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Pediatric HTs account for 13% of all HTs with >60% of recipients surviving at least 10 years post-HT. The purpose of this systematic review is to synthesize the literature on exercise capacity of pediatric HT recipients to improve understanding of the mechanisms that may explain the decreased exercise capacity. Six databases were searched for studies that compared the exercise capacity of HT recipients ≤21 years old with a control group or normative data. Sixteen studies were included. Pediatric HT recipients, as compared to controls or normative data, exhibit significantly higher resting HR, and at peak exercise exhibit significantly decreased HR, VO 2 , power, work, minute ventilation, and exercise duration. Peak VO 2 appears to improve within the first 2.5 years post-HT; peak work remains constant; and there is inconclusive evidence that peak HR, HR recovery, and HR reserve improve with time since HT. These results are discussed in the context of the mechanisms that may explain the impaired exercise capacity of pediatric HT recipients, including chronotropic incompetence, graft dysfunction, side effects of immunosuppression therapy, and deconditioning. In addition, the limited literature on rehabilitation after pediatric HT is summarized., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To investigate whether standardized motor development screening and assessment tools that are used to evaluate motor abilities of children aged 0 to 2 years are valid in cultures other than those in which the normative sample was established., Method: This was a systematic review in which six databases were searched. Studies were selected based on inclusion/exclusion criteria and appraised for evidence level and quality. Study variables were extracted., Results: Twenty-three studies representing six motor development screening and assessment tools in 16 cultural contexts met the inclusion criteria: Alberta Infant Motor Scale (n=7), Ages and Stages Questionnaire, 3rd edition (n=2), Bayley Scales of Infant and Toddler Development, 3rd edition (n=8), Denver Developmental Screening Test, 2nd edition (n=4), Harris Infant Neuromotor Test (n=1), and Peabody Developmental Motor Scales, 2nd edition (n=1). Thirteen studies found significant differences between the cultural context and normative sample. Two studies established reliability and/or validity of standardized motor development assessments in high-risk infants from different cultural contexts. Five studies established new population norms. Eight studies described the cross-cultural adaptation of a standardized motor development assessment., Interpretation: Standardized motor development assessments have limited validity in cultures other than that in which the normative sample was established. Their use can result in under- or over-referral for services., (© 2016 Mac Keith Press.)

Leg joint coordination systematically changes over the first months of life, yet there is minimal data on the underlying change in muscle torques that might account for this change in coordination. The purpose of this study is to investigate the contribution of torque changes to early changes in leg joint coordination. Kicking actions were analyzed of 10 full-term infants between 6 and 15-weeks of age using three-dimensional kinematics and kinetics. We found 11 of 15 joint angle pairs demonstrated a change from more in-phase intralimb coordination at 6-weeks to less in-phase coordination at 15-weeks. Although the magnitude of joint torques normalized to the mass of the leg remained relatively consistent, we noted more complex patterns of torque component contribution across ages. By focusing on the change in torques associated with hip-knee joint coordination, we found that less in-phase hip-knee joint coordination at 15-weeks was associated with decreased influence of knee muscle torque and increased influence of knee gravitational and motion-dependent torques, supporting that infants coordinate hip muscle torque with passive knee gravitational and motion-dependent torques to generate kicks with reduced active knee muscle torque. We propose that between 6 and 15-weeks of age less in-phase hip-knee coordination emerges as infants exploit passive dynamics in the coordination of hip and knee motions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Task-specific actions emerge from spontaneous movement during infancy. It has been proposed that task-specific actions emerge through a discovery-learning process. Here a method is described in which 3-4 month old infants learn a task by discovery and their leg movements are captured to quantify the learning process. This discovery-learning task uses an infant activated mobile that rotates and plays music based on specified leg action of infants. Supine infants activate the mobile by moving their feet vertically across a virtual threshold. This paradigm is unique in that as infants independently discover that their leg actions activate the mobile, the infants' leg movements are tracked using a motion capture system allowing for the quantification of the learning process. Specifically, learning is quantified in terms of the duration of mobile activation, the position variance of the end effectors (feet) that activate the mobile, changes in hip-knee coordination patterns, and changes in hip and knee muscle torque. This information describes infant exploration and exploitation at the interplay of person and environmental constraints that support task-specific action. Subsequent research using this method can investigate how specific impairments of different populations of infants at risk for movement disorders influence the discovery-learning process for task-specific action.

A critical issue in the study of infant development is to identify the processes by which task-specific action emerges from spontaneous movement. Emergent leg action has been studied by providing contingent reinforcement to specific leg movements using an overhead infant-activated mobile, however, there is limited information on the strategies used by infants to support the emergence of task-specific leg action from spontaneous movement. The purpose of this study is to (1) determine the ability of 3 month old infants to learn, through discovery, the contingency between leg action and mobile activation using a virtual threshold, and (2) identify strategies, defined by variance of the end-effectors (feet) and hip-knee joint coordination, used by infants that learned the contingency. Fourteen 3 month old infants participated in 2 sessions of mobile reinforcement on consecutive days. As a group, infants increased the percentage of mobile activation to meet performance criteria on Day 2, but did not meet memory or learning criteria across days. However, five infants learned the contingency based on individual learning criteria. When interacting with the mobile on Day 2 as compared to spontaneous kicking on Day 1, infants who learned the contingency, but not infants who did not learn the contingency, increased variance of the end-effectors (feet) in the vertical, task-specific direction and demonstrated less in-phase hip-knee joint coordination. An important discovery is that infants can discover this very specific contingency, suggesting that this movement behavior (action) can be shaped in future work. This may have implications for the rehabilitation of infants with atypical leg action.

The expression of artemin (ARTN), a glial cell line-derived neurotrophic factor (GDNF) family ligand, increases in pre-clinical models of nociception and recent evidence suggests this growth factor may play a causative role in inflammatory pain mechanisms. The aim of this study was to demonstrate functional inhibition of ARTN with monoclonal antibodies and to determine whether ARTN neutralisation could reverse inflammatory pain in mice. We show that monoclonal antibodies with high affinity to ARTN, completely inhibit ARTN-induced Ret and ERK activation in a human neuroblastoma cell line, and block capsaicin-induced CGRP secretion from primary rat DRG cultures. In addition, administration of anti-ARTN antibodies to mice provides a transient, partial reversal (41%) of FCA-induced mechanical hypersensitivity. Anti-ARTN antibodies had no effect on hypersensitivity in response to partial nerve ligation in mice. These data suggest that ARTN-GFRα3 interactions partially mediate early stage nociceptive signalling following an inflammatory insult., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The EWS/FLI translocation product is the causative oncogene in Ewing sarcoma and acts as an aberrant transcription factor. EWS/FLI dysregulates gene expression during tumorigenesis by abnormally activating or repressing genes. The expression levels of thousands of genes are affected in Ewing sarcoma, however, it is unknown which of these genes contribute to the transformed phenotype. Here we characterize BCL11B as an up-regulated EWS/FLI target that is necessary for the maintenance of transformation in patient derived Ewing sarcoma cells lines. BCL11B, a zinc finger transcription factor, acts as a transcriptional repressor in Ewing's sarcoma and contributes to the EWS/FLI repressed gene signature. BCL11B repressive activity is mediated by the NuRD co-repressor complex. We further demonstrate that re-expression of SPRY1, a repressed target of BCL11B, limits the transformation capacity of Ewing sarcoma cells. These data define a new pathway downstream of EWS/FLI required for oncogenic maintenance in Ewing sarcoma.

Animal models are an integral part of pain research. However, current models tend to rely on evoked responses and there is a belief that non-evoked responses may be a more relevant behavioural readout as the animal responds in a more natural manner. Here, dynamic weight bearing (DWB), a novel method for assessing mechanical hypersensitivity, was evaluated using the Freund's Complete Adjuvant (FCA) model of inflammatory pain in mice. DWB enables the measurement of weight placed through all four paws of a freely moving animal. The data obtained from DWB was compared with data acquired using the standard static weight bearing (incapacitance) test. In both tests reversal of FCA induced mechanical hypersensitivity was investigated using the selective COX2 inhibitor celecoxib. Mice treated with FCA placed less weight through the ipsilateral hindpaw compared to vehicle controls. This reduction was reversed by celecoxib (30mg/kg p.o.) in the dynamic and static weight bearing tests. The data presented here suggests that dynamic weight bearing may provide a novel end point for the development of new analgesics., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Safe and effective anesthesia of dogs and cats rely on preanesthetic patient assessment and preparation. Patients should be premedicated with drugs that provide sedation and analgesia prior to anesthetic induction with drugs that allow endotracheal intubation. Maintenance is typically with a volatile anesthetic such as isoflurane or sevoflurane delivered via an endotracheal tube. In addition, local anesthetic nerve blocks; epidural administration of opioids; and constant rate infusions of lidocaine, ketamine, and opioids are useful to enhance analgesia. Cardiovascular, respiratory, and central nervous system functions are continuously monitored so that anesthetic depth can be modified as needed. Emergency drugs and equipment, as well as an action plan for their use, should be available throughout the perianesthetic period. Additionally, intravenous access and crystalloid or colloids are administered to maintain circulating blood volume. Someone trained in the detection of recovery abnormalities should monitor patients throughout recovery. Postoperatively attention is given to body temperature, level of sedation, and appropriate analgesia.

Purpose: Intrafraction organ motion can produce dosimetric errors in radiotherapy. Commonly, the linear accelerator is gated using real-time breathing phase obtained by way of external sensors. However, the external anatomy does not always correlate well with the internal position. We examined a beam gating technique using signals from implanted wireless transponders that provided real-time feedback on the tumor location without an imaging dose to the patient., Methods and Materials: An interface was developed between Calypso Medical's four-dimensional electromagnetic tracking system and a Varian Trilogy linear accelerator. A film phantom was mounted on a motion platform programmed with lung motion trajectories. Deliveries were performed when the beam was gated according to the signal from the wireless transponders. The dosimetric advantages of beam gating and the system latencies were quantified., Results: Beam gating using on internal position monitoring provided up to a twofold increase in the dose gradients. The percentage of points failing to be within +/-10 cGy of the planned dose (maximal dose, approximately 200 cGy) was 3.4% for gating and 32.1% for no intervention in the presence of motion. The mean latencies between the transponder position and linear accelerator modulation were 75.0 +/-12.7 ms for beam on and 65.1 +/- 12.9 ms for beam off., Conclusion: We have presented the results from a novel method for gating the linear accelerator using trackable wireless internal fiducial markers without the use of ionizing radiation for imaging. The latencies observed were suitable for gating using electromagnetic fiducial markers, which results in dosimetric improvements for irradiation in the presence of motion.

GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.49+/-0.09, respectively) and rat (pK(i)=9.08+/-0.16 and 9.12+/-0.14, respectively) H(3) receptors expressed in cerebral cortex. At the human recombinant H(3) receptor, GSK207040 and GSK334429 were potent functional antagonists (pA(2)=9.26+/-0.04 and 8.84+/-0.04, respectively versus H(3) agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC(50)=9.20+/-0.36 and 8.59+/-0.04 versus basal GTPgammaS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [(3)H]-R-alpha-methylhistamine binding (ED(50)=0.03 and 0.35 mg/kg, respectively). Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50)=0.02 and 0.11 mg/kg p.o. for GSK207040 and GSK334429, respectively). In more pathophysiologically relevant pharmacodynamic models, GSK207040 (0.1, 0.3, 1 and 3mg/kg p.o.) and GSK334429 (0.3, 1 and 3mg/kg p.o.) significantly reversed amnesia induced by the cholinergic antagonist scopolamine in a passive avoidance paradigm. In addition, GSK207040 (0.1, 0.3 and 1mg/kg p.o.) and GSK334429 (3 and 10mg/kg p.o.) significantly reversed capsaicin-induced reductions in paw withdrawal threshold, suggesting for the first time that blockade of H(3) receptors may be able to reduce tactile allodynia. Novel H(3) receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain.

Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. Pyrrolidinyl ureas such as 8 and 15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca2+-based assays showed that compounds such as 8 and 15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore, 15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.

The pathogenic form of the cyclooxygenase (COX) enzyme, COX-2, is also constitutively present in the spinal cord and has been implicated in chronic pain states in rat and man. A number of COX-2 inhibitors, including celecoxib and rofecoxib, are already used in man for the treatment of inflammatory pain. Preclinically, the dual-acting COX-2 inhibitor, GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine, where X denotes the free base], is as effective as rofecoxib and celecoxib in the rat established Freund's Complete Adjuvant model with an ED(50) of 1.5 mg/kg p.o. compared with 1.0 mg/kg p.o. for rofecoxib and 6.6 mg/kg p.o. for celecoxib. However, in contrast to celecoxib (5 mg/kg p.o. b.i.d.) and rofecoxib (5 mg/kg p.o. b.i.d.), which were without significant effect, GW406381X (5 mg/kg p.o. b.i.d.) fully reversed mechanical allodynia in the chronic constriction injury model and reversed thermal hyperalgesia in the mouse partial ligation model, both models of neuropathic pain. GW406381X, was also effective in a rat model of capsaicin-induced central sensitization, when given intrathecally (ED(50) = 0.07 mug) and after chronic but not acute oral dosing. Celecoxib and rofecoxib had no effect in this model. Several hypotheses have been proposed to try to explain these differences in efficacy, including central nervous system penetration, enzyme kinetics, and potency. The novel finding of effectiveness of GW406381X in these models of neuropathic pain/central sensitization, in addition to activity in inflammatory pain models and together with its central efficacy, suggests dual activity of GW406381X compared with celecoxib and rofecoxib, which may translate into greater efficacy in a broader spectrum of pain states in the clinic.

Uptake kinetics of monomethylmercury chloride (MeHgCl) were measured for two species of green algae (Selenastrum capricomutum and Cosmarium botrytis), one blue-green algae (Schizothrix calcicola), and one diatom (Thalassiosira weissflogii), algal species that are commonly found in natural surface waters. Species differences were found with the two green algae giving the highest uptake rates, and one of them (Cosmarium) showing differences between cultures having widely different cell age (exponential versus stationary), where increases in uptake rate for cells 30 days old were about 25 times greater than cells only 3 days old when weights of cells were considered. Both Schizothrix and Thalassiosira exhibited nearly the same lower uptake rates, approximately 20 times lower than the two green algal species. Experiments with photosystem inhibitors, uncouplers, gamma-radiation, light deprivation, and extended range uptake all point to an active transport mechanism for MeHgCl.

Phytoplankton-water monomethylmercury (MeHg) partition constants (KpI) have been determined in the laboratory for two green algae Selenastrum capricornutum and Cosmarium botrytis, the blue-green algae Schizothrix calcicola, and the diatom Thallasiosira spp., algal species that are commonly found in natural surface waters. Two methods were used to determine KpI, the Freundlich isotherm method and the flow-through/dialysis bag method. Both methods yielded KpI values of about 10(6.6) for S. capricornutum and were not significantly different. The KpI for the four algae studied were similar except for Schizothrix, which was significantly lower than S. capricornutum. The KpI for MeHg and S. capricornutum (exponential growth) was not significantly different in systems with predominantly MeHgOH or MeHgCl species. This is consistent with other studies that show metal speciation controls uptake kinetics, but the reactivity with intracellular components controls steady-state concentrations. Partitioning constants determined with exponential and stationary phase S. capricornutum cells at the same conditions were not significantly different, while the partitioning constant for exponential phase, phosphorus-limited cells was significantly lower, suggesting that P-limitation alters the ecophysiology of S. capricornutum sufficiently to impact partitioning, which may then ultimately affect mercury levels in higher trophic species.

BTS 72664, (R)-7-[1-(4-chlorophenoxy)]ethyl]-1,2,4-triazolo(1,5-alpha)pyrimidine, was identified as a drug development candidate from a research program designed to discover novel, broad-spectrum, non-sedative anticonvulsant drugs. BTS 72664 antagonized bicuculline (BIC)- and maximal electroshock (MES)-induced convulsions with ED(50) values of 1.9 and 47.5 mg/kg p.o., respectively. In rodents, it has a wide spectrum of activity preventing seizures induced by picrotoxin, pentylenetetrazol, i.c.v. 4-aminopyridine or NMDA, and audiogenic seizures in DBA-2 mice and GEPR-9 rats. BTS 72664 was also effective in preventing convulsions in amygdala-kindled rats The lack of sedative potential was predicted on the basis of wide separation between ED(50) in anticonvulsant models and TD(50) for motor impairment in mice in rotating rod and inverted horizontal grid tests. BTS 72664 is likely to produce its anticonvulsant effect by enhancing chloride currents through picrotoxin-sensitive chloride channels, and by weak inhibition of Na(+) and NMDA channels. It does not act, however, at the benzodiazepine binding site. In addition to its potential use in the treatment of epilepsy BTS 72664 may be useful in the treatment of stroke. At 50 mg/kg p.o. x 4, given to rats at 12 hourly intervals, starting at 15 min after permanent occlusion of middle cerebral artery (MCA), it reduced cerebral infarct size by 31% (measured at 2 days after insult) and accelerated recovery in a functional behavioral model. BTS 72664 prevented increases in extraneuronal concentrations of glutamate, glycine and serine brain levels induced by a cortical insult to rats (cf. cortical spreading depression). It may, therefore, have also antimigraine activity.

Rationale and Objectives: We compared the safety and imaging efficacy of iodixanol-270 (270 mg I/ml), iodixanol-320 (320 mg I/ml), both of which are isosmolal to blood, and iohexol-300 (300 mg I/ml) for body computed tomography (CT) scanning., Methods: One hundred twenty-six patients from the University of Wisconsin Hospital and Temple University Hospital scheduled to undergo body CT examinations were randomly assigned to receive either iodixanol-270, iodixanol-320, or iohexol-300. Patients were monitored with questioning and vital signs before injection, immediately after injection, and at 24 and 48 hr. Extensive laboratory evaluation also was performed., Results: No serious reactions or deaths occurred in any group. The occurrence of overall minor adverse events (usually warmth, headache, taste distortion, rash) was similar for the different groups. Laboratory results showed no significant difference across groups. There was no significant difference in image quality detected among groups., Conclusion: There was no detectable difference in safety and imaging efficacy among the three contrast groups in this study. However, patients from the University of Wisconsin experienced significantly less injection discomfort with iodixanol-270 than with iohexol-300. Large clinical studies may more definitively determine the presence and nature of the relative advantages of iodixanol compared with currently available ionic and nonionic contrast agents.

The benefit of cytoreductive surgery in the management of glioma remains speculative. We therefore reviewed all confirmed deaths in our Neuro-Oncology Program and examined various clinical factors related to survival. There were 63 patients (34 males/29 females), with an average age of 57.6 years. The pathology was glioblastoma in 44 and anaplastic astrocytoma in 19; median survival was 12 months. Forty patients underwent at least one craniotomy, following which 22.5% achieved a gross total resection, 23 had biopsy only. Only age and gross total resection of tumor as judged by postoperative MR (CT in 2 cases) correlated significantly with outcome. The subtotal craniotomy group and biopsy only cohort were indistinguishable (median survival 11 vs. 10 months, respectively). Although craniotomy associated with gross total resection results in enhanced survival (median 27 months), subtotal tumor excision offers little beyond a diagnosis. Therefore, careful and realistic preoperative assessment of glioma patients ought to be performed to determine optimal surgical management.

A new oxygen monitoring system has been developed that consists of an array of transparent, independently-connected oxygen sensors mounted on a glass plate. This system is intended for continuous monitoring of oxygen at multiple locations on the surface of exteriorized tissues, while simultaneously visualizing microvascular activity. The sensor array is fabricated by techniques similar to those employed for semiconductors, which facilitate customization of sensor size and pattern to best monitor oxygen in a given physiologic preparation. Methods are described for characterizing the performance of the sensor array in vitro, including studies on the oxygen sensitivity, stability of the signal, and detection of oxygen gradients. An example of in vivo application of the sensor array is also presented.

The development of a transparent array of independently connected oxygen sensors is described. With an appropriate sensor pattern, this device may be useful to monitor the distribution of oxygen on the surface of tissues, while permitting simultaneous tissue visualization. The electrochemical characteristics of individual oxygen sensors are examined and models are proposed for the distribution of oxygen in the vicinity of individual sensors.