bluuebunny/crossref_metadata_2025 huggingface dataset:
Attenuated stress-induced catecholamine release in mice lacking the vasopressin V1b receptor
Authors: Itoh Shuji , Yamada Sakiko , Mori Toyoki , Miwa Takashi , Tottori Katsura , Uwahodo Yasufumi , Yamamura Yoshitaka , Fukuda Meiko , Yamamoto Koji , Tanoue Akito , Tsujimoto Gozoh
Published: February 2006

Vasopressin V1b receptor is specifically expressed in the pituitary and mediates adrenocorticotropin release, thereby regulating stress responses via its corticotropin releasing factor-like action. In the present study we examined catecholamine release in response to two types of stress in mice lacking the V1b receptor gene (V1bR−/− mice) vs. wild-type mice. There were no significant differences in the basal plasma levels of catecholamines between the two genotypes. In response to stress induced by forced swimming, norepinephrine (NE), but not epinephrine (E) or dopamine (DA), was increased in wild-type mice, whereas the increases in NE and DA were not observed in V1bR−/− mice. In wild-type mice, E, but not NE or DA, was increased in response to social isolation stress, whereas the increase in E was not observed in V1bR−/− mice. These results suggest that the V1b receptor regulates stress-induced catecholamine release. Because it has been suggested that arginine-vasopressin (AVP) is related to the development of depression, we also evaluated immobility time in the forced swimming test, and we found no significant change in V1bR−/− mice. Taken together, these findings suggest that, in addition to the previously elucidated effect on the hypothalamic-pituitary-adrenal axis, vasopressin activity via V1b receptors regulates stress-induced catecholamine release.
Two-week longitudinal survey of bone architecture alteration in the hindlimb-unloaded rat model of bone loss: sex differences
Authors: David Valentin , Lafage-Proust Marie-Hélène , Laroche Norbert , Christian Alexandre , Ruegsegger Peter , Vico Laurence
Published: February 2006

The goal of this study was to determine, through a longitudinal follow-up, whether sex influences bone adaptation during simulated weightlessness. Twelve-week-old male and female Wistar rats were hindlimb unweighted for 2 wk, and the time course of bone alteration was monitored in vivo by means of densitometry and unbiased three-dimensional quantitative microcomputed tomography at 7 and 14 days. Compared with male rats, female rats had twice more cancellous bone volume at the proximal tibia at baseline, and this bone volume continued to increase, whereas in males it stabilized. Conversely, cortical area was greater in males than in females, and in both sexes cortical bone was still expanding. Hindlimb unloading resulted in larger reductions in males than in females in both cortical and cancellous compartments. In females, trabecular thickness and number decreased mildly, whereas in males trabecular number was dramatically reduced. In both sexes, the trabecular network became less connected and more rod-like shaped. Bone cellular activities evaluated by histomorphometry showed decreased bone formation rate in both sexes and increased resorption activity only in males. In conclusion, in female rats unloaded-related cancellous alterations reversed the growing process, whereas in males, which show lower growth process, it induced an accentuation of age-related cancellous bone changes for most of the parameters.
Prolactin secretory rhythm of mated rats induced by a single injection of oxytocin
Authors: Egli Marcel , Bertram Richard , Toporikova Natalia , Sellix Michael T. , Blanco Wilfredo , Freeman Marc E.
Published: February 2006

Mating or vaginocervical stimulation [copulatory stimulus (CS)] induces two daily surges of the hormone prolactin (PRL) in rats. This unique secretory pattern of PRL surges is characteristic for the first half of pregnancy and is also present in ovariectomized (OVX) rats. Studies have shown that CS additionally provokes an acute release of the hormone oxytocin (OT). In this study, we tested whether a single injection of OT (iv) is sufficient to initiate the PRL secretion pattern of OVX/CS rats. Furthermore, we measured the 24-h profile of dopamine (DA) content in the anterior lobe of the pituitary gland, because DA is the major inhibitory factor of PRL secretion. The results indicated that a single injection of OT induces a PRL secretory rhythm and a DA release pattern similar to that initiated by CS. Immunocytochemical investigation showed that particular OTergic neurons in the hypothalamus express receptors for PRL, as well as for vasoactive intestinal polypeptide, which indicates an involvement in generating the PRL rhythm and entraining it to the ambient photoperiod. On the basis of this study, we suggest that the PRL-DA inhibitory feedback loop between lactotrophs and DAergic neurons plays a crucial role in generating the oscillatory PRL secretion pattern in CS rats. A timing signal, likely provided by the hypothalamic suprachiasmatic nucleus, entrains the autonomous PRL oscillation to a particular time of day. Mathematical modeling was used to illustrate the proposed network function. The experimental results further suggest an additional feedback mechanism in which certain hypothalamic OTergic neurons are influenced by PRL.
Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues
Authors: LeBrasseur Nathan K. , Kelly Meghan , Tsao Tsu-Shuen , Farmer Stephen R. , Saha Asish K. , Ruderman Neil B. , Tomas Eva
Published: February 2006

Thiazolidinediones (TZDs) are insulin-sensitizing agents used in the treatment of type 2 diabetes. A widely held view is that their action is secondary to transcriptional events that occur when TZDs bind to the nuclear receptor PPARγ in the adipocyte and stimulate adipogenesis. It has been proposed that this increases insulin sensitivity, at least in part, by increasing the expression and release of adiponectin, an adipokine that activates the fuel-sensing enzyme AMP-activated protein kinase (AMPK). In this study, we report that TZDs also acutely activate AMPK in skeletal muscle and other tissues by a mechanism that is likely independent of PPARγ-regulated gene transcription. Thus incubation of isolated rat EDL muscles in medium containing 5 μM troglitazone for 15 min (too brief to be attributable to transcription) significantly increased pAMPK and pACC. At a concentration of 100 μM, troglitazone maximally increased these parameters and caused twofold increases in 2-deoxy-d-glucose uptake and the oxidation of exogenous [14C]palmitate. Time course studies revealed that troglitazone-induced increases in pAMPK and pACC abundance at 15 min were paralleled by an increase in the AMP-to-ATP ratio and that by 60 min all of these parameters had returned to baseline values. Increases in pAMPK and pACC were also observed in skeletal muscle, liver, and adipose tissue in intact rats 15 min after the administration of a single dose of troglitazone (10 mg/kg, ip). Likewise, troglitazone and another TZD, pioglitazone, caused rapid increases in pAMPK and pACC of equal magnitude in Swiss 3T3 fibroblasts with and without sufficient PPARγ to mediate the expression of target genes. The results indicate that TZDs can act within minutes to activate AMPK in mammalian tissues. They suggest that this effect is associated with a change in cellular energy state and that it is not dependent on PPARγ-mediated gene transcription.
Influence of TNF-α and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans
Authors: Krogh-Madsen Rikke , Plomgaard Peter , Møller Kirsten , Mittendorfer Bettina , Pedersen Bente K.
Published: February 2006

Inflammation is associated with insulin resistance, and both tumor necrosis factor (TNF)-α and interleukin (IL)-6 may affect glucose uptake. TNF induces insulin resistance, whereas the role of IL-6 is controversial. High plasma levels of IL-18 are associated with insulin resistance in epidemiological studies. We investigated the effects of TNF and IL-6 on IL-18 gene expression in skeletal muscle and adipose tissue. Nine human volunteers underwent three consecutive interventions, receiving an infusion of recombinant human (rh)IL-6, rhTNF, and saline. Insulin sensitivity was assessed by measurement of whole body glucose uptake with the stable isotope tracer method during a euglycemic hyperinsulinemic clamp (20 mU·min−1·kg−1), which was initiated 1 h after the IL-6-TNF-saline infusion. Cytokine responses were measured in plasma, muscle, and fat biopsies. Plasma concentrations of TNF and IL-6 increased 10- and 38-fold, respectively, during the cytokine infusions. Whole body insulin-mediated glucose uptake was significantly reduced during TNF infusion but remained unchanged during IL-6 infusion. TNF induced IL-18 gene expression in muscle tissue, but not in adipose tissue, whereas IL-6 infusion had no effect on IL-18 gene expression in either tissue. We conclude that TNF-induced insulin resistance of whole body glucose uptake is associated with increased IL-18 gene expression in muscle tissue, indicating that TNF and IL-18 interact, and both may have important regulatory roles in the pathogenesis of insulin resistance.
Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content
Authors: Bruce Clinton R. , Thrush A. Brianne , Mertz Valerie A. , Bezaire Veronic , Chabowski Adrian , Heigenhauser George J. F. , Dyck David J.
Published: February 2006

Muscle fatty acid (FA) metabolism is impaired in obesity and insulin resistance, reflected by reduced rates of FA oxidation and accumulation of lipids. It has been suggested that interventions that increase FA oxidation may enhance insulin action by reducing these lipid pools. Here, we examined the effect of endurance training on rates of mitochondrial FA oxidation, the activity of carnitine palmitoyltransferase I (CPT I), and the lipid content in muscle of obese individuals and related these to measures of glucose tolerance. Nine obese subjects completed 8 wk of moderate-intensity endurance training, and muscle biopsies were obtained before and after training. Training significantly improved glucose tolerance, with a reduction in the area under the curve for glucose ( P < 0.05) and insulin ( P = 0.01) during an oral glucose tolerance test. CPT I activity increased 250% ( P = 0.001) with training and became less sensitive to inhibition by malonyl-CoA. This was associated with an increase in mitochondrial FA oxidation (+120%, P < 0.001). Training had no effect on muscle triacylglycerol content; however, there was a trend for training to reduce both the total diacylglcyerol (DAG) content (−15%, P = 0.06) and the saturated DAG-FA species (−27%, P = 0.06). Training reduced both total ceramide content (−42%, P = 0.01) and the saturated ceramide species (−32%, P < 0.05). These findings suggest that the improved capacity for mitochondrial FA uptake and oxidation leads not only to a reduction in muscle lipid content but also a to change in the saturation status of lipids, which may, at least in part, provide a mechanism for the enhanced insulin action observed with endurance training in obese individuals.
Relationship between coronary flow velocity reserve and aortic stiffness
Authors: Nemes A. , Forster Tamás , Csanády Miklós
Published: February 2006

We examined the hypothesis that a stiff aorta is associated with reduced coronary blood flow (CBF) and CBF response to percutaneous coronary intervention (PCI). Aortic mechanical properties are thought to affect CBF, with increased stiffness associated with decreased coronary perfusion. Animal studies are conflicting, and human evidence is lacking. Even less is known about the effects of aortic stiffness on the CBF response to successful PCI. In 18 subjects undergoing elective PCI, a Doppler velocity guidewire was positioned proximal to a severe coronary stenosis to measure resting and adenosine-induced hyperemic CBF before and after PCI. Stenosis severity was assessed with Doppler velocity and pressure guidewires. Aortic mechanical indexes measured included central pulse-wave velocity (cPWV) and central pulse pressure (cPP). PCI was successful in all subjects (diameter stenosis: 88 ± 9% to 2 ± 7%; coronary flow velocity reserve: 1.8 ± 0.6 to 3.0 ± 0.8; fractional flow reserve: 0.57 ± 0.19 to 0.92 ± 0.06; all P < 0.001). With the adjustment for age and gender, resting and hyperemic CBF were inversely related to cPWV irrespective of the presence of stenosis (resting: before PCI, r2 = 0.452, P < 0.01; after PCI, r2 = 0.261, P = 0.043; hyperemic: before PCI r2 = 0.503, P = 0.005; after PCI r2 = 0.500, P = 0.002), whereas they were related to cPP in absence of stenosis (resting: r2 = 0.368, P = 0.022; hyperemic: r2 = 0.370, P = 0.016). Hyperemic CBF response ( P = 0.005) and hyperemic CBF improvement from PCI ( P = 0.025) were less marked in a stiff aorta than a compliant aorta. A stiff aorta is associated with a reduction in CBF, a lower hyperemic CBF response, and may reduce the improvement in hyperemic CBF after successful PCI.
Effect of apocynin treatment on renal expression of COX-2, NOS1, and renin in Wistar-Kyoto and spontaneously hypertensive rats
Authors: Paliege A. , Parsumathy A. , Mizel D. , Yang T. , Schnermann J. , Bachmann S.
Published: February 2006

Macula densa (MD) cells of the juxtaglomerular apparatus (JGA) synthesize type 1 nitric oxide synthase (NOS1) and type 2 cyclooxygenase (COX-2). Both nitric oxide (NO) and prostaglandins have been considered to mediate or modulate the control of renin secretion. Reactive oxygen species (ROS) produced locally by NADPH oxidase may influence NO bioavailability. We have tested the hypothesis that in hypertension elevated ROS levels may modify the expression of NOS1 and COX-2 in the JGA, thereby interacting with juxtaglomerular signaling. To this end, spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats (WKY) received the specific NADPH oxidase inhibitor, apocynin, during 3 wk. Renal functional and histochemical parameters, plasma renin activity (PRA), and as a measure of ROS activity, urinary isoprostane excretion (IP) were evaluated. Compared with WKY, IP levels in untreated SHR were 2.2-fold increased, and NOS1 immunoreactiviy (IR) of JGA 1.5-fold increased, whereas COX-2 IR was reduced to 35%, renin IR to 51%, and PRA to 7%. Apocynin treatment reduced IP levels in SHR to 52%, NOS1 IR to 69%, and renin IR to 62% of untreated SHR, whereas renin mRNA, COX-2 IR, glomerular filtration rate, PRA, and systolic blood pressure remained unchanged. WKY revealed no changes under apocynin treatment. These data show that NADPH oxidase is an important contributor to elevated levels of ROS in hypertension. Upregulation of MD NOS1 in SHR may have the potential of blunting the functional impact of ROS at the level of bioavailable NO. Downregulated COX-2 and renin levels in SHR are apparently unrelated to oxidative stress, since apocynin treatment had no effect on these parameters.
Cosignaling of adenosine and adenosine triphosphate in hypobaric hypoxia-induced hypothermia
Authors: Chevrier Céline , Bourdon Lionel , Canini Frédéric
Published: February 2006

Purines, that is, adenosine and ATP, are not only products of metabolism but are also neurotransmitters. Indeed, purinergic neurotransmission is involved in thermoregulatory processes that occur during normoxia. Exposure to severe hypoxia elicits a sharp decrease in body core temperature (Tco), and adenosinergic mechanisms have been suspected to be responsible for this hypothermia. Because ATP per se and its metabolite adenosine could have complex interactions in some neural networks, we hypothesize that both adenosine and ATP are involved in the central mechanism of hypoxia-induced hypothermia. Their role in the thermoregulatory process was therefore investigated in a 24-h hypobaric hypoxia (FiO2= 10%), using CGS-15943, a nonselective antagonist of adenosine receptors, and suramin, an ATP receptor antagonist. Tcoand spontaneous activity (AS) were monitored by telemetry in conscious rats, receiving CGS-15943 (10 mg/kg ip), suramin (7 nmol icv), or both. The same treatments were done in normoxia to evaluate the specificity of their thermoregulatory action observed in hypoxia. Suramin/CGS-15943 treatment blunted the profound hypothermia observed in control rats throughout the hypoxia exposure, whereas CGS-15943 treatment blunted hypothermia during only 3 h, and suramin treatment had no effect. These results suggest that suramin potentiates the CGS-15943 effects and consequently that adenosine and ATP signaling act in synergy. In normoxia, suramin/CGS-15943 induced an increase in Tcobut to a far lesser extent than observed in hypoxia. Thus it might be suggested that the suramin/CGS-15943 blunting of hypoxia-induced hypothermia would be specific to hypoxia-induced mechanisms.
Role of potassium in regulating blood flow and blood pressure
Authors: Haddy Francis J. , Vanhoutte Paul M. , Feletou Michel
Published: February 2006

Unlike sodium, potassium is vasoactive; for example, when infused into the arterial supply of a vascular bed, blood flow increases. The vasodilation results from hyperpolarization of the vascular smooth muscle cell subsequent to potassium stimulation by the ion of the electrogenic Na+-K+pump and/or activating the inwardly rectifying Kir channels. In the case of skeletal muscle and brain, the increased flow sustains the augmented metabolic needs of the tissues. Potassium ions are also released by the endothelial cells in response to neurohumoral mediators and physical forces (such as shear stress) and contribute to the endothelium-dependent relaxations, being a component of endothelium-derived hyperpolarization factor-mediated responses. Dietary supplementation of potassium can lower blood pressure in normal and some hypertensive patients. Again, in contrast to NaCl restriction, the response to potassium supplementation is slow to appear, taking ∼4 wk. Such supplementation reduces the need for antihypertensive medication. “Salt-sensitive” hypertension responds particularly well, perhaps, in part, because supplementation with potassium increases the urinary excretion of sodium chloride. Potassium supplementation may even reduce organ system complications (e.g., stroke).
Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+-K+- ATPase alterations in ouabain and adducin-dependent hypertension
Authors: Ferrari Patrizia , Ferrandi Mara , Valentini Giovanni , Bianchi Giuseppe
Published: February 2006

The genetic and environmental heterogeneity of essential hypertension is responsible for the individual variability of antihypertensive therapy. An understanding of the molecular mechanisms underlying hypertension and related organ complications is a key aspect for developing new, effective, and safe antihypertensive agents able to cure the cause of the disease. Two mechanisms, among others, are involved in determining the abnormalities of tubular Na+reabsorption observed in essential hypertension: the polymorphism of the cytoskeletal protein α-adducin and the increased circulating levels of endogenous ouabain (EO). Both lead to increased activity and expression of the renal Na+-K+pump, the driving force for tubular Na transport. Morphological and functional vascular alterations have also been associated with EO. Rostafuroxin (PST 2238) is a new oral antihypertensive agent able to selectively antagonize EO, adducin pressor, and molecular effects. It is endowed with high potency and efficacy in reducing blood pressure and preventing organ hypertrophy in animal models representative of both adducin and EO mechanisms. At molecular level, in the kidney, Rostafuroxin antagonizes EO triggering of the Src-epidermal growth factor receptor (EGFr)-dependent signaling pathway leading to renal Na+-K+pump, and ERK tyrosine phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by nanomolar ouabain. A very high safety ratio and an absence of interaction with other mechanisms involved in blood pressure regulation, together with initial evidence of high tolerability and efficacy in hypertensive patients, indicate Rostafuroxin as the first example of a new class of antihypertensive agents designed to antagonize adducin and EO-hypertensive mechanisms.
How does salt retention raise blood pressure?
Authors: Blaustein Mordecai P. , Zhang Jin , Chen Ling , Hamilton Bruce P.
Published: February 2006

A critical question in hypertension research is: How is long-term blood pressure controlled? Excessive NaCl ingestion or NaCl retention by the kidneys and the consequent tendency toward plasma volume expansion lead to hypertension. Nevertheless, the precise mechanisms linking salt to high blood pressure are unresolved. The discovery of endogenous ouabain, an adrenocortical hormone, provided an important clue. Ouabain, a selective Na+pump inhibitor, has cardiotonic and vasotonic effects. Plasma endogenous ouabain levels are significantly elevated in ≈40% of patients with essential hypertension and in animals with several forms of salt-dependent hypertension. Also, prolonged ouabain administration induces hypertension in rodents. Mice with mutant Na+pumps or Na/Ca exchangers (NCX) and studies with a ouabain antagonist and an NCX blocker are revealing the missing molecular mechanisms. These data demonstrate that α2Na+pumps and NCX1 participate in long-term regulation of vascular tone and blood pressure. Pharmacological agents or mutations in the α2Na+pump that interfere with the action of ouabain on the pump, and reduced NCX1 expression or agents that block NCX all impede the development of salt-dependent or ouabain-induced hypertension. Conversely, nanomolar ouabain, reduced α2Na+pump expression, and smooth muscle-specific overexpression of NCX1 all induce hypertension. Furthermore, ouabain and reduced α2Na+pump expression increase myogenic tone in isolated mesenteric small arteries in vitro, thereby tying these effects directly to the elevation of blood pressure. Thus, endogenous ouabain, and vascular α2Na+pumps and NCX1, are critical links between salt and hypertension. New pharmacological agents that act on these molecular links have potential in the clinical management of hypertension.
Automated method for the isolation of collecting ducts
Authors: Miller R. Lance , Zhang Ping , Chen Tong , Rohrwasser Andreas , Nelson Raoul D.
Published: February 2006

The structural and functional heterogeneity of the collecting duct present a tremendous experimental challenge requiring manual microdissection, which is time-consuming, labor intensive, and not amenable to high throughput. To overcome these limitations, we developed a novel approach combining the use of transgenic mice expressing green fluorescent protein (GFP) in the collecting duct with large-particle-based flow cytometry to isolate pure populations of tubular fragments from the whole collecting duct (CD), or inner medullary (IMCD), outer medullary (OMCD), or connecting segment/cortical collecting duct (CNT/CCD). Kidneys were enzymatically dispersed into tubular fragments and sorted based on tubular length and GFP intensity using large-particle-based flow cytometry or a complex object parametric analyzer and sorter (COPAS). A LIVE/DEAD assay demonstrates that the tubules were >90% viable. Tubules were collected as a function of fluorescent intensity and analyzed by epifluorescence and phase microscopy for count accuracy, GFP positivity, average tubule length, and time required to collect 100 tubules. Similarly, mRNA and protein from sorted tubules were analyzed for expression of tubule segment-specific genes using quantitative real-time RT-PCR and immunoblotting. The purity and yield of sorted tubules were related to sort stringency. Four to six replicates of 100 collecting ducts (9.68 ± 0.44–14.5 ± 0.66 cm or 9.2 ± 0.7 mg tubular protein) were routinely obtained from a single mouse in under 1 h. In conclusion, large-particle-based flow cytometry is fast, reproducible, and generates sufficient amounts of highly pure and viable collecting ducts from single or replicate animals for gene expression and proteomic analysis.
Angiotensin II-induced calcium signaling in the afferent arteriole from rats with two-kidney, one-clip hypertension
Authors: Helle Frank , Vågnes Øyvind B. , Iversen Bjarne M.
Published: February 2006

The aim of this study was to investigate ANG II-induced Ca2+signaling in freshly isolated afferent arterioles (AA) from two-kidney, one-clip hypertensive (2K1C) rats, which have an elevated plasma and renal ANG II level, and different perfusion pressure and vascular tone in the clipped and nonclipped kidney. The Ca2+responses in vessels from 2K1C and control rats were similar in all groups ( P > 0.1). The intracellular Ca2+(Cai2+) response in the afferent arteriole after 10−8M ANG II stimulation was 0.57 ± 0.10, 0.50 ± 0.07, 0.48 ± 0.04, and 0.36 ± 0.05 in the control, sham, nonclipped, and clipped kidney, respectively. These data were consistent with the finding of unchanged AT1aR mRNA levels in AAs from all groups. Although the absolute values were similar, the dose-response curves to ANG II were different. In the control, sham, and nonclipped kidney from 2K1C, the dose-response curve leveled off between 10−8and 10−6M ANG II. In the clipped kidney, the dose-response curve was linear, with a significantly increased response at 10−6M compared with 10−8M ANG II ( P < 0.05). Inhibition of cyclooxygenase-1 (COX-1) with indomethacin enhanced the ANG II response in the nonclipped (Δ0.30 ± 0.09) and clipped (Δ0.30 ± 0.09) kidneys from 2K1C ( P < 0.005), but not in control rats (Δ−0.02 ± 0.11, P > 0.8). Conclusively, the ANG II-induced Cai2+response was reduced by COX-1-derived prostaglandins in 2K1C, in contrast to control animals, where the COX-1 inhibition had no effect. COX-2 inhibition with NS-398 did not increase the ANG II-mediated Cai2+response in any of the groups.
Inhibition of p21 modifies the response of cortical proximal tubules to cisplatin in rats
Authors: Zhou Hua , Fujigaki Yoshihide , Kato Akihiko , Miyaji Takehiko , Yasuda Hideo , Tsuji Takayuki , Yamamoto Tatsuo , Yonemura Katsuhiko , Hishida Akira
Published: February 2006

The purpose of this study was to evaluate whether upregulated p21, a cell cycle-inhibitory protein, contributes to cisplatin (CDDP)-induced acute renal failure (ARF) and to acquired resistance to rechallenge injury with CDDP in rats. ARF was induced in rats by injection of CDDP (5 mg/kg) and rechallenge injury to CDDP by the same dose of CDDP 14 days after the first CDDP injection. Rats were treated with p21 antisense oligodeoxynucleotide (ODN) or its vehicle, p21 sense ODN, every 36 h from days 0 to 5 for single CDDP and from days 13 to 19 for rechallenge injury and killed at day 3, 5, 16, or 19. The uptake of FITC-labeled p21 antisense ODNs by cortical proximal tubule (PT) cells was much greater than by PT cells in the outer stripe of outer medulla (OSOM). Administration of antisense induced partial downregulation of p21 mRNA and protein levels in whole kidneys with single CDDP treatment and its rechallenge injury. Antisense significantly aggravated PT necrosis and decreased the number of p21-positive PT cells in the cortex but not in the OSOM in both CDDP-induced ARF and its rechallenge injury. However, antisense did not alter serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Our findings suggested that p21 plays, at least in part, a cytoprotective role in cortical PTs exposed to CDDP, although this does not contribute to renal dysfunction when judged by Scrand BUN levels. Because antisense may not adequately be taken up and/or function in PTs in the OSOM, the role of p21 in PTs in the OSOM in CDDP-induced ARF remains to be clarified.
No effect of menstrual cycle phase on glycerol or palmitate kinetics during 90 min of moderate exercise
Authors: Horton Tracy J. , Miller Emily K. , Bourret Kristen
Published: February 2006

The systemic flux of glycerol and palmitate [a representative nonesterified free fatty acid (NEFA)] was assessed in three different phases of the menstrual cycle at rest and during moderate-intensity exercise. It was hypothesized that circulating glycerol and NEFA turnover would be greatest in the midfollicular (MF) phase of the menstrual cycle, when estrogen is elevated but progesterone low, followed by the midluteal phase (ML; high estrogen and progesterone), and lowest in the early follicular (EF) phase of the menstrual cycle (low estrogen and progesterone). Subjects included moderately active, eumenorrheic, healthy women. Testing occurred after 3 days of diet control and after an overnight fast (12–13 h). Resting and exercise (50% maximal oxygen uptake, 90 min) measurements of tracer-determined glycerol and palmitate kinetics were made. There was a significant increase in both glycerol and palmitate turnover from rest to exercise in all phases of the menstrual cycle ( P < 0.0001). No significant differences, however, were observed between cycle phases in the systemic flux of glycerol or palmitate, at rest or during exercise. Maximal peripheral lipolysis during exercise, as represented by glycerol rate of appearance at 90 min, equaled 8.45 ± 0.96, 8.35 ± 1.12, and 7.71 ± 0.96 μmol·kg−1·min−1in the EF, MF, and ML phases, respectively. Circulating free fatty acid utilization also peaked at 90 min of exercise, as indicated by the palmitate rate of disappearance (3.31 ± 0.35, 3.17 ± 0.39, and 3.47 ± 0.26 μmol·kg−1·min−1) in the EF, MF, and ML phases, respectively. In conclusion, systemic rates of glycerol and NEFA turnover (as represented by palmitate flux) were not significantly affected by the cyclic fluctuations in estrogen and progesterone that occur throughout the normal menstrual cycle, either at rest or during 90 min of moderate exercise.
Lower body negative pressure vs. lower body positive pressure to prevent cardiac atrophy after bed rest and spaceflight. What caused the controversy?
Authors: Pancheva Marieta V. , Panchev Vladimir S. , Suvandjieva Adelina V.
Published: February 2006

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 ( n = 5) and 12 ( n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 ± 2.2% ( P = 0.005) after 6 wk with an additional atrophy of 7.6 ± 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 ± 12.2 vs. 153.4 ± 12.1 g, P = 0.81). Mean wall thickness decreased (4 ± 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 ± 1.7% ( P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 ± 2.7% ( P = 0.06) and RV end-diastolic volume by 16 ± 7.9% ( P = 0.06). After spaceflight, LV mass decreased by 12 ± 6.9% ( P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.
Perivascular nerves and the regulation of cerebrovascular tone
Authors: Hamel Edith
Published: February 2006

Brain perfusion is tightly coupled to neuronal activity, is commonly used to monitor normal or pathological brain function, and is a direct reflection of the interactions that occur between neuronal signals and blood vessels. Cerebral blood vessels at the surface and within the brain are surrounded by nerve fibers that originate, respectively, from peripheral nerve ganglia and intrinsic brain neurons. Although of different origin and targeting distinct vascular beds, these “perivascular nerves” fulfill similar roles related to cerebrovascular functions, a major one being to regulate their tone and, therein, brain perfusion. This utmost function, which underlies the signals used in functional neuroimaging techniques and which can be jeopardized in pathologies such as Alzheimer's disease, stroke, and migraine headache, is thus regulated at several levels. Recently, new insights into our understanding of how neural input regulate cerebrovascular tone resulted in the rediscovery of the functional “neurovascular unit.” These remarkable advances suggest that neuron-driven changes in vascular tone result from interactions that involve all components of the neurovascular unit, transducing neuronal signals into vasomotor responses not only through direct interaction between neurons and vessels but also indirectly via the perivascular astrocytes. Neurovascular coupling is thus determined by chemical signals released from activated perivascular nerves and astrocytes that alter vascular tone to locally adjust perfusion to the spatial and temporal changes in brain activity.
Stimulus-Dependent Changes in the Vestibular Contribution to Human Postural Control
Authors: Cenciarini Massimo , Peterka Robert J.
Published: February 2006

Humans maintain stable stance in a wide variety of environments. This robust behavior is thought to involve sensory reweighting whereby the nervous system adjusts the relative contribution of sensory sources used to control stance depending on environmental conditions. Based on prior experimental and modeling results, we developed a specific quantitative representation of a sensory reweighting hypothesis that predicts that a given reduction in the contribution from one sensory system will be accompanied by a corresponding increase in the contribution from different sensory systems. The goal of this study was to test this sensory-reweighting hypothesis using measures that quantitatively assess the relative contributions of the proprioceptive and graviceptive (vestibular) systems to postural control during eyes-closed stance in different test conditions. Medial/lateral body sway was evoked by side-to-side rotation of the support surface (SS) while simultaneously delivering a pulsed galvanic vestibular stimulus (GVS) through electrodes behind the ears. A model-based interpretation of sway evoked by SS rotations provided estimates of the proprioceptive weighting factor, Wp, and showed that Wp declined with increasing SS amplitude. If the sensory-reweighting hypothesis is true, then the decline in Wp should be accompanied by a corresponding increase in Wg, the graviceptive weighting factor, and responses to the GVS should increase in proportion to the value of Wg derived from responses to SS rotations. Results were consistent with the predictions of the proposed sensory-reweighting hypothesis. GVS-evoked sway increased with increasing SS amplitude, and Wg measures derived from responses to GVS and from responses to SS rotations were highly correlated.
Transient and Steady-State Dynamics of Cortical Adaptation
Authors: Webber Roxanna M. , Stanley Garrett B.
Published: February 2006

Adaptation is a ubiquitous property of all sensory pathways of the brain and thus likely critical in the encoding of behaviorally relevant sensory information. Despite evidence identifying specific biophysical mechanisms contributing to sensory adaptation, its functional role in sensory encoding is not well understood, particularly in the natural environment where transient rather than steady-state activity could dominate the neuronal representation. Here, we show that the heterogeneous transient and steady-state adaptation dynamics of single cortical neurons in the rat vibrissa system were well characterized by an underlying state variable. The state was directly predictable from temporal response properties that capture the time course of postexcitatory suppression following an isolated vibrissa deflection. Altering the initial state, by preceding the periodic stimulus with an additional vibrissa deflection, strongly influenced single-cell transient cortical adaptation responses. Despite the different transient activity, neurons reached the same steady-state adapted response with a time to steady state that was independent of the initial state. However, the differences in transient activity observed on small time scales were not present when activity was integrated over the longer time scale of a stimulus cycle. Taken together, the results here demonstrate that although adaptation can have significant effects on transient neuronal activity and direction selectivity, a simple measure of the time course of suppression following an isolated stimulus predicted a large portion of the observed adaptation dynamics.
Gene expression in human small intestinal mucosa in vivo is mediated by iron-induced oxidative stress
Authors: Troost Freddy J. , Brummer Robert-Jan M. , Haenen Guido R. M. M. , Bast Aalt , van Haaften Rachel I. , Evelo Chris T. , Saris Wim H. M.
Published: February 2006

Iron-induced oxidative stress in the small intestine may alter gene expression in the intestinal mucosa. The present study aimed to determine which genes are mediated by an iron-induced oxidative challenge in the human small intestine. Eight healthy volunteers [22 yr(SD2)] were tested on two separate occasions in a randomized crossover design. After duodenal tissue sampling by gastroduodenoscopy, a perfusion catheter was inserted orogastrically to perfuse a 40-cm segment of the proximal small intestine with saline and, subsequently, with either 80 or 400 mg of iron as ferrous gluconate. After the intestinal perfusion, a second duodenal tissue sample was obtained. Thiobarbituric acid-reactive substances, an indicator of lipid peroxidation, in intestinal fluid samples increased significantly and dose dependently at 30 min after the start of perfusion with 80 or 400 mg of iron, respectively ( P < 0.001). During the perfusion with 400 mg of iron, the increase in thiobarbituric acid-reactive substances was accompanied by a significant, momentary rise in trolox equivalent antioxidant capacity, an indicator of total antioxidant capacity ( P < 0.05). The expression of 89 gene reporters was significantly altered by both iron interventions. Functional mapping showed that both iron dosages mediated six distinct processes. Three of those processes involved G-protein receptor coupled pathways. The other processes were associated with cell cycle, complement activation, and calcium channels. Iron administration in the small intestine induced dose-dependent lipid peroxidation and a momentary antioxidant response in the lumen, mediated the expression of at least 89 individual gene reporters, and affected at least six biological processes.
Functional mapping for genetic control of programmed cell death
Authors: Cui Yuehua , Zhu Jun , Wu Rongling
Published: February 2006

“Naturally occurring” or “programmed” cell death (PCD) in which the cell uses specialized cellular machinery to kill itself is a ubiquitous phenomenon that occurs early in organ development. Such a cell suicide mechanism that enables metazoans to control cell number and eliminate cells threatening the organism’s survival has been thought to be under genetic control. In this report, we develop a novel statistical model for mapping specific genes or quantitative trait loci (QTL) that are responsible for the PCD process based on polymorphic molecular markers. This model incorporates the biological mechanisms of PCD that undergoes two different developmental stages, exponential growth and polynomial death. We derived a parametric approach to model the exponential growth and a nonparametric approach based on the Legendre function to model the polynomial death. A series of stationary and nonstationary models has been used to approximate the structure of the covariance matrix among cell numbers at a multitude of different times. The statistical behavior of our model is investigated through simulation studies and validated by a real example in rice.
Detection of differential gene expression in brown adipose tissue of hibernating arctic ground squirrels with mouse microarrays
Authors: Yan Jun , Burman Adlai , Nichols Calen , Alila Linda , Showe Louise C. , Showe Michael K. , Boyer Bert B. , Barnes Brian M. , Marr Thomas G.
Published: February 2006

Hibernation is an energy-saving strategy adopted by a wide range of mammals to survive highly seasonal or unpredictable environments. Arctic ground squirrels living in Alaska provide an extreme example, with 6- to 9-mo-long hibernation seasons when body temperature alternates between levels near 0°C during torpor and 37°C during arousal episodes. Heat production during hibernation is provided, in part, by nonshivering thermogenesis that occurs in large deposits of brown adipose tissue (BAT). BAT is active at tissue temperatures from 0 to 37°C during rewarming and continuously at near 0°C during torpor in subfreezing conditions. Despite its crucial role in hibernation, the global gene expression patterns in BAT during hibernation compared with the nonhibernation season remain largely unknown. We report a large-scale study of differential gene expression in BAT between winter hibernating and summer active arctic ground squirrels using mouse microarrays. Selected differentially expressed genes identified on the arrays were validated by quantitative real-time PCR using ground squirrel specific primers. Our results show that the mRNA levels of the genes involved in nearly every step of the biochemical pathway leading to nonshivering thermogenesis are significantly increased in BAT during hibernation, whereas those of genes involved in protein biosynthesis are significantly decreased compared with summer active animals in August. Surprisingly, the differentially expressed genes also include adipocyte differentiation-related protein or adipophilin ( Adfp), gap junction protein 1 ( Gja1), and secreted protein acidic and cysteine-rich ( Sparc), which may play a role in enhancing thermogenesis at low tissue temperatures in BAT.
Enteric Flora in Health and Disease
Authors: Guarner Francisco
Published: February 2006

The human gut is the natural habitat for a large and dynamic bacterial community. Recently developed molecular biology tools suggest that a substantial part of these bacterial populations are still to be described. However, the relevance and impact of resident bacteria on host’s physiology and pathology is well documented. Major functions of the gut microflora include metabolic activities that result in salvage of energy and absorbable nutrients, protection of the colonized host against invasion by alien microbes, and important trophic effects on intestinal epithelia and on immune structure and function. Gut bacteria play an essential role in the development and homeostasis of the immune system. It is important to underscore that the specialised lymphoid follicles of the gut mucosa are the major sites for induction and regulation of the immune system. On the other hand, there is evidence implicating the gut flora in certain pathological conditions, including multisystem organ failure, colon cancer and inflammatory bowel diseases.
Experimental and Clinical Pharmacology of Rifaximin, a Gastrointestinal Selective Antibiotic
Authors: Scarpignato Carmelo , Pelosini Iva
Published: February 2006

Rifaximin (4-deoxy-4′-methylpyrido[1′,2′-1,2]imidazo [5,4-c]rifamycin SV) is a product of synthesis experiments designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal (GI) absorption while retaining good antibacterial activity. Both experimental and clinical pharmacology clearly show that this compound is a non-systemic antibiotic with a broad spectrum of antibacterial action covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. Being virtually non-absorbed, its bioavailability within the GI tract is rather high with intraluminal and fecal drug concentrations that largely exceed the minimum inhibitory concentration values observed in vitro against a wide range of pathogenic organisms. The GI tract represents therefore the primary therapeutic target and GI infections the main indication. This antibiotic has therefore little value outside the enteric area and this will minimize both antimicrobial resistance and systemic adverse events. Indeed, the drug proved to be safe in all patient populations, including young children. The appreciation of the pathogenic role of gut bacteria in several organic and functional GI diseases has increasingly broadened its clinical use, which is now extended to hepatic encephalopathy, small intestine bacterial overgrowth, inflammatory bowel disease and colonic diverticular disease.
Management of Hepatic Encephalopathy: Focus on Antibiotic Therapy
Authors: Festi Davide , Vestito Amanda , Mazzella Giuseppe , Roda Enrico , Colecchia Antonio
Published: February 2006

Hepatic encephalopathy (HE) is a major neuropsychiatric complication of both acute and chronic liver failure. Symptoms of HE include attention deficits, alterations of sleep patterns and muscular incoordination progressing to stupor and coma. The pathogenesis of HE is still unknown, although ammonia-induced alterations of cerebral neurotransmitter balance, especially at the astrocyte-neurone interface, may play a major role. Treatment of HE is therefore directed at reducing the production and absorption of gut-derived neurotoxic substances, especially ammonia. The non-absorbable disaccharides lactulose and lactitol were long considered as a first-line pharmacological treatment of HE, but a recent systematic review questioned their efficacy, pointing out that there is insufficient high-quality evidence to support their use. Oral antibiotics are regarded as a suitable therapeutic alternative. However, the prolonged use of antimicrobials is precluded by the possible occurrence of adverse events. Rifaximin, a synthetic antibiotic structurally related to rifamycin, displays a wide spectrum of antibacterial activity against Gram-negative and Gram-positive bacteria, both aerobic and anaerobic, and a very low rate of systemic absorption. Available evidence suggests that rifaximin – thanks to its efficacy and remarkable safety – has the highest benefit-risk ratio in the overall treatment of HE.