bluuebunny/crossref_metadata_2025 huggingface dataset:
Standing up to the challenge of standing: a siphon does not support cerebral blood flow in humans
Authors: Dawson E. A. , Secher N. H. , Dalsgaard M. K. , Ogoh S. , Yoshiga C. C. , González-Alonso J. , Steensberg A. , Raven P. B.
Published: June 2004

Model studies have been advanced to suggest both that a siphon does and does not support cerebral blood flow in an upright position. If a siphon is established with the head raised, it would mean that internal jugular pressure reflects right atrium pressure minus the hydrostatic difference from the brain. This study measured spinal fluid pressure in the upright position, the pressure and the ultrasound-determined size of the internal jugular vein in the supine and sitting positions, and the internal jugular venous pressure during seated exercise. When the head was elevated ∼25 cm above the level of the heart, internal jugular venous pressure decreased from 9.5 (SD 2.8) to 0.2 (SD 1.0) mmHg [ n = 15; values are means (SD); P < 0.01]. Similarly, central venous pressure decreased from 6.2 (SD 1.8) to 0.6 (SD 2.6) mmHg ( P < 0.05). No apparent lumen was detected in any of the 31 left or right internal veins imaged at 40° head-up tilt, and submaximal ( n = 7) and maximal exercise ( n = 4) did not significantly affect internal jugular venous pressure. While seven subjects were sitting up, spinal fluid pressure at the lumbar level was 26 (SD 4) mmHg corresponding to 0.1 (SD 4.1) mmHg at the base of the brain. These results demonstrate that both for venous outflow from the brain and for spinal fluid, the prevailing pressure approaches zero at the base of the brain when humans are upright, which negates that a siphon supports cerebral blood flow.
Predominant postglomerular vascular resistance response to reflex renal sympathetic nerve activation during ANG II clamp in rabbits
Authors: Denton Kate M. , Shweta Amany , Flower Rebecca L. , Anderson Warwick P.
Published: June 2004

We have shown previously that a moderate reflex increase in renal sympathetic nerve activity (RSNA) elevated glomerular capillary pressure, whereas a more severe increase in RSNA decreased glomerular capillary pressure. This suggested that the nerves innervating the glomerular afferent and efferent arterioles could be selectively activated, allowing differential control of glomerular capillary pressure. A caveat to this conclusion was that intrarenal actions of neurally stimulated ANG II might have contributed to the increase in postglomerular resistance. This has now been investigated. Anesthetized rabbits were prepared for renal micropuncture and RSNA recording. One group (ANG II clamp) received an infusion of an angiotensin-converting enzyme inhibitor (enalaprilat, 2 mg/kg bolus plus 2 mg·kg−1·h−1) plus ANG II (∼20 ng·kg−1·min−1), the other vehicle. Measurements were made before (room air) and during 14% O2. Renal blood flow decreased less during ANG II clamp compared with vehicle [9 ± 1% vs. 20 ± 4%, interaction term (PGT) < 0.05], despite a similar increase in RSNA in response to 14% O2in the two groups. Arterial pressure and glomerular filtration rate were unaffected by 14% O2in both groups. Glomerular capillary pressure increased from 33 ± 1 to 37 ± 1 mmHg during ANG II clamp and from 33 ± 2 to 35 ± 1 mmHg in the vehicle group before and during 14% O2, respectively (PGT< 0.05). During ANG II clamp, postglomerular vascular resistance was still increased in response to RSNA during 14% O2, demonstrating that the action of the renal nerves on the postglomerular vasculature was independent of the renin-angiotensin system. This further supports our hypothesis that increases in RSNA can selectively control pre- and postglomerular vascular resistance and therefore glomerular ultrafiltration.
Fetal heart rate variability and brain stem injury after asphyxia in preterm fetal sheep
Authors: George Sherly , Gunn Alistair J. , Westgate Jenny A. , Brabyn Christine , Guan Jian , Bennet Laura
Published: June 2004

This study was undertaken to determine the mechanisms mediating changes in fetal heart rate variability (FHRV) during and after exposure to asphyxia in the premature fetus. Preterm fetal sheep at 0.6 of gestation (91 ± 1 days, term is 147 days) were exposed to either sham occlusion ( n = 10) or to complete umbilical cord occlusion for either 20 ( n = 7) or 30 min ( n = 10). Cord occlusion led to a transient increase in FHRV with abrupt body movements that resolved after 5 min. In the 30 min group there was a marked increase in FHRV in the final 10 min of occlusion related to abnormal atrial activity. After reperfusion, FHRV in both study groups was initially suppressed and progressively increased to baseline levels over the first 4 h of recovery. In the 20 min group this improvement was associated with return of normal EEG activity and movements. In contrast, in the 30 min group the EEG was abnormal with epileptiform activity superimposed on a suppressed background, which was associated with abnormal fetal movements. As the epileptiform activity resolved, FHRV fell and became suppressed for the remainder of the study. Histological assessment after 72 h demonstrated severe brain stem injury in the 30 min group but not in the 20 min group. In conclusion, during early recovery from asphyxia, epileptiform activity and associated abnormal fetal movements related to evolving neural injury can cause a confounding transient increase in FHRV, which mimics the normal pattern of recovery. However, chronic suppression of FHRV was a strong predictor of severe brain stem injury.
5-HT3receptors participate in CCK-induced suppression of food intake by delaying gastric emptying
Authors: Hayes Matthew R. , Moore Rachael L. , Shah Samit M. , Covasa Mihai
Published: June 2004

Serotonin type 3 (5-HT3) receptors have been shown to participate in the negative-feedback control of food intake. We previously reported that cholecystokinin (CCK)-induced suppression of food intake is partly mediated through 5-HT3receptors when rats were tested on a preferred liquid diet, but whether such an effect occurs when they are tested on a solid maintenance diet is unknown. In the present study, we examined the effects of ondansetron, a selective 5-HT3antagonist, on CCK-induced suppression of solid chow intake. Intraperitoneal administration of ondansetron significantly attenuated 30- and 60-min CCK-induced reduction of food intake, with suppression being completely reversed by 120 min. It is not known whether 5-HT3receptors directly mediate CCK-induced satiation or whether their participation depends on CCK acting as part of a feedback cascade to inhibit ongoing intake. Because CCK-induced inhibition of sham feeding does not depend on additive gastric/postgastric-feedback signals, we examined the ability of ondansetron to reverse CCK-induced satiation in sham-feeding rats. Ondansetron did not attenuate reduction of sham feeding by CCK, suggesting that ondansetron does not directly antagonize CCK-satiation signals. CCK suppresses real feeding through a delay in gastric emptying. Ondansetron could attenuate CCK-induced reduction of food intake by reversing CCK-induced inhibition of gastric emptying. We found that blockade of 5-HT3receptors attenuates CCK-induced inhibition of gastric emptying of a solid meal, as well as saline and glucose loads. We conclude that 5-HT3receptors mediate CCK-induced satiation through indirect mechanisms as part of a feedback cascade involving inhibition of gastric emptying.
Pulmonary gas exchange at maximal exercise in Danish lowlanders during 8 wk of acclimatization to 4,100 m and in high-altitude Aymara natives
Authors: Lundby Carsten , Calbet Jose A. L. , van Hall Gerrit , Saltin Bengt , Sander Mikael
Published: June 2004

We aimed to test effects of altitude acclimatization on pulmonary gas exchange at maximal exercise. Six lowlanders were studied at sea level, in acute hypoxia (AH), and after 2 and 8 wk of acclimatization to 4,100 m (2W and 8W) and compared with Aymara high-altitude natives residing at this altitude. As expected, alveolar Po2was reduced during AH but increased gradually during acclimatization (61 ± 0.7, 69 ± 0.9, and 72 ± 1.4 mmHg in AH, 2W, and 8W, respectively), reaching values significantly higher than in Aymaras (67 ± 0.6 mmHg). Arterial Po2(PaO2) also decreased during exercise in AH but increased significantly with acclimatization (51 ± 1.1, 58 ± 1.7, and 62 ± 1.6 mmHg in AH, 2W, and 8W, respectively). PaO2in lowlanders reached levels that were not different from those in high-altitude natives (66 ± 1.2 mmHg). Arterial O2saturation (SaO2) decreased during maximum exercise compared with rest in AH and after 2W and 8W: 73.3 ± 1.4, 76.9 ± 1.7, and 79.3 ± 1.6%, respectively. After 8W, SaO2in lowlanders was not significantly different from that in Aymaras (82.7 ± 1%). An improved pulmonary gas exchange with acclimatization was evidenced by a decreased ventilatory equivalent of O2after 8W: 59 ± 4, 58 ± 4, and 52 ± 4 l·min·l O2−1, respectively. The ventilatory equivalent of O2reached levels not different from that of Aymaras (51 ± 3 l·min·l O2−1). However, increases in exercise alveolar Po2and PaO2with acclimatization had no net effect on alveolar-arterial Po2difference in lowlanders (10 ± 1.3, 11 ± 1.5, and 10 ± 2.1 mmHg in AH, 2W, and 8W, respectively), which remained significantly higher than in Aymaras (1 ± 1.4 mmHg). In conclusion, lowlanders substantially improve pulmonary gas exchange with acclimatization, but even acclimatization for 8 wk is insufficient to achieve levels reached by high-altitude natives.
Differential expression of collagen- and laminin-binding integrins mediates ureteric bud and inner medullary collecting duct cell tubulogenesis
Authors: Chen Dong , Roberts Richard , Pohl Martin , Nigam Sanjay , Kreidberg Jordan , Wang Zemin , Heino Jyrki , Ivaska Johanna , Coffa Sergio , Harris Raymond C. , Pozzi Ambra , Zent Roy
Published: June 2004

Inner medullary collecting ducts (IMCD) are terminally differentiated structures derived from the ureteric bud (UB). UB development is mediated by changes in the temporal and spatial expression of integrins and their respective ligands. We demonstrate both in vivo and in vitro that the UB expresses predominantly laminin receptors (α3β1-, α6β1-, and α6β4-integrins), whereas the IMCD expresses both collagen (α1β1- and α2β1-integrins) and laminin receptors. Cells derived from the IMCD, but not the UB, undergo tubulogenesis in collagen-I (CI) gels in an α1β1- and α2β1-dependent manner. UB cells transfected with the α2-integrin subunit undergo tubulogenesis in CI, suggesting that collagen receptors are required for branching morphogenesis in CI. In contrast, both UB and IMCD cells undergo tubulogenesis in CI/Matrigel gels. UB cells primarily utilize α3β1- and α6-integrins, whereas IMCD cells mainly employ α1β1for this process. These results demonstrate a switch in integrin expression from primarily laminin receptors in the early UB to both collagen and laminin receptors in the mature IMCD, which has functional consequences for branching morphogenesis in three-dimensional cell culture models. This suggests that temporal and spatial changes in integrin expression could help organize the pattern of branching morphogenesis of the developing collecting system in vivo.
Three-dimensional lateral and vertical relationships of inner medullary loops of Henle and collecting ducts
Authors: Pannabecker Thomas L. , Dantzler William H.
Published: June 2004

Functional reconstruction of inner medullary thin limbs of Henle and collecting ducts (CDs) has enabled us to characterize distinctive three-dimensional vertical and lateral relationships between these segments. We previously reported that inner medullary descending thin limbs (DTLs) that form a bend at a distance greater than ∼1 mm below the inner medullary base express detectable aquaporin (AQP) 1 only along the initial 40% of the segment before the bend, whereas ClC-K1 is expressed continuously along all ascending thin limbs (ATLs), beginning with the prebend segment. We have now reconstructed individual CDs that are grouped together in single clusters at the base of the inner medulla; CDs belonging to each separate cluster coalesce into a single CD in the deep papilla. DTLs are positioned predominantly at the periphery of each individual CD cluster at all levels of the inner medulla and are absent from within the cluster. In contrast, ATLs are distributed near uniformly among the CDs and DTLs at all levels of the inner medulla. A second population of inner medullary DTLs averages ∼700 μm in length from base to bend and, as previously reported, expresses no detectable AQP1 and expresses ClC-K1 continuously beginning with the prebend segment. ATLs located within the interior of the CD clusters arise predominantly from these short AQP1-null inner medullary DTLs, suggesting there may be functional interdependence between IMCD1 segments and short-length inner medullary thin limbs exhibiting minimal water permeability along their descending segments. AQP1-expressing DTLs and CDs are apparently separated into two structurally distinct lateral compartments. A similar lateral compartmentation between the ATLs and CDs is not apparent. This architectural arrangement indicates that fluid and solutes may be preferentially transported transversely between multiple inner medullary compartments.
The intrarenal renin-angiotensin system in autosomal dominant polycystic kidney disease
Authors: Loghman-Adham Mahmoud , Soto Carlos E. , Inagami Tadashi , Cassis Lisa
Published: June 2004

Hypertension is a common complication of autosomal dominant polycystic kidney disease (ADPKD), often present before the onset of renal failure. A role for the renin-angiotensin system (RAS) has been proposed, but studies of systemic RAS have failed to show a correlation between plasma renin activity and blood pressure in ADPKD. Ectopic renin expression by cyst epithelium was first reported in 1992 (Torres VE, Donovan KA, Sicli G, Holley KE, Thibodeau ST, Carretero OA, Inagami T, McAteer JA, and Johnson CM. Kidney Int 42: 364–373, 1992). It is not known, however, whether other RAS components are also expressed by cysts in ADPKD. We show that, in addition to renin, angiotensinogen (AGT) is produced by some cysts and dilated tubules. Angiotensin-converting enzyme, ANG II type 1 receptor, and ANG II peptide are also present within cysts and in many tubules; and some cyst fluids contain high ANG II concentrations. Additionally, cyst-derived cells in culture continue to express the components of the RAS at both the protein and mRNA levels. We further show that renin is expressed primarily in cysts of distal tubule origin and in cyst-derived cells with distal tubule characteristics, whereas AGT is expressed primarily in cysts of proximal tubule origin and in cyst-derived cells with proximal tubule characteristics. Renin production by cyst-derived cells appears to be regulated by extracellular Na+concentration. Based on these observations, we propose a model of an autocrine/paracrine RAS in polycystic kidney disease, whereby overactivity of the intrarenal system results in sustained increases in intratubular ANG II concentrations.
Role of the carotid bodies in chemosensory ventilatory responses in the anesthetized mouse
Authors: Izumizaki Masahiko , Pokorski Mieczyslaw , Homma Ikuo
Published: June 2004

We examined the effects of carotid body denervation on ventilatory responses to normoxia (21% O2 in N2 for 240 s), hypoxic hypoxia (10 and 15% O2 in N2 for 90 and 120 s, respectively), and hyperoxic hypercapnia (5% CO2 in O2 for 240 s) in the spontaneously breathing urethane-anesthetized mouse. Respiratory measurements were made with a whole body, single-chamber plethysmograph before and after cutting both carotid sinus nerves. Baseline measurements in air showed that carotid body denervation was accompanied by lower minute ventilation with a reduction in respiratory frequency. On the basis of measurements with an open-circuit system, no significant differences in O2 consumption or CO2 production before and after chemodenervation were found. During both levels of hypoxia, animals with intact sinus nerves had increased respiratory frequency, tidal volume, and minute ventilation; however, after chemodenervation, animals experienced a drop in respiratory frequency and ventilatory depression. Tidal volume responses during 15% hypoxia were similar before and after carotid body denervation; during 10% hypoxia in chemodenervated animals, there was a sudden increase in tidal volume with an increase in the rate of inspiration, suggesting that gasping occurred. During hyperoxic hypercapnia, ventilatory responses were lower with a smaller tidal volume after chemodenervation than before. We conclude that the carotid bodies are essential for maintaining ventilation during eupnea, hypoxia, and hypercapnia in the anesthetized mouse.
Effects of undernutrition on respiratory mechanics and lung parenchyma remodeling
Authors: Dias Cristina Márcia , Pássaro Caroline P. , Cagido Viviane Ramos , Einicker-Lamas Marcelo , Lowe Jennifer , Negri Elnara M. , Capelozzi Vera L. , Zin Walter A. , Rocco Patricia R. M.
Published: June 2004

Undernutrition thwarts lung structure and function, but there are disagreements about the behavior of lung mechanics in malnourished animals. To clarify this issue, lung and chest wall mechanical properties were subdivided into their resistive, elastic, and viscoelastic properties in nutritionally deprived (ND) rats and correlated with the data gathered from histology (light and electron microscopy and elastic fiber content), and bronchoalveolar lavage fluid analysis (lipid and protein content). Twenty-four Wistar rats were assigned into two groups. In the control (Ctrl) group the animals received food ad libitum. In the ND group, rats received one-third of their usual daily food consumption until they lost 40% of their initial body weight. Lung static elastance, viscoelastic and resistive pressures (normalized by functional residual capacity), and chest wall pressures were higher in the ND group than in the Ctrl group. The ND group exhibited patchy atelectasis, areas of emphysema, interstitial edema, and reduced elastic fiber content. The amount of lipid and protein in bronchoalveolar lavage fluid was significantly reduced in the ND group. Electron microscopy showed 1) type II pneumocytes with a reduction in lamellar body content, multilamellated structures, membrane vesicles, granular debris, and structurally aberrant mitochondria; and 2) diaphragm and intercostals with atrophy, disarrangement of the myofibrils, and deposition of collagen type I fibers. In conclusion, undernutrition led to lung and chest wall mechanical changes that were the result from a balance among the following modifications: 1) distorted structure of diaphragm and intercostals, 2) surfactant content reduction, and 3) decrease in elastic fiber content.
Effects of exercise on gene expression in human peripheral blood mononuclear cells
Authors: Connolly Peter H. , Caiozzo Vincent J. , Zaldivar Frank , Nemet Dan , Larson Jennifer , Hung She-pin , Heck J. Denis , Hatfield G. Wesley , Cooper Dan M.
Published: June 2004

Exercise leads to increases in circulating levels of peripheral blood mononuclear cells (PBMCs) and to a simultaneous, seemingly paradoxical increase in both pro- and anti-inflammatory mediators. Whether this is paralleled by changes in gene expression within the circulating population of PBMCs is not fully understood. Fifteen healthy men (18–30 yr old) performed 30 min of constant work rate cycle ergometry (∼80% peak O2uptake). Blood samples were obtained preexercise (Pre), end-exercise (End-Ex), and 60 min into recovery (Recovery), and gene expression was measured using microarray analysis (Affymetrix GeneChips). Significant differential gene expression was defined with a posterior probability of differential expression of 0.99 and a Bayesian P value of 0.005. Significant changes were observed from Pre to End-Ex in 311 genes, from End-Ex to Recovery in 552 genes, and from Pre to Recovery in 293 genes. Pre to End-Ex upregulation of PBMC genes related to stress and inflammation [e.g., heat shock protein 70 (3.70-fold) and dual-specificity phosphatase-1 (4.45-fold)] was followed by a return of these genes to baseline by Recovery. The gene for interleukin-1 receptor antagonist (an anti-inflammatory mediator) increased between End-Ex and Recovery (1.52-fold). Chemokine genes associated with inflammatory diseases [macrophage inflammatory protein-1α (1.84-fold) and -1β (2.88-fold), and regulation-on-activation, normal T cell expressed and secreted (1.34-fold)] were upregulated but returned to baseline by Recovery. Exercise also upregulated growth and repair genes such as epiregulin (3.50-fold), platelet-derived growth factor (1.55-fold), and hypoxia-inducible factor-I (2.40-fold). A single bout of heavy exercise substantially alters PBMC gene expression characterized in many cases by a brisk activation and deactivation of genes associated with stress, inflammation, and tissue repair.
N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals
Authors: Medved I. , Brown M. J. , Bjorksten A. R. , Murphy K. T. , Petersen A. C. , Sostaric S. , Gong X. , McKenna M. J.
Published: June 2004

The production of reactive oxygen species in skeletal muscle is linked with muscle fatigue. This study investigated the effects of the antioxidant compound N-acetylcysteine (NAC) on muscle cysteine, cystine, and glutathione and on time to fatigue during prolonged, submaximal exercise in endurance athletes. Eight men completed a double-blind, crossover study, receiving NAC or placebo before and during cycling for 45 min at 71% peak oxygen consumption (V̇o2 peak) and then to fatigue at 92% V̇o2 peak. NAC was intravenously infused at 125 mg·kg−1·h−1 for 15 min and then at 25 mg·kg−1·h−1 for 20 min before and throughout exercise. Arterialized venous blood was analyzed for NAC, glutathione status, and cysteine concentration. A vastus lateralis biopsy was taken preinfusion, at 45 min of exercise, and at fatigue and was analyzed for NAC, total glutathione (TGSH), reduced glutathione (GSH), cysteine, and cystine. Time to fatigue at 92% V̇o2 peak was reproducible in preliminary trials (coefficient of variation 5.6 ± 0.6%) and with NAC was enhanced by 26.3 ± 9.1% (NAC 6.4 ± 0.6 min vs. Con 5.3 ± 0.7 min; P < 0.05). NAC increased muscle total and reduced NAC at both 45 min and fatigue ( P < 0.005). Muscle cysteine and cystine were unchanged during Con, but were elevated above preinfusion levels with NAC ( P < 0.001). Muscle TGSH ( P < 0.05) declined and muscle GSH tended to decline ( P = 0.06) during exercise. Both were greater with NAC ( P < 0.05). Neither exercise nor NAC affected whole blood TGSH. Whereas blood GSH was decreased and calculated oxidized glutathione increased with exercise ( P < 0.05), both were unaffected by NAC. In conclusion, NAC improved performance in well-trained individuals, with enhanced muscle cysteine and GSH availability a likely mechanism.
Active force inhibition and stretch-induced force enhancement in frog muscle treated with BDM
Authors: Rassier Dilson E. , Herzog Walter
Published: June 2004

There is evidence that the stretch-induced residual force enhancement observed in skeletal muscles is associated with 1) cross-bridge dynamics and 2) an increase in passive force. The purpose of this study was to characterize the total and passive force enhancement and to evaluate whether these phenomena may be associated with a slow detachment of cross bridges. Single fibers from frog lumbrical muscles were placed at a length 20% longer than the plateau of the force-length relationship, and active and passive stretches (amplitudes of 5 and 10% of fiber length and at a speed of 40% fiber length/s) were performed. Experiments were conducted in Ringer solution and with the addition of 2, 5, and 10 mM of 2,3-butanedione monoxime (BDM), a cross-bridge inhibitor. The steady-state active and passive isometric forces after stretch of an activated fiber were higher than the corresponding forces measured after isometric contractions or passive stretches. BDM decreased the absolute isometric force and increased the total force enhancement in all conditions investigated. These results suggest that total force enhancement is directly associated with cross-bridge kinetics. Addition of 2 mM BDM did not change the passive force enhancement after 5 and 10% stretches. Addition of 5 and 10 mM did not change (5% stretches) or increased (10% stretches) the passive force enhancement. Increasing stretch amplitudes and increasing concentrations of BDM caused relaxation after stretch to be slower, and because passive force enhancement is increased at the greatest stretch amplitudes and the highest BDM concentrations, it appears that passive force enhancement may be related to slow-detaching cross bridges.
Cerebral blood flow response to isocapnic hypoxia during slow-wave sleep and wakefulness
Authors: Meadows Guy E. , O'Driscoll Denise M. , Simonds Anita K. , Morrell Mary J. , Corfield Douglas R.
Published: June 2004

Nocturnal hypoxia is a major pathological factor associated with cardiorespiratory disease. During wakefulness, a decrease in arterial O2 tension results in a decrease in cerebral vascular tone and a consequent increase in cerebral blood flow; however, the cerebral vascular response to hypoxia during sleep is unknown. In the present study, we determined the cerebral vascular reactivity to isocapnic hypoxia during wakefulness and during stage 3/4 non-rapid eye movement (NREM) sleep. In 13 healthy individuals, left middle cerebral artery velocity (MCAV) was measured with the use of transcranial Doppler ultrasound as an index of cerebral blood flow. During wakefulness, in response to isocapnic hypoxia (arterial O2 saturation −10%), the mean (±SE) MCAV increased by 12.9 ± 2.2% ( P < 0.001); during NREM sleep, isocapnic hypoxia was associated with a −7.4 ± 1.6% reduction in MCAV ( P < 0.001). Mean arterial blood pressure was unaffected by isocapnic hypoxia ( P > 0.05); R-R interval decreased similarly in response to isocapnic hypoxia during wakefulness (−21.9 ± 10.4%; P < 0.001) and sleep (−20.5 ± 8.5%; P < 0.001). The failure of the cerebral vasculature to react to hypoxia during sleep suggests a major state-dependent vulnerability associated with the control of the cerebral circulation and may contribute to the pathophysiologies of stroke and sleep apnea.
Role of Superior Colliculus in Adaptive Eye–Head Coordination During Gaze Shifts
Authors: Constantin Alina G. , Wang Hongying , Crawford J. Douglas
Published: June 2004

The goal of this study was to determine which aspects of adaptive eye–head coordination are implemented upstream or downstream from the motor output layers of the superior colliculus (SC). Two monkeys were trained to perform head-free gaze shifts while looking through a 10° aperture in opaque, head-fixed goggles. This training produced context-dependent alterations in eye–head coordination, including a coordinated pattern of saccade–vestibuloocular reflex (VOR) eye movements that caused eye position to converge toward the aperture, and an increased contribution of head movement to the gaze shift. One would expect the adaptations that were implemented downstream from the SC to be preserved in gaze shifts evoked by SC stimulation. To test this, we analyzed gaze shifts evoked from 19 SC sites in monkey 1 and 38 sites in monkey 2, both with and without goggles. We found no evidence that the goggle paradigm altered the basic gaze position–dependent spatial coding of the evoked movements (i.e., gaze was still coded in an eye-centered frame). However, several aspects of the context-dependent coordination strategy were preserved during stimulation, including the adaptive convergence of final eye position toward the goggles aperture, and the position-dependent patterns of eye and head movement required to achieve this. For example, when initial eye position was offset from the learned aperture location at the time of stimulation, a coordinated saccade–VOR eye movement drove it back to the original aperture, and the head compensated to preserve gaze kinematics. Some adapted amplitude–velocity relationships in eye, gaze, and head movement also may have been preserved. In contrast, context-dependent changes in overall eye and head contribution to gaze amplitude were not preserved during SC stimulation. We conclude that 1) the motor output command from the SC to the brain stem can be adapted to produce different position-dependent coordination strategies for different behavioral contexts, particularly for eye-in-head position, but 2) these brain stem coordination mechanisms implement only the default (normal) level of head amplitude contribution to the gaze shift. We propose that a parallel cortical drive, absent during SC stimulation, is required to adjust the overall head contribution for different behavioral contexts.
Bayesian Integration in Force Estimation
Authors: Körding Konrad P. , Ku Shih-pi , Wolpert Daniel M.
Published: June 2004

When we interact with objects in the world, the forces we exert are finely tuned to the dynamics of the situation. As our sensors do not provide perfect knowledge about the environment, a key problem is how to estimate the appropriate forces. Two sources of information can be used to generate such an estimate: sensory inputs about the object and knowledge about previously experienced objects, termed prior information. Bayesian integration defines the way in which these two sources of information should be combined to produce an optimal estimate. To investigate whether subjects use such a strategy in force estimation, we designed a novel sensorimotor estimation task. We controlled the distribution of forces experienced over the course of an experiment thereby defining the prior. We show that subjects integrate sensory information with their prior experience to generate an estimate. Moreover, subjects could learn different prior distributions. These results suggest that the CNS uses Bayesian models when estimating force requirements.
Influence of Lateral Connections on the Structure of Cortical Maps
Authors: Carreira-Perpiñán Miguel Á. , Goodhill Geoffrey J.
Published: June 2004

Maps of ocular dominance and orientation in primary visual cortex have a highly characteristic structure. The factors that determine this structure are still largely unknown. In particular, it is unclear how short-range excitatory and inhibitory connections between nearby neurons influence structure both within and between maps. Using a generalized version of a well-known computational model of visual cortical map development, we show that the number of excitatory and inhibitory oscillations in this interaction function critically influences map structure. Specifically, we demonstrate that functions that oscillate more than once do not produce maps closely resembling those seen biologically. This strongly suggests that local lateral connections in visual cortex oscillate only once and have the form of a Mexican hat.
Dissociation of Morphological and Physiological Changes Associated With Long-Term Memory in Aplysia
Authors: Wainwright Marcy L. , Byrne John H. , Cleary Leonard J.
Published: June 2004

Neurite outgrowth is a process commonly thought to contribute to long-term learning by formation of new synaptic contacts. The behavioral effects of long-term sensitization training in Aplysia were restricted to the trained side of the animal as were changes in strength of the sensorimotor synapse. In contrast, training produced varicosity formation on both sides of the animal. Appositions with follower neurons, however, were enhanced only on the trained side. The dissociation of structural and functional correlates suggests that key regulatory steps are downstream from outgrowth, possibly in the targeting of new processes and activation of new synapses.
Effect of Eye Position on Saccades and Neuronal Responses to Acoustic Stimuli in the Superior Colliculus of the Behaving Cat
Authors: Populin Luis C. , Tollin Daniel J. , Yin Tom C. T.
Published: June 2004

We examined the motor error hypothesis of visual and auditory interaction in the superior colliculus (SC), first tested by Jay and Sparks in the monkey. We trained cats to direct their eyes to the location of acoustic sources and studied the effects of eye position on both the ability of cats to localize sounds and the auditory responses of SC neurons with the head restrained. Sound localization accuracy was generally not affected by initial eye position, i.e., accuracy was not proportionally affected by the deviation of the eyes from the primary position at the time of stimulus presentation, showing that eye position is taken into account when orienting to acoustic targets. The responses of most single SC neurons to acoustic stimuli in the intact cat were modulated by eye position in the direction consistent with the predictions of the “motor error” hypothesis, but the shift accounted for only two-thirds of the initial deviation of the eyes. However, when the average horizontal sound localization error, which was ∼35% of the target amplitude, was taken into account, the magnitude of the horizontal shifts in the SC auditory receptive fields matched the observed behavior. The modulation by eye position was not due to concomitant movements of the external ears, as confirmed by recordings carried out after immobilizing the pinnae of one cat. However, the pattern of modulation after pinnae immobilization was inconsistent with the observations in the intact cat, suggesting that, in the intact animal, information about the position of the pinnae may be taken into account.
Gaze Affects Pointing Toward Remembered Visual Targets After a Self-Initiated Step
Authors: Admiraal M. A. , Keijsers N.L.W. , Gielen C.C.A.M.
Published: June 2004

We have investigated pointing movements toward remembered targets after an intervening self-generated body movement. We tested to what extent visual information about the environment or finger position is used in updating target position relative to the body after a step and whether gaze plays a role in the accuracy of the pointing movement. Subjects were tested in three visual conditions: complete darkness (DARK), complete darkness with visual feedback of the finger (FINGER), and with vision of a well-defined environment and with feedback of the finger (FRAME). Pointing accuracy was rather poor in the FINGER and DARK conditions, which did not provide vision of the environment. Constant pointing errors were mainly in the direction of the step and ranged from about 10 to 20 cm. Differences between binocular fixation and target position were often related to the step size and direction. At the beginning of the trial, when the target was visible, fixation was on target. After target extinction, fixation moved away from the target relative to the subject. The variability in the pointing positions appeared to be related to the variable errors in fixation, and the co-variance increases during the delay period after the step, reaching a highly significant value at the time of pointing. The significant co-variance between fixation position and pointing is not the result of a mutual dependence on the step, since we corrected for any direct contributions of the step in both signals. We conclude that the co-variance between fixation and pointing position reflects 1) a common command signal for gaze and arm movements and 2) an effect of fixation on pointing accuracy at the time of pointing.
Current- and Voltage-Clamp Recordings and Computer Simulations of Kenyon Cells in the Honeybee
Authors: Wüstenberg Daniel G. , Boytcheva Milena , Grünewald Bernd , Byrne John H. , Menzel Randolf , Baxter Douglas A.
Published: June 2004

The mushroom body of the insect brain is an important locus for olfactory information processing and associative learning. The present study investigated the biophysical properties of Kenyon cells, which form the mushroom body. Current- and voltage-clamp analyses were performed on cultured Kenyon cells from honeybees. Current-clamp analyses indicated that Kenyon cells did not spike spontaneously in vitro. However, spikes could be elicited by current injection in approximately 85% of the cells. Of the cells that produced spikes during a 1-s depolarizing current pulse, approximately 60% exhibited repetitive spiking, whereas the remaining approximately 40% fired a single spike. Cells that spiked repetitively showed little frequency adaptation. However, spikes consistently became broader and smaller during repetitive activity. Voltage-clamp analyses characterized a fast transient Na+current ( INa), a delayed rectifier K+current ( IK,V), and a fast transient K+current ( IK,A). Using the neurosimulator SNNAP, a Hodgkin–Huxley-type model was developed and used to investigate the roles of the different currents during spiking. The model led to the prediction of a slow transient outward current ( IK,ST) that was subsequently identified by reevaluating the voltage-clamp data. Simulations indicated that the primary currents that underlie spiking are INaand IK,V, whereas IK,Aand IK,STprimarily determined the responsiveness of the model to stimuli such as constant or oscillatory injections of current.
Phage display identification of age-associated TNFα-mediated cardiac oxidative induction
Authors: Edelberg Jay M. , Wong Alvin , Holm Jacquelyne M. , Xaymardan Munira , Duignan Inga , Chin Andrew , Kizer Jorge R. , Cai Dongqing
Published: June 2004

Age-associated alterations in the actions of tumor necrosis factor-α (TNFα) in the heart with impaired cardioprotective pathways and enhanced apoptotic induction may contribute to the increased severity of cardiovascular pathology in older persons. To identify the molecular events mediating these changes in the microvasculature of the aging rodent heart, the biochemical properties of in vivo phage-display cyclic peptide cardiac biopanning were studied. Analysis of individual amino acid positions revealed that the center of the peptide motif (amino acid position 4) had a significantly higher frequency of aromatic amino acid side chains in phage homing to the old hearts compared with young controls (18 mo old, 11% vs. 3 mo old, 3%, P < 0.05). This subset of phage motifs revealed an age-associated homology with oxidoreductase enzymes (homology: 18 mo, 7/7; 3 mo, 0/2), suggesting the substrates and/or binding sites of these enzymes are increased in the aging hearts. Immunostaining for the oxidoreductase substrate 4-hydroxy-2-nonenal (HNE), a cardiotoxic lipid peroxidation product, demonstrated a twofold higher density of HNE(+) cells in PBS-treated hearts of old mice (18 mo) compared with young controls (3 mo) (18 mo, 3.2 ± 2.8 vs. 3 mo, 1.0 ± 0.9 cells/HPF, P < 0.05). Moreover, intracardiac injection of TNFα resulted in a significantly greater increase in HNE staining in the old hearts (18 mo, 16.9 ± 13.8 vs. 3 mo, 9.1 ± 6.0 cells/HPF, P < 0.05). Overall, these studies demonstrate that aging-associated alterations in TNFα-mediated pathways with induction of reactive oxidative species and changes in vascular surface binding sites may contribute mechanistically to the increased cardiovascular pathology of the aging heart.
Muss die Weiterbildung zum Facharzt Gynäkologie und Geburtshilfe in der Schweiz überdacht werden?
Authors: Haller U. , Hepp H. , Winter R.
Published: June 2004

Unser Fachgebiet basiert auf einem Dreisäulenkonzept. Die berufspolitische Entwicklung bedingt erneut eine Diskussion über die Aufteilung in einen «nichtoperativen» und einen «operativen» Facharzt. Dabei ist auch die Thematisierung eines Zukunftsmodells «die Frauenärztin, der Frauenarzt als Hausarzt der Frau» angezeigt. Die Guideline zum Vorgehen bei suspektem und positivem zytologischen Abstrich der Zervix wurde im Hinblick auf die Bethesda-Nomenklatur überarbeitet und wird noch in diesem Jahr erscheinen.
Does Bromocriptine Improve Glycemic Control of Obese Type-2 Diabetics?
Authors: Aminorroaya Ashraf , Janghorbani Mohsen , Ramezani Majid , Haghighi Sassan , Amini Massoud
Published: June 2004

Background: Various oral hypoglycemic agents have already been administered to type-2 diabetic patients to normalize their plasma glucose concentrations but they have not had complete and sustained success. In recent years, bromocriptine has been tried with controversial results. In present study, the effect of bromocriptine on glycemic control was evaluated in obese type-2 diabetic patients. Methods: In a double-blind placebo-controlled clinical trial, 40 obese patients with type-2 diabetes (aged 32–70 years) were randomly allocated to the two treatment groups. The first group received bromocriptine (2.5 mg daily) for a total of 3 months. The second group received placebo. They had been uncontrolled on fixed doses of glibenclamide or its combination with metformin in the 3 months before enrolling in the study. The fasting plasma glucose (FPG) level and glycosylated hemoglobin (HbA1) were measured and body mass index (BMI) was calculated before and 1, 2 and 3 months after treatment. Results: The FPG level decreased in the bromocriptine-treated group from 10.59 ± 0.42 to 9.06 ± 0.41 mmol/l (mean ± SEM; p < 0.01), whereas in the placebo group it was not changed, 10.69 ± 0.52 and 10.6 ± 0.57 mmol/l, respectively. The HbA1 concentration was reduced in the bromocriptine-treated group from 9.9 ± 0.3 to 9.5 ±0.2% (p = 0.06), whereas it increased in the placebo-treated group from 10.2 ± 0.3 to 11.3 ± 0.6% (p < 0.05). The differences in HbA1 (1.8%, p < 0.01) and FPG (1.55 mmol/l, p < 0.05) levels between the bromocriptine and placebo groups at 3 months were significant. No changes in body weight or BMI occurred during the study in either placebo- or bromocriptine-treated group. Conclusion: The data further support the contention that bromocriptine improves glycemic control in obese type-2 diabetic patients, although the mechanism of action remains to be determined.
Relation of Apolipoprotein(a) Size to Alzheimer’s Disease and Vascular Dementia
Authors: Emanuele Enzo , Peros Emmanouil , Tomaino Carmine , Feudatari Enrica , Bernardi Livia , Binetti Giuliano , Maletta Raffaele , Micieli Giuseppe , Bruni Amalia C. , Geroldi Diego
Published: June 2004

Lipoprotein(a) [Lp(a)] level is a newly established vascular risk factor which has been suggested to play a role in dementia. However, the majority of Lp(a) cell-to-cell interactions are mediated by its specific apolipoprotein(a) [apo(a)] moiety. This suggests that the size polymorphism of apo(a) may be of importance in conveying the Lp(a)-related risk. Specifically, we postulated that variation in apo(a) isoform size may lead to increased risk of vascular dementia (VaD), Alzheimer’s disease (AD), stroke, or all three of them. Under a case-control design we compared Lp(a) plasma levels and the distribution of apo(a) phenotypes in groups of subjects consisting of 50 VaD patients, 162 sporadic AD patients, 95 non-demented stroke patients (NDS), and 105 normal controls. The prevalence of small-sized apo(a) isoforms in the VaD group was significantly higher than that in the stroke and normal control groups, with an odds ratio of 5.29 (95% CI 2.24–12.49, p = 0.0001) for the development of VaD for individuals with at least one apo(a) isoform of low molecular weight (LMW). Furthermore, the possession of at least one small-sized apo(a) isoform significantly increased the risk of AD to 1.92 (95% CI 1.02–3.61, p = 0.0434). Our results demonstrate that possession of at least one LMW apo(a) isoform is significantly associated with dementia and specifically offer new evidence of a strong association between the lipoprotein system and post-stroke dementia.
Smoking Cessation Rapidly Increases Circulating Progenitor Cells in Peripheral Blood in Chronic Smokers
Authors: Kondo Takahisa , Hayashi Mutsuharu , Takeshita Kyosuke , Numaguchi Yasushi , Kobayashi Koichi , Iino Shigeo , Inden Yasuya , Murohara Toyoaki
Published: June 2004

Objective—

Circulating endothelial progenitor cells (EPCs) contribute to postnatal angiogenesis. The number of circulating EPCs has an inverse correlation with coronary risk scores. However, the effect of smoking on the number of circulating EPCs is not well-known.

Methods and Results—

We examined the effects of chronic smoking and of smoking cessation on EPC levels. Circulating EPCs were quantified by flow cytometry as CD45
low
CD34
+
CD133
+
(progenitor cells [PCs]) or CD45
low
CD34
+
CD133
+
VEGFR2
+
(EPCs) in 14 nonsmokers and in 15 smokers. All smokers quit smoking. Eight quit smoking with nicotine patch and 7 without nicotine patch. PC/EPC levels were inversely correlated with the number of cigarettes smoked. Circulating PCs/EPCs increased rapidly after cessation (
P
<0.0001) and decreased again after resumption of smoking to the level similar to that before cessation (
P
=0.0031). The magnitude of increase in EPCs was greater in light smokers than in heavy smokers.

Conclusions—

The number of circulating PCs/EPCs was reduced in chronic smokers. Smoking cessation led to a rapid restoration of PC/EPC levels. The recovery of EPC levels was greater in light smokers than in heavy smokers. The decreased number of circulating EPCs would make smokers susceptible to cardiovascular disease, and even short-time cessation of smoking may be an effective means to reduce cardiovascular risk.
Matrix Metalloproteinase-9 Genotype Influences Large Artery Stiffness Through Effects on Aortic Gene and Protein Expression
Authors: Medley Tanya L. , Cole Timothy J. , Dart Anthony M. , Gatzka Christoph D. , Kingwell Bronwyn A.
Published: June 2004

Objective—

Because large artery stiffening contributes to myocardial ischemia, its determinants are of relevance as potential risk markers. This study examined whether matrix metalloproteinase (MMP)-9 (gelatinase B) genotype is associated with large artery stiffening and aortic MMP-9 gene and protein expression.

Methods and Results—

MMP-9 genotype (C-1562T promoter polymorphism) was determined in 84 patients (73 male) with angiographically defined coronary artery disease (CAD). Carotid applanation tonometry was used to assess central blood pressures and, with Doppler velocimetry, to assess aortic stiffness (input and characteristic impedance). Gene expression real-time polymerase chain reaction (RT-PCR) and protein levels (Western blotting) were assessed in relation to genotype in aortic samples from a separate population. T-allele carriers (C/T and T/T) had stiffer large arteries (higher input and characteristic impedance) and higher carotid pulse and systolic blood pressure (all
P
<0.05) than C/C homozygotes. In aortic samples, gene expression was 5-fold higher and active protein levels were >2-fold higher in T-allele carriers.

Conclusions—

Because the T allele was associated with greater MMP-9 mRNA and protein levels, the greater large artery stiffness in T-allele carriers may be secondary to excessive degradation of the arterial elastic matrix. The consequent higher pulse pressure may increase susceptibility to myocardial ischemia.