bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Variation and Effects on Human Eating Behavior
Authors: de Krom Mariken , Bauer Florianne , Collier David , Adan R.A.H. , la Fleur Susanne E.
Published: June 2009

Feeding is a physiological process, influenced by genetic factors and the environment. In recent years, many studies have been performed to unravel the involvement of genetics in both eating behavior and its pathological forms: eating disorders and obesity. In this review, we provide a condensed introduction on the neurological aspects of eating and we describe the current status of research into the genetics of eating behavior, primarily focused on specific traits such as taste, satiation, and hunger. This is followed by an overview on the genetic studies done to unravel the heritable background of obesity and eating disorders. We examine the discussion currently taking place in the field of genetics of complex disorders and phenotypes on how to perform good and powerful studies, with the use of large-scale whole-genome association studies as one of the possible solutions. In the final part of this review, we give our view on the latest developments, including endophenotype approaches and animal studies. Studies of endophenotypes of eating behavior may help to identify core traits that are genetically influenced. Such studies would yield important knowledge on the underlying biological scaffold on which diagnostic criteria for eating disorders could be based and would provide information to influence eating behavior toward healthier living.
The Nutritional Significance of Lipid Rafts
Authors: Yaqoob Parveen
Published: June 2009

The structure, size, stability, and functionality of lipid rafts are still in debate, but recent techniques allowing direct visualization have characterized them in a wide range of cell types. Lipid rafts are potentially modifiable by diet, particularly (but not exclusively) by dietary fatty acids. However, it is not clear whether dietary polyunsaturated fatty acids (PUFAs) are incorporated into raft lipids or whether their low affinity to cholesterol disallows this and causes phase separation from rafts and displacement of raft proteins. This review examines the potential for dietary modification of raft structure and function in the immune system, brain and retinal tissue, the gut, and in cancer cells. Although there is increasing evidence to suggest that membrane microdomains, and their modulation, have an impact in health and disease, it is too early to judge whether modulation of lipid rafts is responsible for the immunomodulatory effects of n-3 PUFA. In addition to dietary fatty acids, gangliosides and cholesterol may also modulate microdomains in a number of tissues, and recent work has highlighted sphingolipids in membrane microdomains as potential targets for inhibition of tumor growth by n-3 PUFA. The roles of fatty acids and gangliosides in cognitive development, age-related cognitive decline, psychiatric disorders, and Alzheimer's disease are poorly understood and require clarification, particularly with respect to the contribution of lipid rafts. The roles of lipid rafts in cancer, in microbial pathogenesis, and in insulin resistance are only just emerging, but compelling evidence indicates the growing importance of membrane microdomains in health and disease.
Roles for Vitamin K Beyond Coagulation
Authors: Booth Sarah L.
Published: June 2009

Recent interest in vitamin K has been motivated by evidence of physiological roles beyond that of coagulation. Vitamin K and vitamin K–dependent (VKD) proteins may be involved in regulation of calcification, energy metabolism, and inflammation. However, the evidence for many of these proposed roles in the maintenance of health is equivocal. There is also an emerging viewpoint that the biochemical function of vitamin K may extend beyond that of a cofactor for the VKD carboxylation of glutamyl residues (Glus) to carboxylated Glus in VKD proteins.
Possible implication of satellite cells in regenerative motoneuritogenesis: HGF upregulates neural chemorepellent Sema3A during myogenic differentiation
Authors: Tatsumi Ryuichi , Sankoda Yoriko , Anderson Judy E. , Sato Yusuke , Mizunoya Wataru , Shimizu Naomi , Suzuki Takahiro , Yamada Michiko , Rhoads Robert P. , Ikeuchi Yoshihide , Allen Ronald E.
Published: June 2009

Regenerative coordination and remodeling of the intramuscular motoneuron network and neuromuscular connections are critical for restoring skeletal muscle function and physiological properties. The regulatory mechanisms of such coordination remain unclear, although both attractive and repulsive axon guidance molecules may be involved in the signaling pathway. Here we show that expression of a neural secreted chemorepellent semaphorin 3A (Sema3A) is remarkably upregulated in satellite cells of resident myogenic stem cells that are positioned beneath the basal lamina of mature muscle fibers, when treated with hepatocyte growth factor (HGF), established as an essential cue in muscle fiber growth and regeneration. When satellite cells were treated with HGF in primary cultures of cells or muscle fibers, Sema3A message and protein were upregulated as revealed by reverse transcription-polymerase chain reaction and immunochemical studies. Other growth factors had no inductive effect except for a slight effect of epidermal growth factor treatment. Sema3A upregulation was HGF dose dependent with a maximum (about 7- to 8-fold units relative to the control) at 10–25 ng/ml and occurred exclusively at the early-differentiation stage, as characterized by the level of myogenin expression and proliferation (bromodeoxyuridine incorporation) of the cells. Neutralizing antibody to the HGF-specific receptor, c-met, did not abolish the HGF response, indicating that c-met may not mediate the Sema3A expression signaling. Finally, in vivo Sema3A was upregulated in the differentiation phase of satellite cells isolated from muscle regenerating following crush injury. Overall, the data highlight a heretofore unexplored and active role for satellite cells as a key source of Sema3A expression triggered by HGF, hence suggesting that regenerative activity toward motor innervation may importantly reside in satellite cells and could be a crucial contributor during postnatal myogenesis.
Evidence that TRPM7 is required for breast cancer cell proliferation
Authors: Guilbert Arnaud , Gautier Mathieu , Dhennin-Duthille Isabelle , Haren Nathalie , Sevestre Henri , Ouadid-Ahidouch Halima
Published: June 2009

Because transient receptor potential (TRP) channels have been implicated in tumor progression, we have investigated the potential role of TRPM7 channel in breast cancer cell proliferation. Under whole cell patch clamp, a Mg2+-inhibited cationic (MIC) current was observed in MCF-7 cells. This current was characterized by an inward current and a strong outward rectifying current that were both inhibited in a concentration-dependent manner by the presence of intracellular Mg2+ or Mg2+-ATP. The inward current was reduced by La3+, and the outward current was sensitive to 2-aminoethoxydiphenyl borate (2-APB), spermine, La3+, and flufenamic acid. Importantly, a similar MIC current was also recorded in the primary culture of human breast cancerous epithelial cells (hBCE). Moreover, TRPM7 transcripts were found in both hBCE and MCF-7 cells. In MCF-7 cells, the MIC current was inhibited by TRPM7 small interfering RNA. Interestingly, we found that cell proliferation and intracellular Ca2+ concentration were also reduced by TRPM7 silencing in MCF-7 cells. TRPM7 channels were also found in both human breast cancer and healthy tissues. Importantly, TRPM7 channel was overexpressed in grade III breast cancer samples associated with important Ki67 or tumor size. Our findings strongly suggest that TRPM7 is involved in the proliferative potentiality of breast cancer cells, probably by regulating Ca2+ influx.
Mechanism of stretch-activated excitatory and inhibitory responses in the lower esophageal sphincter
Authors: Jiang Yanfen , Bhargava Valmik , Mittal Ravinder K.
Published: June 2009

We recently found that an orally directed stretch of the esophagus activates a neurally mediated relaxation of the lower esophageal sphincter (LES). Goals of our study were to characterize the neural mechanisms responsible for axial and transverse stretch-activated responses in the LES. LES pressure was monitored in anesthetized and artificially ventilated mice. Sutures were placed in the esophagus to exert graded stretch in the longitudinal and transverse directions. Effects of bilateral vagotomy and pharmacological agents on the stretch-activated LES responses were investigated. The relationship between vagally stimulated axial stretch and LES relaxation was also studied. Stretch in the longitudinal and transverse directions caused a dose-dependent LES relaxation and contraction, respectively, that were not affected by bilateral vagotomy and sympathectomy but were blocked by tetrodotoxin. In bilateral vagotomized animals, hexamethonium, atropine, pyridoxalphosphate-6-azophenyl-2′,4′ disulfonic acid (PPADS), and ondansetron did not block the stretch-activated LES relaxation and contraction. Axial stretch-activated LES relaxation was blocked by nitric oxide inhibitor and transverse stretch-activated LES contraction was blocked by a combination of atropine and substance P antagonist. Electrical stimulation of the vagus nerve induced LES relaxation and axial stretch on the LES, both of which were blocked by rocuronium. Axial and transverse stretch-activated LES relaxation and contraction were present in the W/Wv mice that lack interstitial cells of Cajal (ICC). Stretch-activated LES relaxation and contraction are mediated through mechanosensitive neurons located in the myenteric plexus, which involves neither synaptic transmission nor ICC.
Helicobacter pyloriinduces gastric mucosal intestinal metaplasia through the inhibition of interleukin-4-mediated HMG box protein Sox2 expression
Authors: Asonuma Sho , Imatani Akira , Asano Naoki , Oikawa Tomoyuki , Konishi Hidetomo , Iijima Katsunori , Koike Tomoyuki , Ohara Shuichi , Shimosegawa Tooru
Published: June 2009

Helicobacter pylori is a major cause of the transdifferentiation into intestinal metaplasia that may develop gastric cancer. However, the molecular pathogenesis of this transdifferentiation is poorly understood. A SRY-related HMG box protein Sox2 is an essential transcription factor of organ development in brain, lung, and stomach. Our aim of this study was to investigate the mechanism responsible for regulation of Sox2 in host Th1-dominant response to H. pylori. Sox2 protein was immunohistochemically expressed in both human oxyntic and pyloric glands with H. pylori infection, but not in intestinal metaplasia. Western immunoblotting of gastric epithelial cell lines showed that IL-4, a Th2-related cytokine, dose dependently enhanced Sox2 expression among H. pylori infection-mediated cytokines. Small changes of Sox2 expression were observed after each treatment with IFN-γ, IL-1β, or TNF-α. IL-4-mediated Sox2 induction was suppressed by the inhibition of STAT6 activation with STAT6 RNA interference, and electrophoretic mobility shift assay indicated that activation of the Sox2 promoter by IL-4 occurred through the action of STAT6. Furthermore, H. pylori and IFN-γ inhibited the phosphorylation of STAT6, resulting in the suppression of IL-4-mediated Sox2 expression. Immunohistochemical analyses showed significantly the suppressed STAT6 activity in H. pylori-infected human gastric mucosa. Additionally, downregulation of Sox2 by knockdown experiments led to intestinal phenotype with expressions of Cdx2 and MUC2. These results suggest that H. pylori and IFN-γ interfere with the differentiation into oxyntic and pyloric glands by the downregulation of Sox2 on IL-4/STAT6 signaling, which may contribute to the transdifferentiation into intestinal metaplasia.
Vascular stasis, intestinal hemorrhage, and heightened vascular permeability complicate acute portal hypertension in cd39-null mice
Authors: Sun Xiaofeng , Cárdenas Andrés , Wu Yan , Enjyoji Keichi , Robson Simon C.
Published: June 2009

Vasoactive factors that regulate splanchnic hemodynamics include nitric oxide, catecholamines, and possibly extracellular nucleosides/nucleotides (adenosine, ATP). CD39/ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1) is the major vascular ectonucleotidase that hydrolyzes extracellular nucleotides. CD39 activity may be modulated by vascular injury, inflammation, and altered oxygen tension. Altered Cd39 expression by the murine hepatosplanchnic vasculature may impact hemodynamics and portal hypertension (PHT) in vivo. We noted that basal portal pressures (PPs) were comparable in wild-type and Cd39-null mice ( n = 9). ATP infusions resulted in increments in PP in wild-type mice, but, in contrast, this significantly decreased in Cd39-null mice ( n = 9) post-ATP in a nitric oxide-dependent manner. We then studied Cd39/NTPDase1 deletion in the regulation of portal hemodynamics, vascular integrity, and intestinal permeability in a murine model of PHT. Partial portal vein ligation (PPVL) was performed in Cd39-null ( n = 44) and wild-type ( n = 23) mice. Sequential measurements obtained after PPVL were indicative of comparable levels of PHT (ranges 14–29 mmHg) in both groups. There was one death in the wild-type group and eight in the Cd39-null group from intestinal bleeding ( P = 0.024). Circulatory stasis in the absence of overt portal vein thrombosis, portal congestion, intestinal hemorrhage, and increased permeability were evident in all surviving Cd39-null mice. Deletion of Cd39 results in deleterious outcomes post-PPVL that are associated with significant microcirculatory derangements and major intestinal congestion with hemorrhage mimicking acute mesenteric occlusion. Absent Cd39/NTPDase1 and decreased generation of adenosine in the splanchnic circulation cause heightened vascular permeability and gastrointestinal hemorrhage in PPVL.
Induced overexpression of Na+/Ca2+ exchanger transgene: altered myocyte contractility, [Ca2+]i transients, SR Ca2+ contents, and action potential duration
Authors: Wang JuFang , Chan Tung O. , Zhang Xue-Qian , Gao Erhe , Song Jianliang , Koch Walter J. , Feldman Arthur M. , Cheung Joseph Y.
Published: June 2009

We have produced mice in which expression of the rat cardiac Na+/Ca2+ exchanger (NCX1) transgene was switched on when doxycycline was removed from the feed at 5 wk. At 8 to 10 wk, NCX1 expression in induced (Ind) mouse hearts was 2.5-fold higher but protein levels of sarco(endo)plasmic reticulum Ca2+-ATPase, α1- and α2-subunits of Na+-K+-ATPase, phospholamban, ryanodine receptor, calsequestrin, and unphosphorylated and phosphorylated phospholemman were unchanged compared with wild-type (WT) or noninduced (non-Ind) hearts. There was no cellular hypertrophy since WT, non-Ind, and Ind myocytes had similar whole cell membrane capacitance. In Ind myocytes, NCX1 current amplitude was ∼42% higher, L-type Ca2+ current amplitude was unchanged, and action potential duration was prolonged compared with WT or non-Ind myocytes. Contraction and intracellular Ca2+ concentration ([Ca2+]i) transient amplitudes in Ind myocytes were lower at 0.6, not different at 1.8, and higher at 5.0 mM extracellular Ca2+ concentration ([Ca2+]o) compared with WT or non-Ind myocytes. Despite similar Ca2+ current amplitude and sarcoplasmic reticulum (SR) Ca2+ uptake, SR Ca2+ content at 5.0 mM [Ca2+]o was significantly higher in Ind compared with non-Ind myocytes, indicating that NCX1 directly contributed to SR Ca2+ loading. Echocardiography demonstrated that heart rate, left ventricular mass, ejection fraction, stroke volume, and cardiac output were similar among the three groups of animals. In vivo close-chest catheterization demonstrated similar contractility and relaxation among the three groups of mice, both at baseline and after stimulation with isoproterenol. We conclude that induced expression of NCX1 transgene resulted in altered [Ca2+]i homeostasis, myocyte contractility, and action potential morphology. In addition, heart failure did not occur 3 to 5 wk after NCX1 transgene was induced to be expressed at levels found in diseased hearts.
Prolonged effects of B-type natriuretic peptide infusion on cardiac remodeling after sustained myocardial injury
Authors: George Isaac , Morrow Brad , Xu Kai , Yi Geng-Hua , Holmes Jeffrey , Wu Ed X. , Li Zhihe , Protter Andrew A. , Oz Mehmet C. , Wang Jie
Published: June 2009

B-type natriuretic peptide (BNP) is an established first-line therapy for acute decompensated heart failure (HF), but its efficacy in preventing left ventricular (LV) remodeling after myocardial injury is unknown. The goal of this study was to evaluate the effects of BNP therapy on remodeling after ischemic injury in an awake canine model. Dogs were chronically instrumented for hemodynamics. Ischemia was created by daily coronary embolization (Embo; 3.1 × 104 beads/day) for 3 wk; 60 min after the first embolization, BNP (100 ng·kg−1·min−1; n = 6) or saline (control; n = 6) was continuously infused via a left atrial catheter for 3 wk. Hemodynamics and echocardiography were performed in an awake state at baseline, 3 wk after Embo + BNP infusion, and 4 wk after stopping Embo + BNP infusion. End-systolic elastance (Ees) and LV change in pressure over time (dP/d t) were preserved throughout Embo + BNP therapy versus control therapy (Ees: 3.76 ± 1.01 vs. 1.41 ± 0.16 mmHg/ml; LV dP/d t: 2,417 ± 96 vs. 2,068 ± 95 mmHg/s; both P < 0.05 vs. control). LV end-diastolic dimension was significantly smaller in BNP-treated dogs compared with control dogs (4.29 ± 0.10 vs. 4.77 ± 0.17 cm), and ejection fraction was maintained in treated dogs vs. control dogs (53 ± 1% vs. 46 ± 2%) (both P < 0.05 vs. control). Cyclooxygenase (COX)-2 expression in terminal LV tissue was significantly reduced after BNP therapy. Treatment with continuous infusion of BNP preserved LV geometry, improved systolic function, and prevented the progression of systolic HF after persistent ischemic injury.
Mild chronic hypoxemia modifies expression of brain stem angiotensin peptide receptors and reflex responses in fetal sheep
Authors: Pulgar Victor M. , Hong Jason Kyung-soo , Jessup Jewell A. , Massmann Angela G. , Diz Debra I. , Figueroa Jorge P.
Published: June 2009

The effects of chronic mild hypoxemia on the binding of angiotensin receptors in selected brain stem nuclei and reflex responses were studied in fetal sheep. Fetal and maternal catheters were placed at 120 days' gestation, and animals received intratracheal maternal administration of nitrogen ( n = 16) or compressed air in controls ( n = 19). Nitrogen infusion was adjusted to reduce fetal brachial artery Po2by 25% during 5 days. Spontaneous baroreflex sensitivity and spectral analysis of the pulse interval were analyzed during the 5 days hypoxemia period using 90 min of daily recording. Brains of control and hypoxemic animals were collected, and brain stem angiotensin receptor binding was studied by in vitro autoradiography at 130 days of gestation. After 5 days of hypoxemia, some animals in each group were submitted to one complete umbilical cord occlusion during 5 min. [125I]sarthran binding showed that chronic mild hypoxemia significantly increases angiotensin type 1 receptor, angiotensin type 2 receptor, and ANG-(1-7) angiotensin receptor binding sites in the nucleus tractus solitarius and dorsal motor nucleus of the vagus ( P < 0.05). Hypoxemia induced lower baroreflex sensitivity and a higher low frequency-to-high frequency ratio in the fetus, consistent with a shift from vagal to sympathetic autonomic cardiac regulation. Cord occlusion to elicit a chemoreflex response induced a greater bradycardic response in hypoxemic fetuses (slope of the initial fall in heart rate; 11.3 ± 1.9 vs. 6.4 ± 1.2 beats·min−1·s−1, P < 0.05). In summary, chronic mild hypoxemia increased binding of angiotensin receptors in brain stem nuclei, decreased spontaneous baroreflex gain, and increased chemoreflex responses to asphyxia in the fetus. These results suggest hypoxemia-induced alterations in brain stem mechanisms for cardiovascular control.
Effect of thermal acclimation on action potentials and sarcolemmal K+channels from Pacific bluefin tuna cardiomyocytes
Authors: Galli G. L. J. , Lipnick M. S. , Block B. A.
Published: June 2009

To sustain cardiac muscle contractility relatively independent of temperature, some fish species are capable of temporarily altering excitation-contraction coupling processes to meet the demands of their environment. The Pacific bluefin tuna, Thunnus orientalis, is a partially endothermic fish that inhabits a wide range of thermal niches. The present study examined the effects of temperature and thermal acclimation on sarcolemmal K+currents and their role in action potential (AP) generation in bluefin tuna cardiomyocytes. Atrial and ventricular myocytes were enzymatically isolated from cold (14°C)- and warm (24°C)-acclimated bluefin tuna. APs and current-voltage relations of K+channels were measured using the whole cell current and voltage clamp techniques, respectively. Data were collected either at the cardiomyocytes' respective acclimation temperature of 14 or 24°C or at a common test temperature of 19°C (to reveal the effects of acclimation). AP duration (APD) was prolonged in cold-acclimated (CA) cardiomyocytes tested at 14°C compared with 19°C and in warm-acclimated (WA) cardiomyocytes tested at 19°C compared with 24°C. This effect was mirrored by a decrease in the density of the delayed-rectifier current ( IKr), whereas the density of the background inward-rectifier current ( IK1) was unchanged. When CA and WA cardiomyocytes were tested at a common temperature of 19°C, no significant effects of temperature acclimation on AP shape or duration were observed, whereas IKrdensity was markedly increased in CA cardiomyocytes. IK1density was unaffected in CA ventricular myocytes but was significantly reduced in CA atrial myocytes, resulting in a depolarization of atrial resting membrane potential. Our results indicate the bluefin AP is relatively short compared with other teleosts, which may allow the bluefin heart to function at cold temperatures without the necessity for thermal compensation of APD.
MATE1 has an external COOH terminus, consistent with a 13-helix topology
Authors: Zhang Xiaohong , Wright Stephen H.
Published: June 2009

The mammalian members of the Multidrug And Toxin Extruder family, i.e., MATE1 and MATE2-K, are suspected of mediating the luminal step in renal secretion of organic cations. The 1,000+ prokaryotic/fungal/plant MATE family members are predicted to have 12 transmembrane helices (TMHs), whereas MATE1/2-K appear to have an additional (13th) COOH-terminal helix. Here, we determined whether rabbit MATE1 has an external COOH terminus, consistent with the presence of 13 TMHs. A V5 epitope tag at the COOH terminus of MATE1 was freely accessible to external V5 antibody, whereas tags at the NH2terminus, or at sites of truncation within the long cytoplasmic loop between predicted TMHs 12 and 13, were only accessible to the V5 antibody following permeabilization of the membrane. The truncated mutants that lacked TMH13 still retained transport activity, indicating that the terminal helix was not necessary for transport function. Cells that expressed a mutant lacking only TMH13 displayed similar Ktand Jmaxvalues to those of the full-length protein, although when normalized to protein expressed at the plasma membrane, the transport rate of the mutant was <10% that of full-length MATE1. An effectively cysteine-less MATE1 mutant (Δ13Cys) was functional and refractory to reaction with the impermeant marker of accessible cysteine residues, maleimide-PEO2-biotin. Δ13Cys mutants with an added cysteine residue at the truncation sites within the terminal cytoplasmic loop reacted with maleimide biotin only after permeabilization of the membrane, whereas a mutant with a cysteine residue at the COOH terminus was freely accessible to maleimide biotin. These data are consistent with a mammalian MATE topology that includes 13 TMHs and indicate that the terminal TMH, although not necessary for transport function, may influence the turnover characteristics of the transporter.
FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1
Authors: Gattineni Jyothsna , Bates Carlton , Twombley Katherine , Dwarakanath Vangipuram , Robinson Michael L. , Goetz Regina , Mohammadi Moosa , Baum Michel
Published: June 2009

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D3[1,25(OH)2D3] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, −3, and −4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3−/−and FGFR4−/−null mice, and in conditional FGFR1−/−mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1−/−, FGFR3−/−, and FGFR4−/−mice and their wild-type counterparts. Administration of FGF23 to FGFR3−/−mice induced hypophosphatemia in these mice (8.0 ± 0.4 vs. 5.4 ± 0.3 mg/dl; p ≤ 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4−/−mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 ± 0.3 vs. 7.6 ± 0.4 mg/dl; p ≤ 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1−/−mice had no effects on serum phosphorus levels (5.6 ± 0.3 vs. 5.2 ± 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.
High-frequency spinal cord stimulation of inspiratory muscles in dogs: a new method of inspiratory muscle pacing
Authors: DiMarco Anthony F. , Kowalski Krzysztof E.
Published: June 2009

Despite clinically available methods of diaphragm pacing, most patients with ventilator-dependent tetraplegia are still dependent on mechanical ventilation. Given the significant disadvantages of these devices, additional pacing options are needed. The objective of this study was to evaluate a novel and potentially more physiological method of inspiratory muscle activation, which involves the application of high-frequency (>200 Hz) stimulation to the ventral surface of the spinal cord in the high thoracic region. Studies were performed in 13 anesthetized dogs. High-frequency spinal cord stimulation (HF-SCS) results in the activation of both the diaphragm and inspiratory intercostal muscles, in concert, at physiological firing frequencies and the generation of large inspired volumes. Mean maximum firing frequencies of motor units in the parasternal (2nd interspace), the external intercostal (3rd interspace), and the diaphragm muscles were 10.6 ± 0.4, 11.7 ± 0.4, and 10.4 ± 0.3 Hz, respectively. These values were not significantly different from those occurring during spontaneous breathing at comparable inspired volumes. Maximum inspired volume was 0.93 ± 0.01 liter, which approximates the inspiratory capacity of these animals. Moreover, ventilation can be maintained on a chronic basis by this method (6 h) without evidence of system fatigue. Our results suggest that HF-SCS results in activation of spinal cord tracts that synapse with the inspiratory motoneuron pools, allowing processing of the stimulus and consequent physiological activation of the inspiratory muscles. HF-SCS has the potential to provide an effective method of inspiratory muscle pacing.
Skeletal muscle blood flow responses to hypoperfusion at rest and during rhythmic exercise in humans
Authors: Casey Darren P. , Joyner Michael J.
Published: June 2009

We evaluated the contribution of changes in systemic arterial pressure and local vasodilation to blood flow restoration in contracting human muscles during acute hypoperfusion. Healthy subjects ( n = 10) performed rhythmic forearm exercise (10% and 20% of maximum) while a balloon in the brachial artery located above the elbow was inflated. Each trial included 3 min of rest, exercise, exercise with balloon inflation, and exercise after balloon deflation. Forearm blood flow (FBF) was measured using Doppler ultrasound. Blood pressure on both sides of the balloon was measured using a brachial artery catheter (distal pressure), and Finometer for proximal (systemic) arterial pressure. Balloon inflation during exercise reduced distal arterial pressure, and FBF fell 37–41%. There was also a surprising acute increase in forearm vascular resistance (distal pressure/FBF). This was followed by recovery of distal arterial pressure and forearm vasodilation that caused a marked (∼75%) restoration of flow that was not associated with significant changes in systemic arterial pressure. During validation trials ( n = 6) at rest and with exercise both balloon and brachial artery diameters were stable when the balloon was inflated. Our findings indicate that at these exercise intensities 1) the restoration of FBF during exercise with hypoperfusion relied primarily on local dilator responses in conjunction with restoration of distal perfusion pressure likely as a result of increased collateral flow around the elbow, and 2) a loss of pulsatile flow and elastic recoil in the forearm may have contributed to the acute increase in vascular resistance seen at the onset of hypoperfusion.
Song Decrystallization in Adult Zebra Finches Does Not Require the Song Nucleus NIf
Authors: Roy Arani , Mooney Richard
Published: June 2009

In adult male zebra finches, transecting the vocal nerve causes previously stable (i.e., crystallized) song to slowly degrade, presumably because of the resulting distortion in auditory feedback. How and where distorted feedback interacts with song motor networks to induce this process of song decrystallization remains unknown. The song premotor nucleus HVC is a potential site where auditory feedback signals could interact with song motor commands. Although the forebrain nucleus interface of the nidopallium (NIf) appears to be the primary auditory input to HVC, NIf lesions made in adult zebra finches do not trigger song decrystallization. One possibility is that NIf lesions do not interfere with song maintenance, but do compromise the adult zebra finch's ability to express renewed vocal plasticity in response to feedback perturbations. To test this idea, we bilaterally lesioned NIf and then transected the vocal nerve in adult male zebra finches. We found that bilateral NIf lesions did not prevent nerve section–induced song decrystallization. To test the extent to which the NIf lesions disrupted auditory processing in the song system, we made in vivo extracellular recordings in HVC and a downstream anterior forebrain pathway (AFP) in NIf-lesioned birds. We found strong and selective auditory responses to the playback of the birds' own song persisted in HVC and the AFP following NIf lesions. These findings suggest that auditory inputs to the song system other than NIf, such as the caudal mesopallium, could act as a source of auditory feedback signals to the song motor network.
Behaviorally Relevant Burst Coding in Primary Sensory Neurons
Authors: Sabourin Patrick , Pollack Gerald S.
Published: June 2009

Bursts of action potentials in sensory interneurons are believed to signal the occurrence of particularly salient stimulus features. Previous work showed that bursts in an identified, ultrasound-tuned interneuron (AN2) of the cricket Teleogryllus oceanicus code for conspicuous increases in amplitude of an ultrasound stimulus, resulting in behavioral responses that are interpreted as avoidance of echolocating bats. We show that the primary sensory neurons that inform AN2 about high-frequency acoustic stimuli also produce bursts. As is the case for AN2, bursts in sensory neurons perform better as feature detectors than isolated, nonburst, spikes. Bursting is temporally correlated between sensory neurons, suggesting that on occurrence of a salient stimulus feature, AN2 will receive strong synaptic input in the form of coincident bursts, from several sensory neurons, and that this might result in bursting in AN2. Our results show that an important feature of the temporal structure of interneuron spike trains can be established at the earliest possible level of sensory processing, i.e., that of the primary sensory neuron.
Regeneration of Vestibular Horizontal Semicircular Canal Afferents in Pigeons
Authors: Haque Asim , Zakir Mridha , Dickman J. David
Published: June 2009

Spontaneous regeneration of vestibular and auditory receptors and their innervating afferents in birds, reptiles, and amphibians are well known. Here, we produced a complete vestibular receptor loss and epithelial denervation using an ototoxic agent (streptomycin), after which we quantitatively characterized the afferent innervation of the horizontal semicircular canals following completed regeneration. We found that calyx, dimorph, and bouton afferents all regenerate in a manner the recapitulates the epithelial topography of normal birds, but over a slow time course. Similar to previous findings in the vestibular otolith maculae, regeneration occurs according to a three-stage temporal sequence. Bouton afferents regenerate during the first month of regeneration, followed by calyceal-bearing afferents in the second and third months. Calyx afferents were the last to regenerate in the final stage of recovery after 3 mo. We also found that regenerated afferents exhibited terminal morphologies that are significantly smaller, less complex, and innervate fewer receptor cells over smaller epithelial areas than those that develop through normative morphogenesis. These structural fiber changes in afferent innervation correlate to alterations in gaze responses during regeneration, although the exact underlying mechanisms responsible for behavioral changes remain unknown. Plasticity in central vestibular neurons processing motion information seem to be required to explain the observed morphologic and response adaptations observed in regenerating vestibular systems.
Activation of PPARγ by Rosiglitazone Does Not Negatively Impact Male Sex Steroid Hormones in Diabetic Rats
Authors: Mansour Mahmoud , Coleman Elaine , Dennis John , Akingbemi Benson , Schwartz Dean , Braden Tim , Judd Robert , Plaisance Eric , Stewart Laura Ken , Morrison Edward
Published: June 2009

Peroxisome proliferator‐activated receptor gamma (PPARγ) activation decreased serum testosterone (T) in women with hyperthecosis and/or polycystic ovary syndrome and reduced the conversion of androgens to estradiol (E2) in female rats. This implies modulation of female sex steroid hormones by PPARγ. It is not clear if PPARγ modulates sex steroid hormones in diabetic males. Because PPARγ activation by thiazolidinedione increased insulin sensitivity in type 2 diabetes, understanding the long term impact of PPARγ activation on steroid sex hormones in males is critical. Our objective was to determine the effect of PPARγ activation on serum and intratesticular T, luteinizing hormone (LH), follicle stimulating hormone (FSH) and E2 concentrations in male Zucker diabetic fatty (ZDF) rats treated with the PPARγ agonist rosiglitazone (a thiazolidinedione). Treatment for eight weeks increased PPARγ mRNA and protein in the testis and elevated serum adiponectin, an adipokine marker for PPARγ activation. PPARγ activation did not alter serum or intratesticular T concentrations. In contrast, serum T level but not intratesticular T was reduced by diabetes. Neither diabetes nor PPARγ activation altered serum E2 or gonadotropins FSH and LH concentrations. The results suggest that activation of PPARγ by rosiglitazone has no negative impact on sex hormones in male ZDF rats.
Low Profile EBG Resonator Antennas
Authors: Chantalat R. , Moustafa L. , Thevenot M. , Monediere T. , Jecko B.
Published: June 2009

An Electromagnetic Band Gap (EBG) antenna is a planar structure which is composed of a cavity and an EBG material. In most applications, the height of the EBG antenna is half wavelength. We present in this paper the conditions to reduce the profile of an EBG antenna to subwavelength values. It could be achieved by using a cavity upper interface which exhibits negative reflection phase. Frequency Selective Surface (FSS) based on Babinet principle, that satisfies this condition, will be described using full wave analysis. These periodic metallic arrays are employed in the design of a low profile EBG antenna which has a directivity of 10 dBi. As this EBG antenna design is similar to a small antenna over an Artificial Magnetic Conductors (AMC) surfaces or High Impedance Surface (HIS), the EBG antenna principle could be a new theory approach for the AMC or HIS. This point is discussed in this paper.
Kimura's Disease
Authors: Guimaraes Cláudia Savassi , Moulton-Levy Natalie , Sapadin Allen , Vidal Claudia
Published: June 2009

Kimuras disease is a chronic inflammatory disorder of unknown etiology. It is rare in the West, but endemic in Asia. It typically presents as solitary or multiple subcutaneous nodules, that slowly increase in size. The lesions are variably painful and pruritic. It often accompanied by regional lymphadenopathy, raised serum eosinophil counts, and markedly elevated serum immunoglobulin E levels. Histologically, the lesions are characterized by reactive lymphoid follicles with eosinophilic infiltration and an increased amount of postcapillary venules. The optimal treatment for KD remains controversial. Although the condition seldom resolves spontaneously, malignant transformation has not been reported to date, and the prognosis is good. We describe a male patient with a 4-year pruritic progressive “bump” in front of his left ear. On physical examination, the patient had 2 discrete lesions on the left side of his face near his ear. Postauricularly, there was a3×5cm erythematous to violaceous, indurated nodule. Preauricularly, there was a similar, but smaller cyst-like nodule. Punch biopsy showed a superficial and deep nodular and interstitial infiltrate, reactive lymphoid follicles with a dense infiltration of eosinophils and areas of eosinophilic follicle lysis. The patient received intralesional triamcinolone acetonide injections 10 mg/cc behind left ear with a good improvement.
Multiplex Detection and Genotyping of Point Mutations Involved in Charcot-Marie-Tooth Disease Using a Hairpin Microarray-Based Assay
Authors: Baaj Yasser , Magdelaine Corinne , Ubertelli Virginie , Valat Christophe , Mousseau Yoanne , Qiu Hao , Funalot Benoît , Vallat Jean-Michel , Sturtz Franck G.
Published: June 2009

We previously developed a highly specific method for detecting SNPs with a microarray-based system using stem-loop probes. In this paper we demonstrate that coupling a multiplexing procedure with our microarray method is possible for the simultaneous detection and genotyping of four point mutations, in three different genes, involved in Charcot-Marie-Tooth disease. DNA from healthy individuals and patients was amplified, labeled with Cy3 by multiplex PCR; and hybridized to microarrays. Spot signal intensities were 18 to 74 times greater for perfect matches than for mismatched target sequences differing by a single nucleotide (discrimination ratio) for “homozygous” DNA from healthy individuals. “Heterozygous” mutant DNA samples gave signal intensity ratios close to 1 at the positions of the mutations as expected. Genotyping by this method was therefore reliable. This system now combines the principle of highly specific genotyping based on stem-loop structure probes with the advantages of multiplex analysis.
Laparoskopische Therapie des Korpuskarzinoms: Datenlage und Evidenz
Authors: Imesch Patrick , Dedes Konstantin , Fink Daniel
Published: June 2009

Das Endometriumkarzinom ist hierzulande die häufigste maligne gynäkologische Erkrankung. Den Eckpfeiler in der kurativen Therapie des Endometriumkarzinoms stellt die Operation dar, welche derzeit meist als Laparotomie durchgeführt wird. Zunehmend wird nun allerdings die minimalinvasive Chirurgie in der Behandlung des frühen Endometriumkarzinoms eingesetzt. In letzter Zeit sind diesbezüglich mehrere Studien publiziert worden, wobei nur relativ wenige Arbeiten kontrolliert prospektiv und randomisiert sind. Aus dem bisherigen Datenmaterial lässt sich aber ableiten, dass die Laparoskopie durchaus eine effektive und sichere Alternative zur bisherigen Standardoperation darstellt und im Gesamtüberleben und krankheitsfreien Intervall vergleichbar zur Laparotomie steht. Die Laparoskopie und gegebenenfalls die roboterassistierte Laparoskopie könnten in Zukunft im ausgewählten Patientinnengut deshalb durchaus als sichere Therapieoption gelten. Bis dahin sind aber noch grössere, prospektive, multizentrische Studien mit längerer Beobachtungszeit nötig.
Stellenwert der Laparoskopie in der gynäkologischen Onkologie
Authors: Altgassen Christopher , Hertel Hermann
Published: June 2009

Die Laparoskopie stellt mittlerweile einen etablierten Zugangsweg in der gynäkologischen Chirurgie dar. Es dauerte Jahre, bis es dazu kam, galt es doch vielfältige Widerstände zu überwinden. Letztlich waren es die niedrigen intra- und postoperativen Komplikationsraten gepaart mit der raschen Rekonvaleszenz der Patientinnen und deren Wunsch nach einer raschen Entlassung, die zur unaufhaltbaren Verbreitung der Methodik führten. Mit zunehmender Anwendung des Verfahrens und Expertise der Operateure infiltrierte sie das Feld der gynäkologischen Onkologie und traf auf vergleichbare Vorbehalte. Erneut halfen die gleichen überzeugenden Vorteile, die Widerstände zu überwinden. So haben laparoskopische Operationsverfahren einen sicheren Platz in der Behandlung des Korpus- und des Zervixkarzinoms, da ihre operative Sicherheit bewiesen wurde. Ziel zukünftiger Untersuchungen sollte der Nachweis der Nichtunterlegenheit im Vergleich zu offenen Techniken sein, weil die Vorteile laparoskopischer Verfahren hinreichend belegt sind. Ungeachtet des geforderten Nachweises schreitet die Technik mit roboterassistierten Verfahren rasant weiter, während Operateure exenterative Techniken entwickeln.
Central Hyperthermia in Acute Stroke
Authors: Sung Chung-Yang , Lee Tsong-Hai , Chu Nai-Shin
Published: June 2009

Background: Central hyperthermia is an unresolved riddle; this study tries to define its characteristics. Methods: Seventy-four previously healthy patients who developed hyperthermia (≥39°C) within 24 h after stroke onset were enrolled. The lesion sites, nature of stroke, and clinical features were studied. Results: Brainstem hemorrhage was the most common cause of hyperthermia (64%), followed by putamino-thalamus hemorrhage (24%), cerebellum hemorrhage (4%), large cortical infarct (4%), basilar artery occlusion (3%), and intraventricular hemorrhage (1%). Whatever the site of the lesion, all patients had brainstem involvement either by direct destruction or indirect compression. Three fourths of the patients reached 39°C within 12 h of stroke, and 82% arrived at the maximum within 24 h. A peculiar finding of central hyperthermia was the marked fluctuation in body temperature within a short period, which was more severe initially then decreased gradually. Leukocytosis was seen in 60%, but shift to the left was rare (1%). The prognosis was grave, nearly 70% of the patients expired within 1 month, especially those with a temperature of >41°C or those who reached 39°C within 6 h after onset of stroke, or those who had severe fluctuations in temperature. Conclusions: Central hyperthermia is characterized by rapid onset of high fever, marked temperature fluctuation and high mortality. It is likely associated with brainstem (mainly pons) damage by direct destruction or indirect compression.
Large Vessel Cerebral Atherosclerosis Is Not in Direct Association with Neuropathological Lesions of Alzheimer’s Disease
Authors: Luoto Teemu M. , Haikonen Satu , Haapasalo Hannu , Goebeler Sirkka , Huhtala Heini , Erkinjuntti Timo , Karhunen Pekka J.
Published: June 2009

Introduction: Cerebral hypoperfusion caused by large vessel atherosclerosis has been suggested to be associated with the pathogenesis of sporadic Alzheimer’s disease (AD). Atherosclerosis and AD share risk factors such as age, diabetes, hypercholesterolemia, hypertension and apolipoprotein E ε4 (APOE ε4) allele. We studied the association between atherosclerosis of the circle of Willis (CW) and AD neuropathology in a large autopsy sample. Methods: The present study comprised a consecutive autopsy series (n = 466) representing noninstitutionalized general population aged 50 years and over (mean 70.8, SD 11.5 years). The atherosclerosis of CW was scored semiquantitatively and the amyloid plaque (AP) load in the frontal cortex and the number of neurofibrillary tangles (NFT) in the hippocampus were measured. Results: In a linear regression model, AP percentage area was associated with age (p < 0.0001) and APOE ε4 allele (p < 0.0001), but not with CW score (p = 0.70) or gender (p = 0.11). Similarly, the NFT count was predicted only by age (p > 0.0001), and not by CW score (p = 0.36), gender (p = 0.41) or APOE ε4 allele (p = 0.072). Conclusion: Our results suggest that cerebral large vessel atherosclerosis is not in direct association with APs or NFTs – hallmarks of AD neuropathology.
Idiopathic Intracranial Hypertension Associated with Iron Deficiency Anaemia: A Lesson for Management
Authors: Mollan S.P. , Ball A.K. , Sinclair A.J. , Madill S.A. , Clarke C.E. , Jacks A.S. , Burdon M.A. , Matthews T.D.
Published: June 2009

Aim: To document the causal association of iron deficiency anaemia (IDA) and intracranial hypertension (IH). Methods: A consecutive case note review of patients with a clinical diagnosis of idiopathic intracranial hypertension (IIH) and anaemia presenting to a tertiary referral unit over a 2.5-year period. Demographics, aetiology and clinical details were recorded and analysed. Results: Eight cases were identified from 77 new cases presenting with IIH. All 8 had documented microcytic anaemia with clinical evidence of raised intracranial pressure. There was no evidence of venous sinus thrombosis on MRI and MR venography in 7 subjects and on repeated CT venography in 1. On correction of anaemia alone, 7 cases resolved. One patient with severe progressive visual loss underwent ventriculoperitoneal shunt in addition to treatment of anaemia, with good outcome. The incidence of this association is 10.3%. Conclusion: These cases present an association between IDA and IH, in the absence of cerebral sinus thrombosis. As a clinically significant proportion of cases presenting with signs of IIH have IDA, we recommend all patients presenting with IIH have full blood counts and if they are found to be anaemic, they should be treated appropriately.