bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of moderate dehydration on soccer performance: physiological responses to 45 min of outdoor match-play and the immediate subsequent performance of sport-specific and mental concentration tests
Authors: Edwards Andrew M , Mann Michael E , Marfell-Jones Michael J , Rankin Dean M , Noakes Timothy D , Shillington David P
Published: February 2007

Objective:To determine whether moderate water loss (∼1.5–2% of body mass (BM)) represents a significant impairment to soccer match-play and the related fitness variables.

Methods:11 moderately active male soccer players (mean (SD) age 24.4 (3) years, BM 74.03 (10.5) kg, peak oxygen consumption 50.91 (4.0) ml/kg/min) volunteered to participate. The experimental procedure comprised: (1) a 45 min pre-match period of cycle ergometry exercise (90% of individual ventilatory threshold); (2) the completion of a 45 min soccer match; and (3) the immediate post-match performance of sport-specific and mental concentration tests. The subjects completed the procedure on three occasions each in a different experimental condition (fluid intake (FL), no fluid (NF) and mouth rinse (MR)) in an individually randomised order. Core temperature (Tc), heart rates, plasma and urine osmolalities, BM, sweat rates and heat storage were all measured.

Results:The only condition-dependent difference during the match-play element of the protocol was a significantly increased Tcin the NF condition compared with the FL condition (39.28°C (0.35°C) and 38.8°C (0.47°C), respectively; p<0.05). The immediate post-match performance of a sport-specific fitness test was significantly impaired where FL had been denied (p<0.01). The post-test evaluation of rating of perceived exertion and thirst indicated that the NF condition was perceived to be the most challenging (p<0.05).

Conclusions:The condition-dependent differences in match-play and post-match tests demonstrate that moderate dehydration is detrimental to soccer performance. However, it remains unclear whether this could be attributable to water loss in itself or the negative psychological associations derived from a greater perception of effort in that condition.
Use of chaperones in the urology outpatient setting: a patient's choice in a “patient-centred” service
Authors: Sinclair Andrew M , Gunendran Thiru , Pearce Ian
Published: February 2007

Background

The use of a chaperone in the clinical setting is a much debated subject. There have been many guidelines and papers written on this topic, but always from the medical profession's point of view. For the first time, this survey focuses on the opinion of the patient.

Methods

800 consecutive patients attending the urology outpatient clinic were asked to complete a questionnaire on basic patient demographics and their opinions on chaperones.

Results

Of 709 patients who completed the questionnaires, 553 (78%) were male. Overall, 535 (75.5%) patients did not want a chaperone present. Only 66 (42%) females stated a preference for the presence of a chaperone. Of the 174 patients requesting a chaperone, 102 (59%) patients wished the role to be taken by a friend or family member. 90% of these patients attended with the appropriate person.

Conclusions

Most patients do not want a chaperone present for intimate examinations. Most women do not wish to have a chaperone present. Of those who do wish to have a chaperone present, more than half want a family member or friend to fill the role. This would be against current guidelines. However, in a “patient-centred” service, these results should be taken into consideration.
Surgery for morbid obesity
Authors: Bennett John M H , Mehta Samir , Rhodes Michael
Published: February 2007

The prevalence of morbid obesity in the UK population is rising, bringing with it increased levels of cardiovascular disease, diabetes, arthritis and early mortality. The overall cost to the health service is high, and is set to increase over the coming decades as the overweight population ages. Dietary, lifestyle and pharmacological interventions offer at best reasonable, short-term weight reduction and often fail. Surgical intervention is a safe and effective means of delivering marked long-term weight reduction. This article compares and contrasts the options available for surgical treatment of morbid obesity based on a review of the current literature.
Importance of red patches diagnosed in cystoscopy for haematuria and lower urinary tract symptoms
Authors: Fernando Herman , Thota Sreenivasa S , Burtt Glyn , Waterfall Nicholas , Husain Imtiaz
Published: February 2007

Background

Biopsy of the red patches in the bladder, when found at cystoscopy, is routinely performed in urological practice. This is done to establish the sinister diagnosis of carcinoma-in-situ among other causes.

Objective

To analyse the pathology of the red patches and to determine if routine biopsy of these patches is warranted.

Patients and methods

This was a retrospective study conducted over a period of 36 months, in which 50 patients were identified, who underwent biopsies of their red patches. All patients with a history of bladder carcinoma and obvious bladder tumours were excluded from this study.

Results

The mean age of the patients was 60.8 years. 25 patients had cystoscopy for lower urinary tract symptoms, 21 for haematuria and 4 for recurrent urinary tract infection. Carcinoma in situ was found in 4 (8%) patients, of whom only 2 had positive urine cytology.

Conclusion

It is prudent to perform a biopsy of all incidentally diagnosed red patches because of a major yield rate of carcinoma in situ. This procedure also picks up other important pathologies, which help in further management.
Committee for the Relief of Distressed Seamen: correspondence from the Admiralty in 1818–19
Authors: Cook G C
Published: February 2007

The Seamen's Hospital Society, which was to become a great Victorian charity, with the object of caring for both the physical and spiritual health of seafarers (most merchant seamen) in the Port of London, was founded at a meeting on 8 March 1821. However, it is not widely known that it had a temporary predecessor—The Committee for the Relief of Distressed (Destitute) Seamen. Ready cooperation was received from the Admiralty in most of its affairs, but “disposal” of many of these “redundant” mariners proved to be a somewhat difficult matter.
HIGHER ORDER CORRECTION TO THE NEUTRINO SELF-ENERGY IN A MEDIUM AND ITS ASTROPHYSICAL APPLICATIONS
Authors: GARCÍA ALBERTO BRAVO , SAHU SARIRA
Published: February 2007

We have calculated the 1/M4 (M the vector boson mass) order correction to the neutrino self-energy in a medium. The possible application of this higher order contribution to the neutrino effective potential is considered in the context of the Early Universe hot plasma and of the cosmological Gamma Ray Burst fireball. We found that, depending on the medium parameters and on the neutrino properties (mixing angle and mass square difference), the resonant oscillation of active to active neutrinos is possible.
TUNNELING RADIATION FROM TOROIDAL BLACK HOLE
Authors: LI GU-QIANG
Published: February 2007

The tunneling radiation from toroidal black hole is studied by applying the method of Parikh. The appearance of higher corrections to the semiclassical rate caused by the law of energy conservation is demonstrated and it is shown that the energy spectrum deviates from exact thermal spectrum.
ON MODELING COMPLEX COLLECTIVE BEHAVIOR IN MYXOBACTERIA
Authors: JIANG YI , SOZINOVA OLGA , ALBER MARK
Published: February 2007

This paper reviews recent progress in modeling collective behaviors in myxobacteria using lattice gas cellular automata approach (LGCA). Myxobacteria are social bacteria that swarm, glide on surfaces and feed cooperatively. When starved, tens of thousands of cells change their movement pattern from outward spreading to inward concentration; they form aggregates that become fruiting bodies. Cells inside fruiting bodies differentiate into round, nonmotile, environmentally resistant spores. Traditionally, cell aggregation has been considered to imply chemotaxis, a long-range cell interaction. However, myxobacteria aggregation is the consequence of direct cell-contact interactions, not chemotaxis. In this paper, we review biological LGCA models based on local cell–cell contact signaling that have reproduced the rippling, streaming, aggregating and sporulation stages of the fruiting body formation in myxobacteria.
ADVANCES IN DISTRIBUTED OPTIMIZATION USING PROBABILITY COLLECTIVES
Authors: WOLPERT DAVID H. , STRAUSS CHARLIE E. M. , RAJNARAYAN DEV
Published: February 2007

Recent work has shown how information theory extends conventional full-rationality game theory to allow bounded rational agents. The associated mathematical framework can be used to solve distributed optimization and control problems. This is done by translating the distributed problem into an iterated game, where each agent's mixed strategy (i.e. its stochastically determined move) sets a different variable of the problem. So the expected value of the objective function of the distributed problem is determined by the joint probability distribution across the moves of the agents. The mixed strategies of the agents are updated from one game iteration to the next so as to converge on a joint distribution that optimizes that expected value of the objective function. Here, a set of new techniques for this updating is presented. These and older techniques are then extended to apply to uncountable move spaces. We also present an extension of the approach to include (in)equality constraints over the underlying variables. Another contribution is that we show how to extend the Monte Carlo version of the approach to cases where some agents have no Monte Carlo samples for some of their moves, and derive an "automatic annealing schedule".
Apoptosis-associated tyrosine kinase scaffolding of protein phosphatase 1 and SPAK reveals a novel pathway for Na-K-2C1 cotransporter regulation
Authors: Gagnon Kenneth B. E. , England Roger , Diehl Lisa , Delpire Eric
Published: February 2007

Previous work from our laboratory and others has established that Ste-20-related proline-alanine-rich kinase (SPAK/PASK) is central to the regulation of NKCC1 function. With no lysine (K) kinase (WNK4) has also been implicated in the regulation of NKCC1 activity through upstream activation of SPAK. Because previous studies from our laboratory also demonstrated a protein-protein interaction between SPAK and apoptosis-associated tyrosine kinase (AATYK), we explore here the possibility that AATYK is another component of the regulation of NKCC1. Heterologous expression of AATYK1 in NKCC1-injected Xenopus laevis oocytes markedly inhibited cotransporter activity under isosmotic conditions. Interestingly, mutation of key residues in the catalytic domain of AATYK1 revealed that the kinase activity does not play a role in the suppression of NKCC1 function. However, mutagenesis of the two SPAK-binding motifs in AATYK1 completely abrogated this effect. As protein phosphatase 1 (PP1) also plays a central role in the dephosphorylation and inactivation of NKCC1, we investigated the possibility that AATYK1 interacts with the phosphatase. We identified a PP1 docking motif in AATYK1 and demonstrated interaction using yeast-2-hybrid analysis. Mutation of a key valine residue (V1175) within this motif prevented protein-protein interaction. Furthermore, the physical interaction between PP1 and AATYK was required for inhibition of NKCC1 activity in Xenopus laevis oocytes. Taken together, our data are consistent with AATYK1 indirectly inhibiting the SPAK/WNK4 activation of the cotransporter by scaffolding an inhibitory phosphatase in proximity to a stimulatory kinase.
Nuclear receptors RXRα:RARα are repressors for human MRP3 expression
Authors: Chen Wensheng , Cai Shi-Ying , Xu Shuhua , Denson Lee A. , Soroka Carol J. , Boyer James L.
Published: February 2007

Multidrug resistance-associated protein MRP3/Mrp3 (ABCC3) is upregulated in cholestasis, an adaptive response that may protect the liver from accumulation of toxic compounds, such as bile salts and bilirubin conjugates. However, the mechanism of this upregulation is poorly understood. We and others have previously reported that fetoprotein transcription factor/liver receptor homolog-1 is an activator of MRP3/Mrp3 expression. In searching for additional regulatory elements in the human MRP3 promoter, we have now identified nuclear receptor retinoic X receptor-α:retinoic acid receptor-α (RXRα:RARα) as a repressor of MRP3 activation by transcription factor Sp1. A luciferase reporter assay demonstrated that cotransfection of transcription factor Sp1 stimulates the MRP3 promoter activity and that additions of RXRα:RARα abrogated this activation in a dose-dependent manner. Site mutations and gel shift assays have identified a Sp1 binding GC box motif at −113 to −108 nts upstream from the MRP3 translation start site, where RXRα:RARα specifically reduced Sp1 binding to this site. Mutation of the GC box also reduced MRP3 promoter activity. The functional role of RXRα:RARα as a repressor of MRP3 expression was further confirmed by RARα small-interfering RNA knockdown in HepG2 cells, which upregulated endogenous MRP3 expression. In summary, our results indicate that activator Sp1 and repressor RXRα:RARα act in concert to regulate MRP3 expression. Since RXRα:RARα expression is diminished by cholestatic liver injury, loss of RXRα:RARα may lead to upregulation of MRP3/Mrp3 expression in these disorders.
Regression of chronic hypoxic pulmonary hypertension by simvastatin
Authors: Girgis Reda E. , Mozammel Shehzin , Champion Hunter C. , Li Dechun , Peng Xinqi , Shimoda Larissa , Tuder Rubin M. , Johns Roger A. , Hassoun Paul M.
Published: February 2007

The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor, simvastatin, has been shown to attenuate chronic hypoxic pulmonary hypertension (CHPH). Here, we assess whether simvastatin is capable of inducing regression of established CHPH and explore potential mechanisms of statin effect. Rats ( n = 8 in each group) were exposed to chronic hypoxia (10% FiO2) for 2 or 4 wk. Simvastatin treatment (20 mg·kg−1·day−1) commenced after 2 wk of hypoxia, at which time CHPH was fully established, reduced mean pulmonary artery pressure (19 ± 0.5 vs. 27 ± 0.9 mmHg; P < 0.001), the ratio of right ventricular free wall to left ventricular plus septal weight (0.41 ± 0.03 vs. 0.54 ± 0.03; P < 0.001), and medial thickening of small pulmonary arteries (13 ± 0.4 vs. 16 ± 0.4%; P < 0.01) compared with 4-wk hypoxic controls. Supplementation with mevalonate (50 mg·kg−1·day−1) prevented the attenuation of CHPH induced by simvastatin during 2 wk of hypoxia. Because statins are known to inhibit Rho-kinase (ROCK), we determined expression of ROCK-1 and -2 in whole lung by Western blot and ROCK activity by phosphorylation of the myosin-binding subunit of myosin phosphatase. Expression of both ROCK-1 and -2 were markedly diminished in simvastatin-treated animals during normoxia and hypoxia (2- and 4-wk) exposure ( P < 0.01). ROCK activity was increased threefold under hypoxic conditions and normalized with simvastatin treatment ( P < 0.001). We conclude that simvastatin attenuates and induces regression of established CHPH through inhibition of HMG-CoA reductase. Inhibition of ROCK expression and activity may be an important mechanism of statin effect.
Escherichia coli lipopolysaccharides produce serotype-specific hypothermic response in biotelemetered rats
Authors: Akarsu Eyup S. , Mamuk Soner
Published: February 2007

We investigated whether LPS-induced hypothermia develops in a serotype-specific manner in biotelemetered conscious rats. Two different Escherichia coli serotypes of LPSs were injected at a dose of 250 μg/kg ip. E. coli O55:B5 LPS elicited an initial hypothermia and subsequent fever, but E. coli O111:B4 LPS caused more potent monophasic hypothermia. Serum tumor necrosis factor (TNF)-α levels were dramatically elevated at the initial phase of the hypothermia induced by both LPSs. This elevation tended to subside at the nadir of E. coli O55:B5 LPS-induced response but progressively increased at the nadir of E. coli O111:B4 LPS hypothermia. Serum IL-10 levels were moderately elevated at the initial phase of the hypothermia and persisted at the same level at the nadir of each LPS-induced response. No change was observed at the serum IL-18 levels. A selective cyclooxygenase (COX)-1 enzyme inhibitor, valeryl salicylate (20 mg/kg sc), abolished the hypothermia without any effect on the elevated cytokine levels. Another COX-1-selective inhibitor, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560; 1 mg/kg sc) inhibited hypothermic responses as well. Meanwhile, cytokine levels were also reduced by SC-560 treatment. These findings suggest that LPS-induced hypothermia may have serotype-specific characteristics in rats. E. coli O111:B4 LPS has more potent hypothermic activity than E. coli O55:B5 LPS; that may presumably be related to its higher or sustained capability to release antipyretic cytokines, such as TNF-α. COX-1 enzyme may be involved in the generation of the hypothermia, regardless of the type of LPS administered.
Enhanced Visual Activity In Vivo Forms Nascent Synapses in the Developing Retinotectal Projection
Authors: Aizenman Carlos D. , Cline Hollis T.
Published: February 2007

Patterned neural activity during development is critical for proper wiring of sensory circuits. Previous work demonstrated that exposing freely swimming Xenopus tadpoles to 4 h of enhanced visual stimulation accelerates the dendritic growth rate of optic tectal neurons in vivo. Here we test whether this same period of visual stimulation increased synaptic maturation and formation of new synapses in the retinotectal pathway. We assessed synaptic properties of stage 48 tadpoles that were exposed to a simulated-motion stimulus for 4–5 h. Based on our findings that immature retinotectal synapses have greater paired-pulse facilitation compared with more mature synapses, consistent with a lower release probability (Pr), we used a paired-pulse protocol to elicit responses selectively from nascent synapses with low Pr. Although AMPA/NMDA ratios for single and paired stimuli were the same in control tadpoles, visual stimulation caused a relative decrease in the AMPA/NMDA ratio of the paired response. We evoked retinotectal synaptic transmission in the presence of Sr2+to record asynchronous vesicle release. We compared evoked mEPSCs induced by single and paired stimuli and found that visual stimulation selectively enhances the amplitude and number of AMPA receptor (AMPAR)–mediated mEPSCs evoked by paired stimuli relative to those evoked by single stimuli. Together these results show that enhanced visual stimulation affects both AMPAR- and NMDAR-mediated responses in a population of synapses revealed by paired-pulse stimulation. This suggests that in vivo visual stimulation increases synapses that have a low Pr and that have properties consistent with immature synapses.
Reach Adaptation and Final Position Control Amid Environmental Uncertainty After Stroke
Authors: Scheidt Robert A. , Stoeckmann Tina
Published: February 2007

We characterized how hemiparetic stroke survivors and neurologically intact individuals adapt reaching movements to compensate for unpredictable environmental perturbations. We tested the hypotheses that like unimpaired subjects, hemiparetic stroke survivors adapt using sensory information obtained during only the most recent movements and that the reliability of target acquisition decreases as the degree of sensorimotor impairment increases. Subjects held the handle of a two-joint robotic arm that applied forces to the hand while reaching between targets in a horizontal plane. The robot simulated a dynamic environment that varied randomly in strength from one trial to the next. The trial sequence of perturbations had a nonzero mean value corresponding to information about the environment that subjects might learn. Stroke subjects were less effective than control subjects at adapting reaches to the perturbations. From a family of potential adaptation models, we found that the compensatory strategy patients used was the same as that used by neurologically intact subjects. However, analysis of model coefficients found that the relative weighting of prior perturbations and prior movement errors on subsequent reach attempts was significantly depressed poststroke. Regulation of final hand position was also impaired in the paretic limbs. Measures of trajectory adaptation and final position regulation deficits were significantly dependent on the integrity of limb proprioception and the amount of time poststroke. However, whereas model coefficients varied systematically with impairment level poststroke, variability of final positioning in the contralesional limb did not. This difference suggests that these two aspects of limb control may be differentially impaired poststroke.
Dorsal Unpaired Median Neurons ofLocusta migratoriaExpress Ivermectin- and Fipronil-Sensitive Glutamate-Gated Chloride Channels
Authors: Janssen Daniel , Derst Christian , Buckinx Roeland , Van den Eynden Jimmy , Rigo Jean-Michel , Van Kerkhove Emmy
Published: February 2007

Together with type A GABA and strychnine-sensitive glycine receptors, glutamate-gated chloride channels (GluCl) are members of the Cys-loop family of ionotropic receptors, which mediate fast inhibitory neurotransmission. To date, GluCls are found in invertebrates only and therefore represent potential specific targets for insecticides, such as ivermectin and fipronil. In this study, we identified the functional expression of GluCls in dorsal unpaired median (DUM) neurons of the metathoracic ganglion of Locusta migratoria using electrophysiological and molecular biological techniques. In whole cell patch-clamped DUM neurons, glutamate-induced changes in both their membrane potentials (current-clamp) and currents (voltage-clamp) were dependent on the chloride equilibrium potential. On continuous application of glutamate, the glutamate-elicited current response became rapidly and completely desensitized. Application of glutamate in the presence of 10 μM fipronil or 100 μM picrotoxin reversibly decreased GluCl-mediated currents by 87 and 39%, respectively. Furthermore, 1 μM ivermectin induced a persistent chloride current, suggesting the expression of ivermectin-sensitive GluCl α subunits. A degenerate PCR/RACE strategy was used to clone the full-length L. migratoria LmGlClα subunit. Finally, RT-PCR experiments demonstrated the presence of LmGluClα transcripts in locust DUM neurons. Our results provide the first direct evidence of a functional ivermectin-sensitive GluCl channel on the cell surface of DUM neurons of L. migratoria.
Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells
Authors: Reinhold William C. , Reimers Mark A. , Maunakea Alika K. , Kim Sohyoung , Lababidi Samir , Scherf Uwe , Shankavaram Uma T. , Ziegler Micah S. , Stewart Claudia , Kouros-Mehr Hosein , Cui Hengmi , Dolginow Douglas , Scudiero Dominic A. , Pommier Yves G. , Munroe David J. , Feinberg Andrew P. , Weinstein John N.
Published: February 2007

E-cadherin (E-cad) is a transmembrane adhesion glycoprotein, the expression of which is often reduced in invasive or metastatic tumors. To assess E-cad's distribution among different types of cancer cells, we used bisulfite-sequencing for detailed, base-by-base measurement of CpG methylation in E-cad's promoter region in the NCI-60 cell lines. The mean methylation levels of the cell lines were distributed bimodally, with values pushed toward either the high or low end of the methylation scale. The 38 epithelial cell lines showed substantially lower (28%) mean methylation levels compared with the nonepithelial cell lines (58%). The CpG site at -143 with respect to the transcriptional start was commonly methylated at intermediate levels, even in cell lines with low overall DNA methylation. We also profiled the NCI-60 cell lines using Affymetrix U133 microarrays and found E-cad expression to be correlated with E-cad methylation at highly statistically significant levels. Above a threshold of ∼20% to 30% mean methylation, the expression of E-cad was effectively silenced. Overall, this study provides a type of detailed analysis of methylation that can also be applied to other cancer-related genes. As has been shown in recent years, DNA methylation status can serve as a biomarker for use in choosing therapy. [Mol Cancer Ther 2007;6(2):391–403]
Calcium-Calmodulin Mediates House Dust Mite-Induced ERK Activation and IL-8 Production in Human Respiratory Epithelial Cells
Authors: Sohn Myung Hyun , Lee Kyung Eun , Kim Kyung-Won , Kim Eun-Soo , Park Jun Young , Kim Kyu-Earn
Published: February 2007

Background:House dust mites (HDM) have been shown to be important sources of indoor allergens associated with asthma and other allergic conditions. While exogenous proteases from allergens have a direct proinflammatory role in the respiratory tract, the precise mechanisms underlying the release of cytokines from the respiratory epithelium are unclear. Objectives: The present study examines that extracellular signal-regulated kinase (ERK) activated downstream of the Ca2+-sensitive tyrosine kinase plays an important role in the efficient activation of the HDM-induced IL-8 signaling pathway. Methods: We examined the effect of HDM, and the role of the Ca2+/calmodulin system and mitogen-activated protein kinases, on IL-8 expression in human lung epithelial cells. Results: In H292 cells, HDM induced IL-8 release in a time- and/or dose-dependent manner. This IL-8 release was abolished by treatment with intracellular Ca2+ chelator (BAPTA-AM), but not by EGTA or nifedipine. Calmodulin inhibitor (calmidazolium) and tyrosine kinase inhibitor (genistein) almost completely blocked IL-8 release by HDM. PD98059, an ERK pathway inhibitor, completely abolished HDM-induced IL-8 release. Moreover, PD98059, BAPTA-AM, calmidazolium and genistein suppressed the HDM-induced ERK phosphorylation. Conclusions: HDM-induced IL-8 production is predominantly regulated by Ca2+/calmodulin signaling, and ERK plays an important role in signal transmission for efficient activation of the HDM-induced IL-8 signaling pathway.
Role of the Multidrug Resistance Protein-1 in Hypertension and Vascular Dysfunction Caused by Angiotensin II
Authors: Widder Julian D. , Guzik Tomasz J. , Mueller Cornelius F.H. , Clempus Roza E. , Schmidt Harald H.H.W. , Dikalov Sergey I. , Griendling Kathy K. , Jones Dean P. , Harrison David G.
Published: February 2007

Objective—

Human endothelial cells use the multidrug resistance protein-1 (MRP1) to export glutathione disulfide (GSSG). This can promotes thiol loss during states of increased glutathione oxidation. We investigated how MRP1 modulates blood pressure and vascular function during angiotensin II-induced hypertension.

Methods and Results—

Angiotensin II–induced hypertension altered vascular glutathione flux by increasing GSSG export and decreasing vascular levels of glutathione in wild-type (FVB) but not in MRP1
−/−
mice. Aortic endothelium-dependent vasodilatation was reduced in FVB after angiotensin II infusion, but unchanged in MRP1
−/−
mice. Aortic superoxide (O
2
·−
) production and expression of several NADPH oxidase subunits were increased by angiotensin II in FVB. These effects were markedly blunted in MRP1
−/−
vessels. The increase in O
2
·−
production in FVB vessels caused by angiotensin II was largely inhibited by L-NAME, suggesting eNOS uncoupling. Accordingly, aortic tetrahydrobiopterin and levels of NO were decreased by angiotensin II in FVB but were unchanged in MRP1
−/−
. Finally, the hypertension caused by angiotensin II was markedly blunted in MRP1
−/−
mice (137±4 versus 158±6 mm Hg).

Conclusion—

MRP1 plays a crucial role in the genesis of multiple vascular abnormalities that accompany hypertension and its presence is essential for the hypertensive response to angiotensin II.
Platelet Adhesion Receptors and Their Ligands in Mouse Models of Thrombosis
Authors: Denis Cécile V. , Wagner Denisa D.
Published: February 2007

Platelet adhesion and aggregation at sites of vascular injury are two key events in hemostasis and thrombosis. Because of exciting advances in genetic engineering, the mouse has become an important and frequently used model to unravel the molecular mechanisms underlying the multistep process leading to the formation of a stable platelet plug. In gene-targeted mice, the crucial importance of platelet adhesion receptors such as glycoprotein Ibα or the αIIbβ3 integrin has been confirmed and further clarified. Their absence leads to highly impaired thrombus formation, independent of the model used to induce vascular injury. In contrast, the relative contribution of other receptors, such as glycoprotein VI, or of various platelet ligands may be regulated by the severity of injury, the type of vessel injured, and the signaling pathways that are generated. Murine models have also helped improve understanding of the second wave of events that leads to stabilization of the platelet aggregate. Despite the current limitations due to lack of standardization and the virtual absence of thrombosis models in diseased vessels, there is no doubt that the mouse will play a key role in the discovery and characterization of the next generation of antithrombotic agents. This review focuses on key findings about the molecular mechanisms supporting hemostasis and thrombosis that have been obtained with genetically engineered mouse models deficient in various platelet adhesion receptors and ligands. Combination of these models with sophisticated methods allowing direct visualization of platelet–vessel wall interactions after injury greatly contributed to recent advances in the field.
Pinch1 Is Required for Normal Development of Cranial and Cardiac Neural Crest-Derived Structures
Authors: Liang Xingqun , Sun Yunfu , Schneider Jurgen , Ding Jian-Hua , Cheng Hongqiang , Ye Maoqing , Bhattacharya Shoumo , Rearden Ann , Evans Sylvia , Chen Ju
Published: February 2007

Pinch1, an adaptor protein composed of 5 LIM domains, has been suggested to play an important role in multiple cellular processes. We found that Pinch1 is highly expressed in neural crest cells and their derivatives. To examine the requirement for Pinch1 in neural crest development, we generated neural crest conditional
Pinch1
knockout mice using the
Wnt1-Cre/loxP
system. Neural crest conditional
Pinch1
mutant embryos die perinatally from severe cardiovascular defects with an unusual aneurysmal common arterial trunk.
Pinch1
mutants also exhibit multiple deficiencies in cranial neural crest-derived structures. Fate mapping demonstrated that initial migration of neural crest cells to the pharyngeal arch region occurs normally in the mutant embryos. However, in the cardiac outflow tract of mutants, neural crest cells exhibited hyperplasia and failed to differentiate into smooth muscle. Markedly increased apoptosis is observed in outflow tract cushions of mutants between embryonic days 11.5 and 13.5, likely contributing to the observed defects in cushion/valve remodeling and ventricular septation. Expression of transforming growth factor-β
2
, which plays a crucial role in outflow tract development, was decreased or absent in the outflow tract of the mutants. The decrease in transforming growth factor-β
2
expression preceded neural crest cell death. Together, our results demonstrate that Pinch1 plays an essential role in neural crest development, perhaps in part through transforming growth factor-β signaling.
Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility
Authors: Burkard Natalie , Rokita Adam G. , Kaufmann Susann G. , Hallhuber Matthias , Wu Rongxue , Hu Kai , Hofmann Ulrich , Bonz Andreas , Frantz Stefan , Cartwright Elizabeth J. , Neyses Ludwig , Maier Lars S. , Maier Sebastian K.G. , Renné Thomas , Schuh Kai , Ritter Oliver
Published: February 2007

The role of the neuronal NO synthase (nNOS or NOS1) enzyme in the control of cardiac function still remains unclear. Results from nNOS
−/−
mice or from pharmacological inhibition of nNOS are contradictory and do not pay tribute to the fact that probably spatial confinement of the nNOS enzyme is of major importance. We hypothesize that the close proximity of nNOS and certain effector molecules like L-type Ca
2+
-channels has an impact on myocardial contractility. To test this, we generated a new transgenic mouse model allowing conditional, myocardial specific nNOS overexpression. Western blot analysis of transgenic nNOS overexpression showed a 6-fold increase in nNOS protein expression compared with noninduced littermates (n=12;
P
<0.01). Measuring of total NOS activity by conversion of [
3
H]-
l
-arginine to [
3
H]-
l
-citrulline showed a 30% increase in nNOS overexpressing mice (n=18;
P
<0.05). After a 2 week induction, nNOS overexpression mice showed reduced myocardial contractility. In vivo examinations of the nNOS overexpressing mice revealed a 17±3% decrease of +dp/dt
max
compared with noninduced mice (
P
<0.05). Likewise, ejection fraction was reduced significantly (42% versus 65%; n=15;
P
<0.05). Interestingly, coimmunoprecipitation experiments indicated interaction of nNOS with SR Ca
2+
ATPase and additionally with L-type Ca
2+
- channels in nNOS overexpressing animals. Accordingly, in adult isolated cardiac myocytes,
I
Ca,L
density was significantly decreased in the nNOS overexpressing cells. Intracellular Ca
2+
-transients and fractional shortening in cardiomyocytes were also clearly impaired in nNOS overexpressing mice versus noninduced littermates. In conclusion, conditional myocardial specific overexpression of nNOS in a transgenic animal model reduced myocardial contractility. We suggest that nNOS might suppress the function of L-type Ca
2+
-channels and in turn reduces Ca
2+
-transients which accounts for the negative inotropic effect.
Importance of CXC Chemokine Receptor 2 in the Homing of Human Peripheral Blood Endothelial Progenitor Cells to Sites of Arterial Injury
Authors: Hristov Mihail , Zernecke Alma , Bidzhekov Kiril , Liehn Elisa A. , Shagdarsuren Erdenechimeg , Ludwig Andreas , Weber Christian
Published: February 2007

Circulating endothelial progenitor cells (EPCs) may contribute to endothelial regeneration; however, the exact mechanisms of their arterial homing remain elusive. We examined the role of the angiogenic chemokine receptor CXCR2 in the homing of human EPCs. Isolated EPCs expressed CXCR2 together with kinase insert domain–containing receptor, CD31, vascular endothelial cadherin, and CXCR4. Adhesion assays under flow conditions showed that EPCs preferentially adhered to β
2
-integrin ligands, that firm arrest on fibronectin or fibrinogen was enhanced by the CXCR2 ligands CXCL1 or CXCL7, and that blockade of CXCR2 significantly reduced EPC adhesion on platelet-coated endothelial matrix. This was corroborated by the involvement of CXCR2 in EPC recruitment to denuded areas of murine carotid arteries ex vivo and in vivo. Notably, blocking CXCR2 inhibited the incorporation of human EPCs expressing CXCR2 at sites of arterial injury in athymic nude mice. Immunoreactivity for the β-thromboglobulin isoform CXCL7 was observed in murine platelets and denuded smooth muscle cells (SMCs) early after wire injury, and transcripts for CXCL7 and CXCL1 were detected in isolated human arterial SMCs. Human KDR
+
CXCR2
+
cells showed better in situ adhesion to injured murine carotid arteries than KDR
+
CXCR2
−
cells, were predominantly CD14
+
, and improved CXCR2-dependent endothelial recovery after injury in nude mice. In conclusion, our data clearly demonstrate the importance of CXCR2 for the homing of circulating EPCs to sites of arterial injury and for endothelial recovery in vivo.
Continuous Monitoring of Cerebrovascular Autoregulation After Subarachnoid Hemorrhage by Brain Tissue Oxygen Pressure Reactivity and Its Relation to Delayed Cerebral Infarction
Authors: Jaeger Matthias , Schuhmann Martin U. , Soehle Martin , Nagel Christoph , Meixensberger Jürgen
Published: February 2007

Background and Purpose—

Disturbances of cerebrovascular autoregulation are thought to be involved in delayed cerebral ischemia and infarction after aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that the continuous monitoring of brain tissue oxygen (PtiO
2
) pressure reactivity enables the detection of impaired autoregulation after SAH and that impaired autoregulation is associated with delayed infarction.

Methods—

In 67 patients after severe SAH, continuous monitoring of cerebral perfusion pressure (CPP) and PtiO
2
was performed for an average of 7.4 days. For assessment of autoregulation, the index of PtiO
2
pressure reactivity (ORx) was calculated as a moving correlation coefficient between values of CPP and PtiO
2
. Higher ORx values indicate disturbed autoregulation, whereas lower ORx values signify intact autoregulation.

Results—

Twenty patients developed delayed cerebral infarction, and 47 did not. Mean ORx was significantly higher in the infarction group compared with the noninfarction group (0.43±0.09 vs 0.23±0.14, respectively;
P
<0.0001). In a day-by-day analysis, ORx did not differ between groups from days 1 to 4 after SAH but was significantly higher from day 5 onward in the infarction group, indicating a deficit of autoregulatory capacity. In a logistic-regression model, ORx values from days 5 and 6 after SAH carried predictive value for the occurrence of delayed infarction but before this event ultimately occurred (
P
=0.003).

Conclusions—

ORx indicates impaired autoregulation in patients who develop delayed infarction after SAH. Furthermore, this index may distinguish between patients who finally develop delayed infarction and those who do not.
Lacunar Infarcts Are the Main Correlate With Cognitive Dysfunction in CADASIL
Authors: Liem Michael K. , van der Grond Jeroen , Haan Joost , van den Boom Rivka , Ferrari Michel D. , Knaap Yvette M. , Breuning Martijn H. , van Buchem Mark A. , Middelkoop Huub A.M. , Lesnik Oberstein Saskia A.J.
Published: February 2007

Background and Purpose—

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is caused by mutations in the
NOTCH3
gene and is clinically characterized by recurrent stroke and cognitive decline. Previous studies have shown an association between white matter hyperintensities on brain MRI and cognitive dysfunction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. In the general population the presence of lacunar infarcts and microbleeds is also associated with cognitive dysfunction. The objective of this study was to determine to what extent lacunar infarcts and microbleeds on MRI contribute to cognitive decline in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Methods—

NOTCH3
mutation analysis was performed in 62 symptomatic and asymptomatic members of 15 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy families. Neuropsychological tests were performed on the same day as the MRI examination. MRI was semi-quantitatively scored for white matter hyperintensities, infarct lesion load, and microbleeds. Regression analysis was performed to test the association between MRI abnormalities and neuropsychological test results.

Results—

Forty individuals had a
NOTCH3
mutation and 22 did not. Severity of cognitive dysfunction in mutation carriers was independently associated with MRI infarct lesion load (
P
<0.05). In contrast, WMH lesion load and microbleeds were not associated with cognitive dysfunction after correcting for age.

Conclusions—

Lacunar infarct lesion load is the most important MRI parameter associated with cognitive dysfunction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Composition of the Stable Carotid Plaque
Authors: Nandalur Kiran R. , Hardie Andrew D. , Raghavan Prashant , Schipper Matthew J. , Baskurt Erol , Kramer Christopher M.
Published: February 2007

Background and Purpose—

Calcification has been associated with carotid plaque stability; however, an acceptable in vivo method to define plaques based on this component remains to be developed. The purpose of our study was to compare calcified and noncalcified volumes of carotid artery culprit symptomatic plaques with asymptomatic plaques using multidetector computed tomography.

Methods—

We identified 102 patients with ≥50% stenosis using NASCET criteria by multidetector computed tomography angiography between January 2004 and May 2006, which included 35 symptomatic (stenosis: 82.0±11.9%) and 67 asymptomatic patients (stenosis: 79.4±10.8%). Total plaque volume, noncalcified plaque volume, calcified plaque volume, and calcified/total ratio were measured for the 102 index plaques causing stenosis.

Results—

In a model including age, stenosis, and cardiovascular risk factors, calcified plaque volume/total plaque volume was significantly inversely associated with the occurrence of symptoms (
P
=0.012; odds ratio, 0.047; 95% CI, 0.004 to 0.511). There was a notable overlap in the calcified plaque volume/total plaque volume ratio between 0% and 45% for symptomatic and asymptomatic plaques. However, calcification >45% of the total plaque was very specific: 97.1% (34/35) for absence of symptoms (sensitivity: 28.4% 19/67). No significant association between total plaque volume, noncalcified plaque volume, or calcified plaque volume and symptomatology was found.

Conclusion—

The proportion of carotid plaque calcification, rather than absolute volume, is associated with stability in patients with stenosis. Specifically, for a subset of patients, plaque calcification >45% of the total volume may represent a clinically useful cutoff. The carotid plaque calcium ratio, determined by multidetector computed tomography volume measurements, may help noninvasively risk stratify patients with asymptomatic stenosis.
Quantified Corticospinal Tract Diffusion Restriction Predicts Neonatal Stroke Outcome
Authors: Kirton Adam , Shroff Manohar , Visvanathan Tharshini , deVeber Gabrielle
Published: February 2007

Background and Purpose—

Neonatal arterial ischemic stroke occurs in ≥1:4000 births. Many children experience motor deficits but acute predictors of outcome are lacking. Diffusion-weighted MRI changes in descending corticospinal tracts remote from arterial ischemic stroke may represent pre-Wallerian degeneration. We verify and quantify this signal and correlate it with motor outcome.

Methods—

Fourteen neonates with acute arterial ischemic stroke and ≥12 months follow-up with the Pediatric Stroke Outcome Measure were included. Quantitative measurements of descending corticospinal tracts diffusion-weighted MRI signal were developed using
Image J
software.

Results—

Ipsilesional descending corticospinal tract diffusion-weighted MRI signal was abnormal in 10 neonates with decreased apparent diffusion coefficients (
P
<0.001). Poor outcome correlated with: (1) percentage of peduncle (
P
=0.002); (2) length of descending corticospinal tracts
P
<0.001); and (3) volume of descending corticospinal tracts (
P
=0.002). None of: (1) any peduncle; (2) any posterior limb of the internal capsule; or (3) infarct volume correlated with outcome. All children without descending corticospinal tracts signal had normal outcome. Chronic Wallerian degeneration was seen in all children with hemiparesis. Software-assisted analysis was superior to visual inspection with excellent reliability (intra-class correlation coefficient ≥0.9).

Conclusion—

Descending corticospinal tracts diffusion-weighted MRI signal is predictive of motor outcome from neonatal arterial ischemic stroke. This accurate, reliable, and simple tool will impact decision making in acute neonatal stroke.
A Prospective Community-Based Study of Stroke in Kolkata, India
Authors: Das Shyamal K. , Banerjee Tapas K. , Biswas Atanu , Roy Trishit , Raut Deepak K. , Mukherjee Chandra S. , Chaudhuri Arijit , Hazra Avijit , Roy Jayanta
Published: February 2007

Background and Purpose—

Information on essential stroke parameters are lacking in India. This population-based study on stroke disorder was undertaken in the city of Kolkata, India, to determine the subtypes, prevalence, incidence, and case fatality rates of stroke.

Methods—

This was a longitudinal descriptive study comprising 2-stage door-to-door survey of a stratified randomly selected sample of the city population, conducted twice per year for 2 successive years from March 2003 to February 2005.

Results—

Out of the screened population of 52 377 (27 626 men, 24 751 women), the age standardized prevalence rate of stroke to world standard population is 545.10 (95% CI, 479.86 to 617.05) per 100 000 persons. The age standardized average annual incidence rate to world standard population of first-ever-in-a-lifetime stroke is 145.30 (95% CI, 120.39 to 174.74) per 100 000 persons per year. Thirty-day case fatality rate is 41.08% (95% CI, 30.66 to 53.80). Women have higher incidence and case fatality rates. Despite divergence on socioeconomic status between the slum and nonslum dwellers, stroke parameters were not significantly different.

Conclusion—

The age standardized prevalence and incidence rates of stroke in this study are similar to or higher than many Western nations. The overall case fatality rate is among the highest category of stroke fatality in the world. The women have higher incidence and case fatality rates compared with men.
V-Raising and Grammar Competition in Korean: Evidence from Negation and Quantifier Scope
Authors: Han Chung-hye , Lidz Jeffrey , Musolino Julien
Published: February 2007

In a head-final language, V-raising is hard to detect since there is no evidence from the string to support a raising analysis. If the language has a cliticlike negation that associates with the verb in syntax, then scope facts concerning negation and a quantified object NP could provide evidence regarding the height of the verb. Even so, such facts are rare, especially in the input to children, and so we might expect that not all speakers exposed to a head-final language acquire the same grammar as far as V-raising is concerned. Here, we present evidence supporting this expectation. Using experimental data concerning the scope of quantified NPs and negation in Korean, elicited from both adults and 4-year-old children, we show that there are two populations of Korean speakers: one with V-raising and one without.
A Gender Perspective on the Daughters of Zelophehad: Bible, Talmudic Midrash, and Modern Feminist Midrash
Authors: Shemesh Yael
Published: February 2007

The biblical story of Zelophehad's daughters (Numbers 26 and 36, Josh. 17:3-6) and its avatars in talmudic midrashim and modern feminist midrashim are studied from a gender perspective. The biblical story is shown to be ambiguous, in that, on the one hand, its heroines are five impressive women who bring about a change in the law that bene ts certain women, while, on the other hand, it is firmly set in an androcentric patriarchal context whose focus is the survival of the father's name. Even though the biblical story is not feminist, it includes elements that made it possible for the feminist aspect to be raised in the talmudic midrashim (which other general praise for women as compared to men or recognition and acknowledgement of male discrimination against women)—and all the more so in modern feminist midrashim that present the five women as possessing a well-developed feminist consciousness and as a positive model of sisterhood.