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Polyethylene glycol (PEG) has previously been reported to improve outcomes of peripheral nerve microsuturing. However, recent studies have challenged this finding. Given its clinical importance, we investigated the potential of PEG as a facilitator of peripheral nerve restoration. The sciatic nerve of 144 rats was transected and submitted either to simple suturing (Group A), PEG-enhanced suturing (Group B), and insertion in an arterial sleeve conduit without PEG (Group C), or with PEG (Group D) in equal numbers. Behavioral recovery was assessed with the sciatic function index (SFI). Nerve impulse conduction was assessed with compound muscle action potentials (CMAPs). Histology comprised standard hematoxylin/eosin staining, electron microscopy and glial cell line-derived neurotrophic factor (GDNF) immunohistochemistry. Expression of GDNF was also assessed with western blotting. Results were evaluated at weeks 1, 4, and 8. PEG treatment significantly improved behavioral recovery and morphology of nerve restoration, particularly in the sleeve conduit group, relative to that of controls. In conclusion, PEG may improve outcomes of peripheral nerve reconstruction.

Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9−T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.

We investigate the properties of fundamental solitons supported by two-dimensional optical lattices with fractional-order diffraction. It is found that the first gap extends, while other finite gaps shrink by increasing the Levy index. There exists a threshold of the Levy index. Below the threshold, the power of soliton decreases monotonically as propagation constant increases. Above it, the power of soliton exists a minimum value. In addition, the Levy index has a great effect on the existence and stability of solitons. Under the same Levy index, the effective widths of solitons first decrease, and then increase by increasing propagation constant. However, for different propagation constants, the effective widths change differently with the increasing of Levy index.

Over the past 9 years since 2007, there has been growing interest in the field of small weight measurement, like determination of sensitivity property of microbalance. This drives the requirement for more accurate small weight measurement down to microgram level. NMIs researched on the microgram from manufacture, material and shape, storage and holding method, measurement equipment and weighing scheme. Subdivision comparison is commonly adopted and matrix method (MM) is used to solve the measurement Eq.. In this paper, the density of test and standard weight rather than the volume were adopted in MM. Details on how to use this method based on Matlab software were presented. Then the comparison between MM, Eqution method (EM) and full air-buoyancy correction method (FACM) were made. Differences between these three methods were analyzed and evaluation results were given out. Experiment showed that EM and FACM were of the same relative uncertainty, but MM had lower measurement uncertainty than EM and FACM.

Remote ischemia preconditioning (RIPC) is a convenient and effective method for alleviating cerebral ischemia-reperfusion injury (CIRI). However, to date, the underlying mechanism has not been fully elucidated. The aim of this research was to explore the protective mechanism of RIPC on the brain after CIRI. Four groups of rats were included in this experiment: the sham group, the middle cerebral artery occlusion (MCAO) group, the RIPC group, and the AG490 group. As an inhibitor of Janus kinase 2 (JAK2), AG490 was used after MCAO in the AG490 group to explore the role of JAK2/signal transducers and activators of transcription 3 (STAT3) after CIRI. Brain tissue was collected for evaluation after 2 h of ischemia and 24 h of reperfusion. ELISA for interleukin (IL)-6, IL-1β and tumor necrosis factor-α, western blot for phosphorylated-JAK2 and phosphorylated-STAT3, the neurological severity score and Longa scoring system for neurological deficit evaluation, triphenyltetrazolium chloride staining for cerebral infarction, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining for apoptotic cells in the brain tissue were performed. Neurological function in the RIPC group was notably better than that in the MCAO group. There were smaller infarction sizes and fewer apoptotic cells in the ischemic area in the RIPC group than in the MCAO group. In the RIPC group, the expression levels of IL-1β, tumor necrosis factor-α, IL-6, and phosphorylated-JAK2 and phosphorylated-STAT3 were significantly lower than those in the MCAO group. The findings in the RIPC and AG490 groups were similar. The inflammatory response and apoptosis are two important processes involved in brain dysfunction after CIRI. The JAK2/STAT3 signaling pathway has an underlying relationship with these two processes. These findings suggest that RIPC can alleviate the damage to brain tissue by CIRI by regulating the JAK2/STAT3 signaling pathway negatively.

Despite decades of animal experimentation, human translation with cell grafts, conduits, and other strategies has failed to cure patients with chronic spinal cord injury (SCI). Recent data show that motor deficits due to spinal cord transection in animal models can be reversed by local application of fusogens, such as Polyethylene glycol (PEG). Results proved superior at short term over all other treatments deployed in animal studies, opening the way to human trials. In particular, removal of the injured spinal cord segment followed by PEG fusion of the two ends along with vertebral osteotomy to shorten the spine holds the promise for a cure in many cases.

Cephalosomatic anastomosis has been carried out in both monkeys and mice with preservation of brain function. Nonetheless the spinal cord was not reconstructed, leaving the animals unable to move voluntarily. Here we review the details of the GEMINI spinal cord fusion protocol, which aims at restoring electrophysiologic conduction across an acutely transected spinal cord. The existence of the cortico-truncoreticulo-propriospinal pathway, a little-known anatomic entity, is described, and its importance concerning spinal cord fusion emphasized. The use of fusogens and electrical stimulation as adjuvants for nerve fusion is addressed. The possibility of achieving cephalosomatic anastomosis in humans has become reality in principle.

Residual stresses and their optimization in terms of machining and service performance represent both a serious barrier to better materials processing, usage, and an opportunity in terms of surface engineering and life extension. It is therefore that there is a considerable amount of researches on developing predictive models for machining-induced residual stress such as analytical model, computational/numerical model. However, these developed models for residual stress prediction are operational complexity, time-consuming and low prediction efficiency. For the purpose of avoiding the large number of time-consuming experimental work, a hybrid technique combining the finite element method and the statistical model is developed in this paper. On the basis of the simulation residual stress, the exponentially damped cosine function is fitted using a particle swarm optimization method. It was found that values of fitting accuracy R2 are ranging from 81.7 to 99.2% in peripheral milling of titanium alloy Ti-6Al-4V. Sensitivity to cutting speed and feed rate of four key features of the residual stress profile including surface residual stress (σr,Sur), compressive stress peak value (σC,ax) and location (hr0), response depth (hry) are investigated. The four key features showed the similar sensitivity to cutting speed and feed rate. Performance of σr,Sur changed from compressive to tensile, while σC,ax decreased, hr0 and hry increased with the increase of cutting speed and feed rate. However, the trend was not significant at low feed rate. Using the proposed procedure, the optimum cutting conditions could be obtained to control the residual stress of milling titanium alloy Ti-6Al-4V and also other metals.

The use of superalloy Inconel 718 is increasing inmost of sophisticated applications such as aircraft and rocket engines. However, the high work hardening behavior of Inconel 718 has not been studied sufficiently yet. In the present work, an experimental work was made to study the relationship between work hardening and cutting parameters (cutting speed and feed rate) in turning Inconel 718. Depths of work hardening and degree of work hardening (DWH) at different depths beneath the machined surfaces were investigated to determine and understand the integrity of machined surfaces. It is observed that there was no significant difference with work hardening characteristics in this experiment to consider the error of measurement. The parameters (v = 50 m/min, f = 0.2 mm/r) may be better than others. An empirical model based on Meyer’s index with a view was utilized to understand the characteristics of machining-affected layers. From the obtained data, the work hardening can be better understood and controlled, which can be used to enhance the machinability and surface integrity characteristics of superalloy Inconel 718.

The evolution of solitons in the two-dimensional mixed linear–nonlinear complex optical lattices is investigated. It is found that the nonlinearity-modulation depth plays a significant role on the existence of solitons. Both the nonlinearity-modulation depth and amplitude of the imaginary part of nonlinear lattice have a great effect on the stability of solitons. Moreover, the period of nonlinear lattice can influence the properties of solitons dramatically. In addition, we also study the mobility of solitons and find that the soliton can maintain its original shape while the mass center of solitons will oscillate periodically in a certain tilt angle range. However, if the tilt angle is large enough, the soliton will be distorted and its mass center oscillates irregularly.

Subdivision comparisons of mass measurement are usually used in the mass dissemination for class $E_{1}$ mass standards from 1 kg to 1 mg or from 1 to 50 kg. Many equations of mass measurement are included in the subdivision comparisons. Therefore, matrix calculations for mass measurement are very convenient to get the true or conventional mass value of every weight compared. In conventional matrix equations, the important air buoyancy corrections are completely neglected, and uncertainties are normally calculated using the variance–covariance matrix. In this paper, we propose a new matrix calculation for both the system of weighing equations as well as the corresponding uncertainty budget using directly partial derivations of the weighting equations. The method is applied to a set of weights from 500 to $50~\mu $ g. An alternative method for evaluating uncertainties of matrix equations is by Monte Carlo simulation, introduced in this paper, to validate the calculation of uncertainty budget by means of the matrix method. (Some figures in this paper are in color only in the electronic version.)

Summary Aims The mouse model of allo-head and body reconstruction (AHBR) has recently been established to further the clinical development of this strategy for patients who are suffering from mortal bodily trauma or disease, yet whose mind remains healthy. Animal model studies are indispensable for developing such novel surgical practices. The goal of this work was to establish head transplant mouse model, then the next step through the feasible biological model to investigate immune rejection and brain function in next step, thereby promoting the goal of translation of AHBR to the clinic in the future. Methods and Results Our approach involves retaining adequate blood perfusion in the transplanted head throughout the surgical procedure by establishing donor-to-recipient cross-circulation by cannulating and anastomosing the carotid artery on one side of the body and the jugular vein on the other side. Neurological function was preserved by this strategy as indicated by electroencephalogram and intact cranial nerve reflexes. Conclusions The results of this study support the feasibility of this method for avoiding brain ischemia during transplantation, thereby allowing for the possibility of long-term studies of head transplantation.

The HEAVEN head transplant initiative needs human data concerning the acute restoration of motor transmission after application of fusogens to the severed cord in man. Data from two centuries ago prove that a fresh cadaver, after hanging or decapitation, can be mobilized by electrical stimulation for up to 3 hours. By administering spinal cord stimulation by applied paddles to the cord or transcranial magnetic stimulation to M1 and recording motor evoked potentials, it should be possible to test fusogens in fresh cadavers. Delayed neuronal death might be the neuropathological reason.

In June 2013, the world was taken by storm by the announcement that a full head (or body) transplant was possible.[1] This key achievement would have been made possible by the GEMINI spinal cord fusion protocol.

Background Cephalosomatic anastomosis (CSA) has never been attempted before in man as the transected spinal cords of the body donor and body recipient could not be "fused" back together. Recent advances made this possible. Here, we report on the surgical steps necessary to reconnect a head to a body at the cervical level. Methods Full rehearsal of a CSA on two recently deceased human cadavers was performed at Harbin Medical University, Harbin, China. Results The surgery took 18 hours to complete within the time frame planned for this surgery. Several advances resulted from this rehearsal, including optimization of the surgical steps, sparing of the main nerves (phrenics, recurrent laryngeal nerves), and assessment of vertebral stabilization. Conclusion Several specialties are involved in a full-scale CSA, including neck surgery, vascular surgery, orthopedic surgery, plastic surgery, gastrointestinal surgery, and neurosurgery, as well as the operating staff. This rehearsal confirmed the surgical feasibility of a human CSA and further validated the surgical plan. Education and coordination of all the operating teams and coordination of the operative staff was achieved in preparation for the live human CSA.

Cephalosomatic anastomosis or what has been called a "head transplantation" requires full reconnection of the respective transected ends of the spinal cords. The GEMINI spinal cord fusion protocol has been developed for this reason. Here, we report the first randomized, controlled study of the GEMINI protocol in large animals.We conducted a randomized, controlled study of a complete transection of the spinal cord at the level of T10 in dogs at Harbin Medical University, Harbin, China. These dogs were followed for up to 8 weeks postoperatively by assessments of recovery of motor function, somato-sensory evoked potentials, and diffusion tensor imaging using magnetic resonance imaging.A total of 12 dogs were subjected to operative exposure of the dorsal aspect of the spinal cord after laminectomy and longitudinal durotomy followed by a very sharp, controlled, full-thickness, complete transection of the spinal cord at T10. The fusogen, polyethylene glycol, was applied topically to the site of the spinal cord transection in 7 of 12 dogs; 0.9% NaCl saline was applied to the site of transection in the remaining 5 control dogs. Dogs were selected randomly to receive polyethylene glycol or saline. All polyethylene glycol-treated dogs reacquired a substantial amount of motor function versus none in controls over these first 2 months as assessed on the 20-point (0-19), canine, Basso-Beattie-Bresnahan rating scale (P.006). Somatosensory evoked potentials confirmed restoration of electrical conduction cranially across the site of spinal cord transection which improved over time. Diffusion tensor imaging, a magnetic resonance permutation that assesses the integrity of nerve fibers and cells, showed restitution of the transected spinal cord with polyethylene glycol treatment (at-injury level difference: P.02).A sharply and fully transected spinal cord at the level of T10 can be reconstructed with restoration of many aspects of electrical continuity in large animals following the GEMINI spinal cord fusion protocol, with objective evidence of motor recovery and of electrical continuity across the site of transection, opening the way to the first cephalosomatic anastomosis. (Surgery 2017;160:XXX-XXX.).

SummaryAims A successful cephalosomatic anastomosis (“head transplant”) requires, among others, the ability to control long-term immune rejection and avoidance of ischemic events during the head transference phase. We developed a bicephalic model of head transplantation to study these aspects. Methods and Results The thoracic aorta and superior vena cava of a donor rat were anastomosed with the carotid artery and extracorporeal veins of a recipient rat by vascular grafts. Before thoracotomy in the donor rat, the axillary artery and vein of the donor were connected to the carotid and the extracranial vein of the third rat through a silicone tube. The silicone tube was passed through a peristaltic pump to ensure donor brain tissue blood supply. There is no ischemia reperfusion injury in donor brain tissue analyzed by electroencephalogram. Postoperative donor has pain reflex and corneal reflex. Conclusions Peristaltic pump application can guarantee the blood supply of donor brain tissue per unit time, while the application of temperature change device to the silicone tube can protect the brain tissue hypothermia, postoperative experimental data show that there is no brain tissue ischemia during the whole operation. The application of vascular grafting can also provide the possibility of long-term survival of the model.

To evaluate the diagnosis model of serum tumor biomarker and several clinical features diagnose and classification for lung cancer, the solid protein chip technology (C-12) was used to detect the biomarkers of SF, CEA, CA242, NSE, CA125, CA19-9 and CA15-3 in serum and several clinical features of tumors and benign disease in elderly lung cancer patients were collected. Set up a discriminating analysis as a function diagnostic model in clinical elderly lung cancer diagnosis and sub-type discrimination. In combination of 2 obvious clinical indicators and 2 serum markers, it is possible to provide a diagnosis tool for lung cancer. With the help of mathematic model, it is promising to reduce the misjudgment risk based on the previous experience and therefore establish a reliable diagnosing function. This model is simple, cost-effective and easy to adapt in practice, and can also be used in screening of large population.

Background: Our study shows that a membrane sealant/fiber fusogen polyethylene glycol (PEG) applied immediately on a sharp section of the spinal cord can mend the cord and lead to exceptional levels of motor recovery, with some animals almost normal. Materials and Methods: Before deploying such technology in man, long-term data in large mammals that exclude delayed complications (e.g., central pain), confirm the stability of motor recovery, and provide histological evidence of fiber regrowth are necessary. Here, we provide such evidence in dogs followed up over 6 months and in 2 cases up to 1 year along with imaging and histologic data. Results: We show that dogs whose dorsal cord has been fully transected recover locomotion after immediate treatment with a fusogen (PEG). No pain syndrome ensued over the long term. Diffusion tensor imaging magnetic resonance and histological, including immunohistochemical, data confirmed the re-establishment of anatomical continuity along with interfacial axonal sprouting. Conclusions: This study proves that a form of irreversible spinal cord injury (SCI) can effectively be treated and points out a way to treat SCI patients.

Abdominal superficial surgical incision elicits cardioprotection against myocardial ischemia reperfusion (I/R) injury in mice. This cardioprotective phenomenon, termed remote preconditioning of trauma (RPCT), results in an 80 to 85 % reduction in cardiac infarct size. We evaluated cardioprotection and the molecular mechanisms of remote postconditioning of trauma (RPostCT) in a murine I/R injury model. Mice were analyzed using a previously established I/R injury model. An abdominal superficial surgical incision was made 45 min after myocardial ischemia at the end of coronary occlusion, and infarct size was determined 24 h after reperfusion. The results indicated that a strong cardioprotective effect occurred during RPostCT (56.94 ± 2.71 % sham vs. 15.58 ± 2.16 % RPostCT; the mean area of the infarct divided by the mean area of the region at risk; p ≤ 0.05; n = 10). Furthermore, pharmacological intervention revealed neurogenic signaling involvement in the beneficial effects of RPostCT via sensory and sympathetic thoracic nerves. Pharmacological experiments in transgenic mice demonstrated that bradykinin receptors, β-adrenergic receptors (AR), and protein kinase C were implicated in the cardioprotective effects of RPostCT. RPostCT significantly decreased myocardial infarction size via neurogenic transmission and various signaling pathways. This study describes a new cardiac I/R injury prevention method that might lead to the development of therapies that are more clinically relevant for myocardial I/R injury.

In order to utilize germplasm resources more efficiently for peanut (Arachis hypogaea L.) genetic improvement, a core collection of 576 accessions and a primary mini core collection of 298 accessions were developed previously from a collection of 6839 cultivated peanut lines stored at the Oil Crops Research Institute of Chinese Academy of Agricultural Sciences at Wuhan. For an efficient evaluation and characterization of the most useful agronomic and disease-resistant traits, an even smaller collection of peanut accessions that represent a spectrum of phenotypes could be more desirable. For this reason, a mini-mini core collection with 99 accessions from the core accessions was developed based on the analysis of 21 morphological traits. It was demonstrated that there were no significant differences between the core and mini-mini core collections in 20 out of the 21 morphological traits studied. Further, the mini-mini core collection captured the ranges of all of the 21 traits displayed in the core collection. The newly developed mini-mini core collection was assessed for resistance to bacterial wilt disease caused by Ralstonia solanacearum. Two accessions showing a high level of resistance to bacterial wilt were identified, demonstrating the usefulness of the mini-mini core collection. The mini-mini-core collection provides a more efficient means of germplasm evaluation and will be resequenced as part of the International Peanut Genome Consortium sequencing project at the UC-Davis Genome Center.

The GEMINI spinal cord fusion protocol exploits the ability of so-called fusogens, such as polyethylene glycol (PEG), to achieve rapid neural restoration of electrical continuity across the ends of a transected spinal cord. Experimental evidence suggests that motor recovery can occur after complete transection of the cervical and dorsal spinal cord in mice and rats following application of PEG. This allows for the possibility of spinal cord "reconstruction" in humans and even the possibility of head transplantation in the future.

A method used to detect anomaly and estimate the state of vehicle in driving was proposed. The kinematics model of the vehicle was constructed and nonholonomic constraint conditions were added, which refer to that once the vehicle encounters the faults that could not be controlled, the constraint conditions are violated. Estimation equations of the velocity errors of the vehicle were given out to estimate the velocity errors of side and forward. So the stability of the whole vehicle could be judged by the velocity errors of the vehicle. Conclusions were validated through the vehicle experiment. This method is based on GPS/INS integrated navigation system, and can provide foundation for fault detections in unmanned autonomous vehicles.

The transcription factor Nuclear Factor Kappa B (NF-κB) has been shown to be cardioprotective after permanent coronary occlusion (PO) and late ischemic preconditioning (IPC), and yet it is cell injurious after ischemia/reperfusion (I/R) in the heart. There is limited information regarding NF-κB-dependent cardioprotection, and the NF-κB-dependent genes that contribute to the cardioprotection after PO are completely unknown. The objective of the study was to identify NF-κB-dependent genes that contribute to cardioprotection after PO. Microarray analysis was used to delineate genes that potentially contribute to the NF-κB-dependent cardioprotection by determining the overlap between the set of PO regulated genes and genes regulated by NF-κB, using mice with genetic abrogation of NF-κB activation in the heart. This analysis identified 16 genes as candidates for NF-κB-dependent effects after PO. This set of genes overlaps with, but is significantly different from the set of genes we previously identified as regulated by NF-κB after IPC. The genes encoding heat shock protein 70.3 (hspa1a) and heat shock protein 70.1 (hspa1b) were the most significantly regulated genes after PO and were up-regulated by NF-κB. Results using knockout mice show that Hsp70.1 contributes to NF-κB-dependent cardioprotection after PO and likely underlies, at least in part, the NF-κB-dependent cardioprotective effect. Our previous results show that Hsp70.1 is injurious after I/R injury. This demonstrates that, like NF-κB itself, Hsp70.1 has antithetical effects on myocardial survival and suggests that this may underlie the similar antithetical effects of NF-κB after different ischemic stimuli. The significance of the research is that understanding the gene network regulated by NF-κB after ischemic insult may lead to identification of therapeutic targets more appropriate for clinical development.

Objective: The histidine-rich Ca-binding protein (HRC) is a Ca-storage protein in cardiac sarcoplasmic reticulum. Recent transgenic studies revealed that this protein inhibits the maximal rates of sarcoplasmic reticulum Ca-transport, leading to cardiac dysfunction. In view of the role of sarcoplasmic reticulum Ca-cycling in myocardial ischemia/reperfusion injury, we designed this study to gain further insight into the role of HRC during ischemia/reperfusion. Methods and results: The transgenic mouse model with cardiac-specific overexpression of HRC was utilized and cardiac contractile parameters were assessed before and after ischemia/reperfusion injury by Langendorff perfusion. After a 20-min stabilization period, the hearts were subjected to 40 min of global ischemia, followed by 60 min of reperfusion. We found that although transgenic (TG) hearts showed depressed cardiac function (25%) compared to wild types (WTs) at baseline, they exhibited better recovery of left ventricular developed pressure (86.6±2.6% in TGs vs. 58.3±4.0% in WTs of pre-ischemic values, Pb0.05) and higher rates of contraction and relaxation after ischemia/reperfusion than WTs. This improvement was accompanied by smaller infarcts (23.1±1.7% in TGs vs. 41.1±2.5% in WTs of infarct region-to-risk region ratio, Pb0.05) and lower creatine kinase release. Notably, the extent of apoptotic cell death was significantly attenuated, as evidenced by decreased DNA fragmentation, upregulation of the antiapoptotic protein Bcl-2, and downregulation of the active caspases (3, 9 and 12) following ischemia/reperfusion in TG hearts, compared with WTs. Extension of these studies to an in vivo model of 30-min myocardial ischemia, via coronary artery occlusion, followed by 24-h reperfusion, showed that the infarct region-to-risk region ratio was 9±0.9% in TGs, compared with 20.4±2.9% in WTs (Pb0.05). Conclusions: Our findings suggest that increased cardiac HRC expression protects against ischemia/reperfusion injury in the heart, resulting in improved recovery of function and reduced infarction.

Cephalosomatic anastomosis requires neuroprotective techniques, such as deep hypothermia, to preserve brain activity. Despite the failure of pharmacologic neuroprotection, new strategies, including ischemic pre- and postconitioning and the use of Perftoran, have to be explored to complement hypothermia. This article summarizes the field of brain protection during CSA and these promising strategies.

Background: A superficial abdominal surgical incision elicits cardioprotection against cardiac ischemia–reperfusion (I/R) injury in mice. This process, called remote preconditioning of trauma (RPCT), has both an early and a late phase. Previous investigations have demonstrated that early RPCT reduces cardiac infarct size by 80% to 85%. We evaluated the cardioprotective and molecular mechanisms of late-phase RPCT in a murine I/R injury model. Methods: Wild-type mice, bradykinin (BK) 2 receptor knockout mice, 3M transgenic mice (nuclear factor κB [NF-κb] repressor inhibitor of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha [IκBα(S32A, S36A, Y42F)]), and inducible nitric oxide synthase (iNOS) knockout mice were analyzed using a previously established I/R injury model. A noninvasive abdominal surgical incision was made 24 hours prior to I/R injury and the infarct size was determined at 24 hours post-I/R injury. Results: The results indicated that a strong cardioprotective effect occurred during late-phase RPCT (58.42% ± 1.89% sham vs 29.41% ± 4.00% late RPCT, mean area of the infarct divided by the mean area of the risk region; P ≤ .05; n = 10). Furthermore, pharmacological intervention revealed the involvement of neurogenic signaling in the beneficial effects of late RPCT via sensory and sympathetic thoracic nerves. Pharmacological experiments in transgenic mice-implicated BK receptors, β-adrenergic receptors, protein kinase C, and NF-κB but not iNOS signaling in the cardioprotective effects of late RPCT. Conclusion: Late RPCT significantly decreased myocardial infarct size via neurogenic transmission and various other signaling pathways. This protective mechanism differentiates late and early RPCT. This study describes a new cardiac I/R injury prevention method and refines the concept of RPCT.

Previous studies indicate that the consumption of a high fat diet (HFD) 24h-2wks prior to the experience of ischemic injury can decrease the size of the infarcted area (normalized to the area at ri...

The role of NF-kappaB in cardiac physiology and pathophysiology has been difficult to delineate due to the inability to specifically block NF-kappaB signaling in the heart. Cardiac-specific transgenic models have recently been developed that repress NF-kappaB activation by preventing phosphorylation at specific serine residues of the inhibitory kappaB (IkappaB) protein isoform IkappaBalpha. However, these models are unable to completely block NF-kappaB because of a second signaling pathway that regulates NF-kappaB function via Tyr42 phosphorylation of IkappaBalpha. We report the development of transgenic (3M) mouse lines that express the mutant IkappaBalpha(S32A,S36A,Y42F) in a cardiac-specific manner. NF-kappaB activation in cardiomyopathic TNF-1.6 mice is completely blocked by the 3M transgene but only partially blocked (70-80%) by the previously described double-mutant 2M [IkappaBalpha(S32A,S36A)] transgene, which demonstrates the action of two proximal pathways for NF-kappaB activation in TNF-alpha-induced cardiomyopathy. In contrast, after acute stimuli including administration of TNF-alpha and ischemia-reperfusion (I/R), NF-kappaB activation is blocked in both 2M and 3M transgenic mice. This result suggests that phosphorylation of the regulatory Ser32 and Ser36 predominantly mediates NF-kappaB activation in these situations. We show that infarct size after I/R is reduced by 70% in 3M transgenic mice, which conclusively demonstrates that NF-kappaB is involved in I/R injury. In summary, we have engineered novel transgenic mice that allow us to distinguish two major proximal pathways for NF-kappaB activation. Our results demonstrate that the serine and tyrosine phosphorylation pathways are differentially activated during different pathophysiological processes (cardiomyopathy and I/R injury) and that NF-kappaB contributes to infarct development after I/R.

Background Ischemic preconditioning (IPC) and remote IPC are cardioprotective phenomena in which ischemia of the myocardium or of a remote tissue, respectively, induces cardioprotection. Despite clinical evidence that surgical trauma can remotely affect myocardial infarction, to date there are no basic science studies addressing the effect of nonischemic trauma at distant sites upon cardiac ischemia/reperfusion (I/R) injury. The objectives of this study were to determine the effects of nonischemic remote surgical trauma upon infarct size after myocardial I/R and to determine the effects of TNF-α ablation upon cardioprotective phenomena. Materials and methods A minimally traumatic mouse model was used to ascertain the effect of remote nonischemic surgical trauma upon I/R injury. TNF-α knockout mice were employed to determine the effect of TNF-α ablation. Results Carotid artery vascular surgery remotely exacerbates cardiac I/R injury increasing infarct size by 287% (remote cardiac injury or RCI). Nonischemic, nonvascular trauma (abdominal incision) results in remote preconditioning of trauma (RPCT), decreasing infarct size by 81% (early phase) and 40% (late phase) relative to controls. Finally, TNF-α is required for late IPC but is not necessary for RCI or for RPCT. Conclusions We show that late IPC is TNF-α-dependent and describe two unique TNF-α-independent remote effects of nonischemic trauma upon myocardial infarction. Understanding the mechanism of these remote effects will allow the development of novel therapies for the treatment of ischemic heart disease. RPCT and TNF-α ablation have an additive protective effect suggesting that combinations of complementary approaches may be a useful strategy for maximizing the clinical efficacy of cardioprotective therapies.

Osteosarcoma cancer is one of the most lethal malignancies, and there is no effective preventive measure to date. Chamaejasmine is the major ingredient in Stellera chamaejasme L. Except its potent pain-relieving efficacy as reported, chamaejasmine also exerted its anti-tumor activity in several tumor models. Here, we reported that chamaejasmine had a profound anti-proliferative effect on human osteosarcoma cells in a concentration-dependent and time-dependent manner, which was associated with an increase of p21 and bax and a decrease of bcl-2 and consequently increased caspase-3 activity. The main mechanism of anti-tumor potency was mainly attributed to the induction of p53. Chamaejasmine hugely elevated the expression of p53. The results of p53 shRNA experiment further demonstrated that p53 knockdown severely impaired the sensitivity of tested cells to chamaejasmine, implicating the important role of p53 played in chamaejasmine's anti-tumor activity. In conclusion, results showed chamaejasmine induced apoptosis in MG63 cells and could be a candidate drug for osteosarcoma cancer chemoprevention.

Previous studies have demonstrated improvement of cardiac function occurs with acute consumption of a high-fat diet (HFD) after myocardial infarction (MI). However, no data exist addressing the effects of acute HFD upon the extent of injury after MI. This study investigates the hypothesis that short-term HFD, prior to infarction, protects the heart against ischemia-reperfusion (I/R) injury through NF-κB-dependent regulation of cell death pathways in the heart. Data show that an acute HFD initiates cardioprotection against MI (>50% reduction in infarct size normalized to risk region) after 24 h to 2 wk of HFD, but protection is completely absent after 6 wk of HFD, when mice are reported to develop pathophysiology related to the diet. Furthermore, cardioprotection after 24 h of HFD persists after an additional 24 h of normal chow feeding and was found to be dependent upon NF-κB activation in cardiomyocytes. This study also indicates that short-term HFD activates autophagic processes (beclin-1, LC-3) preischemia, as seen in other protective stimuli. Increases in beclin-1 and LC-3 were found to be NF-κB-dependent, and administration of chloroquine, an inhibitor of autophagy, abrogated cardioprotection. Our results support that acute high-fat feeding mediates cardioprotection against I/R injury associated with a NF-κB-dependent increase in autophagy and reduced apoptosis, as has been found for ischemic preconditioning.

Echo decorrelation imaging, a pulse-echo method that maps heat-induced changes in ultrasound echoes, was investigated for in vivo monitoring of thermal ablation in a liver cancer model. In open surgical procedures, rabbit liver with VX2 tumor was imaged by 64-element image-ablate arrays and sonicated at 5.00, 5.05, or 5.20 MHz by unfocused 32- or 64-element apertures for bulk ultrasound ablation and electronically focused 64-element apertures for focused ultrasound ablation. Echo decorrelation and integrated backscatter (IBS) images were formed from pulse-echo signals recorded during rest periods following each sonication pulse. Echo decorrelation images were corrected for motion- and noise-induced artifacts using measured echo decorrelation from corresponding sham trials. Sectioned ablated tissue was vitally stained with triphenyl tetrazolium chloride (TTC) and binary images were constructed based on local TTC uptake. Echo decorrelation was significantly greater in ablated regions than in non-ablated regions. Motion correction significantly reduced echo decorrelation in non-ablated regions. Prediction of cell death by echo decorrelation and IBS imaging was assessed using receiver operating characteristic (ROC) curves. Areas under the ROC curve (AUROC) were significantly greater than chance for corrected and uncorrected echo decorrelation as well as IBS. Corrected echo decorrelation predicted ablation significantly better than IBS for the focused ultrasound exposures. AUROC differences between corrected echo decorrelation and IBS were not statistically significant for the unfocused exposure group, for which the IBS AUROC was marginally higher, or for the combination of all exposures, for which the corrected echo decorrelation AUROC was marginally higher. These results confirm that echo decorrelation imaging can effectively predict local thermal ablation in vivo.

Twenty, 15, and 8 months after the first four successful human hand transplant procedures were performed in Lyon (France), Louisville (U. S.), and Guangzhou (China), the transplant teams convened in Louisville, Kentucky, to share their experiences at the Second International Symposium on Composite Tissue Allotransplantation. This article presents reconstructive and immunological data from these landmark procedures in tabular format, in an attempt to answer some key questions about early outcomes of clinical hand transplantation. On the basis of these data, the initial outcomes of the first four hand transplants are encouraging and warrant proceeding with additional hand transplantations.

Composite tissue allotransplantation (CTA) constitutes one of the last frontiers of microsurgery. Prior to its clinical application, the long-term efficacy of modern immunotherapy must be tested in a pre-clinical CTA model. Based on the concept of osteomyocutaneous forearm flap, we developed a CTA flap model in swine. After identifying the vascular territory of the flaps in six pigs (vascular casting), flaps were transplanted from mismatched donor to recipient pigs (n = 6). Rejection was assessed daily by visual inspection and histopathology of biopsy specimens. Recipient pigs were able to ambulate immediately following surgery. There were no flap failures owing to technical or surgical complications. Rejection occurred over a period of 7 days as manifested by edema, cellular infiltration, epidermalysis, and thrombosis. This pre-clinical flap model is excellent for evaluating the effectiveness of modern immunotherapy because it is anatomically and immunologically relevant and because the minimal morbidity caused to the animal permits long-term studies.

Our laboratory previously developed and used an orthotopic radial forelimb osteomyocutaneous flap in the pig as a preclinical composite tissue allograft (CTA) model. To ensure that it mimicked the clinical situation as closely as possible we developed this model taking many immunologic and reconstructive considerations into account. While our original pig CTA model was ideal for studying the methods of preventing skin, muscle, bone, vessel and nerve rejection, and systemic toxicity, it did not include specialized tissues/structures of a joint and digit. Therefore, we were unable to evaluate rejection of these specialized tissues and their functional properties. Recognizing the importance of assessing joint rejection and function in hand transplantation research we developed a new swine forelimb CTA model that included the animal's medial digit. The present study describes the anatomy and the transplantation technique used in this new preclinical CTA model. We transplanted a radial osteomyocutaneous flap that included the medial digit between two size- (17-21 kg) and age- (6-8-week) matched farm pigs. We removed the digit from the recipient pig's forelimb in continuity with a section of the radial bone and replaced it with the same structure transplanted from a donor pig. After transplantation, a full-length cast was placed on the recipient pig's operated limb and changes in flap color, temperature and the presence of edema were monitored continuously for 6 h, and then regularly at predetermined intervals over 4 days. No weight bearing restrictions were placed on the animal's operated limb. After 4 days, the animal was euthanized. Direct visual monitoring of the allograft during 4 days revealed it was viable with no signs of graft failure due to technical complications associated with the transplant procedure. Upon waking from anesthesia, the animal stood and wandered freely about its cage with no apparent difficulty. Based on the animal's high level of activity at this time, we concluded that the procedure caused it minimal morbidity. At 4 days after the operation, early signs of rejection (skin erythema and edema) were observed. By incorporating a digit into our original CTA pig forelimb model we have made it a better model for performing preclinical hand transplant studies. The added advantage of being able to assess methods of preventing rejection in the specialized joint/digital tissues (articular cartilage, digital flexor and extensor systems, the nail complex) and assess long-term function of these structures is important. The fact that the procedure does not cause major morbidity to the animal makes it possible to conduct long-term graft survival and functional studies.

Background. High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment. Methods. Radial forelimb osteomyocutaneous flap transplants were performed between size-matched out-bred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens. Results. In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain. Conclusions. Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction ofFK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.

Background. For the first time, we define and correlate visual and histologic grading systems of composite tissue allograft (CTA) skin rejection in a large-animal model and determine the utility of these grading systems for early diagnosis and monitoring of rejection. Materials and methods. Sixteen pairs of outbred swine underwent transplant of a forelimb osteomyocutaneous free flap. Group I ( n = 6) did not receive immunosuppressive therapy. Group II ( n = 10) received oral cyclosporin A, mycophenolate mofetil, and prednisone. The flap was visually inspected and protocol skin biopsies were taken at frequent intervals over a 90-day period. Visual Grades 0 (no rejection) to 4 (severe rejection) were assigned based on skin color, bleeding from biopsy site, and blister formation. Histologic Grades 0 to 4 were assigned based on the degree of vasculitis, folliculitis, dermal inflammation, and epidermal degeneration present. Results. All Group I animals progressively rejected their graft by Day 7. Group II grafts survived from 19 and 90 days; 93% of 115 biopsy specimens were read to be within ±1 histologic score of their assigned flap visual grade. Visual assessment carried an 8% false positive and 39% false negative rate with regard to biopsy-proven rejection. However, 81% of missed rejection specimens were histologic Grade 1. Biopsy, when visually indicated, would detect all rejection episodes when histologically Grade 1 or 2 and still potentially reversible. Conclusions . Visual scoring of CTA skin serves as a useful tool for initially detecting rejection, but repeated histologic evaluation is necessary for monitoring the subsequent course of the graft.