bluuebunny/crossref_metadata_2025 huggingface dataset:
Power to the legal professionals: Is there an Americanization of European law?
Authors: Van Waarden Frans
Published: September 2009

Twelve years ago, Robert Kagan asked “Should Europe worry about adversarial legalism?” He answered this question with a qualified “no,” and identified a number of sources of resistance to such a trend. More recently, he broadened the issue in this journal by asking whether European countries experience an “Americanization” of their legal systems. The articles in this Symposium on the Americanization of European Law all revisit that question. The present article introduces the topic, discusses the elements that make up adversarial legalism, and summarizes and compares the findings of the articles in the Symposium. The articles find an increase in one dimension of adversarial legalism, namely, more legalism, that is, more litigation, more formalism, and more verdicts interfering with politics, but hardly any increase in adversarialism. Tenacious pre‐existing national legal and political cultures and institutions resist a further move in the direction of American style adversarial legalism. The mix of more litigation, more legalism, and more politicization, overlaid on the pre‐existing hierarchic authority of courts and legal functionaries has, however, strengthened the societal and political power of the judiciary vis‐à‐vis other powers. A professional elite is increasingly making the political choices that in a democratic society ought to be made by democratic representatives. Perhaps Europe should worry about this.
Safety and Feasibility of Achieving Lower Systolic Blood Pressure Goals in Persons With Type 2 Diabetes: The SANDS Trial
Authors: Weir Matthew R. , Yeh Fawn , Silverman Angela , Devereux Richard B. , Galloway James M. , Henderson Jeffrey A. , Howard William J. , Russell Marie , Wilson Charlton , Ratner Robert , Sorkin John , Umans Jason G. , Fleg Jerome L. , Stylianou Mario , Lee Elisa , Howard Barbara V.
Published: September 2009

The Stop Atherosclerosis in Native Diabetics Study (SANDS) was a randomized open‐label clinical trial in type 2 diabetics designed to examine the effects of intensive reduction of blood pressure, aggressive vs standard goals (≤115/75 mm Hg vs ≤130/80 mm Hg), and low‐density lipoprotein (LDL) cholesterol on the composite outcome of change in carotid intimal‐medial thickness and cardiovascular events. The study demonstrated that in conjunction with a lower LDL cholesterol target of 70 mg/dL, aggressive systolic blood pressure–lowering resulted in a reduction in carotid intimal‐medial thickness and left ventricular mass without measurable differences in cardiovascular events. The blood pressure treatment algorithm included renin‐angiotensin system blockade, with other agents added if necessary. The authors conclude that both standard and more aggressive systolic blood pressure reduction can be achieved with excellent safety and good tolerability in patients with type 2 diabetes mellitus.
Cost‐Effectiveness of Treating Resistant Hypertension With an Implantable Carotid Body Stimulator
Authors: Young Kate C. , Teeters J. C. , Benesch Curtis G. , Bisognano John D. , Illig Karl A.
Published: September 2009

The purposes of this study are to investigate the cost‐effectiveness of an implantable carotid body stimulator (Rheos; CVRx, Inc, Minneapolis, MN) for treating resistant hypertension and determine the range of starting systolic blood pressure (SBP) values where the device remains cost‐effective. A Markov model compared a 20‐mm Hg drop in SBP from an initial level of 180 mm Hg with Rheos to failed medical management in a hypothetical 50‐year‐old cohort. Direct costs (2007$), utilities, and event rates for future myocardial infarction, stroke, heart failure, and end‐stage renal disease were modeled. Sensitivity analyses tested the assumptions in the model. The incremental cost‐effectiveness ratio (ICER) for Rheos was $64,400 per quality‐adjusted life‐years (QALYs) using Framingham‐derived event probabilities. The ICER was <$100,000 per QALYs for SBPs ≥142 mm Hg. A probability of device removal of <1% per year or SBP reductions of ≥24 mm Hg were variables that decreased the ICER below $50,000 per QALY. For cohort characteristics similar to Anglo‐Scandinavian Cardiac Outcomes Trial–Blood Pressure–Lowering Arm (ASCOT‐BPLA) participants, the ICER became $26,700 per QALY. Two‐way sensitivity analyses demonstrated that lowering SBP 12 mm Hg from 220 mm Hg or 21 mm Hg from 140 mm Hg were required. Rheos may be cost‐effective, with an ICER between $50,000 and $100,000 per QALYs. Cohort characteristics and efficacy are key to the cost‐effectiveness of new therapies for resistant hypertension .
Impact of Baseline Renal Function on Outcomes of Renal Artery Stenting in Hypertensive Patients
Authors: Singer Gregory M. , Remetz Michael S. , Curtis Jeptha P. , Setaro John F.
Published: September 2009

Renal artery stenting may improve blood pressure (BP) and renal function in resistant hypertension patients; however, benefit may differ depending on the degree of renal dysfunction. The authors analyzed 67 consecutive patients receiving stenting for obstructive renal artery disease between 2002 and 2005. Patients were categorized as normal or mildly impaired according to estimated glomerular filtration rate (eGFR) (≥60 mL/min/1.73 m2), moderately impaired (eGFR 30 to 59 mL/min/1.73 m2), and severely impaired (eGFR <30 mL/min/1.73 m2). In patients with eGFR ≥60, systolic BP did not significantly improve from baseline. However, in patients with an eGFR between 30 and 59 mL/min/1.73 m2, systolic BP decreased by 12 mm Hg at 6 months (P=.02) and 14 mm Hg at 12 months (P=.01). Greater benefit was observed in patients with eGFR <30 mL/min/1.73 m2, with a 16 mm Hg (P=.10) and 21 mm Hg (P=.02) decrease at 6 and 12 months, respectively. Renal function was stable across all groups. Renal artery stenting reduced BP and produced greatest benefit in patients with baseline impaired renal function.
On Ihara’s lemma for Hilbert modular varieties
Authors: Dimitrov Mladen
Published: September 2009

Letρbe a two-dimensional moduloprepresentation of the absolute Galois group of a totally real number field. Under the assumptions thatρhas a large image and admits a low-weight crystalline modular deformation we show that any low-weight crystalline deformation ofρunramified outside a finite set of primes will be modular. We follow the approach of Wiles as generalized by Fujiwara. The main new ingredient is an Ihara-type lemma for the local component atρof the middle degree cohomology of a Hilbert modular variety. As an application we relate the algebraicp-part of the value at one of the adjointL-function associated with a Hilbert modular newform to the cardinality of the corresponding Selmer group.
In Vitro Activity of Nemonoxacin, a Novel Nonfluorinated Quinolone, against 2,440 Clinical Isolates
Authors: Adam Heather J. , Laing Nancy M. , King C. Richard , Lulashnyk Ben , Hoban Daryl J. , Zhanel George G.
Published: September 2009

The in vitro activity of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, was tested against 2,440 clinical isolates. Nemonoxacin was at least fourfold more active than levofloxacin and moxifloxacin against most gram-positive cocci tested (shown by the following MIC
90
/range [μg/ml] values; community-associated methicillin [meticillin]-resistant
Staphylococcus aureus
, 0.5/0.015 to 2;
Staphylococcus epidermidis
, 0.5/0.015 to 4 for methicillin-susceptible staphylococci and 2/0.12 to 2 for methicillin-resistant staphylococci;
Streptococcus pneumoniae
, 0.015/≤0.008 to 0.25;
Enterococcus faecalis
, 1/0.03 to 128). Nemonoxacin activity against gram-negative bacilli was similar to levofloxacin and moxifloxacin (MIC
90
/range [μg/ml];
Escherichia coli
, 32/≤0.015 to ≥512;
Klebsiella pneumoniae
, 2/≤0.015 to 128;
K
.
oxytoca
, 0.5/0.06 to 1;
Proteus mirabilis
, 16/0.25 to ≥512;
Pseudomonas aeruginosa
, 32/≤0.015 to ≥512;
Acinetobacter baumannii
, 1/0.12 to 16).
Population Pharmacokinetics of Ganciclovir after Intravenous Ganciclovir and Oral Valganciclovir Administration in Solid Organ Transplant Patients Infected with Cytomegalovirus
Authors: Caldés A. , Colom H. , Armendariz Y. , Garrido M. J. , Troconiz I. F. , Gil-Vernet S. , Lloberas N. , Pou L. , Peraire C. , Grinyó J. M.
Published: September 2009

A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CLCR) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49·(CLCR/57) liter/h (57 was the mean population value of CLCR); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h−1; bioavailability was 0.825; and lag time was 0.382 h. The CLCRwas the best predictor of CL, making dose adjustment by this covariate important to achieve the most efficacious ganciclovir exposure.
Primary Structure and Antibacterial Activity of Chicken Bone Marrow-Derived β-Defensins
Authors: Derache Chrystelle , Labas Valérie , Aucagne Vincent , Meudal Hervé , Landon Céline , Delmas Agnès F. , Magallon Thierry , Lalmanach Anne-Christine
Published: September 2009

Three biologically active β-defensins were purified by chromatography from chicken bone marrow extract: avian β-defensin 1 (AvBD1), AvBD2, and the newly isolated β-defensin AvBD7. Mass spectrometry analyses showed that bone marrow-derived AvBD1, -2, and -7 peptides were present as mature peptides and revealed posttranslational modifications for AvBD1 and AvBD7 in comparison to their in silico-predicted amino acid sequences. Tandem mass spectrometry analysis using the nanoelectrospray-quadrupole time of flight method showed N-terminal glutaminyl cyclization of mature AvBD7 and C-terminal amidation of mature AvBD1 peptide, while posttranslational modifications were absent in bone marrow-derived mature AvBD2 peptide. Furthermore, mass spectrometry analysis performed on intact cells confirmed the presence of these three peptides in mature heterophils. In addition, the antibacterial activities of the three β-defensins against a large panel of gram-positive and -negative bacteria were assessed. While the three defensins displayed similar antibacterial spectra of activity against gram-positive strains, AvBD1 and AvBD7 exhibited the strongest activity against gram-negative strains in comparison to AvBD2.
Plectasin Shows Intracellular Activity against
Staphylococcus aureus
in Human THP-1 Monocytes and in a Mouse Peritonitis Model
Authors: Brinch Karoline Sidelmann , Sandberg Anne , Baudoux Pierre , Van Bambeke Françoise , Tulkens Paul M. , Frimodt-Møller Niels , Høiby Niels , Kristensen Hans-Henrik
Published: September 2009

Antimicrobial therapy of infections with
Staphylococcus aureus
can pose a challenge due to slow response to therapy and recurrence of infection. These treatment difficulties can partly be explained by intracellular survival of staphylococci, which is why the intracellular activity of antistaphylococcal compounds has received increased attention within recent years. The intracellular activity of plectasin, an antimicrobial peptide, against
S. aureus
was determined both in vitro and in vivo. In vitro studies using THP-1 monocytes showed that some intracellular antibacterial activity of plectasin was maintained (maximal relative efficacy [
E
max
], 1.0- to 1.3-log reduction in CFU) even though efficacy was inferior to that of extracellular killing (
E
max
, >4.5-log CFU reduction). Animal studies included a novel use of the mouse peritonitis model, exploiting extra- and intracellular differentiation assays, and assessment of the correlations between activity and pharmacokinetic (PK) parameters. The intracellular activity of plectasin was in accordance with the in vitro studies, with an
E
max
of a 1.1-log CFU reduction. The parameter most important for activity was
fC
peak
/MIC, where
fC
peak
is the free peak concentration. These findings stress the importance of performing studies of extra- and intracellular activity since these features cannot be predicted from traditional MIC and killing kinetic studies. Application of both the THP-1 and the mouse peritonitis models showed that the in vitro results were similar to findings in the in vivo model with respect to demonstration of intracellular activity. Therefore the in vitro model was a good screening model for intracellular activity. However, animal models should be applied if further information on activity, PK/pharmacodynamic parameters, and optimal dosing regimens is required.
Antimicrobial Susceptibilities of
Mycoplasma genitalium
Strains Examined by Broth Dilution and Quantitative PCR
Authors: Hamasuna Ryoichi , Jensen Jørgen Skov , Osada Yukio
Published: September 2009

Only limited information regarding the antimicrobial susceptibilities of
Mycoplasma genitalium
is available because of difficulties in isolating
M. genitalium
strains from clinical specimens. Antimicrobial susceptibilities of 15 clinical isolates, 7 ATCC strains, and an early passage of the M30 strain were examined by the broth dilution method. Azithromycin, clarithromycin, sitafloxacin, and moxifloxacin were the most active drugs against
M. genitalium
, and their MIC
90
s were 0.002, 0.008, 0.125, and 0.125 mg/liter, respectively.
Structures of Triacetyloleandomycin and Mycalamide A Bind to the Large Ribosomal Subunit of
Haloarcula marismortui
Authors: Gürel Güliz , Blaha Gregor , Steitz Thomas A. , Moore Peter B.
Published: September 2009

Structures have been obtained for the complexes that triacetyloleandomycin and mycalamide A form with the large ribosomal subunit of
Haloarcula marismortui
. Triacetyloleandomycin binds in the nascent peptide tunnel and inhibits the activity of ribosomes by blocking the growth of the nascent peptide chain. Mycalamide A binds to the E site and inhibits protein synthesis by occupying the space normally occupied by the CCA end of E-site-bound tRNAs.
In Vitro Activities of Three New Dihydrofolate Reductase Inhibitors against Clinical Isolates of Gram-Positive Bacteria
Authors: Bowker Karen E. , Caspers Patrick , Gaucher Bérengère , MacGowan Alasdair P.
Published: September 2009

BAL0030543, BAL0030544, and BAL0030545 are dihydrophthalazine inhibitors with in vitro potency against gram-positive pathogens. The MIC50s for methicillin (meticillin)-sensitiveStaphylococcus aureus, methicillin-resistantStaphylococcus aureus, hetero-vancomycin-resistantStaphylococcus aureus, and vancomycin-resistantStaphylococcus aureus(VISA) range from 0.015 to 0.25 μg/ml (MIC90s ≤ 0.5 μg/ml). MIC50s for beta-hemolytic streptococci range from 0.03 to 0.06 μg/ml, MIC50s forStreptococcus pneumoniaerange from 0.06 to 0.12 μg/ml, MIC50s forListeria monocytogenesrange from 0.015 to 0.06 μg/ml, and MIC50s forStreptococcus mitisare ≤0.015 μg/ml. These three dihydrophthalazine antifolates have improved potency compared to that of trimethoprim and activity against gram-positive pathogens resistant to other drug classes. (This work was presented in part at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2008 [1].)
Effect of Varying Amounts of a Liquid Nutritional Supplement on the Pharmacokinetics of Posaconazole in Healthy Volunteers
Authors: Krishna Gopal , Ma Lei , Vickery Donna , Yu Xin , Wu Irene , Power Edward , Beresford Eric , Komjathy Steven
Published: September 2009

The aim of this single-center, phase 1, randomized, 5 by 5 crossover, open-label study was to determine the effects of varying amounts of a nutritional supplement (Boost Plus) on the pharmacokinetics of posaconazole in 30 healthy volunteers. After an overnight fast, subjects were administered a single dose of 400 mg posaconazole oral suspension alone or following Boost Plus (8 fluid ounces [oz] [240 ml], 4 oz [120 ml], 2 oz [60 ml], or 1 oz [30 ml]). Subjects were randomized to receive all five treatments in different sequences, with a 14-day washout between treatments. Primary pharmacokinetic variables—area under the concentration-time curve from time zero to the time of the final quantifiable sample (AUCtf), maximum observed plasma concentration (Cmax), time toCmax(Tmax), and relative bioavailability—were assessed up to 5 days postdose. Safety assessments included testing for adverse events, clinical laboratory tests, measurement of vital signs, physical examinations, and electrocardiograms. Posaconazole bioavailability increased almost linearly with increasing amounts of Boost Plus. Based on log-transformed data, the relative bioavailabilities (AUCs) of posaconazole were 35% (fasting), 48% (1 oz), 60% (2 oz), and 77% (4 oz) of the level reached in the presence of 8 oz Boost Plus, whereasTmaxwas unaffected. Compared with the levels reached under fasting conditions, posaconazoleCmaxand AUC values increased 3.5- and 2.9-fold, respectively, when given with 8 oz Boost Plus. Single doses of posaconazole at 400 mg alone and with 1, 2, 4, or 8 oz Boost Plus were safe and well tolerated in healthy subjects.
Pharmacodynamic Profile of Tigecycline against Methicillin-Resistant
Staphylococcus aureus
in an Experimental Pneumonia Model
Authors: Koomanachai Pornpan , Crandon Jared L. , Banevicius Mary Anne , Peng Li , Nicolau David P.
Published: September 2009

Tigecycline (TGC) is an extended-spectrum antibiotic with activity against
Staphylococcus aureus
, including methicillin (meticillin)-resistant
S. aureus
strains, which are well-recognized pathogens in nosocomial pneumonia. The objective of this study was to characterize the exposure-response relationship for TGC against
S. aureus
in an immunocompromised BALB/c murine pneumonia model. Six
S. aureus
isolates were studied, and the TGC MICs for those isolates ranged from 0.125 to 0.5 mg/liter. The pharmacokinetics (PK) of TGC in serum and bronchoalveolar lavage (BAL) fluid were evaluated, as was the level of protein binding of the compound in this murine species. Administration of TGC at 1.56 to 150 mg/kg of body weight/day in single or two to three divided doses was used in the efficacy studies. TGC displayed linear PK and had a mean half-life of 10.9 ± 2.5 h. Efficacy was highly correlated with the area under the free concentration-time curve (
f
AUC)/MIC (
r
2
= 0.93). The 80% and 50% effective exposure indexes and the stasis exposure index were similar between the isolates (means ± standard deviations, 3.04 ± 1.12, 1.84 ± 1.3, and 1.9 ± 1.5, respectively). Maximal efficacy was predicted at a 2.85-log
10
-CFU reduction. TGC appeared to accumulate in the interstitial space, as the ratios of the
f
AUC from 0 to 8 h of epithelial lining fluid to plasma were 7.02, 15.11, and 23.95 for doses of 12.5, 25, and 50 mg/kg, respectively. TGC was highly effective in this murine pneumonia model. In light of current MIC distributions, the
f
AUC/MIC targets that we defined against
S. aureus
are readily achievable in humans given conventional doses of TGC.
The O Antigen Is a Critical Antigen for the Development of a Protective Immune Response to
Bordetella parapertussis
Authors: Zhang Xuqing , Goebel Elizabeth M. , Rodríguez Maria Eugenia , Preston Andrew , Harvill Eric T.
Published: September 2009

Despite excellent vaccine coverage in developed countries, whooping cough is a reemerging disease that can be caused by two closely related pathogens,
Bordetella pertussis
and
B. parapertussis
. The two are antigenically distinct, and current vaccines, containing only
B. pertussis
-derived antigens, confer efficient protection against
B. pertussis
but not against
B. parapertussis
.
B. pertussis
does not express the O antigen, while
B. parapertussis
retains it as a dominant surface antigen. Since the O antigen is a protective antigen for many pathogenic bacteria, we examined whether this factor is a potential protective antigen for
B. parapertussis
. In a mouse model of infection, immunization with wild-type
B. parapertussis
elicited a strong antibody response to the O antigen and conferred efficient protection against a subsequent
B. parapertussis
challenge. However, immunization with an isogenic mutant lacking the O antigen,
B. parapertussis
Δ
wbm
, induced antibodies that recognized other antigens but did not efficiently mediate opsonophagocytosis of
B. parapertussis
. The passive transfer of sera raised against
B. parapertussis
, but not
B. parapertussis
Δ
wbm
, reduced
B. parapertussis
loads in the lower respiratory tracts of mice. The addition of 10 μg of purified
B. parapertussis
lipopolysaccharide (LPS), which contains the O antigen, but not
B. parapertussis
Δ
wbm
LPS drastically improved the efficacy of the acellular vaccine Adacel against
B. parapertussis
. These data suggest that the O antigen is a critical protective antigen of
B. parapertussis
and its inclusion can substantially improve whooping cough vaccine efficacy against this pathogen.
Electropositive Charge in α-Defensin Bactericidal Activity: Functional Effects of Lys-for-Arg Substitutions Vary with the Peptide Primary Structure
Authors: Llenado R. Alan , Weeks Colby S. , Cocco Melanie J. , Ouellette André J.
Published: September 2009

Cationic amino acids contribute to α-defensin bactericidal activity. Curiously, although Arg and Lys have equivalent electropositive charges at neutral pH, α-defensins contain an average of nine Arg residues per Lys residue. To investigate the role of high α-defensin Arg content, all Arg residues in mouse Paneth cell α-defensin cryptdin 4 (Crp4) and rhesus myeloid α-defensin 4 (RMAD-4) were replaced with Lys to prepare (R/K)-Crp4 and (R/K)-RMAD-4, respectively. Lys-for-Arg replacements in Crp4 attenuated bactericidal activity and slowed the kinetics of
Escherichia coli
ML35 cell permeabilization, and (R/K)-Crp4 required longer exposure times to reduce
E. coli
cell survival. In marked contrast, Lys substitutions in RMAD-4 improved microbicidal activity against certain bacteria and permeabilized
E. coli
more effectively. Therefore, Arg→Lys substitutions attenuated activity in Crp4 but not in RMAD-4, and the functional consequences of Arg→Lys replacements in α-defensins are dependent on the peptide primary structure. In addition, the bactericidal effects of (R/K)-Crp4 and (R/K)-RMAD-4 were more sensitive to inhibition by NaCl than those of the native peptides, suggesting that the high Arg content of α-defensins may be under selection to confer superior microbicidal function under physiologic conditions.
Immunoproteomic Analysis of the Development of Natural Immunity in Subjects Colonized by
Neisseria meningitidis
Reveals Potential Vaccine Candidates
Authors: Williams Jeannette N. , Skipp Paul J. , O'Connor C. David , Christodoulides Myron , Heckels John E.
Published: September 2009

The potential protective effect of existing vaccines against serogroup B meningococci, based on outer membrane proteins, is limited by strain restriction and apparent short duration of immune responses. In contrast, meningococcal colonization is known to stimulate the production of cross-protective antibodies as defined by the development of serum bactericidal activity (SBA) against heterologous serogroup B strains. In the current study, a resource of human serum samples and meningococcal carriage strains from studies of longitudinal carriage has been subjected to immunoproteomic analysis to investigate the outer membrane protein antigens associated with the development of SBA to both homologous and heterologous meningococcal serogroup B strains. Proteins from outer membranes of homologous and heterologous strains were separated by two-dimensional electrophoresis and reacted with paired sera which showed an increase in SBA following colonization. Individuals showed differing patterns of reactivity upon colonization, with an increase in SBA being associated with increases in the number of spots detected before and after colonization and/or with increases in the intensity of individual spots. Analysis of immunoreactive spots by mass spectrometry resulted in the identification of 43 proteins potentially associated with the development of SBA against both homologous and heterologous strains. The list of protein immunogens generated included not only well-established antigens but also novel proteins that represent potentially new candidates for inclusion in defined, multicomponent serogroup B vaccines.
Toxin-Mediated Effects on the Innate Mucosal Defenses: Implications for Enteric Vaccines
Authors: Glenn Gregory M. , Francis David H. , Danielsen E. Michael
Published: September 2009

Recent studies have confirmed older observations that the enterotoxins enhance enteric bacterial colonization and pathogenicity. How and why this happens remains unknown at this time. It appears that toxins such as the heat-labile enterotoxin (LT) fromEscherichia colican help overcome the innate mucosal barrier as a key step in enteric pathogen survival. We review key observations relevant to the roles of LT and cholera toxin in protective immunity and the effects of these toxins on innate mucosal defenses. We suggest either that toxin-mediated fluid secretion mechanically disrupts the mucus layer or that toxins interfere with innate mucosal defenses by other means. Such a breach gives pathogens access to the enterocyte, leading to binding and pathogenicity by enterotoxigenicE. coli(ETEC) and other organisms. Given the common exposure to LT+ETEC by humans visiting or residing in regions of endemicity, barrier disruption should frequently render the gut vulnerable to ETEC and other enteric infections. Conversely, toxin immunity would be expected to block this process by protecting the innate mucosal barrier. Years ago, Peltola et al. (Lancet 338:1285-1289, 1991) observed unexpectedly broad protective effects against LT+ETEC and mixed infections when using a toxin-based enteric vaccine. If toxins truly exert barrier-disruptive effects as a key step in pathogenesis, then a return to classic toxin-based vaccine strategies for enteric disease is warranted and can be expected to have unexpectedly broad protective effects.
Entry ofPorphyromonas gingivalisOuter Membrane Vesicles into Epithelial Cells Causes Cellular Functional Impairment
Authors: Furuta Nobumichi , Takeuchi Hiroki , Amano Atsuo
Published: September 2009

Porphyromonas gingivalis, a periodontal pathogen, secretes outer membrane vesicles (MVs) that contain major virulence factors, including proteases termed gingipains (Arg-gingipain [Rgp] and Lys-gingipain [Kgp]). We recently showed thatP. gingivalisMVs swiftly enter host epithelial cells via an endocytosis pathway and are finally sorted to lytic compartments. However, it remains unknown whether MV entry impairs cellular function. Herein, we analyzed cellular functional impairment following entry ofP. gingivalisinto epithelial cells, including HeLa and immortalized human gingival epithelial (IHGE) cells. After being taken up by endocytic vacuoles, MVs degraded the cellular transferrin receptor (TfR) and integrin-related signaling molecules, such as paxillin and focal adhesion kinase (FAK), which resulted in depletion of intracellular transferrin and inhibition of cellular migration. Few Rgp-null MVs entered the cells, and these negligibly degraded TfR, whereas paxillin and FAK degradation was significant. In contrast, Kgp-null MVs clearly entered the cells and degraded TfR, while they scarcely degraded paxillin and FAK. In addition, both wild-type and Kgp-null MVs significantly impaired cellular migration, whereas the effect of Rgp-null MVs was limited. Our findings suggest that, following entry ofP. gingivalisMVs into host cells, MV-associated gingipains degrade cellular functional molecules such as TfR and paxillin/FAK, resulting in cellular impairment, indicating thatP. gingivalisMVs are potent vehicles for transmission of virulence factors into host cells and are involved in the etiology of periodontitis.
Parental occupational exposure to organic solvents and anencephaly in Mexico
Authors: Aguilar-Garduño C , Lacasaña M , Blanco-Muñoz J , Borja-Aburto V Hugo , García A M
Published: September 2009

Objective:

To assess the relationship between parental occupational exposure to organic solvents, and the risk of anencephaly in Mexico.

Methods:

A case-control study was conducted based on the registers of the Epidemiological Surveillance System for Neural Tube Defects in Mexico; 151 cases of anencephaly of ⩾20 weeks’ gestation were included. A control, born alive and without any apparent congenital malformations at birth, was selected for each case in the same maternity service in which the case was born. Information on occupational exposures, lifestyle habits, reproductive history, use of medicines, supplementation with multivitamins and folic acid, was obtained by a general questionnaire; a food frequency questionnaire was also applied to obtain information of daily intake of folate and other B vitamins. Occupational exposure to organic solvents was based on job title as a proxy for exposure and analysed considering two critical periods around conception.

Results:

In logistic regression analysis, the odds of having a child with anencephaly was higher if the mother or the father was occupationally exposed to organic solvents during the periconceptional period, or when both parents or at least one of them were occupationally exposed during this period with an adjusted odds ratio of 2.97 (95% CI 1.36 to 6.52).

Conclusions:

The results support the hypothesis that both maternal and paternal occupational exposure to organic solvents can increase the probability of having a child with anencephaly.
Incidence of metabolic syndrome among night-shift healthcare workers
Authors: Pietroiusti A , Neri A , Somma G , Coppeta L , Iavicoli I , Bergamaschi A , Magrini A
Published: September 2009

Objective:

Night-shift work is associated with ischaemic cardiovascular disorders. It is not currently known whether it may be causally linked to metabolic syndrome (MS), a risk condition for ischaemic cardiovascular disorders. The syndrome presents with visceral obesity associated with mild alterations in glucidic and lipidic homeostasis, and in blood pressure. The aim of this study was to assess whether a causal relationship exists between night-shift work and the development of MS.

Methods:

Male and female nurses performing night shifts, free from any component of MS at baseline, were evaluated annually for the development of the disorder during a 4-year follow-up. Male and female nurses performing daytime work only, visited during the same time period, represented the control group.

Results:

The cumulative incidence of MS was 9.0% (36/402) among night-shift workers, and 1.8% (6/336) among daytime workers (relative risk (RR) 5.0, 95% CI − 2.1 to 14.6). The annual rate of incidence of MS was 2.9% in night-shift workers and 0.5% in daytime workers. Kaplan–Meier survival curves of the two groups were significantly different (log-rank test; p<0.001). Multiple Cox regression analysis (forward selection method based on likelihood ratio) showed that among selected variables (age, gender, smoking, alcohol intake, familiar history, physical activity, and work schedule) the only predictors of occurrence of MS were sedentariness (hazard ratio (HR) 2.92; 95% CI 1.64 to 5.18; p = 0.017), and night-shift work (HR 5.10; 95% CI 2.15 to 12.11; p<0.001).

Conclusions:

The risk of developing MS is strongly associated with night-shift work in nurses. Medical counselling should be promptly instituted in night-shift workers with the syndrome, and in case of persistence or progression, a change in work schedule should be considered.
DISCOVERING STOCK TRADING PREFERENCES BY SELF-ORGANIZING MAPS AND DECISION TREES
Authors: TSAI CHIH-FONG , LIN YUAH-CHIAO , WANG YI-TING
Published: September 2009

Stock trading activities are always very popular in many countries. Generally, investors with various backgrounds have different preferences over the stocks they trade. In literature, a number of studies examine the institutions' holding preferences for certain stock characteristics when choosing the security portfolio. However, very few studies investigate the stock trading preferences of individual investors. In this paper, we focus on two factors which affect the portfolio choices of investors, which are stock characteristics and investor features. In particular, a self-organizing map (SOM) is used to group a certain number of clusters based on a chosen dataset. Then, the decision tree model is used to extract useful rules from the clusters which contain the most trading records in the sample. We find that if the investors are females, less wealthy, and make stock trades with lower frequencies, they will be more careful and conservative. On the other hand, if the investors are males, having a high level of wealth, and make stock trades very often, they tend to choose stocks with high EPS, high market-to-book, and high prices.
REDUCING DECISION TREE ENSEMBLE SIZE USING PARALLEL DECISION DAGS
Authors: PETERSON ADAM H. , MARTINEZ TONY R.
Published: September 2009

This research presents a new learning model, the Parallel Decision DAG (PDDAG), and shows how to use it to represent an ensemble of decision trees while using significantly less storage. Ensembles such as Bagging and Boosting have a high probability of encoding redundant data structures, and PDDAGs provide a way to remove this redundancy in decision tree based ensembles. When trained by encoding an ensemble, the new model behaves similar to the original ensemble, and can be made to perform identically to it. The reduced storage requirements allow an ensemble approach to be used in cases where storage requirements would normally be exceeded, and the smaller model can potentially execute faster by reducing redundant computation.
A PROTOTYPE FOR EDUCATIONAL PLANNING USING COURSE CONSTRAINTS TO SIMULATE STUDENT POPULATIONS
Authors: HADZILACOS THANASIS , KALLES DIMITRIS , KOUMANAKOS DIMITRIS , MITSIONIS VASSILIS
Published: September 2009

Distance learning universities usually afford their students the flexibility to advance their studies at their own pace. This can lead to a considerable fluctuation of student populations within a program's courses, possibly affecting the academic viability of a program as well as the related required resources. Providing a method that estimates this population could be of substantial help to university management and academic personnel. We describe how to use course precedence constraints to calculate alternative tuition paths and then use Markov models to estimate future populations. In doing so, we identify key issues of a large scale potential deployment.
Nitric oxides mediates a shift from early necrosis to late apoptosis in cytokine-treated β-cells that is associated with irreversible DNA damage
Authors: Hughes Katherine J. , Chambers Kari T. , Meares Gordon P. , Corbett John A.
Published: September 2009

For many cell types, including pancreatic β-cells, nitric oxide is a mediator of cell death; however, it is paradoxical that for a given cell type nitric oxide can induce both necrosis and apoptosis. This report tests the hypothesis that cell death mediated by nitric oxide shifts from an early necrotic to a late apoptotic event. Central to this transition is the ability of β-cells to respond and repair nitric oxide-mediated damage. β-Cells have the ability to repair DNA that is damaged following 24-h incubation with IL-1; however, cytokine-induced DNA damage becomes irreversible following 36-h incubation. This irreversible DNA damage following 36-h incubation with IL-1 correlates with the activation of caspase-3 (cleavage and activity). The increase in caspase activity correlates with reductions in endogenous nitric oxide production, as nitric oxide is an inhibitor of caspase activity. In contrast, caspase cleavage or activation is not observed under conditions in which β-cells are capable of repairing damaged DNA (24-h incubation with cytokines). These findings provide evidence that β-cell death in response to cytokines shifts from an early necrotic process to apoptosis and that this shift is associated with irreversible DNA damage and caspase-3 activation.
The origin of intermuscular adipose tissue and its pathophysiological implications
Authors: Vettor Roberto , Milan Gabriella , Franzin Chiara , Sanna Marta , De Coppi Paolo , Rizzuto Rosario , Federspil Giovanni
Published: September 2009

The intermuscular adipose tissue (IMAT) is a depot of adipocytes located between muscle bundles. Several investigations have recently been carried out to define the phenotype, the functional characteristics, and the origin of the adipocytes present in this depot. Among the different mechanisms that could be responsible for the accumulation of fat in this site, the dysdifferentiation of muscle-derived stem cells or other mesenchymal progenitors has been postulated, turning them into cells with an adipocyte phenotype. In particular, muscle satellite cells (SCs), a heterogeneous stem cell population characterized by plasticity and self-renewal that allow muscular growth and regeneration, can acquire features of adipocytes, including the abilities to express adipocyte-specific genes and accumulate lipids. Failure to express the transcription factors that direct mesenchymal precursors into fully differentiated functionally specialized cells may be responsible for their phenotypic switch into the adipogenic lineage. We proved that human SCs also possess a clear adipogenic potential that could explain the presence of mature adipocytes within skeletal muscle. This occurs under some pathological conditions (i.e., primary myodystrophies, obesity, hyperglycemia, high plasma free fatty acids, hypoxia, etc.) or as a consequence of thiazolidinedione treatment or simply because of a sedentary lifestyle or during aging. Several pathways and factors (PPARs, WNT growth factors, myokines, GEF-GAP-Rho, p66shc, mitochondrial ROS production, PKCβ) could be implicated in the adipogenic conversion of SCs. The understanding of the molecular pathways that regulate muscle-to-fat conversion and SC behavior could explain the increase in IMAT depots that characterize many metabolic diseases and age-related sarcopenia.
Bilateral Limb Phase Relationship and Its Potential to Alter Muscle Activity Phasing During Locomotion
Authors: Alibiglou Laila , López-Ortiz Citlali , Walter Charles B. , Brown David A.
Published: September 2009

It is well established that the sensorimotor state of one limb can influence another limb and therefore bilateral somatosensory inputs make an important contribution to interlimb coordination patterns. However, the relative contribution of interlimb pathways for modifying muscle activation patterns in terms of phasing is less clear. Here we studied adaptation of muscle activity phasing to the relative angular positions of limbs using a split-crank ergometer, where the cranks could be decoupled to allow different spatial angular position relationships. Twenty neurologically healthy individuals performed the specified pedaling tasks at different relative angular positions while surface electromyographic (EMG) signals were recorded bilaterally from eight lower extremity muscles. During each experiment, the relative angular crank positions were altered by increasing or decreasing their difference by randomly ordered increments of 30° over the complete cycle [0° (in phase pedaling); 30, 60, 90, 120, 150, and 180° (standard pedaling); and 210, 240, 270, 300, and 330° out of phase pedaling]. We found that manipulating the relative angular positions of limbs in a pedaling task caused muscle activity phasing changes that were either delayed or advanced, dependent on the relative spatial position of the two cranks and this relationship is well-explained by a sine curve. Further, we observed that the magnitude of phasing changes in biarticular muscles (like rectus femoris) was significantly greater than those of uniarticular muscles (like vastus medialis). These results are important because they provide new evidence that muscle phasing can be systematically influenced by interlimb pathways.
Changes in behavior and gene expression induced by caloric restriction in C57BL/6 mice
Authors: Yamamoto Yuta , Tanahashi Toshihito , Kawai Tomoko , Chikahisa Sachiko , Katsuura Sakurako , Nishida Kensei , Teshima-Kondo Shigetada , Sei Hiroyoshi , Rokutan Kazuhito
Published: September 2009

Caloric restriction (CR) is an effective method for prevention of age-associated diseases as well as overweight and obesity; however, there is controversy regarding the effects of dieting regimens on behavior. In this study, we investigated two different dieting regimens: repeated fasting and refeeding (RFR) and daily feeding of half the amount of food consumed by RFR mice (CR). CR and RFR mice had an approximate 20% reduction in food intake compared with control mice. Open field, light-dark transition, elevated plus maze, and forced swimming tests indicated that CR, but not RFR, reduced anxiety- and depressive-like behaviors, with a reduction peak on day 8. Using a mouse whole genome microarray, we analyzed gene expression in the prefrontal cortex, amygdala, and hypothalamus. In addition to the CR-responsive genes commonly modified by RFR and CR, each regimen differentially changed the expression of distinct genes in each region. The most profound change was observed in the amygdalas of CR mice: 884 genes were specifically upregulated. Ingenuity pathway analysis revealed that these 884 genes significantly modified nine canonical pathways in the amygdala. α-Adrenergic and dopamine receptor signalings were the two top-scoring pathways. Quantitative RT-PCR confirmed the upregulation of six genes in these pathways. Western blotting confirmed that CR specifically increased dopamine- and cAMP-regulated phosphoprotein (Darpp-32), a key regulator of dopamine receptor signaling, in the amygdala. Our results suggest that CR may change behavior through altered gene expression.
Melanoma Proteoglycan Modifies Gene Expression to Stimulate Tumor Cell Motility, Growth, and Epithelial-to-Mesenchymal Transition
Authors: Yang Jianbo , Price Matthew A. , Li Gui Yuan , Bar-Eli Menashe , Salgia Ravi , Jagedeeswaran Ramasamy , Carlson Jennifer H. , Ferrone Soldano , Turley Eva A. , McCarthy James B.
Published: September 2009

Melanoma chondroitin sulfate proteoglycan (MCSP) is a plasma membrane–associated proteoglycan that facilitates the growth, motility, and invasion of tumor cells. MCSP expression in melanoma cells enhances integrin function and constitutive activation of Erk1,2. The current studies were performed to determine the mechanism by which MCSP expression promotes tumor growth and motility. The results show that MCSP expression in radial growth phase, vertical growth phase, or metastatic cell lines causes sustained activation of Erk1,2, enhanced growth, and motility which all require the cytoplasmic domain of the MCSP core protein. MCSP expression in a radial growth phase cell line also promotes an epithelial-to-mesenchymal transition based on changes in cell morphology and the expression of several epithelial-to-mesenchymal transition markers. Finally, MCSP enhances the expression of c-Met and hepatocyte growth factor, and inhibiting c-Met expression or activation limits the increased growth and motility of multiple melanoma cell lines. The studies collectively show the importance of MCSP in promoting progression by an epigenetic mechanism and they indicate that MCSP could be targeted to delay or inhibit tumor progression in patients. [Cancer Res 2009;69(19):7538–47]
Glioma Tumor Stem-Like Cells Promote Tumor Angiogenesis and Vasculogenesis via Vascular Endothelial Growth Factor and Stromal-Derived Factor 1
Authors: Folkins Chris , Shaked Yuval , Man Shan , Tang Terence , Lee Christina R. , Zhu Zhenping , Hoffman Robert M. , Kerbel Robert S.
Published: September 2009

Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow–derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures andtumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cellactivity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow–derived EPC in a vascular endothelial growth factor–dependent and stromal-derived factor 1–dependent manner. [Cancer Res 2009;69(18):7243–51]
Integrin α2 Mediates Selective Metastasis to the Liver
Authors: Yoshimura Kiyoshi , Meckel Kristen F. , Laird Lindsay S. , Chia Christina Y. , Park Jang-June , Olino Kelly L. , Tsunedomi Ryouichi , Harada Toshio , Iizuka Norio , Hazama Shoichi , Kato Yukihiko , Keller Jesse W. , Thompson John M. , Chang Fumin , Romer Lewis H. , Jain Ajay , Iacobuzio-Donahue Christine , Oka Masaaki , Pardoll Drew M. , Schulick Richard D.
Published: September 2009

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin α2. The direct role of integrin α2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin α2–mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV–dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin α2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin α2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation. [Cancer Res 2009;69(18):7320–8]
Tumor Immunology: New Perspectives
Authors: McArdle Stephanie E. , Rees Robert C.
Published: September 2009

This second meeting, organized by the Cancer Immunology Working Group of AACR, concentrated mainly on three areas of importance; these included (a) ways to increase the success rate of vaccination by improving the peptides themselves, improving tumor recognition by using costimulatory molecules or the use of antibodies; (b) how the tumor microenvironment influences T-cell activity and how it can be manipulated to favor survival and action of activated T cells; and (c) a better understanding of myeloid-derived suppressor cells, which represent an ever-growing and diverse group of cells with activities leading to the inhibition of immune responses. It has been accepted that many of these improved therapies may only benefit relatively few patients and recent but rapidly developing research is currently focusing on methods that would allow clinicians to stratify patients receiving immunotherapy into responders and nonresponders, thereby predicting those who are likely to benefit from a specific vaccine therapy; this approach may benefit future clinical trials. [Cancer Res 2009;69(18):7157–9]