bluuebunny/crossref_metadata_2025 huggingface dataset:
Adversarialism versus legalism: Juridification and litigation in corporate governance reform
Authors: Cioffi John W.
Published: September 2009

Recent reforms of corporate governance law and related litigation rules in the US and in Germany indicate that reports of the spread of adversarial legalism are greatly exaggerated. Politics and legislation in the US since the mid‐1990s have turned quite decisively against shareholder litigation even as corporate governance and securities law reforms have expanded the role and scope of the regulatory state. Germany's extraordinary expansion of financial and corporate governance regulation since the early 1990s exemplifies juridification. Although these reforms included some liberalization of shareholder litigation rules, the changes reflected skepticism towards private litigation and imposed new constraints on the most prevalent forms of shareholder suits. Marketization of economic relations and the era of finance capitalism have produced far more legalism than adversarialism, more regulation than judicialization, and more ex ante transparency rules than ex post litigation remedies.
From corporatism to lawyocracy? On liberalization and juridification
Authors: Van Waarden Frans , Hildebrand Youri
Published: September 2009

In 1997 Robert Kagan questioned whether European countries had to fear the coming of American style adversarial legalism. He answered this question with a qualified “no.” Today we are no longer so sure the answer is “no,” even in a country that Kagan considered the antipole of US adversarial legalism, the Netherlands, traditionally characterized by informal and consensual conflict resolution. In the present article we chart a trend of increasing juridification and legalism, that is, more formal and legal conflict resolution, in the Netherlands between 1970 and 2008. The trend is related to major changes in economic governance institutions, which generated a shift from corporatism toward lawyocracy; from power of the associations of civil society toward power of courts, lawyers, and judges. Yet the newly dominant system of governance is modified and merged with elements of the old system, producing a specific Dutch version, which one could call “corporatist lawyocracy.” We identify two types of liberalization as major driving forces: social liberalization in the 1970s and 1980s, followed by economic liberalization in the subsequent decades. If one considers economic liberalization a product of neoliberal “Reaganomics,” the legal changes are in a way an “American export product,” although a different one than the lawyering styles of large international American law firms mentioned by Kelemen and Sibbitt in 2004.
Diuretic‐Induced Potassium Depletion and Glucose Intolerance Are Not Related to Hyperactivity of the Renin‐Angiotensin‐Aldosterone System in Hypertensive Patients With the Metabolic Syndrome
Authors: Barbieri Douglas E. , Ribeiro‐Filho Fernando F. , Ribeiro Artur B. , Zanella Maria T.
Published: September 2009

The metabolic syndrome (MS) has been associated with hyperactivity of the renin‐angiotensin‐aldosterone system (RAAS). To assess the hypothesis that diuretic therapy in MS patients through further stimulation of RAAS would elicit greater potassium (K) depletion, two groups of hypertensive patients with (MS group [MSG]; n=20) and without (control group [CG]; n=19) MS were studied. Plasma renin activity (PRA), aldosterone (PA), and K levels were determined and an oral glucose tolerance test with plasma insulin determinations for calculation of homeostasis model assessment of insulin resistance (HOMA‐IR), sensitivity (ISI), and secretion (HOMA‐β) was performed, both before and 12 weeks after hydrochlorothiazide (HCT; 25 mg/d) therapy. At baseline, higher HOMA IR and HOMA‐β and lower ISI and plasma K were found in the MSG than in the CG, with no differences in PA and PRA between groups. With therapy, PRA increased similarly in both groups while PA increased only in the MSG. However, greater reduction in plasma K occurred in the CG, and the 2 groups reached similar final K values. Impairment in glucose tolerance occurred in both groups, with no change in HOMA‐β in the CG and reduction in the MSG, suggesting that diuretic therapy increases insulin resistance and impairs insulin secretion independent of abdominal obesity. These alterations could not be attributed to hyperactivity of RAAS.
Primary Health Care for Hypertension by Nurses in Rural and Urban Sub‐Saharan Africa
Authors: Kengne Andre P. , Awah Paschal K. , Fezeu Leopold L. , Sobngwi Eugene , Mbanya Jean‐Claude
Published: September 2009

To implement a nurse‐led protocol for the care of hypertension, 5 clinics were established in Yaounde (urban) and Bafut (rural) in Cameroon. International guidelines were adapted and 10 nurses were trained. The initial cohort of patients was referred from a field survey. The program proceeded for 26 months and 454 patients (45% urban) were registered in the clinics. Relative to urban participants, rural participants were more often women (59% vs 45%, P=.002) and less likely to have diabetes (7.2% vs 41.2%, P<.001). Between baseline and final visits, systolic and diastolic blood pressures dropped by 11.7 mm Hg (95% confidence interval, 8.9–14.4) and 7.8 (95% confidence interval, 5.9–9.6), respectively (P<.001). These changes were consistent in subgroups and after adjustment. Most dropouts occurred around the initial visit and among urban participants and nondiabetics. Nurse‐led clinics are effective for improving hypertension care in these settings and require implementation and validation through controlled trials.
Rapid changes in butterfly communities following the abandonment of grasslands: a case study
Authors: STEFANESCU CONSTANTÍ , PEÑUELAS JOSEP , FILELLA IOLANDA
Published: September 2009

Abstract.  1. Abandonment of grasslands is a major threat for the conservation of biodiversity in Europe. The response of butterflies towards secondary succession has been studied in northern temperate grasslands, but always by comparing sites at different seral stages.

2. Here, we present a trajectory study based on the monitoring of butterflies from a series of abandoned grasslands in northeast Spain. One additional meadow was traditionally managed for the whole 8‐year sampling period and provided a useful control. Both general changes at the community level and species population trends were documented through standardised transect counts.

3. The increase in turf height was neither accompanied by an increase in butterfly diversity nor by consistent trends in body size, dispersal ability and host‐plant specialization. However, there was a significant decrease in habitat specialization, consistent with the hypothesis that richness in generalist herbivores is more dependent on biomass production than on plant richness. The number of generations decreased, in line with the hypothesis that species living in habitats subjected to greater disturbance need higher reproductive rates.

4. Butterfly communities underwent substantial changes, as indicated by composition similarity and species population trends. Grassland specialists were forced to disperse from the abandoned meadows and search for refugial habitats, allowing the establishment of new populations in the contiguous managed meadow.

5. Our study shows that grassland abandonment had immediate strong effects on butterflies, acting as an excellent indicator of habitat change. It also points out to the substitution of grassland specialists by common butterflies, less important for conservation purposes.
Molecular phylogeny of Solms‐laubachia (Brassicaceae) s.l., based on multiple nuclear and plastid DNA sequences, and its biogeographic implications
Authors: YUE Ji‐Pei , SUN Hang , BAUM David A. , LI Jian‐Hua , AL‐SHEHBAZ Ihsan A. , REE Richard
Published: September 2009

Abstract  The Hengduan Mountains region of south‐west China is a noted biodiversity hotspot, but the geographic origins and historical assembly of its rich endemic flora, including the sky‐island species of Solms‐laubachia Muschl. (Brassicaceae), have been little studied. Previous molecular studies on the phylogeny of Solms‐laubachia showed it to be paraphyletic, leading to considerable expansion not only of its taxonomic limits, but also its geographic range, with the inclusion of taxa from outside the Hengduan region. However, these studies provided little resolution of interspecific relationships, preventing inferences about historical biogeography within the clade. In the present study, new sequence data from two nuclear genes (LEAFY and G3pdh) and two chloroplast intergenic spacers (petN–psbM and psbM–trnD) were combined with existing markers to increase phylogenetic signals. Phaeonychium villosum (Maxim.) Al‐Shehbaz was found to be nested within Solms‐laubachia s.l. In general, phylogenetic relationships appear to be a good predictor of geography, with the Hengduan Mountain endemics embedded in a paraphyletic grade of species from the western Himalayas and central Asia, but they also imply morphological homoplasy. Incongruence was detected between the nuclear and chloroplast gene trees, perhaps resulting from incomplete lineage sorting of ancestral polymorphisms. The crown age of Solms‐laubachia s.l. was estimated to be approximately 1.42–3.68 mya, using Bayesian relaxed molecular clock analysis. Historical biogeographic analysis using a parametric dispersal–extinction–cladogenesis model inferred central Asia and the western Himalayas as most probable ancestral range of Solms‐laubachia s.l., and estimated higher rates of eastward expansion than westward during the diversification of descendant lineages. In summary, our results suggest that Solms‐laubachia s.l. originated during the Pliocene in central Asia, and subsequently migrated eastward into the Hengduan Mountains, colonizing sky‐island, alpine scree‐slope habitats that may have provided novel ecological opportunity and accelerated speciation, ultimately establishing this region as the present center of diversity of the genus.
Molecular Epidemiology and Mechanisms of Carbapenem Resistance in
Pseudomonas aeruginosa
Authors: Rodríguez-Martínez José-Manuel , Poirel Laurent , Nordmann Patrice
Published: September 2009

The contributions of different mechanisms of resistance to carbapenems among a collection of imipenem- and meropenem-nonsusceptible
Pseudomonas aeruginosa
isolates were investigated. This screening included the recently reported extended-spectrum cephalosporinases (ESACs) weakly hydrolyzing carbapenems. Eighty-seven percent of the studied isolates were resistant to imipenem. Genes encoding metallo-β-lactamases or carbapenem-hydrolyzing oxacillinases were not identified. The main mechanism associated with imipenem resistance was the loss of outer membrane protein OprD. Identification of overexpressed ESACs and loss of OprD were observed for 65% of the isolates, all being fully resistant to imipenem. Resistance to meropenem was observed in 78% of the isolates, with all but one also being resistant to imipenem. Overexpression of the MexAB-OprM, MexXY-OprM, or MexCD-OprJ efflux systems was observed in 60% of the isolates, suggesting the contribution of efflux mechanisms in resistance to meropenem. The loss of porin OprD and the overproduction of ESACs were observed in 100% and 92% of the meropenem-resistant isolates, respectively.
P. aeruginosa
can very often accumulate different resistance mechanisms, including ESAC production, leading to carbapenem resistance.
Alcohols for Skin Antisepsis at Clinically Relevant Skin Sites
Authors: Reichel Mirja , Heisig Peter , Kohlmann Thomas , Kampf Günter
Published: September 2009

The antiseptic efficacy of ethanol, isopropanol, and
n
-propanol at 60%, 70%, and 89.5% (all vol/vol) was analyzed after 2, 3, or 4 min of application to the forehead, back, and abdomen of 180 volunteers by the use of a standardized swab sampling method. Results of recolonization by the aerobic skin flora of the upper arms and backs of 20 volunteers were compared 72 h after treatment with 0.5%, 1%, or 2% chlorhexidine digluconate (CHG) in 89.5%
n
-propanol. The most effective alcohol at all skin sites was
n
-propanol, with a mean log
10
reduction of 1.82 after 2 min on the forehead. Efficacy against the aerobic flora of the forehead was mainly influenced by the type of alcohol (
P
< 0.001), followed by the concentration (
P
< 0.001) and the application time (
P
= 0.006). Ethanol and isopropanol were significantly less effective (both
P
< 0.001). Alcohol supplemented with 0.5% or more CHG was significantly more effective than alcohol alone in the suppression of recolonization (
P
< 0.05). An 89.5% solution of
n
-propanol was the most effective alcohol for the reduction of populations of aerobic skin flora. Its combination with CHG is appropriate whenever recolonization of the skin must be limited. Further studies are needed to determine the most effective concentration of CHG in
n
-propanol to provide the best protection against recolonization of the skin, e.g., for catheter site care.
Noninvasive Pulmonary [
18
F]-2-Fluoro-Deoxy-
d
-Glucose Positron Emission Tomography Correlates with Bactericidal Activity of Tuberculosis Drug Treatment
Authors: Davis Stephanie L. , Nuermberger Eric L. , Um Peter K. , Vidal Camille , Jedynak Bruno , Pomper Martin G. , Bishai William R. , Jain Sanjay K.
Published: September 2009

Tools for monitoring response to tuberculosis (TB) treatment are time-consuming and resource intensive. Noninvasive biomarkers have the potential to accelerate TB drug development, but to date, little progress has been made in utilizing imaging technologies. Therefore, in this study, we used noninvasive imaging to monitor response to TB treatment. BALB/c and C3HeB/FeJ mice were aerosol infected with
Mycobacterium tuberculosis
and administered bactericidal (standard and highly active) or bacteriostatic TB drug regimens. Serial pulmonary [
18
F]-2-fluoro-deoxy-
d
-glucose (FDG) positron emission tomography (PET) was compared with standard microbiologic methods to monitor the response to treatment. [
18
F]FDG-PET correctly identified the bactericidal activity of the drug regimens. Imaging required fewer animals; was available in real time, as opposed to having CFU counts 4 weeks later; and could also detect TB relapse in a time frame similar to that of the standard method. Lesion-specific [
18
F]FDG-PET activity also broadly correlated with TB treatment in C3HeB/FeJ mice that develop caseating lesions. These studies demonstrate the application of noninvasive imaging to monitor TB treatment response. By reducing animal numbers, these biomarkers will allow cost-effective studies of more expensive animal models of TB. Validated markers may also be useful as “point-of-care” methods to monitor TB treatment in humans.
Nosocomial Spread of Colistin-Only-Sensitive Sequence Type 235
Pseudomonas aeruginosa
Isolates Producing the Extended-Spectrum β-Lactamases GES-1 and GES-5 in Spain
Authors: Viedma Esther , Juan Carlos , Acosta Joshi , Zamorano Laura , Otero Joaquín R. , Sanz Francisca , Chaves Fernando , Oliver Antonio
Published: September 2009

The mechanisms responsible for the increasing prevalence of colistin-only-sensitive (COS)
Pseudomonas aeruginosa
isolates in a Spanish hospital were investigated. Pulsed-field gel electrophoresis revealed that 24 (50%) of the studied isolates belonged to the same clone, identified as the internationally spread sequence type 235 (ST235) through multilocus sequence typing. In addition to several mutational resistance mechanisms, an integron containing seven resistance determinants was detected. Remarkably, the extended-spectrum β-lactamase GES-1 and its Gly170Ser carbapenem-hydrolyzing derivative GES-5 were first documented to be encoded in a single integron. This work is the first to describe GES enzymes in Spain and adds them to the growing list of β-lactamases of concern (PER, VIM, and OXA) detected in ST235 clone isolates.
Comparative In Vitro Activity Profile of Oritavancin against Recent Gram-Positive Clinical Isolates
Authors: Arhin Francis F. , Draghi Deborah C. , Pillar Chris M. , Parr Thomas R. , Moeck Gregory , Sahm Daniel F.
Published: September 2009

Oritavancin activity was tested against 15,764 gram-positive isolates collected from 246 hospital centers in 25 countries between 2005 and 2008. Organisms were
Staphylococcus aureus
(
n
= 9,075), coagulase-negative staphylococci (
n
= 1,664),
Enterococcus faecalis
(
n
= 1,738),
Enterococcus faecium
(
n
= 819),
Streptococcus pyogenes
(
n
= 959),
Streptococcus agalactiae
(
n
= 415), group C, G, and F streptococci (
n
= 84), and
Streptococcus pneumoniae
(
n
= 1,010). Among the evaluated staphylococci, 56.7% were resistant to oxacillin. The vancomycin resistance rate among enterococci was 21.2%. Penicillin-resistant and -intermediate rates were 14.7% and 21.4%, respectively, among
S. pneumoniae
isolates. Among nonpneumococcal streptococci, 18.5% were nonsusceptible to erythromycin. Oritavancin showed substantial in vitro activity against all organisms tested, regardless of resistance profile. The maximum oritavancin MIC against all staphylococci tested (
n
= 10,739) was 4 μg/ml; the MIC
90
against
S. aureus
was 0.12 μg/ml. Against
E. faecalis
and
E. faecium
, oritavancin MIC
90
s were 0.06 and 0.12, respectively. Oritavancin was active against glycopeptide-resistant enterococci, including VanA strains (
n
= 486), with MIC
90
s of 0.25 and 1 μg/ml against VanA
E. faecium
and
E. faecalis
, respectively. Oritavancin showed potent activity against streptococci (
n
= 2,468); MIC
90
s for the different streptococcal species were between 0.008 and 1 μg/ml. These data are consistent with previous studies with respect to resistance rates of gram-positive isolates and demonstrate the spectrum and in vitro activity of oritavancin against a wide variety of contemporary gram-positive pathogens, regardless of resistance to currently used drugs. The data provide a foundation for interpreting oritavancin activity and potential changes in susceptibility over time once oritavancin enters into clinical use.
Specific Osmolyte Transporters Mediate Bile Tolerance in
Listeria monocytogenes
Authors: Watson Debbie , Sleator Roy D. , Casey Pat G. , Hill Colin , Gahan Cormac G. M.
Published: September 2009

The food-borne pathogenic bacterium
Listeria monocytogenes
has the potential to adapt to an array of suboptimal growth environments encountered within the host. The pathogen is relatively bile tolerant and has the capacity to survive and grow within both the small intestine and the gallbladder in murine models of oral infection. We have previously demonstrated a role for the principal carnitine transport system of
L. monocytogenes
(OpuC) in gastrointestinal survival of the pathogen (R. Sleator, J. Wouters, C. G. M. Gahan, T. Abee, and C. Hill, Appl. Environ. Microbiol. 67:2692-2698, 2001). However, the mechanisms by which OpuC, or indeed carnitine, protects the pathogen in this environment are unclear. In the current study, systematic analysis of strains with mutations in osmolyte transporters revealed a role for OpuC in resisting the acute toxicity of bile, with a minor role also played by BetL, a secondary betaine uptake system which also exhibits a low affinity for carnitine. In addition, the toxic effects of bile on wild-type
L. monocytogenes
cells were ameliorated when carnitine (but not betaine) was added to the medium.
lux
-promoter fusions to the promoters of the genes encoding the principal osmolyte uptake systems Gbu, BetL, and OpuC and the known bile tolerance system BilE were constructed. Promoter activity for all systems was significantly induced in the presence of bile, with the
opuC
and
bilE
promoters exhibiting the highest levels of bile-dependent expression in vitro and the
betL
and
bilE
promoters showing the highest expression levels in the intestines of orally inoculated mice. A direct comparison of all osmolyte transporter mutants in a murine oral infection model confirmed a major role for OpuC in intestinal persistence and systemic invasion and a minor role for the BetL transporter in fecal carriage. This study therefore demonstrates a previously unrecognized function for osmolyte uptake systems in bile tolerance in
L. monocytogenes
.
SgrA, a Nidogen-Binding LPXTG Surface Adhesin Implicated in Biofilm Formation, and EcbA, a Collagen Binding MSCRAMM, Are Two Novel Adhesins of Hospital-Acquired
Enterococcus faecium
Authors: Hendrickx Antoni P. A. , van Luit-Asbroek Miranda , Schapendonk Claudia M. E. , van Wamel Willem J. B. , Braat Johanna C. , Wijnands Lucas M. , Bonten Marc J. M. , Willems Rob J. L.
Published: September 2009

Hospital-acquired
Enterococcus faecium
isolates responsible for nosocomial outbreaks and invasive infections are enriched in the
orf2351
and
orf2430
genes, encoding the SgrA and EcbA LPXTG-like cell wall-anchored proteins, respectively. These two surface proteins were characterized to gain insight into their function, since they may have favored the rapid emergence of this nosocomial pathogen. We are the first to identify a surface adhesin among bacteria (SgrA) that binds to the extracellular matrix molecules nidogen 1 and nidogen 2, which are constituents of the basal lamina. EcbA is a novel
E. faecium
MSCRAMM (microbial surface component recognizing adhesive matrix molecules) that binds to collagen type V. In addition, both SgrA and EcbA bound to fibrinogen; however, SgrA targeted the alpha and beta chains, whereas EcbA bound to the gamma chain of fibrinogen. An
E. faecium sgrA
insertion mutant displayed reduced binding to both nidogens and fibrinogen. SgrA did not mediate binding of
E. faecium
cells to biotic materials, such as human intestinal epithelial cells, human bladder cells, and kidney cells, while this LPXTG surface adhesin is implicated in
E. faecium
biofilm formation. The
acm
and
scm
genes, encoding two other
E. faecium
MSCRAMMs, were expressed at the mRNA level together with
sgrA
during all phases of growth, whereas
ecbA
was expressed only in exponential and late exponential phase, suggesting orchestrated expression of these adhesins. Expression of these surface proteins, which bind to extracellular matrix proteins and are involved in biofilm formation (SgrA), may contribute to the pathogenesis of hospital-acquired
E. faecium
infections.
Critical Role of the Interleukin-17/Interleukin-17 Receptor Axis in Regulating Host Susceptibility to Respiratory Infection withChlamydiaSpecies
Authors: Zhou Xiaohui , Chen Qiangwei , Moore Jessica , Kolls Jay K. , Halperin Scott , Wang Jun
Published: September 2009

The specific contribution of interleukin-17/interleukin-17 receptor (IL-17/IL-17R)-mediated responses in regulating host susceptibility against obligatory intracellularChlamydiainfection was investigated in C57BL/6 and C3H/HeN mice duringChlamydia muridarumrespiratory infection. We demonstrated thatChlamydiastimulated IL-17/IL-17R-associated responses in bothChlamydia-resistant C57BL/6 andChlamydia-susceptible C3H/HeN mice. However, C3H/HeN mice developed a significantly greater IL-17/IL-17R-associated response than C57BL/6 mice did. This was reflected by an increase in IL-17 mRNA expression, a higher recall IL-17 production from splenocytes upon antigen restimulation, and higher production of Th17-related cytokines (IL-23 and IL-6) and chemokines (chemokine [C-X-C motif] ligand 2 [CXCL1]/keratinocyte-derived chemokine [KC] and CXCL2/macrophage inflammatory protein 1 [MIP2]) in C3H/HeN mice than in C57BL/6 mice. Furthermore, C3H/HeN mice displayed a massive accumulation of activated and preactivated neutrophils in the airway and lung parenchyma compared to their C57BL/6 counterparts. We further demonstrated that the skewed IL-17/Th17 profile in C3H/HeN mice was predisposed by a higher basal level of IL-17 receptor C (IL-17RC) expression and then further amplified by a higher inducible IL-17RA expression in lungs. Most importantly, in vivo delivery of IL-17RA antagonist that resulted in a 50% reduction in the neutrophilic infiltration in lungs was able to reverse the susceptible phenotype of C3H/HeN mice to respiratoryChlamydiainfection. Thus, our data for the first time have demonstrated a critical role for the IL-17/IL-17R axis in regulating host susceptibility toChlamydiainfection in mice.
Identification of the Binding Domain of
Streptococcus oralis
Glyceraldehyde-3-Phosphate Dehydrogenase for
Porphyromonas gingivalis
Major Fimbriae
Authors: Nagata Hideki , Iwasaki Mio , Maeda Kazuhiko , Kuboniwa Masae , Hashino Ei , Toe Masahiro , Minamino Naoto , Kuwahara Hiromiki , Shizukuishi Satoshi
Published: September 2009

Porphyromonas gingivalis
forms communities with antecedent oral biofilm constituent streptococci.
P. gingivalis
major fimbriae bind to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) present on the streptococcal surface, and this interaction plays an important role in
P. gingivalis
colonization. This study identified the binding domain of
Streptococcus oralis
GAPDH for
P. gingivalis
fimbriae.
S. oralis
recombinant GAPDH (rGAPDH) was digested with lysyl endopeptidase. Cleaved fragments of rGAPDH were applied to a reverse-phase high-pressure liquid chromatograph equipped with a C
18
column. Each peak was collected; the binding activity toward
P. gingivalis
recombinant fimbrillin (rFimA) was analyzed with a biomolecular interaction analysis system. The fragment displaying the strongest binding activity was further digested with various proteinases, after which the binding activity of each fragment was measured. The amino acid sequence of each fragment was determined by direct sequencing, mass spectrometric analysis, and amino acid analysis. Amino acid residues 166 to 183 of
S. oralis
GAPDH exhibited the strongest binding activity toward rFimA; confocal laser scanning microscopy revealed that the synthetic peptide corresponding to amino acid residues 166 to 183 of
S. oralis
GAPDH (pep166-183, DNFGVVEGLMTTIHAYTG) inhibits
S. oralis
-
P. gingivalis
biofilm formation in a dose-dependent manner. Moreover, pep166-183 inhibited interbacterial biofilm formation by several oral streptococci and
P. gingivalis
strains with different types of FimA. These results indicate that the binding domain of
S. oralis
GAPDH for
P. gingivalis
fimbriae exists within the region encompassing amino acid residues 166 to 183 of GAPDH and that pep166-183 may be a potent inhibitor of
P. gingivalis
colonization in the oral cavity.
Antibody-Mediated Protection against Infection withHelicobacter pyloriin a Suckling Mouse Model of Passive Immunity
Authors: Gorrell Rebecca J. , Robins-Browne Roy M.
Published: September 2009

Studies of active immunization againstHelicobacter pyloriindicate that antibodies play a minor role in immunity. There is also evidence, however, that the translocation of antibodies in the stomach may be insufficient to achieve functional antibody levels in the gastric lumen. We have used a suckling mouse model of passive immunity to determine if perorally delivered antibodies can protect against infection withH. pylori. Female C57BL/6 mice were immunized parenterally with formalin-fixed cells of three clinical isolates ofH. pylori(3HP) or the mouse-adaptedH. pyloristrain SS1 before mating. Their pups were challenged with the SS1 strain at 4 days of age and left to suckle before determination of bacterial loads 14 days later. Compared to age-matched controls, pups suckled by 3HP-vaccinated dams were significantly protected against infection (>95% reduction in median bacterial load;P< 0.0001). Pups suckled by SS1-vaccinated dams were also significantly protected in terms of both median bacterial load (>99.5% reduction;P< 0.0001) and the number of culture-negative pups (28% versus 2% for immune and nonimmune cohorts, respectively;P< 0.0001). Similar results were obtained with pups suckled by dams immunized with a urease-deficient mutant of SS1. Fostering experiments demonstrated that protection was entirely attributable to suckling from an immunized dam, and antibody isotype analysis suggested that protection was mediated by the immunoglobulin G fraction of immune milk. Analysis of the bacterial loads in pups sampled before and after weaning confirmed that infection had been prevented in culture-negative animals. These data indicate that antibodies can prevent colonization byH. pyloriand suppress the bacterial loads in animals that are colonized.
CD46 Transgenic Mouse Model of Necrotizing Fasciitis Caused by
Streptococcus pyogenes
Infection
Authors: Matsui Hidenori , Sekiya Yukie , Nakamura Masahiko , Murayama Somay Yamagata , Yoshida Haruno , Takahashi Tetsufumi , Imanishi Ken'ichi , Tsuchimoto Kanji , Uchiyama Takehiko , Sunakawa Keisuke , Ubukata Kimiko
Published: September 2009

We developed a human CD46-expressing transgenic (Tg) mouse model of subcutaneous (s.c.) infection into both hind footpads with clinically isolated 11 group A streptococcus (GAS) serotype M1 strains. When the severity levels of foot lesions at 72 h and the mortality rates by 336 h were compared after s.c. infection with 1 × 10
7
CFU of each GAS strain, the GAS472 strain, isolated from the blood of a patient suffering from streptococcal toxic shock syndrome (STSS), induced the highest severity levels and mortality rates. GAS472 led to a 100% mortality rate in CD46 Tg mice after only 168 h postinfection through the supervention of severe necrotizing fasciitis (NF) of the feet. In contrast, GAS472 led to a 10% mortality rate in non-Tg mice through the supervention of partial necrotizing cutaneous lesions of the feet. The footpad skin sections of CD46 Tg mice showed hemorrhaging and necrotic striated muscle layers in the dermis, along with the exfoliation of epidermis with intracellular edema until 48 h after s.c. infection with GAS472. Thereafter, the bacteria proliferated, reaching a 90-fold or 7-fold increase in the livers of CD46 Tg mice or non-Tg mice, respectively, for 24 h between 48 and 72 h after s.c. infection with GAS472. As a result, the infected CD46 Tg mice appeared to suffer severe liver injuries. These findings suggest that human CD46 enhanced the progression of NF in the feet and the exponential growth of bacteria in deep tissues, leading to death.
Kinetics of the Immune Response Profile in Guinea Pigs after Vaccination withMycobacterium bovisBCG and Infection withMycobacterium tuberculosis
Authors: Grover Ajay , Taylor Jennifer , Troudt JoLynn , Keyser Andrew , Arnett Kimberly , Izzo Linda , Rholl Drew , Izzo Angelo
Published: September 2009

The guinea pig model of tuberculosis is used extensively in assessing novel vaccines, sinceMycobacterium bovisBCG vaccination effectively prolongs survival after low-dose aerosol infection with virulentM. tuberculosis. To better understand how BCG extends time to death after pulmonary infection withM. tuberculosis, we examined cytokine responses postvaccination and recruitment of activated T cells and cytokine response postinfection. At 10 weeks postvaccination, splenic gamma interferon (IFN-γ) mRNA was significantly elevated compared to the levels at 5 weeks in ex vivo stimulation assays. At 15, 40, 60, and 120 days postinfection, T-cell activation (CD4+CD62Llowand CD8+CD62Llow) and mRNA expression of IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-10, IL-12, and eomesodermin were assessed. Our data show that at day 40, BCG-vaccinated guinea pigs had significantly increased levels of IFN-γ mRNA expression but decreased TNF-α mRNA expression in their lungs compared to the levels in nonvaccinated animals. At day 120, a time when nonvaccinated guinea pigs succumbed to infection, low levels of IFN-γ mRNA were observed even though there were increasing levels of IL-1, IL-12, and IL-10, and the numbers of activated T cells did not differ from those in BCG-vaccinated animals. BCG vaccination conferred the advantage of recruiting greater numbers of CD4+CD62LlowT cells at day 40, although the numbers of CD8+CD62LlowT cells were not elevated compared to the numbers in nonvaccinated animals. Our data suggest that day 40 postinfection may be a pivotal time point in determining vaccine efficacy and prolonged survival and that BCG promotes the capacity of T cells in the lungs to respond to infection.
The
Mycoplasma pneumoniae
MPN490 and
Mycoplasma genitalium
MG339 Genes Encode RecA Homologs That Promote Homologous DNA Strand Exchange
Authors: Sluijter Marcel , Spuesens Emiel B. M. , Hartwig Nico G. , van Rossum Annemarie M. C. , Vink Cornelis
Published: September 2009

The P1, P40, and P90 proteins of
Mycoplasma pneumoniae
and the MgPa and P110 proteins of
Mycoplasma genitalium
are immunogenic adhesion proteins that display sequence variation. Consequently, these proteins are thought to play eminent roles in immune evasive strategies. For each of the five proteins, a similar underlying molecular mechanism for sequence variation was hypothesized, i.e., modification of the DNA sequences of their respective genes. This modification is thought to result from homologous recombination of parts of these genes with repeat elements (RepMp and MgPar elements in
M. pneumoniae
and
M. genitalium
, respectively) that are dispersed throughout the bacterial genome. Proteins that are potentially involved in homologous DNA recombination have been suggested to be implicated in recombination between these repeat elements and thereby in antigenic variation. To investigate this notion, we set out to study the function of the RecA homologs that are encoded by the
M. pneumoniae
MPN490 and
M. genitalium
MG339 genes. Both proteins, which are 79% identical on the amino acid level, were found to promote recombination between homologous DNA substrates in an ATP-dependent fashion. The recombinational activities of both proteins were Mg
2+
and pH dependent and were strongly supported by the presence of single-stranded DNA binding protein, either from
M. pneumoniae
or from
Escherichia coli
. We conclude that the MPN490- and MG339-encoded proteins are RecA homologs that have the capacity to recombine homologous DNA substrates. Thus, they may play a central role in recombination between repetitive elements in both
M. pneumoniae
and
M. genitalium
.
Bacillus anthracis
Capsule Activates Caspase-1 and Induces Interleukin-1β Release from Differentiated THP-1 and Human Monocyte-Derived Dendritic Cells
Authors: Cho Min-Hee , Ahn Hae-Jeong , Ha Hyun-Joon , Park Jungchan , Chun Jeong-Hoon , Kim Bong-Su , Oh Hee-Bok , Rhie Gi-eun
Published: September 2009

The poly-γ-
d
-glutamic acid (PGA) capsule is one of the major virulence factors of
Bacillus anthracis
, which causes a highly lethal infection. The antiphagocytic PGA capsule disguises the bacilli from immune surveillance and allows unimpeded growth of bacilli in the host. Recently, efforts have been made to include PGA as a component of anthrax vaccine; however, the innate immune response of PGA itself has been poorly investigated. In this study, we characterized the innate immune response elicited by PGA in the human monocytic cell line THP-1, which was differentiated into macrophages with phorbol 12-myristate 13-acetate (PMA) and human monocyte-derived dendritic cells (hMoDCs). PGA capsules were isolated from the culture supernatant of either the pXO1-cured strain of
B. anthracis
H9401 or
B. licheniformis
ATCC 9945a. PGA treatment of differentiated THP-1 cells and hMoDCs led to the specific extracellular release of interleukin-1β (IL-1β) in a dose-dependent manner. Evaluation of IL-1β processing by Western blotting revealed that cleaved IL-1β increased in THP-1 cells and hMoDCs after PGA treatment. Enhanced processing of IL-1β directly correlated with increased activation of its upstream regulator, caspase-1, also known as IL-1β-converting enzyme (ICE). The extracellular release of IL-1β in response to PGA was ICE dependent, since the administration of an ICE inhibitor prior to PGA treatment blocked induction of IL-1β. These results demonstrate that
B. anthracis
PGA elicits IL-1β production through activation of ICE in PMA-differentiated THP-1 cells and hMoDCs, suggesting the potential for PGA as a therapeutic target for anthrax.
REINFORCEMENT FUZZY-RULE EMULATED NETWORKS AND ITS APPLICATION ON NONLINEAR DISCRETE-TIME SYSTEMS
Authors: TREESATAYAPUN CHIDENTREE
Published: September 2009

The adaptive control algorithm based on Multi-Input Fuzzy Rules Emulated Networks (MIFRENs) with the reinforcement learning algorithm is introduced for a class of nonlinear discrete-time systems. Because of the unknown future values of systems, the long term cost function is estimated by the first MIFREN through the human knowledge with the defined IF-THEN rules and the proposed learning algorithm. The main controller is constructed by another MIFREN and the parameters in side this network have been tuned to minimize the estimated cost function and the control system error. All designed parameters are given with the Lyapunov method and the proposed theorem. The numerical simulation results are demonstrated the system performance with the selected nonlinear discrete-time systems
P3M— POSSIBILISTIC MULTI-STEP MAXMIN AND MERGING ALGORITHM WITH APPLICATION TO GENE EXPRESSION DATA MINING
Authors: ROMDHANE LOTFI BEN , SHILI HECHMI , AYEB BECHIR
Published: September 2009

Gene expression data generated by DNA microarray experiments provide a vast resource of medical diagnostic and disease understanding. Unfortunately, the large amount of data makes it hard, sometimes impossible, to understand the correct behavior of genes. In this work, we develop a possibilistic approach for mining gene microarray data. Our model consists of two steps. In the first step, we use possibilistic clustering to partition the data into groups (or clusters). The optimal number of clusters is evaluated automatically from data using the Partition Information Entropy as a validity measure. In the second step, we select from each computed cluster the most representative genes and model them as a graph called a proximity graph. This set of graphs (or hyper-graph) will be used to predict the function of new and previously unknown genes. Benchmark results on real-world data sets reveal a good performance of our model in computing optimal partitions even in the presence of noise; and a high prediction accuracy on unknown genes.
A TOOL FOR ADDRESSING THE RAMIFICATION PROBLEM IN TEMPORAL DATABASES
Authors: PAPADAKIS NIKOS , PLEXOUSAKIS DIMITRIS , ANTONIOU GRIGORIS , PAPADAKIS MYRON , BOUTSIKA KATERINA
Published: September 2009

In this paper we study the ramification problem in the setting of temporal databases. Standard solutions from the literature on reasoning about action are inadequate because they rely on the assumption that fluents persist, and because actions have effects on the next situation only. In this paper we provide a solution to the ramification problem based on an extension of the situation calculus and the work of McCain and Turner. We present a tool with a graphical user interface for addressing the ramification problem in temporal databases.
Transformation in the Neural Code for Whisker Deflection Direction Along the Lemniscal Pathway
Authors: Bale Michael R. , Petersen Rasmus S.
Published: September 2009

A prominent characteristic of neurons in the whisker system is their selectivity to the direction in which a whisker is deflected. The aim of this study was to determine how information about whisker direction is encoded at successive levels of the lemniscal pathway. We made extracellular recordings under identical conditions from the trigeminal ganglion, ventro-posterior medial thalamus (VPM), and barrel cortex while varying the direction of whisker deflection. We found a marked increase in the variability of single unit responses along the pathway. To study the consequences of this for information processing, we quantified the responses using mutual information. VPM units conveyed 48% of the mutual information conveyed by ganglion units, and cortical units conveyed 12%. The fraction of neuronal bandwidth used for transmitting direction information decreased from 40% in the ganglion to 24% in VPM and 5% in barrel cortex. To test whether, in cortex, population coding might compensate for this information loss, we made simultaneous recordings. We found that cortical neuron pairs conveyed 2.1 times the mutual information conveyed by single neurons. Overall, these findings indicate a marked transformation from a subcortical neural code based on small numbers of reliable neurons to a cortical code based on populations of unreliable neurons. However, the basic form of the neural code in ganglion, thalamus, and cortex was similar—at each stage, the first poststimulus spike carried the majority of the information.
Translational informatics: enabling high-throughput research paradigms
Authors: Payne Philip R. O. , Embi Peter J. , Sen Chandan K.
Published: September 2009

A common thread throughout the clinical and translational research domains is the need to collect, manage, integrate, analyze, and disseminate large-scale, heterogeneous biomedical data sets. However, well-established and broadly adopted theoretical and practical frameworks and models intended to address such needs are conspicuously absent in the published literature or other reputable knowledge sources. Instead, the development and execution of multidisciplinary, clinical, or translational studies are significantly limited by the propagation of “silos” of both data and expertise. Motivated by this fundamental challenge, we report upon the current state and evolution of biomedical informatics as it pertains to the conduct of high-throughput clinical and translational research and will present both a conceptual and practical framework for the design and execution of informatics-enabled studies. The objective of presenting such findings and constructs is to provide the clinical and translational research community with a common frame of reference for discussing and expanding upon such models and methodologies.
Inhibition of Tumor Growth Progression by Antiandrogens and mTOR Inhibitor in aPten-Deficient Mouse Model of Prostate Cancer
Authors: Zhang Weisheng , Zhu Joe , Efferson Clay L. , Ware Chris , Tammam Jennifer , Angagaw Minilik , Laskey Jason , Bettano Kimberly A. , Kasibhatla Shailaja , Reilly John F. , Sur Cyrille , Majumder Pradip K.
Published: September 2009

Androgen receptors have been shown to play a critical role in prostate cancer. We used ultrasound imaging techniques to track tumor response to antiandrogen and rapamycin treatment in a prostate-specific Pten-deleted mouse model of cancer. Depletion of androgens by either surgical or chemical castration significantly inhibited tumor growth progression without altering the activation of Akt and mammalian target of rapamycin (mTOR). We also showed for the first time that targeting mTOR along with antiandrogen treatment exhibited additive antitumor effects in vivo when compared with single agents. Our preclinical data suggest that combination of antiandrogens with mTOR inhibitors might be more effective in treating androgen-dependent prostate cancer patients. [Cancer Res 2009;69(18):7466–72]
Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism
Authors: Escoubet-Lozach Laure , Lin I-Lin , Jensen-Pergakes Kristen , Brady Helen A. , Gandhi Anita K. , Schafer Peter H. , Muller George W. , Worland Peter J. , Chan Kyle W.H. , Verhelle Dominique
Published: September 2009

Lenalidomide and pomalidomide have both been evaluated clinically for their properties as anticancer agents, with lenalidomide being available commercially. We previously reported that both compounds cause cell cycle arrest in Burkitt's lymphoma and multiple myeloma cell lines by increasing the level of p21WAF-1 expression. In the present study, we unravel the molecular mechanism responsible for p21WAF-1 up-regulation using Namalwa cells as a human lymphoma model. We show that the increase of p21WAF-1 expression is regulated at the transcriptional level through a mechanism independent of p53. Using a combination of approaches, we show that several GC-rich binding transcription factors are involved in pomalidomide-mediated up-regulation of p21WAF-1. Furthermore, we report that p21WAF-1 up-regulation is associated with a switch from methylated to acetylated histone H3 on p21WAF-1 promoter. Interestingly, lysine-specific demethylase-1 (LSD1) silencing reduced both pomalidomide and lenalidomide up-regulation of p21WAF-1, suggesting that this histone demethylase is involved in the priming of the p21WAF-1 promoter. Based on our findings, we propose a model in which pomalidomide and lenalidomide modify the chromatin structure of the p21WAF-1 promoter through demethylation and acetylation of H3K9. This effect, mediated via LSD1, provides GC-rich binding transcription factors better access to DNA, followed by recruitment of RNA polymerase II and transcription activation. Taken together, our results provide new insights on the mechanism of action of pomalidomide and lenalidomide in the regulation of gene transcription, imply possible efficacy in p53 mutated and deleted cancer, and suggest new potential clinical uses as an epigenetic therapy. [Cancer Res 2009;69(18):7347–56]
Role of Cyclic AMP Response Element–Binding Protein in Insulin-like Growth Factor-I Receptor Up-regulation by Sex Steroids in Prostate Cancer Cells
Authors: Genua Marco , Pandini Giuseppe , Sisci Diego , Castoria Gabriella , Maggiolini Marcello , Vigneri Riccardo , Belfiore Antonino
Published: September 2009

Insulin-like growth factor-I receptor (IGF-IR) overexpression may play a role in prostate cancer progression. We found previously that, in prostate cancer cells, IGF-IR is up-regulated by both androgens and estrogens via a nongenotropic pathway. We now show that, in prostate cancer cells, stimulation with either androgens or estrogens up-regulates IGF-IR by inducing cyclic AMP response element–binding protein (CREB) activation. Both sex steroids phosphorylated CREB at Ser133 in a dose-dependent manner in androgen receptor (AR)–positive LNCaP cells, whereas only estrogens phosphorylated CREB in AR-negative PC3 cells. CREB phosphorylation involved c-Src–dependent extracellular signal-regulated kinase 1/2 activation, but not protein kinase A, protein kinase C, or calmodulin-dependent kinase II, and occurred also in cells transfected with AR or estrogen receptor mutants that do not localize into the nucleus. CREB silencing abrogated IGF-IR up-regulation and promoter activation. We also showed that CREB binds to IGF-IR promoter region and identified the relevant CREB-binding site at the 5′-untranslated region fragment of IGF-IR promoter. In conclusion, we describe a novel mechanism of IGF-IR up-regulation and promoter activity by CREB activation, induced by sex steroids, through a nongenotropic signaling. [Cancer Res 2009;69(18):7270–7]