bluuebunny/crossref_metadata_2025 huggingface dataset:
Autoinducer 2 Is Required for Biofilm Growth ofAggregatibacter(Actinobacillus)actinomycetemcomitans
Authors: Shao Hanjuan , Lamont Richard J. , Demuth Donald R.
Published: June 2007

Autoinducer 2 (AI-2) is required for the growth ofAggregatibacter(Actinobacillus)actinomycetemcomitansin culture under conditions of iron limitation. However, in vivo this organism thrives in a complex multispecies biofilm that forms in the human oral cavity. In this report, we show that adherent growth ofA. actinomycetemcomitanson a saliva-coated surface, but not planktonic growth under iron-replete conditions, is defective in a LuxS-deficient background. Biofilm growth of theluxSmutant exhibited lower total biomass and lower biofilm depth than those for the wild-type strain. Normal biofilm growth of theluxSmutant was restored genetically by introduction of a functional copy ofluxSand biochemically by addition of partially purified AI-2. Furthermore, introduction ofS-adenosylhomocysteine hydrolase, which restores the metabolism ofS-adenosylmethionine in the absence of LuxS, intoA. actinomycetemcomitansdid not complement theluxSmutation unless AI-2 was added intrans. This suggests that AI-2 itself is required for biofilm growth byA. actinomycetemcomitans. A biofilm growth deficiency similar to that of the LuxS-deficient strain was also observed when a gene encoding the AI-2-interacting protein RbsB or LsrB was inactivated. Biofilm formation byA. actinomycetemcomitanswas virtually eliminated upon inactivation of bothrbsBandlsrB. In addition, biofilm growth by wild-typeA. actinomycetemcomitanswas reduced in the presence of ribose, which competes with AI-2 for binding to RbsB. These results suggest that RbsB and LsrB function as AI-2 receptors inA. actinomycetemcomitansand that the development ofA. actinomycetemcomitansbiofilms requires AI-2.
Protease-Activated Receptor 2 Mediates Human Beta-Defensin 2 and CC Chemokine Ligand 20 mRNA Expression in Response to Proteases Secreted byPorphyromonas gingivalis
Authors: Dommisch Henrik , Chung Whasun O. , Rohani Maryam G. , Williams David , Rangarajan Minnie , Curtis Mike A. , Dale Beverly A.
Published: June 2007

The oral pathogenPorphyromonas gingivalissecretes proteases such as Arg-gingipain B (RgpB) that activate protease-activated receptors (PARs). Human beta-defensins (hBDs) and the macrophage inflammatory protein 3α/CC chemokine ligand 20 (CCL20) produced by epithelial cells are antimicrobial peptides that provide cytokine function and play an important role in innate immunity. The aim of the present study was to determine whether specific members of the PAR family mediate the expression of these innate immunity markers in gingival epithelial cells (GECs) when exposed toP. gingivaliscell-free culture supernatant or purified RgpB. hBD-2 mRNA in GECs was induced in response to supernatant and purified RgpB fromP. gingivalis(P= 0.02 andP= 0.016, respectively). This effect was abrogated by the protease inhibitor tosyl-l-lysine chloromethyl ketone (TLCK) (P< 0.05). In response toP. gingivalissupernatant and to purified RgpB, the hBD-2 mRNA expression was significantly decreased in PAR-2 gene knockdown cells, whereas no change was detected in PAR-1 gene knockdown cells. CCL20 mRNA expression also increased in response to the supernatant ofP. gingivalis, and this effect was blocked by the protease inhibitor, TLCK (P= 0.05 andP= 0.024, respectively), and was blocked in PAR-2 gene knockdown cells. Our data indicate that hBD-2 and CCL20 mRNA up-regulation byP. gingivalissupernatant and purified RgpB was mediated via PAR-2, but not via PAR-1, and that proteases play a role in the regulation of innate immune responses in GECs. GECs use PARs to recognizeP. gingivalisand mediate cell responses involved in innate immunity.
Glutathione-Dependent Alcohol Dehydrogenase AdhC Is Required for Defense against Nitrosative Stress in
Haemophilus influenzae
Authors: Kidd Stephen P. , Jiang Donald , Jennings Michael P. , McEwan Alastair G.
Published: June 2007

In
Haemophilus influenzae
Rd KW20, we identified a gene,
adhC
, which encodes a class III alcohol dehydrogenase (AdhC) and has
S
-nitrosoglutathione reductase activity.
adhC
exists on an operon with
estD
, which encodes an esterase. Divergent to the
adhC
-
estD
operon is the
Haemophilus influenzae nmlR
gene (
nmlR
HI
), which encodes a MerR family regulator that is homologous to the
Neisseria
MerR-like regulator (NmlR). Analysis of an
nmlR
HI
mutant indicated that expression of the
adhC
-
estD
operon is regulated by NmlR
HI
in strain Rd KW20. Chromosomal inactivation of either
adhC
or
nmlR
HI
resulted in sensitivity to
S
-nitrosoglutathione and decreased
S
-nitrosoglutathione reductase activity. Examination of the NmlR
HI
-AdhC system in the genome sequences of nontypeable
H. influenzae
strains R2846, R2866, and 86-028NP identified significant variations. The
adhC
gene of 86-028NP was predicted to be nonfunctional due to a premature stop codon. Polymorphisms in the operator/promoter region of R2866 resulted in reduced enzyme activity. This correlated with an increased sensitivity to
S
-nitrosoglutathione. The
adhC
-
nmlR
HI
system was examined in thirty-three clinical isolates (both capsular and nontypeable strains). Nucleic acid sequence data showed that only strain 86-028NP contained a premature stop codon. There were some variations in the DNA sequence of the operator/promoter region which altered the
nmlR
HI
promoter. However, the clinical isolates still possessed
S
-nitrosoglutathione reductase activity and showed at least the equivalent ability to grow in the presence of
S
-nitrosoglutathione as Rd KW20. These data suggest that the
nmlR
HI
-
adhC
system has a role in the defense against nitrosative stress in
Haemophilus influenzae
.
Differential Effects of Epinephrine, Norepinephrine, and Indole on
Escherichia coli
O157:H7 Chemotaxis, Colonization, and Gene Expression
Authors: Bansal Tarun , Englert Derek , Lee Jintae , Hegde Manjunath , Wood Thomas K. , Jayaraman Arul
Published: June 2007

During infection in the gastrointestinal tract, enterohemorrhagic
Escherichia coli
(EHEC) O157:H7 is exposed to a wide range of signaling molecules, including the eukaryotic hormones epinephrine and norepinephrine, and bacterial signal molecules such as indole. Since these signaling molecules have been shown to be involved in the regulation of phenotypes such as motility and virulence that are crucial for EHEC infections, we hypothesized that these molecules also govern the initial recognition of the large intestine environment and attachment to the host cell surface. Here, we report that, compared to indole, epinephrine and norepinephrine exert divergent effects on EHEC chemotaxis, motility, biofilm formation, gene expression, and colonization of HeLa cells. Using a novel two-fluorophore chemotaxis assay, it was found that EHEC is attracted to epinephrine and norepinephrine while it is repelled by indole. In addition, epinephrine and norepinephrine also increased EHEC motility and biofilm formation while indole attenuated these phenotypes. DNA microarray analysis of surface-associated EHEC indicated that epinephrine/norepinephrine up-regulated the expression of genes involved in surface colonization and virulence while exposure to indole decreased their expression. The gene expression data also suggested that autoinducer 2 uptake was repressed upon exposure to epinephrine/norepinephrine but not indole. In vitro adherence experiments confirmed that epinephrine and norepinephrine increased attachment to epithelial cells while indole decreased adherence. Taken together, these results suggest that epinephrine and norepinephrine increase EHEC infection while indole attenuates the process.
Pneumococcal Cell Wall-Induced Meningitis Impairs Adult Hippocampal Neurogenesis
Authors: Hoffmann Olaf , Mahrhofer Cordula , Rueter Nina , Freyer Dorette , Bert Bettina , Fink Heidrun , Weber Joerg R.
Published: June 2007

Bacterial meningitis is a major infectious cause of neuronal degeneration in the hippocampus. Neurogenesis, a continuous process in the adult hippocampus, could ameliorate such loss. Yet the high rate of sequelae from meningitis suggests that this repair mechanism is inefficient. Here we used a mouse model of nonreplicative bacterial meningitis to determine the impact of transient intracranial inflammation on adult neurogenesis. Experimental meningitis resulted in a net loss of neurons, diminished volume, and impaired neurogenesis in the dentate gyrus for weeks following recovery from the insult. Inducible nitric oxide synthase (iNOS) immunoreactivity was prominent in microglia in nonproliferating areas of the dentate gyrus and hilus region after meningitis induction. Treatment with the specific iNOS inhibitorN6-(1-iminoethyl)-l-lysine restored neurogenesis in experimental meningitis. These data suggest that local central nervous system inflammation in and of itself suppresses adult neurogenesis by affecting both proliferation and neuronal differentiation. Repair of cognitive dysfunction following meningitis could be improved by intervention to interrupt these actively suppressive effects.
THE CONDENSATION OF MATTER — A MODEL OF PHASE TRANSITION OF THE FIRST KIND
Authors: APOSTOL M.
Published: June 2007

A model of phase transition of the first kind is introduced, based on the assumption that a classical gas of particles condenses in composite particles made up of various numbers of gas molecules. The transition temperature and the latent heat are derived, and the phase diagram is characterized.
EFFICIENT SCHEME FOR TELEPORTATION OF UNKNOWN ATOMIC STATES USING NON-MAXIMALLY ENTANGLED STATES
Authors: XIONG KUANG-WEI
Published: June 2007

We propose a feasible scheme for teleporting an unknown atomic state by using non-maximally entangled states in cavity QED. The distinct advantage of the scheme is that, not only can the teleportation and distillation procedure be realized simultaneously, but the scheme is also insensitive to the cavity decay and thermal field with the assistance of a strong classical driving field. In addition, the joint Bell-state measurement can be distinguished via detecting the atomic state.
USING DISCRETE VARIABLE REPRESENTATION PATH INTEGRAL MONTE CARLO WITH METROPOLIS SAMPLING TO COMPUTE GROUND STATE WAVEFUNCTIONS
Authors: XIAO YINGSHENG , POIRIER BILL
Published: June 2007

The discrete variable representation (DVR) matrix dynamics formulation of the path integral Monte Carlo (PIMC) method, implemented numerically in a way that enables Metropolis sampling to be employed, is proposed as a means of computing ground state quantum wavefunctions. A key advantage of the DVR-PIMC approach is that customized marginal potentials may be employed, leading to significantly larger PIMC time step sizes, and substantial reductions in computational (CPU) effort. An additional key advantage of the present implementation is that the DVR provides a natural set of interpolant functions that can be used for accurate interpolation and extrapolation of function and tensor quantities away from predefined grid points. The new method is applied here to compute the ground state wavefunction of a model one degree-of-freedom (1 DOF) Morse oscillator system. A one-to-two order-of-magnitude reduction in CPU effort is observed, in comparison with a conventional PIMC simulation. The generalization for many DOFs is straightforward, and expected to result in even greater performance enhancement.
DETERMINATION OF THE OXIDATION POTENTIALS OF PYROGALLOL AND SOME OF ITS DERIVATIVES: THEORY AND EXPERIMENT
Authors: RIAHI SIAVASH , MOGHADDAM ABDOLMAJID BAYANDORI , GANJALI MOHAMMAD REZA , NOROUZI PARVIZ
Published: June 2007

The Oxidation potentials of pyrogallol and some of its derivatives in aqueous solutions have been calculated. The calculations have been performed using ab initio molecular orbital calculations (HF), and density functional theory (DFT) with the inclusion of entropic and thermochemical corrections to yield free energies of redox reactions. The polarizable continuum model is used to describe the solvent. It was also obtained experimentally with the aid of an electrochemical technique (cyclic voltammetry). The theoretical and experimental values for the oxidation potential of the studied pyrogallol and some derivatives are in excellent agreement with each other and there is only a discrepancy of 0.025 V and 0.020 V for B3LYP and HF methods, respectively, between experimental and theoretical results. The agreement mutually verifies the accuracy of the experimental method and the validity of the applied mathematical model.
QSAR AND MOLECULAR DESIGN OF BENZO[B]ACRONYCINE DERIVATIVES AS ANTITUMOR AGENTS
Authors: WU WEN JUAN , CHEN JIN CAN , QIAN LI , ZHENG KANG CHENG
Published: June 2007

Quantitative structure-activity relationship (QSAR) studies of a series of benzo[b]acronycine derivatives as a novel class of antitumor agents have been carried out using the density functional theory (DFT), molecular mechanics (MM+) and statistical methods. Some calculated parameters of geometric structures, electronic structures and molecular properties of the compounds were adopted as generalized descriptors (variables). Via a stepwise regression analysis, some main independent factors affecting the activities of the compounds were selected out, and then the quantitative structure-activity relationship (QSAR) equation was established. The results suggest that the energy difference (Δ εL-H) between the lowest unoccupied molecular orbital and the highest occupied molecular orbital, the net charges of the nitrogen atom N 11 and the first atom of the substituent R2, and the hydrophobic parameter (log P1) of the substituent R1 are the main independent factors contributing to the antitumor activities of the compounds. The fitting correlation coefficient (r2) and the cross-validation coefficient (q2) for the model established by this study are 0.865 and 0.721, respectively, showing this model with a good predictability. The QSAR equation can be used to estimate unknown antitumor activity of this kind of compound, and thus design new compounds with high antitumor activities. Here, based on this QASR study, 4 new compounds with predicted high antitumor activities have been theoretically designed and they are expecting experimental verification.
A multitracer stable isotope quantification of the effects of arginine intake on whole body arginine metabolism in neonatal piglets
Authors: Urschel Kristine L. , Rafii Mahroukh , Pencharz Paul B. , Ball Ronald O.
Published: June 2007

We have previously shown that deficient arginine intake increased the rate of endogenous arginine synthesis from proline. In this paper, we report in vivo quantification of the effects of arginine intake on total endogenous arginine synthesis, on the rates of conversion between arginine, citrulline, ornithine, and proline, and on nitric oxide synthesis. Male piglets, with gastric catheters for diet and isotope infusion and femoral vein catheters for blood sampling, received a complete diet for 2 days and then either a generous (+Arg; 1.80 g·kg−1·day−1; n = 5) or deficient (−Arg; 0.20 g·kg−1·day−1; n = 5) arginine diet for 5 days. On day 7, piglets received a primed, constant infusion of [guanido-15N2]arginine, [ureido-13C;5,5-2H2]citrulline, [U-13C5]ornithine, and [15N;U-13C5]proline in an integrated study of the metabolism of arginine and its precursors. Arginine synthesis (μmol·kg−1·h−1) from both proline (+Arg: 42, −Arg: 74, pooled SE: 5) and citrulline (+Arg: 67, −Arg: 120; pooled SE: 15) were higher in piglets receiving the −Arg diet ( P < 0.05); and for both diets proline accounted for ∼60% of total endogenous arginine synthesis. The conversion of proline to citrulline (+Arg: 39, −Arg: 67, pooled SE: 6) was similar to the proline-to-arginine conversion, confirming that citrulline formation limits arginine synthesis from proline in piglets. Nitric oxide synthesis (μmol·kg−1·h−1), measured by the rate conversion of [guanido-15N2]arginine to [ureido-15N]citrulline, was greater in piglets receiving the +Arg diet (105) than in those receiving the −Arg diet (46, pooled SE: 10; P < 0.05). This multi-isotope method successfully allowed many aspects of arginine metabolism to be quantified simultaneously in vivo.
Enhanced iNOS Gene Expression in the Steatotic Rat Liver after Normothermic Ischemia
Authors: Koeppel Thomas A. , Mihaljevic Nicolas , Kraenzlin Bettina , Loehr Matthias , Jesenofsky Ralf , Post Stefan , Palma Pablo
Published: June 2007

Background: Impaired hepatic microcirculation in the steatotic liver has been identified as a considerable factor for increased vulnerability after ischemia/reperfusion (I/R). Changes in regulation and synthesis of vasoactive mediators, such as nitric oxide (NO) and endothelin (ET-1), may result in functional impairment of postischemic sinusoidal perfusion. The aim of the current study was to assess the impact of I/R injury on postischemic gene expression of NO and ET-1 in steatotic livers. Materials and Methods: Male Sprague-Dawley rats with or without hepatic steatosis (induced by carbon tetrachloride treatment) were subjected to normothermic I/R injury. Steady-state mRNA levels were assessed using RT-PCR to study the expression of genes encoding ET-1, NO synthase (endothelial cell NO synthase and inducible NO synthase, iNOS). Immunohistochemistry was performed for detection of iNOS. Results: I/R injury was followed by increased iNOS gene expression (RT-PCR/immunohistochemistry) in animals with hepatic steatosis, predominately in hepatocytes with fatty degeneration. A mild increase in mRNA levels for ET-1 was found in steatotic rat livers. I/R induced a further increase in ET-1 gene expression in some but not all reperfused steatotic livers. Conclusions: We show an enhanced gene expression of iNOS in postischemic steatotic rat livers. Hepatocytes with fatty degeneration appear to be the major source for NO generation. Furthermore, I/R may also induce ET-1 gene expression. Dysregulation of sinusoidal perfusion by NO and ET-1 is therefore likely to contribute to I/R injury of the steatotic liver.
Pharmacodynamic Studies of Vancomycin, Metronidazole and Fusidic Acid against Clostridium difficile
Authors: Odenholt Inga , Walder Mats , Wullt Marlene
Published: June 2007

Background: Pharmacodynamic studies of antibiotics have attracted great interest in recent years. However, studies on the pharmacodynamics of different antibiotics against Clostridium difficile are scarce. Methods: The postantibiotic effects (PAE) and the postantibiotic sub-minimum inhibitory concentration (MIC) effects (PA SME) of vancomycin, metronidazole and fusidic acid were investigated by viable counts against three different strains of C. difficile. The killing rate and extent of the three antibiotics against the same strains were also studied by adding 2, 4, 8, 16 and 32× MIC of the three antibiotics, respectively. Results: Metronidazole exerted a very rapid bactericidal effect at concentrations of 8× MIC and above against all three strains investigated. Vancomycin gave overall less kill in comparison to metronidazole and was bacteriostatic against two of the three strains. Fusidic acid exerted a concentration-dependent killing against two of the strains. Vancomycin exerted short PAEs and PA SMEs against all three strains. Significantly longer PAEs and PA SMEs were noted for fusidic acid. Metronidazole gave similar short PAEs like vancomycin but longer PA SMEs were noted against two of the investigated strains. Conclusion: Metronidazole exerted the most prominent bactericidal effect greater than fusidic acid and greater than vancomycin. Fusidic acid gave overall the longest PAEs and PA SMEs greater than metronidazole and greater than vancomycin.
l
-Arginine Supplementation in Peripheral Arterial Disease
Authors: Wilson Andrew M. , Harada Randall , Nair Nandini , Balasubramanian Naras , Cooke John P.
Published: June 2007

Background—

l
-Arginine is the precursor of endothelium-derived nitric oxide, an endogenous vasodilator.
l
-Arginine supplementation improves vascular reactivity and functional capacity in peripheral arterial disease (PAD) in small, short-term studies. We aimed to determine the effects of long-term administration of
l
-arginine on vascular reactivity and functional capacity in patients with PAD.

Methods and Results—

The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study was a randomized clinical trial of oral
l
-arginine (3 g/d) versus placebo for 6 months in 133 subjects with intermittent claudication due to PAD in a single-center setting. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol.
l
-Arginine supplementation significantly increased plasma
l
-arginine levels. However, measures of nitric oxide availability (including flow-mediated vasodilation, vascular compliance, plasma and urinary nitrogen oxides, and plasma citrulline formation) were reduced or not improved compared with placebo. Although absolute claudication distance improved in both
l
-arginine- and placebo-treated patients, the improvement in the
l
-arginine-treated group was significantly less than that in the placebo group (28.3% versus 11.5%;
P
=0.024).

Conclusions—

In patients with PAD, long-term administration of
l
-arginine does not increase nitric oxide synthesis or improve vascular reactivity. Furthermore, the expected placebo effect observed in studies of functional capacity was attenuated in the
l
-arginine-treated group. As opposed to its short-term administration, long-term administration of
l
-arginine is not useful in patients with intermittent claudication and PAD.
Oxidant Stress Impairs In Vivo Reendothelialization Capacity of Endothelial Progenitor Cells From Patients With Type 2 Diabetes Mellitus
Authors: Sorrentino Sajoscha A. , Bahlmann Ferdinand H. , Besler Christian , Müller Maja , Schulz Svenja , Kirchhoff Nina , Doerries Carola , Horváth Tibor , Limbourg Anne , Limbourg Florian , Fliser Danilo , Haller Hermann , Drexler Helmut , Landmesser Ulf
Published: June 2007

Background—

Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury. We therefore compared in vivo reendothelialization capacity of EPCs derived from patients with diabetes mellitus and healthy subjects. Moreover, we examined the effect of treatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone on oxidant stress, nitric oxide (NO) bioavailability, and the in vivo reendothelialization capacity of EPCs from diabetic individuals.

Methods and Results—

In vivo reendothelialization capacity of EPCs from diabetic patients (n=30) and healthy subjects (n=10) was examined in a nude mouse carotid injury model. Superoxide and NO production of EPCs was determined by electron spin resonance spectroscopy. Thirty patients with diabetes mellitus were randomized to 2 weeks of rosiglitazone (4 mg BID PO) or placebo treatment. In vivo reendothelialization capacity of EPCs derived from diabetic subjects was severely reduced compared with EPCs from healthy subjects (reendothelialized area: 8±3% versus 37±10%;
P
<0.001). EPCs from diabetic individuals had a substantially increased superoxide production and impaired NO bioavailability. Small-interfering RNA silencing of NAD(P)H oxidase subunit p47

phox

reduced superoxide production and restored NO bioavailability and in vivo reendothelialization capacity of EPCs from diabetic patients. Importantly, rosiglitazone therapy normalized NAD(P)H oxidase activity, restored NO bioavailability, and improved in vivo reendothelialization capacity of EPCs from diabetic patients (reendothelialized area: placebo versus rosiglitazone, 8±1% versus 38±5%;
P
<0.001).

Conclusions—

In vivo reendothelialization capacity of EPCs derived from individuals with diabetes mellitus is severely impaired at least partially as a result of increased NAD(P)H oxidase–dependent superoxide production and subsequently reduced NO bioavailability. Rosiglitazone therapy reduces NAD(P)H oxidase activity and improves reendothelialization capacity of EPCs from diabetic individuals, representing a potential novel mechanism whereby peroxisome proliferator-activated receptor-γ agonism promotes vascular repair.
Intake of Added Sugar and Sugar-Sweetened Drink and Serum Uric Acid Concentration in US Men and Women
Authors: Gao Xiang , Qi Lu , Qiao Ning , Choi Hyon K. , Curhan Gary , Tucker Katherine L. , Ascherio Alberto
Published: June 2007

Fructose-induced hyperuricemia might have a causal role in metabolic syndrome, hypertension, and other chronic disease. However, no study has investigated whether sugar added to foods or sugar-sweetened beverages, which are major sources of fructose, are associated with serum uric acid concentration in free-living populations. We examined the relationship between the intakes of added sugars and sugar-sweetened beverages and serum uric acid concentrations in the National Health and Nutrition Examination Survey 2001–2002, a nationally representative sample of men and women. We included 4073 subjects (1988 men and 2085 women) >18 years of age in the current study. Dietary intake was assessed by a single 24-hour recall. We used multivariate linear regression to adjust for age, gender, intake of energy and alcohol, body mass index, use of diuretics, β-blockers, and other covariates. Male subjects in the highest intake quartile of estimated intake of added sugars or sugar-sweetened drinks had higher plasma uric acid concentrations than those in the lowest intake quartiles (
P
<0.001 for both) after adjusting for potential confounders, whereas we did not observe significant associations for females (
P
for trend>0.2;
P
for interaction <0.01). Further research is needed to confirm causality of these associations and the observed difference by gender.
HMG-CoA Reductase Inhibitors Decrease Angiotensin II–Induced Vascular Fibrosis
Authors: Rupérez Mónica , Rodrigues-Díez Raquel , Blanco-Colio Luis Miguel , Sánchez-López Elsa , Rodríguez-Vita Juan , Esteban Vanesa , Carvajal Gisselle , Plaza Juan José , Egido Jesús , Ruiz-Ortega Marta
Published: June 2007

3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II–induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II–induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II–mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a vascular fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardiovascular diseases.
Increased Dietary Salt Enhances Sympathoexcitatory and Sympathoinhibitory Responses From the Rostral Ventrolateral Medulla
Authors: Adams Julye M. , Madden Christopher J. , Sved Alan F. , Stocker Sean D.
Published: June 2007

Increased dietary salt exaggerates arterial blood pressure (ABP) responses evoked from the rostral ventrolateral medulla (RVLM). The present study determined whether these enhanced pressor responses were directly attributable to a greater increase in sympathetic nerve activity (SNA) and whether these enhanced responses were balanced by a greater responsiveness of RVLM neurons to inhibitory input. Male Sprague-Dawley rats were fed normal chow and given access to either water or a 1% NaCl solution for 14 days. Injection of
l
-glutamate (0.03, 0.1, 1.0, and 3.0 nmol) into the RVLM produced a significantly greater increase in renal SNA, splanchnic SNA, and ABP in rats drinking 1% NaCl versus water. Conversely, injection of the inhibitory amino acid γ-aminobutyric acid (0.1, 1.0, and 10 nmol) into the RVLM produced significantly greater decreases in renal SNA, splanchnic SNA, and ABP of rats drinking 1% NaCl versus water. These enhanced SNA and ABP responses to
l
-glutamate and γ-aminobutyric acid were not observed in rats drinking 1% NaCl for 1 or 7 days but were present in rats drinking 1% NaCl for 21 days. Moreover, the dietary salt-induced enhancement of both sympathoexcitatory and sympathoinhibitory responses from the RVLM persisted after the 1% NaCl solution was replaced with water for 1, but not 7, days. These findings indicate that the potentiated ABP responses observed previously are mediated by parallel changes in SNA, and these responses depend on a slowly developing and reversible form of neuronal plasticity.
Left Ventricular Hypertrophy in Hypertensive Adolescents
Authors: McNiece Karen L. , Gupta-Malhotra Monesha , Samuels Joshua , Bell Cynthia , Garcia Kathleen , Poffenbarger Timothy , Sorof Jonathan M. , Portman Ronald J.
Published: June 2007

The National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents recently recommended staging hypertension (HTN) in children and adolescents based on blood pressure severity. The use of blood pressure staging and its corresponding therapeutic approach was examined in this pooled analysis assessing the risk for end-organ damage, specifically left ventricular hypertrophy among hypertensive adolescents stratified by working group criteria. Newly diagnosed hypertensive adolescents and normotensive control subjects similar in age, race/ethnicity, gender, and body mass index completed casual and 24-hour ambulatory blood pressure measurements, M-mode echocardiography, and fasting serum laboratories. Hypertensive subjects had higher insulin and cholesterol but similar glucose levels as compared with control subjects. Among subjects with stage 1 HTN by casual blood pressure, 34% had white-coat HTN as opposed to 15% of stage 2 hypertensive subjects. Of the subjects with normal casual measurements, 20% had HTN by ambulatory monitoring. Subjects with stage 2 HTN by casual measurement alone (odds ratio: 4.13; 95% CI: 1.04 to 16.48) and after 24-hour ambulatory confirmation (odds ratio: 7.23; 95% CI: 1.28 to 40.68) had increased odds for left ventricular hypertrophy. In addition, the risk for left ventricular hypertrophy was similar for subjects with masked and confirmed stage 1 HTN, whereas subjects with white-coat HTN had a risk comparable to normotensive subjects. Thus, recommendations that adolescents with stage 2 HTN by casual measurements alone receive medication initially along with therapeutic lifestyle counseling are reasonable, though ambulatory blood pressure monitoring remains a valuable tool for evaluating children with stage 2 HTN, because >10% have white-coat HTN.
Making Process, Not Progress: ASEAN and the Evolving East Asian Regional Order
Authors: Jones David Martin , Smith Michael L.R.
Published: June 2007

Since the Asian financial crisis of 1998, regional scholars and diplomats have maintained that the Association of Southeast Asian Nations (ASEAN) represents an evolving economic and security community. In addition, many contend that what is known as the ASEAN process not only has transformed Southeast Asia's international relations, but has started to build a shared East Asian regional identity. ASEAN's deeper integration into a security, economic, and political community, as well as its extension into the ASEAN Plus Three processes that were begun after the 1997 financial crisis, offers a test case of the dominant assumptions in both ASEAN scholarship and liberal and idealist accounts of international relations theory. Three case studies of ASEAN operating as an economic and security community demonstrate, however, that the norms and practices that ASEAN promotes, rather than creating an integrated community, can only sustain a pattern of limited intergovernmental and bureaucratically rigid interaction.
In the Crossfire or the Crosshairs? Norms, Civilian Casualties, and U.S. Conduct in Iraq
Authors: Kahl Colin H.
Published: June 2007

The belief that U.S. forces regularly violate the norm of noncombatant immunity (i.e., the notion that civilians should not be targeted or disproportionately harmed during hostilities) has been widely held since the outset of the Iraq War. Yet the evidence suggests that the U.S. military has done a better job of respecting noncombatant immunity in Iraq than is commonly thought. It also suggests that compliance has improved over time as the military has adjusted its behavior in response to real and perceived violations of the norm. This behavior is best explained by the internalization of noncombatant immunity within the U.S. military's organizational culture, especially since the Vietnam War. Contemporary U.S. military culture is characterized by an “annihilation-restraint paradox”: a commitment to the use of overwhelming but lawful force. The restraint portion of this paradox explains relatively high levels of U.S. adherence with the norm of noncombatant immunity in Iraq, while the tension between annihilation and restraint helps to account for instances of noncompliance and for why Iraqi civilian casualties from U.S. operations, although low by historical standards, have still probably been higher than was militarily necessary or inevitable.
The World Bank Administrative Tribunal's External Sources of Law: A Retrospective of the Tribunal's First Quarter-Century (1981–2005)
Authors: Hansen Peter
Published: June 2007

The jurisprudence of the World Bank Administrative Tribunal has grown and evolved dramatically over its first quarter-century. Mr. Hansen's study comprehensively surveys the numerous doctrinal contributions provided by external sources during this time. Organized under rubrics suggested by Article 38 of the Statute of the International Court of Justice, which sets out that Court's sources of law, Mr. Hansen's study reviews: (i) the roles of the contract of employment, Bank rules, international treaties and national laws in the composition of the pactum established between a staff member and the Bank; (ii) the development of binding custom from the practices of the Bank, other institutions and national governments; (iii) the Tribunal's use of general legal principles drawn from other legal systems; and (iv) the Tribunal's use of international and domestic tribunal precedents. Extensively footnoted, Mr. Hansen's study is intended for both academics and practitioners specializing in international administrative law and dispute settlement.
The Iran-United States Claims Tribunal: What Lies Ahead?
Authors: Weiner Allen
Published: June 2007

The Iran-United States Tribunal has recently celebrated its 25th anniversary. Although it has resolved all of the cases brought by private claimants, it is still likely to be many more years before the Tribunal is able to complete the remaining government-to-government cases on its docket. There are multiple reasons why so much time will be required: the pending cases are extremely complex, the governments brief them slowly, and the Tribunal's decision-making process itself is slow. There does not for the foreseeable future appear to be an alternative to continued litigation, because the prospects of a global settlement of the remaining claims before the Tribunal are remote. The parties face challenges in developing reasonable assessments of the legal and economic costs and benefits of settlement. Beyond this, the strained political relations between the United States and Iran would make even a legally and economically rationale settlement extremely difficult to achieve. The challenge facing the Tribunal in the remaining years of its existence, in which the Iran and United States are the only parties before it, is to continue to decide cases in a principled fashion on the basis of the law and the facts, and to resist the temptation to reach compromise decisions in the interests of political expediency.
Transparency versus Confidentiality in International Investment Arbitration – The Biwater Gauff Compromise
Authors: Reinisch August , Knahr Christina
Published: June 2007

Recent years have seen a trend towards increasing transparency in international investment arbitration. This trend has been reflected in arbitral practice and in the amendments to the ICSID Arbitration Rules in 2006, which now expressly allow for participation of non-disputing parties as amicus curiae. Still more problematic, however, is the publication of arbitral documents, which has recently been controversial in Biwater Gauff v. Tanzania. This paper will discuss the core provisions on the publication of documents of the UNCITRAL Arbitration Rules, the ICSID Arbitration Rules and NAFTA Chapter 11. It will analyze the reasoning and the findings of the Biwater Tribunal in this regard as well as the pertinent practice of previous investment tribunals. Important policy issues underlying the decision of the Biwater Tribunal will also be analyzed.
Recent Fact-Finding Developments at the International Court of Justice
Authors: Teitelbaum Ruth
Published: June 2007

This article discusses the Court's treatment of evidence and the burden of proof with emphasis on recent cases involving armed conflict, genocide and violations of human rights. The article frames the discussion by examining the Court's powers within its Statute and Rules and asks whether the Court is making adequate use of those powers. The article evaluates the Court's use of its fact-finding powers in relation to the following matters: the standard and burden of proof, the drawing of inferences and the use of secondary evidence, the treatment of facts derived from U.N. Reports, the reliance on outside commissions and fact-finding bodies for gathering evidence, and finally, the treatment of evidence based on the decisions of other international courts.
Interpretation of Jurisdictional Instruments in International Dispute Settlement
Authors: Orakhelashvili Alexander
Published: June 2007

The field of international judicial jurisdiction constantly witnesses the presence of interpretative argument and consent-based argument. The principle of consent is sometimes presented as the crucial factor in interpreting the instruments conferring jurisdiction to international tribunals. This contribution examines the relevant practice from the times of the Permanent Court of International Justice to the present, and demonstrates that although the jurisdiction of international tribunals is based on consent, the relevance of consent ceases once the relevant tribunal engages in interpreting the actual instrument interpreting jurisdiction. In this area, the normal principles of interpretation applicable to treaties determine the outcome. The reference to consensual principle has no autonomous relevance to determine or upset the outcomes in this process.
Victim and Witness Measures of the International Criminal Court: A Comparative Analysis
Authors: Mclaughlin Colin
Published: June 2007

The protections of victims and witnesses have evolved from the inception of the ICTY and continue through to the creation of the ICC. The ICTY set the benchmark on victim and witness protection through reliance on varying national court systems as well as on international standards. The ICTY's approach has been followed by the ICTR and the SCSL, though each tribunal made important advances in victim and witness protection.Today, ICC continues to follow the lead of the other tribunals. Although it is still unknown how well the ICC will protect victims and witnesses, if the Rules of Procedure and Evidence are any indication, the ICC will provide proper protection measures for victims and witnesses in the international tribunal arena.After comparing the different victim and witness measures implemented by the ICC to similar measures of the other Tribunals, as well as various national court systems, it is apparent that the ICC has developed extensive victim and witness measures that mirror those established by the other tribunals. Understanding both the benefits as well as possible shortcomings of each measure, the ICC will be better equipped to implement the measures deemed necessary for the victims and witnesses whose lives have been impacted by the crimes that come before the Court.
Nasa's Tropical Cloud Systems and Processes Experiment
Authors: Halverson J. , Black M. , Braun S. , Cecil D. , Goodman M. , Heymsfield A. , Heymsfield G . , Hood R. , Krishnamurti T. , McFarquhar G. , Mahoney M. J. , Molinari J. , Rogers R. , Turk J. , Velden C. , Zhang D.-L. , Zipser E. , Kakar R.
Published: June 2007

In July 2005, the National Aeronautics and Space Administration investigated tropical cyclogenesis, hurricane structure, and intensity change in the eastern North Pacific and western Atlantic using its ER-2 high-altitude research aircraft. The campaign, called the Tropical Cloud Systems and Processes (TCSP) experiment, was conducted in conjunction with the National Oceanic and Atmospheric Administration/Hurricane Research Division's Intensity Forecasting Experiment. A number of in situ and remote sensor datasets were collected inside and above four tropical cyclones representing a broad spectrum of tropical cyclone intensity and development in diverse environments. While the TCSP datasets directly address several key hypotheses governing tropical cyclone formation, including the role of vertical wind shear, dynamics of convective bursts, and upscale growth of the initial vortex, two of the storms sampled were also unusually strong, early season storms. Highlights from the genesis missions are described in this article, along with some of the unexpected results from the campaign. Interesting observations include an extremely intense, highly electrified convective tower in the eyewall of Hurricane Emily and a broad region of mesoscale subsidence detected in the lower stratosphere over landfalling Tropical Storm Gert.
Cloudnet
Authors: Illingworth A. J. , Hogan R. J. , O'Connor E.J. , Bouniol D. , Brooks M. E. , Delanoé J. , Donovan D. P. , Eastment J. D. , Gaussiat N. , Goddard J. W. F. , Haeffelin M. , Baltink H. Klein , Krasnov O. A. , Pelon J. , Piriou J.-M. , Protat A. , Russchenberg H. W. J. , Seifert A. , Tompkins A. M. , van Zadelhoff G.-J. , Vinit F. , Willén U. , Wilson D. R. , Wrench C. L.
Published: June 2007

The Cloudnet project aims to provide a systematic evaluation of clouds in forecast and climate models by comparing the model output with continuous ground-based observations of the vertical profiles of cloud properties. In the models, the properties of clouds are simplified and expressed in terms of the fraction of the model grid box, which is filled with cloud, together with the liquid and ice water content of the clouds. These models must get the clouds right if they are to correctly represent both their radiative properties and their key role in the production of precipitation, but there are few observations of the vertical profiles of the cloud properties that show whether or not they are successful. Cloud profiles derived from cloud radars, ceilometers, and dual-frequency microwave radiometers operated at three sites in France, Netherlands, and the United Kingdom for several years have been compared with the clouds in seven European models. The advantage of this continuous appraisal is that the feedback on how new versions of models are performing is provided in quasi-real time, as opposed to the much longer time scale needed for in-depth analysis of complex field studies. Here, two occasions are identified when the introduction of new versions of the ECMWF and Météo-France models leads to an immediate improvement in the representation of the clouds and also provides statistics on the performance of the seven models. The Cloudnet analysis scheme is currently being expanded to include sites outside Europe and further operational forecasting and climate models.
Documentation of Uncertainties and Biases Associated with Surface Temperature Measurement Sites for Climate Change Assessment
Authors: Pielke Roger , Nielsen-Gammon John , Davey Christopher , Angel Jim , Bliss Odie , Doesken Nolan , Cai Ming , Fall Souleymane , Niyogi Dev , Gallo Kevin , Hale Robert , Hubbard Kenneth G. , Lin Xiaomao , Li Hong , Raman Sethu
Published: June 2007

The objective of this research is to determine whether poorly sited long-term surface temperature monitoring sites have been adjusted in order to provide spatially representative independent data for use in regional and global surface temperature analyses. We present detailed analyses that demonstrate the lack of independence of the poorly sited data when they are adjusted using the homogenization procedures employed in past studies, as well as discuss the uncertainties associated with undocumented station moves. We use simulation and mathematics to determine the effect of trend on station adjustments and the associated effect of trend in the reference series on the trend of the adjusted station. We also compare data before and after adjustment to the reanalysis data, and we discuss the effect of land use changes on the uncertainty of measurement.

A major conclusion of our analysis is that there are large uncertainties associated with the surface temperature trends from the poorly sited stations. Moreover, rather than providing additional independent information, the use of the data from poorly sited stations provides a false sense of confidence in the robustness of the surface temperature trend assessments.
Mixing in Symmetric Holmboe Waves
Authors: Smyth W. D. , Carpenter J. R. , Lawrence G. A.
Published: June 2007

Direct simulations are used to study turbulence and mixing in Holmboe waves. Previous results showing that mixing in Holmboe waves is comparable to that found in the better-known Kelvin–Helmholtz (KH) billows are extended to cover a range of stratification levels. Mixing efficiency is discussed in detail, as are effective diffusivities of buoyancy and momentum. Entrainment rates are compared with results from laboratory experiments. The results suggest that the ratio of the thicknesses of the shear layer and the stratified layer is a key parameter controlling mixing. With that ratio held constant, KH billows mix more rapidly than do Holmboe waves. Among Holmboe waves, mixing increases with increasing density difference, despite the fact that the transition to turbulence is delayed or prevented entirely by the stratification. Results are summarized in parameterizations of the effective viscosity and diffusivity of Holmboe waves.