bluuebunny/crossref_metadata_2025 huggingface dataset:
TRANSCENDENCE OF SPECIAL VALUES OF POCHHAMMER FUNCTIONS
Authors: TRETKOFF MARVIN D. , TRETKOFF PAULA
Published: June 2009

In this paper, we examine the set of algebraic numbers at which higher order hypergeometric functions take algebraic values. In particular, we deduce criteria for this set to be finite and for it to be infinite.
Diabetes mellitus and expression of the enterocyte renin-angiotensin system: implications for control of glucose transport across the brush border membrane
Authors: Wong Tung Po , Debnam Edward S. , Leung Po Sing
Published: June 2009

Streptozotocin-induced (Type 1) diabetes mellitus (T1DM) in rats promotes jejunal glucose transport, but the trigger for this response remains unclear. Our recent work using euglycemic rats has implicated the enterocyte renin-angiotensin system (RAS) in control of sodium-dependent glucose transporter (SGLT1)-mediated glucose uptake across the jejunal brush border membrane (BBM). The aim of the present study was to examine whether expression of enterocyte RAS components is influenced by T1DM. The effects of mucosal addition of angiotensin II (AII) on [14C]-d-glucose uptake by everted diabetic jejunum was also determined. Two-week diabetes caused a fivefold increase in blood glucose level and reduced mRNA and protein expression of AII type 1 (AT1) and AT2 receptors and angiotensin-converting enzyme in isolated jejunal enterocytes. Angiotensinogen expression was, however, stimulated by diabetes while renin was not detected in either control or diabetic enterocytes. Diabetes stimulated glucose uptake into everted jejunum by 58% and increased the BBM expression of SGLT1 and facilitated glucose transporter 2 (GLUT2) proteins, determined by Western blotting by 25% and 135%, respectively. Immunohistochemistry confirmed an enhanced BBM expression of GLUT2 in diabetes and also showed that this was due to translocation of the transporter from the basolateral membrane to BBM. AII (5 μM) or L-162313 (1 μM), a nonpeptide AII analog, decreased glucose uptake by 18% and 24%, respectively, in diabetic jejunum. This inhibitory action was fully accountable by an action on SGLT1-mediated transport and was abolished by the AT1 receptor antagonist losartan (1 μM). The decreased inhibitory action of AII on in vitro jejunal glucose uptake in diabetes compared with that noted previously in jejunum from normal animals is likely to be due to reduced RAS expression in diabetic enterocytes, together with a disproportionate increase in GLUT2, compared with SGLT1 expression at the BBM.
Genistein stimulates electrogenic Cl− secretion via phosphodiesterase modulation in the mouse jejunum
Authors: Chao Pin-Chun , Hamilton Kirk L.
Published: June 2009

Previously, we demonstrated that genistein stimulated Cl− secretion in the mouse jejunum (Baker MJ and Hamilton KL, Am J Physiol Cell Physiol 287: C1636–C1645, 2004); however, the mode of action of genistein still remains unclear. Here, we examined the activation of Cl− secretion by the modulation of phosphodiesterases (PDEs) by genistein (75 μM) in the mouse jejunum with the Ussing short-circuit current ( Isc) technique. Drugs tested included theophylline (10 mM), a nonspecific PDE inhibitor; 8-methoxymethyl-3-isobutyl-1-methylxanthine (8-MM-IBMX; 100 μM), erythro-9-(2-hydroxyl-3-nonyl)-adenine (EHNA; 40 μM), milrinone (100 μM), and rolipram (40 and 100 μM), which are specific inhibitors of PDE1–PDE4, respectively. Theophylline stimulated a bumetanide-sensitive Isc, indicative of Cl− secretion, and abolished genistein's stimulatory action on Isc. Neither 8-MM-IBMX nor EHNA altered the basal Isc nor did these PDE inhibitors affect the stimulatory action of genistein on the Isc of the mouse jejunum. Rolipram had no effect on basal Isc, but it reduced the genistein-stimulated Isc compared with time-matched control tissues. Milrinone stimulated a concentration-dependent increase in Isc. Bumetanide (10 μM) inhibited 60 ± 4% of milrinone-induced Isc. Pretreating tissues with milrinone prevented genistein from stimulating Isc, and pretreatment with genistein reduced the effect of milrinone on Isc. H89 (50 μM), a PKA inhibitor, reduced the milrinone-stimulated Isc. Likewise, H89 reduced the genistein-stimulated Isc. Here, we demonstrate, for the first time, that genistein activates Cl− secretion of the mouse jejunum via inhibition of a PDE3-dependent pathway.
Uric acid attenuates trophoblast invasion and integration into endothelial cell monolayers
Authors: Bainbridge Shannon A. , Roberts James M. , von Versen-Höynck Frauke , Koch Jessa , Edmunds Lia , Hubel Carl A.
Published: June 2009

Hyperuricemia develops as early as 10 wk of gestation in women who later develop preeclampsia. At this time the invasive trophoblast cells are actively remodeling the uterine spiral arterioles, integrating into and finally replacing the vascular endothelial lining. In the nonpregnant population uric acid has several pathogenic effects on vascular endothelium. We therefore sought to examine the effects of uric acid (0–7 mg/dl) on trophoblast cell invasion through an extracellular matrix using an in vitro Matrigel invasion assay. We also assessed trophoblast integration into a uterine microvascular endothelial cell monolayer in a trophoblast-endothelial cell coculture model. Additionally, we addressed the importance of redox signaling and trophoblast-induced endothelial cell apoptosis. Uric acid elicited a concentration-dependent attenuation of trophoblast invasion and integration into a uterine microvascular endothelial cell monolayer. The attenuated trophoblast integration appeared to be the result of reduced trophoblast-induced endothelial cell apoptosis, likely through the intracellular antioxidant actions of uric acid. In a test of relevance, pooled serum (5% vol/vol) from preeclamptic women attenuated the ability of trophoblast cells to integrate into the endothelial cell monolayers compared with pooled serum from healthy pregnant controls, and this response was partially rescued when endogenous uric acid was previously removed with uricase. Taken together these data support the hypothesis that elevations in circulating uric acid in preeclamptic women contribute to the pathogenesis of the disorder, in part, through attenuation of normal trophoblast invasion and spiral artery vascular remodeling.
Amino acids in the rat intestinal lumen regulate their own absorption from a distant intestinal site
Authors: Mourad Fadi H. , Barada Kassem A. , Khoury Carmen , Hamdi Tamim , Saadé Nayef E. , Nassar Camille F.
Published: June 2009

Intestinal nutrient transport is altered in response to changes in dietary conditions and luminal substrate level. It is not clear, however, whether an amino acid in the intestinal lumen can acutely affect its own absorption from a distant site. Our aim is to study the effect of an amino acid present in rat small intestinal segment on its own absorption from a proximal or distal site and elucidate the underlying mechanisms. The effect of instillation of alanine (Ala) in either jejunum or ileum on its own absorption at ileal or jejunal level was examined in vivo. The modulation of this intestinal regulatory loop by the following interventions was studied: tetrodotoxin (TTX) added to Ala, subdiaphragmatic vagotomy, chemical ablation of capsaicin-sensitive primary afferent (CSPA) fibers, and IV administration of calcitonin gene-related peptide (CGRP) antagonist. In addition, the kinetics of jejunal Ala absorption and the importance of Na+-dependent transport were studied in vitro after instilling Ala in the ileum. Basal jejunal Ala absorption [0.198 ± 0.018 μmol·cm−1·20 min−1 (means ± SD)] was significantly decreased with the instillation of 20 mM Ala in the ileum or in an adjacent distal jejunal segment (0.12 ± 0.015; P < 0.0001 and 0.138 ± 0.014; P < 0.002, respectively). Comparable inhibition was observed in the presence of proline in the ileum. Moreover, basal Ala absorption from the ileum (0.169 ± 0.025) was significantly decreased by the presence of 20 mM Ala in the jejunum (0.103 ± 0.027; P < 0.01). The inhibitory effect on jejunal Ala absorption was abolished by TTX, subdiaphragmatic vagotomy, neonatal capsaicin treatment, and CGRP antagonism. In vitro studies showed that Ala in the ileum affects Na+-mediated transport and increases Km without affecting Vmax. Intraluminal amino acids control their own absorption from a distant part of the intestine, by affecting the affinity of the Na+-mediated Ala transporter, through a neuronal mechanism that involves CSPA and CGRP.
Trans fat feeding results in higher serum alanine aminotransferase and increased insulin resistance compared with a standard murine high-fat diet
Authors: Koppe Sean W. P. , Elias Marc , Moseley Richard H. , Green Richard M.
Published: June 2009

Diets high in trans fats are associated with an increased risk of cardiovascular disease and components of the metabolic syndrome. The influence of these toxic fatty acids on the development of nonalcoholic fatty liver disease has not been significantly examined. Therefore, we sought to compare the effect of a murine diet high in trans fat to a standard high-fat diet that is devoid of trans fats but high in saturated fats. Male AKR/J mice were fed a calorically identical trans fat diet or standard high-fat diet for 10 days, 4 wk, and 8 wk. Serum alanine aminotransferase (ALT), lipid, insulin, and leptin levels were determined and the quantitative insulin-sensitivity check index (QUICKI) was calculated as a measure of insulin resistance. Additionally, hepatic triglyceride content and gene expression of several proinflammatory genes were assessed. By 8 wk, trans fat-fed mice exhibited higher ALT values than standard high-fat-fed mice (126 ± 16 vs. 71 ± 7 U/l, P < 0.02) despite similar hepatic triglyceride content at each time point. Trans fat-fed mice also had increased insulin resistance compared with high-fat-fed mice at 4 and 8 wk with significantly higher insulin levels and lower QUICKI values. Additionally, hepatic interleukin-1β (IL-1β) gene expression was 3.6-fold higher at 4 wk ( P < 0.05) and 5-fold higher at 8 wk ( P < 0.05) in trans fat-fed mice compared with standard high-fat-fed mice. Trans fat feeding results in higher ALT values, increased insulin resistance, and elevated IL-1β levels compared with standard high-fat feeding.
Repeated binge access to a palatable food alters feeding behavior, hormone profile, and hindbrain c-Fos responses to a test meal in adult male rats
Authors: Bello Nicholas T. , Guarda Angela S. , Terrillion Chantelle E. , Redgrave Graham W. , Coughlin Janelle W. , Moran Timothy H.
Published: June 2009

Repetitive cycles of palatable food access and chronic calorie restriction alter feeding behaviors and forebrain neural systems. The purpose of this study was to determine the behavioral, endocrine, and meal-related hindbrain neural activation in adult male Sprague-Dawley rats exposed to a binge-access feeding schedule. The binge-access schedule consisted of repeated twice-per-week episodes of acute calorie restriction (to one-third of the previous day's intake) followed by 2 h of concurrent access to high-calorie palatable food (sweetened fat: 90% vegetable shortening-10% sucrose) and chow. The binge-access rats consumed more calories during the “binge” period than rats with continuous access to sweetened fat (continuous-access group) or subjected to repeated acute calorie restriction only (chow-restricted group). The binge-access group also exhibited a ∼25% increase in sweetened fat intake from week 1 to week 6. Persistence of the binge phenotype in the binge-access animals was demonstrated 2 wk, but not 4 wk, after ad libitum chow. The binge-access and chow-restricted groups maintained a similar normal body composition and hormonal profiles, whereas the continuous-access animals developed an obese phenotype. Terminal ghrelin levels were significantly higher in the binge-access group than in the continuous-access group. Consumption of a standardized meal resulted in more c-Fos-positive cells along the anterior-posterior nucleus of the solitary tract regions in the binge-access group than in naive controls. These results suggest that repeated cycles of acute calorie restriction followed by palatable food produce physiological alterations that may facilitate overconsumption of a highly palatable food during limited-access periods.
Sweetness and bitterness taste of meals per se does not mediate gastric emptying in humans
Authors: Little Tanya J. , Gupta Nili , Case R. Maynard , Thompson David G. , McLaughlin John T.
Published: June 2009

In cell line and animal models, sweet and bitter tastants induce secretion of signaling peptides (e.g., glucagon-like peptide-1 and cholecystokinin) and slow gastric emptying (GE). Whether human GE and appetite responses are regulated by the sweetness or bitterness per se of ingested food is, however, unknown. We aimed to determine whether intragastric infusion of “equisweet” ( Study A) or “equibitter” ( Study B) solutions slow GE to the same extent, and whether a glucose solution made sweeter by the addition of saccharin will slow GE more potently than glucose alone. Healthy nonobese subjects were studied in a single-blind, randomized fashion. Subjects received 500-ml intragastric infusions of predetermined equisweet solutions of glucose (560 mosmol/kgH2O), fructose (290 mosmol/kgH2O), aspartame (200 mg), and saccharin (50 mg); twice as sweet glucose + saccharin, water (volumetric control) ( Study A); or equibitter solutions of quinine (0.198 mM), naringin (1 mM), or water ( Study B). GE was evaluated using a [13C]acetate breath test, and hunger and fullness were scored using visual analog scales. In Study A, equisweet solutions did not empty similarly. Fructose, aspartame, and saccharin did not slow GE compared with water, but glucose did ( P < 0.05). There was no additional effect of the sweeter glucose + saccharin solution ( P > 0.05, compared with glucose alone). In Study B, neither bitter tastant slowed GE compared with water. None of the solutions modulated perceptions of hunger or fullness. We conclude that, in humans, the presence of sweetness and bitterness taste per se in ingested solutions does not appear to signal to influence GE or appetite perceptions.
Altered skeletal muscle insulin signaling and mitochondrial complex II-III linked activity in adult offspring of obese mice
Authors: Shelley Piran , Martin-Gronert Malgorzata S. , Rowlerson Anthea , Poston Lucilla , Heales S. J. R. , Hargreaves Iain P. , McConnell Josie M. , Ozanne Susan E. , Fernandez-Twinn Denise S.
Published: June 2009

We recently reported insulin resistance in adult offspring of obese C57BL/6J mice. We have now evaluated whether parameters of skeletal muscle structure and function may play a role in insulin resistance in this model of developmental programming. Obesity was induced in female mice by feeding a highly palatable sugar and fat-rich diet for 6 wk prior to pregnancy, and during pregnancy and lactation. Offspring of obese dams were weaned onto standard laboratory chow. At 3 mo of age, skeletal muscle insulin signaling protein expression, mitochondrial electron transport chain activity (ETC), muscle fiber type, fiber density, and fiber cross-sectional area were compared with that of offspring of control dams weaned onto the chow diet. Female offspring of obese dams demonstrated decreased skeletal muscle expression of p110β, the catalytic subunit of PI3K ( P < 0.01), as well as reduced Akt phosphorylation at Serine residue 473 compared with control offspring. Male offspring of obese dams demonstrated increased skeletal muscle Akt2 and PKCζ expression ( P < 0.01; P < 0.001, respectively). A decrease in mitochondrial-linked complex II-III was observed in male offspring of obese dams ( P < 0.01), which was unrelated to CoQ deficiency. This was not observed in females. There were no differences in muscle fiber density between offspring of obese dams and control offspring in either sex. Sex-related alterations in key insulin-signaling proteins and in mitochondrial ETC may contribute to a state of insulin resistance in offspring of obese mice.
Sex-specific alterations in placental 11β-hydroxysteroid dehydrogenase 2 activity and early postnatal clinical course following antenatal betamethasone
Authors: Stark Michael J. , Wright Ian M. R. , Clifton Vicki L.
Published: June 2009

Placental 11β-hydroxysteroid dehydrogenase-2 (11βHSD2) limits fetal glucocorticoid exposure and is associated with physiological stability in the premature newborn infant. Antenatal betamethasone alters 11βHSD2 activity and confers sex-specific advantages in neonatal outcome. We investigated the influence of betamethasone and sex on 11βHSD2 activity, neonatal adrenal function and clinical course in 24- to 36-wk gestation neonates from birth to day 5 of life. Univariate analyses demonstrated an interaction between timing of betamethasone exposure and sex for 11βHSD2 activity rate ( P = 0.02) and umbilical arterial cortisol ( P = 0.01). For infants born < 72 h following antenatal betamethasone, females had higher 11βHSD2 activity ( P < 0.01) and umbilical arterial cortisol ( P = 0.01) than males. Females born < 72 h of betamethasone exposure had higher day 1 urinary cortisol, if exposed to perinatal stress, than males ( P < 0.01). For infants born < 72 h after betamethasone exposure, 11βHSD2 activity was negatively correlated with Clinical Illness Severity Score score ( r = −0.79 P = 0.01) and positively correlated with mean arterial blood pressure ( r = 0.8 P = 0.01) only in females. Sex-specific placental 11BHSD2 autoregulation following antenatal betamethasone exposure may limit adrenal suppression in females influencing physiological stability following preterm birth. A lack of adjustment in 11βHSD2 and adrenal response may contribute to the increased incidence of poor outcome observed in preterm males.
Characteristics and mechanisms of hypothalamic neuronal fatty acid sensing
Authors: Le Foll Christelle , Irani Boman G. , Magnan Christophe , Dunn-Meynell Ambrose A. , Levin Barry E.
Published: June 2009

We assessed the mechanisms by which specialized hypothalamic ventromedial nucleus (VMN) neurons utilize both glucose and long-chain fatty acids as signaling molecules to alter their activity as a potential means of regulating energy homeostasis. Fura-2 calcium (Ca2+) and membrane potential dye imaging, together with pharmacological agents, were used to assess the mechanisms by which oleic acid (OA) alters the activity of dissociated VMN neurons from 3- to 4-wk-old rats. OA excited up to 43% and inhibited up to 29% of all VMN neurons independently of glucose concentrations. In those neurons excited by both 2.5 mM glucose and OA, OA had a concentration-dependent effective excitatory concentration (EC50) of 13.1 nM. Neurons inhibited by both 2.5 mM glucose and OA had an effective inhibitory concentration (IC50) of 93 nM. At 0.5 mM glucose, OA had markedly different effects on these same neurons. Inhibition of carnitine palmitoyltransferase, reactive oxygen species formation, long-chain acetyl-CoA synthetase and ATP-sensitive K+channel activity or activation of uncoupling protein 2 (UCP2) accounted for only ∼20% of OA's excitatory effects and ∼40% of its inhibitory effects. Inhibition of CD36, a fatty acid transporter that can alter cell function independently of intracellular fatty acid metabolism, reduced the effects of OA by up to 45%. Thus OA affects VMN neuronal activity through multiple pathways. In glucosensing neurons, its effects are glucose dependent. This glucose-OA interaction provides a potential mechanism whereby such “metabolic sensing” neurons can respond to differences in the metabolic states associated with fasting and feeding.
Mechanisms of coronary microvascular adaptation to obesity
Authors: Bagi Zsolt
Published: June 2009

The metabolic syndrome (MetS) is associated with clustering of cardiovascular risk factors in individuals that may greatly increase their risk of developing coronary artery disease. Obesity and related metabolic dysfunction are the driving forces in the prevalence of MetS. It is believed that obesity has detrimental effects on cardiovascular function, but its overall impact on the vasomotor regulation of small coronary arteries is still debated. Emerging evidence indicates that in obesity coronary arteries adapt to hemodynamic changes via maintaining and/or upregulating cellular mechanism(s) intrinsic to the vascular wall. Among other factors, endothelial production of cyclooxygenase-2-derived prostacyclin and reactive oxygen species, as well as increased nitric oxide sensitivity and potassium channel activation in smooth muscle cells, have been implicated in maintaining coronary vasodilator function. This review aims to examine studies that have been primarily focused on alterations in coronary vasodilator function in obesity. A better understanding of cellular mechanisms that may contribute to coronary microvascular adaptation may provide insight into the sequence of pathological events in obesity and may allow the harnessing of these effects for therapeutic purposes.
Impairment of coronary endothelial cell ETB receptor function after short-term inhalation exposure to whole diesel emissions
Authors: Cherng Tom W. , Campen Matthew J. , Knuckles Travis L. , Gonzalez Bosc Laura , Kanagy Nancy L.
Published: June 2009

Air pollutant levels positively correlate with increases in both acute and chronic cardiovascular disease. The pollutant diesel exhaust (DE) increases endothelin (ET) levels, suggesting that this peptide may contribute to DE-induced cardiovascular disease. We hypothesized that acute exposure to DE also enhances ET-1-mediated coronary artery constrictor sensitivity. Constrictor responses to KCl, U-46619, and ET-1 were recorded by videomicroscopy in pressurized intraseptal coronary arteries from rats exposed for 5 h to DE (300 μg/m3) or filtered air (Air). ET-1 constriction was augmented in arteries from DE-exposed rats. Nitric oxide synthase (NOS) inhibition [ Nω-nitro-l-arginine (l-NNA), 100 μM] and endothelium inactivation augmented ET-1 responses in arteries from Air but not DE rats so that after either treatment responses were not different between groups. DE exposure did not affect KCl and U-46619 constrictor responses, while NOS inhibition augmented KCl constriction equally in both groups. Thus basal NOS activity does not appear to be affected by DE exposure. The endothelin type B (ETB) receptor antagonist BQ-788 (10 μM) inhibited ET-1 constriction in DE but not Air arteries, and constriction in the presence of the antagonist was not different between groups. Cytokine levels were not different in plasma from DE and AIR rats, suggesting that acute exposure to DE does not cause an immediate inflammatory response. In summary, a 5-h DE exposure selectively increases constrictor sensitivity to ET-1. This augmentation is endothelium-, NOS-, and ETB receptor dependent. These data suggest that DE exposure diminishes ETB receptor activation of endothelial NOS and augments ETB-dependent vasoconstriction. This augmented coronary vasoreactivity to ET-1 after DE, coupled with previous reports that DE induces production of ET-1, suggests that ET-1 may contribute to the increased incidence of cardiac events during acute increases in air pollution levels.
Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats
Authors: Du Jun , Fan Yu-Yan , Hitomi Hirofumi , Kiyomoto Hideyasu , Kimura Shoji , Kong Chui-Ze , Noma Takahisa , Kohno Masakazu , Nishiyama Akira , Nakano Daisuke
Published: June 2009

We hypothesized that combination treatment with the mineralocorticoid receptor antagonist eplerenone and the calcium channel blocker amlodipine elicits better renoprotective effects than monotherapy with either drug, via different mechanisms in Dahl salt-sensitive (DS) hypertensive rats. DS rats were fed a high-salt diet (4% NaCl) for 10 wk and were treated with vehicle ( n = 12), eplerenone (50 mg·kg−1·day−1, po, n = 12), amlodipine (3 mg·kg−1·day−1, po, n = 12), or eplerenone plus amlodipine ( n = 12) after 2 wk of salt feeding. Vehicle-treated DS rats developed proteinuria, which was attenuated by eplerenone or amlodipine. Interestingly, eplerenone attenuated the glomerulosclerosis and podocyte injury, but amlodipine did not. Conversely, treatment with amlodipine markedly improved interstitial fibrosis, while the effect of eplerenone was minimal. Combination treatment markedly improved proteinuria, glomerulosclerosis, podocyte injury, and interstitial fibrosis in DS rats. Renal hypoxia estimated by pimonidazole, vascular endothelial growth factor expression, and density of peritubular endothelial cells was exacerbated by salt feeding. Amlodipine, either as monotherapy or in combination, ameliorated the renal hypoxia, whereas eplerenone treatment had no effect. In conclusion, both eplerenone and amlodipine attenuated renal injuries in high salt-fed DS rats, but the targets for renoprotection differed between these two drugs, with eplerenone predominantly acting on glomeruli and amlodipine acting on interstitium. The combination of eplerenone and amlodipine improved renal injury more effectively than either monotherapy in high salt-fed DS rats, presumably by achieving their own renoprotective effects.
The long-term label retaining population of the renal papilla arises through divergent regional growth of the kidney
Authors: Adams Derek C. , Oxburgh Leif
Published: June 2009

Long-term pulse chase experiments previously identified a sizable population of BrdU-retaining cells within the renal papilla. The origin of these cells has been unclear, and in this work we test the hypothesis that they become quiescent early during the course of kidney development and organ growth. Indeed, we find that BrdU-retaining cells of the papilla can be labeled only by pulsing with BrdU from embryonic (E) day 11.25 to postnatal (P) day 7, the approximate period of kidney development in the mouse. BrdU signal in the cortex and outer medulla is rapidly diluted by cellular proliferation during embryonic development and juvenile growth, whereas cells within the papilla differentiate and exit the cell cycle during organogenesis. Indeed, by E17.5, little or no active proliferation can be seen in the distal papilla, indicating maturation of this structure in a distal-to-proximal manner during organogenesis. We conclude that BrdU-retaining cells of the papilla represent a population of cells that quiesce during embryonic development and localize within a region of the kidney that matures early. We therefore propose that selective papillary retention of BrdU arises through a combination of regionalized slowing of, and exit from, the cell cycle within the papilla during the period of ongoing kidney development, and extensive proliferative growth of the juvenile kidney resulting in dilution of BrdU below the detection level in extra-papillary regions.
Regulation of mRNA translation in renal physiology and disease
Authors: Kasinath Balakuntalam S. , Feliers Denis , Sataranatarajan Kavithalakshmi , Ghosh Choudhury Goutam , Lee Myung Ja , Mariappan Meenalakshmi M.
Published: June 2009

Translation, a process of generating a peptide from the codons present in messenger RNA, can be a site of independent regulation of protein synthesis; it has not been well studied in the kidney. Translation occurs in three stages (initiation, elongation, and termination), each with its own set of regulatory factors. Mechanisms controlling translation include small inhibitory RNAs such as microRNAs, binding proteins, and signaling reactions. Role of translation in renal injury in diabetes, endoplasmic reticulum stress, acute kidney injury, and, in physiological adaptation to loss of nephrons is reviewed here. Contribution of mRNA translation to physiology and disease is not well understood. Because it is involved in such diverse areas as development and cancer, it should prove a fertile field for investigation in renal science.
Comparison of regional patch collection vs. whole body washdown for measuring sweat sodium and potassium loss during exercise
Authors: Baker Lindsay B. , Stofan John R. , Hamilton Adam A. , Horswill Craig A.
Published: June 2009

This study compared simultaneous whole body washdown (WBW) and regional skin surface (REG) sweat collections to generate regression equations to predict WBW sweat Na+ concentration ([Na+]) and K+ concentration ([K+]) from single- and five-site REG sweat patch collections. Athletes (10 men, 10 women) cycled in a plastic chamber for 90 min in the heat. Before exercise, the subject and bike were washed with deionized water. After the onset of sweating, sterile patches were attached to the forearm, back, chest, forehead, and thigh and removed on saturation. After exercise, the subject and bike were washed with ammonium sulfate solution to collect all sweat electrolyte loss and determine the volume of unevaporated sweat. All individual patch sites and five-site REG (weighted for local sweat rate and body surface area) were significantly ( P = 0.000) correlated with WBW sweat [Na+]. The equation for predicting WBW sweat [Na+] from five-site REG was y = 0.68 x + 0.44 [ r = 0.97, intraclass correlation coefficient (ICC) = 0.70] and did not differ between sexes. There were sex differences in the regression results between five-site REG and WBW sweat [K+] (men: y = 0.74 x + 0.30, r = 0.89, ICC = 0.73; women: y = 0.04 x + 3.18, r = 0.03, ICC = 0.00). Five-site REG sweat [Na+] and [K+] significantly overestimated that of WBW sweat (59 ± 27 vs. 41 ± 19 meq/l, P = 0.000 and 4.4 ± 0.7 vs. 3.6 ± 0.7 meq/l, P = 0.000, respectively). For both sexes, the best sites for predicting WBW sweat [Na+] and [K+] were the thigh (1 ± 8 meq/l < WBW, P = 1.000, y = 0.75 x + 11.37, r = 0.96, ICC = 0.93) and chest (0.2 ± 0.3 meq/l > WBW, P = 1.000, y = 0.76 x + 0.55, r = 0.89, ICC = 0.87), respectively. In conclusion, regression equations can be used to accurately and reliably predict WBW sweat [Na+] and [K+] from REG sweat collections when study conditions and techniques are similar to that of the present protocol.
Tissue memory in healing tendons: short loading episodes stimulate healing
Authors: Andersson Therese , Eliasson Pernilla , Aspenberg Per
Published: June 2009

Intact tendons adapt slowly to changes in mechanical loading, whereas in healing tendons the effect of mechanical loading or its absence is dramatic. The longevity of the response to a single loading episode is, however, unknown. We hypothesized that the tissue has a “memory” of loading episodes and that therefore short loadings are sufficient to elicit improved healing. The Achilles tendon of 70 female rats was transected and unloaded by tail suspension for 12 days (suspension started on day 2 after surgery). Each day, the rats were let down from suspension for short daily training episodes according to different regimes: 15 min of cage activity or treadmill running for 15, 30, 60, or 2 × 15 min. Rats with transected Achilles tendons and full-time cage activity served as controls. The results demonstrated that full-time cage activity increased the peak force over three times compared with unloading. Short daily loading episodes (treadmill running) increased the peak force about half as much as full-time activity. Prolongation of treadmill running above 15 min or dividing the daily training in two separate episodes had minimal further effect. This mechanical stimulation increased the cross-sectional area but had no effect on the mechanical properties of the repair tissue. The findings indicate that once the tissue had received information from a certain loading type and level, this is “memorized” and leads to a response lasting many hours. This suggests that patients might be allowed early short loading episodes following, e.g., an Achilles tendon rupture for a better outcome.
Rat Achilles tendon healing: mechanical loading and gene expression
Authors: Eliasson Pernilla , Andersson Therese , Aspenberg Per
Published: June 2009

Injured tendons require mechanical tension for optimal healing, but it is unclear which genes are upregulated and responsible for this effect. We unloaded one Achilles tendon in rats by Botox injections in the calf muscles. The tendon was then transected and left to heal. We studied mechanical properties of the tendon calluses, as well as mRNA expression, and compared them with loaded controls. Tendon calluses were studied 3, 8, 14, and 21 days after transection. Intact tendons were studied similarly for comparison. Altogether 110 rats were used. The genes were chosen for proteins marking inflammation, growth, extracellular matrix, and tendon specificity. In intact tendons, procollagen III and tenascin-C were more expressed in loaded than unloaded tendons, but none of the other genes was affected. In healing tendons, loading status had small effects on the selected genes. However, TNF-α transforming growth factor-β1, and procollagens I and III were less expressed in loaded callus tissue at day 3. At day 8 procollagens I and III, lysyl oxidase, and scleraxis had a lower expression in loaded calluses. However, by days 14 and 21, procollagen I, cartilage oligomeric matrix protein, tenascin-C, tenomodulin, and scleraxis were all more expressed in loaded calluses. In healing tendons, the transverse area was larger in loaded samples, but material properties were unaffected, or even impaired. Thus mechanical loading is important for growth of the callus but not its mechanical quality. The main effect of loading during healing might thereby be sought among growth stimulators. In the late phase of healing, tendon-specific genes (scleraxis and tenomodulin) were upregulated with loading, and the healing tissue might to some extent represent a regenerate rather than a scar.
Direct Actions of Carbenoxolone on Synaptic Transmission and Neuronal Membrane Properties
Authors: Tovar Kenneth R. , Maher Brady J. , Westbrook Gary L.
Published: June 2009

The increased appreciation of electrical coupling between neurons has led to many studies examining the role of gap junctions in synaptic and network activity. Although the gap junctional blocker carbenoxolone (CBX) is effective in reducing electrical coupling, it may have other actions as well. To study the non–gap junctional effects of CBX on synaptic transmission, we recorded from mouse hippocampal neurons cultured on glial micro-islands. This recording configuration allowed us to stimulate and record excitatory postsynaptic currents (EPSCs) or inhibitory postsynaptic currents (IPSCs) in the same neuron or pairs of neurons. CBX irreversibly reduced evoked α-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptor–mediated EPSCs. Consistent with a presynaptic site of action, CBX had no effect on glutamate-evoked whole cell currents and increased the paired-pulse ratio of AMPA and N-methyl-d-aspartate (NMDA) receptor–mediated EPSCs. CBX also reversibly reduced GABAA receptor–mediated IPSCs, increased the action potential width, and reduced the action potential firing rate. Our results indicate CBX broadly affects several neuronal membrane conductances independent of its effects on gap junctions. Thus effects of carbenoxolone on network activity cannot be interpreted as resulting from specific block of gap junctions.
Auditory Responses in the Barn Owl's Nucleus Laminaris to Clicks: Impulse Response and Signal Analysis of Neurophonic Potential
Authors: Wagner Hermann , Brill Sandra , Kempter Richard , Carr Catherine E.
Published: June 2009

We used acoustic clicks to study the impulse response of the neurophonic potential in the barn owl's nucleus laminaris. Clicks evoked a complex oscillatory neural response with a component that reflected the best frequency measured with tonal stimuli. The envelope of this component was obtained from the analytic signal created using the Hilbert transform. The time courses of the envelope and carrier waveforms were characterized by fitting them with filters. The envelope was better fitted with a Gaussian than with the envelope of a gamma-tone function. The carrier was better fitted with a frequency glide than with a constant instantaneous frequency. The change of the instantaneous frequency with time was better fitted with a linear fit than with a saturating nonlinearity. Frequency glides had not been observed in the bird's auditory system before. The glides were similar to those observed in the mammalian auditory nerve. Response amplitude, group delay, frequency, and phase depended in a systematic way on click level. In most cases, response amplitude decreased linearly as stimulus level decreased, while group delay, phase, and frequency increased linearly as level decreased. Thus the impulse response of the neurophonic potential in the nucleus laminaris of barn owls reflects many characteristics also observed in responses of the basilar membrane and auditory nerve in mammals.
Real-Time Measurements of Synaptic Autoinhibition Produced by Serotonin Release in Cultured Leech Neurons
Authors: Cercós Montserrat G. , De-Miguel Francisco F. , Trueta Citlali
Published: June 2009

We studied autoinhibition produced immediately after synaptic serotonin (5-HT) release in identified leech Retzius neurons, cultured singly or forming synapses onto pressure-sensitive neurons. Cultured Retzius neurons are isopotential, thus allowing accurate recordings of synaptic events using intracellular microelectrodes. The effects of autoinhibition on distant neuropilar presynaptic endings were predicted from model simulations. Following action potentials (APs), cultured neurons produced a slow hyperpolarization with a rise time of 85.4 ± 5.2 ms and a half-decay time of 252 ± 17.4 ms. These inhibitory postpotentials were reproduced by the iontophoretic application of 5-HT and became depolarizing after inverting the transmembranal chloride gradient by using microelectrodes filled with potassium chloride. The inhibitory postpotentials were reversibly abolished in the absence of extracellular calcium and absent in reserpine-treated neurons, suggesting an autoinhibition due to 5-HT acting on autoreceptors coupled to chloride channels. The autoinhibitory responses increased the membrane conductance and decreased subsequent excitability. Increasing 5-HT release by stimulating with trains of ten pulses at 10 or 30 Hz produced 23 ± 6 and 47 ± 2% of AP failures, respectively. These failures were reversibly abolished by the serotonergic antagonist methysergide (140 μM). Moreover, reserpine-treated neurons had only 5 ± 4% of failures during trains at 10 Hz. This percentage was increased to 35 ± 4% by iontophoretic application of 5-HT. Increases in AP failures correlated with smaller postsynaptic currents. Model simulations predicted that the autoinhibitory chloride conductance reduces the amplitude of APs arriving at neuropilar presynaptic endings. Altogether, our results suggest that 5-HT autoinhibits its subsequent release by decreasing the excitability of presynaptic endings within the same neuron.
Effects of Dopamine D1and D2Receptor Antagonists on Laryngeal Neurophysiology in the Rat
Authors: Feng Xin , Henriquez Victor M. , Walters Judith R. , Ludlow Christy L.
Published: June 2009

Hypophonia is an early symptom in Parkinson's disease (PD) that involves an increase in laryngeal muscle activity, interfering with voice production. Our aim was to use an animal model to better understand the role of different dopamine receptor subtypes in the control of laryngeal neurophysiology. First, we evaluated the combined effects of SCH23390—a D1receptor antagonist with a D2receptor antagonist (eticlopride) on laryngeal neurophysiology, and then tested the separate effects of selective receptor antagonists. Thyroarytenoid (TA) and gastrocnemius (GN) muscle activity was measured at rest and while stimulating the internal branch of superior laryngeal nerve to elicit the laryngeal adductor response (LAR) in alpha-chloralose–anesthetized rats. Paired stimuli at different interstimulus intervals between 250 and 5,000 ms measured central conditioning of the LAR. Changes in resting muscle activity, response latency, amplitude, and LAR conditioning after each drug were compared with the saline control. SCH23390 alone increased the resting TA muscle activity ( P < 0.05). With the combined SCH23390 + eticlopride or SCH23390 alone, response latency decreased ( P < 0.01), amplitude increased ( P < 0.01), and the test LAR was reduced at 2,000-ms ISI ( P < 0.01). No LAR changes occurred when eticlopride was administered alone at a low dose and only a tendency to suppress responses was found at a high dose. No changes in GN muscle activity occurred in any of the groups. The results suggest that a loss of stimulation of D1receptors plays a significant role in laryngeal pathophysiology in PD.
Convergence of Submodality-Specific Input Onto Neurons in Primary Somatosensory Cortex
Authors: Pei Yu-Cheng , Denchev Peter V. , Hsiao Steven S. , Craig James C. , Bensmaia Sliman J.
Published: June 2009

At the somatosensory periphery, slowly adapting type 1 (SA1) and rapidly adapting (RA) afferents respond very differently to step indentations: SA1 afferents respond throughout the entire stimulus interval (sustained response), whereas RA afferents respond only at stimulus onset (on response) and offset (off response). We recorded the responses of cortical neurons to step indentations and found many neurons in areas 3b and 1 to exhibit properties that are intermediate between these two extremes: These neurons responded during the sustained portion of the stimulus and also at the offset of the stimulus. Several lines of evidence indicate that these neurons, which exist in large proportions even at these early stages of somatosensory cortical processing, receive input from both populations of afferents. First, we show that many cortical neurons have both a significant sustained response and a significant off response. Second, the strength of the off response is uncorrelated with that of the sustained response, which is to be expected if sustained and off responses stem from different populations of afferent fibers. Third, the bulk of the variance in cortical responses to step indentations can be accounted for using a linear combination of both SA1 and RA responses. Finally, we show that the off response in cortical neurons does not reflect rebound from inhibition. We conclude that the convergence of modality specific input onto individual neurons is common in primary somatosensory cortex and discuss how this conclusion might be reconciled with previous findings.
Control of Stepping Velocity in the Stick InsectCarausius morosus
Authors: Gruhn Matthias , von Uckermann Géraldine , Westmark Sandra , Wosnitza Anne , Büschges Ansgar , Borgmann Anke
Published: June 2009

We performed electrophysiological and behavioral experiments in single-leg preparations and intact animals of the stick insect Carausius morosus to understand mechanisms underlying the control of walking speed. At the level of the single leg, we found no significant correlation between stepping velocity and spike frequency of motor neurons (MNs) other than the previously shown modification in flexor (stance) MN activity. However, pauses between stance and swing motoneuron activity at the transition from stance to swing phase and stepping velocity are correlated. Pauses become shorter with increasing speed and completely disappear during fast stepping sequences. By means of extra- and intracellular recordings in single-leg stick insect preparations we found no systematic relationship between the velocity of a stepping front leg and the motoneuronal activity in the ipsi- or contralateral mesothoracic protractor and retractor, as well as flexor and extensor MNs. The observations on the lack of coordination of stepping velocity between legs in single-leg preparations were confirmed in behavioral experiments with intact stick insects tethered above a slippery surface, thereby effectively removing mechanical coupling through the ground. In this situation, there were again no systematic correlations between the stepping velocities of different legs, despite the finding that an increase in stepping velocity in a single front leg is correlated with a general increase in nerve activity in all connectives between the subesophageal and all thoracic ganglia. However, when the tethered animal increased walking speed due to a short tactile stimulus, provoking an escape-like response, stepping velocities of ipsilateral legs were found to be correlated for several steps. These results indicate that there is no permanent coordination of stepping velocities between legs, but that such coordination can be activated under certain circumstances.
Effects of Dopamine Depletion on Network Entropy in the External Globus Pallidus
Authors: Cruz Ana V. , Mallet Nicolas , Magill Peter J. , Brown Peter , Averbeck Bruno B.
Published: June 2009

Dopamine depletion in cortical-basal ganglia circuits in Parkinson's disease (PD) grossly disturbs movement and cognition. Classic models relate Parkinsonian dysfunction to changes in firing rates of basal ganglia neurons. However, disturbances in other dynamics of neural activity are also common. Taking both inappropriate firing rates and other dynamics into account and determining how changes in the properties of these neural circuits that occur during PD impact on information coding are thus imperative. Here, we examined in vivo network dynamics in the external globus pallidus (GPe) of rats before and after chronic dopamine depletion. Dopamine depletion led to decreases in the firing rates of GPe neurons and increases in synchronized network oscillations in the β frequency (13–30 Hz) band. Using logistic regression models, we determined the combined and separate impacts of these factors on network entropy, a measure of the upper bound of information coding capacity. Importantly, changes in these features in dopamine-depleted rats led to a significant decrease in GPe network entropy. Changes in firing rates had the largest impact on entropy, with changes in synchrony also decreasing entropy at the network level. Changes in autocorrelations tended to offset these effects because autocorrelations decreased entropy more in the control animals. Thus it is possible that reduced information coding capacity within basal ganglia networks may contribute to the behavioral deficits accompanying PD.
Temporal Analysis of Stochastic Turning Behavior of SwimmingC. elegans
Authors: Srivastava Nikhil , Clark Damon A. , Samuel Aravinthan D.T.
Published: June 2009

Caenorhabditis elegans exhibits spontaneous motility in isotropic environments, characterized by periods of forward movements punctuated at random by turning movements. Here, we study the statistics of turning movements—deep Ω-shaped bends—exhibited by swimming worms. We show that the durations of intervals between successive Ω-turns are uncorrelated with one another and are effectively selected from a probability distribution resembling the sum of two exponentials. The worm initially exhibits frequent Ω-turns on being placed in liquid, and the mean rate of Ω-turns lessens over time. The statistics of Ω-turns is consistent with a phenomenological model involving two behavioral states governed by Poisson kinetics: a “slow” state generates Ω-turns with a low probability per unit time; a “fast” state generates Ω-turns with a high probability per unit time; and the worm randomly transitions between these slow and fast states. Our findings suggest that the statistics of spontaneous Ω-turns exhibited by swimming worms may be described using a small number of parameters, consistent with a two-state phenomenological model for the mechanisms that spontaneously generate Ω-turns.