bluuebunny/crossref_metadata_2025 huggingface dataset:
Visualization of the Membrane Temperature Field of a Polymer Electrolyte Fuel Cell
Authors: Shimoi Ryoichi , Masuda Masao , Fushinobu Kazuyoshi , Kozawa Yoshiyuki , Okazaki Ken
Published: December 2004

Membrane temperature field of a polymer electrolyte fuel cell (PEFC) has been visualized experimentally. PEFCs need further breakthrough for deployment in the market. One of the major issues is the temperature management of the polymer membrane and the whole cell that strongly govern system performance through electrochemical reactions, ion transport, water management, and gas supply. The temperature field of the membrane, however, had not been visualized due to the cell configuration. In our experiment, the thermography technique is applied to visualize an operating test cell. Despite the unique configuration, measured i-V characteristics guarantee the cell performance. The visualization results revealed several important characteristics that help us understanding the physics and suggest design knowledge. One major result is the existence of so called a hot spot. The membrane does have a temperature distribution, and a local temperature maximum may exceed the membrane design limitation. This trend, of course, is not favorable for design purposes. Also, the impact of the major operation parameters, such as current density, humidification, and gas flow configuration, have been clearly exhibited. The experimental results are examined by using the results of our previously developed numerical code. The code includes the conjugate nature of the electrochemical reaction and the heat and mass transport processes. By comparing the experiment and the calculation, the mechanisms of the hot-spot generation and the parameter dependence have been explained. The results revealed the physics and suggested essential design criteria.
Pharmacokinetics, Serum Inhibitory and Bactericidal Activity, and Safety of Telavancin in Healthy Subjects
Authors: Shaw J. P. , Seroogy J. , Kaniga K. , Higgins D. L. , Kitt M. , Barriere S.
Published: December 2004

The pharmacokinetics, tolerability, and serum inhibitory and bactericidal titers of telavancin, a new rapidly bactericidal lipoglycopeptide with multiple mechanisms of action against gram-positive pathogens, were assessed in a two-part, randomized, double-blind, placebo-controlled, ascending-dose study with 54 healthy men. In part 1, single ascending intravenous doses of 0.25 to 15 mg/kg of body weight were studied. In part 2, multiple ascending doses (30-min infusions of 7.5 to 15 mg/kg/day) were studied over 7 days. Following the administration of multiple doses, steady state was achieved by days 3 to 4. At day 7 after the administration of telavancin at 7.5, 12.5, and 15 mg/kg/day, peak concentrations in plasma were 96.7, 151.3, and 202.5 μg/ml, respectively, and steady-state area-under-the-curve values were 700, 1,033, and 1,165 μg · h/ml, respectively. The elimination half-life ranged from 6.9 to 9.1 h following the administration of doses ≥5 mg/kg. Most adverse events were mild in severity. At 24 h postinfusion, serum from subjects given telavancin demonstrated potent bactericidal activity against methicillin-resistant
Staphylococcus aureus
and penicillin-resistant
Streptococcus pneumoniae
strains. The results suggest that telavancin may be an effective once-daily therapy for serious bacterial infections caused by these pathogens.
OXA-58, a Novel Class D β-Lactamase Involved in Resistance to Carbapenems inAcinetobacter baumannii
Authors: Poirel Laurent , Marqué Sophie , Héritier Claire , Segonds Christine , Chabanon Gérard , Nordmann Patrice
Published: December 2004

A carbapenem-resistantAcinetobacter baumanniistrain was isolated in Toulouse, France, in 2003. Cloning and expression inEscherichia coliidentified the carbapenem-hydrolyzing β-lactamase OXA-58, which is weakly related (less than 50% amino acid identity) to other oxacillinases. It hydrolyzed penicillins, oxacillin, and imipenem but not expanded-spectrum cephalosporins. TheblaOXA-58gene was located on a ca. 30-kb non-self-transferable plasmid. After electrotransformation in theA. baumanniiCIP7010Treference strain, it conferred reduced susceptibility to carbapenems. TheblaOXA-58gene was bracketed by two novel ISAba3-like insertion elements. This study describes a newly characterized β-lactamase that may contribute to carbapenem resistance inA. baumannii.
Effects of Antifungal Interventions on the Outcome of Experimental Infections with Phenotypic Switch Variants ofCryptococcus neoformans
Authors: Fries Bettina C. , Cook Emily , Wang Xiabo , Casadevall Arturo
Published: December 2004

In cryptococcal infection, phenotypic switching from a smooth to a mucoid variant can occur in vivo, producing variants with enhanced virulence that are subsequently selected and affect the outcome of infection. Here, we demonstrate that antifungal treatment of the chronically infected host can promote this phenomenon. Amphotericin B treatment reduces fungal burden less effectively in mucoid variant-infected than in smooth variant-infected mice. Consequently, amphotericin B treatment resulted in a more pronounced prolongation of survival in smooth variant-infected than in mucoid variant-infected mice (20 versus 42 days;P< 0.05). Administration of anticapsular monoclonal antibody mediated better protection in smooth variant-infected than in mucoid variant-infected mice, although a protective effect was not consistently observed at all doses. Most interestingly, both antifungal drug therapy and administration of anticapsular monoclonal antibody promoted the selection of mucoid variants in smooth variant-infected mice, a phenomenon manifested by a statistically higher percentage of mucoid colonies in smooth variant-infected mice than in nontreated control mice. This finding suggests that both chemotherapeutic and immunological antifungal interventions may promote the selection of the more virulent mucoid variant, which could affect the outcome of infection in chronically infected hosts.
Increased Expression of Two Multidrug Transporter-Like Genes Is Associated with Ethidium Bromide and Ciprofloxacin Resistance in
Mycoplasma hominis
Authors: Raherison S. , Gonzalez P. , Renaudin H. , Charron A. , Bébéar C. , Bébéar C. M.
Published: December 2004

Two genes,
md1
and
md2
, coding for multidrug resistance ATP-binding cassette transporters were identified in
Mycoplasma hominis
PG21. Expression of these two genes, quantified by quantitative competitive reverse transcription-PCR, was significantly increased in ethidium bromide-resistant strains of
M. hominis
compared to that in
M. hominis
PG21.
Influence of Carbon Dioxide on the MIC of Telithromycin for
Streptococcus pneumoniae
: an In Vitro
-
In Vivo Study
Authors: Batard Eric , Juvin Marie Emmanuelle , Jacqueline Cédric , Bugnon Denis , Caillon Jocelyne , Potel Gilles , Drugeon Henri B.
Published: December 2004

Incubation in CO
2
resulted in higher (≥3 doubling dilution) MICs of telithromycin than those found in ambient air for 31.2% of 346
Streptococcus pneumoniae ermB
-positive strains. An increased telithromycin MIC in CO
2
was not correlated with loss of its activity in the murine sepsis/peritonitis model.
Molecular Aspects of Biogenesis of
Escherichia coli
Dr Fimbriae: Characterization of DraB-DraE Complexes
Authors: Piątek Rafał , Zalewska Beata , Kolaj Olga , Ferens Michał , Nowicki Bogdan , Kur Józef
Published: December 2004

The Dr hemagglutinin of uropathogenic
Escherichia coli
is a fimbrial homopolymer of DraE subunits encoded by the
dra
operon. The
dra
operon includes the
draB
and
draC
genes, whose products exhibit homology to chaperone-usher proteins involved in the biogenesis of surface-located polymeric structures. DraB is one of the periplasmic proteins belonging to the superfamily of PapD-like chaperones. It possesses two conserved cysteine residues characteristic of the FGL subfamily of Caf1M-like chaperones. In this study we obtained evidence that DraB cysteines form a disulfide bond in a mature chaperone and have the crucial function of forming the DraB-DraE binary complex. Expression experiments showed that the DraB protein is indispensable in the folding of the DraE subunit to a form capable of polymerization. Accumulation of DraB-DraE
n
oligomers, composed of head-to-tail subunits and the chaperone DraB, was observed in the periplasm of a recombinant
E. coli
strain which expressed DraB and DraE (but not DraC). To investigate the donor strand exchange mechanism during the formation of DraE oligomers, we constructed a series of DraE N-terminal deletion mutants. Deletion of the first three N-terminal residues of a potential donor strand resulted in a DraE protein lacking an oligomerization function. In vitro data showed that the DraE disulfide bond was not needed to form a binary complex with the DraB chaperone but was essential in the polymerization process. Our data suggest that assembly of Dr fimbriae requires a chaperone-usher pathway and the donor strand exchange mechanism.
Kinetics and Avidity of Antibodies Evoked by Heptavalent Pneumococcal Conjugate Vaccines PncCRM and PncOMPC in the Finnish Otitis Media Vaccine Trial
Authors: Ekström Nina , Åhman Heidi , Verho Jouko , Jokinen Jukka , Väkeväinen Merja , Kilpi Terhi , Käyhty Helena
Published: December 2004

The licensure of new pneumococcal conjugate vaccines (PCVs) relies on immunogenicity data. When defining correlates of protection, vaccine efficacy data must be included. In the FinOM Vaccine Efficacy Trial, the PncOMPC vaccine showed an efficacy profile similar to that of the licensed PncCRM vaccine despite different antibody responses after primary and booster vaccinations. We determined antibody kinetics and avidities in a subgroup of infants participating in the FinOM trial. A total of 166 infants in three vaccine groups were immunized at 2, 4, 6, and 12 months of age with 7-valent PCV, PncCRM or PncOMPC, or hepatitis B vaccine. Concentrations of serum immunoglobulin G (IgG) against pneumococcal capsular polysaccharides were determined at 2, 4, 6, 7, 12, 13, and 24 months of age, and the avidity index (AI) to serotypes 6B, 19F, and 23F were determined at 7, 12, 13, and 24 months of age by enzyme immunoassay. Both PCVs were highly immunogenic, but they demonstrated different kinetics of antibody response; the concentration of IgG against serotypes 6B, 19F, and 23F declined faster after the third and fourth doses of vaccine in the PncCRM group than in the PncOMPC group. For both PCVs, the mean AI of anti-6B and -23F, but not of anti-19F, increased during the follow-up, which is in line with serotype-specific protection in the FinOM trial. Our data suggest that the kinetics and avidities of antibodies should be considered, in addition to antibody responses, when defining correlates of protection.
Transient Neutralization of Tumor Necrosis Factor Alpha Can Produce a Chronic Fungal Infection in an Immunocompetent Host: Potential Role of Immature Dendritic Cells
Authors: Herring Amy C. , Falkowski Nicole R. , Chen Gwo-Hsiao , McDonald Rod A. , Toews Galen B. , Huffnagle Gary B.
Published: December 2004

The mechanisms underlying induction of immune dysregulation and chronic fungal infection by a transient tumor necrosis factor alpha (TNF-α) deficiency remain to be defined. The objective of our studies was to determine the potential contribution of neutropenia and immature dendritic cells to the immune deviation. Administration of an anti-TNF-α monoclonal antibody at day 0 neutralized TNF-α only during the first week of a pulmonaryCryptococcus neoformansinfection. Transient neutralization of TNF-α resulted in transient depression of interleukin-12 (IL-12), monocyte chemotactic protein 1 (MCP-1), and gamma interferon (IFN-γ) production but permanently impaired long-term clearance of the infection from the lungs even after the levels of these cytokines increased and a vigorous inflammatory response developed. Early neutrophil recruitment was defective in the absence of TNF-α. However, as demonstrated by neutrophil depletion studies, this did not account for the decrease in IL-12 and IFN-γ levels and did not play a role in establishing chronic pulmonary cryptococcal infection. Transient TNF-α neutralization also produced a deficiency in CD11c+MHC II+cells and IL-12 in the lymph nodes, potentially implicating a defect in mature dendritic cell trafficking. Transfer of cryptococcal antigen-pulsed immature dendritic cells into naïve mice prior to intratracheal challenge resulted in the development of a nonprotective immune response toC. neoformansthat was similar to that observed in anti-TNF-α-treated mice (increased IL-4, IL-5, and IL-10 levels, pulmonary eosinophilia, and decreased clearance). Thus, stimulation of an antifungal response by immature dendritic cells can result in an immune deviation similar to that produced by transient TNF-α deficiency, identifying a new mechanism by which a chronic fungal infection can occur in an immunocompetent host.
Enterococcus faecalis
Mammalian Virulence-Related Factors Exhibit Potent Pathogenicity in the
Arabidopsis thaliana
Plant Model
Authors: Jha Ajay K. , Bais Harsh P. , Vivanco Jorge M.
Published: December 2004

Some pathogenic bacteria belong to a large, diverse group of species capable of infecting plants, animals, and humans.
Enterococcus faecalis
is an opportunistic human pathogen capable of infecting patients with a deficient immune system. Here we report that three
E. faecalis
strains (FA-2-2, V583, and OG1RF) are capable of infecting the leaves and roots of the model plant species
Arabidopsis thaliana
, causing plant mortality 7 days postinoculation. We found that
E. faecalis
pathogenesis in
A. thaliana
leaves is determined by the following series of events: attachment to leaf surface, entry through stomata or wounds, and colonization in intercellular spaces, leading to rotting and to the disruption of plant cell wall and membrane structures. The three
E. faecalis
strains colonize the roots of
A. thaliana
by forming a mosaic of large clusters of live bacteria on the root surface, as observed by scanning electron microscopy, phase-contrast microscopy, and fluorescence microscopy. To dissect the involvement of mammalian virulence-related factors in plant pathogenicity, we tested
E. faecalis
mutant strains Δ
fsrA
(TX5240), Δ
fsrB
(TX5266), Δ
fsrC
(TX5242), Δ
gelE
(TX5264), and Δ
sprE
(TX5243), which correspond to virulence factors involved in pathogenesis in different animal models. Two
E. faecalis
virulence-related factors that play an important role in mammalian and nematode models of infection, a putative quorum-sensing system (Δ
fsrB
) and serine protease (Δ
sprE
), were also found to be important for plant pathogenesis. The development of an
E. faecalis
-
A. thaliana
model system could potentially be used to circumvent certain inherent limitations that an animal model imposes on the identification and study of virulence factors. Furthermore, our study suggests an evolutionary crossover of virulence factors in plant, animal, and nematode pathogenesis.
CXCR3 and Its Ligands Participate in the Host Response toBordetella bronchisepticaInfection of the Mouse Respiratory Tract but Are Not Required for Clearance of Bacteria from the Lung
Authors: Widney Daniel P. , Hu Yan , Foreman-Wykert Amy K. , Bui Kim C. , Nguyen Tam T. , Lu Bao , Gerard Craig , Miller Jeff F. , Smith Jeffrey B.
Published: December 2004

Intranasal inoculation of mice withBordetella bronchisepticaproduces a transient pneumonia that is cleared over several weeks in a process known to require both neutrophils and lymphocytes. In this study, we evaluated the roles of the chemokines MIG (CXCL9), IP-10 (CXCL10), and I-TAC (CXCL11) and their common receptor, CXCR3. Following bacterial inoculation, message expression of interleukin-1 (IL-1), IL-6, and the neutrophil-attracting chemokines KC, LIX, and MIP-2 was rapidly induced, with maximal expression found at 6 h. In contrast, message expression of gamma interferon, MIG, IP-10, and I-TAC peaked at 2 days. Expression of all of these chemokines and cytokines returned to near baseline by 5 days, despite the persistence of high levels of live bacteria at this time. Induced MIG, IP-10, and I-TAC protein expression was localized in areas of inflammation at 2 to 3 days and was temporally associated with increased levels of CXCR3+lymphocytes in bronchoalveolar lavage fluid. There was no increase in mortality in mice lacking CXCR3. However, the clearance of bacteria from the lung and trachea was delayed, and the recruitment of lymphocytes and NK cells was slightly decreased, for CXCR3−/−mice relative to CXCR3+/+mice. We conclude that the CXCR3 receptor-ligand system contributes to pulmonary host defense inB. bronchisepticainfection by recruiting lymphocytes and NK cells into the lung.
Mucosal
FOXP3
-Expressing CD4
+
CD25
high
Regulatory T Cells in
Helicobacter pylori
-Infected Patients
Authors: Lundgren Anna , Strömberg Erika , Sjöling Åsa , Lindholm Catharina , Enarsson Karin , Edebo Anders , Johnsson Erik , Suri-Payer Elisabeth , Larsson Pia , Rudin Anna , Svennerholm Ann-Mari , Lundin B. Samuel
Published: December 2004

Helicobacter pylori
chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear
H. pylori
infections is a consequence of active suppression of the immune response. Here we show that
H. pylori
-infected individuals have increased frequencies of CD4
+
CD25
high
T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express
FOXP3
, a key gene for the development and function of regulatory T cells, as well as high levels of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) protein. In contrast, mucosal CD4
+
CD25
low
and CD4
+
CD25
−
cells express little
FOXP3
mRNA and low levels of the CTLA-4 protein. Mucosal CD4
+
CD25
high
T cells are present in individuals with asymptomatic
H. pylori
infections as well as in duodenal ulcer patients. The frequencies of CD4
+
CD25
high
cells are also increased in the stomachs of
H. pylori
-infected patients with gastric adenocarcinoma, particularly in cancer-affected tissues. These findings suggest that regulatory T cells may suppress mucosal immune responses and thereby contribute to the persistence of
H. pylori
infections.
Endurance training and testing with the ball in young elite soccer players
Authors: Chamari K , Hachana Y , Kaouech F , Jeddi R , Moussa-Chamari I , Wisløff U
Published: December 2004

Background:The aerobic capacity of soccer players substantially influences their technical performance and tactical choices. Thus, the assessment of soccer players’ aerobic performance should be of interest for soccer coaches in order to evaluate and improve their endurance training sessions. In this study, we present a new test to assess aerobic performance in soccer by means of a specific dribbling track: the Hoff test. We further determined whether improvement in maximal oxygen uptake was reflected in increased distance covered in the Hoff test.

Methods:We tested 18 male soccer players (14 years old) both in the laboratory and using the Hoff test before and after 8 weeks of soccer training.

Results:The distance covered in the Hoff test correlated significantly with maximum oxygen uptake, and improved by 9.6% during the 8 week training period, while maximum oxygen uptake and running economy improved by 12 and 10%, respectively. Backward multiple regression showed maximum oxygen uptake to be the main explanatory variable for the distance covered in the Hoff test.

Conclusion:The present study demonstrated a significant correlation between laboratory testing of VO2maxand performance in the Hoff test. Furthermore, training induced improvements in VO2maxwere reflected in improved performance in the Hoff test. We suggest that it should be a goal for active U-15 soccer players to cover more than 2100 metres in the Hoff test, as this requires a VO2maxof above 200 ml/kg0.75/min, which should serve as a minimum in modern soccer.
Repression of protein synthesis and mTOR signaling in rat liver mediated by the AMPK activator aminoimidazole carboxamide ribonucleoside
Authors: Reiter Ali K. , Bolster Douglas R. , Crozier Stephen J. , Kimball Scot R. , Jefferson Leonard S.
Published: December 2004

The studies described herein were designed to investigate the effects of 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR), an activator of the AMP-activated protein kinase (AMPK), on the translational control of protein synthesis and signaling through the mammalian target of rapamycin (mTOR) in rat liver. Effects of AICAR observed in vivo were compared with those obtained in an in situ perfused liver preparation to investigate activation of AMPK in the absence of accompanying changes in hormones and nutrients. AMPK became hyperphosphorylated, as assessed by a gel-shift analysis, in response to AICAR both in vivo and in situ; however, increased relative phosphorylation at the Thr172 site on the kinase was observed only in perfused liver. Phosphorylation of AMPK either in vivo or in situ was associated with a repression of protein synthesis as well as decreased phosphorylation of a number of targets of mTOR signaling including ribosomal protein S6 kinase 1, eukaryotic initiation factor (eIF)4G, and eIF4E-binding protein (4E-BP)1. The phosphorylation changes in eIF4G and 4E-BP1 were accompanied by a reduction in the amount of eIF4E present in the active eIF4E·eIF4G complex and an increase in the amount present in the inactive eIF4E·4E-BP1 complex. Reduced insulin signaling as well as differences in nutrient availability may have contributed to the effects observed in vivo as AICAR caused a fall in the serum insulin concentration. Overall, however, the results from both experimental models support a scenario in which AICAR directly represses protein synthesis and mTOR signaling in the liver through an AMPK-dependent mechanism.
AT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats
Authors: Duke Lisa M. , Evans Roger G. , Widdop Robert E
Published: December 2004

The aims of this study were to determine the contribution of the AT2 receptor to the antihypertensive and regional vasodilatory effects of AT1 receptor blockade in adult spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive (2K1C) rats, and sham-operated normotensive rats. Several studies have provided evidence to support the notion that the AT2 receptor may have opposing effects to those mediated by the AT1 receptor. We therefore tested the hypothesis that the depressor and vasodilator effects of acute AT1 receptor blockade are dependent on AT2 receptor activation. Heart rate, mean arterial pressure, and regional hemodynamics were measured over a 4-day protocol in rats that received the following treatments in randomized order: saline vehicle, the AT1 receptor antagonist candesartan (0.1 mg/kg iv bolus), the AT2 receptor antagonist PD-123319 (50 μg·kg−1·min−1), or both antagonists. Intravenous candesartan reduced mean arterial pressure in all groups of rats, and this was accompanied by renal and mesenteric vasodilation. Neither saline nor PD-123319 significantly affected these variables. Concomitant PD-123319 administration partially reversed the depressor and mesenteric vasodilator effects of candesartan in sham-operated normotensive rats but not in SHR or 2K1C rats. These data indicate that the AT2 receptor contributes to the blood pressure-lowering and mesenteric vasodilator effects of AT1 receptor blockade in the acute setting in conscious normotensive but not hypertensive rats.
Postnatal developmental expressions of neurotransmitters and receptors in various brain stem nuclei of rats
Authors: Liu Qiuli , Wong-Riley Margaret T. T.
Published: December 2004

Previously, we reported that the expression of cytochrome oxidase in a number of brain stem nuclei exhibited a plateau or reduction at postnatal day (P) 3–4 and a dramatic decrease at P12, against a general increase with age. The present study examined the expression of glutamate, N-methyl-d-aspartate receptor subunit 1 (NMDAR1), GABA, GABAB receptors, glycine receptors, and glutamate receptor subunit 2 (GluR2) in the ventrolateral subnucleus of the solitary tract nucleus, nucleus ambiguus, hypoglossal nucleus, medial accessory olivary nucleus, dorsal motor nucleus of the vagus, and cuneate nucleus, from P2 to P21 in rats. Results showed that 1) the expression of glutamate increased with age in a majority of the nuclei, whereas that of NMDAR1 showed heterogeneity among the nuclei; 2) GABA and GABAB expressions decreased with age, whereas that of glycine receptors increased with age; 3) GluR2 showed two peaks, at P3–4 and P12; and 4) glutamate and NMDAR1 showed a significant reduction, whereas GABA, GABAB receptors, glycine receptors, and GluR2 exhibited a concomitant increase at P12. These features were present but less pronounced in hypoglossal nucleus and dorsal motor nucleus of the vagus and were absent in the cuneate nucleus. These data suggest that brain stem nuclei, directly or indirectly related to respiratory control, share a common developmental trend with the pre-Bötzinger complex in having a transient period of imbalance between inhibitory and excitatory drives at P12. During this critical period, the respiratory system may be more vulnerable to excessive exogenous stressors.
Perceptual Consequences of Disrupted Auditory Nerve Activity
Authors: Zeng Fan-Gang , Kong Ying-Yee , Michalewski Henry J. , Starr Arnold
Published: December 2004

Perceptual consequences of disrupted auditory nerve activity were systematically studied in 21 subjects who had been clinically diagnosed with auditory neuropathy (AN), a recently defined disorder characterized by normal outer hair cell function but disrupted auditory nerve function. Neurological and electrophysical evidence suggests that disrupted auditory nerve activity is due to desynchronized or reduced neural activity or both. Psychophysical measures showed that the disrupted neural activity has minimal effects on intensity-related perception, such as loudness discrimination, pitch discrimination at high frequencies, and sound localization using interaural level differences. In contrast, the disrupted neural activity significantly impairs timing related perception, such as pitch discrimination at low frequencies, temporal integration, gap detection, temporal modulation detection, backward and forward masking, signal detection in noise, binaural beats, and sound localization using interaural time differences. These perceptual consequences are the opposite of what is typically observed in cochlear-impaired subjects who have impaired intensity perception but relatively normal temporal processing after taking their impaired intensity perception into account. These differences in perceptual consequences between auditory neuropathy and cochlear damage suggest the use of different neural codes in auditory perception: a suboptimal spike count code for intensity processing, a synchronized spike code for temporal processing, and a duplex code for frequency processing. We also proposed two underlying physiological models based on desynchronized and reduced discharge in the auditory nerve to successfully account for the observed neurological and behavioral data. These methods and measures cannot differentiate between these two AN models, but future studies using electric stimulation of the auditory nerve via a cochlear implant might. These results not only show the unique contribution of neural synchrony to sensory perception but also provide guidance for translational research in terms of better diagnosis and management of human communication disorders.
Identification of the K efflux channel coupled to the gastric H-K-ATPase during acid secretion
Authors: Lambrecht Nils W. G. , Yakubov Iskandar , Scott David , Sachs George
Published: December 2004

Genomic microarray analysis of genes specifically expressed in a pure cell isolate from a heterocellular organ identified the likely K efflux channel associated with the gastric H-K-ATPase. The function of this channel is to supply K to the luminal surface of the pump to allow H for K exchange. KCNQ1-KCNE2 was the most highly expressed and significantly enriched member of the large variety of K channels expressed in the gastric epithelium. The function of this K channel in acid secretion was then shown by inhibition of secretion in isolated gastric glands with specific KCNQ inhibitors and by colocalization of the channel with the H-K-ATPase in the secretory canaliculus of the parietal cell. KCNQ1-KCNE2 appears to be the K efflux channel that is essential for gastric acid secretion.
Inherited and Acquired Vulnerability to Ventricular Arrhythmias: Cardiac Na+and K+Channels
Authors: Clancy Colleen E. , Kass Robert S.
Published: December 2004

Mutations in cardiac Na+and K+channels can disrupt the precise balance of ionic currents that underlies normal cardiac excitation and relaxation. Disruption of this equilibrium can result in arrhythmogenic phenotypes leading to syncope, seizures, and sudden cardiac death. Congenital defects result in an unpredictable expression of phenotypes with variable penetrance, even within single families. Additionally, phenotypically opposite and overlapping cardiac arrhythmogenic syndromes can stem from one mutation. A number of these defects have been characterized experimentally with the aim of understanding mechanisms of mutation-induced arrhythmia. Improving understanding of abnormalities may provide a basis for the development of therapeutic approaches.
Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture
Authors: Newby Andrew C.
Published: December 2004

Intimal thickening, the accumulation of cells and extracellular matrix within the inner vessel wall, is a physiological response to mechanical injury, increased wall stress, or chemical insult (e.g., atherosclerosis). If excessive, it can lead to the obstruction of blood flow and tissue ischemia. Together with expansive or constrictive remodeling, the extent of intimal expansion determines final lumen size and vessel wall thickness. Plaque rupture represents a failure of intimal remodeling, where the fibrous cap overlying an atheromatous core of lipid undergoes catastrophic mechanical breakdown. Plaque rupture promotes coronary thrombosis and myocardial infarction, the most prevalent cause of premature death in advanced societies. The matrix metalloproteinases (MMPs) can act together to degrade the major components of the vascular extracellular matrix. All cells present in the normal and diseased blood vessel wall upregulate and activate MMPs in a multistep fashion driven in part by soluble cytokines and cell-cell interactions. Activation of MMP proforms requires other MMPs or other classes of protease. MMP activation contributes to intimal growth and vessel wall remodeling in response to injury, most notably by promoting migration of vascular smooth muscle cells. A broader spectrum and/or higher level of MMP activation, especially associated with inflammation, could contribute to pathological matrix destruction and plaque rupture. Inhibiting the activity of specific MMPs or preventing their upregulation could ameliorate intimal thickening and prevent myocardial infarction.
Molecular Diversity and Regulation of Renal Potassium Channels
Authors: Hebert Steven C. , Desir Gary , Giebisch Gerhard , Wang Wenhui
Published: December 2004

K+channels are widely distributed in both plant and animal cells where they serve many distinct functions. K+channels set the membrane potential, generate electrical signals in excitable cells, and regulate cell volume and cell movement. In renal tubule epithelial cells, K+channels are not only involved in basic functions such as the generation of the cell-negative potential and the control of cell volume, but also play a uniquely important role in K+secretion. Moreover, K+channels participate in the regulation of vascular tone in the glomerular circulation, and they are involved in the mechanisms mediating tubuloglomerular feedback. Significant progress has been made in defining the properties of renal K+channels, including their location within tubule cells, their biophysical properties, regulation, and molecular structure. Such progress has been made possible by the application of single-channel analysis and the successful cloning of K+channels of renal origin.
Profiling Gene Expression in Kidney Development
Authors: Patterson Larry T. , Potter S. Steven
Published: December 2004

Rapid determination of the expression levels of all genes can be achieved with microarrays. This technology is beginning to revolutionize the study of kidney development. Genome-wide expression studies of the developing rat, mouse and human kidneys have found thousands of expressed genes, with many hundreds showing changes in expression as a function of developmental time. The resulting gene expression profiles provide an important discovery function, identifying new genes and pathways not previously implicated in kidney organogenesis. In combination with microdissection techniques, microarrays further extend global gene expression analysis to discrete components or cell types within the kidney. The resulting detailed molecular portrait of normal kidney development provides a baseline for studies of the many mouse mutants available with abnormal kidney development.
Effect of Dietary Sodium Intake on the Expression of Endothelin-Converting Enzyme in the Renal Medulla
Authors: Fattal I. , Abassi Z. , Ovcharenko E. , Shimada K. , Takahashi M. , Hoffman A. , Winaver J.
Published: December 2004

Background/Aim: Endothelin-converting enzyme (ECE) catalyzes the generation of endothelin-1 (ET-1) from its inactive precursor big-ET-1. Previous studies suggested that the ET-1 system is involved in the regulation of sodium excretion by the kidney. In particular, ET-1 via the ETB receptor-mediated signaling has been shown to increase renal medullary blood flow and decrease sodium transport in the collecting duct, both acting to promote renal sodium excretion. The present study was designed to evaluate the possibility that alterations in dietary salt intake may regulate the ECE-1. Methods: Wistar rats were fed for 3 days either with a diet containing low salt (0.01% NaCl), normal salt (0.5% NaCl), or high salt intake, either by high salt diet (4% NaCl) or normal salt diet plus 0.9% saline drinking. The expression of and immunoreactive protein levels of ECE-1 in the renal medulla was studied by RT-PCR, Northern blotting and Western blotting techniques. Results: The expression of ECE-1 mRNA (by RT-PCR and Northern blotting), as well as the immunoreactive levels of ECE-1, were significantly higher in the renal medulla of rats exposed to high salt intake than in rats on normal salt diet. Conclusion: The findings suggest that upregulation of ECE-1, leading to increased generation of ET-1 in the renal medulla, may be a compensatory mechanism promoting enhanced sodium excretion by the kidney in response to high salt intake.
Long-Term Oxygen Therapy in Ioannina
Authors: Katsenos Stamatis , Froudarakis Marios E. , Charisis Alexandros , Vassiliou Miltiadis P. , Constantopoulos Stavros H.
Published: December 2004

Background: Long-term oxygen treatment (LTOT) is very important, especially in patients with severe chronic obstructive pulmonary disease (COPD), but its efficacy is closely related to patient compliance. Objectives: The aim of the present study was to investigate the compliance of patients under LTOT in the Prefecture of Ioannina (north-western Greece) and to identify factors that might be involved. Methods: The study included 249 patients treated with LTOT during a 1-year period. They were visited at home by the investigating staff (a chest specialist and a primary care nurse). Compliance to therapy was defined by the daily use of the O2 concentrator (in hours). Patients underwent pulse oximetry, basic spirometry, and trial inhalation of bronchodilators. Results: Only 67 patients (26.9%) complied with therapy, while the daily concentrator use lasted 9.7 ± 6.09 h. SaO2, FEV1 and FVC were negatively correlated to patient compliance. No significant differences concerning LTOT compliance were noted between men and women, urban and rural population, and between smokers, ex-smokers and non-smokers. A chest physician recommended LTOT for the majority of patients (86.3%), while COPD was the main reason for LTOT prescription (74.7%). Nevertheless, compliance to LTOT was not significantly higher when prescribed by a respiratory physician. No specific medical instructions and information was recorded for the majority of the study patients treated with LTOT. Conclusions: Our results suggest that an organized home care program establishing the relative guidelines is necessary for substantial improvement in patient compliance to LTOT in Greece.
Analysis of Subcarinal Lymph Nodes in (Suspected) Non-Small-Cell Lung Cancer after a Negative Transbronchial Needle Aspiration – What’s Next?
Authors: Annema Jouke T. , Veseliç Maud , Rabe Klaus F.
Published: December 2004

Background: Transbronchial needle aspiration (TBNA) of subcarinal lymph nodes (LN) has a variable yield. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has demonstrated a high accuracy in the analysis of enlarged subcarinal LN. Objective: To assess the diagnostic accuracy of EUS-FNA in the analysis of enlarged subcarinal LN previously staged tumor negative by TBNA. Methods and Patients: In this retrospective study, we included all patients with (suspected) lung cancer and enlarged (>1 cm on CT) subcarinal LNs staged tumor negative by TBNA, who were subsequently staged by EUS-FNA. In addition, surgical-pathological information had to be available in those cases in which EUS-FNA was tumor negative. Results: Subcarinal LN metastases were assessed by EUS-FNA in 10 of 14 patients (71%). In 1 patient granulomas without necrosis were found. The remaining 3 patients staged tumor negative by both TBNA and EUS-FNA had reactive LN tissue, which was confirmed by surgical-pathological staging. Sensitivity, specificity and diagnostic accuracy of EUS in analyzing TBNA-negative LNs was 100% in all. Conclusions: In patients with (suspected) lung cancer and enlarged subcarinal LNs staged tumor negative by TBNA, additional staging by EUS-FNA confirmed subcarinal LN metastasis in 71% of the patients. These data suggest that for the analysis of the subcarinal LNs the real-time controlled technique of EUS-FNA is superior to the ‘blind’ technique of TBNA.
Nebulized Fentanyl for Palliation of Dyspnea in a Cystic Fibrosis Patient
Authors: Graff Gavin R. , Stark James M. , Grueber Ryan
Published: December 2004

Dyspnea, the subjective symptom feeling of breathlessness, is a common symptom in terminally ill patients with cystic fibrosis (CF). The palliation of the dyspnea is a reasonable goal to improve patient comfort as the progression of the disease worsens. We report the successful use of inhaled fentanyl for 3 days in a 17-year-old female with terminal CF lung disease, as measured by improved oxygenation and a reduction in the modified Borg score, and the subjective feeling of less air hunger reported by parents and patient.
Diagnostic Yield of Capsule Endoscopy in Obscure Gastrointestinal Bleeding
Authors: Fireman Zvi , Friedman Shosh
Published: December 2004

Objectives:Chronic occult blood loss from the gastrointestinal tract is a recognized major cause of iron-deficiency anemia. After conventional investigation of the upper and lower parts of the gastrointestinal tract, the source of bleeding remains unidentified in ~10% of these patients. We evaluated the diagnostic yield of capsule endoscopy from patients enrolled in clinical studies due to persistent or recurrent iron-deficiency anemia. Methods: In this large cohort study, patients with obscure gastrointestinal bleeding were identified in a company-sponsored clinical study (Given Imaging, Ltd.) database which contains data from >50 clinical studies. Information on suitable patients was derived from 31 of them. Each subject swallowed an M2A® Given Capsule containing a miniature video camera, batteries, a transmitter and an antenna. Recording time was ~8 h. The capsule was excreted naturally in the patient’s bowel movement, and the data it transmitted were retrieved and interpreted the next day. Results: 293 patients were studied (135 males, 46.1%, mean age 59.4 ± 16.8 years) whose mean number of bleeding episodes was 4.3 ± 5.5 and mean hemoglobin level was 9.8 ± 2.4 g/dl. The average number of diagnostic procedures per patient prior to the capsule endoscopy study was 5.59. Capsule endoscopy detected definitive findings in 213/293 patients (72%) and findings missed by other diagnostic procedures in 22/293 patients (8%). Neither capsule endoscopy nor the other diagnostic procedures yielded diagnoses in 58/293 patients (20%). Conclusions: Capsule endoscopy has a high diagnostic yield in evaluating patients with obscure gastrointestinal bleeding.
Nonlinear Complexity and Spectral Analyses of Heart Rate Variability in Medicated and Unmedicated Patients with Schizophrenia1
Authors: Mujica-Parodi L.R. , Yeragani Vikram , Malaspina Dolores
Published: December 2004

Objective: Heart rate variability (HRV) reflects functioning of the autonomic nervous system and possibly also regulation by the neural limbic system, abnormalities of which have both figured prominently in various etiological models of schizophrenia, particularly those that address patients’ vulnerability to stress in connection to psychosis onset and exacerbation. This study provides data on cardiac functioning in a sample of schizophrenia patients that were either medication free or on atypical antipsychotics, as well as cardiac data on matched healthy controls. We included a medication-free group to investigate whether abnormalities in HRV previously reported in the literature and associated with atypical antipsychotics were solely the effect of medications or whether they might be a feature of the illness (or psychosis) itself. Method: We collected 24-hour ECGs on 19 patients and 24 controls. Of the patients, 9 were medication free and 10 were on atypical antipsychotics. All subject groups were matched for age and gender. Patient groups showed equivalent symptom severity and type, as well as duration of illness. We analyzed the data using nonlinear complexity (symbolic dynamic) HRV analyses as well as standard and relative spectral analyses. Results: For the medication-free patients as compared to the healthy controls, our data show decreased R–R intervals during sleep, and abnormal suppression of all frequency ranges, but particularly the low frequency range, which persisted even after adjusting the spectral data for the mean R–R interval. This effect was exacerbated for patients on atypical antipsychotics. Likewise, nonlinear complexity analysis showed significantly impaired HRV for medication-free patients that was exacerbated in the patients on atypical antipsychotics. Conclusions: Altogether, the data suggest a pattern of significantly decreased cardiac vagal function of patients with schizophrenia as compared to healthy controls, apart from and beyond any differences due to medication side effects. The data additionally confirm earlier reports of a deleterious effect of atypical antipsychotics on HRV, which may exacerbate an underlying vulnerability in patients. These results support previous evidence that autonomic abnormalities may be a core feature of the illness (or psychosis), and that an even more conservative approach to cardiac risk in schizophrenia than previously thought may therefore be clinically appropriate.
Metabolism of Isovanillin by Aldehyde Oxidase, Xanthine Oxidase, Aldehyde Dehydrogenase and Liver Slices
Authors: Panoutsopoulos Georgios I. , Beedham Christine
Published: December 2004

Aromatic aldehydes are good substrates of aldehyde dehydrogenase activity but are relatively poor substrates of aldehyde oxidase and xanthine oxidase. However, the oxidation of xenobiotic-derived aromatic aldehydes by the latter enzymes has not been studied to any great extent. The present investigation compares the relative contribution of aldehyde dehydrogenase, aldehyde oxidase and xanthine oxidase activities in the oxidation of isovanillin in separate preparations and also in freshly prepared and cryopreserved liver slices. The oxidation of isovanillin was also examined in the presence of specific inhibitors of each oxidizing enzyme. Minimal transformation of isovanillin to isovanillic acid was observed in partially purified aldehyde oxidase, which is thought to be due to residual xanthine oxidase activity. Isovanillin was rapidly metabolized to isovanillic acid by high amounts of purified xanthine oxidase, but only low amounts are present in guinea pig liver fraction. Thus the contribution of xanthine oxidase to isovanillin oxidation in guinea pig is very low. In contrast, isovanillin was rapidly catalyzed to isovanillic acid by guinea pig liver aldehyde dehydrogenase activity. The inhibitor studies revealed that isovanillin was predominantly metabolized by aldehyde dehydrogenase activity. The oxidation of xenobiotic-derived aromatic aldehydes with freshly prepared or cryopreserved liver slices has not been previously reported. In freshly prepared liver slices, isovanillin was rapidly converted to isovanillic acid, whereas the conversion was very slow in cryopreserved liver slices due to low aldehyde dehydrogenase activity. The formation of isovanillic acid was not altered by allopurinol, but considerably inhibited by disulfiram. It is therefore concluded that isovanillin is predominantly metabolized by aldehyde dehydrogenase activity, with minimal contribution from either aldehyde oxidase or xanthine oxidase.
Regulation of Taurocholate Transport in Freshly Isolated Proximal Tubular Cells of the Rat Kidney by Protein Kinases
Authors: Schlattjan Jan Henrik , Benger Susanne , Herrler Andreas , von Rango Ulrike , Greven Joachim
Published: December 2004

Background/Aims: The bile acids filtered through the glomeruli nearly completely escape urinary excretion due to an efficient tubular reabsorption process. Reabsorption is mediated mainly by the sodium-dependent bile acid transporter (ASBT) which is located in the brush border membranes of proximal tubular cells. The present study addresses the question whether this transporter is subject to short-term regulation by protein kinases. Methods: The effects of specific activators or inhibitors of eight different protein kinases (PKs) on 3H-taurocholate uptake of proximal tubular cells were investigated. The cells were freshly isolated from rat kidneys by nycodenz density gradient centrifugation. Results: Activation of the cAMP/PKA system by forskolin, 8-Br-cAMP, or the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine significantly diminished cellular 3H-taurocholate uptake whereas 8-Br-cGMP had no effect. Also the MEK1/2 inhibitors PD98059 and U0126, and the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 decreased 3H-taurocholate uptake. Phorbol myristate acetate and dioctanolglycerol, activators of PKC, and chelerythrine, a selective inhibitor of PKC, did not affect 3H-taurocholate uptake. Likewise the phosphatidylinositol-3 kinase inhibitor wortmannin and the tyrosine kinase inhibitor genistein induced no significant change of cellular 3H-taurocholate uptake. In a sodium-free medium forskolin and PD98059 did not affect 3H-taurocholate uptake but SB203580 significantly decreased it. Conclusion: It is concluded that PKA and MAP kinases are involved in the regulation of the ASBT-mediated taurocholate uptake into proximal tubular cells. p38 MAP kinase may have an additional effect on a sodium-independent tubular taurocholate transporter.