bluuebunny/crossref_metadata_2025 huggingface dataset:
Undersensing of VF in a Patient With Optimal R Wave Sensing During Sinus Rhythm
Authors: DEKKER LUKAS R.C. , SCHRAMA TIM A.M. , STEINMETZ FRANS H.L. , TUKKIE RAYMOND
Published: May 2004

We describe a case of potentially fatal undersensing of VF by a third generation ICD with predetermined automatic gain control. In this patient, ventricular sensing was optimal, as R wave amplitudes during sinus rhythm were at least 16 mV. Cyclical, high amplitude signals during VF elevated the sensing floor to such an extent that complete undersensing of subsequent lower amplitude local electrograms occurred. This led to bradypacing and complete ICD therapy failure. Therefore, high R wave amplitudes during sinus rhythm do not warrant flawless sensing during VF. (PACE 2004; 27[Pt. I] 833–834)
Chronic Right Ventricular Pacing and Cardiac Performance:
Authors: KARPAWICH PETER P.
Published: May 2004

Cardiac stimulation from right ventricular apical or free‐wall lead positions alters inter‐ and intraventricular impulse conduction and distorts biventricular contractility. This may contribute to eventual cellular remodeling and the development of histopathological changes which, over time, adversely affect left ventricular systolic and diastolic functions. This concept has especially important implications when pacemaker therapy is initiation in young patients. Recent studies demonstrating physiological benefits of right ventricular septal, outflow, or bundle of His pacing, in deference to the apical implant site, have gained interest to potentially prevent dysfunction and improve paced myocardial contractility. Pacing initiated in children can be expected to have more far‐reaching consequences than pacing initiated in the elderly. Unfortunately, there have been limited clinical pediatric studies that evaluate precise site‐specific lead locations. This current report presents a review of pacemaker applications in children, both with and without structural congenital heart defects, including the earliest applications in which patient survival was the prime concern, to more recent studies attempting to optimize physiological and histological parameters associated with pacemaker induced contractility. The past decade has seen direct evidence that right ventricular apical pacing in children contributes to adverse histological remodeling and eventual contractile dysfunction. More recent studies demonstrate that selective site pacing can be effectively applied to all children with and without structural congenital defects and shows promise in the prevention of previously documented adverse remodeling and deterioration of systemic ventricular contractility. (PACE 2004; 27[Pt. II]:844–849)
Selective Site Pacing:
Authors: FRÖHLIG GERD , SCHWAAB BERNHARD , KINDERMANN MICHAEL
Published: May 2004

Animal data and recent findings in humans have questioned the appropriateness of pacing the heart from the right ventricular apex. Numerous, mostly small sized, studies have evaluated alternative sites within the right ventricle. There is now sufficient evidence that right ventricular apical pacing in patients with left ventricular dysfunction with or without heart failure is detrimental. Pacing from the right side of the heart as an attempt at nonpharmacological therapy for heart failure, turns out to be obsolete. In antibradycardia pacing with the need for continuous ventricular support, the interest in preserving left ventricular function drives the ongoing search for the most favorable pacing site within the right ventricle. Results, so far, are conflicting which may be attributed to the inhomogeneity of patient groups, the small cohorts studied, the differing protocols used, and the lack of accepted definitions of right ventricular lead positions. Larger studies are needed to evaluate intraoperative criteria for optimal lead placement and the potential benefit of nonapical right ventricular pacing. (PACE 2004; 27[Pt. II]:855–861)
Implantable Transvenous Pacing Leads:
Authors: MOND HARRY G. , GRENZ DAVID
Published: May 2004

With the dawn of a new millennium, physicians' demands for very thin transvenous leads able to be positioned in nontraditional sites like the Bachmann's bundle, the high and mid‐right ventricular septum, and the His bundle have created new and exciting challenges for lead engineers. Bipolar leads can now be as thin and reliable as unipolar leads. Cathode electrodes are very small, porous, and demonstrate high impedance. To optimize stimulation thresholds, steroid‐eluting passive‐ and active‐fixation electrodes have become popular for use in the atrium and ventricle. To create thin lead body diameters, new insulation and conductor materials and lead body designs are necessary. Hybrid medical materials having the best features of silicone rubber and polyurethane will allow for reliable insulation. Conductor cables instead of helical coils permit strong thin diameter leads to be designed. Transvenous lead implantation using the traditional stylet may not be possible with thin diameter leads, necessitating the use of sophisticated workstations using steerable catheters to guide these new active‐fixation leads to selective sites in the right heart. The pacing lead of the future may be very different from the one used today. Ironically, it will have features and implantation techniques similar to the transvenous leads designed prior to the use of the stylet. We are now approaching full circle in lead development, retracing the footprints of the early implanters of three and a half decades ago. (PACE 2004; 27[Pt. II]:887–893)
Sonographic features of drug‐induced splenic congestion
Authors: O'Brien Robert T. , Waller Kenneth R. , Osgood Teresa L.
Published: May 2004

Drug‐induced splenic congestion has been reported in dogs secondary to barbiturate administration. This research attempted to verify and quantify size changes associated with drug‐induced splenic congestion in dogs. Transverse plane ultrasound images of the spleen in normal dogs were collected to determine the maximum diameter in the minimum dimension prior to, and 15 min after, administration of acepromazine, thiopental, or propofol. Significant splenic enlargement was seen after administration of acepromazine (P<0.01) and thiopental (P=0.02), but no enlargement was seen after administration of propofol. Significantly increased attenuation (P<0.01) and a trend of increased backscatter (P=0.09) were measured after administration of acepromazine. These results indicate that measurable splenomegaly occurs after acepromazine and thiopental administration. This represents the first report of a condition causing measurable diffuse increased attenuation in the spleen. Propofol does not cause measurable splenic enlargement under the conditions of this research.
Mapping receptive fields in primary visual cortex
Authors: Ringach Dario L.
Published: May 2004

Nearly 40 years ago, in the pages of this journal, Hubel and Wiesel provided the first description of receptive fields in the primary visual cortex of higher mammals. They defined two classes of cortical cells, ‘simple’ and ‘complex’, based on neural responses to simple visual stimuli. The notion of a hierarchy of receptive fields, where increasingly intricate receptive fields are constructed from more elementary ones, was introduced. Since those early days we have witnessed the birth of quantitative methods to map receptive fields and mathematical descriptions of simple and complex cell function. Insights gained from these models, along with new theoretical concepts, are refining our understanding of receptive field structure and the underlying cortical circuitry. Here, I provide a brief historical account of the evolution of receptive field mapping in visual cortex along with the associated conceptual advancements, and speculate on the shape novel theories of the cortex may take as a result these measurements.
Protein Kinase G from Pathogenic Mycobacteria Promotes Survival Within Macrophages
Authors: Walburger Anne , Koul Anil , Ferrari Giorgio , Nguyen Liem , Prescianotto-Baschong Cristina , Huygen Kris , Klebl Bert , Thompson Charles , Bacher Gerald , Pieters Jean
Published: May 2004

Pathogenic mycobacteria resist lysosomal delivery after uptake into macrophages, allowing them to survive intracellularly. We found that the eukaryotic-like serine/threonine protein kinase G from pathogenic mycobacteria was secreted within macrophage phagosomes, inhibiting phagosome-lysosome fusion and mediating intracellular survival of mycobacteria. Inactivation of protein kinase G by gene disruption or chemical inhibition resulted in lysosomal localization and mycobacterial cell death in infected macrophages. Besides identifying a target for the control of mycobacterial infections, these findings suggest that pathogenic mycobacteria have evolved eukaryotic-like signal transduction mechanisms capable of modulating host cell trafficking pathways.
DEVELOPING CASE-BASED REASONING FOR DISCOVERY OF BREAST CANCER
Authors: FOK S. C. , NG E. Y. K. , THIMM G. L.
Published: May 2004

The treatment of early development of breast tumor has a higher success rate. This paper presents a framework for the early discovery of breast cancer. The objective is to assist the general practitioners and specialists in the detection of breast tumor. The proposed detection process consists of a preliminary screening process and a prediction process. The preliminary screening process using thermography aims to complement the detailed screening operation using mammography. The prediction process using artificial intelligence techniques aims to use past records of other similar cases to enhance the forecast of breast cancer development. The paper discusses the issues and techniques for the implementation of the proposed framework. These include the preliminary screening process, the retrieval of the relevant cases, and the prediction of the risk of developing breast cancer based on the thermographs, environmental/social data, physiological information, genetic factors, and medical records. This work constitutes initial effort to lessen the burden of medical professionals and increase the chances of successful treatment for patients in the fight against breast cancer.
SPATIAL AND MECHANOEMISSION CHAOS OF MECHANICALLY DEFORMED TUMOR CELLS
Authors: OREL VALERIY E. , GRINEVICH YURI A. , DZYATKOVSKAYA NATALIYA N. , DANKO MICHAIL I. , ROMANOV ANDRIY V. , MEL'NIK YURI I. , MARTYNENKO SVETLANA V.
Published: May 2004

The development and spend of the tumor process is accompanied by changes in non-linear (chaotic) dynamics of mechanochemical interaction process in the group of cells. Taking into consideration spatial irregularity and heterogeneity of internal structures of tumor cells, we suggested that treatment by mechanically deformed (MD) syngeneic tumor cells (STC) would be accompanied by changed influence on malignant growth. The objective of this work was to compare spatial, mechanoemission (ME) chaos of MD STC of carcinoma Lewis and melanoma B16 and their malignant growth. MD STC preparation included the aseptic removal of the animal tumor, lyophilization and next mechanical deformation in the microvibratory mill. The suspension of non-deformed or MD STC was injected intraperitoneally. Morphological, morphometric and mechanoemission studies were used for the estimate of spatial chaos and heterogeneity structure in tumor cells and blood. For Lewis carcinoma, the reduction of spatial and ME chaos of cells is accompanied by regression in tumor growth and metastasis. For melanoma B16, the decrease of spatial chaos and the increase of ME chaos in cells are accompanied by the initiation of tumor growth and metastasis. These results illustrated equivalent tendencies in chaos changing in spatial and ME chaos for carcinoma Lewis, while opposite tendencies were observed for melanoma B16. Blood ME of mice with melanoma B16 have greater ME chaos in comparison with animals with Lewis carcinoma. This confirmed that the concept of deterministic chaos is hierarchical for the host during cancer process. Results of comparative analysis between spatial, mechanoemission chaos of MD STC and malignant growth could be useful to gain a better understanding relationship of non-linear biomechanical processes to tumor cells.
Calcium-dependent regulation of calcium efflux by the cardiac sodium/calcium exchanger
Authors: Chernysh Olga , Condrescu Madalina , Reeves John P.
Published: May 2004

Allosteric regulation by cytosolic Ca2+ of Na+/Ca2+ exchange activity in the Ca2+ efflux mode has received little attention because it has been technically difficult to distinguish between the roles of Ca2+ as allosteric activator and transport substrate. In this study, we used transfected Chinese hamster ovary cells to compare the Ca2+ efflux activities in nontransfected cells and in cells expressing either the wild-type exchanger or a mutant, Δ(241–680), that operates constitutively; i.e., its activity does not require allosteric Ca2+ activation. Expression of the wild-type exchanger did not significantly lower the cytosolic Ca2+ concentration ([Ca2+]i) compared with nontransfected cells. During Ca2+ entry through store-operated Ca2+ channels, Ca2+ efflux by the wild-type exchanger became evident only after [Ca2+]i approached 100–200 nM. A subsequent decline in [Ca2+]i was observed, suggesting that the activation process was time dependent. In contrast, Ca2+ efflux activity was evident under all experimental conditions in cells expressing the constitutive exchanger mutant. After transient exposure to elevated [Ca2+]i, the wild-type exchanger behaved similarly to the constitutive mutant for tens of seconds after [Ca2+]i had returned to resting levels. We conclude that Ca2+ efflux activity by the wild-type exchanger is allosterically activated by Ca2+, perhaps in a time-dependent manner, and that the activated state is briefly retained after the return of [Ca2+]i to resting levels.
Interleukin-6-induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow
Authors: Ni Chih-Wen , Hsieh Hsyue-Jen , Chao Yuen-Jen , Wang Danny Ling
Published: May 2004

Endothelial cells (ECs) are constantly exposed to shear stress, the action of which triggers signaling pathways and cellular responses. During inflammation, cytokines such as IL-6 increase in plasma. In this study, we examined the effects of steady flow on IL-6-induced endothelial responses. ECs exposed to IL-6 exhibited STAT3 activation via phosphorylation of Tyr705. However, when ECs were subjected to shear stress, shear force-dependent suppression of IL-6-induced STAT3 phosphorylation was observed. IL-6 treatment increased the phosphorylation of JAK2, an upstream activator of STAT3. Consistently, shear stress significantly reduced IL-6-induced JAK2 activation. Pretreatment of ECs with an inhibitor of MEK1 did not alter this suppression by shear stress, indicating that extracellular signal-regulated kinase (ERK1/2) was not involved. However, pretreatment of ECs with an endothelial nitric oxide synthase inhibitor (nitro-l-arginine methyl ester) attenuated this inhibitory effect of shear stress on STAT3 phosphorylation. Shear stress-treated ECs displayed decreased nuclear transmigration of STAT3 and reduced STAT3 binding to DNA. Intriguingly, ECs exposed to IL-6 entered the cell cycle, as evidenced by increasing G2/M phase, and shear stress to these ECs significantly reduced IL-6-induced cell cycle progression. STAT3-mediated IL-6-induced cell cycle was confirmed by the inhibition of the cell cycle in ECs infected with adenovirus carrying the inactive mutant of STAT3. Our study clearly shows that shear stress exerts its inhibitory regulation by suppressing the IL-6-induced JAK2/STAT3 signaling pathway and thus inhibits IL-6-induced EC proliferation. This shear force-dependent inhibition of IL-6-induced JAK2/STAT3 activation provides new insights into the vasoprotective effects of steady flow on ECs against cytokine-induced responses.
Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis
Authors: Deng Jiangping , Muthu Kuzhali , Gamelli Richard , Shankar Ravi , Jones Stephen B.
Published: May 2004

Enhanced adrenergic stimulation and catecholamine release are important components of the pathophysiology of sepsis. Under physiological conditions, adrenergic stimulation has been shown to be a negative regulator of proinflammatory cytokine production through increasing IL-10 production. Here we have investigated if adrenergic stimulation similarly inhibits TNF-α and IL-6 production by splenic macrophages isolated from a polymicrobial sepsis model. Male B6D2F1 mice were subjected to sham (S), laparotomy (Lap), and cecal ligation and puncture (CLP) under anesthesia. Splenic macrophages were isolated 72 h after the initial injury and were stimulated with endotoxin (LPS) in the presence and absence of epinephrine. Compared with S and Lap, splenic macrophages from the CLP group produced significantly less TNF-α and IL-6 and more IL-10 when stimulated with LPS. Macrophage cultures from CLP animals incubated with either epinephrine or IL-10 for 2 h had significantly reduced TNF-α and IL-6 release in response to LPS. However, similar cultures pretreated with IL-10 antibody before the addition of exogenous epinephrine failed to reverse the attenuation of LPS-stimulated cytokines. Pretreatment of macrophage cultures with β2- (ICI-118551) but not β1-adrenergic (atenolol) receptor antagonists reversed the epinephrine-mediated cytokine attenuation following LPS treatment. Data are also presented that demonstrate the involvement of protein kinase A activation with adrenergic agonist but not with IL-10 stimulation. Taken together, these findings suggest that adrenergic mechanisms may influence peripheral tissue macrophage inflammatory cytokine response following trauma and sepsis, independent of the effects of IL-10.
Postexercise protein metabolism in older and younger men following moderate-intensity aerobic exercise
Authors: Sheffield-Moore M. , Yeckel C. W. , Volpi E. , Wolf S. E. , Morio B. , Chinkes D. L. , Paddon-Jones D. , Wolfe R. R.
Published: May 2004

Regular aerobic exercise strongly influences muscle metabolism in elderly and young; however, the acute effects of aerobic exercise on protein metabolism are not fully understood. We investigated the effect of a single bout of moderate walking (45 min at ∼40% of peak O2 consumption) on postexercise (POST-EX) muscle metabolism and synthesis of plasma proteins [albumin (ALB) and fibrinogen (FIB)] in untrained older ( n = 6) and younger ( n = 6) men. We measured muscle phenylalanine (Phe) kinetics before (REST) and POST-EX (10, 60, and 180 min) using l-[ ring-2H5]phenylalanine infusion, femoral arteriovenous blood samples, and muscle biopsies. All data are presented as the difference from REST (at 10, 60, and 180 min POST-EX). Mixed muscle fractional synthesis rate (FSR) increased significantly at 10 min POST-EX in both the younger (0.0363%/h) and older men (0.0830%/h), with the younger men staying elevated through 60 min POST-EX (0.0253%/h). ALB FSR increased at 10 min POST-EX in the younger men only (2.30%/day), whereas FIB FSR was elevated in both groups through 180 min POST-EX (younger men = 4.149, older men = 4.107%/day). Muscle protein turnover was also increased, with increases in synthesis and breakdown in younger and older men. Phe rate of disappearance (synthesis) was increased in both groups at 10 min POST-EX and remained elevated through 60 min POST-EX in the older men. A bout of moderate-intensity aerobic exercise induces short-term increases in muscle and plasma protein synthesis in both younger and older men. Aging per se does not diminish the protein metabolic capacity of the elderly to respond to acute aerobic exercise.
Foxl1null mice have abnormal intestinal epithelia, postnatal growth retardation, and defective intestinal glucose uptake
Authors: Katz Jonathan P. , Perreault Nathalie , Goldstein Bree G. , Chao Hann-Hsiang , Ferraris Ronaldo P. , Kaestner Klaus H.
Published: May 2004

Mice lacking the mesenchymal winged helix transcription factor Foxl1 exhibit markedly abnormal small intestinal epithelia and postnatal growth retardation. We investigated whether defects in intestinal nutrient uptake and specific transport processes exist in mice homozygous for a Foxl1 null allele ( Foxl1−/−). Foxl1−/−mice and controls on a defined genetic background were weighed regularly and killed at 2, 4, and 12 wk of age. Intestinal uptake studies, quantitative real-time PCR, RNase protection assays, and Western blot analyses were performed. Foxl1−/−mice have dysmorphic small intestinal epithelia and postnatal growth retardation. Foxl1−/−mice demonstrate decreased small intestinal uptake of d-glucose in all age groups studied. Intestinal uptake of d-fructose and two amino acids, l-proline and l-leucine, is not altered. Consistent with these findings, Foxl1−/−mice show decreased levels of the intestinal d-glucose transporter SGLT1. Expression of sucrase-isomaltase, lactase, GLUT2, and Na+-K+ATPase are not changed. Foxl1−/−mice demonstrate markedly abnormal intestinal epithelia, postnatal growth retardation, and decreased intestinal uptake of d-glucose. The specific effect of Foxl1 on intestinal d-glucose uptake is due to decreased production of SGLT1 protein in the small intestine. Thus we identified, for the first time, a link between a mesenchymal factor, Foxl1, and the regulation of a specific epithelial transport process.
Nitric oxide synthase stimulates prostaglandin synthesis and barrier function inC. parvum-infected porcine ileum
Authors: Gookin Jody L. , Duckett Laurel L. , Armstrong Martha U. , Stauffer Stephen H. , Finnegan Colleen P. , Murtaugh Michael P. , Argenzio Robert A.
Published: May 2004

Cell culture models implicate increased nitric oxide (NO) synthesis as a cause of mucosal hyperpermeability in intestinal epithelial infection. NO may also mediate a multitude of subepithelial events, including activation of cyclooxygenases. We examined whether NO promotes barrier function via prostaglandin synthesis using Cryptosporidium parvum-infected ileal epithelium in residence with an intact submucosa. Expression of NO synthase (NOS) isoforms was examined by real-time RT-PCR of ileal mucosa from control and C. parvum-infected piglets. The isoforms mediating and mechanism of NO action on barrier function were assessed by measuring transepithelial resistance (TER) and eicosanoid synthesis by ileal mucosa mounted in Ussing chambers in the presence of selective and nonselective NOS inhibitors and after rescue with exogenous prostaglandins. C. parvum infection results in induction of mucosal inducible NOS (iNOS), increased synthesis of NO and PGE2, and increased mucosal permeability. Nonselective inhibition of NOS ( NG-nitro-l-arginine methyl ester) inhibited prostaglandin synthesis, resulting in further increases in paracellular permeability. Baseline permeability was restored in the absence of NO by exogenous PGE2. Selective inhibition of iNOS [l- N6-(1-iminoethyl)-l-lysine] accounted for ∼50% of NOS-dependent PGE2synthesis and TER. Using an entire intestinal mucosa, we have demonstrated for the first time that NO serves as a proximal mediator of PGE2synthesis and barrier function in C. parvum infection. Expression of iNOS by infected mucosa was without detriment to overall barrier function and may serve to promote clearance of infected enterocytes.
Neuroprotection by a selective estrogen receptor β agonist in a mouse model of global ischemia
Authors: Carswell H.V.O. , Macrae I.M. , Gallagher L. , Harrop E. , Horsburgh K.J.
Published: May 2004

The present study employs selective estrogen receptor (ER) agonists to determine whether 17β-estradiol-induced neuroprotection in global ischemia is receptor mediated and, if so, which subtype of receptor (ERα or ERβ) is predominantly responsible. Halothane-anesthetized female C57Bl/6J mice were ovariectomized, and osmotic minipumps containing ERβ agonist diarylpropiolnitrile (DPN) (8 mg·kg−1·day−1, n = 12) or vehicle (50% DMSO in 0.9% saline) ( n = 9) or ERα agonist propyl pyrazole triol (PPT) (2 mg·kg−1·day−1, n = 13) or vehicle (50% DMSO in 0.9% saline) ( n = 10) were implanted subcutaneously. One week later transient global ischemia was induced by bilateral carotid artery occlusion under halothane anesthesia, and the mice were perfusion fixed 72 h later. ERβ agonist DPN significantly reduced ischemic damage by 70% in the caudate nucleus and 55% in the CA1 region compared with vehicle controls ( P < 0.05, Mann-Whitney U-statistic). In contrast, pretreatment with the ERα agonist PPT had no effect on the extent of neuronal damage compared with controls. The data indicate a significant estrogen receptor-mediated neuroprotection in a global cerebral ischemia model involving ERβ.
Mechanical and energetic effects of chronic chagasic patients' antibodies on rat myocardium
Authors: Savio-Galimberti Eleonora , Dos Santos Costa Patrícia , Campos de Carvalho Antônio Carlos , Ponce-Hornos Jorge Emilio
Published: May 2004

Chagasic (Ch) and nonchagasic (NCh) IgG fraction (20 μg/ml) effects on cardiac performance of adult Wistar rat ventricles were studied with a novel approach applying a microcalorimetric technique. Resting heat ( Hr) was significantly decreased by Ch antibodies (Δ HrCh = 4.8 ± 0.9 mW/g). Although the Hr decrease can be associated with diminished activity of the Na+/K+ pump, the magnitude of the effect (25% of control Hr) indicates that additional processes may also be affected. Ch antibodies induced an initial increase in developed pressure (P), which was associated with a decreased contractile economy. However, after 30 min of Ch antibody perfusion, P reached a significantly lower level (ΔPCh = 3.8 ± 1.2 mN/mm2) without changes in active heat per beat ( Ha). Consequently, Ha/P ratio increased, indicating that the energetic cost per unit of P was higher. In contrast, P and Ha were both significantly and reversibly decreased by NCh antibodies (ΔPNCh = 4.4 ± 1.2 mN/mm2; Δ HaNCh = 9.7 ± 2.2 mJ/g), but Ha/P remained unaffected. According to these data, normal hearts exposed to Ch antibodies present a biphasic mechanical response: 1) an initial period of increased contractility (and decreased global muscle economy) consistent with antibodies with β1-adrenergic activity, such as those used in the present study, and 2) a decrease in P at 30 min of Ch antibody perfusion, which suggests that another Ca2+-related mechanism is compromised. These data contribute to redefine the role of antibody-mediated responses in the pathophysiology of chronic chagasic cardiomyopathy as agents of myocardial failure.
Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure
Authors: Fratz Sohrab , Meyrick Barbara , Ovadia Boaz , Johengen Michael J. , Reinhartz Olaf , Azakie Anthony , Ross Greg , Fitzgerald Robert , Oishi Peter , Hess John , Black Stephen M. , Fineman Jeffrey R.
Published: May 2004

Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in utero placement of an aortopulmonary shunt. Immediately after spontaneous birth, shunt lambs were treated lifelong with either an endothelin A receptor antagonist (PD-156707) or placebo. At 4 wk of age, PD-156707-treated shunt lambs ( n = 6) had lower pulmonary vascular resistance and right atrial pressure than placebo-treated shunt lambs ( n = 8, P < 0.05). Smooth muscle thickness or arterial number per unit area was not different between the two groups. However, the number of alveolar profiles per unit area was increased in the PD-156707-treated shunt lambs (190.7 ± 5.6 vs. 132.9 ± 10.0, P < 0.05). Plasma endothelin-1 and cGMP levels and lung NOS activity, cGMP, eNOS, preproendothelin-1, endothelin-converting enzyme-1, endothelin A, and endothelin B receptor protein levels were similar in both groups. We conclude that chronic endothelin A receptor blockade attenuates the progression of pulmonary hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.
Thyroid hormone induces erythropoietin gene expression through augmented accumulation of hypoxia-inducible factor-1
Authors: Ma Yaluan , Freitag Patricia , Zhou Jie , Brüne Bernhard , Frede Stilla , Fandrey Joachim
Published: May 2004

Oxygen is of vital importance for the metabolism and function of all cells in the human body. Hypoxia, the reduction of oxygen supply, results in adaptationally appropriate alterations in gene expression through the activation of hypoxia-inducible factor 1 (HIF-1) to overcome any shortage of oxygen. Thyroid hormones are required for normal function of nearly all tissues, with major effects on oxygen consumption and metabolic rate. Thyroid hormones have been found to augment the oxygen capacity of the blood by increasing the production of erythropoietin (EPO) and to improve perfusion by vasodilation through the augmented expression of adrenomedullin (ADM). Because the hypoxic expression of both genes depends on HIF-1, we studied the influence of thyroid hormone on HIF-1 activation in the human hepatoma cell line HepG2 under normoxic and hypoxic conditions. We found that thyroid hormones increased HIF-1α protein accumulation by increasing HIF-1α protein synthesis rather than attenuating its proteasomal degradation. HIF-1α expression directly correlated with augmented HIF-1 DNA binding and transcriptional activity of luciferase reporter plasmids, whereas HIF-1β levels remained unaffected. Knocking down HIF-1α by short interfering RNA (siRNA) clearly demonstrated that thyroid hormone-induced target gene expression required the presence of HIF-1. Although an increased association of the two known coactivators of HIF-1, p300 and SRC-1, was found, thyroid hormone did not affect the activity of the isolated COOH-terminal transactivating domain of HIF-1α. Increased synthesis of HIF-1α may contribute to the adaptive response of increased oxygen demand under hyperthyroid conditions.
Entrainment of the master circadian clock by scheduled feeding
Authors: Castillo Marina R. , Hochstetler Kelly J. , Tavernier Ronald J. , Greene Dana M. , Bult-Ito Abel
Published: May 2004

The master circadian clock, located in the mammalian suprachiasmatic nuclei (SCN), generates and coordinates circadian rhythmicity, i.e., internal organization of physiological and behavioral rhythms that cycle with a near 24-h period. Light is the most powerful synchronizer of the SCN. Although other nonphotic cues also have the potential to influence the circadian clock, their effects can be masked by photic cues. The purpose of this study was to investigate the ability of scheduled feeding to entrain the SCN in the absence of photic cues in four lines of house mouse ( Mus domesticus). Mice were initially housed in 12:12-h light/dark cycle with ad libitum access to food for 6 h during the light period followed by 4–6 mo of constant dark under the same feeding schedule. Wheel running behavior suggested and circadian PER2 protein expression profiles in the SCN confirmed entrainment of the master circadian clock to the onset of food availability in 100% (49/49) of the line 2 mice in contrast to only 4% (1/24) in line 3 mice. Mice from line 1 and line 4 showed intermediate levels of entrainment, 57% (8/14) and 39% (7/18), respectively. The predictability of entrainment vs. nonentrainment in line 2 and line 3 and the novel entrainment process provide a powerful tool with which to further elucidate mechanisms involved in entrainment of the SCN by scheduled feeding.
CCK-induced inhibition of presympathetic vasomotor neurons: dependence on subdiaphragmatic vagal afferents and central NMDA receptors in the rat
Authors: Verberne Anthony J. M. , Sartor Daniela M.
Published: May 2004

Systemic administration of cholecystokinin (CCK) inhibits a subpopulation of rostral ventrolateral medulla (RVLM) presympathetic vasomotor neurons. This study was designed to determine whether this effect involved subdiaphragmatic vagal afferents and/or central N-methyl-d-aspartic acid (NMDA) receptors. Recordings were made from CCK-sensitive RVLM presympathetic vasomotor neurons in halothane-anesthetized, paralyzed male Sprague-Dawley rats. The responses of the neurons to CCK (2 and 4 μg/kg iv), phenylephrine (PE; 5 μg/kg iv), and phenylbiguanide (PBG; 5 μg/kg iv) were tested before and after application of the local anesthetic lidocaine (2% wt/vol gel; 1 ml) to the subdiaphragmatic vagi at the level of the esophagus. In seven separate experiments, lidocaine markedly reduced the inhibitory effects of CCK on RVLM presympathetic neuronal discharge rate. In other experiments, the effect of systemic administration of dizocilpine (1 mg/kg iv), a noncompetitive antagonist at NMDA receptor ion channels, on the RVLM presympathetic neuronal responses to CCK, PBG, and PE was tested. In all cases ( n = 6 neurons in 6 individual rats), dizocilpine inhibited the effects of CCK, PBG, and PE on RVLM presympathetic neuronal discharge. These results suggest that the effects of systemic CCK on the discharge of RVLM presympathetic neurons is mediated via an action on receptors located on subdiaphragmatic vagal afferents. Furthermore, the data suggest that CCK activates a central pathway involving NMDA receptors to produce inhibition of RVLM presympathetic neuronal discharge.
Effects of age on brachial artery myogenic responses in humans
Authors: Lott Mary E. J. , Herr Michael D. , Sinoway Lawrence I.
Published: May 2004

The myogenic response, the inherent ability of blood vessels to rapidly respond to changes in transmural pressure, is involved in local blood flow autoregulation. Animal studies suggest that aging impairs the myogenic response. The purpose of this study was to compare the effects of changes in transmural pressure on mean blood velocity (MBV, cm/s) in young and older subjects. Twelve younger men and women (25 ± 1 yr) were gender and body composition matched to twelve older men and women (65 ± 1 yr). A specially designed tank raised or lowered forearm pressure by 50 mmHg within 0.2 s. Brachial artery MBV was measured directly above the site of forearm pressure change using Doppler methods. In response to increasing transmural pressure (i.e., release of +50 mmHg), older subjects compared with younger subjects had significantly lower peak MBV (Δ 12.43 ± 1.16 vs. Δ 17.97 ± 2.01 cm/s; P < 0.05), reduced rates in the dynamic fall of MBV after peak values were achieved (vasoconstriction) (−1.88 ± 0.17 vs. −2.90 ± 0.28 cm·s−1·s−1; P < 0.05), and lower MBV values with sustained suction. In response to decreasing transmural pressure (i.e., change to +50 mmHg), there was a significantly greater increase in MBV (Δ peak flow from trough 7.71 ± 1.32 vs. 4.38 ± 0.71 cm/s; P < 0.05) and a trend toward a greater rate of rise in MBV (vasodilation; 1.61 ± 0.29 vs. 0.96 ± 0.21 cm·s−1·s−1; P = 0.08) in the older subjects. Older subjects compared with the younger subjects exhibited decreased dynamic vasoconstriction, enhanced steady-state constriction, as well as evidence for enhanced dynamic vasodilation responses to sustained alterations in forearm transmural pressure.
Basolateral ammonium transport by the mouse inner medullary collecting duct cell (mIMCD-3)
Authors: Handlogten Mary E. , Hong Seong-Pyo , Westhoff Connie M. , Weiner I. David
Published: May 2004

The renal collecting duct is the primary site for the ammonia secretion necessary for acid-base homeostasis. Recent studies have identified the presence of putative ammonia transporters in the collecting duct, but whether the collecting duct has transporter-mediated ammonia transport is unknown. The purpose of this study was to examine basolateral ammonia transport in the mouse collecting duct cell (mIMCD-3). To examine mIMCD-3 basolateral ammonia transport, we used cells grown to confluence on permeable support membranes and quantified basolateral uptake of the radiolabeled ammonia analog [14C]methylammonia ([14C]MA). mIMCD-3 cell basolateral MA transport exhibited both diffusive and transporter-mediated components. Transporter-mediated uptake exhibited a Kmfor MA of 4.6 ± 0.2 mM, exceeded diffusive uptake at MA concentrations below 7.0 ± 1.8 mM, and was competitively inhibited by ammonia with a Kiof 2.1 ± 0.6 mM. Transporter-mediated uptake was not altered by inhibitors of Na+-K+-ATPase, Na+-K+-2Cl−cotransporter, K+channels or KCC proteins, by excess potassium, by extracellular sodium or potassium removal or by varying membrane potential, suggesting the presence of a novel, electroneutral ammonia-MA transport mechanism. Increasing the outwardly directed transmembrane H+gradient increased transport activity by increasing Vmax. Finally, mIMCD-3 cells express mRNA and protein for the putative ammonia transporter Rh B-glycoprotein (RhBG), and they exhibit basolateral RhBG immunoreactivity. We conclude that mIMCD-3 cells express a basolateral electroneutral NH4+/H+exchange activity that may be mediated by RhBG.
Respiratory sinus arrhythmia in freely moving and anesthetized rats
Authors: Bouairi Evguenia , Neff Robert , Evans Cory , Gold Allison , Andresen Michael C. , Mendelowitz David
Published: May 2004

Heart rate increases during inspiration and slows during postinspiration; this respiratory sinus arrhythmia helps match pulmonary blood flow to lung inflation and maintain an appropriate diffusion gradient of oxygen in the lungs. This cardiorespiratory pattern is found in neonatal and adult humans, baboons, dogs, rabbits, and seals. Respiratory sinus arrhythmia occurs mainly due to inhibition of cardioinhibitory parasympathetic cardiac vagal neurons during inspiration. Surprisingly, however, a recent study in anesthetized rats paradoxically found an enhancement of cardiac vagal activity during inspiration, suggesting that rats have an inverted respiratory sinus arrhythmia (Rentero N, Cividjian A, Trevaks D, Pequignot JM, Quintin L, and McAllen RM. Am J Physiol Regul Integr Comp Physiol 283: R1327–R1334, 2002). To address this controversy, this study examined respiratory sinus arrhythmia in conscious freely moving rats and tested whether the commonly used experimental anesthetics urethane, pentobarbital sodium, or ketamine-xylazine alter respiratory sinus arrhythmia. Heart rate significantly increased 21 beats/min during inspiration in conscious rats, a pattern similar to the respiratory sinus arrhythmia that occurs in other species. However, anesthetics altered normal respiratory sinus arrhythmia. Ketamine-xylazine (87 mg/kg and 13 mg/kg) depressed and pentobarbital sodium (60 mg/kg) abolished normal respiratory sinus arrhythmia. Urethane (1 g/kg) inverted the cardiorespiratory pattern so that heart rate significantly decreased during inspiration. Our study demonstrates that heart rate normally increases during inspiration in conscious, freely moving rats, similar to the respiratory sinus arrhythmia pattern that occurs in other species but that this pattern is disrupted in the presence of general anesthetics, including inversion in the case of urethane. The presence and consequences of anesthetics need to be considered in studying the parasympathetic control of heart rate.
Excitation of Cerebellar Interneurons by Group I Metabotropic Glutamate Receptors
Authors: Karakossian Movses H. , Otis Thomas S.
Published: May 2004

Cerebellar basket and stellate neurons (BSNs) provide feed-forward inhibition to Purkinje neurons (PNs) and thereby play a principal role in determining the output of the cerebellar cortex. During low-frequency transmission, glutamate released at parallel fiber synapses excites BSNs by binding to AMPA receptors; high-frequency transmission also recruits N-methyl-d-aspartate (NMDA) receptors. We find that, in addition to these ligand-gated receptors, a G-protein–coupled glutamate receptor subtype participates in exciting BSNs. Stimulation of metabotropic glutamate receptor 1α (mGluR1α) with the mGluR agonist ( RS)-3,5-dihydroxyphenylglycine (DHPG) leads to an increase in spontaneous firing of BSNs and indirectly to an increase in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in PNs. Under conditions in which ligand-gated glutamate receptors are blocked, parallel fiber stimulation generates a slow excitatory postsynaptic current (EPSC) in BSNs that is inhibited by mGluR1α-selective antagonists. This slow EPSC is capable of increasing BSN spiking and indirectly increasing sIPSCs frequency in PNs. Our findings reinforce the idea that distinct subtypes of glutamate receptors are activated in response to different patterns of activity at excitatory synapses. The results also raise the possibility that mGluR1α-dependent forms of synaptic plasticity may occur at excitatory inputs to BSNs.
Neural Basis for the Hyperalgesic Action of Cholecystokinin in the Rostral Ventromedial Medulla
Authors: Heinricher Mary M. , Neubert Miranda J.
Published: May 2004

The analgesic actions of opioids can be modified by endogenous “anti-opioid” peptides, among them cholecystokinin (CCK). CCK is now thought to have a broader, pronociceptive role, and contributes to hyperalgesia in inflammatory and neuropathic pain states. The aim of this study was to determine whether anti-opioid and pronociceptive actions of CCK have a common underlying mechanism. We showed previously that a low dose of CCK microinjected into the rostral ventromedial medulla (RVM) blocked the analgesic effect of systemically administered morphine by preventing activation of off-cells, which are the antinociceptive output of this well characterized pain-modulating region. At this anti-opioid dose, CCK had no effect on the spontaneous activity of these neurons or on the activity of on-cells (hypothesized to facilitate nociception) or “neutral cells” (which have no known role in pain modulation). In this study, we used microinjection of a higher dose of CCK into the RVM to test whether activation of on-cells could explain the pronociceptive action of this peptide. Paw withdrawal latencies to noxious heat and the activity of a characterized RVM neuron were recorded in rats lightly anesthetized with methohexital. CCK (30 ng/200 nl) activated on-cells selectively and produced behavioral hyperalgesia. Firing of off-cells and neutral cells was unaffected. These data show that direct, selective activation of RVM on-cells by CCK is sufficient to produce thermal hyperalgesia and indicate that the anti-opioid and pronociceptive effects of this peptide are mediated by actions on different RVM cell classes.
Aldosterone Potentiates Angiotensin II–Induced Signaling in Vascular Smooth Muscle Cells
Authors: Mazak Istvan , Fiebeler Anette , Muller Dominik N. , Park Joon-Keun , Shagdarsuren Erdenechimeg , Lindschau Carsten , Dechend Ralf , Viedt Christiane , Pilz Bernhard , Haller Hermann , Luft Friedrich C.
Published: May 2004

Background—

In a double-transgenic human renin and human angiotensinogen rat model, we found that mineralocorticoid receptor (MR) blockade ameliorated angiotensin II (Ang II)–induced renal and cardiac damage. How Ang II and aldosterone (Ald) might interact is ill defined.

Methods and Results—

We investigated the effects of Ang II (10
−7
mol/L) and Ald (10
−7
mol/L) on extracellular signal–regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling in vascular smooth muscle cells (VSMCs) with Western blotting and confocal microscopy. Ang II induced ERK 1/2 and JNK phosphorylation by 2 minutes. Ald achieved the same at 10 minutes. Ang II+Ald had a potentiating effect by 2 minutes. Two oxygen radical scavengers and the epidermal growth factor receptor (EGFR) antagonist AG1478 reduced Ang II–, Ald-, and combination-induced ERK1/2 phosphorylation. Preincubating the cells with the MR blocker spironolactone (10
−6
mol/L) abolished Ang II–induced ROS generation, EGFR transactivation, and ERK1/2 phosphorylation.

Conclusions—

Ald potentiates Ang II–induced ERK-1/2 and JNK phosphorylation. Oxygen radicals, the MR, and the EGFR play a role in early signaling induced by Ang II and Ald in VSMCs. These in vitro data may help explain the effects of MR blockade on Ang II–induced end-organ damage in vivo.
Intra-Arrest Cooling Improves Outcomes in a Murine Cardiac Arrest Model
Authors: Abella Benjamin S. , Zhao Danhong , Alvarado Jason , Hamann Kim , Vanden Hoek Terry L. , Becker Lance B.
Published: May 2004

Background—

Recent clinical studies have demonstrated that hypothermia to 32° to 34°C provides significant clinical benefit when induced after resuscitation from cardiac arrest. However, cooling during the postresuscitation period was slow, requiring 4 to 8 hours to achieve target temperatures after return of spontaneous circulation (ROSC). Whether more rapid cooling would further improve survival remains unclear. We sought to determine whether cooling during cardiac arrest before ROSC (ie, “intra-arrest” hypothermia) has survival benefit over more delayed post-ROSC cooling, using a murine cardiac arrest model.

Methods and Results—

A model of potassium-induced cardiac arrest was established in C57BL/6 mice. After 8 minutes of untreated cardiac arrest, resuscitation was attempted with chest compression, ventilation, and intravenous fluid. Mice were randomized to 3 treatment groups (n=10 each): an intra-arrest hypothermia group, in which mice were cooled to 30°C just before attempted resuscitation, and then rewarmed after 1 hour; a post-ROSC hypothermia group, in which mice were kept at 37°C for 20 minutes after successful ROSC and then were cooled to 30°C for 1 hour; and a normothermic control group, in which mice were kept at 37°C. The intra-arrest hypothermia group demonstrated better 72-hour survival than delayed hypothermia and normothermia groups (6/10 versus 1/10 and 1/10 survivors, respectively,
P
<0.05), with similar differences seen at 6-hour survival and on neurological scoring.

Conclusions—

Timing of hypothermia is a crucial determinant of survival in the murine arrest model. Early intra-arrest cooling appears to be significantly better than delayed post-ROSC cooling or normothermic resuscitation.