been screened in animal models. The most outstanding of these compounds include deferiprone (L1); pyridoxal isonicotinoyl hydrazone (PIH) and; bishydroxy- phenyl thiazole. Deferiprone has been used extensively as a substitute for DFO in clinical trials involving hundreds of patients. However, L1 treatment alone fails to achieve a negative iron balance in a substantial proportion of subjects. Deferiprone is less effective than DFO and its potential hepatotoxicity is an issue of current controversy. A new orally effective iron chelator should not necessarily be regarded as one displacing the presently accepted and highly effective parenteral drug DFO. Rather, it could be employed to extend the scope of iron chelating strategies in a manner analogous with the combined use of medications in the management of other conditions such as hypertension or diabetes. Coadministration or alternating use of DFO and a suitable oral chelator may allow a decrease in dosage of both drugs and improve compliance by decreasing the demand on tedious parenteral drug administration. Combined use of DFO and L1 has already been shown to result in successful depletion of iron stores in patients previously failing to respond to single drug therapy, and to lead to improved compliance with treatment. It may also result in a “shuttle effect” between weak intracellular chelators and powerful extracellular chelators or exploit the entero-hepatic cycle to promote fecal iron excretion. All of these innovative ways of chelator usage are now awaiting evaluation in experimental models and in the clinical setting.     

Quantum and classical dynamics in biochemical reactions

The classic experiment of deVault and Chance touched off a long series of theoretical and experimental studies of the interplay between quantum and classical dynamics in photosynthetic electron transfer. More recently these issues have also been addressed in experiments on ligand binding reactions in heme proteins and through the study of kinetic isotope effects in enzymatic proton transfer. Theoretical effort has focused on a class of relatively simple models which display a surprisingly rich spectrum of dynamical behavior. Much less attention has been paid to a very important issue: Why are we allowed to use such simple models to describe such obviously complex molecules? Here we provide some tentative answers to this question, contrasting the cases of electron and proton transfer. We suggest that ideas based on simple models can inspire novel strategies for ‘realistic’ simulations, and that we can begin to think about the general problems of enzymatic catalysis in terms of dynamical pictures that previously have been applied only to the simpler case of electron transfer.     

Stem cell therapy and diabetic erectile dysfunction: A critical review

Erectile dysfunction (ED) has been identified as one of the most frequent chronic complications of diabetes mellitus (DM). The prevalence of ED is estimated to be about 67.4% in all DM cases worldwide. The pathophysiological process leading to ED involves endothelial, neurological, hormonal, and psychological factors. In DM, endothelial and neurological factors play a crucial role. Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM. The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery. However, these treatments are limited in terms of just relieving the symptoms, but not resolving the cause of the problem. The use of stem cells for treating ED is currently being studied mostly in experimental animals. The stem cells used are derived from adipose tissue, bone, or human urine. Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue. However, research on stem cell therapy for ED in humans remains to be limited. Nevertheless, significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.     

飞秒激光在白内障手术中的应用新进展

飞秒激光辅助的白内障手术是目前最热门的白内障手术之一。即在计算机系统引导下利用飞秒激光进行透明角膜切口的制作,晶状体核裂解和晶状体前囊膜的切开,明显降低了传统超声乳化手术中的并发症,具有十分广阔的临床应用前景。然而飞秒激光辅助的白内障手术目前仍然处于临床应用初级阶段,其昂贵的价格是影响其研究和应用的主要原因,手术安全性及远期屈光效果仍然需要长期的随访观察。本文根据文献资料,就飞秒激光在白内障手术中的优势及临床应用的局限性进行综述。     

Does Applicability Domain Exist in Microarray-Based Genomic Research?

Constructing an accurate predictive model for clinical decision-making on the basis of a relatively small number of tumor samples with high-dimensional microarray data remains a very challenging problem. The validity of such models has been seriously questioned due to their failure in clinical validation using independent samples. Besides the statistical issues such as selection bias, some studies further implied the probable reason was improper sample selection that did not resemble the genomic space defined by the training population. Assuming that predictions would be more reliable for interpolation than extrapolation, we set to investigate the impact of applicability domain (AD) on model performance in microarray-based genomic research by evaluating and comparing model performance for samples with different extrapolation degrees. We found that the issue of applicability domain may not exist in microarray-based genomic research for clinical applications. Therefore, it is not practicable to improve model validity based on applicability domain.