bluuebunny/crossref_metadata_2025 huggingface dataset:
Do recommended textbooks contain adequate information about bile salt transporters for medical students?
Authors: Azer Samy A.
Published: May 2004

Several studies have recently highlighted a number of limitations in medical textbooks. The aims of this study were to 1) to assess whether available medical textbooks provided students with adequate information about bile salt transporters, 2) compare the level of detail and the amount of information provided in current textbooks on hepatic transport mechanisms with those available in the literature, and 3) compare the amount of information provided in medical textbooks on hepatocyte transport mechanisms with those involving other transporters e.g., those found in the nephron. Seventy medical textbooks from disciplines including physiology, pathology, cell biology, medicine, pediatrics, pharmacology, pathophysiology, and histology published during the past six years were examined. The literature on bile salt transport has been searched mainly from the Internet (MEDLINE and PubMed). Most textbooks failed to provide any information on transporters found in the basolateral and canalicular membranes of hepatocytes. There are also deficiencies in information on bile salt transporters in the terminal ileum. However, up to the end of 2002, 3,610 articles and reviews had been published on hepatobiliary and enterocyte transport of bile salts. During the same period (from 1965), 10,757 articles had been published on renal transport. Thus the contents of textbooks may reflect the overall volume of research knowledge on renal transport. However, despite our current understanding of hepatic and intestinal transport of bile salts and extensive research, particularly over the past 12 years, there are major deficiencies in textbooks in this area. These findings indicate that there is an imbalance in the contents of current textbooks and a lack of information about hepatobiliary physiology, bile salt transporters, bile formation, and mechanisms underlying cholestasis and drug-induced injury. Authors, editors, and publishers of medical textbooks should consider the need to update the information provided on bile salt transporters.
Two models for an effective undergraduate research experience in physiology and other natural sciences
Authors: Randall David C. , Wilbur Frank H. , Burkholder Timothy J.
Published: May 2004

68A realistic research experience is beneficial to undergraduate students, but it is often difficult for liberal arts colleges to offer this opportunity. We describe two approaches for developing and maintaining an interdisciplinary research program at small colleges. An active and continuing involvement of an individual with extensive research experience is an essential element in both. One model was developed by the faculty of Taylor University, Upland, IN and a research scientist who had retired from a major university to join the Taylor faculty as their first Research Professor. The school’s Science Research Training Program was initially funded by a modest endowment provided by interested alumni and by extramural grants awarded to the Research Professor and to the institution; the program now enjoys significant funding from diverse sources. Taylor is not located near any large research university and consequently supplies all resources required for the experiments and stipends for students pursuing projects full-time during the summer. The second model was developed by the faculty at Asbury College in Wilmore, KY, working with a scientist having a full-time appointment at the University of Kentucky and a part-time appointment at the college. In this approach, Asbury faculty may place their students for a period of training, often during the summer, in a laboratory of a cooperating host faculty at the University of Kentucky or other institution. The host faculty funds the research and pays a stipend to those students who work full-time during the summer. Relationships established between faculty at the College and at the University of Kentucky have been mutually beneficial. The success of both programs is evidenced by the students’ presenting their data at state and national scientific meetings, by their publishing their results in national journals, and by the undergraduate school faculty developing independent research programs.
Structural domains involved in substrate selectivity in two neutral amino acid transporters
Authors: Soragna Andrea , Mari Stefania Anna , Pisani Rossana , Peres Antonio , Castagna Michela , Sacchi V. Franca , Bossi Elena
Published: May 2004

The ability of the two highly homologous Na+/Cl−-dependent neutral amino acid transporters KAAT1 and CAATCH1, cloned from the midgut epithelium of the larva Manduca sexta, to transport different amino acids depends on the cotransported ion, on pH, and on the membrane voltage. Different organic substrates give rise to transport-associated currents with their own characteristics, which are notably distinct between the two proteins. Differences in amplitude, kinetics, and voltage dependence of the transport-associated currents have been observed, as well as different substrate selectivity patterns measured by radioactive amino acid uptake assays. These diversities represent useful tools to investigate the structural determinants involved in the substrate selectivity. To identify these regions, we built four chimeric proteins between the two transporters. These proteins, heterologously expressed in Xenopus laevis oocytes, were analyzed by two-electrode voltage clamp and uptake measurements. Initially, we exchanged the first three domains, obtaining the chimeras C3K9 and K3C9 (where numbers indicate the transmembrane domains and letters represent the original proteins), which showed electrophysiological and [3H]amino acid uptake characteristics resembling those of KAAT1 and CAATCH1, respectively. Subsequent substitution of the last four domains in C3K9 and K3C9 gave the proteins C3K5C4 and K3C5K4, which showed the same behavior as KAAT1 and CAATCH1 in electrophysiological and transport determinations. These results suggest that in KAAT1 and CAATCH1, only the central transmembrane domains (from 4 to 8) of the protein are responsible for substrate selectivity.
Inhibition of NHE-1 Na+/H+ exchanger by natriuretic peptides in ocular nonpigmented ciliary epithelium
Authors: Fidzinski Pawel , Salvador-Silva Mercedes , Choritz Lars , Geibel John , Coca-Prados Miguel
Published: May 2004

The natriuretic peptides (NPs) atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) display hypotensive effects in the mammalian eye by lowering the intraocular pressure (IOP), a function that is mediated by the bilayer ocular ciliary epithelium (CE), in conjunction with the trabecular meshwork. ANP regulates Na+/H+ exchanger (NHE) activity, and inhibitors of NHE have been shown to lower IOP. We examined whether NPs influence the NHE activity of the CE, which is comprised of pigmented (PE) and nonpigmented (NPE) epithelial cells, by directly recording the rate of intracellular pH (pHi) recovery from its inner NPE cell layer. NPs inhibited, in a dose-dependent manner (1–100 nM), the rate of pHi recovery with the order of potency CNP > ANP > BNP, indicative that this inhibition is mediated by the presence of NPR type B receptors. 8-Bromo-cGMP (8-BrcGMP), a nonhydrolyzable analog of cGMP, mimicked NPs in inhibiting the rate of Na+-dependent pHi recovery. In contrast, ethylisopropyl amiloride (EIPA, 100 nM) or amiloride (10 μM) completely abolished the pHi recovery by NHE. 18α-Glycyrrhetinic acid (18α-GA), a gap junction blocker, attenuated the inhibitory effect of CNP on the rate of pHi recovery, suggesting that NHE activity in both cell layers of the CE is coregulated. This interpretation was supported, in part, by the coexpression of NHE-1 isoform mRNA in both NPE and PE cells. The mechanism by which the inhibitory effect of NPs on NHE-1 activity might influence the net solute movement or fluid transport by the bilayer CE remains to be determined.
Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice
Authors: Liu Jun-Li , Coschigano Karen T. , Robertson Katie , Lipsett Mark , Guo Yubin , Kopchick John J. , Kumar Ujendra , Liu Ye Lauren
Published: May 2004

Growth hormone, acting through its receptor (GHR), plays an important role in carbohydrate metabolism and in promoting postnatal growth. GHR gene-deficient (GHR−/−) mice exhibit severe growth retardation and proportionate dwarfism. To assess the physiological relevance of growth hormone actions, GHR−/−mice were used to investigate their phenotype in glucose metabolism and pancreatic islet function. Adult GHR−/−mice exhibited significant reductions in the levels of blood glucose and insulin, as well as insulin mRNA accumulation. Immunohistochemical analysis of pancreatic sections revealed normal distribution of the islets despite a significantly smaller size. The average size of the islets found in GHR−/−mice was only one-third of that in wild-type littermates. Total β-cell mass was reduced 4.5-fold in GHR−/−mice, significantly more than their body size reduction. This reduction in pancreatic islet mass appears to be related to decreases in proliferation and cell growth. GHR−/−mice were different from the human Laron syndrome in serum insulin level, insulin responsiveness, and obesity. We conclude that growth hormone signaling is essential for maintaining pancreatic islet size, stimulating islet hormone production, and maintaining normal insulin sensitivity and glucose homeostasis.
Regulation of rat pituitary cocaine- and amphetamine-regulated transcript (CART) by CRH and glucocorticoids
Authors: Stanley S. A. , Murphy K. G. , Bewick G. A. , Kong W. M. , Opacka-Juffry J. , Gardiner J. V. , Ghatei M. , Small C. J. , Bloom S. R.
Published: May 2004

Cocaine- and amphetamine-regulated transcript (CART) was originally isolated from rat brain, but CART is also synthesized and stored in the anterior pituitary. The localization of pituitary CART and factors regulating its synthesis are largely unknown. The regulation of pituitary CART synthesis and release in response to CRH and glucocorticoids was examined in vitro and in vivo. CART immunoreactivity (CART-IR) was released from anterior pituitary segments. This release was increased 15-fold in response to corticotropin-releasing hormone (CRH). Intraperitoneal administration of CRH to rats significantly increased plasma CART-IR. Furthermore, CART-IR content and plasma CART-IR were significantly increased in adrenalectomized rats, and anterior pituitary CART mRNA expression, CART-IR content, and plasma CART-IR were significantly decreased in corticosterone-treated rats. Plasma CART-IR showed a pattern of diurnal variation similar to that of ACTH and corticosterone, and plasma CART-IR was positively correlated with corticosterone. CART-IR was detectable in the medium of the corticotroph cell line AtT-20. Dual in situ hybridization for prepro-CART (ppCART) mRNA expression and immunocytochemistry for ACTH showed localization of ppCART mRNA to a subpopulation of ACTH-immunoreactive cells. These findings demonstrate that pituitary CART expression and release are regulated by CRH and the glucocorticoid environment and that pituitary CART is partly localized to corticotrophs.
Dynamic interaction between airway epithelial cells andStaphylococcus aureus
Authors: da Silva Mauricio C. A. , Zahm Jean-Marie , Gras Delphine , Bajolet Odile , Abely Michel , Hinnrasky Jocelyne , Milliot Magali , de Assis Maria Cristina , Hologne Coralie , Bonnet Noël , Merten Marc , Plotkowski Maria Cristina , Puchelle Edith
Published: May 2004

Staphylococcus aureus is a major cause of pulmonary infection, particularly in cystic fibrosis (CF) patients. However, few aspects of the interplay between S. aureus and host airway epithelial cells have been investigated thus far. We investigated by videomicroscopy the time- and bacterial concentration-dependent (104, 106, and 108CFU/ml) effect of S. aureus on adherence, internalization, and the associated damage of the airway epithelial cells. The balance between the secretion by S. aureus of the α-toxin virulence factor and by the airway cells of the antibacterial secretory leukoproteinase inhibitor (SLPI) was also analyzed. After 1 h of interaction, whatever the initial bacterial concentration, a low percentage of S. aureus (<8%) adhered to airway cells, and no airway epithelial cell damage was observed. In contrast, after 24 h of incubation, more bacteria adhered to airway epithelial cells, internalized bacteria were observed, and a bacterial concentration-dependent effect on airway cell damage was observed. At 24 h, most airway cells incubated with bacteria at 108CFU/ml exhibited a necrotic phenotype. The necrosis was preceded by a transient apoptotic process. In parallel, we observed a time- and bacterial concentration-dependent decrease in SLPI and increase in α-toxin expression. These results suggest that airway cells can defend against S. aureus in the early stages of infection. However, in later phases, there is a marked imbalance between the bactericidal capacity of host cells and bacterial virulence. These findings reinforce the potential importance of S. aureus in the pathogenicity of airway infections, including those observed early in CF patients.
Contractile properties of human placental anchoring villi
Authors: Farley Anne E. , Graham Charles H. , Smith Graeme N.
Published: May 2004

The presence of myofibroblasts arranged parallel to the longitudinal axes of anchoring villi of the placenta has previously been described. Furthermore, it has been suggested that intraplacental blood volume, and hence fetal-maternal oxygen-nutrient exchange, may in part be regulated through the longitudinal contraction of anchoring villi. We demonstrate here that anchoring villi have the ability to contract and relax longitudinally. Anchoring villi from normal term human placentae were dissected and suspended from force-displacement transducers to determine their longitudinal contractility in response to potassium chloride (KCl), Nω-nitro-l-arginine methyl ester (l-NAME) and the nitric oxide donors sodium nitroprusside (SNP) and glyceryl trinitrate (GTN). Treatment with both KCl and l-NAME resulted in up to a 62% and 74% increase, respectively, in longitudinal contraction over resting tone. In contrast, both SNP and GTN caused a dose-dependent relaxation of precontracted villi. Immunohistochemistry of longitudinal sections of villi confirmed the presence of α-actin-containing cells in the extravascular space. Histological staining with hemotoxylin and eosin confirm that the tissue used in these experiments were anchoring villi. These findings suggest that the contraction of anchoring villi may be an important mechanism whereby the placenta may regulate intraplacental volume.
Single muscle fiber contractile properties during a competitive season in male runners
Authors: Harber M. P. , Gallagher P. M. , Creer A. R. , Minchev K. M. , Trappe S. W.
Published: May 2004

The purpose of this investigation was to examine the contractile properties of individual myofibers in response to periodized training periods throughout a collegiate cross-country season in male runners. Muscle biopsies of the gastrocnemius were taken after a summer base training phase (T1), an 8-wk intense training period (T2), and a 4-wk taper phase (T3). Five runners ( n = 5; age = 20 ± 1 yr; wt = 65 ± 4 kg; ht = 178 ± 3 cm) completed all three time points. A total of 328 individual muscle fibers [myosin heavy chain (MHC) I = 66%; MHC IIa = 33%; hybrids = 1%] were isolated and studied at 15°C for their contractile properties. Diameter of MHC I fibers was 3% smaller ( P < 0.05) at T2 compared with T1 and an additional 4% smaller ( P < 0.05) after the taper. Cell size was unaltered in the MHC IIa fibers. MHC I and IIa fiber strength increased 18 and 11% ( P < 0.05), respectively, from T1 to T2. MHC I fibers produced 9% less force ( P < 0.05) after the taper, whereas MHC IIa fibers were 9% stronger ( P < 0.05). Specific tension increased 38 and 26% ( P < 0.05) for MHC I and IIa fibers, respectively, from T1 to T2 and was unchanged with the taper. Maximal shortening velocity ( Vo) of the MHC I fibers decreased 23% ( P < 0.05) from T1 to T2 and 17% ( P < 0.05) from T2 to T3, whereas MHC IIa Vowas unchanged. MHC I peak power decreased 20% ( P < 0.05) from T1 to T2 and 25% ( P < 0.05) from T2 to T3, whereas MHC IIa peak power was unchanged. Power corrected for cell size decreased 15% ( P < 0.05) from T2 to T3 and was 24% ( P < 0.05) lower at T3 compared with T1 for the MHC I fibers only. These data suggest that changes in run training alter myocellular physiology via decreases in fiber size, Vo, and power of MHC I fibers and through increases in force per cross-sectional area of slow- and fast-twitch muscle fibers.
High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism
Authors: Chu Shaoyou , Bohlen H. Glenn
Published: May 2004

Kidney glomeruli are important targets of diabetic nephropathy. We hypothesized a high concentration of glucose could suppress glomerular endothelial nitric oxide synthase (eNOS) by a protein kinase C (PKC) mechanism, as has been found in other tissues. Mouse kidney slices (150–200 μm) were bathed in Hanks' solution with 100 μM l-arginine and exposed to either 5 or 20–30 mM d-glucose. Immunofluorescence identified only eNOS in normal mouse glomeruli. Measurements of glomerular NO concentration with NO-sensitive fluorescent dye (4,5-diaminofluorescein diacetate) using confocal microscopy and NO-sensitive microelectrodes verified that resting glomeruli had active production of NO that was inhibited by NG-nitro-l-arginine methyl ester. High-concentration (20–30 mM) d-glucose inhibited 60–70% of the NO production within 15–30 min; l-glucose at the same concentration did not have any effect. Inhibition of PKC-β with 100 nM ruboxistaurin prevented eNOS suppression in high-glucose media. Activation of PKC with 100 nM phorbol ester also suppressed the glomerular NO concentration. We concluded that eNOS in the renal glomerular capillary endothelial cells is suppressed by activity of PKC at high-glucose concentrations comparable to those in diabetic animals and humans. The consequence is a rapid decline in the generation of NO in the glomerular endothelial cells in the presence of a high concentration of glucose.
Interactive effects of habitual physical activity and calcium intake on bone density in boys and girls
Authors: Rowlands Ann V. , Ingledew David K. , Powell Sarah M. , Eston Roger G.
Published: May 2004

The purpose of this study was to assess the interactive effects of habitual physical activity (total and vigorous intensity) and calcium intake on bone mineral content (BMC) in prepubertal boys and girls. Seventy-six children, aged 8–11 yr, wore accelerometers for up to 7 days to assess activity. Calcium intake was estimated by a 4-day weighted food diary. BMC and areal density (bone mineral density) were measured at the total body, proximal femur, and femoral neck by using dual-energy X-ray absorptiometry. Moderated regression analyses were used to assess the contributions of physical activity (total and vigorous) and calcium intake to BMC, residualized for bone area and body mass. Interactive effects of vigorous activity (≥6 metabolic equivalents) and calcium intake were found at the total body in boys ( b = 2.90 × 10−3) and in girls ( b = 6.58 × 10−3) and at the proximal femur ( b = 9.87 × 10−5) and femoral neck ( b = 2.29 × 10−5; where b is the regression coefficient from final equation) in boys only; residualized BMC was high only if both vigorous activity and calcium intake were high. There were no interactive effects of total activity and calcium intake. This study provides evidence for synergistic action of habitual vigorous activity and calcium intake on bone mass in children. Recommendations for optimizing bone mass should reflect this synergism.
Gender differences in insulin action after a single bout of exercise
Authors: Perreault Leigh , Lavely Jennifer M. , Bergman Bryan C. , Horton Tracy J.
Published: May 2004

Effects of a single exercise bout on insulin action were compared in men ( n = 10) and women ( n = 10). On an exercise day, subjects cycled for 90 min at 85% lactate threshold, whereas on a rest (control) day, they remained semirecumbent. The period of exercise, or rest, was followed by a 3-h hyperinsulinemic-euglycemic clamp (30 mU·m−2·min−1) and indirect calorimetry. Glucose kinetics were measured isotopically by using an infusion of [6,6-2H2]glucose. Glucose infusion rate (GIR) during the clamp on the rest day was not different between the genders. However, GIR on the exercise day was significantly lower in men compared with women ( P = 0.01). This was mainly due to a significantly lower glucose rate of disappearance in men compared with women ( P = 0.05), whereas no differences were observed in the endogenous glucose rate of appearance. Nonprotein respiratory quotient (NPRQ) increased significantly during the clamp from preclamp measurements in men and women on the rest day ( P < 0.01). Exercise abolished the increase in NPRQ seen during the clamp on the rest day and tended to decrease NPRQ in men. Our results indicate the following: 1) exercise abolishes the usual increase in NPRQ observed during a hyperinsulinemic-euglycemic clamp in both genders, 2) men exhibit relatively lower whole body insulin action in the 3–4 h after exercise compared with women, and 3) gender differences in insulin action may be explained by a lower glucose rate of disappearance in the men after acute exercise. Together, these data imply gender differences in insulin action postexercise exist in peripheral tissues and not in liver.
Effects of moderate exercise and oat β-glucan on lung tumor metastases and macrophage antitumor cytotoxicity
Authors: Murphy E. A. , Davis J. M. , Brown A. S. , Carmichael M. D. , Mayer E. P. , Ghaffar A.
Published: May 2004

Both moderate exercise and the soluble fiber β-glucan can have beneficial effects on the initiation and growth of tumors, but the data are limited, and there is no information on their combined effects. This study tested the independent and combined effects of short-term moderate-exercise training and the soluble oat fiber β-glucan (OβG) on the metatastic spread of injected tumor cells and macrophage antitumor cytotoxicity. Male C57BL/6 mice were assigned to one of four groups: exercise (Ex)-H2O, Ex-OβG, control (Con)-H2O, or Con-OβG. OβG was fed in the drinking water for 10 days before tumor administration and death. Exercise consisted of treadmill running (1 h/day) for 6 days. After rest or exercise on the last day of training, syngeneic B16 melanoma cells (2 × 105) were administered via intravenous injection ( n = 8–11 per group). Lungs were removed 14 days later, and tumor foci were counted. Additional mice ( n = 8 per group) were killed, and peritoneal macrophages were assayed for cytotoxicity against the same mouse tumor cell line at various effector-to-target ratios. Both moderate exercise and OβG decreased lung tumor foci and increased macrophage cytotoxicity. However, there were no differences in lung tumor foci and macrophage cytotoxicity between Ex-OβG and either Ex-H2O or Con-OβG. These data suggest that, although not additive in their effects, both short-term moderate-exercise training and consumption of the soluble OβG can decrease the metatastic spread of injected B16 melanoma cells, and these effects may be mediated in part by an increase in macrophage cytotoxicity to B16 melanoma.
Differential modulation by estrogen of α2-adrenergic and I1-imidazoline receptor-mediated hypotension in female rats
Authors: El-Mas Mahmoud M. , Abdel-Rahman Abdel A.
Published: May 2004

We have recently shown that estrogen negatively modulates the hypotensive effect of clonidine (mixed α2-/I1-receptor agonist) in female rats and implicates the cardiovascular autonomic control in this interaction. The present study investigated whether this effect of estrogen involves interaction with α2- and/or I1-receptors. Changes evoked by a single intraperitoneal injection of rilmenidine (600 μg/kg) or α-methyldopa (100 mg/kg), selective I1- and α2-receptor agonists, respectively, in blood pressure, hemodynamic variability, and locomotor activity were assessed in radiotelemetered sham-operated and ovariectomized (Ovx) Sprague-Dawley female rats with or without 12-wk estrogen replacement. Three time domain indexes of hemodynamic variability were employed: the standard deviation of mean arterial pressure as a measure of blood pressure variability and the standard deviation of beat-to-beat intervals (SDRR) and the root mean square of successive differences in R-wave-to-R-wave intervals as measures of heart rate variability. In sham-operated rats, rilmenidine or α-methyldopa elicited similar hypotension that lasted at least 5 h and was associated with reductions in standard deviation of mean arterial pressure. SDRR was reduced only by α-methyldopa. Ovx significantly enhanced the hypotensive response to α-methyldopa, in contrast to no effect on rilmenidine hypotension. The enhanced α-methyldopa hypotension in Ovx rats was paralleled with further reduction in SDRR and a reduced locomotor activity. Estrogen replacement (17β-estradiol subcutaneous pellet, 14.2 μg/day, 12 wk) of Ovx rats restored the hemodynamic and locomotor effects of α-methyldopa to sham-operated levels. These findings suggest that estrogen downregulates α2- but not I1-receptor-mediated hypotension and highlight a role for the cardiac autonomic control in α-methyldopa-estrogen interaction.
Effects of tourniquet-induced ischemia on the release of proopiomelanocortin derivatives determined in peripheral blood plasma
Authors: Matejec Reginald , Schulz Axel , Harbach Heinz-W. , Uhlich Holger , Hempelmann Gunter , Teschemacher Hansjörg
Published: May 2004

Proopiomelanocortin (POMC) is expressed in pituitary, central nervous system, and in a few peripheral tissues. This study addresses the hypothesis that metabolic stressors, such as acidosis, may induce the release of POMC derivatives into the cardiovascular system not only from the pituitary but also from other sites of POMC expression. In our study, we investigated the liberation of POMC derivatives from peripheral tissues under a state of acidosis achieved by tourniquet-induced ischemia, alteration of lactate concentration, and base excess. In eight patients undergoing knee arthroplasty under spinal anesthesia, catheters were inserted into the femoral vein proximally to thigh tourniquet location. Blood was drawn from these catheters 5 min before and 40 s, 5 min, and 10 min after tourniquet deflation to measure plasma concentrations of N-acetyl-β-endorphin immunoreactive material (IRM), β-endorphin IRM, authentic β-endorphin, adrenocorticotropin, lactate, pH, and base excess. In five of eight patients, we found a significant increase of β-endorphin IRM levels 40 s after tourniquet deflation compared with predeflation levels; 5 and 10 min after tourniquet deflation, the β-endorphin IRM levels were below the detection limit. Thus β-endorphin IRM was released from ischemic limb tissues into the cardiovascular system. Only a small part of the determined β-endorphin IRM corresponded to authentic β-endorphin. Forty seconds after tourniquet deflation, the β-endorphin IRM concentration correlated with base excess ( r < 0.71; P < 0.05); no significant correlations were found with pH or lactate levels. Thus it was shown here for the first time that ischemic stress may induce the release of β-endorphin IRM from nonpituitary tissues.
Unilateral Labyrinthectomy Modifies the Membrane Properties of Contralesional Vestibular Neurons
Authors: Beraneck Mathieu , Idoux Erwin , Uno Atsuhiko , Vidal Pierre-Paul , Moore Lee E. , Vibert Nicolas
Published: May 2004

Vestibular compensation after a unilateral labyrinthectomy leads to nearly complete disappearance of the static symptoms triggered by the lesion. However, the dynamic vestibular reflexes associated with head movements remain impaired. Because the contralesional labyrinth plays a prominent role in the generation of these dynamic responses, intracellular recordings of contralesional medial vestibular nucleus neurons (MVNn) were done after 1 mo of compensation. Their firing properties and cell type were characterized at rest, and their response dynamics investigated using step, ramp, and sinusoidal current stimulations. The sensitivity of the contralesional MVNn firing rates to applied current was increased, which, along with increased phase leads, suggests that significant changes in active conductances occurred. We found an increased proportion of the phasic type B neurons relative to the tonic type A neurons in the contralesional MVN. In addition, the remaining contralesional type A MVNn response dynamics tended to approach those of type B MVNn. Thus the contralesional MVNn in general showed more phasic response dynamics than those of control MVNn. Altogether, the firing properties of MVNn are differentially modified on the ipsilesional and contralesional sides of the brain stem 1 mo after unilateral labyrinthectomy. Ipsilesional MVNn acquire more “type A–like” tonic membrane properties, which would contribute to the stabilization of the spontaneous activity that recovers in the deafferented neurons during vestibular compensation. The bilateral increase in the sensitivity of MVNn and the acquisition of more “B-like” phasic membrane properties by contralesional MVNn should promote the restoration of the vestibular reflexes generated by the remaining, contralesional labyrinth.
Relative Distribution of Ca2+Channels at the Crayfish Inhibitory Neuromuscular Junction
Authors: Allana Tariq N. , Lin Jen-Wei
Published: May 2004

We investigated the Ca2+channel-synaptic vesicle topography at the inhibitor of the crayfish ( Procambarus Clarkii) neuromuscular junction (NMJ) by analyzing the effect of different modes of Ca2+channel block on transmitter release. Initial identification of Ca2+channels revealed the presence of two classes, P and non-P-type with P-type channels governing ∼70% of the total Ca2+influx. The remaining Ca2+influx was completely blocked by Cd2+but not by saturating concentrations of ω-conotoxins MVIIC and GVIA, or nifedipine and SNX-482. To examine the relative spatial distribution of Ca2+channels with respect to synaptic vesicles, we compared changes in inhibitory postsynaptic current amplitude and synaptic delay resulting from different spatial profiles of [Ca2+]iaround release sites. Specifically, addition of either [Mg2+]o, which decreases single-channel current, or ω-Aga IVA, which completely blocks P-type channels, prolonged synaptic delay by a similar amount when Ca2+influx block was <40%. Because non-P-type channels are able to compensate for blocked P-type channels, it suggests that these channels overlap considerably in their distribution. However, when Ca2+influx was blocked by ∼50%, ω-Aga IVA increased delay significantly more than Mg2+, suggesting that P-type channels are located closer than non-P-type channels to synaptic vesicles. This distribution of Ca2+channels was further supported by the observations that non-P-type channels are unable to trigger release in physiological saline and EGTA preferentially prolongs synaptic delay dominated by non-P-type channels when transmitter release is evoked with broad action potentials. We therefore conclude that although non-P-type channels do not directly trigger release under physiological conditions, their distribution partially overlaps with P-type channels.
Somatosensory Corticothalamic Projections: Distinguishing Drivers From Modulators
Authors: Reichova Iva , Sherman S. Murray
Published: May 2004

We used a juvenile mouse thalamocortical slice preparation with whole cell recording to investigate synaptic properties of corticothalamic inputs from somatosensory cortex to the ventral posterior medial and posterior medial nuclei (98 cells). We compared these data to those obtained from activating retinal and cortical inputs to the lateral geniculate nucleus (8 cells), the former representing a prototypical driver input and the latter, a typical modulator. Retinogeniculate activation evoked large, all-or-none excitatory postsynaptic potentials (EPSPs) that showed paired-pulse depression antagonized by N-methyl-d-aspartate (NMDA) and AMPA receptor blockers but with no sign of a metabotropic glutamate receptor (mGluR) component. Corticogeniculate activation evoked small, graded EPSPs showing paired-pulse facilitation, and the EPSPs showed both NMDA and AMPA receptor component plus an mGluR1 component. In the somatosensory thalamic relays, cortical stimulation elicited glutamatergic EPSPs in all thalamic cells, and these EPSPs fell into two groups. One, elicited from cortical layer 6 to cells of both nuclei, involved small, graded EPSPs with paired-pulse facilitation, and most also showed an mGluR1 component. The other, elicited from layer 5 to cells only of the posterior medial nucleus, involved large, all-or-none EPSPs with paired-pulse depression, and none showed an mGluR component. By analogy with results from the lateral geniculate nucleus, we conclude that the input from layer 6 to both nuclei acts as a modulator but that the layer 5 input to the posterior medial nucleus serves as a driver. Our data extend a common organizing principle from first-order nuclei to higher-order thalamic relays and further implicate the latter in corticocortical communication.
Fast Inhibition Alters First Spike Timing in Auditory Brainstem Neurons
Authors: Paolini Antonio G. , Clarey Janine C. , Needham Karina , Clark Graeme M.
Published: May 2004

Within the first processing site of the central auditory pathway, inhibitory neurons (D stellate cells) broadly tuned to tonal frequency project on narrowly tuned, excitatory output neurons (T stellate cells). The latter is thought to provide a topographic representation of sound spectrum, whereas the former is thought to provide lateral inhibition that improves spectral contrast, particularly in noise. In response to pure tones, the overall discharge rate in T stellate cells is unlikely to be suppressed dramatically by D stellate cells because they respond primarily to stimulus onset and provide fast, short-duration inhibition. In vivo intracellular recordings from the ventral cochlear nucleus (VCN) showed that, when tones were presented above or below the characteristic frequency (CF) of a T stellate neuron, they were inhibited during depolarization. This resulted in a delay in the initial action potential produced by T stellate cells. This ability of fast inhibition to alter the first spike timing of a T stellate neuron was confirmed by electrically activating the D stellate cell pathway that arises in the contralateral cochlear nucleus. Delay was also induced when two tones were presented: one at CF and one outside the frequency response area of the T stellate neuron. These findings suggest that the traditional view of lateral inhibition within the VCN should incorporate delay as one of its principle outcomes.
Conserved and muscle-group-specific gene expression patterns shape postnatal development of the novel extraocular muscle phenotype
Authors: Cheng Georgiana , Merriam Anita P. , Gong Bendi , Leahy Patrick , Khanna Sangeeta , Porter John D.
Published: May 2004

Current models in skeletal muscle biology do not fully account for the breadth, causes, and consequences of phenotypic variation among skeletal muscle groups. The muscle allotype concept arose to explain frank differences between limb, masticatory, and extraocular (EOM) muscles, but there is little understanding of the developmental regulation of the skeletal muscle phenotypic range. Here, we used morphological and DNA microarray analyses to generate a comprehensive temporal profile for rat EOM development. Based upon coordinate regulation of morphologic/gene expression traits with key events in visual, vestibular, and oculomotor system development, we propose a model that the EOM phenotype is a consequence of extrinsic factors that are unique to its local environment and sensory-motor control system, acting upon a novel myoblast lineage. We identified a broad spectrum of differences between the postnatal transcriptional patterns of EOM and limb muscle allotypes, including numerous transcripts not traditionally associated with muscle fiber/group differences. Several transcription factors were differentially regulated and may be responsible for signaling muscle allotype specificity. Significant differences in cellular energetic mechanisms defined the EOM and limb allotypes. The allotypes were divergent in many other functional transcript classes that remain to be further explored. Taken together, we suggest that the EOM allotype is the consequence of tissue-specific mechanisms that direct expression of a limited number of EOM-specific transcripts and broader, incremental differences in transcripts that are conserved by the two allotypes. This represents an important first step in dissecting allotype-specific regulatory mechanisms that may, in turn, explain differential muscle group sensitivity to a variety of metabolic and neuromuscular diseases.
Protein C Levels Are Regulated by a Quantitative Trait Locus on Chromosome 16
Authors: Buil Alfonso , Soria José Manuel , Souto Juan Carlos , Almasy Laura , Lathrop Mark , Blangero John , Fontcuberta Jordi
Published: May 2004

Objective—

Protein C (PC) is a component of the protein C anticoagulant pathway. PC deficiency is a risk factor associated with venous thromboembolism. As part of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project, we conducted a genome-wide linkage scan to localize genes that influence variation in PC plasma levels.

Methods and Results—

PC levels were measured in 398 individuals belonging to 21 Spanish families. A total of 485 DNA microsatellite markers were genotyped to provide a 7.1-cM genetic map. Variance component linkage methods were used to evaluate linkage and to detect quantitative trait loci (QTL). A region on chromosome 16 (16q23), flanked by markers D16S3106 and D16S516, showed strong evidence of linkage with PC levels (LOD=3.69). This region contains 1 positional candidate gene, the
NAD(P)H:dehydrogenase quinone 1
(
NQO1
), involved in vitamin K metabolism. The association of 1 SNP of this gene with PC levels (
P
=0.005) strongly supports the implication of
NQO1
gene in the variability of PC levels.

Conclusions—

These results illustrate the application of genomic scans to identify the genetic determinants of quantitative variation in a component of the hemostatic pathways. They provide strong evidence for a locus (QTL) on chromosome 16 that influences PC levels.
Double-Blind, Randomized Controlled Trial on the Effect of Leukocyte-Depleted Erythrocyte Transfusions in Cardiac Valve Surgery
Authors: Bilgin Y.M. , van de Watering L.M.G. , Eijsman L. , Versteegh M.I.M. , Brand R. , van Oers M.H.J. , Brand A.
Published: May 2004

Background—

Leukocytes in allogeneic blood transfusions are believed to be the cause of immunomodulatory events. A few trials on leukocyte removal from transfusions in cardiac surgery have been conducted, and they showed inconclusive results. We found in a previous study a decrease in mortality rates and number of infections in a subgroup of more heavily transfused patients.

Methods and Results—

Patients (n=496) undergoing valve surgery (with or without CABG) were randomly assigned in a double-blind fashion to receive standard buffy coat–depleted (PC) or prestorage, by filtration, leukocyte-depleted erythrocytes (LD). The primary end point was mortality at 90 days, and secondary end points were in-hospital mortality, multiple organ dysfunction syndrome, infections, intensive care unit stay, and hospital stay. The difference in mortality at 90 days was not significant (PC 12.7% versus LD 8.4%; odds ratio [OR], 1.52; 95% confidence interval [CI], 0.84 to 2.73). The in-hospital mortality rate was almost twice as high in the PC group (10.1% versus 5.5% in the LD group; OR, 1.99; 95% CI, 0.99 to 4.00). The incidence of multiple organ dysfunction syndrome in both groups was similar, although more patients with multiple organ dysfunction syndrome died in the PC group. LD was associated with a significantly reduced infection rate (PC 31.6% versus LD 21.6%; OR, 1.64; 95% CI, 1.08 to 2.49). In both groups, intensive care unit stay and hospital stay were similar, and postoperative complications increased with the number of transfused units.

Conclusions—

Mortality at 90 days was not significantly different; however, a beneficial effect of LD in valve surgery was found for the secondary end points of in-hospital mortality and infections.
Ethnic Differences in the Vasoconstrictor Activity of Endogenous Endothelin-1 in Hypertensive Patients
Authors: Campia Umberto , Cardillo Carmine , Panza Julio A.
Published: May 2004

Background—

The pathogenesis of essential hypertension in blacks may differ from that in whites. In particular, black patients usually present with a salt-sensitive, low-renin form, which in animal models is associated with enhanced activity of endothelin-1 (ET-1). This study aimed to assess whether ethnic differences exist in the vascular activity of ET-1 in normotensive and hypertensive blacks and whites.

Methods and Results—

Forearm blood flow (FBF) responses to intraarterial infusion of an ET
A
receptor blocker (BQ-123) were analyzed by plethysmography in 37 normotensive patients and 27 hypertensive patients according to race. BQ-123 did not affect FBF in normotensive subjects (
P
=0.30), whereas it produced significant vasodilation in hypertensive subjects (
P
<0.001). In normotensives, FBF response to BQ-123 was similar in white (n =22) and black (n =15) patients (
P
=0.85). In contrast, in hypertensive patients, the vasodilator effect of ET
A
receptor blockade was significantly higher in blacks (n =13) than in whites (n =14) (
P
=0.01). To rule out differences in smooth muscle reactivity, the effects of race on FBF responses to exogenous ET-1 were analyzed in the hypertensive subgroups. Endothelin-1 induced a significant vasoconstriction in both white (n =7) and black patients (n =5) (both
P
<0.001), without differences between them (
P
=0.46). In 8 black hypertensives, the response to selective ET
A
blockade was not modified by nonselective blockade of ET-1 receptors by co-infusion of BQ-123 and BQ-788 (
P
=0.66).

Conclusions—

Hypertensive blacks have enhanced ET
A
-dependent vasoconstrictor tone, probably related to increased production of ET-1. Given the negative vascular effects of ET-1, this abnormality may contribute to the pathogenesis of hypertension and its complications in black patients.
Electrical and Mechanical Components of Dyssynchrony in Heart Failure Patients With Normal QRS Duration and Left Bundle-Branch Block
Authors: Turner Mark S. , Bleasdale Rob A. , Vinereanu Dragos , Mumford Catherine E. , Paul Vince , Fraser Alan G. , Frenneaux Michael P.
Published: May 2004

Background—

Resynchronization pacing is an effective symptomatic treatment for heart failure patients with prolongation of the QRS duration (QRSd). Dyssynchronous contraction of the left ventricle is also observed with normal QRSd. We set out to determine how electrical activation of the left ventricular (LV) free wall differed between patients with left bundle-branch block (LBBB) and normal QRSd and if synchrony improved during pacing in patients with normal QRSd.

Methods and Results—

Twenty-two patients were implanted with resynchronization pacemakers, 13 with LBBB (mean QRS, 171 ms) and 9 with normal QRSd <120 ms (mean, 100 ms). LV lead electrograms and surface ECGs in sinus rhythm (unpaced) were recorded. Conventional and tissue Doppler echocardiography were performed without pacing, with LV and biventricular pacing at optimal atrioventricular delay. Lead electrograms from the LV free wall were later in the LBBB patients in absolute terms (155 ms [SD 23] versus 65.5 ms [SD 25];
P
=0.05) and also relative to the surface QRS (90.5% [SD 8] versus 65.5% [SD 24]). Improved synchrony of the left and right ventricles (interventricular synchrony) and of the LV myocardial segments (intraventricular synchrony) was observed for patients with LBBB and normal QRSd. Baseline LV synchrony correlated with timing of LV free-wall electrical activation. Improved intraventricular synchrony during pacing also correlated with LV free-wall electrical activation time.

Conclusions—

Resynchronization of systole can be achieved for patients with normal QRSd and LBBB during biventricular and LV pacing. The timing of LV free-wall electrical activation correlated with the improvement in synchrony.
Persistent Lowering of Pressure by Transplanting Kidneys From Adult Spontaneously Hypertensive Rats Treated With Brief Antihypertensive Therapy
Authors: Smallegange Corry , Hale Taben M. , Bushfield Terri L. , Adams Michael A.
Published: May 2004

Kidney function is critical in determining the level of arterial pressure and in the pathogenesis of hypertension. Important evidence comes from studies in which the level of blood pressure is dictated by the donor when kidneys are transplanted between genetically hypertensive and normotensive rats. We have hypothesized that pharmacotherapy modifies specific properties of the kidney, particularly the vasculature, such that after kidney transplantation, there are persistent changes in the level of arterial pressure. Consistent with previous studies, a 2-week aggressive treatment of adult (15 weeks) spontaneously hypertensive rats with an angiotensin-converting enzyme inhibitor (enalapril) combined with a low-salt diet induced a persistent change in the kidney and a decrease in arterial pressure (18%). These persistent changes in arterial pressure could be completely transferred to untreated adult spontaneously hypertensive rats by kidney transplantation (ie, pressure in untreated rats was decreased after transplantation of a kidney donated from a previously treated rat). Further, the importance of kidney-specific changes was demonstrated by finding that the treatment-induced lowering of arterial pressure was completely reversed by transferring an untreated kidney into a previously treated rat. The specific treatment-induced changes to the kidney included a decrease in structurally based renal vascular resistance that was similar to the persistent lowering of arterial pressure. These data provide evidence for a link between the treatment-induced changes in kidney vascular structure and the persistent lowering of arterial pressure. The findings also suggest that a key pharmacotherapeutic target in hypertension should be kidney-specific changes, such as renal vascular structure.