bluuebunny/crossref_metadata_2025_split huggingface dataset:
Folding pathway of the B1 domain of protein G explored by a multiscale modeling
Authors: Kolinski Andrzej , Kmiecik Sebastian 
Published: June 2007

AbstractThe understanding of the folding mechanisms of single domain proteins is an essential step in the understanding of protein folding in general. Recently, we developed a mesoscopic CABS protein model which was successfully applied in protein structure prediction, studies of protein thermodynamics and modeling of protein complexes. In the present research this model is employed in a detailed characterization of the folding process of a simple globular protein, the B1 domain of IgG-binding protein G (GB1). There is a vast body of experimental facts and theoretical findings for this protein. Performing unbiased, ab initio simulations, we demonstrated that the GB1 folding proceeds via the successive formation of an extended folding nucleus, followed by slow structure fine-tuning. Remarkably, a subset of native interactions drives the folding from the very beginning. The emerging comprehensive picture of GB1 folding perfectly matches and extends the previous experimental and theoretical studies.
Open access and accuracy: author‐archived manuscripts vs. published articles
Authors: GOODMAN David , DOWSON Sarah , YAREMCHUK Jean 
Published: June 2007

ABSTRACTSome approaches to open access (OA) use authors' manuscript copies for the OA version, in the form accepted after peer review but prior to full editing. Advocates of such approaches are certain that these versions differ only trivially from the publishers' versions; many of those who oppose them are equally certain that there can be major discrepancies. In a pilot study, we have examined the actual differences in a small number of such article pairs in the social sciences and in biology. Using an operational classification of the extent of error, we have determined that neither pronouncement is likely to be correct. We found numerous small differences that affect readability; we also found a low frequency of potentially confusing errors, but sometimes it was the publisher's and sometimes the manuscript version that was more accurate. In two cases errors introduced by the publisher omit technical details that are necessary to evaluate the validity of the conclusions. However, we found no error that actually affected the validity of the data or results. Interestingly, we did find problems with the stability of the document locations on authors' sites, and, in some cases, with their disappearance from PubMed Central after initial placement there.
A medical journal's beta site: experimentation at NEJM
Authors: ANDERSON Kent R. , NUGENT Jean 
Published: June 2007

ABSTRACTWhen continuous development becomes the norm on the social web, finding a way to put forward new development ideas to your audience and get their feedback at an early stage is the natural result. This article discusses how one major medical journal created a ‘beta’ site to support new online development and gather user feedback, speeding development initiatives and creating intrinsic value in the experimental environment. The goals of the site, organization of the teams, and practical and brand benefits are discussed.
Improving peer review with CARMA
Authors: CARMI Ran , KOCH Christof 
Published: June 2007

ABSTRACTWe propose to test and improve the quality of peer review through CARMA (Community‐based Assessment of Review Materials): an online repository of review materials that will include all intermediate versions of published manuscripts, associated reviews, and author replies to reviewer comments. CARMA would add the content of reviews to the public scientific record without compromising the anonymity of reviewers. The benefits to the relevant stakeholders are as follows:• For readers, CARMA would reveal the actual impact of peer review on scholarly manuscripts;• CARMA would encourage reviewers to provide thorough evaluations without jeopardizing their candor;• Editors could utilize CARMA for quality assurance by soliciting ratings of reviews from their readership;• For publishers, implementing CARMA would incur minimal costs, and could increase revenues.Whatever the present quality of peer review, making this process more transparent would be in the best interest of meritocratic scholars and society at large.
Bulleyaconitine A Isolated from Aconitum Plant Displays Long-acting Local Anesthetic Properties In Vitro and In Vivo
Authors: Wang Chi-Fei , Gerner Peter , Wang Sho-Ya , Wang Ging Kuo 
Published: June 2007

Abstract

Background:
Bulleyaconitine A (BLA) is an active ingredient of Aconitum bulleyanum plants. BLA has been approved for the treatment of chronic pain and rheumatoid arthritis in China, but its underlying mechanism remains unclear.

Methods:
The authors examined (1) the effects of BLA on neuronal voltage-gated Na+ channels in vitro under the whole cell patch clamp configuration and (2) the sensory and motor functions of rat sciatic nerve after single BLA injections in vivo.

Results:
BLA at 10 μm did not affect neuronal Na+ currents in clonal GH3 cells when stimulated infrequently to +50 mV. When stimulated at 2 Hz for 1,000 pulses (+50 mV for 4 ms), BLA reduced the peak Na+ currents by more than 90%. This use-dependent reduction of Na+ currents by BLA reversed little after washing. Single injections of BLA (0.2 ml at 0.375 mm) into the rat sciatic notch not only blocked sensory and motor functions of the sciatic nerve but also induced hyperexcitability, followed by sedation, arrhythmia, and respiratory distress. When BLA at 0.375 mm was coinjected with 2% lidocaine (approximately 80 mm) or epinephrine (1:100,000) to reduce drug absorption by the bloodstream, the sensory and motor functions of the sciatic nerve remained fully blocked for approximately 4 h and regressed completely after approximately 7 h, with minimal systemic effects.

Conclusions:
BLA reduces neuronal Na+ currents strongly at +50 mV in a use-dependent manner. When coinjected with lidocaine or epinephrine, BLA elicits prolonged block of both motor and sensory functions in rats with minimal adverse effects.
Contribution of Calcium Channel Subtypes to the Intracellular Calcium Signal in Sensory Neurons
Authors: Fuchs Andreas , Rigaud Marcel , Sarantopoulos Constantine D. , Filip Patrick , Hogan Quinn H. 
Published: June 2007

Abstract

Background:
Although the activation-induced intracellular Ca2+ signal is disrupted by sensory neuron injury, the contribution of specific Ca2+ channel subtypes is unknown.

Methods:
Transients in dissociated rat dorsal root ganglion neurons were recorded using fura-2 microfluorometry. Neurons from control rats and from neuropathic animals after spinal nerve ligation were activated either by elevated bath K+ or by field stimulation. Transients were compared before and after application of selective blockers of voltage-activated Ca2+ channel subtypes.

Results:
Transient amplitude and area were decreased by blockade of the L-type channel, particularly during sustained K+ stimulation. Significant contributions to the Ca2+ transient are attributable to the N-, P/Q-, and R-type channels, especially in small neurons. Results for T-type blockade varied widely between cells. After injury, transients lost sensitivity to N-type and R-type blockers in axotomized small neurons, whereas adjacent small neurons showed decreased responses to blockers of R-type channels. Axotomized large neurons were less sensitive to blockade of N- and P/Q-type channels. After injury, neurons adjacent to axotomy show decreased sensitivity of K+-induced transients to L-type blockade but increased sensitivity during field stimulation.

Conclusions:
All high-voltage–activated Ca2+ current subtypes contribute to Ca2+ transients in sensory neurons, although the L-type channel contributes predominantly during prolonged activation. Injury shifts the relative contribution of various Ca2+ channel subtypes to the intracellular Ca2+ transient induced by neuronal activation. Because this effect is cell-size specific, selective therapies might potentially be devised to differentially alter excitability of nociceptive and low-threshold sensory neurons.
Protein C Concentrations Correlate with Organ Dysfunction and Predict Outcome Independent of the Presence of Sepsis
Authors: Brunkhorst Frank , Sakr Yasser , Hagel Stefan , Reinhart Konrad 
Published: June 2007

Abstract

Background:
Characterizing the evolution of protein C concentrations in critically ill patients may help in identifying high risk groups and potential therapeutic targets. The authors investigated the time courses of protein C concentrations and their relation to the presence of sepsis, organ dysfunction/failure, and outcome.

Methods:
This observational cohort study, in a university hospital surgical intensive care unit (ICU), included 312 consecutive patients with an estimated ICU length of stay more than 48 h. Plasma protein C concentrations and parameters of organ dysfunction were measured daily until discharge or death.

Results:
Protein C concentrations were below the lower limit of normal in 50.6% of patients (n = 158) on admission and decreased to a nadir within 3–4 days after admission before almost normalizing by 2 weeks thereafter, irrespective of the presence of sepsis, sex, source and type of admission, and type of surgery. The minimum protein C concentration was lower in patients with severe sepsis/septic shock (n = 54) than in those with sepsis (n = 63) and those who never had sepsis (n = 195), and was negatively correlated to the maximum Sequential Organ Failure Assessment score (R
2 = 0.345, P < 0.001). Protein C levels were lower in nonsurvivors (n = 46; 14.7%) than in survivors, especially in the first 4 days after admission. In a multivariable analysis with ICU mortality as the dependent variable, a minimum protein C concentration less than 45% was an independent risk factor for ICU death.

Conclusions:
In critically ill surgical patients, protein C concentrations were generally low, associated with organ dysfunction/failure, and independently associated with a higher risk of ICU mortality.
Electrophysiologic Mechanism Underlying Action Potential Prolongation by Sevoflurane in Rat Ventricular Myocytes
Authors: Chae Jee Eun , Ahn Duck Sun , Kim Myung Hee , Lynch Carl , Park Wyun Kon 
Published: June 2007

Abstract

Background:
Despite prolongation of the QTc interval in humans during sevoflurane anesthesia, little is known about the mechanisms that underlie these actions. In rat ventricular myocytes, the effect of sevoflurane on action potential duration and underlying electrophysiologic mechanisms were investigated.

Methods:
The action potential was measured by using a current clamp technique. The transient outward K+ current was recorded during depolarizing steps from −80 mV, followed by brief depolarization to −40 mV and then depolarization up to +60 mV. The voltage dependence of steady state inactivation was determined by using a standard double-pulse protocol. The sustained outward current was obtained by addition of 5 mm 4-aminopyridine. The inward rectifier K+ current was recorded from a holding potential of −40 mV before their membrane potential was changed from −130 to 0 mV. Sevoflurane actions on L-type Ca2+ current were also obtained.

Results:
Sevoflurane prolonged action potential duration, whereas the amplitude and resting membrane potential remained unchanged. The peak transient outward K+ current at +60 mV was reduced by 18 ± 2% (P < 0.05) and 24 ± 2% (P < 0.05) by 0.35 and 0.7 mm sevoflurane, respectively. Sevoflurane had no effect on the sustained outward current. Whereas 0.7 mm sevoflurane did not shift the steady state inactivation curve, it accelerated the current inactivation (P < 0.05). The inward rectifier K+ current at −130 mV was little altered by 0.7 mm sevoflurane. L-type Ca2+ current was reduced by 28 ± 3% (P < 0.05) and 33 ± 1% (P < 0.05) by 0.35 and 0.7 mm sevoflurane, respectively.

Conclusions:
Action potential prolongation by clinically relevant concentrations of sevoflurane is due to the suppression of transient outward K+ current in rat ventricular myocytes.
Population Volume Kinetics Predicts Retention of 0.9% Saline Infused in Awake and Isoflurane-anesthetized Volunteers
Authors: Norberg Åke , Hahn Robert G. , Li Husong , Olsson Joel , Prough Donald S. , Børsheim Elisabet , Wolf Scott , Minton Regina K. , Svensén Christer H. 
Published: June 2007

Abstract

Background:
In previous work, extravascular expansion was observed to be enhanced by isoflurane anesthesia in sheep when a crystalloid bolus was administered. The aim of the current study was to further elaborate these investigations to humans and to explore the use of population kinetics in the analysis of fluid shifts.

Methods:
Eleven healthy volunteers participated in two experiments each, either awake or isoflurane anesthetized, during which they received 25 ml/kg saline, 0.9%, intravenously over 20 min. Plasma dilution data were derived from repeated sampling of hemoglobin concentration, and population pharmacokinetic analysis was conducted using the WinNonMix 2.0.1 software (Pharsight Corporation, Mountain View, CA). Plasma hormones were measured, and hemodynamic values were monitored.

Results:
Fluid infusion during isoflurane anesthesia was followed by a higher cardiac output, lower arterial pressure, and lower urinary excretion as compared with the awake protocol (P < 0.05). Albumin dilution was greater than hemoglobin concentration–derived plasma dilution, which indicates a transcapillary leak of albumin. A two-compartment model with an isoflurane-depressed, intercompartmental distribution parameter predicted that more than 50% of the infused volume was retained in the peripheral compartment at 180 min in both protocols. Isoflurane markedly increased the plasma levels of renin and aldosterone, whereas vasopressin was mostly unchanged.

Conclusion:
Fluid retention after rapid infusion of 0.9% saline was prominent in both awake and isoflurane-anesthetized subjects. Altered kinetics of infused 0.9% saline during isoflurane anesthesia was expressed as reduced clearance and a slower distribution, resulting in a small but significant increase in fluid accumulation in the body fluid compartments. These changes may be due to the associated decreasing of mean arterial pressure and increased release of renin and aldosterone.
Lidocaine Induces Apoptosis via the Mitochondrial Pathway Independently of Death Receptor Signaling
Authors: Werdehausen Robert , Braun Sebastian , Essmann Frank , Schulze-Osthoff Klaus , Walczak Henning , Lipfert Peter , Stevens Markus F. 
Published: June 2007

AbstractBackground:Local anesthetics, especially lidocaine, can lead to persistent cauda equina syndrome after spinal anesthesia. Recently, lidocaine has been reported to trigger apoptosis, although the underlying mechanisms remain unknown. To elucidate the pathway of lidocaine-induced apoptosis, the authors used genetically modified cells with overexpression or deficiencies of key regulators of apoptosis.Methods:Human Jurkat T-lymphoma cells overexpressing the antiapoptotic protein B-cell lymphoma 2 as well as cells deficient of caspase 9, caspase 8, or Fas-associated protein with death domain were exposed to lidocaine and compared with parental cells. The authors evaluated cell viability, mitochondrial alterations, cytochromecrelease, caspase activation, and early apoptosis. Apoptosis was in addition investigated in neuroblastoma cells.Results:In Jurkat cells, lidocaine reduced viability, associated with a loss of the mitochondrial membrane potential. At low concentrations (3–6 mm) of lidocaine, caspase 3 was activated and release of cytochromecwas detected, whereas at higher concentrations (10 mm), no caspase activation was found. Apoptosis by lidocaine was strongly reduced by B-cell lymphoma-2 protein overexpression or caspase-9 deficiency, whereas cells lacking the death receptor pathway components caspase 8 and Fas-associated protein with death domain were not protected and displayed similar apoptotic alterations as the parental cells. Lidocaine also induced apoptotic caspase activation in neuroblastoma cells.Conclusions:Apoptosis is triggered by concentrations of lidocaine occurring intrathecally after spinal anesthesia, whereas higher concentrations induce necrosis. The data indicate that death receptors are not involved in lidocaine-induced apoptosis. In contrast, the observation that B-cell lymphoma-2 protein overexpression or the lack of caspase 9 abolished apoptosis clearly implicates the intrinsic mitochondrial death pathway in lidocaine-induced apoptosis.
Isoform-selective Effects of Isoflurane on Voltage-gated Na+ Channels
Authors: OuYang Wei , Hemmings Hugh C. 
Published: June 2007

Abstract

Background:
Voltage-gated Na+ channels modulate membrane excitability in excitable tissues. Inhibition of Na+ channels has been implicated in the effects of volatile anesthetics on both nervous and peripheral excitable tissues. The authors investigated isoform-selective effects of isoflurane on the major Na+ channel isoforms expressed in excitable tissues.

Methods:
Rat Nav1.2, Nav1.4, or Nav1.5 α subunits heterologously expressed in Chinese hamster ovary cells were analyzed by whole cell voltage clamp recording. The effects of isoflurane on Na+ current activation, inactivation, and recovery from inactivation were analyzed.

Results:
The cardiac isoform Nav1.5 activated at more negative potentials (peak INa at −30 mV) than the neuronal Nav1.2 (0 mV) or skeletal muscle Nav1.4 (−10 mV) isoforms. Isoflurane reversibly inhibited all three isoforms in a concentration- and voltage-dependent manner at clinical concentrations (IC50 = 0.70, 0.61, and 0.45 mm, respectively, for Nav1.2, Nav1.4, and Nav1.5 from a physiologic holding potential of −70 mV). Inhibition was greater from a holding potential of −70 mV than from −100 mV, especially for Nav1.4 and Nav1.5. Isoflurane enhanced inactivation of all three isoforms due to a hyperpolarizing shift in the voltage dependence of steady state fast inactivation. Inhibition of Nav1.4 and Nav1.5 by isoflurane was attributed primarily to enhanced inactivation, whereas inhibition of Nav1.2, which had a more positive V1/2 of inactivation, was due primarily to tonic block.

Conclusions:
Two principal mechanisms contribute to Na+ channel inhibition by isoflurane: enhanced inactivation due to a hyperpolarizing shift in the voltage dependence of steady state fast inactivation (Nav1.5 ≈ Nav1.4 > Nav1.2) and tonic block (Nav1.2 > Nav1.4 ≈ Nav1.5). These novel mechanistic differences observed between isoforms suggest a potential pharmacologic basis for discrimination between Na+ channel isoforms to enhance anesthetic specificity.
OPTIMAL DISTRIBUTION OF POWERS IN A FEDERATION: A SIMPLE, UNIFIED FRAMEWORK
Authors: Dhami Sanjit , Al‐Nowaihi Ali 
Published: June 2007

ABSTRACTIn a federation with n≥ 2 regions the relative optimality of five regimes – autarky, centralization, unregulated devolution, regulated devolution and direct democracy – is examined. Public policy consists of redistribution and regional public good provision. Regional incomes are uncertain and correlated. Estimates of the usefulness of regional public goods are uncertain and the federal government's estimates are noisier relative to those of regional governments. The optimality of each regime is influenced by four margins – regional insurance, coarseness of federal information, internalization of spillovers and raiding the commons. Regulated devolution is the only regime that is capable of producing the constrained first best level of public goods. Federal insurance under direct democracy can be inadequate relative to that under a utilitarian federal government. An increase in the number of regions allows better risk pooling but also greater opportunities for raiding the commons.
BERTRAND COMPETITION CAN YIELD HIGHER PRICES THAN MONOPOLY
Authors: Sanner Helge 
Published: June 2007

ABSTRACTIf we take into account the spatial dimension of markets, prices of incumbent firms may be higher and consumer surplus may be lower with competition than with monopoly. This result obtains unambiguously, even in the supposedly highly competitive case of Bertrand competition. Moreover, we are able to show that consumers of the commodity may be worse off with duopoly, if the distance between the firms' sites is sufficiently large.
QUALITY‐CORRECTED PRICE CAPS
Authors: Currier Kevin M. 
Published: June 2007

ABSTRACTAlthough price caps have desirable efficiency properties, it is well known that they may create incentives for a regulated firm to attempt to lower its costs via reductions in service quality. Thus, the regulators often employ quality standards or other methods designed to have allowed prices reflect delivered service quality levels. In this paper, we present a system of quality‐corrected price caps that results in efficient pricing and quality provision.
Efficacy and safety of preprandial versus postprandial administration of low‐dose cyclosporin microemulsion (Neoral) in patients with psoriasis vulgaris
Authors: HASHIZUME Hideo , ITO Taisuke , YAGI Hiroaki , TAKIGAWA Masahiro , KAGEYAMA Hazuki , FURUKAWA Fukiko , HATA Maki , SHIRAHAMA Shigeho , TANAKA Masato , HIGASHISHIBA Teruomi , MACHIDA Hideki , TSUSHIMA Tomoo , MATSUSHITA Kayo 
Published: June 2007

ABSTRACTA study of therapeutic drug monitoring indicated that cyclosporin administered before meals produces higher blood concentrations than an equivalent dose administered after meals. Our objective was to compare the efficacy of cyclosporin administered before and after meals, respectively, in psoriasis vulgaris patients. We performed an open trial study. Patients were randomly assigned to receive cyclosporin before (group B, n = 20) or after meals (group A, n = 17), and were followed up in 10 dermatology clinics. The difference between groups was evaluated in severity. The percent reduction in psoriasis area and severity index score from baseline was 29.8% in group A and 75.4% in group B (A vs B, P = 0.00005). Two patients in each group withdrew due to abnormality of laboratory data. Short‐term, low‐dose treatment with cyclosporin before rather than after meals is suggested as a new effective treatment regimen for psoriasis, with the added advantage of lowering costs.
Comparison of the efficacy of local narrowband ultraviolet B (NB‐UVB) phototherapy versus psoralen plus ultraviolet A (PUVA) paint for palmoplantar psoriasis
Authors: SEZER Engin , ERBIL Ahmet Hakan , KURUMLU Zafer , TAŞTAN Halis Bülent , ETIKAN Ilker 
Published: June 2007

ABSTRACTPalmoplantar psoriasis is an idiopathic disabling condition, often resistant to conventional therapies. The purpose of this study was to evaluate the efficacy and safety of local narrowband ultraviolet B (NB‐UVB) phototherapy and to compare it with local psoralen plus ultraviolet A (PUVA) paint in patients with palmoplantar psoriasis unresponsive to conventional therapies other than phototherapy. A cohort of 25 patients with palmoplantar psoriasis were included in this study, which was based on a left‐to‐right comparison pattern. The treatments were administered with local narrowband UVB irradiation on one side and local PUVA on the other side three times a week over 9 weeks. Clinical assessments were performed at baseline and every 3 weeks during the 9‐week treatment. There was a statistically significant decrease in the mean clinical scores at the third, sixth and ninth week with both treatments. The difference in clinical response between the two treatment modalities was statistically significant at the end of the treatment period, with the percentage reduction in severity index scores with the PUVA‐paint‐treated side being 85.45% compared with 61.08% for the NB‐UVB treated side (t = 5.379, P = 0.0001, Student's t‐test for unpaired samples). Our results show that, although some clinical improvement was achieved with local NB‐UVB phototherapy, the results were better with local PUVA, and such a treatment option may be reserved for patients with palmoplantar psoriasis who experience phototoxic reaction to psoralens.