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P106 Multimodal assessment of TMS-induced acute effects

Question Transcranial magnetic stimulation (TMS) has become a promising therapeutic treatment and neuroscientific research tool, yet how it works is not fully understood. We developed a dedicated MR coil array positioned beneath the TMS coil that allows for concurrent stimulation and imaging and flexible positioning while ensuring TMS efficiency, high MR sensitivity and the use of parallel/multiband imaging sequences. Here we aimed to explain acute effects of TMS over left DLPFC using a new online TMS/fMRI setup in combination with advanced imaging and neuronavigation methods. Resting State functional connectivity and DTI Tractography shall further explain resulting activation patterns at a network level. Methods The study was performed on a 3T Tim Trio scanner (Siemens, Erlangen, Germany). The TMS system used included a MagProX100 stimulator and MRi-B91 MR-compatible TMS coil (Magventure, Farum, Denmark). Five right-handed female subjects (age: 28.6 ± 4.3 years) were examined. Functional images were acquired using EPI (echo-planar imaging) sequence with TR/TE = 1000/33 ms, 28 slices, 1.5 × 1.5 × 3mm3. The experimental procedure is depicted in Fig. 1. FMRI data analyses were performed using SPM12. The design matrix comprised four regressors representing different stimulation amplitudes. DTI tractography was performed using DSI Studio. Figure options Download full-size image Download high-quality image (729 K) Download as PowerPoint slide Results TMS led to intensity-dependent activation increase in the left DLPFC and the contralateral DLPFC ( Figure options Download full-size image Download high-quality image (874 K) Download as PowerPoint slide Fig. 2): Higher stimulation intensities evoked higher bilateral activation. ACC showed a more complex response pattern. Resting-state functional connectivity maps using the stimulation target as seed-voxel showed a network very similar to the TMS-derived activation pattern (Fig. 2). DTI tractography provided additional information about the axonal connection between the left DLPFC stimulation site and the right DLPFC activation cluster. Conclusion This is the first study to assess the acute influence of TMS over DLPFC at an individual level, made possible by a dedicated concurrent TMS/fMRI coil array. Here we show a dose-dependent increase in activity not only underneath the stimulation site but also on the contralateral homologous area and apparent mediating responses in the ACC. This network is confirmed by additional resting-state and tractography data.

P293 Assessment of primary motor cortex plastic changes following the use of a new prosthetic system able to provide somatosensory feedback from the missing hand in an amputee patient: A TMS study

Introduction The cortical representation of a muscle can be significantly modified by plastic reorganization following a limb amputation. These plastic changes are not immutable and can be further modified restoring by the use of prosthesis like new bionic anthropomorphic prosthesis connected to the peripheral nervous system via bidirectional neural interfaces. Transcranial magnetic stimulation (TMS) is a non-invasive technique commonly used to assess topographical reorganization of motor brain areas. Objective The aim of this study is to evaluate the motor cortical reorganization of primary motor cortex with the TMS mapping technique in a left trans-radial amputee patient following the use of a novel prosthetic system able to provide somatosensory feed-back from the lost hand of the user. Materials and methods Cortical motor output was mapped via TMS (intensity 10% above standardized excitability motor Threshold) for each hemisphere at the beginning, after 1 month and 2 month of training with the new prosthetic system. Peripheral responses were recorded from forearm flexor and extensor carpi ulnaris muscles of both limbs. Resting and Active motor threshold were also collected during separate mapping of right and left hemispheres. Results No significant differences were found in the motor thresholds between the two hemispheres before and after implantation. Pre-surgical TMS motor maps showed a slight abnormal interhemispheric asymmetry of motor cortex topography, resulted in a smaller area of representation of muscles governing the stump compared to the area for the intact limb. Following training, post-surgical maps, showed a reduction and a partial reversal of this asymmetry because of an enlargement of the excitable area on the right hemisphere contralateral to the stump, leading towards a more symmetrical muscle representation in the two hemispheres, as in control subjects. Conclusions Our experiment provides a direct and unique evidence of brain plasticity changes occurring in the motor cortex following the use of a prosthetic system able to restore a somatosensory feedback from the missing limb after amputation. Figure options Download full-size image Download high-quality image (378 K) Download as PowerPoint slide Figure options Download full-size image Download high-quality image (399 K) Download as PowerPoint slide

P191 Cerebellum and defensive behavior within the peripersonal space

Question The cerebellum is involved in a wide number of integrative functions, ranging from working memory and associative learning to motor control; it also plays a role in the sensory-motor integration aimed at antinociceptive behavior, as well as in salience-related affective and behavioral responses to nociceptive stimulation. In healthy subjects we evaluated the role of cerebellum in defensive responses, as assessed with the so-called hand blink reflex (HBR), by modulating cerebellar activity with transcranial direct current stimulation (tDCS). Methods TDCS was applied using a pair of electrodes with a surface area of 25 cm2. The active electrode was centered on the median line 2 cm below the inion, with its lateral borders about 1 cm medially to the mastoid apophysis, and the return one over the right shoulder. Direct current was applied for 20 min with an intensity of 1.5 mA. For the recording of HBR, electrical stimuli were delivered using a surface bipolar electrode placed on the median nerve at the wrist and EMG activity was recorded from the orbicularis oculi muscle, bilaterally, using pairs of surface electrodes with the active electrode over the mid-lower eyelid and the reference electrode a few centimeters laterally to the outer canthus. Depending on the hand position respective to the face, we explored four different conditions: “hand far”, “hand near” (eyes open), “hand side”, “hand near” (eyes closed). EMG signals from each participant were high-pass filtered (55 Hz), full-wave rectified, and averaged separately for the four conditions at the ipsilateral and contralateral recording sides. Results While anodal stimulation had no significant effect, cathodal one dramatically dampened the magnitude of the HBR, as measured by the area under the curve (AUC), when the stimulated hand was inside the peripersonal space surrounding the face at eyes closed (p < 0.0001) or when it was placed laterally (p = 0.004). Concurrently, HBR latency increased in both conditions “hand near” (eyes closed) and “hand side” (p = 0.002 and 0.023, respectively). Conclusions These results support a critical role of the cerebellum in the defensive responses within the peripersonal space, thus modulating defensive behavior even when the visuomotor feedback is lacking. Figure options Download full-size image Download high-quality image (276 K) Download as PowerPoint slide

P094 Method for EEG guided transcranial Electrical Stimulation without models

Objective There is a long interest in using EEG measurements to inform transcranial Electrical Stimulation (tES) but adoption is lacking. The conventional approach is to use anatomical head-models for both source localization (the EEG inverse problem) and current flow modeling (the tES forward model), but this approach is computationally demanding, requires an anatomical MRI, and strict assumptions about the target brain regions. We evaluate techniques whereby tES dose is derived from EEG without the need for an anatomical head model or assumptions. Approach The approaches are verified using a Finite Element Method (FEM) simulation of the EEG generated by a dipole, oriented either tangential or radial to the surface, and then simulating brain current flow produced by various model-free techniques including: (1) Voltage-to-voltage, (2) Voltage-to-Current; (3) Laplacian; and two Ad-Hoc techniques (4) Dipole sink-to-sink; and (5) Sink to Concentric Ring. These model-free approaches are compared to a numerically optimized dose that assumes perfect understanding of the dipole location and head anatomy. We vary the number of electrodes from a few to over three hundred, with focality or intensity as optimization criterion. Main results Our results demonstrate how simple Ad-Hoc approaches can achieve reasonable targeting for the case of a cortical dipole with 2–8 electrodes and no need for a model of the head. Significance For its simplicity and linearity, model-free EEG guided lends itself to broad adoption and can be applied to a static (tDCS), time-variant (e.g. tACS, tRNS, tPCS), or closed-loop tES. Figure options Download full-size image Download high-quality image (1118 K) Download as PowerPoint slide Figure options Download full-size image Download high-quality image (1499 K) Download as PowerPoint slide

Ligation of HLA class ii molecules on endothelial cells induces p-selectin cell surface expression and myeloid cell recruitment

Aim A hallmark of chronic antibody-mediated rejection is the presence of leukocytes infiltrates within the allograft. We tested the hypothesis that ligation of HLA class II on EC mediates myeloid cell recruitment by inducing p-selectin presentation through Weibel Palade body exocytosis. Methods Class II expression was induced by adenoviral transfection of EC with CIITA. Western blots were used to quantitate protein phosphorylation. Monocyte adherence was measured by counting CFSE-labeled monocytes (MonoMac 6) recruited to HLA-class II Ab stimulated EC in the presence/absence of Fc receptor blockade with human IgG. Transendothelial cell migration was determined using a transwell assay. P-selectin expression was detected by Cell ElISA. Results Class II ligation by antibody (Ab) against a monomorphic epitope determinant on class II antigens significantly increased monocyte transendothelial migration in a Fc-independent manner. Class II Ab-mediated myeloid cell transendothelial migration was attenuated by blockading with recombinant PSGL-1 (rPSGL-1). Class II Ab caused a 1.54 ±± 0.11 fold increases in monocyte adherence that was inhibited by pretreatment with rPSGL-1. In addition, pretreatment of EC with Src inhibitor PP2 and ERK inhibitor U0126 resulted in decreased myeloid cell recruitment (Fig. 1). Furthermore, PP2 and U0126 diminished class II induced p-selectin cell surface expression (Fig. 2). Conclusions We provide evidence that class II DSA promotes a MAPK-mediated monocyte adherence by upregulating EC p-selectin expression, stimulating monocyte adherence and infiltration into allografts, leading to transplant vasculopathy. Figure options Download full-size image Download as PowerPoint slide Figure options Download full-size image Download as PowerPoint slide

The body weight change during the first year of HEMODIALYSIS IS a strong predictor of patient survival

Hemodialysis patients are exposed to a high risk of death. We report the influence of the body weight (BW) change (Δ) on the survival in an incident HD patient cohort.Between January 2000 to 2009, 251 patients (age=65,8±14,8 y.o.; F/M=93/158; diabetes=36%) survived at least one year after HD onset and were followed for 44,9 months. The prescribed BW decreased by 6.5±5% at Week 8 (W8) and then increased again. From W8 to W52, the BW Δ was+1,9±7,4%. According to the median of W52-W8 BW Δ (+2.35%), the Kaplan Meier analysis (see figure below) displayed a significant better survival in patients with a BW Δ above the median. These two groups were not different according to age, diabetes or cardiovascular event history but had a significant higher interdialytic weight gain and protein intake. In the Cox model analysis the patient overall mortality was related to age (p<0.0001), to the W52W8 BW Δ (p=0.017), to the CRP level at W52 (p=0.035) and to serum albumin at W52 (p=0.036). Hence weight gain during the first year of HD treatment was found a strong predictor of survival in HD patients. It was associated with a better food intake whereas the patient case-mix was not different. These data highlight the need for understanding what drives food intake in dialysis patients and for careful nutritional follow-up and support in incident HD patients. Figure options Download full-size image Download as PowerPoint slide

Dietary Protein Intake and Survival in 100,088 Maintenance Hemodialysis Patients: The Role of Race and Albumin

Decreased dietary protein intake may be associated with increased mortality risk in individuals undergoing maintenance hemodialysis (MHD). We examined 8−year all-cause mortality in 100,088 MHD patients from DaVita dialysis clinics in the US (2001–2009) and hypothesized that survival is better across higher levels of nPNA, (nPCR, a dietary protein intake surrogate) with consistent trends across race and in hypoalbuminemic patients. Time-averaged Cox models were used to estimate death hazard ratios for quarterly averaged nPNA categories controlled for case-mix, comorbidity, dialysis dose, and available markers of malnutrition-inflammation-complex syndrome (MICS). In all patients, both low (<0.6 g/kg/day, HR 1.53, [1.47–1.59]) and high nPNA (≥1.4 g/kg/day, HR 1.26, [1.19-1.34]) were associated with higher all-cause mortality when compared with the reference (1.0–<1.1 g/kg/day). This reverse–J–shape association was also found in sub-analyses performed among racial groups and in hypoalbuminemic patients (Figure). Hence, hypoalbuminemic patients of all races may benefit from higher protein intake, which needs controlled trial to verify. Figure options Download full-size image Download as PowerPoint slide

Association of malnutrition-inflammation complex and responsiveness to erythropoiesis stimulating agents in hemodialysis patients

Protein-energy wasting, inflammation and refractory anemia are common in long-term hemodialysis patients. A decreased responsiveness to erythropoiesis stimulating agents (ESA) is often the cause of the refractory anemia. A 6-year prospective cohort study of 754 hemodialysis patients, we hypothesized that malnutrition-inflammation score (MIS) is an independent predictor of decreased responsiveness to ESAs (ERI) in hemodialysis patients. Mean age of patients was 54±15 years, 53% were diabetic and 49% Hispanic. A positive correlation was found between ERI and inflammatory markers including C-reactive protein (CRP) (r=0.16) and interleukin-6 (IL-6) (r=0.16). We also found negative correlations between ERI and serum albumin (r=−0.22). Each 5 unit higher MIS, 1 mg/L higher CRP and 0.5 g/dl lower albumin were associated with 46%, 45% and 140% higher likelihood of highest vs. lowest ERI in fully adjusted logistic regression models (odds ratio [and 95% CI] of 1.46 [1.05-2.05], 1.45 [1.06-1.98], and 2.40 [1.54-3.74]) respectively. Cubic splines illustrated continuous and incremental nature of MIS and ERI associations (Figure). Malnutrition-inflammation complex is a significant and independent predictor of decreased responsiveness to ESAs in hemodialysis patients. Figure options Download full-size image Download as PowerPoint slide

66 Fabrication of Engineered Pulsatile 3-Dimensional Scaffold-Free Cardiac Tissue from Embryonic Stem Cells

Purpose Transplantation of healthy regenerative cardiomyocytes into the injured heart is effective option to improve cardiac function. The optimal transplantation of cardiomyocytes must be developed. The aim of this study is to fabricate scaffold-free 3-Dimensional pulsatile cardiac tissue by nobel tissue engineering technology. Methods and Materials Approximately two thousands of mouse embryonic stem cells (ESc) derived cardiomyocyte were formed into spheroids. To construct 3-dimensional cardiac tissue, a large number of spheroids are fused via our nobel technology, named bio-rapid prototyping system (BRP). This technolog is based on the original characteristic of cells to form spheroid cell aggregates. The constructs were produced semi-automatically by stabbing spheroids with numerous needles. Finally, we succeeded in fabricating scaffold-free contractile cardiac tissue 3×1×1mm in diameter. Electrophysiological and histological analysis are performed to evaluate the function of the constructs. Results Electrophysiological studies revealed that electrical spikes detected on the construct. Immunofluorescent images with anti-connexin43 antibody demonstrated that gap junctions also established within the construct within 24 hours. This constructs continued pulsation for two weeks in vitro. Figure options Download full-size image Download high-quality image (99 K) Download as PowerPoint slide Conclusions These results demonstrate that electrically communicative pulsatile 3-D cardiac constructs were achieved in vitro by fusing cardiomyocytes spheroids. We concluded that cardiac tissue engineering based on this technology may prove useful for heart model fabrication and cardiovascular tissue repair.

71 Application of the Destination Therapy Risk Score to HeartMate II Clinical Trial Data

Purpose The Destination Therapy Risk Score (DTRS) was developed to preoperatively predict the risk of 90 day in-hospital mortality with pulsatile flow LVADs as DT from 2002-2005 (Lietz et al Circulation 2007;116:497). Mortality by risk category was 6% (low), 14% (medium), 74% (high). However the clinical utility of the DTRS in the contemporary LVAD patient is unclear. Methods and Materials The DTRS was determined in 1124 patients with the HeartMate II continuous flow LVAD in the BTT (n=486) and DT (n=638) clinical trials, and 114 DT patients randomized to receive the pulsatile HeartMate XVE. Patients were divided into the same risk groups based upon DTRS: low (0-8), medium (9-16), and high (>16). Results The median age was 55 (BTT), 67 (DT), 63 (DTXVE), etiology was ischemic in 44% (BTT), 60%(DT), 67%(DTXVE). The risk of 90 day in-hospital mortality increased with each risk category for all groups of patients, but was only statistically significant for the high risk HMII patients in the BTT+DT and DT populations, compared to the low risk groups. These high risk groups had more than a twofold increased risk of mortality compared to the low risk group. In the XVE group, the 90 day in-hospital mortality was similar to the initial DTRS cohort with the exception of a much lower mortality in the highest risk group. Goodness of fit for 90 day in-hospital mortality yielded modest c-statistics of 0.54 to 0.59 for the groups. Figure options Download full-size image Download high-quality image (61 K) Download as PowerPoint slide Conclusions Patients with the lowest DTRS have the lowest in-hospital mortality with both devices. However, due to improvements in outcomes the overall discrimination of operative mortality with the DTRS is modest in patients with a HMII. Risk prediction models derived from the current era of continuous flow LVADs are needed.

ChemInform Abstract: Novel Phenylpiperazine Derivatives as Dual Cytokine Regulators with TNF-α Suppressing and IL-10 Augmenting Activity.

Phenylpiperazine derivatives were synthesized as dual cytokine regulators with TNF-α suppressing and IL-10 augmenting activity. Lead optimization led to compound 5k Scheme 2. Reagents and conditions: (a) Ac2O, NaOH, H2O, rt (87%); (b) cH2SO4, MeOH, reflux (72%); (c) LiAlH4, THF, 0 °C–rt (98%); (d) SOCl2, CHCl3, reflux (91%); (e) arylpiperazines, K2CO3, DMF, 80 °C (49–58%). Figure options Download full-size image Download high-quality image (32 K) Download as PowerPoint slide having the potent regulatory activity and demonstrating remarkable protective effects against the lethal challenge of LPS in mice, suggesting that 5k would be a promising drug candidate for the treatment of TNF-α associated diseases including septic shock.

F022 Healing of coronary endothelium by chronic 17beta-estradiol after ischemia/reperfusion injury in mice

Endothelial protective actions of estrogens have been observed in various cardiovascular pathophysiological states. In particular, we showed that chronic 17beta-estradiol (E2) treatment prevents acute ischemia/reperfusion-induced coronary endothelial dysfunction in mice and accelerates reendothelialization after carotid injury. Whether such an endothelial healing effect occurs in a context of chronic reperfusion is unknown. Figure options Download full-size image Download as PowerPoint slide Thus, ischemia was induced by a left anterior descending coronary ligation for 30 minutes followed by one month of reperfusion (IR) in ovariectomized (OVX) mice, implanted or not 24 hours after ischemia (in order to avoid any effect on ischemic and/or early reperfusion injury) with an E2-releasing pellet (80 μg/kg/day). Coronary segments (internal diameter 180 to 220 μm) were removed distal to the site of occlusion and mounted in a wire myograph to study the relaxing response to acetylcholine (Ach). At 24 hours reperfusion (i.e. immediately before the onset of E2 treatment), OVX mice displayed a marked endothelial dysfunction (maximal relaxation to Ach: sham 55+/-4; IR 31+/-4 %; p<0.05). One month after reperfusion, untreated OVX mice showed a persistent decreased relaxation, whereas chronic E2 markedly increased the relaxing responses in IR mice (to a level similar to that of untreated sham mice) (Figure). E2 also slightly increased the relaxing responses in sham mice. In vitro NO Synthase inhibition abolished the differences between mice, suggesting that E2 restored the decreased NO production induced by IR. We thus demonstrate for the first time a marked beneficial effect of E2 on coronary endothelial healing after chronic reperfusion, leading to a restoration of coronary endothelial function.

Changing land use and its impact on biodiversity

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Development of tolerance to experimental cardiac allografts in utero: updated in 2001

As Originally Published in 1994:

Multiple substituent effects in the CC reduction of phenyl styryl ketones: cyclic voltammetry as a tool

Figure options Download full-size image Download as PowerPoint slide Cyclic voltammetric studies on 16 mono- and disubstituted phenyl styryl ketones (PSKs) or chalcones have been performed. Multiple substituent effects on the first reduction potential (E) were analysed with the help of the Hammett equation and the ρ values were evaluated for various substituents in one ring for each substituent in the other ring and vice versa. An interactive Gibbs energy relationship was applicable to this system. The reduction of alkenyl instead of carbonyl is expected to give similar values for cross-interaction constants qx and qy and the same were obtained (qx=−0.6720 and qy=−0.6710).

Applications of lasers in chemical spectroscopy and dynamics: higher order susceptibility effects

Abstract

Molecular reaction dynamics by the crossed molecular beam technique: a few recent examples

Abstract

Thermodynamics of Adsorption and Gibbsian Distance Parameters in Two- and Three-Phase Systems

In a multicomponent, 2-phase system, the Gibbs dividing surfaces for the respective components are separated by characteristic distances, (I). Figure options Download full-size image Download as PowerPoint slide More generally, if b designates an arbitrary criterion defining a surface, e.g. j = i, and d designates another criterion, e.g. the surface of tension, (II). Figure options Download full-size image Download as PowerPoint slide For a binary, liquid–liquid system (III). Figure options Download full-size image Download as PowerPoint slide In a 3-phase system with a line of 3-phase contact, it is possible to set up the one-dimensional analog of the Gibbs dividing surface, and to treat a linear excess mass that corresponds to the Gibbsian surface excess mass. The line of tension is the analog of the surface of tension. A linear thermodynamics can be developed, that is the one-dimensional analog of Gibbsian surface thermodynamics. Applications of eqns (I and III) are reported, for the estimation of λ. For the interface between air and solutions of water and ethanol, at mole fraction ethanol = 0.18, λ12 is 8.8 a. For the benzene-water system, λ12 is found to be about 0.1 a.