bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased 11β-hydroxysteroid dehydrogenase type-1 and hexose-6-phosphate dehydrogenase in liver and adipose tissue of rat offspring exposed to alcohol in utero
Authors: Nammi Srinivas , Dembele Korami , Nyomba B. L. Grégoire
Published: November 2006

Rat offspring prenatally exposed to alcohol display features of metabolic syndrome characterized by a low birth weight, catch-up growth, dyslipidemia, and insulin-resistant diabetes with increased gluconeogenesis, during adult life. Gluconeogenesis is partly regulated by cyclic AMP- and glucocorticoid-dependent mechanisms. Glucocorticoid action at the receptor level depends on its circulating concentrations and is amplified at the prereceptor level by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates active glucocorticoids from inactive forms. To determine whether 11β-HSD1 is dysregulated in this rat model, we examined the expression and enzyme activity of 11β-HSD1 and its regulator enzyme hexose-6-phosphate dehydrogenase (H6PD) in the liver of postnatal day 7 (neonatal) and 3-mo-old (adult) rat offspring prenatally exposed to alcohol. Measurements of 11β-HSD1 and H6PD were also performed in the omental fat of adult rat offspring. In both neonatal and adult rats, prenatal alcohol exposure resulted in increased tissue corticosterone concentrations, increased expression, and oxoreductase activity of 11β-HSD1, and a parallel increase of H6PD expression. The data suggest that due to both transcriptional and posttranscriptional dysregulations, rats exposed to alcohol early in life have increased 11β-HSD1 activity, which may explain insulin-resistant diabetes in these animals later in life.
Intrinsic pump-conduit behavior of lymphangions
Authors: Quick Christopher M. , Venugopal Arun M. , Gashev Anatoliy A. , Zawieja David C. , Stewart Randolph H.
Published: November 2006

Lymphangions, segments of lymphatic vessels bounded by valves, have characteristics of both ventricles and arteries. They can act primarily like pumps when actively transporting lymph against a pressure gradient. They also can act as conduit vessels when passively transporting lymph down a pressure gradient. This duality has implications for clinical treatment of several types of edema, since the strategy to optimize lymph flow may depend on whether it is most beneficial for lymphangions to act as pumps or conduits. To address this duality, we employed a simple computational model of a contracting lymphangion, predicted the flows at both positive and negative axial pressure gradients, and validated the results with in vitro experiments on bovine mesenteric vessels. This model illustrates that contraction increases flow for normal axial pressure gradients. With edema, limb elevation, or external compression, however, the pressure gradient might reverse, and lymph may flow passively down a pressure gradient. In such cases, the valves may be forced open during the entire contraction cycle. The vessel thus acts as a conduit, and contraction has the effect of increasing resistance to passive flow, thus inhibiting flow rather than promoting it. This analysis may explain a possible physiological benefit of the observed flow-mediated inhibition of the lymphatic pump at high flow rates.
Effect of dietary hempseed intake on cardiac ischemia-reperfusion injury
Authors: Al-Khalifa A. , Maddaford T. G. , Chahine M. N. , Austria J. A. , Edel A. L. , Richard M. N. , Ander B. P. , Gavel N. , Kopilas M. , Ganguly R. , Ganguly P. K. , Pierce G. N.
Published: November 2006

Polyunsaturated fatty acids (PUFAs) have significant, cardioprotective effects against ischemia. Hempseed contains a high proportion of the PUFAs linoleic acid (LA) and α-linolenic acid (ALA), which may have opposing effects on postischemic heart performance. There are no reported data concerning the cardiovascular effects of dietary hempseed intake. A group of 40 male Sprague-Dawley rats were distributed evenly into four groups that were fed for 12 wk a normal rat chow supplemented with hempseed (5% and 10%), palm oil (1%), or a 10% partially delipidated hempseed that served as a control. Plasma ALA and γ-linolenic acid levels were significantly elevated in the rats that were fed a 5% or 10% hempseed-supplemented diet, but in heart tissue only ALA levels were significantly elevated in the rats fed these diets compared with control. After the dietary interventions were completed, postischemic heart performance was evaluated by measuring developed tension, resting tension, the rates of tension development and relaxation, and the number of extrasystoles. Hearts from rats fed a hempseed-supplemented diet exhibited significantly better postischemic recovery of maximal contractile function and enhanced rates of tension development and relaxation during reperfusion than hearts from the other groups. These hearts, however, were not protected from the occurrence of extrasystoles, nor were the increases in resting tension altered during ischemia or reperfusion as a function of any dietary intervention. Our data demonstrate that dietary hempseed can provide significant cardioprotective effects during postischemic reperfusion. This appears to be due to its highly enriched PUFA content.
Effect of renal injury-induced neurogenic hypertension on NO synthase, caveolin-1, AKt, calmodulin and soluble guanylate cyclase expressions in the kidney
Authors: Bai Y. , Ye S. , Mortazavi R. , Campese V. , Vaziri N. D.
Published: November 2006

Single injection of a small quantity of phenol into the cortex of one kidney in rats results in development of persistent hypertension (HTN) which is thought to be mediated by activation of renal afferent and efferent sympathetic pathways and sodium retention. Nitric oxide (NO) plays a major role in regulation of renal vascular resistance, tubular Na+ reabsorption, pressure natriuresis, and thereby systemic arterial pressure. The present study was performed to test the hypothesis that chronic renal injury-induced HTN may be associated with dysregulation of NO system in the kidney. Accordingly, urinary NO metabolite (NOx) and cGMP excretions as well as renal cortical tissue (right kidney) expressions of NO synthase (NOS) isoforms [endothelial, neuronal, and inducible NOS, respectively (eNOS, nNOS, and iNOS)], NOS-regulatory factors (Caveolin-1, phospho-AKt, and calmodulin), and second-messenger system (soluble guanylate cyclase [sGC] and phosphodiesterase-5 [PDE-5]) were determined in male Sprague-Dawley rats 4 wk after injection of phenol (50 μl of 10% phenol) or saline into the lower pole of left kidney. The phenol-injected group exhibited a significant elevation of arterial pressure, marked reductions of urinary NOx and cGMP excretions, downregulations of renal tissue nNOS, eNOS, Phospho-eNOS, iNOS, and alpha chain of sGC. However, renal tissue AKt, phospho-AKT, Calmodulin, and PDE-5 proteins were unchanged in the phenol-injected animals. In conclusion, renal injury in this model results in significant downregulations of NOS isoforms and sGC and consequent reductions of NO production and cGMP generation by the kidney, events that may contribute to maintenance of HTN in this model.
Acute unilateral ureteral distension inhibits glutamate-dependent spinal pelvic-urethra reflex potentiation via GABAergic neurotransmission in anesthetized rats
Authors: Chen Kuo-Jung , Peng Hsien-Yu , Cheng Chen-Li , Chen Cheng-Hsu , Liao Jiuan-Miaw , Ho Yu-Cheng , Liou Jung-Tong , Tung Kwong-Chung , Hsu Tien-Huan , Lin Tzer-Bin
Published: November 2006

The effects of an acute increase in intraureteral pressure (IUP) on pelvic-urethra reflex potentiation were examined in urethane-anesthetized rats by recording the external urethral sphincter electromyogram activities evoked by the pelvic afferent stimulation. Compared with a single action potential elicited by the test stimulation (TS; characterized by an intensity that evoked a constant reflex response without facilitation, 1/30 Hz, 1.03 ± 0.12 spikes/stimulation, n = 7), the repetitive stimulation [RS; identical stimulation intensity as the TS (1 Hz)] significantly induced spinal reflex potentiation (SRP; 16.90 ± 2.00 spikes/stimulation, P < 0.01, n = 7). Such SRP was significantly attenuated by intrathecal 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline [NBQX; a glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionat (AMPA) receptor antagonist] and d-2-amino-5-phosphonovalerate [APV; a glutamatergic N-methyl-d-aspartate (NMDA) antagonist; the spike number per stimulation: 11.0 ± 0.70 for NBQX, 1.01 ± 0.30 for APV, and 16.90 ± 2.0 for RS, respectively, n = 7, P < 0.01]. Acute stepwise elevations of IUP gradually attenuated and eventually abolished the RS-induced SRP (16.80 ± 1.30, 17.00 ± 1.30, 16.30 ± 1.30, 10.50 ± 1.80, 8.80 ± 1.90, 3.50 ± 1.60, 0.80 ± 0.20, 0.70 ± 0.20, and 0.20 ± 0.10 spikes/stimulation at intraureteral pressure of 0, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, and 20 cmH2O, respectively, n = 7). Intrathecal NMDA (a glutamatergic NMDA receptor agonist) and bicuculline (a GABA receptor antagonist) both reversed the abolition of RS-induced SRP caused by unilateral ureteral distension (14.0 ± 4.04 and 8.00 ± 1.53 spikes/stimulation, respectively, n = 7, P < 0.01). All the results suggested unilateral ureteral distension might compensatorily relax the urethra via GABAergic inhibition of NMDA-dependent SRP.
Interaction of the Ca2+-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function
Authors: Huang Chunfa , Sindic Aleksandra , Hill Ceredwyn E. , Hujer Kristine M. , Chan Kim W. , Sassen Martin , Wu Zhenzhen , Kurachi Yoshihisa , Nielsen Soren , Romero Michael F. , Miller R. Tyler
Published: November 2006

The Ca2+-sensing receptor (CaR), a G protein-coupled receptor, is expressed in many epithelial tissues including the parathyroid glands, kidney, and GI tract. Although its role in regulating PTH levels and Ca2+metabolism are best characterized, it may also regulate salt and water transport in the kidney as demonstrated by recent reports showing association of potent gain-of-function mutations in the CaR with a Bartter-like, salt-wasting phenotype. To determine whether this receptor interacts with novel proteins that control ion transport, we screened a human adult kidney cDNA library with the COOH-terminal 219 amino acid cytoplasmic tail of the CaR as bait using the yeast two-hybrid system. We identified two independent clones coding for ∼125 aa from the COOH terminus of the inwardly rectifying K+channel, Kir4.2. The CaR and Kir4.2 as well as Kir4.1 (another member of Kir4 subfamily) were reciprocally coimmunoprecipitated from HEK-293 cells in which they were expressed, but the receptor did not coimmunoprecipitate with Kir5.1 or Kir1.1. Both Kir4.1 and Kir4.2 were immunoprecipitated from rat kidney extracts with the CaR. In Xenopus laevis oocytes, expression of the CaR with either Kir4.1 or Kir4.2 channels resulted in inactivation of whole cell current as measured by two-electrode voltage clamp, but the nonfunctional CaR mutant CaRR796W, and that does not coimmunoprecipitate with the channels, had no effect. Kir4.1 and the CaR were colocalized in the basolateral membrane of the distal nephron. The CaR interacts directly with Kir4.1 and Kir4.2 and can decrease their currents, which in turn could reduce recycling of K+for the basolateral Na+-K+-ATPase and thereby contribute to inhibition of Na+reabsorption.
Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle
Authors: Adhihetty Peter J. , O'Leary Michael F. N. , Chabi Beatrice , Wicks Karen L. , Hood David A.
Published: November 2006

Chronic muscle disuse induced by denervation reduces mitochondrial content and produces muscle atrophy. To investigate the molecular mechanisms responsible for these adaptations, we assessed 1) mitochondrial biogenesis- and apoptosis-related proteins and 2) apoptotic susceptibility and cell death following denervation. Rats were subjected to 5, 7, 14, 21, or 42 days of unilateral denervation of the sciatic or peroneal nerve. Muscle mass and mitochondrial content were reduced by 40–65% after 21 and 42 days of denervation. Denervation-induced decrements in mitochondrial content occurred along with 60% and 70% reductions in transcription factor A (Tfam) and peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, respectively. After 42 days of denervation, Bax was elevated by 115% and Bcl-2 was decreased by 89%, producing a 16-fold increase in the Bax-to-Bcl-2 ratio. Mitochondrial reactive oxygen species production was markedly elevated by 5- to 7.5-fold in subsarcolemmal mitochondria after 7, 14, and 21 days of denervation, whereas reactive oxygen species production in intermyofibrillar (IMF) mitochondria was reduced by 40–50%. Subsarcolemmal and IMF mitochondrial levels of MnSOD were also reduced by 40–50% after 14–21 days of denervation. The maximal rate of IMF mitochondrial pore opening ( Vmax) was elevated by 25–35%, and time to Vmaxwas reduced by 20–25% after 14 and 21 days, indicating increased apoptotic susceptibility. Myonuclear decay, assessed by DNA fragmentation, was elevated at 7–21 days of denervation. Our data indicate that PGC-1α and Tfam are important factors that likely contribute to the reduced mitochondrial content after chronic disuse. In addition, our results illustrate that, despite the reduced mitochondrial content, denervated muscle has greater mitochondrial apoptotic susceptibility, which coincided with elevated apoptosis, and these processes may contribute to denervation-induced muscle atrophy.
Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart
Authors: Jonker Sonnet S. , Zhang Lubo , Louey Samantha , Giraud George D. , Thornburg Kent L. , Faber J. Job
Published: November 2006

The generation of new myocytes is an essential process of in utero heart growth. Most, or all, cardiac myocytes lose their capacity for proliferation during the perinatal period through the process of terminal differentiation. An increasing number of studies focus on how experimental interventions affect cardiac myocyte growth in the fetal sheep. Nevertheless, fundamental questions about normal growth of the fetal heart remain unanswered. In this study, we determined that during the last third of gestation the hearts of fetal sheep grew primarily by four processes. 1) Myocyte proliferation contributed substantially to daily cardiac mass gain, and the number of cardiac myocytes continued to increase to term. 2) The (hitherto unrecognized) contribution to cardiac growth by the increase in myocyte size associated with the transition from mononucleation to binucleation (terminal differentiation) became considerable from ∼115 days of gestational age (dGA) until term (145dGA). Because binucleation became the more frequent outcome of myocyte cell cycle activity after ∼115dGA, the number of binucleated myocytes increased at the expense of the number of mononucleated myocytes. Both the interval between nuclear divisions and the duration of cell cycle activity in myocytes decreased substantially during this same period. Finally, cardiac growth was in part due to enlargement of 3) mononucleated and 4) binucleated myocytes, which grew in cross-sectional diameter but not length during the last third of gestation. These data on normal cardiac growth may enable a more detailed understanding of the consequences of experimental and pathological interventions in prenatal life.
Inactivity induces increases in abdominal fat
Authors: Laye Matthew J. , Thyfault John P. , Stump Craig S. , Booth Frank W.
Published: November 2006

Previously, inducing inactivity for 53 h after 21 days of voluntary running resulted in a 25 and 48% increase in epididymal and omental fat pad weights, respectively, while rats continued to eat more than a group that never had access to a running wheel ( J Physiol 565: 911–925, 2005). We wanted to test the hypothesis that inactivity, independent of excessive caloric intake, could induce an increase in fat pad mass. Twenty-one-day-old rats were given access to voluntary running wheels for 42–43 days so that they were running ∼9 km/day in the last week of running, after which wheels were locked for 5, 53, or 173 h (WL5, WL53, WL173) before the rats were killed. During the 53 and 173 h of inactivity, one group of animals was pair fed (PF) to match sedentary controls, whereas the other continued to eat ad libitum (AL). Epididymal and retroperitoneal fat masses were significantly increased in the WL173-PF vs. the WL5 group, whereas epididymal, perirenal, and retroperitoneal fat masses were all significantly increased in the WL173-AL group compared with the WL5 group. Additionally, hyperplasia, and not hypertrophy, of the epididymal fat mass was responsible for the increase at WL173-AL as demonstrated by a significant increase in cell number vs. WL5, with no change in cell diameter or volume. Thus two important findings have been elucidated: 1) increases in measured abdominal fat masses occur in both AL and PF groups at WL173, and 2) adipocyte expansion via hyperplasia occurred with an ad libitum diet following cessation of voluntary running.
Distinct Roles for Glycine and GABA in Shaping the Response Properties of Neurons in the Superior Paraolivary Nucleus of the Rat
Authors: Kulesza Randy J. , Kadner Alexander , Berrebi Albert S.
Published: November 2006

The superior paraolivary nucleus (SPON) is a prominent periolivary cell group of the superior olivary complex. SPON neurons use γ-aminobutyric acid (GABA) as their neurotransmitter and are contacted by large numbers of glycinergic and GABAergic punctate profiles, representing a dense inhibitory innervation from the medial nucleus of the trapezoid body (MNTB) and from collaterals of SPON axons, respectively. SPON neurons have low rates of spontaneous activity, respond preferentially to the offset of pure tones, and phase-lock to amplitude-modulated tones. To determine the roles of glycine and GABA in shaping SPON responses, we recorded from single units in the SPON of anesthetized rats before, during, and after application of the glycine receptor antagonist strychnine, the GABAA receptor antagonist bicuculline, or both drugs applied simultaneously. Strychnine caused a major increase in spike counts during the stimulus presentation, followed by the disappearance of offset spikes. In half of the recorded units, bicuculline caused moderately increased firing during the stimulus. However, in 86% of units bicuculline also caused a large increase in the magnitude of the offset response. Application of the drug cocktail caused increased spontaneous activity, dramatically increased spike counts during the stimulus presentation, and eliminated the offset response in most units. We conclude that glycinergic inhibition from the MNTB suppresses SPON spiking during sound stimulation and is essential in generating offset responses. GABAergic inhibition, presumably from intrinsic SPON collaterals, plays a subtler role, contributing in some cells to suppression of firing during the stimulus and in most cells to restrict firing after stimulus offset.
Spastic Tail Muscles Recover From Myofiber Atrophy and Myosin Heavy Chain Transformations in Chronic Spinal Rats
Authors: Harris R. Luke W. , Putman Charles T. , Rank Michelle , Sanelli Leo , Bennett David J.
Published: November 2006

Without intervention after spinal cord injury (SCI), paralyzed skeletal muscles undergo myofiber atrophy and slow-to-fast myofiber type transformations. We hypothesized that chronic spasticity-associated neuromuscular activity after SCI would promote recovery from such deleterious changes. We examined segmental tail muscles of chronic spinal rats with long-standing tail spasticity (7 mo after sacral spinal cord transection; older chronic spinals), chronic spinal rats that experienced less spasticity early after injury (young chronic spinals), and rats without spasticity after transection and bilateral deafferentation (spinal isolated). These were compared with tail muscles of age-matched normal rats. Using immunohistochemistry, we observed myofiber distributions of 15.9 ± 3.5% type I, 18.7 ± 10.7% type IIA, 60.8 ± 12.6% type IID(X), and 2.3 ± 1.3% type IIB (means ± SD) in young normals, which were not different in older normals. Young chronic spinals demonstrated transformations toward faster myofiber types with decreased type I and increased type IID(X) paralleled by atrophy of all myofiber types compared with young normals. Spinal isolated rats also demonstrated decreased type I myofiber proportions and increased type II myofiber proportions, and severe myofiber atrophy. After 4 mo of complete spasticity (older chronic spinals), myofiber type transformations were reversed, with no significant differences in type I, IIA, IID(X), or IIB proportions compared with age-matched normals. Moreover, after this prolonged spasticity, type I, IIA, and IIB myofibers recovered from atrophy, and type IID(X) myofibers partially recovered. Our results indicate that early after transection or after long-term spinal isolation, relatively inactive tail myofibers atrophy and transform toward faster myofiber types. However, long-term spasticity apparently produces neuromuscular activity that promotes recovery of myofiber types and myofiber sizes.
Multiple Sensory Cues Underlying the Perception of Translation and Path
Authors: Yong N. Au , Paige G. D. , Seidman S. H.
Published: November 2006

The translational linear vestibuloocular reflex compensates most accurately for high frequencies of head translation, with response magnitude decreasing with declining stimulus frequency. However, studies of the perception of translation typically report robust responses even at low frequencies or during prolonged motion. This inconsistency may reflect the incorporation of nondirectional sensory information associated with the vibration and noise that typically accompany translation, into motion perception. We investigated the perception of passive translation in humans while dissociating nondirectional cues from actual head motion. In a cue-dissociation experiment, interaural (IA) motion was generated using either a linear sled, the mechanics of which generated noise and vibration cues that were correlated with the motion profile, or a multiaxis technique that dissociated these cues from actual motion. In a trajectory-shift experiment, IA motion was interrupted by a sudden change in direction (±30° diagonal) that produced a change in linear acceleration while maintaining sled speed and therefore mechanical (nondirectional) cues. During multi-axis cue-dissociation trials, subjects reported erroneous translation perceptions that strongly reflected the pattern of nondirectional cues, as opposed to nearly veridical percepts when motion and nondirectional cues coincided. During trajectory-shift trials, subjects' percepts were initially accurate, but erroneous following the direction change. Results suggest that nondirectional cues strongly influence the perception of linear motion, while the utility of cues directly related to translational acceleration is limited. One key implication is that “path integration” likely involves complex mechanisms that depend on nondirectional and contextual self-motion cues in support of limited and transient otolith-dependent acceleration input.
Sensorimotor Integration in S2, PV, and Parietal Rostroventral Areas of the Human Sylvian Fissure
Authors: Hinkley Leighton B. , Krubitzer Leah A. , Nagarajan Srikantan S. , Disbrow Elizabeth A.
Published: November 2006

We explored cortical fields on the upper bank of the Sylvian fissure using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) to measure responses to two stimulus conditions: a tactile stimulus applied to the right hand and a tactile stimulus with an additional movement component. fMRI data revealed bilateral activation in S2/PV in response to tactile stimulation alone and source localization of MEG data identified a peak latency of 122 ms in a similar location. During the tactile and movement condition, fMRI revealed bilateral activation of S2/PV and an anterior field, while MEG data contained one source at a location identical to the tactile-only condition with a latency of 96 ms and a second rostral source with a longer latency (136 ms). Furthermore, Region-of-interest analysis of fMRI data identified increased bilateral activation in S2/PV and the rostral area in the tactile and movement condition compared with the tactile only condition. An area of cortex immediately rostral to S2/PV in monkeys has been called the parietal rostroventral area (PR). Based on location, latency, and conditions under which this field was active, we have termed the rostral area of human cortex PR as well. These findings indicate that humans, like non-human primates, have a cortical field rostral to PV that processes proprioceptive inputs, both S2/PV and PR play a role in somatomotor integration necessary for manual exploration and object discrimination, and there is a temporal hierarchy of processing with S2/PV active prior to PR.
Agonist-Dependent Postsynaptic Effects of Opioids on Miniature Excitatory Postsynaptic Currents in Cultured Hippocampal Neurons
Authors: Liao Dezhi , Grigoriants Olga O. , Loh Horace H. , Law Ping-Yee
Published: November 2006

Although chronic treatment with morphine is known to alter the function and morphology of excitatory synapses, the effects of other opioids on these synapses are not clear. Here we report distinct effects of several opioids (morphine, [d-ala2,me-phe4,gly5-ol]enkephalin (DAMGO), and etorphine) on miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons: 1) chronic treatment with morphine for >3 days decreased the amplitude, frequency, rise time and decay time of mEPSCs. In contrast, “internalizing” opioids such as etorphine and DAMGO increased the frequency of mEPSCs and had no significant effect on the amplitude and kinetics of mEPSCs. These results demonstrate that different opioids can have distinct effects on the function of excitatory synapses. 2) mu opioid receptor fused with green fluorescence protein (MOR-GFP) is clustered in dendritic spines in most hippocampal neurons but is concentrated in axon-like processes in striatal and corticostriatal nonspiny neurons. It suggests that MORs might mediate pre- or postsynaptic effects depending on cell types. 3) Neurons were cultured from MOR knock-out mice and were exogenously transfected with MOR-GFP. Chronic treatment with morphine suppressed mEPSCs only in neurons that contained postsynaptic MOR-GFP, indicating that opioids can modulate excitatory synaptic transmission postsynaptically. 4) Morphine acutely decreased mEPSC amplitude in neurons expressing exogenous MOR-GFP but had no effect on neurons expressing GFP. It indicates that the low level of endogenous MORs could only allow slow opioid-induced plasticity of excitatory synapses under normal conditions. 5) A theoretical model suggests that morphine might affect the function of spines by decreasing the electrotonic distance from synaptic inputs to the soma.
Kappa Opioid Inhibition of Somatodendritic Dopamine Inhibitory Postsynaptic Currents
Authors: Ford Christopher P. , Beckstead Michael J. , Williams John T.
Published: November 2006

In the midbrain, dopamine neurons can release dopamine somatodendritically. This results in an inhibitory postsynaptic current (IPSC) within adjacent dopamine cells that occurs by the activation of inhibitory D2autoreceptors. Kappa, but not mu/delta, opioid receptors inhibit this IPSC. The aim of the present study was to determine the mechanism by which κ-opioid receptors inhibit the dopamine IPSC. In both the ventral tegmental area (VTA) and substantia nigra compacta (SNc) the κ-receptor agonist U69593 inhibited the IPSC, but not the current induced by the exogenous iontophoretic application of dopamine. The endogenous peptide dynorphin A (1–13) also inhibited IPSCs in the VTA and SNc, but also the dopamine iontophoretic current in the VTA. Although both kappa agonists induced a postsynaptic outward current in the VTA, the current induced by dynorphin was dramatically larger. This suggests that the decrease in iontophoretic dopamine current was the result of occlusion. Occlusion alone, however, could not completely account for suppression of the IPSC. The kappa opioid inhibition of the IPSC was not affected by global increases or decreases in dopamine cell activity within the slice. These findings suggest that, although kappa opioid receptors can hyperpolarize dopamine neurons, they also suppress dopamine release by direct actions at the release site. The results thus demonstrate both pre- and postsynaptic actions of kappa receptor agonists. The actions of dynorphin indicate that VTA dopamine cells are selectively regulated by kappa receptors.
Recovery of Electromyographic Activity After Transection and Surgical Repair of the Rat Sciatic Nerve
Authors: English Arthur W. , Chen Yi , Carp Jonathan S. , Wolpaw Jonathan R. , Chen Xiang Yang
Published: November 2006

The recovery of soleus (SOL), gastrocnemius (GAS), and tibialis anterior (TA) electromyographic activity (EMG) after transection and surgical repair of the sciatic nerve was studied in Sprague–Dawley rats using chronically implanted stimulation and recording electrodes. Spontaneous EMG activity in SOL and GAS and direct muscle (M) responses to posterior tibial nerve stimulation persisted for ≤2 days after sciatic nerve transection, but SOL and GAS H-reflexes disappeared immediately. Spontaneous EMG activity began to return 2–3 wk after transection, rose nearly to pretransection levels by 60 days, and persisted for the duration of the study period (120 days). Recovery of stimulus-evoked EMG responses began about 30 days after sciatic nerve transection as multiple small responses with a wide range of latencies. Over time, the latencies of these fractionated responses shortened, their amplitudes increased, and they merged into a distinct short-latency component (the putative M response) and a distinct long-latency component (the putative H-reflex). The extent of recovery of stimulation-evoked EMG was modest: even 100 days after sciatic nerve transection, the responses were still much smaller than those before transection. Similar gradual development of responses to posterior tibial nerve stimulation was also seen in TA, suggesting that some regenerating fibers sent branches into both tibial and common peroneal nerves.
RNASEN Regulates Cell Proliferation and Affects Survival in Esophageal Cancer Patients
Authors: Sugito Nobuyoshi , Ishiguro Hideyuki , Kuwabara Yoshiyuki , Kimura Masahiro , Mitsui Akira , Kurehara Hiroki , Ando Takuya , Mori Ryota , Takashima Nobuhiro , Ogawa Ryo , Fujii Yoshitaka
Published: November 2006

Purpose: MicroRNAs (miRNA) are small noncoding RNAs thought to be involved in physiologic and developmental processes by negatively regulating the expression of target genes. Little is known about the role of miRNAs in normal and cancer cells. It is possible that deregulation of miRNA may contribute to the oncogenesis of some cancers. We studied the expression level of the miRNA processing enzyme (DICER1, DGCR8, and RNASEN) in esophageal squamous cell carcinoma (ESCC).

Experimental Design: The expression levels of DICER1, DGCR8, and RNASEN mRNA in 73 ESCC tissues were compared with that in corresponding normal esophageal epithelium by Taqman real-time reverse-transcription PCR. We also examined RNASEN protein expression in 27 cell lines. The role of RNASEN in cell proliferation in ESCC cells was assessed by small interfering RNA. Paraffin sections of ESCC patients were immunohistochemically investigated.

Results: We found that RNASEN expression levels were enhanced in a fraction of esophageal cancers. Multivariate Cox regression analysis showed that the prognostic effect of RNASEN (P = 0.0036) seems to be independent of disease stage (P = 0.0060). Knockdown of RNASEN in esophageal cancer cell lines resulted in a 46% to 85% reduction in cell number. In an immunohistochemical study, the intensity of RNASEN expression was often increased in the tumor compared with that in normal epithelium.

Conclusions: The relationship between the RNASEN expression and the prognosis of the ESCC patients warrants a further study on the role of miRNA and tumor progression.
A Neoadjuvant/Adjuvant Randomized Trial of Colorectal Cancer Patients Vaccinated with an Anti-Idiotypic Antibody, 105AD7, Mimicking CD55
Authors: Ullenhag Gustav J. , Spendlove Ian , Watson Nicholas F.S. , Indar Adrian A. , Dube Mukul , Robins Richard A. , Maxwell-Armstrong Charles , Scholefield John H. , Durrant Lindy G.
Published: November 2006

Purpose: To assess the tolerability and effectiveness of 105AD7 vaccination in colorectal cancer patients. 105AD7 is a human anti-idiotypic antibody mimicking CD55, a glycoprotein, which is more than expressed on colorectal cancer cells and protects them from attack by complement.

Experimental Design: Colorectal cancer patients (n = 67) eligible for primary surgery were randomized to receive the anti-idiotypic antibody 105AD7±Bacillus Calmette-Guerin/alum or to no treatment (control group). The immunizations were given i.d./i.m. before surgery and continued for a period of 2 years. The patients were monitored in enzyme-linked immunospot (ELISPOT; γ-IFN), proliferation assay, and Luminex cytokine assays.

Results: No serious adverse events were recorded. Of the 32 investigated immunized patients, 14 (44%) were considered to be responders in the ELISPOT assay. Induced proliferative responses were noted in 17 of 40 (43%) monitored patients. There was no correlation between the ELISPOT and proliferation assays. Luminex analyses revealed tumor necrosis factor-α and granulocyte macrophage colony-stimulating factor responses not only to the vaccine but also toward the native antigen CD55 in 9 of 13 (69%) patients.

Conclusions: Immune responses to vaccination were induced in a majority of monitored patients measured by ELISPOT and proliferation assay. The lack of correlation between the ELISPOT and proliferation assays may reflect the fact that the two methods measure different T-cell responses and highlights the importance of multiple readouts in evaluating a potential cancer vaccine. Responses to both the anti-idiotype and the CD55 antigen were measurable, adding support to the use of CD55 as a target in cancer treatment.
Hemodynamic Shear Stresses in Mouse Aortas
Authors: Suo Jin , Ferrara Dardo E. , Sorescu Dan , Guldberg Robert E. , Taylor W. Robert , Giddens Don P.
Published: November 2006

Objective—

The hemodynamic environment is a determinant of susceptibility to atherosclerosis in the vasculature. Although mouse models are commonly used in atherosclerosis studies, little is known about local variations in wall shear stress (WSS) in the mouse and whether the levels of WSS are comparable to those in humans. The objective of this study was to determine WSS values in the mouse aorta and to relate these to expression of gene products associated with atherosclerosis.

Methods and Results—

Using micro-CT and ultrasound methodologies we developed a computational fluid dynamics model of the mouse aorta and found values of WSS to be much larger than those for humans. We also used a quantum dot-based approach to study vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression on the aortic intima and demonstrated that increased expression for these molecules occurs where WSS was relatively low for the mouse.

Conclusions—

Despite large differences in WSS in the two species, the spatial distributions of atherogenic molecules in the mouse aorta are similar to atherosclerotic plaque localization found in human aortas. These results suggest that relative differences in WSS or in the direction of WSS, as opposed to the absolute magnitude, may be relevant determinants of flow-mediated inflammatory responses.
Bone Marrow Oct3/4
+
Cells Differentiate Into Cardiac Myocytes via Age-Dependent Paracrine Mechanisms
Authors: Pallante Benedetta A. , Duignan Inga , Okin Daniel , Chin Andrew , Bressan Michael C. , Mikawa Takashi , Edelberg Jay M.
Published: November 2006

The mechanisms that govern the capacity of the bone marrow stem cells to generate cardiac myocytes are still unknown. Herein we demonstrate that the cardiomyogenic potential of bone marrow–derived Oct3/4
+
/cKit
+/−
/CXCR4
+/−
/CD34
−
/Sca1
−
cells is governed by age-dependent paracrine/juxtacrine platelet-derived growth factor (PDGF) pathways. Specifically, bone marrow cell cultures from both 3- and 18-month-old mice formed aggregates of Oct3/4
+
cells circumscribed by PDGFRα
+
/Oct3/4
−
/Sca1
+
cells. In young (3-month) bone marrow cell cultures, induction of PDGF-AB preceded the induction of cardiac genes and was required for the generation of cardiomyogenesis. Indeed, in old (18-month) cultures, diminished PDGF-B induction was associated with impaired cardiomyogenic potential, despite having Oct3/4 levels similar to those in the young cells. Importantly, supplementation with PDGF-AB specifically restored the cardiac differentiation capacity of the old bone marrow cells. Together these results demonstrate that, regardless of age, the bone marrow niche contains Oct3/4 stem cells that are capable of differentiating into cardiac myocytes. Moreover, this differentiation is governed by age-dependent PDGF-AB–mediated paracrine/juxtacrine pathways that may be essential in the translation of bone marrow cell–mediated cardiomyogenesis.
Regulation of Smooth Muscle Cell Proliferation by β-Catenin/T-Cell Factor Signaling Involves Modulation of Cyclin D1 and p21 Expression
Authors: Quasnichka Helen , Slater Sadie C. , Beeching Cressida A. , Boehm Manfred , Sala-Newby Graciela B. , George Sarah J.
Published: November 2006

We previously observed that stimulation of vascular smooth muscle cell (VSMC) proliferation with growth factors is associated with dismantling of cadherin junctions and nuclear translocation of β-catenin. In this study we demonstrate directly that growth factors stimulate β-catenin/T-cell factor (TCF) signaling in primary VSMCs. To determine whether β-catenin/TCF signaling regulates VSMC proliferation via modulation of the β-catenin/TCF responsive cell cycle genes, cyclin D1 and p21, we inhibited β-catenin/TCF signaling by adenoviral-mediated over-expression of N-Cadherin, ICAT (an endogenous inhibitor of β-catenin/TCF signaling), or a dominant negative (dn) mutant of TCF-4. N-cadherin, ICAT or dnTCF-4 over-expression significantly reduced proliferation of isolated human VSMCs by approximately 55%, 80%, and 45% respectively. Similar effects were observed in human saphenous vein medial segments where proliferation was reduced by approximately 55%. Transfection of dnTCF-4 in the ISS10 human VSMC line significantly lowered TCF and cyclin D1 reporter activity but significantly elevated p21 reporter activity, indicating regulation of these genes by β-catenin/TCF signaling. In support of this, over-expression of N-cadherin, ICAT or dnTCF-4 in isolated human VSMCs significantly lowered levels of cyclin D1 mRNA and protein levels. In contrast, over-expression of N-Cadherin, ICAT or dnTCF4 significantly elevated p21 mRNA and protein levels. In summary, we have demonstrated that increasing N-cadherin and inhibiting β-catenin/TCF signaling reduces VSMC proliferation, decreases the expression of cyclin D1 and increases levels of the cell cycle inhibitor, p21. We therefore suggest that the N-cadherin and β-catenin/TCF signaling pathway is a key modulator of VSMC proliferation via regulation of these 2 β-catenin/TCF responsive genes.
Enhanced Thrombogenesis but Not Platelet Activation Is Associated With Transcatheter Closure of Patent Foramen Ovale in Patients With Cryptogenic Stroke
Authors: Bédard Elisabeth , Rodés-Cabau Josep , Houde Christine , Mackey Ariane , Rivest Donald , Cloutier Stéphanie , Noël Martin , Marrero Alier , Côté Jean-Marc , Chetaille Philippe , Delisle George , Leblanc Marie-Helene , Bertrand Olivier F.
Published: November 2006

Background and Purpose—

No studies have yet determined whether antiplatelet or anticoagulant therapy is the more appropriate treatment after transcatheter closure of patent foramen ovale (PFO) in patients with cryptogenic stroke. The objective of this study was to prospectively evaluate the presence, degree, and timing of activation of the platelet and coagulation systems after transcatheter closure of PFO in patients with cryptogenic stroke.

Methods—

Twenty-four consecutive patients (mean age, 44±10 years; 11 men) with previous cryptogenic stroke who had undergone successful transcatheter closure of PFO were included in the study. Prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin III (TAT) were used as markers of coagulation activation, and soluble P-selectin and soluble CD40 ligand were used as markers of platelet activation. Measurements of all hemostatic markers were taken at baseline just before the procedure and at 7, 30, and 90 days after device implantation.

Results—

F1+2 and TAT levels increased from 0.41±0.16 nmol/L and 2.34±1.81 ng/mL, respectively, at baseline to a maximal value of 0.61±0.16 nmol/L and 4.34±1.83 ng/mL, respectively, at 7 days, gradually returning to baseline levels at 90 days (
P
<0.001 for both markers). F1+2 and TAT levels at 7 days after PFO closure were higher than those obtained in a group of 25 healthy controls (
P
<0.001 for both markers). Levels of soluble P-selectin and soluble CD40 ligand did not change at any time after PFO closure.

Conclusions—

Transcatheter closure of PFO is associated with significant activation of the coagulation system, with no increase in platelet activation markers. These findings raise the question of whether optimal antithrombotic treatment after PFO closure should be short-term anticoagulant rather than antiplatelet therapy.
Cholinergic Neuronal Deficits in CADASIL
Authors: Keverne Jessica S. , Low Wee Chuang R. , Ziabreva Iryna , Court Jenny A. , Oakley Arthur E. , Kalaria Raj N.
Published: November 2006

Background and Purpose—

Previous evidence from MRI and acetylcholinesterase histochemistry suggests cholinergic fibers are affected in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Methods—

As a measure of cholinergic function, we assessed choline acetyltransferase (ChAT) activities in the frontal and temporal neocortices and the immunocytochemical distribution of ChAT and p75 neurotrophin receptor (P75
NTR
) by in vitro imaging in the nucleus basalis of Meynert of CADASIL subjects.

Results—

ChAT activities were significantly reduced by 60% to 70% in frontal and temporal cortices of CADASIL cases, as were ChAT and P75
NTR
immunoreactivities in the nucleus basalis.

Conclusions—

Our findings suggest cholinergic neuronal impairment in CADASIL and implicate cholinomimetic therapy for subcortical vascular dementias.
Cost-Effectiveness of Intravenous Thrombolysis With Alteplase Within a 3-Hour Window After Acute Ischemic Stroke
Authors: Ehlers Lars , Andersen Grethe , Clausen Lone Beltoft , Bech Merete , Kjølby Mette
Published: November 2006

Background and Purpose—

The aim of this study was to assess the costs and cost-effectiveness of intravenous thrombolysis treatment with alteplase (Actilyse) of acute ischemic stroke with 24-hour in-house neurology coverage and use of magnetic resonance imaging.

Methods—

A health economic model was designed to calculate the marginal cost-effectiveness ratios for time spans of 1, 2, 3 and 30 years. Effect data were extracted from a meta-analysis of six large-scale randomized and placebo-controlled studies of thrombolytic therapy with alteplase. Cost data were extracted from thrombolysis treatment at Aarhus Hospital, Denmark, and from previously published literature.

Results—

The calculated cost-effectiveness ratio after the first year was $55 591 US per quality-adjusted life-year (base case). After the second year, computation of the cost-effectiveness ratio showed that thrombolysis was cost-effective. The long-term computations (30 years) showed that thrombolysis was a dominant strategy compared with conservative treatment given the model premises.

Conclusions—

A high-quality thrombolysis treatment with 24-hour in-house neurology coverage and magnetic resonance imaging might not be cost-effective in the short term compared with conservative treatment. In the long term, there are potentially large-scale health economic cost savings.
The Real Estate Factor
Authors: Menezes Nina M. , Ay Hakan , Wang Zhu Ming , Lopez Chloe J. , Singhal Aneesh B. , Karonen Jari O. , Aronen Hannu J. , Liu Yawu , Nuutinen Juho , Koroshetz Walter J. , Gregory Sorensen A.
Published: November 2006

Background and Purpose—

The severity of the neurological deficit after ischemic stroke is moderately correlated with infarct volume. In the current study, we sought to quantify the impact of location on neurological deficit severity and to delineate this impact from that of volume.

Methods—

We developed atlases consisting of location-weighted values indicating the relative importance in terms of neurological deficit severity for every voxel of the brain. These atlases were applied to 80 first-ever ischemic stroke patients to produce estimates of clinical deficit severity. Each patient had an MRI and National Institutes of Health Stroke Scale (NIHSS) examination just before or soon after hospital discharge. The correlation between the location-based deficit predictions and measured neurological deficit (NIHSS) scores were compared with the correlation obtained using volume alone to predict the neurological deficit.

Results—

Volume-based estimates of neurological deficit severity were only moderately correlated with measured NIHSS scores (
r
=0.62). The combination of volume and location resulted in a significantly better correlation with clinical deficit severity (
r
=0.79,
P
=0.032).

Conclusions—

The atlas methodology is a feasible way of integrating infarct size and location to predict stroke severity. It can estimate stroke severity better than volume alone.
Risk of Rebleeding After Treatment of Acute Hydrocephalus in Patients With Aneurysmal Subarachnoid Hemorrhage
Authors: Hellingman Catharine A. , van den Bergh Walter M. , Beijer Inge S. , van Dijk Gert W. , Algra Ale , van Gijn Jan , Rinkel Gabriël J.E.
Published: November 2006

Background and Purpose—

Cerebrospinal fluid drainage is often indicated in patients with acute hydrocephalus after aneurysmal subarachnoid hemorrhage but is believed to increase the risk of rebleeding. We studied the risk of rebleeding in patients with subarachnoid hemorrhage during treatment for acute hydrocephalus.

Methods—

We included patients with hydrocephalus treated with external ventricular drainage or lumbar punctures within 4 days after the hemorrhage and before aneurysm occlusion. Each treated patient was matched with a control patient with untreated hydrocephalus and a control patient without ventricular enlargement. Patients and controls were matched for interval since subarachnoid hemorrhage, duration of exposure, use of tranexamic acid, clinical condition on admission, and age. We used Cox regression to calculate hazard ratios and we adjusted for rebleeding that had occurred before starting the cerebrospinal fluid drainage.

Results—

In the group treated with external ventricular drainage, rebleeding occurred in seven of 34 patients (21%) with treatment, in seven of 34 controls (21%) with untreated hydrocephalus, and in six of 34 controls (18%) without hydrocephalus. In the group treated with one or more lumbar punctures, rebleeding occurred in one of 21 patients (5%) with treatment, in three of 21 controls (14%) with untreated hydrocephalus, and in none of the 21 controls without hydrocephalus. The hazard ratios for rebleeding were 1.0 (95% CI: 0.4 to 2.7) for external ventricular drainage treatment and 0.7 (95% CI: 0.1 to 6.4) for lumbar puncture treatment.

Conclusion—

This study does not confirm an importantly increased risk of rebleeding during external ventricular drainage or lumbar punctures for acute hydrocephalus after aneurysmal subarachnoid hemorrhage.