bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetic behavior of the major multidrug efflux pump AcrB of
Escherichia coli
Authors: Nagano Keiji , Nikaido Hiroshi
Published: March 2009

Multidrug efflux transporters, especially those that belong to the resistance-nodulation-division (RND) family, often show very broad substrate specificity and play a major role both in the intrinsic antibiotic resistance and, with increased levels of expression, in the elevated resistance of Gram-negative bacteria. However, it has not been possible to determine the kinetic behavior of these important pumps so far. This is partly because these pumps form a tripartite complex traversing both the cytoplasmic and outer membranes, with an outer membrane channel and a periplasmic adaptor protein, and it is uncertain if the behavior of an isolated component protein reflects that of the protein in this multiprotein complex. Here we use intact cells of
Escherichia coli
containing the intact multiprotein complex AcrB-AcrA-TolC, and measure the kinetic constants for various cephalosporins, by assessing the periplasmic concentration of the drug from their rate of hydrolysis by periplasmic β-lactamase and the rate of efflux as the difference between the influx rate and the hydrolysis rate. Nitrocefin efflux showed a
K
m
of about 5 μM with little sign of cooperativity. For other compounds (cephalothin, cefamandole, and cephaloridine) that showed lower affinity to the pump, however, kinetics showed strong positive cooperativity, which is consistent with the rotating catalysis model of this trimeric pump. For the very hydrophilic cefazolin there was little sign of efflux.
Maternal serum endostatin at gestational weeks 16–20 is elevated in subsequent pre‐eclampsia but not in intrauterine growth retardation
Authors: WATHÉN KATJA‐ANNELI , YLIKORKALA OLAVI , ANDERSSON STURE , ALFTHAN HENRIK , STENMAN ULF‐HÅKAN , VUORELA PIIA
Published: March 2009

Objective. Endostatin, an important anti‐angiogenic factor produced by endothelial cells, is elevated in established pre‐eclampsia. We measured maternal serum endostatin concentrations in early pregnancy associated with later pre‐eclampsia and intrauterine growth retardation (IUGR). Design. Retrospective case–control study. Setting. University Central Hospital. Sample. Serum samples were collected at 12–15 and 16–20 gestational weeks from a total of 124 pregnant women of whom 49 developed pre‐eclampsia, 16 gave birth to infants with IUGR without pre‐eclampsia, and 59 remained normotensive giving birth to healthy, normal‐weight infants. Methods. Enzyme‐linked immunosorbent assay. Main outcome measures. Endostatin concentrations in serum. Results. At 12–15 gestational weeks, there was no difference in median endostatin concentrations between the groups. At 16–20 gestational weeks, the median endostatin concentration was higher in the women with subsequent pre‐eclampsia (p = 0.026), especially preceding a later severe form of the disease (p = 0.041), than in the controls. The results were further confirmed by receiver operating characteristic (ROC) analysis showing an area under the curve (AUC) of 0.64 (95% confidence interval: 0.50–0.81) for endostatin to identify subsequent pre‐eclampsia, and 0.71 (0.53–0.89) in cases of severe pre‐eclampsia. Optimal cut‐off values were determined and used for calculations of sensitivity and specificity, which were 80 and 52% (cut‐off value = 58.0 μg/L) in pre‐eclampsia, and 80 and 65% (cut‐off value = 65.5 μg/L) in the severe form of the disease. Conclusions. The concentrations of endostatin in maternal serum at 16–20 weeks’ of gestation are associated with an increased risk of pre‐eclampsia but not IUGR.
Validation of epithelial ovarian cancer and fallopian tube cancer and ovarian borderline tumor data in the Danish Gynecological Cancer Database
Authors: PETRI ANETTE LYKKE , KJAER SUSANNE KRÜGER , CHRISTENSEN IB J. , BLAAKAER JAN , HOGDALL ESTRID , JEPPESEN ULLA , MOSGAARD BERIT J. , PAGEL JENS D. , STILLING LINE , THRANOV INGRID , HOGDALL CLAUS
Published: March 2009

Objective. To validate the data on epithelial ovarian cancer, fallopian tube cancer and borderline ovarian tumors registered in the nationwide Danish Gynecological Cancer Database (DGCD) in 2005 and 2006. The DGCD is a multidisciplinary database that contains data for research and quality improvement. Design. Comparative registry‐based study supplemented with data from medical records. Setting. Six hospitals in Denmark. Participants. Women registered with epithelial ovarian cancer, fallopian tube cancer and borderline ovarian tumor. Main outcome measure. Data completeness and strength of agreement. Results. The estimated completeness of reporting to the DGCD was 94.2% and the strength of agreement between the variables in the DGCD and the medical file varied from moderate to very good. The important quality indicator ‘complication’ had the lowest strength of agreement. Conclusion. The validity of ovarian cancer data in the DGCD is sufficient for quality monitoring in gynecological oncology.
Concentrations of vascular endothelial growth factor C and D in amniotic fluid and maternal plasma
Authors: WATHÉN KATJA‐ANNELI , STENMAN ULF‐HÅKAN , LEINONEN ELINA , ANDERSSON STURE , VUORELA PIIA
Published: March 2009

Objective. Vascular endothelial growth factor‐C (VEGF‐C) and VEGF‐D promote both endothelial and lymphatic vascularization during embryonic development. We studied their presence in amniotic fluid (AF) and maternal plasma during pregnancy. Design. Descriptive study. Setting. University Central Hospital, Helsinki, Finland. Samples. AF at 14–20 weeks (n = 20) and 38–41 weeks’ of gestation (n = 20), serial plasma samples (n = 38) from 16 healthy pregnant women during 8–40 weeks of pregnancy, and plasma from 15 non‐pregnant controls. Methods. Enzyme‐linked immunosorbent assay (ELISA). Main outcome measures. Concentrations of VEGF‐C and ‐D in AF and maternal plasma. Results. VEGF‐C concentrations in AF decrease as pregnancy advances (p = 0.002) and are about 10‐fold lower than in plasma at the corresponding gestational age (p = 0.001). Plasma VEGF‐C concentrations are higher in the first trimester (p = 0.014) and the early second trimester (p = 0.016) than in non‐pregnant women. VEGF‐D is not detectable in AF, but in plasma its concentrations become higher at term compared with non‐pregnant women (p = 0.039). Conclusions. VEGF‐C and ‐D are present in high concentrations in maternal plasma, while only VEGF‐C can be detected in AF.
Angiotensin II type 1 and 2 receptors gene polymorphisms in pre‐eclampsia and normal pregnancy in three different populations
Authors: AKBAR SYED ALI , KHAWAJA NUZHAT P. , BROWN PAUL R. , TAYYEB RAKHSHANDA , BAMFO JACQUELINE , NICOLAIDES KYPROS H.
Published: March 2009

Objectives.To investigate a possible association between pre‐eclampsia (PE) and the genotype for the angiotensin II type‐1 receptor (AT1R) and the angiotensin type‐2 receptor (AT2R) in various population groups.Design.The study was retrospective in a case‐controlled design.Samples.Two hundred thirty‐six pregnant women with PE/eclampsia (E) and 426 non‐hypertensive pregnant women were included.Method.Polymorphic sites of AT1R (A1166C) and AT2R (A1675G) were amplified by polymerase chain reaction, digested with a restriction enzyme that differentiated between the alternative alleles, and analyzed.Main outcome measures.Maternal genotypes and their correlation with clinical parameters.Results.The frequency of the AT2R‐GG genotype (A1675G) in the PE group was significantly greater than in controls for Afro‐Caribbean women (49.3% vs 26.9%,p= 0.004), but the frequency difference in Asian or Caucasian women was not significant (23.0% vs 25.4%,p= 0.63; 27.7% vs 14.8%,p= 0.17, respectively). The highly significant difference in Afro‐Caribbean women was maintained after controlling for the effects of age, BMI and parity (p= 0.005). There was no significant association of the molecular variant of AT1R (A1166C) with PE in Afro‐Caribbean, Caucasian or Asian women. However, in the whole PE group compared to the controls there was a higher proportion of the AT2R‐GG genotype with AT1R‐AC (56% vs 44%, OR 2.37; 95% CI: 1.06–5.32). In Afro‐Caribbean women, the combination of AT1R‐AC with AT2R‐AG genotypes was significantly higher in controls compared to PE group (93.8% vs 6.3%, OR 0.11; 95% CI: 0.01–0.81).Conclusion.There is an association between PE/E and the GG‐genotype of AT2R in Afro‐Caribbean women.
Solitary fibrous tumor of the lung: Three rare cases of intraparenchymal nodules
Authors: Cardinale L. , Ardissone F. , Cataldi A. , Familiari U. , Solitro F. , Fava C.
Published: March 2009

Solitary fibrous tumor (SFT) of the pleura usually presents as a peripheral mass, in contact with the surface of the pleura. However, on occasion, it can occur separately from the pleura, in the lung parenchyma. We describe the radiological and imaging features of three SFTs of the lung, diagnosed in our department, with relevant clinical data. The diagnosis of SFT of the lung, although rare, should be considered in a slow-growing solitary lung parenchymal nodule.
Dynamic Locomotion of a Biomorphic Quadruped ‘Tekken’ Robot Using Various Gaits: Walk, Trot, Free‐Gait and Bound
Authors: Fukuoka Y. , Kimura H.
Published: March 2009

Numerous quadruped walking and running robots have been developed to date. Each robot walks by means of a crawl, walk, trot or pace gait, or runs by means of a bound and/or gallop gait. However, it is very difficult to design a single robot that can both walk and run because of problems related to mechanisms and control. In response to this, we adapted a biological control method for legged locomotion in order to develop a dog‐like quadruped robot we have named ‘Tekken’. Tekken has a control system that incorporates central pattern generators, reflexes and responses as well as a mechanism that makes the most of the control system. Tekken, which is equipped with a single mechanism, an unchangeable control method, and modifiable parameters, is capable of achieving walking and trotting on flat terrain, can walk using a free gait on irregular terrain, and is capable of running on flat terrain using a bounding gait. In this paper, we describe the mechanism, the control method and the experimental results of our new development.
Risk Factors for Gram-Negative Bacterial Surgical Site Infection Do Allergies to Antibiotics Increase Risk?
Authors: Trinh Jane V. , Chen Luke F. , Sexton Daniel J. , Anderson Deverick J.
Published: March 2009

Objective.

To determine the relationship between indequate antimicrobial prophylaxis and development of gram-negative bacterial (GNB) surgical site infection (SSI).

Design.

Retrospective case-control study.

Setting.

A 369-bed acute care community hospital in Durham, North Carolina.

Patients.

Case patients were defined as patients who developed a GNB SSI after undergoing a surgical procedure during the period from January 1, 1998, through January 1, 2007. Control patients were uninfected patients who underwent surgery during the same study period and were matched to case patients by surgeon and type of procedure. Both patient groups were selected on the basis of prospectively collected data on patients who underwent surgery.

Methods.

Patient data were collected from patient medical records. Multivariable analysis was performed using logistic regression with backward selection, to identify variables independently associated with GNB SSI.

Results.

Case patients were similar to control patients with respect to demographics and comorbid conditions, but were older (P = .04), more obese (P = .03), and more likely to have diabetes mellitus (P = .03). Inappropriate timing of antimicrobial prophylaxis was the predominant reason that prophylaxis was deemed inadequate for both patient groups (59.1% of case patients vs 64.0% of control patients; P = .56). Case patients who had a history of allergic reactions to antimicrobial prophylaxis were significantly less likely to receive antimicrobial prophylaxis in a timely manner (P = .03). Variables independently associated with GNB SSI in multivariable analysis included urinary catheterization before surgery (odds ratio [OR], 3.74 [95% confidence interval {CI}, 1.11-12.62), diabetes mellitus (OR, 2.25 [95% CI, 1.02-4.94]), and an American Society of Anesthesiologists score greater than 2 (OR, 2.14 [95% CI, 1.13-4.06]).

Conclusions.

A β-lactam allergy was not associated with increased risk for GNB SSI. Further studies, using patient data from larger hospital databases, are needed to examine the relationship between use of urinary catheter before surgery and risk of GNB SSI.
Gingyo‐San Enhances Immunity and Potentiates Infectious Bursal Disease Vaccination
Authors: Hung Che-Ming , Yeh Chia-Chou , Chong Kowit-Yu , Chen Hsiao-Ling , Chen Jiun-Yu , Kao Shung-Te , Yen Chih-Ching , Yeh Ming-Hsien , Lin Maw-Sun , Chen Chuan-Mu
Published: March 2009

The purpose of the present study was to investigate the effects of Gingyo‐san (GGS), a traditional Chinese medical formula, on peripheral lymphocyte proliferation and serum antibody titers in chickens vaccinated against the infectious bursal disease (IBD) virus. Treatment groups were fed one of three doses of GGS in their diet (0.5%, 1.0% and 2.0%, w/w), and the IBD vaccine was administered at 1 and 3 weeks of age. At Weeks 8, 12 and 16, changes in serum IBD antibody titers were measured via the micro‐method and T cell proliferation. In gene expression experiments, GGS‐treated peripheral T lymphocytes were stimulated with concanavalin A (ConA) for 24 h. The mRNA expression of interleukin‐2 (IL‐2), interferon‐γ (IFN‐γ), interleukin‐4 (IL‐4) and interleukin‐12 (IL‐12) was determined using a semi‐quantitative RT‐PCR assay. The results showed that a low dose of GGS could significantly raise the antibody titers. Medium and high doses of GGS enhanced IL‐2 and IFN‐γ production. GGS altered the expression of IL‐4 and IL‐12 in T lymphocytes. CD4+ T lymphocyte development was also skewed towards the Th1 phenotype. GGS enhanced cell‐mediated immunity and augmented the effects of IBD vaccination in strengthening subsequent anti‐viral responses.
Mass bleaching of soft coral, Sarcophyton spp. in Thailand and the role of temperature and salinity stress
Authors: Chavanich Suchana , Viyakarn Voranop , Loyjiw Thepsuda , Pattaratamrong Priyapat , Chankong Anchalee
Published: March 2009

Chavanich, S., Viyakarn, V., Loyjiw, T., Pattaratamrong, P., and Chankong, A. 2009. Mass bleaching of soft coral, Sarcophyton spp. in Thailand and the role of temperature and salinity stress. – ICES Journal of Marine Science, 66: 1515–1519. From June to October 2006 and 2007, mass bleaching of the soft coral, Sarcophyton spp., occurred for the first time in the upper Gulf of Thailand. Approximately 90% of the populations experienced extensive bleaching, and almost 95% of colonies were affected. Field observations also revealed that fragmentation of Sarcophyton spp. set in 1 month after the onset of bleaching. Some colonies started to recover to some extent by the end of July, with 95% of the population of Sarcophyton spp. recovering by October. Both acute and chronic trials were conducted to determine whether temperature and/or salinity triggered bleaching. In the acute tests, Sarcophyton spp. at 40°C and salinity 20 psu were completely bleached, and death occurred after 57 and 204 h, respectively. However, the colonies at 40 psu could survive through the experimental trial. In the chronic tests, Sarcophyton spp. died when exposed to 34°C, whereas complete bleaching and mortality of Sarcophyton spp. occurred at salinities of 10 and 49 psu. We conclude that elevated temperatures had a greater effect on the bleaching of Sarcophyton spp. than did salinity.
Examining unsupervised time with peers and the role of association with delinquent peers on adolescent smoking
Authors: Greene Kathryn , Banerjee Smita C.
Published: March 2009

Introduction:

This study explored the association between unsupervised time with peers and adolescent smoking behavior both directly and indirectly through interaction with delinquent peers, social expectancies about cigarette smoking, and cigarette offers from peers.

Methods:

A cross-sectional survey was used for the study and included 248 male and female middle school students.

Results:

Results of structural equation modeling revealed that unsupervised time with peers is associated indirectly with adolescent smoking behavior through the mediation of association with delinquent peers, social expectancies about cigarette smoking, and cigarette offers from peers.

Discussion:

Interventions designed to motivate adolescents without adult supervision to associate more with friends who engage in prosocial activities may eventually reduce adolescent smoking. Further implications for structured supervised time for students outside of school time are discussed.
A new phase-field model for strongly anisotropic systems
Authors: Torabi Solmaz , Lowengrub John , Voigt Axel , Wise Steven
Published: March 2009

We present a new phase-field model for strongly anisotropic crystal and epitaxial growth using regularized, anisotropic Cahn–Hilliard-type equations. Such problems arise during the growth and coarsening of thin films. When the anisotropic surface energy is sufficiently strong, sharp corners form and unregularized anisotropic Cahn–Hilliard equations become ill-posed. Our models contain a high-order Willmore regularization, where the square of the mean curvature is added to the energy, to remove the ill-posedness. The regularized equations are sixth order in space. A key feature of our approach is the development of a new formulation in which the interface thickness is independent of crystallographic orientation. Using the method of matched asymptotic expansions, we show the convergence of our phase-field model to the general sharp-interface model. We present two- and three-dimensional numerical results using an adaptive, nonlinear multigrid finite-difference method. We find excellent agreement between the dynamics of the new phase-field model and the sharp-interface model. The computed equilibrium shapes using the new model also match a recently developed analytical sharp-interface theory that describes the rounding of the sharp corners by the Willmore regularization.
On solutions to the non-Abelian Hirota–Miwa equation and its continuum limits
Authors: Li C.X. , Nimmo J.J.C. , Tamizhmani K.M.
Published: March 2009

In this paper, we construct Grammian-like quasideterminant solutions of a non-Abelian Hirota–Miwa equation. Through continuum limits of this non-Abelian Hirota–Miwa equation and its quasideterminant solutions, we construct a cascade of non-commutative differential-difference equations ending with the non-commutative KP equation. For each of these systems, the quasideterminant solutions are constructed as well.
Existence and spectral properties of shear horizontal surface acoustic waves in vertically periodic half-spaces
Authors: Shuvalov A.L. , Poncelet O. , Golkin S.V.
Published: March 2009

The paper is concerned with the propagation of shear horizontal surface waves (SHSW) in semi-infinite elastic media with vertically periodic continuous and/or discrete variation of material properties. The existence and spectral properties of the SHSW are shown to be intimately related to the shape of the properties variation profile. Generally, the SHSW dispersion branches represent randomly broken spectral intervals on the (
ω
, 
k
) plane. They may, however, display a particular regularity in being confined to certain distinct ranges of slowness
s
=
ω
/
k
, which can be predicted and estimated directly from the profile shape. The SHSW spectral regularity is especially prominent when the material properties at the opposite edge points of a period are different. In particular, a unit cell can be arranged so that the SHSW exists within a single slowness window, narrow in the measure of material contrast between the edges, and does not exist elsewhere or vice versa. Explicit analysis in the (
ω
, 
k
) domain is complemented and verified through the numerical simulation of the SH wave field in the time–space domain. The results also apply to a longitudinally periodic semi-infinite strip with a homogeneous boundary condition at the faces.
An asymptotic model for the formation and evolution of air gaps in vertical continuous casting
Authors: Vynnycky M.
Published: March 2009

The formation of an air gap at the mould–metal interface in vertical continuous casting has long been known to have a detrimental effect on the efficiency of the process, and has therefore attracted attempts at mathematical modelling. While almost all current efforts consist of complex three-dimensional numerical simulations of the phenomenon, this paper considers instead an asymptotic model that captures the essential characteristics. The model is thermomechanical and is derived for a geometry, where the generalized plane strain approximation is appropriate. Although two-way coupling between the thermal and mechanical problems is accounted for, it is found that the problems decouple at leading order anyway, and that the thickness of the air gap does not depend on the constitutive relation used for describing the inelastic strains. Furthermore, a criterion for the onset of air-gap formation is derived in terms of the process operating parameters. Mathematically, we obtain a moving boundary problem for a parabolic partial differential equation with a degenerate initial condition and a non-standard Neumann-type boundary condition. Sample computations are performed using parameters for the continuous casting of the copper, and the results, qualitative trends and possible extensions are discussed.
Linear dynamics of elastic helical springs: asymptotic analysis of wave propagation
Authors: Sorokin S.V.
Published: March 2009

Helical springs serve as vibration isolators in virtually any suspension system. A variety of theories to describe the dynamic behaviour of these structural elements, which involves interaction of flexural, torsion and longitudinal waves, can be found in the literature. Alongside this, various approximate methods are employed to determine the eigenfrequencies of vibrations of springs. In this paper, the validity ranges of alternative theories are assessed by comparison of the location of the dispersion curves. This paper also contains a rigorous asymptotic analysis of the exact dispersion equation with two small parameters being employed. It allows for the identification of significant regimes of linear wave motion in a helical spring. In each of these regimes, simple formulae for wavenumbers are obtained by the dominant balance method and their validity ranges are checked against direct numerical solution. Mode shapes associated with each wavenumber are also analysed.
Switching criteria for hybrid rarefied gas flow solvers
Authors: Lockerby Duncan A. , Reese Jason M. , Struchtrup Henning
Published: March 2009

Switching criteria for hybrid hydrodynamic/molecular gas flow solvers are developed, and are demonstrated to be more appropriate than conventional criteria for identifying thermodynamic non-equilibrium. For switching from a molecular/kinetic solver to a hydrodynamic (continuum-fluid) solver, the criterion is based on the difference between the hydrodynamic near-equilibrium fluxes (i.e. the Navier–Stokes stress and Fourier heat flux) and the actual values of stress and heat flux as computed from the molecular solver. For switching from hydrodynamics to molecular/kinetic, a similar criterion is used but the values of stress and heat flux are approximated through higher order constitutive relations; in this case, we use the R13 equations. The efficacy of our proposed switching criteria is tested within an illustrative hybrid kinetic/Navier–Stokes solver. For the test cases investigated, the results from the hybrid procedure compare very well with the full kinetic solution, and are obtained at a fraction of the computational cost.
Temperature Dependence of Total AC Loss in High-Temperature Superconducting Tapes
Authors: Nguyen Doan N. , Sastry Pamidi V. P. S. S. , Knoll David C. , Schwartz Justin
Published: March 2009

A versatile experimental facility was designed and set up to measure transport ac losses, magnetization ac losses, and total ac losses in high-temperature superconductors at variable temperatures. Several sets of measurements were carried out in the temperature range of 35 K to 100 K. Sample temperature during the measurements could be controlled within plusmn0.5 K of set temperature. Temperature dependence of transport losses reflects variation of critical current density of the tapes with temperature. Temperature dependence of magnetization losses exhibits an interesting behavior with a peak, whose position shifts to lower temperatures as the magnetic field is increased. Experimental data of ac losses at various temperatures are compared with those calculated using numerical methods. Generally, the simulated results reproduce well the experimental data.
Interaction of acenocoumarol and sitaxentan in pulmonary arterial hypertension
Authors: Pulido T. , Sandoval J. , Roquet I. , Gutiérrez R. , Rueda T. , Peña H. , Santos E. , Miranda M. T. , Lupi E.
Published: March 2009

Background  Sitaxentan inhibits the metabolism of warfarin, resulting in a need for adjustment of warfarin dose when both drugs are coadministered. We report the long‐term effects on bleeding of acenocoumarol co‐administered as part of conventional therapy for pulmonary hypertension with sitaxentan in a subset of patients enrolled in the Sitaxentan To Relieve ImpaireD Exercise‐3 (STRIDE‐3) study.

Materials and methods  STRIDE‐3 is an ongoing, long‐term, open‐label trial, evaluating the safety and efficacy of sitaxentan, 100 mg once daily, in patients with pulmonary arterial hypertension. Information on bleeding events was collected prospectively, including the type of event, severity, anticoagulant use and investigator attribution of causality. Coagulation tests were performed on a monthly basis. A clinically significant interaction was defined as an international normalized ratio (INR) ≥ 5·0, or any minor bleeding event plus an INR > 2·0 and < 5·0.

Results  Of 55 patients enrolled in STRIDE‐3, 50 received acenocoumarol. Average follow‐up was 158·6 ± 57·6 weeks. The average dose of anticoagulant therapy was 3·9 ± 1·3 mg week−1 (range, 1·5–7·0 mg week−1). Following treatment, an INR ≥ 5 in at least one INR determination was observed in 13 patients, although none of these patients had a clinically significant bleeding event. Dose reductions in acenocoumarol were performed to adjust target INR to 1·5–2·0. Two patients died of massive haemoptysis, but these episodes were not attributed to a drug interaction. Four patients with an INR > 2·0 and < 5·0 experienced a minor bleeding event (nosebleeds/gingivitis).

Conclusions  No clinically significant bleeding events were recorded with coadministration of sitaxentan and acenocoumarol in this patient subgroup. These results suggest that coadministration of sitaxentan and acenocoumarol is clinically manageable and well tolerated.
A review of STRIDE‐2 and STRIDE‐2X: the case for selective endothelin receptor blockade
Authors: Langleben D. , Cacoub P.
Published: March 2009

Background  Pulmonary arterial hypertension remains incurable and has previously required difficult parenteral therapy. Endothelin‐1(ET‐1) is an important mediator of pulmonary arterial hypertension. The recent availability of oral therapies, including endothelin receptor antagonists, has improved ease of use for patients, but most patients remain symptomatic to a significant degree. Two classes of ET‐1 receptors have been described, ETA and ETB. It has previously been unclear whether both receptors must be blocked in pulmonary arterial hypertension, or only the ETA receptor.

Materials and methods  The Sitaxsentan To Relieve ImpaireD Exercise‐2 (STRIDE‐2) study followed by STRIDE‐2X exposed patients with pulmonary arterial hypertension to the highly selective ETA antagonist sitaxsentan (n = 145), or to bosentan (n = 84), a nonselective ETA and ETB antagonist. The total exposure duration and follow‐up period was 1 year. Pre‐specified comparisons included time to discontinuation of monotherapy, time to clinical worsening, incidence of elevated hepatic transaminase levels > 3 × upper limit of normal and survival.

Results  Sitaxsentan therapy showed significant benefit over bosentan with respect to discontinuation of monotherapy at 1 year (24% vs. 43%, P = 0·002), clinical worsening at 1 year (28% vs. 39%, P = 0·0425), elevated hepatic transaminases at 1 year (4% vs. 14%, P = 0·014) and 1‐year survival (96% vs. 88%, P = 0·028).

Conclusions  STRIDE‐2 and its extension, STRIDE‐2X, suggest significant benefit of sitaxsentan compared with bosentan, in terms of efficacy and reduced hepatotoxicity. The former may be related to the high ETA receptor selectivity of sitaxsentan.
Endothelin receptor selectivity in chronic renal failure
Authors: Longaretti L. , Benigni A.
Published: March 2009

Chronic kidney diseases are increasing worldwide at an alarming rate, and they are emerging as a major public health problem. Treatments that slow the progression of chronic kidney disease are needed. Endothelin‐1 (ET‐1) is a potent vasoconstrictor with proinflammatory, mitogenic and profibrotic effects that is closely involved in both normal renal physiology and pathology. Increasing evidence suggests that ET‐1 and its cognate receptors are involved in a variety of progressive renal disorders to the extent that renal ET‐1 expression correlates with disease severity and renal function impairment. Endothelin receptor antagonists have been used in renoprotection studies owing to their capacity of improving renal hemodynamics and reducing proteinuria. Whether selective ETA or non‐selective ETA/ETB receptor antagonists are preferable is still a matter of debate. As angiotensin II blockers are not invariably effective in retarding disease progression when treatment is started late in the course of the disease, it is foreseeable that an ET‐1 antagonist in addition to angiotensin‐converting enzyme inhibitors could represent a combined treatment for progressive nephropathies. The focus of this review is to examine the role endothelin‐1 plays in kidney diseases and to determine the ideal setting for antagonizing its biological activity in chronic nephropathies.
Endothelin receptor selectivity in chronic kidney disease: rationale and review of recent evidence
Authors: Neuhofer W. , Pittrow D.
Published: March 2009

Endothelin (ET) is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two pharmacologically distinct receptor subtypes, namely ETAand ETB. In addition to its substantial contribution to normal renal function, a large body of evidence suggests that derangement of the renal ET system is involved in the initiation and progression of chronic kidney disease (CKD) in diabetes, hypertension and glomerulonephritis. Thus, the use of ET receptor antagonists (ERAs) may offer potential novel treatment strategies in CKD. Recent literature on the role of the renal ET system in the healthy kidney was reviewed. In addition, an unbiased PubMed search was performed for studies published during the last 5 years that addressed the effects of ERAs in CKD. A particular objective was to extract information regarding whether selective or nonselective ERAs may have therapeutic potential in humans. ET‐1 acts primarily as an autocrine or paracrine factor in the kidney. In normal physiology, ET‐1 promotes diuresis and natriuresis by local production and action through ETBreceptors in the renal medulla. In pathology, ET‐1 mediates vasoconstriction, mesangial‐cell proliferation, extracellular matrix production and inflammation, effects that are primarily conveyed by ETAreceptors. Results obtained in animal models and in humans with the use of ERAs in CKD are encouraging; nevertheless, it is still under debate which receptor subtype should be targeted. According to most studies, selective inhibition of ETAreceptors appears superior compared with nonselective ERAs because this approach does not interfere with the natriuretic, antihypertensive and ET clearance effects of ETBreceptors. Although preliminary data in humans are promising, the potential role of ERAs in patients with CKD and the question of which receptor subtype should be targeted can only be clarified in randomized clinical trials.
Endothelin receptor antagonism and cancer
Authors: Bhalla A. , Haque S. , Taylor I. , Winslet M. , Loizidou M.
Published: March 2009

The endothelin peptides have an important role in the cancer‐stromal interactions that promote tumour growth. Endothelin‐1 (ET‐1), clinically the most investigated endothelin, is a vital agent in the growth and progression of several tumours including prostate, ovarian, colorectal, bladder, breast and lung carcinomas. ET‐1 exerts its effects through the activation of two distinct receptors, ETA and ETB. Once activated, these receptors transmit signals via numerous intracellular signalling pathways. The effects of ET receptor stimulation in cancer cells or cancer‐associated cells include proliferation, resistance to apoptosis, angiogenesis, migration and subsequent invasion. At present, the manipulation of the endothelin axis within the pre‐clinical setting is the subject of intense investigation. Recent studies into ET receptor antagonism have produced interesting results highlighting the fact that these receptors may provide novel targets for a new generation of chemotherapeutic agents in a variety of cancers.
Determination by HPLC fluorescence analysis of the natural enantiomers of sex pheromones in the New World screwworm fly, Cochliomyia hominivorax
Authors: AKASAKA K. , CARLSON D. A. , OHTAKA T. , OHRUI H. , MORI K. , BERKEBILE D. R.
Published: March 2009

Abstract Bioassays of six racemic synthesized candidate sex pheromone compounds against male New World screwworm Cochliomyia hominivorax (Coquerel) flies showed that the most potent bioactivity was found with 6‐acetoxy‐19‐methylnonacosane and 7‐acetoxy‐15‐methylnonacosane compared with four other isomeric acetoxy nonacosanes and a larger aliphatic ketone. As all these methyl‐branched compounds have two asymmetric carbons and four possible enantiomers, characterization of the natural enantiomers was essential. All four enantiomers for the two most bioactive isomers of the natural sex pheromone were synthesized for bioassay. Hydrolysis and derivatization of these enantiomers with different fluorescent reagents was followed by column‐switched high‐performance liquid chromatography. The use of two linked, reversed‐phase columns of different polarity held at sub‐ambient temperatures allowed good separation of each enantiomer. This analysis applied to natural material was successful, as (6R,19R)‐6‐acetoxy‐19‐methylnonanocosane, and (7R,15R)‐ and (7R,15S)‐7‐acetoxy‐15‐methylnonanocosane were detected in extracts of recently colonized female flies.
Molecular characterization of esterase E3 gene associated with organophosphorus insecticide resistance in the New World screwworm fly, Cochliomyia hominivorax
Authors: CARVALHO R. A. , TORRES T. T. , PANIAGO M. G. , AZEREDO‐ESPIN A. M. L.
Published: March 2009

Abstract The New World screwworm, Cochliomyia hominivorax (Coquerel) (Diptera: Calliphoridae), is one of the most important myiasis‐causing flies in South America. It is responsible for severe economic losses to livestock producers, mainly because it causes mortality in newborn calves and reductions in the quality of leather and in the production of milk and meat. The economic losses caused by myiasis, along with those caused by other internal and external parasites, are the main factors limiting meat production. In Brazil, C. hominivorax has been controlled by applying insecticides, particularly organophosphate (OP)‐based compounds. However, the improper and continuous use of these chemicals can lead to the selection of OP‐resistant strains. This, associated with the fast development of OP resistance in other myiasis‐causing flies, shows the importance of investigating resistance in C. hominivorax. Based on the findings of previous studies, the objective of the current work was to isolate and sequence the E3 gene in C. hominivorax. Mutations at the positions (Gly137 and Trp251) responsible for conferring OP resistance in Lucilia cuprina and Musca domestica L. (Muscidae) were identified in C. hominivorax. In addition, the orthologous region in C. hominivorax contained motifs that are highly conserved among carboxyl/cholinesterases and contribute to the catalytic mechanism of the active site. The characterization of this gene in natural populations of New World screwworm can be an important tool for monitoring resistance to insecticides throughout its current geographic distribution. This will provide information for the selection and implementation of more effective pest management programmes.
Complementary action of jasmonic acid on salicylic acid in mediating fungal elicitor‐induced flavonol glycoside accumulation of Ginkgo biloba cells
Authors: XU MAOJUN , DONG JUFANG , WANG HUIZHONG , HUANG LUQI
Published: March 2009

The antagonistic action between jasmonic acid (JA) and salicylic acid (SA) in plant defence responses has been well documented. However, their relationship in secondary metabolite production is largely unknown. Here, we report that PB90, a protein elicitor from Phytophthora boehmeriae, triggers JA generation, SA accumulation and flavonol glycoside production of Ginkgo biloba cells. JA inhibitors suppress not only PB90‐triggered JA generation, but also the elicitor‐induced flavonol glycoside production. However, the elicitor can still enhance flavonol glycoside production even though the JA generation is totally inhibited. Over‐expression of SA hydrolase gene NahG not only abolishes SA accumulation, but also suppresses the elicitor‐induced flavonol glycoside production when JA signalling is inhibited. Interestingly, expression of NahG does not inhibit the elicitor‐induced flavonol glycoside accumulation in the absence of JA inhibitors. Moreover, JA levels are significantly enhanced when SA accumulation is impaired in the transgenic cells. Together, the data suggest that both JA and SA are involved in PB90‐induced flavonol glycoside production. Furthermore, we demonstrate that JA signalling might be enhanced to substitute for SA to mediate the elicitor‐induced flavonol glycoside accumulation when SA signalling is impaired, which reveals an unusual complementary relationship between JA and SA in mediating plant secondary metabolite production.
Picking battles wisely: plant behaviour under competition
Authors: NOVOPLANSKY ARIEL
Published: March 2009

Plants are limited in their ability to choose their neighbours, but they are able to orchestrate a wide spectrum of rational competitive behaviours that increase their prospects to prevail under various ecological settings. Through the perception of neighbours, plants are able to anticipate probable competitive interactions and modify their competitive behaviours to maximize their long‐term gains. Specifically, plants can minimize competitive encounters byavoidingtheir neighbours; maximize their competitive effects by aggressivelyconfrontingtheir neighbours; ortoleratethe competitive effects of their neighbours. However, the adaptive values of these non‐mutually exclusive options are expected to depend strongly on the plants' evolutionary background and to change dynamically according to their past development, and relative sizes and vigour. Additionally, the magnitude of competitive responsiveness is expected to be positively correlated with the reliability of the environmental information regarding the expected competitive interactions and the expected time left for further plastic modifications. Concurrent competition over external and internal resources and morphogenetic signals may enable some plants to increase their efficiency and external competitive performance by discriminately allocating limited resources to their more promising organs at the expense of failing or less successful organs.
Antagonism between salicylic and abscisic acid reflects early host–pathogen conflict and moulds plant defence responses
Authors: De Torres Zabala Marta , Bennett Mark H. , Truman William H. , Grant Murray R.
Published: March 2009

The importance of phytohormone balance is increasingly recognized as central to the outcome of plant–pathogen interactions. Recently it has been demonstrated that abscisic acid signalling pathways are utilized by the bacterial phytopathogen Pseudomonas syringae to promote pathogenesis. In this study, we examined the dynamics, inter‐relationship and impact of three key acidic phytohormones, salicylic acid, abscisic acid and jasmonic acid, and the bacterial virulence factor, coronatine, during progression of P. syringae infection of Arabidopsis thaliana. We show that levels of SA and ABA, but not JA, appear to play important early roles in determining the outcome of the infection process. SA is required in order to mount a full innate immune responses, while bacterial effectors act rapidly to activate ABA biosynthesis. ABA suppresses inducible innate immune responses by down‐regulating SA biosynthesis and SA‐mediated defences. Mutant analyses indicated that endogenous ABA levels represent an important reservoir that is necessary for effector suppression of plant‐inducible innate defence responses and SA synthesis prior to subsequent pathogen‐induced increases in ABA. Enhanced susceptibility due to loss of SA‐mediated basal resistance is epistatically dominant over acquired resistance due to ABA deficiency, although ABA also contributes to symptom development. We conclude that pathogen‐modulated ABA signalling rapidly antagonizes SA‐mediated defences. We predict that hormonal perturbations, either induced or as a result of environmental stress, have a marked impact on pathological outcomes, and we provide a mechanistic basis for understanding priming events in plant defence.
Neonatal MRI in preterm infants with periventricular leukomalacia and mild disability
Authors: Jinnou Hideo , Kouwaki Masanori , Kiyosawa Syusuke , Yokochi Kenji
Published: March 2009

Background:  The aim of the present study was to describe the neonatal magnetic resonance imaging (MRI) findings of preterm infants with periventricular leukomalacia and mild neurological disability.

Methods:  MRI findings at term equivalent were retrospectively investigated in eight preterm infants with mild disability and periventricular leukomalacia diagnosed on MRI in infancy.

Results:  Linear, spotted, or macular areas of hyperintensity on T1‐weighted imaging and hypointensity on T2‐weighted imaging were identified in all subjects in the white matter lateral to the body of the lateral ventricle. No cystic lesions were seen. These findings were more widespread and more clearly visualized on T2‐weighted imaging than T1‐weighted imaging.

Conclusions:  Linear, spotted, or macular lesions that are hyperintense on T1‐weighted imaging and hypointense on T2‐weighted imaging are possibly compatible with periventricular leukomalacia.
Questionnaire survey on pediatric hypertension in Japan and Korea
Authors: Yim Hyung Eun , Lee Eun Hee , Jang Gi Young , Yoo Kee Hwan , Son Chang Sung , Hong Young Sook , Lee Joo Won , Ito Yuhei , Ikezumi Yohei , Uchiyama Makoto
Published: March 2009

Background:  Hypertension (HTN) is no longer viewed as an adult disease. The purpose of the present study was to understand how hypertensive children are evaluated and managed, by surveying pediatricians in Japan and South Korea.

Methods:  A questionnaire was mailed to 109 Japanese (JA) and 159 Korean (KO) pediatric cardiologists, pediatric nephrologists, and other pediatricians.

Results:  A total of 127 replies were received (response rate 47%). Most of respondents did not check blood pressure (BP) routinely in outpatient clinics (JA 77%, KO 88%). A mercury sphygmomanometer was the most commonly used method for BP measurements (JA 72%, KO 62%). BP treatment goals were usually set at the 95th percentile for age, gender, and height (JA 47%, KO 54%). More KO used a lower goal in children with primary HTN than JA. KO respondents preferred angiotensin‐converting enzyme inhibitors (ACEI) as initial agents regardless of underlying diseases whereas JA respondents chose various medications, that is, calcium channel blockers, diuretics, and ACEI. For BP monitoring, self‐monitoring was found to be most frequent in both countries (JA 80%, KO 57%). Ambulatory BP monitoring was not frequently utilized in both countries (JA 33% KO 34%).

Conclusion:  The current assessment, management and differing trends in pediatric HTN in Japan and Korea have been identified in the present study. Pediatricians should be aware of the growing implications of HTN in children.
The Use of Simple Reparameterizations to Improve the Efficiency of Markov Chain Monte Carlo Estimation for Multilevel Models with Applications to Discrete Time Survival Models
Authors: Browne William J. , Steele Fiona , Golalizadeh Mousa , Green Martin J.
Published: March 2009

We consider the application of Markov chain Monte Carlo (MCMC) estimation methods to random-effects models and in particular the family of discrete time survival models. Survival models can be used in many situations in the medical and social sciences and we illustrate their use through two examples that differ in terms of both substantive area and data structure. A multilevel discrete time survival analysis involves expanding the data set so that the model can be cast as a standard multilevel binary response model. For such models it has been shown that MCMC methods have advantages in terms of reducing estimate bias. However, the data expansion results in very large data sets for which MCMC estimation is often slow and can produce chains that exhibit poor mixing. Any way of improving the mixing will result in both speeding up the methods and more confidence in the estimates that are produced. The MCMC methodological literature is full of alternative algorithms designed to improve mixing of chains and we describe three reparameterization techniques that are easy to implement in available software. We consider two examples of multilevel survival analysis: incidence of mastitis in dairy cattle and contraceptive use dynamics in Indonesia. For each application we show where the reparameterization techniques can be used and assess their performance.
Prediction in Multilevel Generalized Linear Models
Authors: Skrondal Anders , Rabe-Hesketh Sophia
Published: March 2009

We discuss prediction of random effects and of expected responses in multilevel generalized linear models. Prediction of random effects is useful for instance in small area estimation and disease mapping, effectiveness studies and model diagnostics. Prediction of expected responses is useful for planning, model interpretation and diagnostics. For prediction of random effects, we concentrate on empirical Bayes prediction and discuss three different kinds of standard errors; the posterior standard deviation and the marginal prediction error standard deviation (comparative standard errors) and the marginal sampling standard deviation (diagnostic standard error). Analytical expressions are available only for linear models and are provided in an appendix. For other multilevel generalized linear models we present approximations and suggest using parametric bootstrapping to obtain standard errors. We also discuss prediction of expectations of responses or probabilities for a new unit in a hypothetical cluster, or in a new (randomly sampled) cluster or in an existing cluster. The methods are implemented in gllamm and illustrated by applying them to survey data on reading proficiency of children nested in schools. Simulations are used to assess the performance of various predictions and associated standard errors for logistic random-intercept models under a range of conditions.