bluuebunny/crossref_metadata_2025 huggingface dataset:
Partial neuromuscular blockade in humans enhances muscle blood flow during exercise independently of muscle oxygen uptake and acetylcholine receptor blockade
Authors: Hellsten Ylva , Krustrup Peter , Iaia F. Marcello , Secher Niels H. , Bangsbo Jens
Published: February 2009

This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one-legged knee-extensor exercise (18 W) during control conditions and with cisatracurium blockade, as well as with cisatracurium blockade with prior glycopyrrone infusion. Thigh blood flow and vascular conductance in control and with cisatracurium infusion were similar at rest and during passive movement of the leg, but higher ( P < 0.05) during exercise with cisatracurium than in control (3.83 ± 0.42 vs. 2.78 ± 0.21 l/min and 26.9 ± 3.4 vs. 21.8 ± 2.0 ml·min−1·mmHg−1 at the end of exercise). Thigh oxygen uptake was similar in control and with cisatracurium infusion both at rest and during exercise, being 354 ± 33 and 406 ± 34 ml/min, at the end of exercise. Combined infusion of cisatracurium and glycopyrrone caused a similar increase in blood flow as cisatracurium infusion alone. The current results demonstrate that neuromuscular blockade leads to enhanced thigh blood flow and vascular conductance during exercise, events that are not associated with either acetylcholine or an increased oxygen demand. The results do not support an essential role for acetylcholine, released form the neuromuscular junction, in exercise hyperemia or for the enhanced blood flow during neuromuscular blockade. The enhanced exercise hyperemia during partial neuromuscular blockade may be related to a greater recruitment of fast-twitch muscle fibers.
Appetitive and consummatory ingestive behaviors stimulated by PVH and perifornical area NPY injections
Authors: Dailey Megan J. , Bartness Timothy J.
Published: February 2009

Food is acquired (obtained by foraging) and frequently stored (hoarded) across animal taxa, including humans, but the physiological mechanisms underlying these behaviors are virtually unknown. We found that peptides that stimulate food intake in rats stimulate food foraging and/or hoarding more than intake in Siberian hamsters. Neuropeptide Y (NPY) is a potent orexigenic peptide that increases food foraging and hoarding (appetitive behavior) and food intake (consummatory behavior). Given that NPY injections into the hypothalamic paraventricular nucleus (PVH) or perifornical area (PFA) increase food intake by rats, it is possible that these injections may stimulate food foraging or hoarding by Siberian hamsters. We also tested whether antagonism of the NPY Y1 receptor (Y1-R), the agonism of which stimulates hoarding, would inhibit post-food-deprivation increases in foraging and hoarding. We injected one of three doses of NPY or vehicle into the PVH or PFA of animals housed in a simulated foraging-hoarding housing system and measured these behaviors at 1, 2, 4, and 24 h. A subset of animals was subsequently food deprived and then given PVH or PFA Y1-R antagonist microinjections before they were refed. NPY PVH microinjections decreased foraging but increased hoarding and food intake, whereas NPY PFA microinjections increased all three behaviors, but the greatest increase was in hoarding. Y1-R antagonist inhibited post-food-deprivation increases in hoarding when injected into the PVH and PFA and inhibited foraging when injected into the PFA. These results support the view that NPY is involved in appetitive and consummatory ingestive behaviors, but each may be controlled by different brain areas and/or NPY receptor subtypes.
Colonic bacterial translocation as a possible factor in stress-worsening experimental stroke outcome
Authors: Caso Javier R. , Hurtado Olivia , Pereira Marta P. , García-Bueno Borja , Menchén Luis , Alou Luis , Gómez-Lus María Luisa , Moro María A. , Lizasoain Ignacio , Leza Juan C.
Published: February 2009

Stress is known to be one of the risk factors of stroke, but only a few experimental studies have examined the possible mechanisms by which prior stress may affect stroke outcome. In stroke patients, infections impede neurological recovery and increase morbidity as well as mortality. We previously reported that stress induces a bacterial translocation and that prior immobilization stress worsens experimental stroke outcome through mechanisms that involve inflammatory mediators such as release of proinflammatory cytokines and enzyme activation. We now investigate whether bacterial translocation from the intestinal flora of rats with stress before experimental ischemia is involved in stroke outcome. We used an experimental paradigm consisting of exposure of Fischer rats to repeated immobilization sessions before permanent middle cerebral artery occlusion (MCAO). The presence of bacteria and the levels and expression of different mediators involved in the bacterial translocation were analyzed. Our results indicate that stress before stroke is related to the presence of bacteria in different organs (mesenteric nodes, spleen, liver, and lung) after MCAO and increases inflammatory colonic parameters (such as cyclooxygenase-2, inducible nitric oxide synthase, and myeloperoxidase), but decreases colonic immunoglobulin A, and these results are correlated with colonic inflammation and bacterial translocation. Understanding the implication of bacterial translocation during stress-induced stroke worsening is of great potential clinical relevance, given the high incidence of infections after severe stroke and their main role in mortality and morbidity in stroke patients.
Chaotic dynamics of cardioventilatory coupling in humans: effects of ventilatory modes
Authors: Mangin Laurence , Clerici Christine , Similowski Thomas , Poon Chi-Sang
Published: February 2009

Cardioventilatory coupling (CVC), a transient temporal alignment between the heartbeat and inspiratory activity, has been studied in animals and humans mainly during anesthesia. The origin of the coupling remains uncertain, whether or not ventilation is a main determinant in the CVC process and whether the coupling exhibits chaotic behavior. In this frame, we studied sedative-free, mechanically ventilated patients experiencing rapid sequential changes in breathing control during ventilator weaning during a switch from a machine-controlled assistance mode [assist-controlled ventilation (ACV)] to a patient-driven mode [inspiratory pressure support (IPS) and unsupported spontaneous breathing (USB)]. Time series were computed as R to start inspiration (RI) and R to the start of expiration (RE). Chaos was characterized with the noise titration method (noise limit), largest Lyapunov exponent (LLE) and correlation dimension (CD). All the RI and RE time series exhibit chaotic behavior. Specific coupling patterns were displayed in each ventilatory mode, and these patterns exhibited different linear and chaotic dynamics. When switching from ACV to IPS, partial inspiratory loading decreases the noise limit value, the LLE, and the correlation dimension of the RI and RE time series in parallel, whereas decreasing intrathoracic pressure from IPS to USB has the opposite effect. Coupling with expiration exhibits higher complexity than coupling with inspiration during mechanical ventilation either during ACV or IPS, probably due to active expiration. Only 33% of the cardiac time series (RR interval) exhibit complexity either during ACV, IPS, or USB making the contribution of the cardiac signal to the chaotic feature of the coupling minimal. We conclude that 1) CVC in unsedated humans exhibits a complex dynamic that can be chaotic, and 2) ventilatory mode has major effects on the linear and chaotic features of the coupling. Taken together these findings reinforce the role of ventilation in the CVC process.
Developmental programming of lipid metabolism and aortic vascular function in C57BL/6 mice: a novel study suggesting an involvement of LDL-receptor
Authors: Chechi Kanta , McGuire John J. , Cheema Sukhinder K.
Published: February 2009

We have previously shown that a maternal high-fat diet, rich in saturated fatty acids (SFA), alters the lipid metabolism of their adult offspring. The present study was designed to investigate 1) whether alterations in hepatic LDL-receptor (LDL-r) expression may serve as a potential mechanism of developmental programming behind the altered lipid metabolism of the offspring, 2) whether altered lipid metabolism leads to aortic vascular dysfunction in the offspring, 3) whether deleterious effects of SFA exposure preweaning are influenced by postweaning diet, and 4) whether gender-specific programming effects are observed. Female C57Bl/6 mice were fed a high-SFA diet or regular chow during gestation and lactation while their pups, both male and female, received either SFA or a chow diet after weaning. Male offspring obtained from mothers fed an SFA diet and those who continued on chow postweaning had higher plasma triglycerides and total cholesterol, whereas female offspring had higher plasma total and LDL cholesterol levels, lower hepatic LDL-r mRNA expression, and reduced aortic contractile responses compared with the offspring that were fed chow throughout the study. A comparison of the postweaning diet revealed significantly lower hepatic LDL-r expression along with significantly higher plasma LDL-cholesterol concentration in the female offspring that were obtained from mothers fed an SFA diet and who continued on an SFA diet postweaning, compared with the female offspring that were obtained from mothers fed an SFA diet but who continued on chow postweaning. In conclusion, we report a novel observation of hepatic LDL-r-mediated programming of altered lipid metabolism, along with aortic vascular dysfunction, in the female offspring of mothers fed a high-SFA diet. Male offspring only exhibited dyslipidemia, suggesting gender-mediated programming. This study further highlighted the role of postweaning diets in overriding the effects of maternal programming.
Resistin acutely impairs insulin-stimulated glucose transport in rodent muscle in the presence, but not absence, of palmitate
Authors: Junkin Kathryn A. , Dyck David J. , Mullen Kerry L. , Chabowski Adrian , Thrush A. Brianne
Published: February 2009

Resistin is a cytokine implicated in the development of insulin resistance. However, there has been little investigation of the effects of resistin on fatty acid (FA) metabolism and insulin response in skeletal muscle, a key tissue for glucose disposal. The purpose of the present study was to examine the role of altered FA metabolism as a cause of resistin's inhibition of insulin-stimulated glucose transport in muscle. Isolated rat soleus muscles were incubated acutely (2 h) in the presence or absence of 600 ng/ml resistin, with or without 2 mM palmitate. Resistin acutely impaired insulin-stimulated glucose transport and Akt phosphorylation, but only in the presence of palmitate, implicating a role for altered FA metabolism. This impairment of glucose transport induced by resistin plus palmitate could be pharmacologically rescued by the inclusion of aimidazole carboxamide ribonucleotide, a stimulator of AMP-activated protein kinase and FA oxidation, as well as inhibitors of ceramide synthesis (myriocin, fumonisin). However, to our surprise, resistin actually blunted the palmitate-induced increase in muscle ceramide content; as expected, ceramide content was significantly lowered by fumonisin. In summary, the acute impairment of insulin response by resistin was manifested only in the presence of high palmitate and was alleviated when FA metabolism was manipulated (increased oxidation, inhibited ceramide synthesis). Resistin's acute impairment of insulin response does not appear to require an absolute increase in ceramide content; however, reducing ceramide content alleviated the impairment in glucose transport and insulin signaling.
The transcription factor, glial cell missing 2, is involved in differentiation and functional regulation of H+-ATPase-rich cells in zebrafish (Danio rerio)
Authors: Chang Wei-Jen , Horng Jiun-Lin , Yan Jia-Jiun , Hsiao Chung-Der , Hwang Pung-Pung
Published: February 2009

H+-ATPase-rich (HR) cells in zebrafish are known to be involved in acid secretion and Na+uptake mechanisms in zebrafish gills/skin; however, little is known about how HR cells are functionally regulated. In the present work, we studied the roles of Drosophila glial cell missing ( gcm), a cell fate-related transcription factor, in the differentiation and functional regulation of zebrafish HR cells. Zebrafish gcm2 ( zgcm2) was found to begin expression in zebrafish embryos at 10 h postfertilization (hpf), and to be extensively expressed in gills but only mildly so in eyes, heart, muscles, and testes. By whole mount in situ hybridization, zgcm2 mRNA signals were found in a group of cells on the zebrafish yolk sac surface initially in the tail bud stage (10 hpf); they had disappeared at 36 hpf and thereafter appeared again in the gill region from 48 hpf. Double fluorescence in situ hybridization further demonstrated specific colocalization of zgcm2 mRNA in HR cells in zebrafish embryos. Knockdown of zgcm2 with a specific morpholino oligonucleotide caused the complete disappearance of HR cells with a concomitant decrease in H+activity at the apical surface of HR cells, but it did not affect the occurrence of Na+-K+-ATPase-rich cells. A decrease in the H+-ATPase subunit A ( zatp6v1a) expression and no change in zgcm2 expression in zebrafish gills were seen from 12 h to 3 days after transfer to acidic fresh water, but a compensatory stimulation in the expressions of both genes appeared 4 days posttransfer. In conclusion, functional regulation of HR cells is probably achieved by enhancing cell differentiation via zGCM2 activation.
Rosiglitazone decreases blood pressure and renal injury in a female mouse model of systemic lupus erythematosus
Authors: Venegas-Pont Marcia , Sartori-Valinotti Julio C. , Maric Christine , Racusen Lorraine C. , Glover Porter H. , McLemore Gerald R. , Jones Allison V. , Reckelhoff Jane F. , Ryan Michael J.
Published: February 2009

Women with systemic lupus erythematosus (SLE) exhibit a high prevalence of hypertension and renal injury. Rosiglitazone (Rosi), a peroxisome proliferator activator receptor gamma (PPARγ) agonist, has renal protective and antihypertensive effects. We tested whether Rosi ameliorates hypertension and renal injury in a female mouse model of SLE (NZBWF1). Thirty-week-old SLE and control (NZW/LacJ) mice ( n ≥ 6/group) were fed Rosi (5 mg·kg−1·day−1in standard chow) or standard chow for 4 wk. SLE mice had increased blood pressure (BP in mmHg) compared with controls (139 ± 4 vs. 111 ± 4, P < 0.05). Rosi treatment lowered BP in SLE mice (127 ± 4, P < 0.05) but not in controls (111 ± 4). Urinary albumin (μg/mg creatinine) was increased in SLE mice compared with controls (12,396 ± 6,525 vs. 50 ± 6) and reduced with Rosi treatment (148 ± 117). Glomerulosclerosis (% of glomeruli with sclerosis) was reduced in Rosi-treated SLE mice (4.2 ± 1.6 vs. 0.4 ± 0.3, P < 0.05). Renal monocyte/macrophage numbers (cell number/1,320 points counted) were reduced in SLE mice treated with Rosi (32.6 ± 11.0 vs. 10.6 ± 3.6, P < 0.05) but unchanged in controls (3.7 ± 1.6 vs. 3.7 ± 2.0). Renal osteopontin expression, a cytokine-regulating macrophage recruitment, was reduced in Rosi-treated SLE mice. Urinary endothelin (in pg/mg creatinine) was increased in SLE mice compared with controls (1.9 ± 0.59 vs. 0.6 ± 0.04, P < 0.05) and reduced in SLE mice treated with Rosi (0.8 ± 0.11, P < 0.05). PPARγ protein expression in the renal cortex was significantly lower in SLE mice compared with controls and was unaffected by Rosi. These data suggest that Rosi may be an important therapeutic option for the treatment of SLE hypertension and renal injury.
1,25-Dihydroxyvitamin D3suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-κB pathway
Authors: Deb Dilip K. , Chen Yunzi , Zhang Zhongyi , Zhang Yan , Szeto Frances L. , Wong Kari E. , Kong Juan , Li Yan Chun
Published: February 2009

The renin-angiotensin system (RAS) is a major mediator of renal injury in diabetic nephropathy. Our previous studies demonstrated that 1,25-dihydroxyvitamin D3[1,25(OH)2D3] plays a renoprotective role by suppressing the RAS, with renin and angiotensinogen (AGT) as the main targets. The mechanism whereby 1,25(OH)2D3transcriptionally suppresses renin gene expression has been elucidated; however, how vitamin D regulates AGT remains unknown. Exposure of mesangial cells or podocytes to high glucose (HG; 30 mM) markedly stimulated AGT expression. In mesangial cells, the stimulation was inhibited by 1,25(OH)2D3(20 nM) or NF-κB inhibitor BAY 11–7082, suggesting the involvement of NF- κB in HG-induced AGT expression and the interaction between 1,25(OH)2D3and NF-κB in the regulation. Plasmid pNF-κB-Luc luciferase reporter assays showed that 1,25(OH)2D3blocked HG-induced NF-κB activity. EMSA and ChIP assays demonstrated increased p65/p50 binding to a NF-κB binding site at −1734 in the AGT gene promoter upon high glucose stimulation, and the binding was disrupted by 1,25(OH)2D3treatment. Overexpression of p65/p50 overcame 1,25(OH)2D3suppression, and mutation of this NF-κB binding site blunted 1,25(OH)2D3suppression of the promoter activity. In mice lacking the vitamin D receptor, AGT mRNA expression in the kidney was markedly increased compared with wild-type mice, and AGT induction in diabetic mice was suppressed by treatment with a vitamin D analog. These data indicate that 1,25(OH)2D3suppresses hyperglycemia-induced AGT expression by blocking NF-κB-mediated pathway.
Effects of receptor-mediated endocytosis and tubular protein composition on volume retention in experimental glomerulonephritis
Authors: Kastner Christian , Pohl Marcus , Sendeski Mauricio , Stange Gerti , Wagner Carsten A. , Jensen Boye , Patzak Andreas , Bachmann Sebastian , Theilig Franziska
Published: February 2009

Human glomerulonephritis (GN) is characterized by sustained proteinuria, sodium retention, hypertension, and edema formation. Increasing quantities of filtered protein enter the renal tubule, where they may alter epithelial transport functions. Exaggerated endocytosis and consequent protein overload may affect proximal tubules, but intrinsic malfunction of distal epithelia has also been reported. A straightforward assignment to a particular tubule segment causing salt retention in GN is still controversial. We hypothesized that 1) trafficking and surface expression of major transporters and channels involved in volume regulation were altered in GN, and 2) proximal tubular endocytosis may influence locally as well as downstream expressed tubular transporters and channels. Effects of anti-glomerular basement membrane GN were studied in controls and megalin-deficient mice with blunted proximal endocytosis. Mice displayed salt retention and elevated systolic blood pressure when proteinuria had reached 10–15 mg/24 h. Surface expression of proximal Na+-coupled transporters and water channels was in part [Na+-Picotransporter IIa (NaPi-IIa) and aquaporin-1 (AQP1)] increased by megalin deficiency alone, but unchanged (Na+/H+exchanger 3) or reduced (NaPi-IIa and AQP1) in GN irrespective of the endocytosis defect. In distal epithelia, significant increases in proteolytic cleavage products of α-epithelial Na+channel (ENaC) and γ-ENaC were observed, suggesting enhanced tubular sodium reabsorption. The effects of glomerular proteinuria dominated over those of blunted proximal endocytosis in contributing to ENaC cleavage. Our data indicate that ENaC-mediated sodium entry may be the rate-limiting step in proteinuric sodium retention. Enhanced proteolytic cleavage of ENaC points to a novel mechanism of channel activation which may involve the action of filtered plasma proteases.
Abundance of the Na-K-2Cl cotransporter NKCC2 is increased by high-fat feeding in Fischer 344 X Brown Norway (F1) rats
Authors: Riazi Shahla , Tiwari Swasti , Sharma Nikhil , Rash Arjun , Ecelbarger C. M.
Published: February 2009

Insulin resistance is associated with hypertension by mechanisms likely involving the kidney. To determine how the major apical sodium transporter of the thick ascending limb, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) is regulated by high-fat feeding, we treated young male, Fischer 344 X Brown Norway (F344BN) rats for 8 wk with diets containing either normal (NF, 4%) or high (HF, 36%) fat, by weight, primarily as lard. HF-fed rats had impaired glucose tolerance, increased urine excretion of 8-isoprostane (a marker of oxidative stress), increased protein levels for NKCC2 (50–125%) and the renal outer medullary potassium channel (106%), as well as increased natriuretic response to furosemide (20–40%). To test the role of oxidative stress in this response, in study 2, rats were fed the NF or HF diet plus plain drinking water, or water containing NG-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor (100 mg/l), or tempol, a superoxide dismutase mimetic (1 mmol/l). The combination of tempol with HF nullified the increase in medullary NKCC2, while l-NAME with HF led to the highest expression of medullary NKCC2 (to 498% of NF mean). However, neither of these drugs dramatically affected the elevated natriuretic response to furosemide with HF. Finally, l-NAME led to a marked increase in blood pressure (measured by radiotelemetry), which was significantly enhanced with HF. Mean arterial blood pressure at 7 wk was as follows (mmHg): NF, 100 ± 2; NF plus l-NAME, 122 ± 3; and HF plus l-NAME, 131 ± 2. Overall, HF feeding increased the abundance of NKCC2. Inappropriately high sodium reabsorption in the thick ascending limb via NKCC2 may contribute to hypertension with insulin resistance.
NHE8 is an intracellular cation/H+exchanger in renal tubules of the yellow fever mosquitoAedes aegypti
Authors: Piermarini Peter M. , Weihrauch Dirk , Meyer Heiko , Huss Markus , Beyenbach Klaus W.
Published: February 2009

The goal of this study was to identify and characterize the hypothesized apical cation/H+exchanger responsible for K+and/or Na+secretion in the renal (Malpighian) tubules of the yellow fever mosquito Aedes aegypti. From Aedes Malpighian tubules, we cloned “ AeNHE8,” a full-length cDNA encoding an ortholog of mammalian Na+/H+exchanger 8 (NHE8). The expression of AeNHE8 transcripts is ubiquitous among mosquito tissues and is not enriched in Malpighian tubules. Western blots of Malpighian tubules suggest that AeNHE8 is expressed primarily as an intracellular protein, which was confirmed by immunohistochemical localizations in Malpighian tubules. AeNHE8 immunoreactivity is expressed in principal cells of the secretory, distal segments, where it localizes to a subapical compartment (e.g., vesicles or endosomes), but not in the apical brush border. Furthermore, feeding mosquitoes a blood meal or treating isolated tubules with dibutyryl-cAMP, both of which stimulate a natriuresis by Malpighian tubules, do not influence the intracellular localization of AeNHE8 in principal cells. When expressed heterologously in Xenopus laevis oocytes, AeNHE8 mediates EIPA-sensitive Na/H exchange, in which Li+partially and K+poorly replace Na+. The expression of AeNHE8 in Xenopus oocytes is associated with the development of a conductive pathway that closely resembles the known endogenous nonselective cation conductances of Xenopus oocytes. In conclusion, AeNHE8 does not mediate cation/H+exchange in the apical membrane of Aedes Malpighian tubules; it is more likely involved with an intracellular function.
Increased superoxide formation induced by irradiation preconditioning triggers kidney resistance to ischemia-reperfusion injury in mice
Authors: Kim Jinu , Park Jeen-Woo , Park Kwon Moo
Published: February 2009

One of the obstacles in irradiation therapy is cytoresistance, acquired by activation of self-defense systems, such as antioxidant or molecular chaperone systems, to cope with stress. We investigated whether irradiation preconditioning (IP) rendered resistance of the kidney against subsequent ischemia-reperfusion (I/R) and attempted to elucidate any such protective mechanisms. Mice were irradiated with a total of 4, 6, or 8 Gy using a cesium-137 source irradiator and then, 6 days later, were subjected to 28 min of bilateral renal ischemia followed by reperfusion. Eight Gy of IP significantly attenuated the increases in plasma creatinine (PCr) and blood urea nitrogen (BUN) concentration, structural damage, lipid peroxidation, superoxide formation, expression and activity of NADPH oxidase (NOX)-2, nitrotyrosine level, and hydrogen peroxide production after I/R in kidney tissues, indicating that IP protects the kidneys from I/R injury. IP markedly increased the activity of NOX, resulting in increased superoxide formation, manganese superoxide dismutase (MnSOD) activity and expression, and heat shock protein (HSP)-27 expression in kidneys. However, it did not change expressions of catalase, copper-zinc superoxide dismutase (CuZnSOD), and HSP-72. To investigate whether the protection afforded by IP was associated with increases in MnSOD and HSP-27 expression triggered by increased superoxide formation after IP, we administered manganese (III) tetrakis(1-methyl-4-pyridyl)porphyrin, a superoxide scavenger, to IP mice. This administration blocked superoxide formation and subsequent increases in MnSOD and HSP-27 expression and accelerated the post-I/R increases in PCr and BUN. In conclusion, IP renders kidney resistance to I/R injury, and this resistance is mediated by increased superoxide formation, which activates MnSOD activity and expression as well as HSP-27 expression.
Multiple Rhythmic States in a Model of the Respiratory Central Pattern Generator
Authors: Rubin Jonathan E. , Shevtsova Natalia A. , Ermentrout G. Bard , Smith Jeffrey C. , Rybak Ilya A.
Published: February 2009

The three-phase respiratory pattern observed during normal breathing changes with alterations in metabolic or physiological conditions. A recent study using in situ perfused rat brain preparations demonstrated a reorganization of the respiratory pattern with sequential reduction of the brain stem respiratory network. Specifically, with removal of the pons, the normal three-phase pattern transformed to a two-phase inspiratory–expiratory pattern and, with more caudal transections, to one-phase, intrinsically generated inspiratory oscillations. A minimal neural network proposed to reproduce these transformations includes 1) a ringlike mutually inhibitory network composed of the postinspiratory, augmenting expiratory, and early-inspiratory neurons and 2) an excitatory preinspiratory neuron, with persistent sodium current ( INaP)-dependent intrinsic bursting properties, that dynamically participates in the expiratory–inspiratory phase transition and inspiratory phase generation. We used activity-based single-neuron models and applied numerical simulations, bifurcation methods, and fast–slow decomposition to describe the behavior of this network in the functional states corresponding to the three-, two-, and one-phase oscillatory regimes, as well as to analyze the transitions between states and between respiratory phases within each state. We demonstrate that, although INaPis not necessary for the generation of three- and two-phase oscillations, it contributes to control of the oscillation period in each state. We also show that the transitions between states can be produced by progressive changes of drives to particular neurons and proceed through intermediate regimes, featuring high-amplitude late-expiratory and biphasic-expiratory activities or ectopic burst generation. Our results provide important insights for understanding the state-dependent mechanisms for respiratory rhythm generation and control.
Intracellular Responses of Neurons in the Mouse Inferior Colliculus to Sinusoidal Amplitude-Modulated Tones
Authors: Geis H.-R. , Borst J. G. G.
Published: February 2009

Changes in the temporal envelope are important defining features of natural acoustic signals. Many cells in the inferior colliculus (IC) respond preferentially to certain modulation frequencies, but how they accomplish this is not yet clear. We therefore made whole cell patch-clamp recordings in the IC of anesthetized mice while presenting sinusoidal amplitude-modulated (SAM) tones. The relation between the number of evoked spikes and modulation frequency was used to construct rate modulation transfer functions (rMTFs). We observed different types of rate tuning, including band-pass (16%), band-reject (13%), high-pass (6%), and low-pass (6%) tuning. In the high-pass rMTF neurons and some of the low-pass rMTF neurons, the tuning characteristics appeared to be already present in the inputs. In both band-pass and band-reject rMTF neurons, the nonlinear relation between membrane potential and spike probability ensured preferential spiking during only a small part of the modulation period. Band-pass rMTF neurons had rapidly rising excitatory postsynaptic potentials, allowing good phase-locking to brief tones and intermediate modulation frequencies. At low modulation frequencies, adaptation of their spike threshold contributed to the onset response. In contrast, band-reject rMTF neurons responded with small excitatory or inhibitory postsynaptic potentials to brief tones. In these cells, a power law could describe the supralinear relation between average membrane potential and spike rate. Differences in timing of synaptic input and presence or absence of spike adaptation therefore define band-pass and band-reject rate tuning to SAM tones in the mouse IC.
Axonal Sodium-Channel Bands Shape the Response to Electric Stimulation in Retinal Ganglion Cells
Authors: Fried Shelley I. , Lasker Aaron C. W. , Desai Neal J. , Eddington Donald K. , Rizzo Joseph F.
Published: February 2009

Electric stimulation of the retina reliably elicits light percepts in patients blinded by outer retinal diseases. However, individual percepts are highly variable and do not readily assemble into more complex visual images. As a result, the quality of visual information conveyed to patients has been quite limited. To develop more effective stimulation methods that will lead to improved psychophysical outcomes, we are studying how retinal neurons respond to electric stimulation. The situation in the retina is analogous to other neural prosthetic applications in which a better understanding of the underlying neural response may lead to improved clinical outcomes. Here, we determined which element in retinal ganglion cells has the lowest threshold for initiating action potentials. Previous studies suggest multiple possibilities, although all were within the soma/proximal axon region. To determine the actual site, we measured thresholds in a dense two-dimensional grid around the soma/proximal axon region of rabbit ganglion cells in the flat mount preparation. In directionally selective (DS) ganglion cells, the lowest thresholds were found along a small section of the axon, about 40 μm from the soma. Immunochemical staining revealed a dense band of voltage-gated sodium channels centered at the same location, suggesting that thresholds are lowest when the stimulating electrode is closest to the sodium-channel band. The size and location of the low-threshold region was consistent within DS cells, but varied for other ganglion cell types. Analogously, the length and location of sodium channel bands also varied by cell type. Consistent with the differences in band properties, we found that the absolute (lowest) thresholds were also different for different cell types. Taken together, our results suggest that the sodium-channel band is the site that is most responsive to electric stimulation and that differences in the bands underlie the threshold differences we observed.
Homeostatic Presynaptic Suppression of Neuronal Network Bursts
Authors: Cohen Dror , Segal Menahem
Published: February 2009

Spontaneous synchronized bursts of activity play an essential role in the maturation and plasticity of neuronal networks. To investigate the cellular properties that enable spontaneous network activity, we used dissociated cultures of hippocampal neurons that express prolonged network activity bursts. Acute exposure to a low concentration of N-methyl-d-aspartate (NMDA) caused an increase in spontaneous firing rates and intracellular calcium concentration ([Ca2+]i). However, in the course of a chronic (>1 day) exposure to NMDA, [Ca2+]i recovered back to normal baseline levels, and only sporadic asynchronous calcium transients were detected. Spontaneous network bursts were still absent 1 h after the removal of NMDA, indicating a persistent downregulation of network activity, which did recover eventually 2 days later. This effect of NMDA was activity-dependent as it was blocked by co-application of tetrodotoxin (TTX). The chronic NMDA-treated neurons expressed normal morphology and active membrane properties as well as spontaneous miniature excitatory postsynaptic currents and postsynaptic reactivity to glutamate. However, in response to trains of afferent stimulation in paired recordings, the treated neurons expressed synaptic depression as opposed to synaptic potentiation seen in control cells. Also, treated neurons did not respond to low-intensity electrical field stimulation as did control cells. Finally, Western blot analysis revealed that chronic exposure to NMDA altered presynaptic but not postsynaptic protein expression patterns, suggesting a presynaptic locus of effect. Thus a long-lasting increase in activity downregulates neurotransmitter release to prevent over-excitation of the network and, consequently, blocks the generation of network bursts.
Excitability at the Motoneuron Pool and Motor Cortex Is Specifically Modulated in Lengthening Compared to Isometric Contractions
Authors: Gruber M. , Linnamo V. , Strojnik V. , Rantalainen T. , Avela J.
Published: February 2009

Neural control of muscle contraction seems to be unique during muscle lengthening. The present study aimed to determine the specific sites of modulatory control for lengthening compared with isometric contractions. We used stimulation of the motor cortex and corticospinal tract to observe changes at the spinal and cortical levels. Motor-evoked potentials (MEPs) and cervicomedullary MEPs (CMEPs) were evoked in biceps brachii and brachioradialis during maximal and submaximal lengthening and isometric contractions at the same elbow angle. Sizes of CMEPs and MEPs were lower in lengthening contractions for both muscles (by ∼28 and ∼16%, respectively; P < 0.01), but MEP-to-CMEP ratios increased (by ∼21%; P < 0.05). These results indicate reduced excitability at the spinal level but enhanced motor cortical excitability for lengthening compared with isometric muscle contractions.
Timing-Dependent Regulation of Evoked Spiking in Nucleus Accumbens Neurons by Integration of Limbic and Prefrontal Cortical Inputs
Authors: McGinty Vincent B. , Grace Anthony A.
Published: February 2009

Single nucleus accumbens (NAcc) neurons receive excitatory synaptic input from cortical and limbic structures, and the integration of converging goal- and motivation-related signals in these neurons influences reward-directed actions. While limbic/cortical synaptic input summation has been characterized at subthreshold intensities, the manner in which multiple inputs govern NAcc neuron spike discharge has not been measured and is poorly understood. Single NAcc neurons were recorded in urethane-anesthetized rats, and spiking was evoked by coincident stimulation of two major NAcc afferent regions: the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). BLA input increased NAcc spiking elicited by mPFC stimulation depending on the timing of the stimulation pulses, consistent with the summation of monosynaptically evoked excitatory activity. When mPFC input intensity was below threshold for evoked spiking, the addition of BLA input produced the largest facilitation of evoked spiking, and the latency of the evoked spikes reflected the latency of the individual inputs. When mPFC inputs were stimulated at higher intensities, BLA-mediated facilitation was weaker, and the spike latency reflected only the mPFC input. Thus NAcc neurons integrate both the magnitude and timing of afferent synaptic activity, suggesting that NAcc neuron output is strongly dependent on the comparative magnitude of synaptic activity in its afferent structures. These interactions may be crucial integrative mechanisms that allow motivational and cognitive information to produce appropriate reward-directed actions.
Design of PCB Impedance Matching Inductors and Antennas for Single-Chip Communication Systems
Authors: Chung J. , Hamedi-Hagh S.
Published: February 2009

This paper presents the design of an inductor and an antenna for a portable device with GPS and FM capabilities. The inductor is designed to operate at the lower frequency FM band as part of a matching network and the antenna is designed to operate at the higher frequency GPS L1 band. The FR4 PCB used has a thickness of 1.6 mm with a dielectric constant of 3.8 and has two metallization layers. The inductor is designed with 1.5 mm trace width, 3.5 turns, and has a dimension of 14.5 mm × 14.5 mm. It has an inductance of 95 nH, a resistance of 2.9 Ω, a self-resonance frequency of 500 MHz, and a maximum Q of 51 from 100 MHz to 200 MHz (FM band). The antenna has a dimension of 49 mm × 36 mm and is designed to operate at 1.5754 GHz L1 band. It also has a return loss of −36 dB and a measured bandwidth of 250 MHz.
Esophageal Carcinoma Histology Affects Perioperative Morbidity Following Open Esophagogastrectomy
Authors: Woodall Charles E. , Duvall Ryan , Scoggins Charles R. , McMasters Kelly M. , Martin Robert C. G.
Published: February 2009

Background. Esophagectomy for esophageal cancer is being practiced routinely with favorable results at many centers. We sought to determine if tumor histology is a powerful surrogate marker for perioperative morbidity.Methods. Seventy three consecutive patients managed operatively were reviewed from our prospectively maintained database.Results. Adenocarcinoma (AC) was present in 52 (71%) and squamous cell (SCC) in 21 (29%). The use of neoadjuvant therapy was similar for the AC (34.62%) and SCC (42.86%) groups. The SCC group had a higher incidence of prior pulmonary disease than the AC group (23.8% versus 5.8%, resp.; SCC patients were more likely to have a prolonged ICU stay than AC patients () despite similar complication rates, EBL, and prognostic nutritional index. The SCC group did, however, experience higher grades of complications ().Conclusions. Presence of SCC was the single best predictor of prolonged ICU stay and more severe complications as defined by this study. Only a past history of pulmonary disease was different between the two histologic subgroups.
Raman Spectroscopy for the Nondestructive Testing of Carbon Fiber
Authors: Washer Glenn , Blum Frank
Published: February 2009

The goal of this research is to evaluate the potential of Raman spectroscopy as a method of condition assessment for carbon fiber composite materials used in high performance situations such as composite overwrapped pressure vessels (COPVs). There are currently limited nondestructive evaluation (NDE) technologies to evaluate these composite materials in situ. Variations in elastic strain in the composite material can manifest from degradation or damage, and as such could provide a tool for condition assessment. The characterization of active Raman bands and the strain sensitivity of these bands for commercially available carbon fibers are reported.
Wing Color of Monarch Butterflies (Danaus plexippus) in Eastern North America across Life Stages: Migrants Are “Redder” than Breeding and Overwintering Stages
Authors: Davis Andrew K.
Published: February 2009

Monarch butterflies are famous among insects for their unique migration in eastern North America to overwinter sites in Mexico and their bright orange wing color, which has an aposematic function. While capturing migrating monarchs in northeast Georgia, USA, I noticed that many appeared to have unusually deep orange wings. I initiated the current study to compare wing hues (obtained using image analysis of scanned wings) of migrants (captured in 2005 and 2008) to samples of breeding and overwintering monarchs. Consistent with initial observations, migrants had significantly lower orange hues (reflecting deeper, redder orange colors) than breeding and overwintering monarchs. There was also a difference in hue between sexes and a relationship with wing size, such that larger monarchs had deeper, redder hues. The reasons for the color difference of migrants are not apparent, but one possibility is that the longer-lived migrant generation has denser scalation to allow for scale loss over their lifespan. Alternatively, this effect could be confined to the subpopulation of monarchs in the Southeastern United States, which may not be well represented at the Mexican overwintering sites. In any case, this discovery highlights the many questions emerging on the significance of wing color variation in this species.
Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling ofβ-Adrenergic Receptors to Phosphoinositide 3-Kinase
Authors: Simard Julie , Boucher Matthieu , Massé Rachel , Hébert Terence E. , Rousseau Guy
Published: February 2009

An agonist-occupiedβ2-adrenergic receptor (β2-AR) recruits G protein receptor kinase-2 (GRK2) which is recruited to the membrane. Thus, the physical proximity of activatedβ2-AR and PI-3K allows the activation of the latter. In contrast, it has been observed that theβ1-AR is unable to activate the PI-3K/Akt pathway. We hypothesized that the difference might be due to molecular determinants present in the carboxy termini of the twoβ-AR subtypes. Using transiently transfected HEK 293 cells expressing eitherβ1- orβ2-AR, we also observed that in presence of an agonist,β2-AR, but notβ1-AR, is able to activate the PI-3K/Akt pathway. Switching the seventh transmembrane domain and the carboxy tail between the two receptors reverses this phenotype; that is,β1×β2-AR can activate the PI-3K/Akt pathway whereasβ2×β1-AR cannot. Pretreatment with pertussis toxin abolished the activation of PI-3K byβ2- orβ1×β2-AR stimulation. Ligand-mediated internalization of theβ2-AR induced by a 15-minute stimulation with agonist was abolished in the presence of a dominant negative of PI-3K or following pertussis toxin pretreatment. These results indicate that the subtype-specific differences in the coupling to PI-3K/Akt pathway are due to molecular determinants present in the carboxy tail of the receptor and further thatβ2-AR activates PI-3K via a pertussis toxin-sensitive mechanism.
A Short-term Rat Mammary Carcinogenesis Model for the Prevention of Hormonally Responsive and NonresponsiveIn situCarcinomas
Authors: Woditschka Stephan , Haag Jill D. , Sullivan Ruth , Gould Michael N.
Published: February 2009

Preclinical models that accurately reproduce specific aspects of human disease etiology are invaluable for the initial development and evaluation of chemopreventive agents. We developed a novel, short-term prevention model, which is particularly useful for assessing the efficacy of a compound to prevent hormonally responsive and nonresponsive in situ carcinomas. In this model, carcinogenesis is induced by a high titer of neu-containing, replication-defective retrovirus. The multiplicity and size of the resulting in situ carcinomas are scored in whole-mounted, aluminum carmine–stained mammary glands at 15 days postinfusion. These in situ carcinomas represent a distinct biological time point in the development of neu-induced mammary cancer in the rat. They are characterized by high rates of proliferation (40.0%; P < 0.0001) and apoptosis (2.8%; P < 0.005) compared with mammary carcinomas. The majority of in situ carcinomas regress spontaneously after 20 days postinfusion. The in situ carcinomas at 15 days postinfusion exhibit hormonal responsiveness. The effects of the chemoprevention agents tamoxifen, celecoxib, and targretin on hormonally responsive and nonresponsive in situ carcinomas recapitulate those observed on mammary carcinomas at 12 and 18 weeks postinfusion for intact and ovariectomized rats, respectively. Neu-induced in situ carcinomas in the rat represent etiologically relevant intermediate time points of mammary carcinogenesis. Our prevention model represents a cost-efficient in vivo system to determine whether the preventive effects of a compound extend to hormonally nonresponsive mammary lesions, for which new chemoprevention approaches are needed.
Lack of Efficacy of the Statins Atorvastatin and Lovastatin in Rodent Mammary Carcinogenesis
Authors: Lubet Ronald A. , Boring Daniel , Steele Vernon E. , Ruppert J. Michael , Juliana M. Margaret , Grubbs Clinton J.
Published: February 2009

The statins are highly effective in lowering cholesterol by inhibiting 3-hydroxy-3-methylglutaryl CoA reductase. Recently, there has been conflicting epidemiologic data indicating that statins decrease the incidence of certain types of cancer, including breast cancer. Atorvastatin and lovastatin, statins with different lipophicilities, were administered in diet either as single agents or in combination with suboptimal doses of tamoxifen or the retinoid X receptor agonist bexarotene were evaluated for prevention of estrogen receptor–positive mammary cancers induced in the rat with methylnitrosourea. Atorvastatin (125 or 500 mg/kg diet) alone did not significantly alter cancer incidence or multiplicity. Suboptimal doses of tamoxifen (0.4 mg/kg diet) or bexarotene (80 mg/kg diet) reduced cancer multiplicity from 3.8 (control) to 2.9 and 0.9, respectively. Combining atorvastatin (500 mg/kg diet) with either of these effective agents minimally altered their efficacy. Although this dose of atorvastatin did not decrease serum triglyceride levels in control rats, it significantly decreased triglyceride levels that had been increased in bexarotene-treated rats. Experiments done with a second statin, lovastatin (100 and 400 mg/kg diet), yielded similar results: (a) limited activity when administered alone, (b) no obvious synergy with bexarotene, and (c) an ability to decrease bexarotene-induced increases in serum triglycerides. Thus, the statins had minimal activity in this model of mammary cancer in which approximately half of the cancers are mutated in the Ha Ras oncogene. Similarly, atorvastatin failed to alter the development of estrogen receptor–negative mammary carcinomas in a new animal model using bitransgenic mice (MMTV-Neu+/−/p53KO+/−), whereas bexarotene (250 mg/kg diet) was effective.
Gender Differences in Delinquency and Juvenile Justice Processing
Authors: Tracy Paul E. , Kempf-Leonard Kimberly , Abramoske-James Stephanie
Published: February 2009

This article traces the historical coverage of the gender issue in the criminological literature. It also provides contemporary empirical evidence about differences and similarities between girls and boys with respect to juvenile crime and to processing by the juvenile justice system, by analyzing several national juvenile crime data series, all of which have been recently updated. This research has produced numerous results that indicate that female and male delinquents possess more similarities than differences concerning arrest rates, arrest statistics, juvenile court data, and juvenile corrections data.